<?xml version="1.0" encoding="iso-8859-1"?><rss version="2.0" xmlns:drug="http://www.aidsinfo.nih.gov/" d1p1:noNamespaceSchemaLocation="http://www.aidsinfo.nih.gov/DrugsNew/drugRSSFeedschema.xsd" xmlns:d1p1="drug"><channel><title>AidsInfo Drugs RSS Feed</title><link><![CDATA[http://aidsinfo.nih.gov/DrugsNew/]]></link><description><![CDATA[This RSS Feed provides information about the drugs used in the treatment of HIV/AIDS.]]></description><item><title><![CDATA[AMD070]]></title><description><![CDATA[AMD070, also known as AMD11070, is a type of medicine called a CXCR4 inhibitor. This type of medicine works by blocking the entry of HIV into cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=382]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[AMD070]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[AMD070]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The investigational agent AMD070, also known as AMD11070, is a specific and reversible CXCR4 inhibitor. AMD070 is a derivative of AMD3100, a previously studied investigational CXCR4 inhibitor.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[AMD070 is an investigational agent with in vitro activity against HIV-1. The safety, tolerability, dosing, and pharmacokinetics of AMD070 are being studied in Phase II clinical trials.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[AMD070 has been studied in doses of 50, 100, 200, and 400 mg. Dosages of 100 mg and 200 mg AMD070 twice daily have been studied for up to 10 days in Phase II trials.]]></drug:dosageform><drug:storage><![CDATA[Store between 2 C and 8 C (36 F to 46 F) and protect from moisture.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[AMD070 prevents viral entry into cells by binding to the chemokine receptor CXCR4, the coreceptor used by CXCR4-tropic HIV for membrane fusion and viral entry. AMD070 does not bind to CCR5, the coreceptor that mediates entry of macrophage-tropic HIV. The CXCR4 strains are considerably more pathogenic; their appearance late in HIV infection correlates with CD4 count decline and rapid disease progression.

AMD070 has not yet been fully evaluated in human trials. A small Phase I safety study of AMD070 in HIV uninfected male volunteers evaluated the safety, pharmacokinetic profile, and bioavailability of single and multiple doses of AMD070. Thirty subjects participated in this study. Single doses of 50, 100, 200, and 400 mg and multiple doses of 100, 200, and 400 mg twice daily (five doses, with pharmacokinetic sampling performed following the last dose) were examined. Dose-dependent increases in the peak plasma concentration (Cmax) and the median area under the concentration-time curve (AUC) were observed following both single and multiple doses. Evidence of AMD070 accumulation was noted with repeated administration.

AMD 070 is readily absorbed in humans after oral administration. When studied in HIV infected patients with CXCR4-tropic virus, AMD070 displayed a greater-than-proportional increase in exposure across 100 and 200 mg twice-daily dosage groups, consisting of eight and two participants, respectively. Mean Cmax were 346.5 ng/ml and 1,271.2 ng/ml in the 100 and 200 mg groups, respectively. Mean AUC were 1,123.5 mg(h)/ml and 6,471.8 ng(h)/ml in the same groups, respectively. The half-life of 200 mg AMD070 twice daily was 5.5 h. AMD070 accumulates with repeat administration, although minimum plasma concentrations in this study did not achieve steady-state levels after 10 days of administration. AMD070 Cmax, AUC, and half-life are increased when administered concurrent with steady-state levels of ritonavir as a pharmacokinetic booster.

Because no information concerning the reproductive toxicity of AMD070 is currently available, AMD070 is not being tested in women at this time, and male volunteers in AMD070 clinical trials are advised to avoid participating in conception activities during AMD070 administration and for 2 weeks after stopping the drug. AMD070 is not mutagenic in vitro; however, CXCR4 may play a role in hematopoiesis in utero.

AMD070 is 84% to 97% protein bound at pharmacologically active concentrations; however, protein binding does not appear to have a significant effect in vitro. Limited information is available concerning the metabolism of AMD070. AMD070 represents the major circulating form of the drug in plasma; several putative metabolites have been noted in plasma samples from in vivo preclinical studies. Based on preliminary laboratory studies, AMD070 is a substrate for cytochrome P450 (CYP) 3A4 but has a low potential for induction. AMD070 moderately inhibits CYP2D6 and exhibits time-dependent inhibition of CYP3A4.

Median total body clearance of AMD070 is 216 l/hr. AMD070 is eliminated in at least a biexponential manner, and the median terminal half-life is 16 hours.

AMD070 appears to share nearly overlapping binding sites with a previously investigated CXCR4 inhibitor, AMD3100. However, the amino acid residue D97 on the CXCR4 receptor interacts specifically with AMD070 alone. Decreased AMD070 binding potency of more than 100-fold has been associated with W94A, D97N, D171N, and E288A mutations. Binding potency decreases of 10- to 50-fold have been observed with 445A and D262N mutations.

A small safety trial of AMD070 monotherapy for 10 days compared 100 and 200 mg twice-daily dosages in eight and two participants, respectively. All patients had CXCR4- or mixed-tropic virus and were treatment-naive or at least free from antiretroviral treatment for 14 days. By Day 5, two of four responding participants experienced a tropism switch to CCR5-tropic virus, and one more participant experienced a tropism switch at Day 10.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Because AMD070 and AMD3100 are both investigational CXCR4 inhibitors and AMD070 is a derivative of AMD3100, the adverse events reported for AMD3100 may be similar to those for AMD070. In a study of 40 HIV infected people, AMD3100 was administered intravenously via a 10-day continuous infusion up to 160 mcg/kg/hour. The most common subjective complaints from study participants, regardless of whether they were attributed to study drug, included diarrhea (48%), flatulence (43%), headache (40%), nausea (35%), abdominal pain (33%), abdominal distension (25%), tachycardia (25%), dizziness (25%) and paresthesias (23%). Vital sign abnormalities, including hypertension (67%), hypotension (25%), and tachycardia (47%), were observed transiently in many participants, although there were no dose-related trends. Several-fold increases in white blood cells, CD4 counts, and lymphocytes were seen in all participants but were not of clinical concern.

In a small, Phase I safety study of AMD070 in HIV uninfected volunteers, the drug was generally well tolerated; 3 of 12 participants complained of a transient, mild-to-moderate headache after taking a single dose of AMD070 on an empty stomach. No serious adverse events were reported, and adverse events were generally mild (mainly Grade 1 or 2). The most common adverse effects were pain, gastrointestinal disturbances, and Grade 1 tachycardia; other reported events included lightheadedness, palpitations, insomnia, shaky and unsteady hands, a flushed feeling, seasonal allergies, a buzzing sensation, and heartburn.

Short-term administration has a potential for acute gastrointestinal toxicity, characterized by vomiting and diarrhea that usually occurs within 1 to 2 hours of administration. These effects are expected to be transient. Bone marrow hypocellularity has been observed at the highest dose levels; reversibility of this effect has not been demonstrated. Lymphoid atrophy has been observed in the thymus, lymph nodes, and spleen. Heart rate elevations and blood pressure changes have also been noted.

Dosages of 200 mg AMD070 twice daily for 10 days have been well tolerated in HIV infected patients. No Grade 3 or greater toxicities were observed during and up to 7 days after treatment. In two small studies of 100 or 200 mg AMD070 twice daily, given alone or coadministered with ritonavir, no serious, drug-related adverse events or laboratory abnormalities were reported. The most common adverse effects experienced in HIV infected patients taking 10-day monotherapy were mild gastrointestinal symptoms and headache.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In animal studies, the bioavailability of AMD070 was substantially reduced when the drug was administered 30 minutes after a meal. Current studies are investigating AMD070 when administered both on an empty stomach and with food. In a small study of HIV uninfected volunteers, absorption of AMD070 did not appear affected by food.

In vitro studies using five different CD4 cell lines, CXCR-transfected cell lines, and peripheral blood mononuclear cells indicated that AMD070 had additive or synergistic antiviral activity when combined with other known HIV inhibitors, including fusion inhibitors (enfuvirtide), nucleoside reverse transcriptase inhibitors (zidovudine and tenofovir), and protease inhibitors (amprenavir).

Because AMD070 is a substrate of CYP3A4 and p-glycoprotein, it will likely be administered with a ritonavir booster. The hypothesis of favorably altered pharmacokinetics of AMD070 was tested in healthy volunteers, who received single doses of 200 mg AMD070 on Days 1, 3, and 17, and ritonavir 100 mg every 12 hours on Days 3 through 18. Ritonavir boosting at steady-state decreased the time to maximum concentration of AMD070 by 25%, increased the Cmax of AMD070 by 47%, increased the AUC of AMD979 by 24%, and increased the half-life of AMD070 by 16%.

As a substrate of CYP3A4, AMD070 has low induction potential and time-dependent inhibition activity. In addition, AMD070 is a moderate inhibitor of CYP2D6. When a single dose of AMD070 was tested in combination with midazolam, a CYP3A4 substrate, and dextromethorphan, a CYP2D6 substrate, statistically significant increases in AUC were observed for both midazolam and dextromethorphan. A statistically significant increase in Cmax of dextromethorphan was observed as well. The clinical effects and dose-altering requirements of these increases are unknown.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[AMD 070]]></drug:casname><drug:casnumber><![CDATA[690656-53-2]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[Solid crystalline.]]></drug:physicaldescription><drug:stability><![CDATA[After the bottle is opened, AMD070 capsules have a shelf-life of 28 days.]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[AMD11070]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17452489 Stone ND, Dunaway SB, Flexner CW, Tierney C, Calandra GB, Becker S, Cao YJ, Wiggins IP, Conley J, Macfarland RT, Park JG, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW. Multiple Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a selective CXCR4 Receptor Inhibitor, in Human Subjects (ACTG A5191). Antimicrob Agents Chemother. 2007 Apr 23; [Epub ahead of print]]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17452489&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Boffito M, Moyle G, Wong R, Chee P, MacFarland R, Calandra G, Bridger G, and Becker S. Pharmacokinetics of AMD11070, a CXCR4 Antagonist, in HIV-infected Patients Carrying X4-tropic Virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 571, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Cao Y, Flexner C, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J, Radebaugh C, Becker S, Hendrix C, and the A5191 Study Team. Ritonavir Increases Concentrations of the CXCR4 Antagonist AMD070 in Healthy Volunteers. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 570, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Schols D, Claes S, Hatse S, Princen K, Vermeire K, De Clercq E, Skerlj R, Bridger G, and Calandra G. Anti-HIV activity profile of AMD070, an orally bioavailable CXCR4 antagonist. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, Paper 563, 2003.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[AMD070]]></drug:drugname><drug:companyname><![CDATA[Genzyme Corporation]]></drug:companyname><drug:address1><![CDATA[500 Kendall Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Cambridge]]></city><drug:state><![CDATA[MA]]></drug:state><drug:zipcode><![CDATA[02142]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(617) 252-7500]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 6, 2007]]></drug:lastupdated></item><item><title><![CDATA[PRO 140]]></title><description><![CDATA[PRO 140 is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking the entry of HIV into human cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=423]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140 is a humanized monoclonal antibody against CCR5 and is designed to block the ability of HIV to enter and infect cells.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140 is an investigational entry inhibitor being studied for the treatment of HIV infection. PRO 140 has potential utility in both treatment-experienced and treatment-naive HIV infected individuals. To date, two Phase I studies of the safety and pharmacokinetics (PK) of PRO 140 given intravenously have been completed, one in HIV uninfected males and another in HIV-1 infected individuals of both sexes. PRO 140 was granted fast-track status by the FDA in February 2006.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous infusion.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Intravenous infusions of 0.1, 0.5, 2, and 5 mg/kg doses of PRO 140 have been administered to both HIV infected and uninfected individuals in clinical trials.

Future studies of PRO 140 administered by subcutaneous injection are planned.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The CCR5 receptor is found on certain human inflammatory cells; HIV uses this receptor as a portal to enter and infect healthy cells. PRO 140 inhibits entry of HIV into cells by preventing virus-cell binding at a distinct site on the CCR5 coreceptor without interfering with the natural activity of CCR5. It binds an extracellular (not a transmembrane) site, inhibiting HIV via a competitive (rather allosteric) mechanism. PRO 140 exhibits dose-dependent binding to CCR5-expressing cells, significantly coating and protecting such cells for up to 60 days. PRO 140 broadly and potently inhibits wild-type and drug-resistant, R5-tropic HIV in vitro. It is also synergistic with small-molecule CCR5 antagonists. This synergistic effect seen when combining PRO 140 with other investigational CCR5 inhibitors suggests that PRO 140 may represent a distinct subclass of CCR5 inhibitors.

A Phase I, randomized, double-blind, placebo-controlled study was conducted to examine the safety, PK, and pharmacodynamics of single-dose PRO 140 in 20 healthy males. Participants received intravenous PRO 140 doses of 0.1, 0.5, 2, and 5 mg/kg in sequential, dose-rising cohorts of 5 (4 active, 1 placebo) each and were evaluated for 60 days post-treatment. Serum concentrations of PRO 140 increased proportionally with dose; the serum half-life was approximately 2 weeks. Cellular CCR5 receptors remained coated with PRO 140 for greater than 60 days at the 5 mg/kg dose. No anti-PRO 140 antibodies were observed in preliminary bioanalytical testing.

In another Phase I, randomized, double-blind, placebo-controlled study, the safety, tolerability, antiviral activity, and PK of single-dose PRO 140 administered intravenously were studied in 39 HIV infected participants. Doses of PRO 140 of 0.5, 2, or 5 mg/kg were administered. A 10-fold (90%) reduction in viral load from baseline was observed as early as Day 5; the average viral load reduction by Day 10 was approximately 99%. All participants who received 5 mg/kg PRO 140 experienced at least a 10-fold reduction in viral load from baseline. The 2.0 mg/kg dose reduced viral load by an average of 90%; the 0.5 mg/kg dose reduced viral load by an average of 50%. A 29% (p=0.055) average increase in CD4 cells by Day 8 was also observed, suggesting a trend of increased CD4 count with PRO 140 use. Potent, rapid, prolonged, dose-dependent significant antiviral activity was observed across all dose groups. PK studies indicated that peak and total exposure increased proportionally or better with dose. Peak levels of PRO 140 were achieved within 3 to 60 minutes, and the terminal half-life of PRO 140 was determined to be about 4 days. Low titer anti-PRO 140 antibodies developed in one participant who received the 5.0 mg/kg dose; no obvious effect on PK or antiviral response could be discerned. Ex vivo fluorescently-labeled lymphocytes analyzed by flow cytometry indicated obvious coating of CCR5 lymphocytes by PRO 140, with a duration of coating of 1 to 2 weeks consistent with the compound's antiviral effects.

In vitro antiviral activity of PR0 140 was independent of HIV-1 subtype and resistance to existing antiretroviral treatment classes. PRO 140 exhibited potent, broad-spectrum activity in laboratory studies of more than 40 genetically diverse HIV strains. The strains failed to develop resistance to PRO 140, even after 40 weeks of continued exposure in vitro.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140 was generally well tolerated in two, Phase I safety and pharmacokinetics studies conducted in healthy volunteers. No obvious, infusion-related, or dose-limiting toxicities, drug-related adverse effects, or electrocardiogram changes occurred with single doses ranging from 0.1 to 5 mg/kg.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 140 exhibits potent and reproducible synergy in vitro with the entry inhibitors enfuvirtide and maraviroc and with investigational small-molecule CCR5 antagonists, such as SCH-D (vicriviroc).]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[]]></drug:casname><drug:casnumber><![CDATA[674782-26-4]]></drug:casnumber><drug:molecularformula><![CDATA[Unspecified]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17472538 Biswas P, Tambussi G, Lazzarin. A. Access denied? The status of co-receptor inhibition to counter HIV entry. Expert Opin Pharmacother. 2007 May;8(7):923-33.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17472538&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17005807 Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother - 2006 Oct;50(10):3289-96.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17005807&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Ketas TJ, DiPippo VA, Lam E, Maddon PJ, Olson WC. PRO 140, a Humanized CCR5 Monoclonal Antibody, is Active Against Genotypically Diverse and Enfuvirtide-Resistant Strains of HIV-1. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, Abstract WEPEA093, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Saag MS, Jacobson JM, Thompson M, Fischl M, Liporace R, Reichman RC, Redfield RR, Fichtenbaum CJ, Zingman BS, Patel MC, D'Ambrosio P, Michael M, Kroger H, Ly H, Rotshteyn Y, Stavola JJ, Maddon PG, Kremer AB, Olson WC. Antiviral Effects and Tolerability of the CCR5 Monoclonal Antibody PRO 140: A Proof of Concept Study in HIV-Infected Individuals. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, Abstract WESS201, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[PRO 140]]></drug:drugname><drug:companyname><![CDATA[Progenics Pharmaceuticals, Inc.]]></drug:companyname><drug:address1><![CDATA[777 Old Saw Mill Road]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Tarrytown]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10591]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[October 16, 2007]]></drug:lastupdated></item><item><title><![CDATA[TNX-355]]></title><description><![CDATA[TNX-355 is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking HIV from entering human cells. ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=399]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TNX-355]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TNX-355]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TNX-355 is a nonimmunosuppressive, humanized IgG4, anti-CD4, domain 2 monoclonal antibody that prevents HIV entry into human cells.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TNX-355 is being investigated in Phase II trials as part of combination therapy for the treatment of HIV-1 infection in treatment-experienced patients. TNX-355 was granted fast-track status by the FDA in October 2003.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous infusion.]]></drug:modeofdelivery><drug:dosageform><![CDATA[In clinical trials, TNX-355 is given intravenously once every other week, sometimes with a loading dose of once-weekly treatment. Doses evaluated include 6, 10, 15, and 25 mg/kg; the 10 and 15 mg/kg doses are being evaluated in an ongoing Phase II study. An additional dose-finding study is needed to determine the most effective dose and schedule for TNX-355.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TNX-355 inhibits HIV entry into lymphocytes and binds to an epitope in domain 2 of the CD4 receptor on a cell's surface, preventing HIV entry into the cell. TNX-355 does not deplete CD4. Unlike anti-CD4 antibodies that target domain 1 of CD4, TNX-355 does not appear to interfere with immunologic functions involving antigen presentation and is not immunosuppressive.

In vitro laboratory studies of HIV-1 subtype B isolates from 82 triple-class-experienced patients evaluated TNX-355 susceptibility based on viral tropism. Of the 82 isolates, 49 were M-tropic, 2 were T-tropic, and 27 were dual- or mixed-tropic. All isolates were similarly susceptible to TNX-355, and degree of efficacy did not appear associated with tropism.

A Phase Ia study evaluated single 0.3 to 25 mg/kg doses of TNX-355; these doses reduced viral load from baseline by 50% to 90%. This effect was transient, with most levels returning to baseline by Day 28. Significant viral load reductions were observed with the 10 and 25 mg/kg doses and were sustained for 2 to 3 weeks.

In a Phase Ib study, 23% of patients had reduced viral loads by greater than 95%, and 64% had reduced loads by greater than 90%. However, these reductions were also transient, implying that monotherapy may cause quick development of resistance.

An ongoing Phase II, multicenter, randomized, double-blind, placebo-controlled trial is evaluating TNX-355 efficacy and safety in 82 triple-class-experienced patients also on optimized background therapy. The trial is comparing HIV infected patients who have failed or are failing highly active antiretroviral therapy (HAART) assigned to one of three arms: TNX-355 10 mg/kg once weekly for nine doses followed by 10 mg/kg every other week; TNX-355 15 mg/kg every other week; or placebo. The study is evaluating virologic failure rates and viral load reduction between the two doses and between each dose and placebo. Enrolled patients must have a viral load of 10,000 copies/ml or greater, a CD4 count greater than 50 cells/ml, and triple-class experience with HAART. At the Week 24 interim analysis, viral load decreased by -0.95log in the 15 mg/kg arm, by -1.16log in the 10 mg/kg arm, and by -0.2log in the placebo arm. Both treatment arm reductions were statistically greater than the placebo reduction. At Week 48, patients receiving TNX-355 experienced sustained viral load suppression compared with those receiving placebo. Viral load decreased by -0.71log in the 15 mg/kg arm, by -0.96 in the 10 mg/kg arm, and by -0.14log in the placebo arm; both treatment arms displayed statistically significant reductions compared with the placebo arm. In addition, CD4 counts increased significantly from baseline in both treatment arms compared with the placebo arm. CD4 counts increased by 51 cells/mm3 in the 15 mg/kg arm, by 48 cells/mm3 in the 10 mg/kg arm, and by 1 cell/mm3 in the placebo arm.

This Phase II trial has been extended to 144 weeks, and all enrolled patients have been given the opportunity to receive TNX-355. Because the interim analysis of this trial reported greater viral load decreases in the 10 mg/kg arm than in the 15 mg/kg arm, the FDA is requiring an additional dose-finding study to identify an appropriate TNX-355 dose and regimen.

TNX-355 has potential advantages over currently available anti-HIV therapies because of the low risk of cross resistance. Susceptibility of enfuvirtide-resistant viral envelopes to TNX-355 was studied in vitro using G36D, V38A, and N43D substitutions. Envelopes exhibited 11- to 32-fold reduced susceptibility to enfuvirtide but less than twofold reduced susceptibility to TNX-355. No cross resistance to TNX-355 was observed.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In Phase Ia and Ib safety studies, TNX-355 was well tolerated. No serious adverse effects were reported in the Phase Ia study. Depression recurrence, vasovagal reaction with new onset seizure, and acute renal failure with renal insufficiency were reported in three patients in a Phase Ib, 22-patient study.

At the 48-week interim analysis of a Phase II study, adverse events experienced with TNX-355 10 mg/kg and 15 mg/kg every other week were similar to placebo. All treatment-related adverse events were mild or moderate in severity, and no injection site reactions were reported.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In vitro, TNX-355 demonstrates synergy in laboratory and in clinical HIV-1 strains with enfuvirtide, an FDA-approved entry inhibitor. This synergy, along with the differing mechanisms of action and resistance between these two entry inhibitors, supports a strategy of coadministration.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[]]></drug:casname><drug:casnumber><![CDATA[872357-57-8]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/14722894 Kuritzkes DR, Jacobson J, Powderly WG, Godofsky E, DeJesus E, Haas F, Reimann KA, Larson JL, Yarbough PO, Curt V, Shanahan WR Jr. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis. 2004 Jan 15;189(2):286-91. Epub 2004 Jan 8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14722894&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15180541 Vermeire K, Schols D, Bell TW. CD4 down-modulating compounds with potent anti-HIV activity. Curr Pharm Des. 2004;10(15):1795-803. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15180541&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16723592 Zhang XQ, Sorensen M, Fung M, Schooley RT. Synergistic in vitro antiretroviral activity of a humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Chemother. 2006 Jun;50(6):2231-3.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16723592&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Lewis S, Jackson J, Frazier K, Fagan EA, Shanahan WR. Phase 1b Study of the Anti-CD4 Monoclonal Antibody TNX-355 in HIV-1-infected Subjects: Safety and Antiretroviral Activity of Multiple Doses. Eleventh Conference on Retroviruses and Opportunistic Infections,San Francisco, CA, February 2004. Abstract 536.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[TNX-355 With Optimized Background Therapy (OBT) in Treatment-Experienced Subjects With HIV-1. Available at: http://clinicaltrials.gov/ct/show/NCT00089700. Accessed 02/12/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[TNX-355]]></drug:drugname><drug:companyname><![CDATA[Tanox, Inc.]]></drug:companyname><drug:address1><![CDATA[10555 Stella Link]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Houston]]></city><drug:state><![CDATA[TX]]></drug:state><drug:zipcode><![CDATA[77025]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(866) 312-5200]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 12, 2007]]></drug:lastupdated></item><item><title><![CDATA[Vicriviroc maleate]]></title><description><![CDATA[Vicriviroc, also known as SCH-D, is a type of medicine called an entry inhibitor. It is a drug also referred to as a chemokine antagonist. Entry inhibitors work by preventing HIV from infecting human cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=405]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Vicriviroc maleate]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[veye-krih-VIR-ok]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Vicriviroc maleate]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Vicriviroc, also known as SCH-D and vicriviroc maleate, is a piperazine-based CCR5 receptor antagonist designed to block the entry of HIV into CD4 cells.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Vicriviroc is a piperazine-based CCR5 antagonist currently in Phase II/III trials. It is a novel, orally active entry and fusion inhibitor that holds promise for use in HIV infected patients who are resistant to enfuvirtide and other antiretrovirals. Vicriviroc received fast-track approval status from the FDA in 2005.

A Phase II trial in treatment-naive patients was discontinued in October 2005, because detectable viral levels returned in some patients taking vicriviroc and lamivudine/zidovudine compared with the patients in the control group who were taking efavirenz and lamivudine/zidovudine. No significant adverse events contributed to the discontinuation.

A second Phase II trial testing vicriviroc in treatment-experienced patients without similar viral level concerns remains ongoing, and a set of Phase III trials in treatment-experienced patients was initiated in 2007.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Vicriviroc doses of 5, 10, and 15 mg once daily in addition to existing background regimens have been studied in one randomized, controlled trial of 40 patients who were coinfected with HIV and hepatitis C virus (HCV). In this setting, vicriviroc had no clinical impact on HCV viral load.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Clinical studies of vicriviroc have evaluated 5-, 10-, 15-, 25-, 30-, and 50-mg tablets.

The 5-mg dose was discontinued early in trials conducted in treatment-experienced patients. This dose was associated with poor efficacy, and eight patients receiving vicriviroc developed malignancies.

The manufacturer is continuing study of vicriviroc 30 mg once daily in multiple phase III trials.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Chemokine receptors expressed on the surface of immune cells are known to play a critical role in HIV infection and transmission. Entry and fusion inhibitors act differently than other classes of anti-HIV drugs (e.g., protease inhibitors [PIs], nucleoside reverse transcriptase inhibitors) by preventing HIV from infecting and entering cells, rather than trying to eradicate HIV after the virus has infected a cell. The CCR5 receptor acts with the CD4 receptor on the surface of T cells to facilitate entry of HIV into cells. Because previous research has suggested that individuals who lack a functional CCR5 receptor are largely resistant to HIV infection, the CCR5 receptor has been a target of investigation in development of anti-HIV therapy.

Vicriviroc is a small-molecule inhibitor that binds to the cell's CCR5 receptor. When the drug binds to the CCR5 receptor, the receptor's conformation changes. This prevents HIV's gp120 protein from binding to CCR5 and consequently prevents the virus from entering the cell.

Vicriviroc has been safe and well tolerated in HIV infected, treatment-naive patients participating in vicriviroc Phase I trials receiving 10-, 25-, and 50-mg twice-daily dosages of the drug. At these doses, a nadir of HIV-1 viral load was observed after 10 to 14 days of dosing. Phase I trial data in treatment-naive HIV patients suggest that vicriviroc's suppression of HIV viral load is dose dependent. Vicriviroc does not appear to induce cytochrome P450 (CYP) 3A4 and has an elimination half-life of approximately 24 hours. Vicriviroc has excellent oral bioavailability, is rapidly absorbed, and has a large apparent volume of distribution. The rapid absorption and a half-life range of 28 to 33 hours both support once-daily dosing of vicriviroc. Minimum (trough) plasma concentrations, or trough concentrations (Cmin), of vicriviroc appear to predict virologic response, as evidenced in ACTG A5211, a Phase II study of vicriviroc 5, 10, or 15 mg given once daily in 86 HIV infected participants with CCR5-tropic virus. At 2 weeks, Cmins averaged 42.3 ng/ml with the 5-mg dose, 90.9 ng/ml with the 10-mg dose, and 121 ng/ml with the 15-mg dose. In participants with Cmins greater than or equal to 53.7 ng/ml, 70% had at least a 10-fold reduction in viral load levels compared with 44% of participants who had lower Cmins.

In the Phase II ACTG A5211 trial, 118 treatment-experienced patients with CCR5-tropic HIV were randomized to receive vicriviroc 5, 10, or 15 mg once daily or placebo in addition to ritonavir-boosted, PI-containing regimens. Vicriviroc demonstrated potent and sustained viral suppression through 48 weeks of therapy. At Day 14 and at Week 24, the median viral load reductions from baseline were statistically greater in the 5-, 10- and 15-mg vicriviroc groups (approximately 85% and 97%, 90% and 99%, and 85% and 98%, respectively) than in the placebo group (slight increase and 50% reduction, respectively). At Week 48, patients in the 10- and 15-mg treatment groups achieved a median decrease in viral load of 99% and 96%, respectively, and a median CD4 count increase from baseline of 130 and 96 cells/mm3, respectively. More patients in the vicriviroc groups had undetectable virus at 48 weeks (HIV-1 viral load less than 50 copies/ml) compared with those in the placebo group (57/37% and 43/27% vs. 14/11%, respectively), and fewer patients in the vicriviroc groups experienced virologic failure compared to those in the placebo group (27 and 33% vs. 86%, respectively). Among participants in the 10- and 15-mg treatment groups who had viral load levels less than 50 copies at Week 24, 70% retained that level through Week 48. Although all participants had CCR5-tropic virus at baseline screening, 12 participants (10%) had dual/mixed virus when the study regimen began. The time to virologic failure tended to be faster in people with dual/mixed virus when the study began than in those with R5-only virus. In addition, tropism switches from CCR5-tropic to CXCR4- or dual/mixed-tropic virus occurred in 7 (12%) of 60 participants taking vicriviroc 10 or 15 mg and in 8 participants taking vicriviroc 5 mg. Among 26 vicriviroc-treated people who had a virologic failure, 9 (35%) saw their virus change coreceptor preference from CCR5 to CXCR4 or dual/mixed tropism. After dual/mixed or X4-using virus emerged in people taking vicriviroc, viral loads and CD4 counts remained relatively stable through Week 48.

After completion of the expanded, 48-week ACTG A5211 trial, 39 HIV infected participants voluntarily continued taking vicriviroc 15 mg in combination with optimized background therapy (OBT). Two-year results of the open-label study showed long-lasting viral load reductions of more than 99% from prestudy levels. Sixty percent of participants maintained viral load levels less than 50 copies. In addition, CD4 levels after 2 years of vicriviroc treatment were approximately 84 cells/mm3 greater than prestudy levels. Two patients experienced viral load rebound, and 6 patients experienced a tropism switch from CCR5-tropic virus to either CXCR4- or dual/mixed-tropic virus. This study found that patients with dual/mixed-tropic virus had significantly lower CD4 counts than patients with CCR5-tropic virus only. This finding emphasizes the importance of evaluating coreceptor use in the clinical development of CCR5 and CXCR4 inhibitors.

Another Phase II trial, VICTOR-E1, is ongoing to compare vicriviroc 20 and 30 mg with placebo in combination with a ritonavir-boosted, PI-containing antiretroviral regimen. VICTOR-E1 is a randomized, double-blind, placebo-controlled, dose-finding study in 116 antiretroviral-experienced participants with CCR5-tropic HIV-1. At Week 12, during a safety evaluation, CD4 levels were generally sustained or increased. Tropism changes from CCR5-tropic to dual/mixed-tropic virus were noted in six participants after screening but before drug administration began. Further, treatment-emergent tropism shifts generally did not result in reduced CD4 counts and were not associated with immune decline. This trial also examined coreceptor usage and tropism-associated variables. Approximately 35% of screened participants had dual or mixed-tropic virus, 4% had CXCR4-tropic virus, and 45% had CCR5-tropic virus; the assay failed in the remaining 15%. Dual/mixed- or CXCR4-tropic virus at screening was associated with lower mean CD4 counts than CCR5-tropic virus; participants with CCR5-tropic virus experienced significantly greater CD4 counts compared with those with non-CCR5-tropic virus. In contrast, age, resistance mutations, gender, and baseline viral load levels had no correlation with coreceptor usage. Efficacy of both vicriviroc 20 and 30 mg was examined at a Week 24 analysis, and viral load was reduced significantly in both groups compared with placebo. HIV RNA was reduced by -2.04 log in both treatment arms. However, undetectable HIV RNA levels (less than 50 copies/ml) were achieved in 64% of patients on vicriviroc 30 mg but in 58% of patients on vicriviroc 20 mg. At a Week 48 analysis, vicriviroc 20 and 30 mg continued to display efficacy in reducing HIV RNA. Viral load was reduced to less than 50 copies/ml in 56% of patients on vicriviroc 30 mg and in 52% of patients on vicriviroc 20 mg. On the basis of the Week 24 and Week 48 efficacy at achieving undetectable virus, the manufacturer continued further study in Phase III trials with the 30-mg dose as the more efficacious option.

Two large, Phase III trials of vicriviroc 30 mg once daily in combination with a ritonavir-boosted, PI- containing OBT have also been initiated in 2007 in treatment-experienced participants with multidrug-resistant HIV and with CCR5-tropic virus at baseline screening. VICTOR-E3 and -E4 will evaluate the efficacy of the addition of vicriviroc to OBT compared with OBT alone. They will also evaluate the safety and tolerability of vicriviroc compared with placebo. The primary efficacy endpoint of both studies will be the proportion of patients with viral load levels less than 50 copies/ml at Week 48.

Mutation in V3 loop sites of HIV's env gene have occurred in some participants who experienced treatment failure in Phase II studies. None of these mutations developed in participants who received vicriviroc 15 mg. The V3 mutations arose at different loop sites in each case and did not correlate directly with reduced viral susceptibility to vicriviroc; thus, it is unlikely that these mutations explain these instances of virologic failure. Although all participants with virologic failure initially had CCR5-tropic virus, repeat testing after failure identified CXCR4-tropic virus; this may explain the treatment failure, although that link is also unclear.

Further study of the effect of mutations on viral resistance to vicriviroc has found that mutations in the V3 loop stem introduce resistance to vicriviroc and cross resistance to TAK779, another investigational CCR5 antagonist agent. Increased susceptibility to HGS004, a third investigational CCR5 antagonist agent, likely was caused by decreased binding of vicriviroc to the CCR5 receptor.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[No drug-specific toxicity was identified in a small Phase I study in HIV infected, treatment-naive patients; vicriviroc was safe, well tolerated, and active at all dose levels tested in the study. In a Phase II study of vicriviroc that was conducted in 118 treatment-experienced patients, 4 cases of lymphoma and 1 case of stomach cancer occurred in the vicriviroc-treated group. A causal association between vicriviroc and the lymphoma cases could not be established at the time, and all those who developed cancers had very advanced HIV disease.

In another Phase II, dose-escalating study of vicriviroc, there were no significant differences in Grade 3 or 4 adverse events across the vicriviroc and placebo groups, but eight patients randomly assigned to receive vicriviroc 5 mg and two patients randomly assigned to receive placebo developed malignancies. The relationship of malignancy development to vicriviroc is uncertain. The study consequently was unblinded in March 2006, and the 5-mg dose group was discontinued.

A safety evaluation of 116 participants enrolled on the Phase II VICTOR-E1 trial showed no safety concerns after a mean duration of 14 weeks (range of 12 to 28 weeks) of treatment with vicriviroc 20 or 30 mg compared with placebo. Specifically, no hepatotoxicity, malignancies, or drug-related seizures were noted. At Week 48, vicriviroc was well tolerated in both treatment arms, and Grade 3/4 adverse events occurred in approximately 20% of these and the placebo arms. Vicriviroc 20 mg and 30 mg administered once daily in combination with a ritonavir-boosted, PI-containing ART regimen appear well tolerated in this treatment-experienced population.

Safety data at Week 24 of an ongoing Phase III trial showed no evidence of safety concerns regarding cardiac toxicity, hepatotoxicity, drug related seizures, infections or malignancy; most adverse events were mild to moderate and were similar to placebo. The most common adverse events included nausea, headache, and fatigue. Other common adverse events noted in 2-year follow-up of Phase II studies included pharyngitis, abdominal pain, and fatigue. Fatigue was the only Grade 3 adverse event reported in more than 1% of the participants.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[1-((4,6-dimethyl-5-pyrimidinyl) carbonyl)-4-(4-(2-methoxy-4-(trifluoromethyl) phenyl) ethyl-3-methyl-1-piperazinyl)-4- methylpiperidine (vicriviroc)]]></drug:casname><drug:casnumber><![CDATA[599179-03-0 (vicriviroc maleate)]]></drug:casnumber><drug:molecularformula><![CDATA[C28-H38-F3-N5-O2 x C4H4O4 (vicriviroc maleate)]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[649.7 (vicriviroc maleate)]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[SCH-D]]></drug:othername><drug:othername><![CDATA[Vicriviroc]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17570119 Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, Gross R, Krambrink A, Coakley E, Greaves WL, Zolopa A, Reichman R, Godfrey C, Hirsch M, Kuritzkes DR; AIDS Clinical Trials Group 5211 Team. Phase II Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV-1-Infected, Treatment-Experienced Patients: AIDS Clinical Trials Group 5211. J Infect Dis. 2007;196:304-12.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17570119&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17545705 Schaurmann D, Fautkenheuer G, Reynes J, Michelet C, Raffi F, van Lier J, Caceres M, Keung A, Sansone-Parsons A, Dunkle LM, Hoffmann C. Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS. 2007 Jun 19;21(10):1293-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17545705&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16304152 Strizki JM, Tremblay C, Xu S, Wojcik L, Wagner N, Gonsiorek W, Hipkin RW, Chou CC, Pugliese-Sivo C, Xiao Y, Tagat JR, Cox K, Priestley T, Sorota S, Huang W, Hirsch M, Reyes GR, Baroudy BM. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2005 Dec;49(12):4911-9.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16304152&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17243065 Wilkin TJ, Su Z, Kuritzkes DR, Hughes M, Flexner C, Gross R, Coakley E, Greaves W, Godfrey C, Skolnik PR, Timpone J, Rodriguez B, Gulick RM. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis. 2007 Feb 15;44(4):591-5. Epub 2007 Jan 17.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17243065&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Gulick R, Zu S, Flexner C, et al. ACTG 5211: Phase 2 Study of the safety and efficacy of vicriviroc (VCV) in HIV+ treatment-experienced subjects: 48-week results. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, Abstract TUAB102, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Safety and Effectiveness of the Oral HIV Entry Inhibitor SCH 417690 in HIV Infected Patients. Available at: http://clinicaltrials.gov/ct/show/NCT00082498. Accessed 04/01/08.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Vicriviroc maleate]]></drug:drugname><drug:companyname><![CDATA[Schering - Plough Corp]]></drug:companyname><drug:address1><![CDATA[2000 Galloping Hill Rd]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Kenilworth]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[07033-0530]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 526-4099]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[April 1, 2009]]></drug:lastupdated></item><item><title><![CDATA[GS 9137 (elvitegravir)]]></title><description><![CDATA[GS 9137 is a type of medicine called an integrase inhibitor. Integrase inhibitors work by blocking integrase, a protein that HIV needs to insert its viral genetic material into the genetic material of an infected cell.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=421]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[GS 9137 (elvitegravir)]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[el-vy-TEH-gra-veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[GS 9137 (elvitegravir)]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Integrase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[GS 9137 is a low-molecular-weight, highly selective integrase inhibitor that shares the core structure of quinolone antibiotics. Integrase inhibitors are a new class of antiretrovirals that interfere with HIV replication by blocking viral ability to integrate into human cell genetic material.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[GS 9137 has shown in vitro activity against B and non-B subtypes of HIV-1. It is being studied in Phase II trials for the treatment of HIV-1 infection in treatment-naive and -experienced patients.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[GS 9137 has been studied alone and in combination with low-dose ritonavir at doses of 200, 400, and 800 mg twice daily (BID) and 50 and 800 mg once daily (QD). Phase II studies in treatment-experienced patients are evaluating once-daily doses of 25, 50, and 125 mg in combination with ritonavir 100 mg.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[GS 9137 is a modified quinolone antibiotic with potent activity against HIV-1 on in vitro assays. GS 9137 has the ability to bind magnesium cations. Integrase has a single binding site for magnesium, an ion required for strand transfer reactions and the assembly of integrase onto specific viral donor DNA. GS 9137 may be a selective inhibitor of the strand transfer process. GS 9137 retains antiretroviral activity against multiple-drug-resistant HIV-1 in vitro.

A Phase I pharmacokinetics study using single oral doses of GS 9137 was conducted in 32 healthy volunteers. Six patients in each group received daily GS 9137 doses of 100, 200, 400, or 800 mg with food or 400 mg fasting. When administered with food, GS 9137 had a half-life of approximately 3 hours, compared with a fasting half-life of approximately 6 hours. The mean maximum plasma concentration (Cmax) achieved with food was 903 ng/ml; the mean area under the concentration-time curve (AUC) with food was 3,942 ng h/ml. The mean Cmax in a fasted state was 264 ng/ml, and the mean fasting AUC was 1,451 ng h/ml. Cmax was achieved by 0.5 to 4 hours post-dose. Both Cmax and AUC increased across escalating daily doses of 100 to 800 mg in a less than dose-proportional manner.

GS 9137 is mostly metabolized by the cytochrome P (CYP) 450 enzyme system, particularly CYP3A4. Glucuronidation is a minor metabolic pathway. Steady-state exposure and minimum plasma concentrations of GS 9137 increase 20-fold and 90-fold, respectively, with ritonavir boosting. Boosting also prolongs the half-life of GS 9137 to a maximum of 9.5 hours and a median of 7.6 hours. This allows for once-daily dosing of GS 9137.

The minimum plasma concentration (Cmin) of GS 9137, rather than Cmax and AUC, appears more reflective of efficacy in pharmacokinetic models. This view is supported by a lower-than-expected antiviral effect with daily GS 9137 800 mg dosages; therefore, maintenance of effective trough concentrations is required for antiviral activity. Trough concentrations with once-daily, ritonavir-boosted dosing of GS 9137 50 mg provide estimated Cmins above the 95% inhibitory concentration for more than 48 hours post-dose.

A randomized, double-blind, placebo-controlled trial in 40 HIV-1 infected patients not currently receiving antiretroviral therapy evaluated the effects of GS 9137 with food for 10 days. The following dosages were studied: 200, 400, and 800 mg BID; 800 mg QD; and 50 mg QD plus ritonavir 100 mg QD. In each dosage group, six patients received GS 9137, and two patients received placebo. All groups completed the 10-day dosing period and the 21 total days of evaluation, and all groups demonstrated significant antiviral activity compared with placebo. Twice-daily GS 9137 dosages of 400 or 800 mg and once-daily dosages of GS 9137 50 mg plus ritonavir exhibited potent antiviral activity, with mean viral load reductions of at least 80-fold in each group. All patients achieved at least 50-fold viral load reduction, and half of the patients achieved at least 100-fold reduction. Maximum reductions were observed on days 10 or 11 in all but one patient. Once-daily GS 9137 dosages of 800 mg achieved a less than 10-fold viral load reduction, which was a statistically significant activity difference compared with these dosages groups.

An ongoing, Phase II, randomized, dose-ranging monotherapy study of once-daily GS 9137 assessed noninferiority of GS 9137 to boosted comparator protease inhibitors (PIs) in HIV infected participants. GS 9137 dosages of 20, 50, or 125 mg with ritonavir 100 mg, or comparator PIs, were administered in combination with enfuvirtide and nucleoside reverse transcriptase inhibitors (NRTIs). The 20 mg arm was closed after Week 8 because of high rate of virologic failure, and the addition of PIs darunavir or tipranavir was permitted when new data showed a lack of drug interaction. Prior to Week 16, most participants taking GS 9137 received only two NRTIs; by Week 24, 26% of the GS 9137 50 mg and 125 mg arms added a PI as well.

Several resistance-conferring mutations, including E92Q, H51Y, S147G, and E157Q, have been observed during serial passage studies of GS 9137. The E29Q mutation occurred after 30 passages; the other mutations occurred after at least 60 passages. In addition, cross resistance was observed between GS 9137 and prior investigational integrase inhibitors. A similar study compared GS 9137 susceptibility with zidovudine and the prior investigational integrase inhibitor L-870,810. Susceptibility of HIV-1 to GS-9137 and to L-870,810 decreased dramatically in the presence of two or three identified mutations. The E29Q mutation alone conferred resistance to GS-9137 and cross resistance to L-870,810. HIV susceptibility to GS 9137 was reduced 36-fold with the E29Q mutation alone. Additional resistance mutations identified by in vitro culturing included T66I in the integrase catalytic core, R263K in the C-terminal DNA binding domain, S153Y, and F121Y. HIV susceptibility was reduced 15-fold with the T66I mutation and 98-fold with the combined T66I/R263K mutation.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In a single-blind, randomized, placebo-controlled trial, GS 9137 was safe and well tolerated in healthy participants; no Grade 3 or 4 adverse events occurred. One participant experienced mild anorexia, and one experienced increased liver enzyme levels; both problems resolved on their own.  A randomized, double-blind, placebo-controlled trial in HIV infected participants also reported only mild adverse effects, with no Grade 3 or 4 events. In a drug-interaction study of ritonavir-boosted GS 9137 and zidovudine, 2 of 24 participants experienced headache and/or gastrointestinal symptoms, both of which occurred during the zidovudine-only dosing period. No serious adverse events or discontinuations resulting from adverse events occurred in this or other drug-interaction studies of GS 9137.

In a 10-day monotherapy study of six participants treated with daily ritonavir-boosted GS 9137, no relationship to dose was observed in treatment-emergent Grade 3 or 4 adverse events or laboratory abnormalities. Fewer patients in the GS 9137 treatment arms than comparator arms discontinued the study drug because of adverse events.

A randomized, double-blind, placebo-controlled trial of GS 9137 in 40 HIV infected participants reported no dosage interruptions, discontinuations, or serious adverse events. Eight participants (27%) receiving GS 9137 and four (40%) receiving placebo experienced Grade 2 or 3 adverse events. Headache was the most common adverse event (occurring in three participants) and was the only adverse event to occur in more than one participant receiving GS 9137. Muscle spasm, the only Grade 3 adverse event in the treatment group, was experienced by one participant receiving GS 9137 800 mg twice daily. Three participants receiving placebo and two receiving GS 9137 experienced a Grade 3 or 4 laboratory abnormality: one participant receiving twice-daily GS 9137 400 mg experienced Grade 3 elevated nonfasting triglycerides, and one receiving daily ritonavir-boosted GS 9137 50 mg  experienced Grade 3 elevated total amylase without increase in serum lipase.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The absorption of GS 9137 increased approximately threefold when administered with food in a Phase I study.

GS 9137 displays additive to highly synergistic antiviral activity in vitro with the following antiretroviral medications: lamivudine, lamivudine/zidovudine, zidovudine, tenofovir disoproxil fumarate (tenofovir DF), tenofovir DF/lamivudine, efavirenz, indinavir, and nelfinavir.

Potential drug interactions between ritonavir-boosted GS 9137 (GS 9137/r) and zidovudine or emtricitabine/tenofovir DF have been studied for up to 10 days in healthy participants. No clinically relevant interactions were observed during GS 9137/r administration with either zidovudine or emtricitabine/tenofovir DF.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[6-(3-chloro-2-fluorobenzyl)-1- [(2S)-1hydroxy-3-methylbutan-2-yl] -7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid]]></drug:casname><drug:casnumber><![CDATA[697761-98-1]]></drug:casnumber><drug:molecularformula><![CDATA[C23-H23-Cl-F-N-O5]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[447.88]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/16936557 DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK, McColl D, Kearney BP; for the 183-0101 Study Team. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006 Sep;43(1):1-5.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16936557&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16839248 Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS. 2006 Jul;20(7):489-501.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16839248&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16509568 Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics. J Med Chem 2006 Mar 9;49(5):1506-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16509568&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Ritonavir-Boosted GS-9137 Vs. Ritonavir-Boosted Protease Inhibitor(s) in Combination With Background ART. Available at:  http://clinicaltrials.gov/ct/show/NCT00298350. Accessed 03/14/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[GS 9137 (elvitegravir)]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[March 14, 2007]]></drug:lastupdated></item><item><title><![CDATA[BMS-378806]]></title><description><![CDATA[BMS-378806, also known as BMS-806, is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking HIV from entering human cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=422]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806, or BMS-806, is a small molecule entry inhibitor of HIV-1 that targets the viral envelope protein.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806 is being investigated for the treatment of subtype B HIV-1 infection, including both CCR5 and CXR4 strains. BMS-378806 is also being investigated in formulations for vaginal administration for the prevention of HIV-1 transmission when used in combination with other vaginal microbicides.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Topical.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Vaginal gel for topical use.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806 targets viral entry by inhibiting the binding of HIV-1 gp120 to the CD4 receptor. The affinity of BMS-378806 for the gp120 molecule is similar to that of soluble CD4 cells, and binding occurs close to the CD4 cell-binding pocket. Binding of gp120 is the first step of HIV infection at the cellular level; BMS-378806 appears to be the first compound to block this binding.

BMS-378806 shows good oral bioavailability in animals and has low protein binding. It is active against viral strains with both the CCR5 and the CXCR4 coreceptors and is selective for HIV-1, specifically subtype B.

BMS-378806 retains activity against HIV strains resistant to protease inhibitors and reverse transcriptase inhibitors. Resistance maps to substitutions located primarily near the CD4 binding sites of gp120, including A204D, F423Y, M434/I/V/T, and M475I. Other reported mutations include M475I, M434I/V, M426L, D350K, D185N, K655E, 1595F, V68A, and S440R.

BMS-378806 has recently been tested as a topically administered vaginal microbicide in combination with other investigational entry inhibitors. BMS-378806 and CMPD 167 appear to be synergistic in vitro, inhibiting different stages of the viral-cell attachment and entry process. When combined in vitro, CMPD167, C52L, and BMS-378806 inhibited infection of T cells and cervical tissue explants. Significant protection was achieved in macaques when BMS-378806 was used alone and in combination, even when applied up to 6 hours before challenge.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BMS-378806 displayed an excellent safety profile in animal studies. No significant cytotoxicity has been noted.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Piperazine, 4-benzoyl-1-(2-(4-methoxy-1H-pyrrolo(2,3-b) pyridin-3-yl)-1,2-dioxoethyl)-2-methyl-, (2R)-]]></drug:casname><drug:casnumber><![CDATA[357263-13-9]]></drug:casnumber><drug:molecularformula><![CDATA[C22-H22-N4-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C65%,H5.4%,N13.8%,O15.8%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[406]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17428517 Ketas TJ, Schader SM, Zurita J, Teo E, Polonis V, Lu M, Klasse PJ, Moore JP. Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology. 2007 Aug 1;364(2):431-40. Epub 2007 Apr 10. 
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17428517&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12930892 Lin, PR. A Small Molecule HIV-1 Inhibitor That Targets the HIV-1 Envelope and Inhibits CD4 Receptor Binding. Proc Natl Acad Sci USA 2003;100(19):11013-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12930892&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16258536 Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP.  Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 2005 Nov 3;438(7064):99-102.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16258536&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Madani N, Hubicki A, Ng D, Smith A, Sodroski J. The road to finding potent HIV-1 entry inhibitors: Lessons learned from requirements for BMS-806 binding to HIV-1 envelope glycoprotein. 16th International AIDS Conference, Toronto, Canada, Abstract MOPE0001, 2006.

]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[BMS-378806]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 6, 2008]]></drug:lastupdated></item><item><title><![CDATA[C31G]]></title><description><![CDATA[C31G is a type of medicine called a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection. ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=393]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[C31G]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[C31G]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[C31G, also known as Savvy, is an antimicrobial and spermicidal agent that contains two surface-active compounds, cetyl betaine (a C16 alkyl betaine) and myristamine oxide (a C14 alkyl amino oxide). C31G is an equimolar mixture of these two amphoteric, surface-active molecules. The vaginal gel is formulated with hydroxyethyl cellulose (HEC).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[C31G has been investigated in Phase III clinical trials as a surface-active microbicide in a vaginal gel formulation for the prevention of HIV-1 and HIV -2 transmission. However, both Phase III trials have been halted, because neither trial appeared likely to detect a reduction in HIV transmission risk. Based on interim data available from the halted trials, C31G is not expected to be effective at preventing HIV transmission. The trial partners, U.S. Agency for International Development and Family Health International, do not plan further studies of C31G for the prevention of HIV transmission. The manufacturer, Cellegy Pharmaceuticals, continues to investigate C31G in an existing contraceptive trial. The trial partners, U.S. Agency for International Development and Family Health International, do not plan further studies of C31G for the prevention of HIV transmission. The trial partners, U.S. Agency for International Development and Family Health International, do not plan further studies of C31G for the prevention of HIV transmission. The manufacturer, Cellegy Pharmaceuticals, may continue to investigate C31G as a contraceptive.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro. Early studies suggest that C31G, when used alone, may be approximately 85% effective in pregnancy prevention. A Phase III efficacy study has been initiated in the United States to further evaluate the contraceptive efficacy of C31G. 

C31G displays activity against gram-positive and -negative bacteria, fungi, yeast, and enveloped viruses. C31G has demonstrated activity against numerous viruses that cause sexually transmitted diseases, including chlamydia, herpes simplex virus (HSV)-1 and -2, and gonorrhea.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[C31G is administered intravaginally via a prefilled applicator prior to sexual intercourse.

Doses of 0.5%, 1.0%, and 1.7% C31G have been tested in Phase I studies. The 1.0% concentration has been selected for testing of a marketable formulation in Phase III trials.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The nonmetabolic mode of action of C31G is thought to give C31G an advantage over systemic drugs that inhibit specific metabolic pathways, because organisms usually develop resistance to such drugs. The C31G micelle binds to the surface of a microorganism, causing an irreversible disruption of the phospholipid membrane, resulting in destruction of the cell.

C31G has been tested against several different subtypes, clades, and strains of HIV; all are equally susceptible to C31G. C31G also inhibits HSV-1 and -2 as measured by in vitro plaque assays. Studies in mouse xenograft models have shown that C31G inhibits transmission of HSV.

In three separate Phase I studies of the safety of and tolerance to C31G, this microbicide appears to be at least as safe, acceptable, and well tolerated compared with a currently available spermicide (Extra Strength Gynol II) containing nonoxynol-9 (N-9). Minimal genital irritation in both men and women was observed in all three trials. Based on clinical trial results comparing three different concentrations of C31G against the N-9 spermicide, the 0.5% and 1.0% concentrations appear to be less irritating in women than either the 1.7% concentration of C31G or the N-9 spermicide. C31G demonstrated significant contraceptive activity in women at each of these concentrations, emphasizing the promising potential of C31G as a future contraceptive. Phase III trials of C31G are planned to further evaluate its contraceptive effectiveness.

Two Phase III clinical trials were being conducted in Africa to test C31G's efficacy in the prevention of HIV transmission in women. Both the Nigeria and Ghana trials were halted, because an independent data monitoring committee concluded that neither trial would be able to detect a reduction of HIV risk if continued. The Ghana trial was halted in November 2005, as fewer HIV infections than expected were observed; therefore, the trial would be unable to determine C31G's effectiveness. The Nigeria trial was halted in August 2006 for similar reasons.

An additional Phase III contraceptive efficacy trial was initiated in the United States in 2004.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In an early Phase I clinical study, 80% of the women using C31G vaginal gel experienced symptoms of vaginal burning or heat, compared with 25% of women using 2% N-9 and 5% of women using an HEC gel.

Mild genital irritation with C31G was minimal in further studies of men and women. Product-related adverse effects reported by men in a Phase I study who applied 1.0% C31G gel nightly at bedtime were deemed mild by the investigator. In a dose-escalating study, doses of the 0.5% and 1.0% C31G gel used in women were found to be less irritating than the 1.7% C31G dose as well as 3% N-9.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[C 31G]]></drug:casname><drug:casnumber><![CDATA[86903-77-7]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[Clear, colorless, odorless gel when formulated with HEC.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[Savvy]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15793133 Catalone BJ, Kish-Catalone TM, Neely EB, Budgeon LR, Ferguson ML, Stiller C, Miller SR, Malamud D, Krebs FC, Howett MK, Wigdahl B. Comparative safety evaluation of the candidate vaginal microbicide C31G. Antimicrob Agents Chemother. 2005 Apr;49(4):1509-20.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15793133&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16154721 Catalone BJ, Miller SR, Ferguson ML, Malamud D, Kish-Catalone T, Thakker NJ, Krebs FC, Howett MK, Wigdahl B, Toxicity, inflammation , and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G. Biomed Pharmacother. 2005 Sep:59(8):430-7.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16154721&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15325892 Mauck CK, Creinin MD, Barnhart KT, Ballagh SA, Archer DF, Callahan MM, Schmitz SW, Bax R. A phase I comparative postcoital testing study of three concentrations of C31G. Contraception. 2004 Sep;70(3):227-31.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15325892&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15325891 Mauck CK, Frezieres RG, Walsh TL, Schmitz SW, Callahan MM, Bax R. Male tolerance study of 1% C31G. Contraception. 2004 Sep;70(3):221-5.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15325891&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15325893 Mauck CK, Weiner DH, Creinin MD, Barnhart KT, Callahan MM, Bax R. A randomized Phase I vaginal safety study of three concentrations of C31G vs. Extra Strength Gynol II. Contraception. 2004 Sep;70(3):233-40.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15325893&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[C31G]]></drug:drugname><drug:companyname><![CDATA[Cellegy Pharmaceuticals, Inc]]></drug:companyname><drug:address1><![CDATA[3490 Oyster Point Boulevard]]></drug:address1><drug:address2><![CDATA[Suite 200]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[South San Francisco]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94080]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(650) 616-2200]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 19, 2007]]></drug:lastupdated></item><item><title><![CDATA[Carbomer 974]]></title><description><![CDATA[Carbomer 974, also known as BufferGel, is a type of medicine called a microbicide. Microbicides are substances that protect the body from microorganisms such as bacteria, viruses, and fungi.  Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=343]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[BufferGel]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974 is a water-based, detergent-free, buffering agent that contributes to the acidic buffering action of BufferGel, an investigational microbicide and spermicide gel. Carbomer 974, a cross-linked polyacrylic acid, is highly negatively charged, containing thousands of ionizable carboxyl groups per molecule, and has a molecular weight of several billion. These carboxyl groups can release hydrogen ions, the active agents that provide the acid-buffering action of BufferGel. In addition, these carboxyl groups, with the polymer's high molecular weight, prevent transmucosal absorption of the buffer agent. Moreover, as a polymeric buffer, the product will not become hypertonic when high concentrations of buffer material are used and will not cause the cytotoxicity that is seen with use of small, absorbable buffers such as acetic or lactic acid.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974, as the source of acid-buffering action in BufferGel, maintains vaginal acidity, impairing or preventing the transmission of HIV. BufferGel is being investigated in Phase I/II trials for the prevention of sexual transmission of HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974, formulated as BufferGel, is being studied for use as a contraceptive. As a microbicidal spermicide, carbomer 974 provides buffering activity to maintain vaginal acidity in the presence of alkaline semen. BufferGel has been proven safe and effective as a contraceptive in Phase III trials. Two contraceptive trials of more than 1,200 women showed BufferGel combined with a diaphragm to be non-inferior to Gynol II (a nonoxynol-9 based spermicide) used with a diaphragm.

In addition, carbomer 974 blocks the alkalinizing action of semen that enables acid-sensitive pathogens that cause sexually transmitted diseases (STDs) to transmit infection. Carbomer 974 is effective in vitro against herpes simplex viruses, Chlamydia trachomatis, Neisseria gonorrhea, and other STD pathogens.

In a pilot study of 10 women, BufferGel was moderately effective as a treatment for bacterial vaginosis. An international, Phase I study of BufferGel as a contraceptive reported an 80% decrease in prevalence of bacterial vaginosis in women using the drug once daily for 1 week.

Carbomer 974 polymer also is used as a gelling or tableting agent in many pharmaceuticals.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Topical gel.

BufferGel contains 5% carbomer 974. In Phase II studies, BufferGel is packaged as a single-use, prefilled applicator to be administered up to 60 minutes prior to sexual intercourse.]]></drug:dosageform><drug:storage><![CDATA[Store at room temperature.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carbomer 974 is a negatively charged, high--molecular-weight polymer that provides active, ionizable carboxyl groups for acid-buffering activity. Carbomer 974 is not absorbed and can neutralize twice its volume of base buffers, such as semen. Carbomer 974 is formulated to buffer the concentration of free hydrogen ions at 0.1 mM, the level normally found in the vaginal lumen (pH 3.8 to 4.0). Hydrogen ions are buffered by the carboxyl groups that occur in large quantities on the carbomer 974 polymer. Carbomer 974 acidifies semen to a pH less than or equal to 5. In vitro, sperm and many STD pathogens are inactivated at a pH less than 5. HIV specifically is inactivated in the acidic environment below pH 4 to 5.8.

BufferGel is being compared with another investigational microbicide agent, PRO 2000 gel, in a Phase II/IIb, four-arm, randomized, single-blind, placebo-controlled trial. Unlike BufferGel, PRO 2000 inhibits viral entry into cells. Participants will be given single-dose, prefilled applicators of gel containing BufferGel, PRO 2000, placebo gel, or no treatment to use intravaginally up to 60 minutes before each act of intercourse.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In a Phase I clinical trial, BufferGel showed minimal toxicity and was well tolerated, although two-thirds of participants reported at least one mild or moderate adverse event. The most common adverse events were vaginal itching and irritation. Some symptoms disappeared within 1 hour after application of the product. Vaginal candidiasis and hyperkeratotic lesions required discontinuation of the product in a small percentage of trial participants. Three colposcopic abnormalities were observed, but no cases of epithelial disruption occurred.

An international Phase I clinical trial had similar results. Adverse events were categorized as mild to moderate and included presence of Candida on wet mount, vaginal and vulvar itching or burning after gel insertion or when passing urine, labial rash, lower abdominal pain, and vaginal discharge. Irritation was reported in approximately 25% of women in the study and was generally mild and of short duration. Epithelial abnormalities detected by pelvic exam or colposcopy were uncommon. In both trials, adverse effects of BufferGel were generally self limiting and readily resolved. Both trials reported a high degree of compliance and acceptability.

In a Phase I clinical trial of penile application of BufferGel, no serious adverse events or urethral inflammation were reported, and adverse event rates were not significantly different from placebo.

In two Phase I trials of BufferGel conducted in 125 women, a significant decrease in bacterial vaginosis was noted, along with some self-limiting, local genitourinary signs and symptoms, including erythema, pruritis, and dysuria.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Carbomer 974P]]></drug:casname><drug:casnumber><![CDATA[151687-96-6]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[Colorless, tasteless, odorless, and aqueous gel, formulated at pH 3.9 to 4.0, with sufficient buffer capacity to acidify (to pH less than 5) approximately twice its own volume of human semen.]]></drug:physicaldescription><drug:stability><![CDATA[Carbomer 974 as formulated in BufferGel contains no oils and so is compatible with condoms and diaphragms. It is osmotically balanced with the following physiological salt constituents: dibasic potassium phosphate, magnesium sulfate, dibasic sodium phosphate, sorbic acid, monobasic sodium phosphate, and disodium EDTA.]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[ClinicalTrials.gov - Phase II/IIb Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000/5 Gel (P) for the Prevention of HIV Infection in Women. Available at: http://www.clinicaltrials.gov/ ct/show/NCT00074425. Accessed 04/10/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15226137 Bentley ME, Fullem AM, Tolley EE, Kelly CW, Jogelkar N, Srirak N, Mwafulirwa L, Khumalo-Sakutukwa G, Celentano DD. Acceptability of a microbicide among women and their partners in a 4-country phase I trial. Am J Public Health. 2004 Jul;94(7):1159-64.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15226137&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16740164 Cone RA, Hoen T, Wong X, Abusuwwa R, Anderson DJ, Moench TR. Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis. 2006 Jun 1;6:90.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16740164&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16323129 Dahwan D, Mayer KH. Microbicides to prevent HIV transmission: overcoming obstacles to chemical barrier protection. J Infect Dis 2006;193:36-44.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16323129&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12804356 Harwell JI, Moench T, Mayer KH, Chapman S, Rodriguez I, Cu-Uvin S.  A pilot study of treatment of bacterial vaginosis with a buffering vaginal microbicide. J Womens Health (Larchmt). 2003 Apr;12(3):255-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12804356&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12869836 Tabet SR, Callahan MM, Mauck CK, Gai F, Coletti AS, Profy AT, Moench TR, Soto-Torres LE, Poindexter III AN, Frezieres RG, Walsh TL, Kelly CW, Richardson BA, Van Damme L, Celum CL. Safety and acceptability of penile application of 2 candidate topical microbicides: BufferGel and PRO 2000 Gel: 3 randomized trials in healthy low-risk men and HIV-positive men. J Acquir Immune Defic Syndr. 2003 Aug 1;33(4):476-83. Erratum in: J Acquir Immune Defic Syndr. 2003 Sep 1;34(1):118.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12869836&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Carbomer 974]]></drug:drugname><drug:companyname><![CDATA[Lubrizol Corporation]]></drug:companyname><drug:address1><![CDATA[29400 Lakeland Boulevard]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Wickliffe]]></city><drug:state><![CDATA[OH]]></drug:state><drug:zipcode><![CDATA[44092]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[BufferGel]]></drug:drugname><drug:companyname><![CDATA[ReProtect, Inc.]]></drug:companyname><drug:address1><![CDATA[703 Stags Head Road]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Baltimore]]></city><drug:state><![CDATA[MD]]></drug:state><drug:zipcode><![CDATA[21286]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(410) 516-7260]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[April 29, 2007]]></drug:lastupdated></item><item><title><![CDATA[Carrageenan]]></title><description><![CDATA[Carrageenan is a chemical found in certain types of seaweed.  Scientists have discovered that carrageenan can protect laboratory cells from becoming infected with many viruses, including HIV.  ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=400]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carrageenan]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[kar-a-GEE-nan]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carraguard]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carrageenan]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carrageenan is a water-soluble mixture of sulfated polysaccharides extracted from red seaweed (Rhodophyceae), or Irish moss, found off the Atlantic coasts. The kappa, iota, and lambda forms of carrageenan are distinguished by the position of sulfate and the presence or absence of anhydrogalactose on the main polysaccharide backbone. Carrageenan is a mixture of lambda and kappa carrageenan. Kappa carrageenans have a helical tertiary structure that allows gelling; lambda carrageenans are non-gelling.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carrageenan is being investigated in Phase III trials as a topical microbicide to prevent the sexual transmission of HIV. A combined kappa and lambda carrageenan formulation comprises the active pharmaceutical ingredient in Carraguard, a vaginal gel being investigated in clinical trials. Carrageenan is also being studied in combination with other investigational microbicide agents.

A recently completed, randomized, double-blind, Phase III trial compared carrageenan gel with placebo in more than 6,000 women. However, the study did not find carrageenan statistically significantly more effective than placebo at preventing HIV transmission because of the high rate of HIV infection in both arms.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Carrageenan is used as a gelling, emulsifying, and stabilizing agent and viscosity builder in foods and nonfoods, particularly in milk and water systems. Carrageenan is used as a clarifier for beverages and is used to suspend cocoa in chocolate manufacturing. Carrageenan is used in cough and cold preparations, topical creams, and medicated shampoos. Carrageenan compounds are on the FDA's list of GRAS (generally recognized as safe) products for consumption and topical application.

Carrageenan is a potent in vitro inhibitor of herpes simplex virus, human cytomegalovirus, vesicular stomatitis virus, and Sindbis virus, in addition to HIV. Laboratory tests have shown that carrageenan gel also blocks human papillomavirus and gonorrhea infection in vitro and in vivo.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal gel.]]></drug:modeofdelivery><drug:dosageform><![CDATA[3% gel inserted just prior to sexual activity and studied in applications up to once daily.

Prefilled, single-dose, disposable, plastic Micralax® applicators providing delivery of approximately 4 mL gel.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[HIV infected macrophages may mediate sexual transmission of HIV. Carrageenan provides microbicidal activity by blocking macrophage migration, or cell trafficking, from vaginal tissue to lymph nodes. In one study, carrageenan reduced the number of macrophages in lymph nodes by greater than 90% compared to a 50% reduction by placebo. Carrageenan appears to prevent cell trafficking by coating the surfaces of vaginal cells to prevent adhesion of macrophages to the epithelial surface.

Carrageenan is bound to the vaginal epithelium for up to 4 hours. An in vivo study showed that significant quantities of carrageenan could be detected up to 24 hours post-application, and that the duration of activity was retained without loss for 3 hours.

Carrageenan gel studied in cervical samples did not appear to interfere with testing for other sexually transmitted diseases.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Phase II safety trials have been conducted in women, who applied carrageenan before each act of intercourse or at least three times weekly. Few adverse effects, including mild itching, burning, and pain, were reported. No women developed visible cervical or vaginal abnormalities. Most women considered the applicator and the gel itself easy to use, not messy, and of reasonable volume. No significant differences in rate of side effects or development of lesions were noted between gel and placebo users.

In a Phase II trial of 55 HIV uninfected couples who used the gel or a placebo prior to each act of intercourse, no differences in side effects were reported in men exposed to the microbicide compared to those exposed to placebo.

In vitro comparison of carrageenan and nonoxynol-9 (N-9) showed carrageenan to be 20- to 50-fold less toxic than N-9 to cervical and colorectal epithelial cells.

In a recently completed Phase III clinical trial, carrageenan was studied for 2 years and was found safe for vaginal use throughout that time. Adverse effects from carrageenan use were not different than with placebo and were considered minor.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Covalently coupled AZT and kappa-carrageenan are synergistic in vitro in tests of MT-4 cells incubated with HIV-1.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Carrageenan]]></drug:casname><drug:casnumber><![CDATA[9000-07-1]]></drug:casnumber><drug:molecularformula><![CDATA[Unspecified]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[Carrageenan is a gel derived from seaweed.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Kappa and lambda carrageenan are both soluble in very polar solvents. Kappa carrageenan is soluble in water above 60 C. Lambda carrageenan is soluble in water and in concentrated salt solution.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[PC-515]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/14754390 D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. Review. PMID: 14754390]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14754390&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12773428 Perotti ME, Pirovano A, Phillips DM. Carrageenan formulation prevents macrophage trafficking from vagina: implications for microbicide development. Biol Reprod. 2003 Sep;69(3):933-9. 
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12773428&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Kilmarx PH, Supawitkul S,  Yanpaisarn S, Jones H, van de Wijgert J, Young NL, Srivirojana N, Guest P. A year-long, randomized, controlled clinical trial of a carrageenan gel as a vaginal microbicide: Effect on reproductive tract infection (RTI) rates. International AIDS Conf, Barcelona. Abstract WeOrD1318. 2002.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Morar NS, Braunstein S, Jones H, Moodley M, Aboobaker J, Ndaba M, Ndlovu G, van de Wijgert J, Ramjee G. Safety of Carraguard® among HIV-positive women and men in South Africa. Microbicides Conf, London. Abstract 02463. 2004.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Carrageenan]]></drug:drugname><drug:companyname><![CDATA[FMC Biopolymer]]></drug:companyname><drug:address1><![CDATA[1735 Market Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Philadelphia]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[10021]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Carrageenan]]></drug:drugname><drug:companyname><![CDATA[Population Council]]></drug:companyname><drug:address1><![CDATA[Center for Biomedical Research]]></drug:address1><drug:address2><![CDATA[Weiss Research Building]]></drug:address2><drug:address3><![CDATA[1230 York Avenue]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10021]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Carraguard]]></drug:drugname><drug:companyname><![CDATA[Population Council]]></drug:companyname><drug:address1><![CDATA[Center for Biomedical Research]]></drug:address1><drug:address2><![CDATA[Weiss Research Building]]></drug:address2><drug:address3><![CDATA[1230 York Avenue]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10021]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 21, 2008]]></drug:lastupdated></item><item><title><![CDATA[Cellulose sulfate]]></title><description><![CDATA[Cellulose sulfate, or CS, is being studied as an experimental HIV microbicide called Ushercell. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=409]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cellulose sulfate]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Ushercell]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cellulose sulfate]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cellulose sulfate, also known as CS, is a high molecular weight carboxymethylcellulose-based polymer. It is a noncytotoxic, antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Two Phase III clinical trials to study cellulose sulfate's effectiveness in preventing the sexual transmission of HIV have been halted as of January 2007. One trial in HIV uninfected women being conducted in South Africa, Benin, Uganda, and India was halted because preliminary results at some trial sites indicated using the microbicide could lead to potential increased risk of HIV infection in these women. Simultaneously, a Nigerian study of cellulose sulfate was halted. Although the second study did not detect an increased risk of HIV infection associated with the microbicide, the trial was halted as a precautionary measure in light of the preliminary results from the first study. At interim analysis of the first trial, 24 women using cellulose sulfate and 11 women using placebo developed HIV. Possible causes for the increased infection rate include inflammatory reactions, local immune dysfunction, or vaginal flora disruption. After the final study visit, conducted in May 2007, analysis showed no statistically significant difference in onset of HIV infection (25 women using cellulose sulfate and 16 using placebo) and no potential to prevent HIV transmission.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cellulose sulfate is being tested for effectiveness in prevention of sexually transmitted diseases and for contraceptive use. Preclinical and clinical studies have demonstrated a high level of safety. Laboratory tests reveal the potential of cellulose sulfate to be an effective safeguard against pregnancy and infections from gonorrhea, chlamydia, and herpes simplex virus (HSV)-1 and -2. Placebo-controlled Phase III trials are evaluating its use in the prevention of male-to-female transmission of Neisseria gonorrhoeae and Chlamydia trachomatis.

Cellulose sulfate displays direct microbicidal activity against human papillomavirus in vitro. In January 2006, Polydex Pharmaceuticals received a European patent regarding the use of cellulose sulfate and other sulfated polysaccharides to prevent and treat papilloma virus infections in humans and other mammals. The patent acknowledges that microbicidal agents that may otherwise have a broad spectrum of prevention capabilities have thus far been ineffective against papilloma viruses.

Two CONRAD-sponsored studies tested contraceptive activity of cellulose sulfate, and both efficacy trials ended in 2006. One of these studies tested the contraceptive effectiveness of cellulose sulfate in preventing pregnancy when used by a woman in a sexually active, HIV uninfected couple for 6 months.

In vitro, cellulose sulfate inhibits Gardnerella vaginalis and anaerobes that cause bacterial vaginosis (BV). BV may act as a cofactor in the heterosexual transmission of HIV, so the impact of cellulose sulfate and other vaginal microbicides on BV warrants evaluation. Because cellulose sulfate inhibits BV pathogens, cellulose sulfate may provide contraceptive and antimicrobial activity without increasing a patient's risk of BV.

Studies have also been conducted to test the safety of cellulose sulfate in conjunction with use of a diaphragm or magnetic resonance imaging (MRI).]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Cellulose sulfate 6% vaginal gel in a 3.5 ml prefilled applicator for insertion prior to sexual intercourse.

Cellulose sulfate 200-mg vaginal tablets containing excipients generally regarded as safe (GRAS). Tablets disintegrate in less than 30 seconds in 10 ml of fluid to form a smooth, homogenous, viscous, and bioadhesive dispersion.

Cellulose sulfate 6% vaginal gel has been tested in women up to four times daily for up to 14 consecutive days.

Cellulose sulfate 0.1% vaginal gel has been tested for contraceptive use.

Because the optimal applied volume of gel is not known, volumes ranging from 2.5 to 5 ml have been tested.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In vitro, cellulose sulfate blocks cell surface receptors, inhibits HIV binding and penetration of epithelial layers and dendritic cells, blocks the gp120-CD4 coreceptor interaction, and acts against coreceptors CCR5 and CXCR4 in primary isolates and laboratory strains. Cellulose sulfate gel 6% has been shown to stimulate acrosomal loss, inhibit hyaluronidase, and impede sperm penetration into cervical mucus in vitro. Cellulose sulfate inhibits HIV entry and sperm-egg interaction in vitro, reaching 95% or greater inhibition of sperm binding capacity at a concentration of 1 mg/mL. Cellulose sulfate does not affect sperm motility and is not cytotoxic. Cellulose sulfate inhibits HIV-1 strains with a 50% inhibitory concentration (IC50) of 50 ug/ml. It is especially effective against HSV-1 and -2 at an IC50 of 0.12 to 0.25 ug/ml.

Linear gel spread, as evaluated in a study of 2.5 ml and 3.5 ml gel volumes inserted vaginally, takes place primarily in the first 5 minutes after gel insertion. Lateral spreading (surface contact) appears to continue after linear spreading slows or stops. Upright patient movement has a greater effect on gel distribution than gel volume does. Using a larger gel volume increases linear spreading but provides less consistent lateral spreading. The greatest linear and lateral spreading have been noted 50 minutes after insertion in women using 3.5 ml of gel who have walked around after insertion. Even under these conditions, women had bare spots in coverage, particularly in the proximal vagina. Thus, the spreading of cellulose sulfate without intercourse did not result in complete vaginal coverage, even at 50 minutes after product insertion.

Vaginal cellulose sulfate tablet inhibition of sperm enzyme and of HIV, HSV, and Chlamydia appears comparable to that of the gel formulation. Cellulose sulfate tablets do not inhibit Lactobacillus in vitro.

In rabbit models, cellulose sulfate 6% gel was active as a contraceptive for at least 18 hours after application and was partially active for at least 24 hours. A gel concentration as low as 0.1% was an effective contraceptive when applied within 30 minutes of insemination.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Results of all 11 cellulose sulfate studies sponsored by CONRAD have indicated the microbicide is safe, acceptable, and effective as currently marketed spermicides and sexual lubricants. These 11 studies include 5 safety studies in women,2 safety studies in men, 2 contraceptive effectiveness studies, and studies testing the safety of the microbicide when used with a diaphragm or MRI.

Cellulose sulfate 6% gel administered vaginally four times daily for 14 days did not differ with respect to epithelial disruption, candidiasis, BV, and acceptability from K-Y jelly placebo. A blinded crossover study of 6% gel was conducted with 2.5 and 3.5 ml volumes. Each woman used each gel volume twice; after one application, women had restricted upright movement, and after the other, they were allowed to walk around. Excessive leakage was not noted with either volume.

In a safety and acceptability study conducted in the United States and the Dominican Republic, HIV uninfected women used cellulose sulfate 6% gel or K-Y jelly placebo twice daily for 14 days. Some level of product leakage was reported by all study participants. There was no noticeable difference in the proportion of overall vaginal leakage of moderate or severe intensity between the cellulose sulfate and K-Y jelly placebo groups.

In a Phase I, two-part cohort study of 180 women in India, Nigeria, and Uganda using cellulose sulfate 6% gel or K-Y jelly placebo, the majority of women had no problem with either gel, and most found the gels easy to use. Fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms in Cohort 1; new colposcopic findings were detected in only 9% of women using cellulose sulfate, compared to 21% of women using K-Y jelly. In Cohort 2, fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms; 11% in each group had new colposcopy findings. Differences between the groups were not considered to be statistically significant.

In a survey study of HIV infected women using 6% gel once or twice daily for 14 days, women liked the gel's color, smell, and consistency somewhat to a lot. Overall, 31% of women reported that the gel soiled clothing or bed linens. In women using the gel once daily, 4 out of 7 reported leakage during sex; 4 out of 7 also reported leakage after sex. Many women reported that they would prefer a microbicide that could go unnoticed by a sex partner. Primary issues with the gel were soiling of clothes and leakage of gel during sex.

In a Phase I trial in which men directly applied either cellulose sulfate gel or an active control containing nonoxynol-9 for 7 consecutive days, the cellulose sulfate gel was not more irritating than the active control. Symptoms reported by one patient after using cellulose sulfate included slight stinging and mild tingling.

One South African clinical trial tested the safety of the Ortho All flex diaphragm when used with cellulose sulfate gel or with K-Y jelly, compared with cellulose gel use alone, over 6 months in HIV uninfected women. Very few of the participants in this study had ever used diaphragms before. This combination was found to be safe with no serious adverse events or adverse events related to diaphragm use reported. Colposcopic findings were observed in 60% to 80% of study participants. Seven severe findings were observed in those using the microbicide in combination with the diaphragm; however, these differences were not statistically significant. The location of these findings on the external genitalia suggest that they may have been due to trauma following diaphragm insertion.

Cellulose sulfate vaginal tablets are not cytotoxic. The gel formulation has shown an acceptable safety profile in macaques.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Cellulose, hydrogen sulfate]]></drug:casname><drug:casnumber><![CDATA[9032-43-3]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[Cellulose sulfate is a thick and odorless gel with a slightly hazy, light brown tint.]]></drug:physicaldescription><drug:stability><![CDATA[Vaginal tablets stored in accelerated stability conditions recommended by the International Council on Harmonization (ICH) for Zone IV countries were stable for a period of 3 months.]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[CS]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15504382 Anderson RA, Feathergill K, Diao XH, Chany C 2nd, Rencher WF, Zaneveld LJ, Waller DP. Contraception by Ushercell (cellulose sulfate) in formulation: duration of effect and dose effectiveness. Contraception. 2004 Nov;70(5):415-22.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15504382&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15155195 Cheshenko N, Keller MJ, MasCasullo V, Jarvis GA, Cheng H, John M, Li JH, Hogarty K, Anderson RA, Waller DP, Zaneveld LJ, Profy AT, Klotman ME, Herold BC. Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread. Antimicrob Agents Chemother. 2004 Jun;48(6):2025-36.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15155195&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14754390 D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14754390&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16691061 El-Sadr WM, Mayer KH, Maslankowski L, Hoesley C, Justman J, Gai F, Mauck C, Absalon J, Morrow K, Masse B, Soto-Torres L, Kwiecien A. Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women. AIDS. 2006 May 12;20(8):1109-16.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16691061&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16860051 Schwartz JL, Mauck C, Lai JJ, Creinin MD, Brache V, Ballagh SA, Weiner DH, Hillier SL, Fichorova RN, Callahan M. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception. 2006 Aug;74(2):133-40. Epub 2006 May 2.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16860051&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Cellulose sulfate]]></drug:drugname><drug:companyname><![CDATA[Polydex Pharmaceuticals Ltd]]></drug:companyname><drug:address1><![CDATA[Sandringham House]]></drug:address1><drug:address2><![CDATA[83 Shirley Street]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Nassau]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[Bahamas]]></drug:country><drug:phone><![CDATA[242 322 8571]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Ushercell]]></drug:drugname><drug:companyname><![CDATA[Polydex Pharmaceuticals Ltd]]></drug:companyname><drug:address1><![CDATA[Sandringham House]]></drug:address1><drug:address2><![CDATA[83 Shirley Street]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Nassau]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[Bahamas]]></drug:country><drug:phone><![CDATA[242 322 8571]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 19, 2007]]></drug:lastupdated></item><item><title><![CDATA[Cyanovirin-N]]></title><description><![CDATA[Cyanovirin-N, also known as CV-N, is a type of medicine called a fusion inhibitor. Cyanovirin-N is being studied as a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=395]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N, also known as CV-N, is a protein from the cyanobacterium Nostoc ellipsosporum (blue-green algae). The protein exists as either a quasi-symmetric, two-domain monomer or a domain-swapped dimer.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N is a potent HIV fusion inhibitor with activity against both HIV-1 and HIV-2 in vitro and in animal models.  It is in preclinical development as a microbicide for the prevention of sexual transmission of HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N has potent in vitro activity against almost all strains of influenza A and B virus. Cyanovirin-N is moderately active in vitro against some herpes viruses and is potentially active against hepatitis C virus.

In studies in vitro and in mouse models, cyanovirin-N was active against the Zaire strain of the Ebola virus.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Topical gel. Preclinical studies are evaluating 0.5%, 1%, and 2% preparations in aqueous gel with hydroxyethyl cellulose.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cyanovirin-N is a protein derived from cultures of the cyanobacterium, (blue-green algae) Nostoc ellipsosporum.

Cyanovirin-N binds to certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) on viral surface envelope glycoprotein gp120, blocking its interaction with cellular receptors. This unique and effectively irreversible interaction renders gp120 incapable of mediating virus-to-cell or cell-to-cell fusion. Cyanovirin interacts with one sugar at a primary binding site with high affinity and to another sugar (a secondary binding site) with low affinity. In addition, cyanovirin-N appears to bind to viral oligosaccharides with high affinity and to mammalian oligosaccharides with low affinity, potentially providing potent inactivation of HIV-1 and -2 without potent adverse effects to the body.

Cyanovirin-N's anti-HIV effects are expressed during the initial binding or fusion process. These effects may occur after the initial virus-to-cell attachment phase, but prior to the completion of viral entry and replication.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[]]></drug:casname><drug:casnumber><![CDATA[184539-38-6]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[11 kDa]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[CV-N]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/12678493 Botos I, Wlodawer A. Cyanovirin-N: a sugar-binding antiviral protein with a new twist. Cell Mol Life Sci. 2003 Feb;60(2):277-87. Review. PMID: 12678493]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12678493&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15000694 Tsai CC, Emau P, Jiang Y, Agy MB, Shattock RJ, Schmidt A, Morton WR, Gustafson KR, Boyd MR. Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses. 2004 Jan;20(1):11-18. PMID: 15000694]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15000694&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14529524 Tziveleka LA, Vagias C, Roussis V. Natural products with anti-HIV activity from marine organisms. Curr Top Med Chem. 2003;3(13):1512-35. PMID: 14529524]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14529524&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Cyanovirin-N]]></drug:drugname><drug:companyname><![CDATA[Cellegy Pharmaceuticals, Inc]]></drug:companyname><drug:address1><![CDATA[3490 Oyster Point Boulevard]]></drug:address1><drug:address2><![CDATA[Suite 200]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[South San Francisco]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94080]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(650) 616-2200]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 12, 2008]]></drug:lastupdated></item><item><title><![CDATA[Hydroxyethyl cellulose]]></title><description><![CDATA[Hydroxyethyl cellulose, also known as HEC, is a gel-like substance that is a common ingredient in vaginal gels. Hydroxyethyl cellulose is not an active drug. Drugs to prevent and fight infection are mixed with hydroxyethyl cellulose so that they can be applied vaginally.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=392]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[hye-drox-ee-ETH-il SELL-yoo-lose]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Cellulosize]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose (HEC) is a nonionic, water-soluble polymer that can thicken, suspend, bind, emulsify, form films, stabilize, disperse, retain water, and provide protective colloid action.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose is used as an inactive ingredient in the formulation of many vaginal microbicides. These microbicides are designed to prevent the transmission of sexually transmitted diseases, including HIV. Hydroxyethyl cellulose has been studied for use as a placebo gel in clinical trials of HIV microbicides. The use of hydroxyethyl cellulose gel as a universal placebo for HIV microbicide trials has been adopted, and the safety of this product is being evaluated further.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose is used in numerous architectural and industrial coatings.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Topical.]]></drug:modeofdelivery><drug:dosageform><![CDATA[]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hydroxyethyl cellulose is inactive against HIV.

Hydroxyethyl cellulose is being studied for its safety and use in clinical trials of microbicides. A proper base and placebo formulation is critical in the evaluation of safety and efficacy of active microbicide formulations. Efficacy of a microbicide would be underestimated if the placebo itself provided a degree of protection. A placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. A useful placebo must be stable without altering the active drug, and it itself must be safe and well tolerated. A recent study demonstrated the safety, stability, inactivity, and efficacy of hydroxyethyl cellulose as a universal placebo for clinical trials of microbicides.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[A recent study found hydroxyethyl cellulose was safe when used as a placebo or base in the clinical study of investigational microbicides.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Cellulose, 2-hydroxyethyl ether]]></drug:casname><drug:casnumber><![CDATA[9004-62-0]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[Hydroxyethyl cellulose is sufficiently stable as a vaginal gel formulation.]]></drug:stability><drug:solubility><![CDATA[Readily soluble in hot or cold water.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[HEC]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/16225411 Tien D, Schnaare RL, Kang F, Cohl G, McCormick TJ, Moench TR, Doncel G, Watson K, Buckheit RW, Lewis MG, Schwartz J, Douville K, Romano JW. In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses. 2005 Oct;21(10):845-53. PMID: 16225411]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16225411&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[An Imaging Trial of the Distribution of Topical Gel in the Human Vagina: Assessment of Bare Spots. Available at: http://www.clinicaltrials.gov/show/ct/NCT00214812. Accessed 09/26/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Imaging Trial of the Distribution of Topical Gel in the Human Vagina: Enhanced MRI Techniques to Increase Resolution. Available at: http://www.clinicaltrials.gov/show/ct/NCT00260767. Accessed 09/26/07.
]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Hydroxyethyl cellulose]]></drug:drugname><drug:companyname><![CDATA[Union Carbide]]></drug:companyname><drug:address1><![CDATA[A Subsidiary of The Dow Chemical Company ]]></drug:address1><drug:address2><![CDATA[39 Old Ridgebury Road ]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Danbury]]></city><drug:state><![CDATA[CT]]></drug:state><drug:zipcode><![CDATA[06817-0001]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Cellulosize]]></drug:drugname><drug:companyname><![CDATA[Union Carbide]]></drug:companyname><drug:address1><![CDATA[A Subsidiary of The Dow Chemical Company ]]></drug:address1><drug:address2><![CDATA[39 Old Ridgebury Road ]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Danbury]]></city><drug:state><![CDATA[CT]]></drug:state><drug:zipcode><![CDATA[06817-0001]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 26, 2007]]></drug:lastupdated></item><item><title><![CDATA[PRO 2000]]></title><description><![CDATA[PRO 2000, also known as PRO 2000/5, is a type of medicine called a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection. ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=330]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 2000]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 2000]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 2000 is a synthetic, long-chain, naphthalene sulfonic acid polymer. The polymer is polyanionic and consists of alternating 2-naphthalene sulfonic acid sodium salt and methylene units.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[PRO 2000 is an antimicrobial intravaginal gel being investigated for the prevention of HIV and other sexually transmitted diseases. It is being studied in Phase II/IIb and Phase III trials for safety and efficacy.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In laboratory tests and animal studies, PRO 2000 demonstrated activity against Chlamydia trachomatis, Neisseriae gonorrheae, and herpes simplex virus.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[The investigational product is a clear, aqueous gel formulation containing naphthalene 2-sulfonate polymer, a synthetic carbomer gelling agent, a pH 4.5 buffer, and a combination of preservatives. In Phase II/IIb and III studies, 0.5% and 2% formulations of PRO 2000 are being investigated.]]></drug:dosageform><drug:storage><![CDATA[Store at 15 C to 35 C (59 F to 86 F) and protect from light.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Mechanistically, PRO 2000 disrupts the initial binding and membrane fusion steps of HIV-1 infection. PRO 2000 binds to CD4 with nanomolar affinity and blocks CD4 binding to HIV gp120. It inhibits infection by a wide range of HIV isolates in a variety of cell types.

Following topical administration of naphthalene 2-sulfonate polymer in animals and intravaginal application in humans, no systemic absorption was detected. PRO 2000 was undetectable in plasma samples collected from three separate Phase I studies, suggesting that negligible systemic absorption of PRO 2000 occurs following intravaginal administration.

PRO 2000 is completely compatible with the use of latex condoms. This may offer women an appealing alternative or complement to condoms, providing women with a means to control disease transmission. PRO 2000 has demonstrated greater safety in use than nonoxynol-9 spermicides, which have been shown to increase users' risk of contracting HIV and other sexually transmitted diseases; it is also highly stable, easy to store, and easy to apply.

In a randomized trial comparing 5% PRO 2000 to inactive placebo for 14 days in 24 HIV negative women, levels of cytokines, interleukin-1 receptor antagonist, immunoglobulins, and human beta-defensin 2 secreted into the blood were lower in the PRO 2000 arm compared with the placebo group. In contrast, in a study comparing PRO 2000, placebo, and nonoxynol-9, mice receiving intravaginal nonoxynol-9 experienced increased inflammatory responses, whereas mice treated with PRO 2000 experienced responses similar to placebo and responded with minimal inflammation.

Cervicovaginal lavage has been performed in a randomized study to identify activity of PRO 2000 after vaginal application. This study found that 0.5% PRO 2000 retains substantial anti-HIV activity after vaginal application and remains sufficiently bioavailable.

An ongoing Phase II/IIb trial is evaluating the safety and efficacy of 0.5% PRO 2000 compared with placebo, and an ongoing Phase III trial is evaluating the safety and efficacy of 0.5% and 2% PRO 2000 compared with placebo.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In Phase I clinical trials, PRO 2000 was safe and well tolerated. Side effects were generally mild and infrequent and included vulvovaginal ulceration, irritation, itching, burning, bleeding, and mild gastrointestinal effects. Pain on passing urine was also reported.

In a Phase I trial of 63 sexually active HIV uninfected women and abstinent HIV infected women, no serious adverse events were reported. Seventy-three percent of participants experienced at least 1 adverse event, of which 82% were classified as mild. In a second Phase I trial of 73 abstinent HIV uninfected women, three women developed cervical abrasion. In both trials, the 0.5% gel formulation was better tolerated than the 4% gel formulation.

During a Phase I safety and acceptability study of penile application of PRO 2000, no serious adverse events or urethral inflammation were reported following a week of daily PRO 2000 application in 72 HIV uninfected and 25 HIV infected men. Seventeen percent of uninfected participants and 4% of infected participants reported at least 1 mild adverse event.

In a Phase I safety and acceptability study of the 0.5% gel formulation in 42 HIV uninfected women in Pune, India of low and higher risk for HIV transmission, 24 (57%) of the participants experienced at least 1 adverse event judged possibly related to product use. Of these 24, 7 (17%) participants experienced a moderate adverse event and 17 (40%) experienced only mild adverse events. No serious adverse events were observed.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2-naphthalenesulfonic acid, sodium salt, polymer with formaldehyde]]></drug:casname><drug:casnumber><![CDATA[29321-75-3]]></drug:casnumber><drug:molecularformula><![CDATA[(C10-H8-O3-S.C-H2O.Na)x-]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[Approximately 5 kD]]></drug:molecularweight><drug:physicaldescription><![CDATA[Light brown solid (active ingredient of PRO 2000).

PRO 2000 is odorless and virtually colorless.]]></drug:physicaldescription><drug:stability><![CDATA[Manufacturer data indicate that PRO 2000 is stable at 40 C and 75% relative humidity for 12 months.]]></drug:stability><drug:solubility><![CDATA[Highly water soluble (approximately 1 g/5 ml).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[Naphthalene 2-sulfonate polymer]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17397004 Galen GT, Martin AP, Hazrati I, Garin A, Guzman E, Wilson SS, Porter DD, Lira SA, Keller MJ, Herold BC.  A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. Journal of Infectious Diseases 2007 May;195(9):1332-1339.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17397004&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17301565 Keller MJ, Guzman E, Hazrati E, Kasowitz A, Cheshenko N, Wallenstein S, Cole AL, Cole AM, Profy AT, Wira CR, Hogarty K, Herold BC. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 2007 Feb;21(4):467-476.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17301565&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16127029 Scordi-Bello IA, Mosoian A, He C, Chen Y, Cheng Y, Jarvis GA, Keller MJ, Hogarty K, Waller DP, Profy AT, Herold BC, Klotman ME. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother. 2005 Sep;49(9):3607-15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16127029&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Ramjee G, Shattock R, Delany S, McGowan I, Morar N, Gottemoeller M. Short report: Microbicides 2006 Conference. AIDS Research and Therapy 2006, 3:25. Available at: http://www.aidsrestherapy.com/content/3/1/25. Accessed 10/09/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[An International Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of 0.5% and 2% PRO 2000/5 Gels for the Prevention of Vaginally Acquired HIV Infection.  Available at: http://www.clinicaltrials.gov/ct/show/NCT00262106. Accessed 10/09/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Phase II/IIb Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000/5 Gel (P) for the Prevention of HIV Infection in Women. Available at: http://www.clinicaltrials.gov/ct/show/NCT00074425. Accessed 10/09/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[PRO 2000]]></drug:drugname><drug:companyname><![CDATA[Indevus Pharmaceuticals, Inc. ]]></drug:companyname><drug:address1><![CDATA[99 Hayden Avenue, Suite 200]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Lexington]]></city><drug:state><![CDATA[MA]]></drug:state><drug:zipcode><![CDATA[02421]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[October 9, 2007]]></drug:lastupdated></item><item><title><![CDATA[SPL7013]]></title><description><![CDATA[SPL7013, also known as VivaGel, is a type of medicine called a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=419]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[SPL7013]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[VivaGel]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[SPL7013]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[SPL7013 is a lysine-based dendrimer with naphthalene disulfonic acid surface groups. It is the active ingredient of VivaGel, a water-based vaginal microbicide gel.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[SPL7013 is a potent inhibitor of HIV-1 in vitro and appears active against numerous strains. It is being studied for use as the active ingredient in VivaGel, a vaginal microbicide, in the prevention of vaginal transmission of HIV and genital herpes. VivaGel was granted fast-track status by the FDA in January 2006.

A study to test VivaGel's safety, acceptability, and ease of use in healthy, sexually active young women in the United States and Puerto Rico began enrollment in July 2007.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[SPL7013 has demonstrated activity against herpes simplex virus-2 (HSV-2).

A Phase I study in healthy, sexually active American and Kenyan women testing VivaGel's safety and tolerability began enrollment in October 2006. This trial is the first microbicide clinical development program specifically for the prevention of HSV-2 (genital herpes).

In an independent study conducted at Johns Hopkins University, SPL7013 also exhibited a potent contraceptive effect when tested in animals.

In mid-July 2007, Starpharma signed an agreement with a leading condom company in relation to the use of VivaGel as a condom coating.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Phase I studies have evaluated VivaGel at concentrations of 0.5, 1, and 3% applied vaginally once daily for 7 days. In addition, a 5.0% vaginal gel has been evaluated in macaques.

VivaGel would be used via a single-use, prefilled vaginal applicator.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Dendrimers such as SPL7013 are polymers that contain a central core, interior branches, and terminal surface groups adapted to specific targets. SPL7013 has a polyanionic outer surface that provides for multiple target interactions. The active surface groups bind to gp120 proteins on HIV's surface, preventing CD4 receptor binding by healthy cells and thus blocking transmission of HIV to healthy cells.

A Phase I, double-blind, placebo-controlled trial evaluated the plasma absorption of SPL7013 in 36 healthy, sexually abstinent women. Women were assigned to 1 of 3 arms of 0.5, 1.0, and 3.0% gel, respectively, and all doses were administered once daily for 7 days. Eight women received active gel and 4 received placebo in each arm. Plasma samples after the first, third, fifth, and seventh doses showed no plasma SPL7013 levels, confirming localized activity of the drug.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[A Phase I placebo-controlled trial in healthy women evaluated the safety and tolerability of VivaGel. No serious or significant adverse events occurred with the 0.5, 1.0, or 3.0% doses. Mild adverse effects attributed to SPL7013 were abdominal pain and painful urination. Vaginal flora levels decreased similarly across all treatment and placebo groups but rebounded to normal levels by 7 days post-treatment.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[L-Lysine, homopolymer [polylysine]]]></drug:casname><drug:casnumber><![CDATA[676271-69-5]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[16,582 Da]]></drug:molecularweight><drug:physicaldescription><![CDATA[SPL7013: white to off-white solid.

VivaGel: water-based gel.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Both SPL7013 and VivaGel are highly water soluble.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[SPL 7013]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/16219368 Gong E, Matthews B, McCarthy T, Chu J, Holan G, Raff J, Sacks S. Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses. Antiviral Res. 2005 Dec;68(3):139-46. Epub 2005 Sep 27.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16219368&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15795526 Jiang YH, Emau P, Cairns JS, Flanary L, Morton WR, McCarthy TD, Tsai CC. SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses. 2005 Mar;21(3):207-13.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15795526&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16053334 McCarthy TD, Karellas P, Henderson SA, Giannis M, O'Keefe DF, Heery G, Paull JR, Matthews BR, Holan G.  Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol Pharm. 2005 Jul-Aug;2(4):312-8. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16053334&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16181143 Rosa Borges A, Schengrund CL. Dendrimers and antivirals: a review. Curr Drug Targets Infect Disord. 2005 Sep;5(3):247-54. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16181143&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17404008 Roth S, Monsour M, Dowland A, Guenthner PC, Hancock K, Ou CY, Dezzutti CS. Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. Antimicrob Agents Chemother. 2007 Jun;51(6):1972-8. Epub 2007 Apr 2.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17404008&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[SPL7013]]></drug:drugname><drug:companyname><![CDATA[Starpharma Ltd]]></drug:companyname><drug:address1><![CDATA[PO Box 6535]]></drug:address1><drug:address2><![CDATA[St. Kilda Road Central]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Melbourne, Victoria]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[Australia]]></drug:country><drug:phone><![CDATA[61385322736]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 24, 2007]]></drug:lastupdated></item><item><title><![CDATA[Tenofovir]]></title><description><![CDATA[Tenofovir gel, also known as PMPA gel, is a type of medicine called a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=272]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[te-NOE-fo-veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir is an adenosine nucleoside monophosphate reverse transcriptase inhibitor and viral replication inhibitor.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir gel, also known as PMPA gel, is being investigated in Phase II monotherapy studies as a vaginal microbicide for the prevention of HIV transmission. Tenofovir is also being studied in combination with PRO 2000, another investigational vaginal microbicide. Approved oral formulations of its prodrug, tenofovir disoproxil fumarate (tenofovir DF), are used to treat HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In vitro testing of tenofovir demonstrated antiviral activity against hepatitis B virus (HBV). Tenofovir disoproxil fumarate, the orally bioavailable prodrug of tenofovir, is being evaluated in HBV/HIV coinfected patients who developed HBV breakthrough during treatment with lamivudine.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tenofovir gel is available in 0.3% and 1% concentrations. In clinical studies, it is applied vaginally once or twice daily. Precoital applications are also being investigated.

Tenofovir gel is packaged in 6-gram tubes and in 4-gram, single-dose applicators.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir, a nucleotide analogue, is characterized by its ability to enter and inhibit viral replication in HIV infected, HIV uninfected, and resting cells, thus forming active drug reservoirs.

Tenofovir has a long intracellular half-life. Serum plasma concentrations with tenofovir gel application have ranged from 3 to 25.8 ng/ml, remaining lower than the 50 ng/ml minimum plasma concentration achieved with oral tenofovir DF.

Animal studies support the use of tenofovir gel as a microbicide. One small study of tenofovir gel administed vaginally to four macaques resulted in 100% protection, compared with observed HIV transmission in two macaques administered placebo gel.

HPTN 050, an open-label, Phase I trial, evaluated tenofovir 0.3% and 1% gels, administered daily or twice-daily for 2 weeks in sexually abstinent HIV infected and HIV uninfected women to determine toxicity, pharmacokinetics, and gel acceptability. Fourteen of 25 women (56%) experienced low but detectable serum tenofovir levels. Asymptomatic bacterial vaginosis in 29 women resolved in 14 (48%) after gel administration. No new resistance mutations evolved, and no patients had high-level tenofovir mutations, such as K65R.

HPTN 059 is an ongoing, multicenter, randomized, Phase II trial in HIV uninfected women to determine the safety and acceptability of tenofovir 1% gel administered over 24 weeks with a 48-week follow-up. Patients will be assigned to one of four cohorts: tenofovir 1% daily; placebo daily; tenofovir 1%, coitally dependent; or placebo, coitally dependent.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In an open-label, Phase I trial to evaluate tenofovir 0.3% and 1% gel concentrations in HIV uninfected and HIV infected women, the gel was well tolerated. Although 92% of patients experienced at least one adverse effect, 87% were mild and 70% were genitourinary. Thirty-two percent of patients experienced gastrointestinal effects. One severe adverse effect, lower abdominal cramping, was considered possibly drug-related. 

The most common adverse effects noted were itching (23%), redness (18%), discharge (15%), irregular menstruation (13%), and uterine bleeding (11%). Vaginal candidiasis occurred in 5% of women while using the gel.

In irritation studies, tenofovir 0.3% and 1% gels, adjusted to pH 4 to 5, appear nearly equal to carrier vehicles in irritation scores.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Phosphonic acid, (((1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy)methyl)-]]></drug:casname><drug:casnumber><![CDATA[147127-20-6]]></drug:casnumber><drug:molecularformula><![CDATA[C9-H14-N5-O4-P]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C37.64%, H4.91%, N24.38%, O22.28%,  P10.78%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[279 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[287.21]]></drug:molecularweight><drug:physicaldescription><![CDATA[Clear, transparent, viscous gel.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[PMPA gel]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/12227991 Tenofovir gel studied. AIDS Patient Care STDS. 2002 Aug;16(8):401-2.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12227991&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14754390 D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14754390&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16470118 Meyer KH, Maslankowski LA, Gai F, El-Sadr WM, Justman J, Kwiecien A, Masse B, Eshleman SH, Hendrix C, Morrow K, Rooney JF, Soto-Torres L; HPTN 050 Protocol Team. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS 2006 Feb 28;20(4):543-551.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16470118&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[HPTN059: Phase II Expanded Safety and Acceptability Study of the Vaginal Microbicide 1% Tenofovir Gel. Available at: http://www.hptn.org/research_studies/hptn059.asp. Accessed 06/04/08.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Safety and Acceptability of a Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/show/NCT00111943. Accessed 06/04/08.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Tenofovir]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 4, 2008]]></drug:lastupdated></item><item><title><![CDATA[UC-781]]></title><description><![CDATA[UC-781 is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is being studied as a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. NNRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself. Microbicides work by either destroying the microbes or preventing them from establishing an infection.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=394]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[UC-781]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[UC-781]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Microbicides]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[UC-781 is a thiocarboxanilide non-nucleoside reverse transcriptase inhibitor (NNRTI).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[UC-781 is an NNRTI currently being developed as a vaginal microbicide to prevent HIV transmission. UC-781 has been studied in animal models and has entered a Phase I clinical trial in humans. UC-781 is now in Phase II trials in the United States and in Thailand.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravaginal. Rectal.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Topical gel in 0.1%, 0.25%, or 1.0% concentrations. UC-781 has been studied in once-daily dosages for up to 7 days and in twice-daily dosages for up to 14 days.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In vitro studies have shown UC-781 to be a rapid, tight-binding inhibitor of HIV-1 reverse transcriptase. It is effective against transmission of both free-floating HIV particles and cell-associated HIV. UC-781 has an intracellular antiviral protective effect and a half-life of 5.5 days.

In vitro exposure of human cervical tissue to UC-781 for 30 minutes has resulted in 95% reduction of subsequent HIV infection. Furthermore, greater concentrations of UC-781 pretreatment have resulted in total protection of the cervical tissue from both X4- and R5-tropic HIV-1 isolates as well as from cell-associated HIV-1 infection. Twenty-minute incubation with UC-781 has completely protected the cervical tissue up to 48 hours post-treatment without associated tissue toxicity.

UC-781 administered to cellular and tissue explant models as a 0.1% carbopol gel formulation has demonstrated a potent, dose-dependent effect against R5- and X4-tropic HIV infections in T cells. In human cervical explant cultures, UC-781 was able to not only inhibit direct infection of mucosal tissue but also to prevent dissemination of virus by migratory cells. UC-781 retained significant activity against direct tissue infection and migratory cell infection. UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post-treatment. In addition, a 2-hour exposure to UC-781 prevented infection of lymphoid tissue when challenged up to 2 days later. Although a greater dose of UC-781 was required to inhibit infections of lymphoid versus cervical explant, that dose, equivalent to a 1:3.000 dilution, was less than the full dose provided in a 0.1% formulation.

The prolonged protective effect of UC-781, characterized as a memory effect that continues to protect drug-treated cells from HIV-1 replication, has been demonstrated for up to 12 days.

UC-781 has been studied with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine in vitro. A 1:1 molar combination of zidovudine plus UC-781 showed high-level synergy in inhibiting replication of a zidovudine-resistant clinical isolate of HIV. When a 1:1 molar combination of zidovudine and UC-781 was compared to use of either drug alone, HIV resistance development was significantly slower.

The microbicidal activity of UC-781 has been studied in vitro against strains of HIV-1 resistant to UC-781 (UCR), efavirenz (EFVR), and nevirapine (NVPR). UC-781 was 10- to 100-fold less effective against resistant strains than wild-type virus. The drug was more effective against NVPR strains than UCR strains, and was less effective against EFVR strains than UCR strains. Efficacy of UC-781 was dose-dependent; 25 mcM UC-781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wild-type virus. UC-781 formulations under current development contain concentrations approximately 100-fold greater than the 25 mcM concentration necessary for efficacy.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[UC-781 exhibits synergy with the NRTI zidovudine in vitro. The combination of UC-781 and another candidate microbicide, cellulose acetate 1,2-benzenedicarboxylate, resulted in effective synergy for inhibition of HIV-1 in vitro and in peripheral blood mononuclear cells. Concomitant administration provided complementary mechanisms of action and protected ex vivo lymphoid tissues from HIV infection.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[3-Furancarbothioamide, N-(4-chloro-3-((3-methyl-2-butenyl)oxy)phenyl)-2-methyl-]]></drug:casname><drug:casnumber><![CDATA[178870-32-1]]></drug:casnumber><drug:molecularformula><![CDATA[C17-H18-Cl-N-O2-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C60.8%, H5.4%, Cl10.6%, N4.2%, O9.5%, S9.5%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[335.5]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15855503 Liu S, Lu H, Neurath AR, Jiang S. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC-781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection.  Antimicrob Agents Chemother. 2005 May;49(5):1830-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15855503&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17353420 Patton DL, Sweeney YT, Balkus JE, Rohan LC, Moncla BJ, Parniak MA, Hillier SL. Preclinical safety assessments of UC-781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother. 2007 May;51(5):1608-15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17353420&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17404008 Roth S, Monsour M, Dowland A, Guenthner PC, Hancock K, Ou CY, Dezzutti CS. Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. Antimicrob Agents Chemother. 2007 Jun;51(6):1972-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17404008&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17922539 Sassi AB, Isaacs CE, Moncla BJ, Gupta P, Hillier SL, Rohan LC. Effects of physiological fluids on physical-chemical characteristics and activity of topical vaginal microbicide products. J Pharm Sci. 2007 Oct 5 [Epub ahead of print].]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17922539&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14693562 Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004 Jan;48(1):337-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14693562&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[ClinicalTrals.gov- Phase I Study of Safety and Persistence of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00441909?term=NCT00441909&rank=1. Accessed 02/12/08.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[UC-781]]></drug:drugname><drug:companyname><![CDATA[Cellegy Pharmaceuticals, Inc]]></drug:companyname><drug:address1><![CDATA[3490 Oyster Point Boulevard]]></drug:address1><drug:address2><![CDATA[Suite 200]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[South San Francisco]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94080]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(650) 616-2200]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 12, 2008]]></drug:lastupdated></item><item><title><![CDATA[Rilpivirine (TMC278)]]></title><description><![CDATA[TMC278 is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs work by blocking reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=426]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Rilpivirine (TMC278)]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Rilpivirine (TMC278)]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Non-nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TMC278, a diarylpyrimidine derivative, is an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TMC278 is being studied in Phase IIb trials for the treatment of HIV infection in treatment-naive patients and in those treatment-experienced patients with drug-resistant HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablet.

Oral solution.

TMC278 is being studied at 25, 75, and 150 mg daily dosages. The once-daily 75 mg dosage will be developed specifically for use in treatment-naive patients.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TMC278 is a potent investigational NNRTI with activity against NNRTI-resistant HIV.

TMC278 has strong binding properties and conformational flexibility that allows the drug to overcome mutations conferring NNRTI resistance. Its effective half-life of 38 hours provides for once-daily dosing. TMC278 exhibits dose-proportional pharmacokinetic activity over the studied range of 25 to 150 mg once daily. No active metabolites have been discovered. TMC278 is well absorbed, and administration with food increases TMC278 bioavailability by 45%.

TMC278 has displayed no teratogenicity in trials conducted thus far, unlike some approved NNRTIs that are contraindicated in women who are or may become pregnant.

In a Phase IIa, randomized, double-blind trial examining TMC278 oral solution in 47 treatment-naive, HIV infected male participants, dosages of 25, 50, 100, and 150 mg once daily were administered for 7 days to determine safety, efficacy, and tolerability. Mean viral load levels decreased significantly compared with placebo, by more than 10-fold at Day 7, and no differences were noted among the treatment arms. Plasma concentrations of TMC278 remained above the target concentration of 13.5 ng/ml at all time points. No selection of NNRTI-resistance-associated mutations was observed during the study period.

An ongoing, Phase IIb, randomized, active-control, partially-blind trial is evaluating the safety and efficacy of once-daily doses of TMC278 compared with efavirenz in 368 treatment-naive, HIV infected participants. Study arms consisted of 25, 75, or 150 mg TMC278 or of efavirenz 600 mg active control as part of a combination regimen. Treatment and active control arms displayed similar efficacy during and up to Week 48, with viral load reductions of more than 100-fold in the efavirenz control and TMC278 treatment arms. Approximately 80% of patients in all arms reached the primary endpoint of confirmed plasma viral load less than 50 copies/ml at Week 48.

When tested against 10 strains of NNRTI-resistant HIV, TMC278 retained a 50% effective concentration against all of the following mutations: L100I, K103N, V106A, G190A, G190S, K101E, Y181C, Y188L, L100I/K103N, and K103N/Y181C. In contrast, the approved NNRTI efavirenz exhibited reduced activity to all but 2 of these mutations. Similarly, in a panel of more than 1,500 NNRTI-resistant isolates of HIV, TMC278 retained at least some activity against most of the isolates, whereas nearly all isolates proved resistant to nevirapine and approximately 40% were highly resistant to efavirenz. Although only 1 mutation was needed to induce nevirapine or efavirenz resistance, 8 mutations were required to reduce susceptibility to TMC278. TMC278 retains activity against HIV with the L100I/K103N and the K103N/Y181C mutations, both of which confer resistance to all FDA-approved NNRTIs.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In a Phase IIa trial that studied 25 to 150 mg doses of TMC278 in treatment-naive, HIV infected participants, rates of adverse events were similar among all TMC278 dose groups and placebo. No serious adverse events occurred. The most common adverse events reported were headache, fatigue, nausea, and somnolence.

In a Phase IIb dose-ranging trial comparing the efficacy and safety of TMC278 to that of efavirenz in a combination regimen, TMC278 was generally well tolerated up to Week 48. The most common adverse events associated with TMC278 were nausea (35%) and headache (18%), both of which occurred more frequently with TMC278 than with efavirenz. Other adverse events, including dizziness, sleepiness, vertigo, rash, and lipid changes, occurred less frequently with TMC278 than with efavirenz. Serious adverse events and Grade 3 or 4 laboratory abnormalities were similar in the TMC278 and efavirenz arms. However, the incidence of Grade 3 or 4 adverse events was 25% in the TMC278 arms compared with 16% in the efavirenz arm.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[When 100 mg TMC278 was administered with food to 12 healthy volunteers, the bioavailability of TMC278 increased by 45%; therefore, TMC278 should be administered with food.

When 150 mg TMC278 was coadministered once daily with the cytochrome P450 (CYP) 3A4 substrate ketoconazole 400 mg, the area under the concentration-time curve (AUC) of TMC278 increased by 49%, the Cmax increased by 30%, and the Cmin increased by 76% compared with TMC278 administration alone. The ketoconazole AUC decreased by 24%, and the Cmax and Cmin decreased by 15% and 66%, respectively.
 
TMC278 is being studied in Phase IIb trials with tenofovir DF and other nucleoside reverse transcriptase inhibitors. When TMC278 was coadministered with tenofovir DF, no clinically relevant interactions were observed.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Benzonitrile, 4-([4-([4-([1E]-2- cyanoethenyl)- 2,6-dimethylphenyl] amino)- 2-pryimidinyl] amino)-]]></drug:casname><drug:casnumber><![CDATA[500287-72-9]]></drug:casnumber><drug:molecularformula><![CDATA[C22-H18-N16]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C52.2%, H3.5%, N44.3%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[506]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/16931936 Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Bethune MP, Peeters M, Woodfall B. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects. AIDS. 2006 Aug 22;20(13):1721-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16931936&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15771434 Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Bethune MP, Pauwels R, Das K, Clark AD Jr, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl] -2,6-dimethylphenyl] amino]-2-pyrimidinyl]amino] benzonitrile (R278474, rilpivirine). J Med Chem. 2005 Mar 24;48(6):1901-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15771434&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 144LB, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Rilpivirine (TMC278)]]></drug:drugname><drug:companyname><![CDATA[Tibotec]]></drug:companyname><drug:address1><![CDATA[1029 Stony Hill Road]]></drug:address1><drug:address2><![CDATA[Suite 300]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Yardley]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[19067]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(609) 730-7500]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 21, 2007]]></drug:lastupdated></item><item><title><![CDATA[Apricitabine]]></title><description><![CDATA[]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=415]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine, previously known as AVX754 and SPD754, is a nucleoside reverse transcriptase inhibitor (NRTI). Apricitabine is the negative enantiomer of a member of the 4-thio heterosubstituted nucleoside analogue class. It is a novel cytidine analogue with activity against HIV strains that are resistant to other NRTIs.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine is a deoxycytidine analogue entering Phase IIb studies for the treatment of HIV infection. It is being studied as a first choice, second regimen drug for the treatment of HIV infection in people who have failed treatment with lamivudine. Ampricitabine received fast-track approval status from the FDA.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Apricitabine is manufactured in capsule form. Apricitabine has been studied at doses of 200, 400, 600, and 800 mg twice daily and at doses of 800, 1,200, and 1,600 mg once daily. No apparent differences have been seen between daily and twice daily dosing schedules. The twice daily dosing schedule provides adequate and sustained intracellular accumulation and has been chosen as the primary schedule for continued study; once daily dosing may be determined in later trials.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine selectively inhibits the HIV replication enzyme reverse transcriptase (RT) in the same manner as traditional NRTIs. Apricitabine is the negative enantiomer of a failed investigational racemic mixture NRTI and appears to retain pharmacodynamic activity with reduced toxicity. The drug does not convert to the positive enantiomer or racemic mixture in vivo.

Apricitabine must be metabolized intracellularly to its triphosphate form, apricitabine-TP, to exhibit antiviral activity. Intracellular concentrations of the active triphosphate are proportional to plasma concentrations of apricitabine. Apricitabine-TP accumulates intracellularly with twice-daily dosing, has a half-life of 6 to 7 hours, and achieves maximum plasma concentrations (Cmax) at approximately 4 hours post dose. In Phase I studies, oral bioavailability of AVX754 was 65% to 80% with 1,600 mg to 400 mg single doses, respectively. Apricitabine is rapidly absorbed. The time to Cmax ranged from 1.5 to 1.7 hours and was unaffected by dose or gender. Plasma protein binding of apricitabine is less than 4%. The drug appears to penetrate the cerebrospinal fluid. Apricitabine exhibits linear pharmacokinetics following administration of single and multiple doses. Apricitabine is renally eliminated by glomerular filtration and active tubular secretion in the kidney. Elimination is unaffected by gender. Most of the parent drug is excreted within the first 8 hours. Apricitabine and its active triphosphate metabolite do not appear to inhibit or induce any of the major cytochrome P (CYP) 450 isozymes, including CYP1A2, 2A6, 2C9, 2D6, and 3A4.

A pharmacokinetic study compared single and multiple doses of apricitabine 800 mg in 39 HIV uninfected and in 18 healthy participants. In addition, pharmacokinetics of the active triphosphate, apricitabine -TP, were compared in 9 HIV infected and 21 healthy participants who received apricitabine 600 mg twice daily for 8 or 4 days, respectively. Pharmacokinetics of apricitabine appear similar in HIV uninfected and healthy groups. After a single 800 mg dose, the maximum plasma concentration (Cmax) was 7.9 mcg/ml in healthy participants and 7.2 mcg/ml in HIV infected participants. The area under the concentration-time curve (AUC) was similar between the groups as well at 44.9 mg h/l and 39.5 mg h/l, respectively. After 8 days of apricitabine 800 mg once daily administration, Cmax was 8.4 mcg/ml and 9.7 mcg/ml in healthy and HIV infected groups, respectively; AUC was 41.8 mg h/l and 38.1 mg h/l, respectively. Apricitabine-TP Cmax after 8 days in HIV infected participants was twofold higher than Cmax observed after 4 days in healthy participants.

In a 10-day study of apricitabine in antiretroviral-naive, HIV infected adults, single apricitabine doses of 400, 800, 1,200, and 1,600 mg were evaluated. Viral load decreased significantly at 1 week across all doses: approximately 90% with 400 mg; nearly 95% with 800 mg; nearly 97% with 1,200 mg; and 95% with 1,600 mg. After 10 days of daily apricitabine treatment, viral load reductions of nearly 98% with 1,200 mg and 1,600 mg were significantly greater than the approximately 90% reduction seen with 400 mg. No CD4 count changes were observed. 

A Phase IIb dose-ranging trial in treatment-experienced HIV infected patients is ongoing to determine apricitabine activity in patients with HIV strains resistant to lamivudine and that have the M184V mutation. Responses to doses will be compared to each other and to lamivudine for 21 days and 24 weeks.

Resistance to apricitabine develops slowly compared with other NRTIs such as lamivudine and is associated with the K65R, V75I, and M184V mutations. Apricitabine is active against zidovudine- and lamivudine-resistant viruses. The presence of five thymidine analogue mutations (TAMs) resulted in a less than twofold median change in apricitabine activity. No new resistance-conferring mutations emerged after 10 days of monotherapy; patients with baseline nucleoside analogue mutations showed promising decreases in viral load.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Unlike its racemic mixture predecessor BCH-10652, apricitabine showed little sign of mitochondrial toxicity in an early safety study in monkeys. After 52 weeks of 100 mg/kg/day treatment with apricitabine, mild but reversible hyperpigmentation, gastrointestinal effects, and minimal red blood cell count changes were observed. No bone marrow or mitochondrial abnormalities occurred in the liver, heart, or skeletal muscle. Apricitabine is not mutagenic. No evidence of mitochondrial toxicity has been observed in vitro at concentrations 30 times greater than Cmax.

In a 10-day, dose-ranging study of apricitabine monotherapy in 63 antiretroviral-naive, HIV infected patients, apricitabine was well tolerated at all doses. No serious adverse events were reported, and no treatment required discontinuation. Headache was the most commonly reported adverse event in patients taking apricitabine (42% of study participants), but headache frequency was similar to that of the placebo group. Nasal congestion appeared slightly more common with apricitabine than with placebo. Myalgia was reported by 10% of patients receiving apricitabine, but the relationship between myalgia and apricitabine is unclear. Low-level lipase changes similar to those in the placebo group and six cases of increased serum lipase that appeared unrelated to apricitabine were reported. Otherwise, no clinically significant laboratory changes were reported.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Apricitabine bioavailability appears unaffected by food.

Apricitabine displayed additive to synergistic antiviral activity in vitro against wild-type HIV-1 when combined with a range of antiretrovirals. Specifically, apricitabine and lamivudine had additive antiviral activity by sharing a common anabolic pathway. In a Phase I study that combined apricitabine and lamivudine, lamivudine reduced intracellular AVX754-TP concentrations in a dose-dependent manner by four- to sixfold relative to the apricitabine-TP concentration alone. Apricitabine had no effect on lamivudine or lamivudine-triphosphate concentrations.

The effect of trimethoprim on apricitabine excretion was studied in isolated perfused rat kidney because trimethoprim inhibits the excretion of lamivudine, which is structurally similar to apricitabine. Trimethoprim inhibited the excretion of apricitabine and its metabolite BCH-335. Because renal excretion of apricitabine and lamivudine are inhibited by trimethoprim to similar extents, exposure of apricitabine would also be expected to increase in the presence of therapeutic concentrations of trimethoprim.

Because apricitabine does not induce or inhibit any of the major CYP450 isozymes, there is a low potential for interaction with drugs that undergo hepatic CYP metabolism.

A Phase I study in 18 healthy participants compared apricitabine monotherapy versus apricitabine combined with tipranavir. Tipranavir significantly reduces the plasma levels of some NRTIs, such as zidovudine and abacavir. However, no reduction in apricitabine plasma levels occurred with concomitant tipranavir. 

Coadministration of lamivudine and apricitabine to HIV infected cells in vitro decreased the conversion of apricitabine to its triphosphate, but apricitabine did not affect lamivudine phosphorylation.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2(1H)-Pyrimidinone, 4-amino-1-((2R,4R)-2-(hydroxymethyl)-1,3-oxathiolan-4-yl)-]]></drug:casname><drug:casnumber><![CDATA[160707-69-7]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H11-N3-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C45%, H5%, N20%, O22%, S8%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[215.0]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[A Phase II, Randomised, Double-Blind, Dose-Ranging Study of AVX754 Versus Lamivudine in Treatment-Experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase. Available at: http://www.clinicaltrials.gov/ct/show/NCT00126880. Accessed 03/13/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16245645 Bethdeel et al. In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs.  Antivir Chem Chemother. 2005;16(5):295-302.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16245645&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16816554 Cahn P, Cassetti I, Wood R, Phanuphak P, Shiveley L, Bethell RC, Sawyer J. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 2006;20(9):1261-1268.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16816554&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14508885 Otto MJ.  New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr Opin Pharmacol. 2004 Oct;4(5):431-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14508885&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16926264 Tomoko Nakatani-Freshwater, Mariana Babayeva, Aruna Dontabhaktuni, and David R. Taft Effects of Trimethoprim on the Clearance of Apricitabine, a Deoxycytidine Analog Reverse Transcriptase Inhibitor, and Lamivudine in the Isolated Perfused Rat Kidney. J. Pharmacol. Exp. Ther. 2006;319: 941-947.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16926264&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Apricitabine]]></drug:drugname><drug:companyname><![CDATA[Avexa Limited]]></drug:companyname><drug:address1><![CDATA[576 Swan Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Richmond Victoria]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[Australia]]></drug:country><drug:phone><![CDATA[61-3-9208-4300]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[March 13, 2007]]></drug:lastupdated></item><item><title><![CDATA[Elvucitabine]]></title><description><![CDATA[Elvucitabine is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=385]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[el-vue-SYE-ta-been]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine, or ELV, is an L-cytosine nucleoside analogue of stavudine with potent activity against HIV.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine is a nucleoside reverse transcriptase inhibitor (NRTI) currently under investigation in Phase II/III trials for the treatment of chronic HIV infection and infection by lamivudine-resistant HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine exhibits potent activity against hepatitis B virus (HBV). A Phase I/II study of elvucitabine in patients with chronic HBV infection demonstrated acceptable pharmacokinetics and safety profiles. Phase II studies of elvucitabine in chronically HBV infected patients are underway.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[In clinical trials, dosages studied include 5 and 10 mg once daily and 20 mg once every other day.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine is a beta-L-(-) nucleoside analogue developed to improve upon the antiviral activity of lamivudine, an FDA-approved beta-L-(-) nucleoside analogue. Compared with lamivudine, elvucitabine may allow for less frequent dosing and less escalation of dosage to overcome viral resistance. Elvucitabine, a stavudine-substituted NRTI, has potent antiretroviral activity, even at doses low enough to avoid bone marrow toxicity. Elvucitabine inhibits wild-type HIV and HIV expressing the M184V mutation associated with lamivudine resistance.

Elvucitabine has excellent oral bioavailability and a prolonged half-life of more than 100 hours.

When elvucitabine dosages of 5 or 10 mg once daily or 20 mg once every other day were tested in 24 HIV infected patients for 21 days with concomitant lopinavir/ritonavir (LPV/r) every 12 hours, viral load decreased 1.8, 1.9, and 2.0 log, respectively. Elvucitabine's extended half-life required continuation of LPV/r doses for 35 days total in the 10 and 20 mg cohorts. Concentrations of elvucitabine remained above the 50% inhibitory concentration (IC50) at Day 28, supporting weekly or twice-weekly dosing. The every-other-day cohort appeared most efficacious and minimized resistance and adherence concerns.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Elvucitabine induces bone marrow toxicity when used at dosages higher than elvucitabine 50 mg daily. Preliminary study results reported at the 12th International HIV Drug Resistance Workshop in June 2003 indicated that elvucitabine induced reversible bone marrow suppression. Six of 56 patients experienced myelosuppression while taking elvucitabine; of these six patients, four received 100 mg daily and two received 50 mg daily. Mild to moderate macropapular rash occurred with the 50 and 100 mg doses but resolved with drug discontinuation. Mild headache and gastrointestinal distress were also reported.

For 21 days at dosages of elvucitabine 5 and 10 mg once daily and 20 mg once every other day, no bone marrow suppression was observed, and elvucitabine was generally nontoxic.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The half-life of elvucitabine was approximately 150 hours when administered with LPV/r. Elvucitabine exhibited decreased bioavailability and slower absorption rates with concomitant LPV/r but was otherwise unchanged.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2(1H)-Pyrimidinone, 4-amino-1-((2S,5R)-2,5-dihydro-5-]]></drug:casname><drug:casnumber><![CDATA[181785-84-2]]></drug:casnumber><drug:molecularformula><![CDATA[C9-H10-F-N3-O3]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C47.8%, H4.4%, F8.0%, N18.6%, O21.2%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[226]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/11966452 Chen, SH. Comparative evaluation of L-Fd4C and related nucleoside analogs as promising antiviral agents. Curr Med Chem. 2002 May;9(9):899-912.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=11966452&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15105115 Dutschman GE, Grill SP, Gullen EA, Haraguchi K, Takeda S, Tanaka H, Baba M, Cheng YC. Novel 4'-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity. Antimicrob Agents Chemother. 2004 May;48(5):1640-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15105115&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12476956 Patel J, Mitra AK. ACH-126443 Achillion/Yale University. Curr Opin Investig Drugs. 2002 Nov;3(11):1580-4. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12476956&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation. Available at: http://www.clinicaltrials.gov/ct/NCT00312039. Accessed 08/03/06.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Elvucitabine]]></drug:drugname><drug:companyname><![CDATA[Achillion Pharmaceuticals]]></drug:companyname><drug:address1><![CDATA[300 George Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New Haven]]></city><drug:state><![CDATA[CT]]></drug:state><drug:zipcode><![CDATA[06511]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(202) 624-7000]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[August 3, 2006]]></drug:lastupdated></item><item><title><![CDATA[KP-1461]]></title><description><![CDATA[KP-1461, also known as SN1461 and SN1212, is a type of medicine called a nucleoside analogue. KP-1461 works by introducing changes to HIV's genetic makeup that eventually kill the viral particles.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=416]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[KP-1461]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[KP-1461]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[KP-1461 is a potent, non--chain-terminating, mutagenic deoxyribonucleoside analogue. Designated a DNA covert nucleoside, the drug consists of a modified base that incorporates randomly into HIV and pairs with multiple bases.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[KP-1461, also known as SN1461, is in Phase Ia and IIa trials for the treatment of HIV-1 infection in adults.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[KP-1461 is the oral prodrug of KP-1212.  KP-1461 is also known as SN1212. KP-1461 introduces continual mutations into HIV during viral replication by reverse transcriptase (RT). These mutations decrease virus viability and are eventually lethal. This mechanism, selective viral mutagenesis or lethal mutagenesis, is novel to the nucleoside analogue class.

Unlike approved nucleoside RT inhibitors (NRTIs) that contain a modified sugar and unmodified base, KP-1461 has a modified base that allows multiple base pairing. Because KP-1461 pairs with multiple bases, it is able to target all viral proteins rather than a single protein.

KP-1461, after conversion to KP-1212, is metabolized to a triphosphate and incorporated into the HIV-1 genome by RT. The drug is similarly incorporated into human mitochondrial DNA polymerase. The active substance KP-1212 has been shown to inhibit antiviral activity in tissues after just one pass; accumulation has been shown to eradicate the virus entirely. HIV strains treated with KP-1212 also showed increased sensitivity to zidovudine.

KP-1461 is being evaluated in an ongoing Phase Ib, randomized trial. In this trial, 40 HIV infected people who have failed prior antiretroviral therapy are receiving escalating doses of KP-1461 or placebo in four cohorts. KP-1461 also is entering a Phase IIa, open-label trial to evaluate its safety, efficacy, and tolerability as monotherapy in 32 treatment-experienced, HIV infected people.

In laboratory tests, multiple tissue passes failed to induce resistant HIV isolates after several attempts. No cross resistance has been observed with HIV strains resistant to common nucleoside analogues such as zidovudine, lamivudine, stavudine, and abacavir.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[No significant genotoxicity was observed in vitro in Chinese hamster ovary cells or in human B cells. At doses up to 2 g/kg, no toxicity was observed in dogs; lactate levels did not increase, reflecting a lack of mitochondrial toxicity. KP-1461 appears safe and well tolerated in humans in Phase I studies, and no dose-related toxicities were observed in a completed Phase I study.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[]]></drug:casname><drug:casnumber><![CDATA[]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[SN1461]]></drug:othername><drug:othername><![CDATA[SN1212 [metabolized drug]]]></drug:othername><drug:othername><![CDATA[KP-1212 [metabolized drug]]]></drug:othername><drug:othername><![CDATA[KP-1212/1461]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/17678417 Novel anti-HIV agent enters Phase IIa clinical trial. Expert Rev Anti Infect Ther. 2007 Aug;5(4):540-1.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17678417&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15890415 Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res. 2005 Jul;67(1):1-9. PMID: 15890415]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15890415&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Harris K, Brabant B, Li L, Styrchak S, Gall A, Daifuku R. SN1212/1461 a Novel Mutagenic Deoxyribonucleoside Analog with Activity Against HIV. San Francisco, Abstract 532, 2004.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[ClinicalTrials.Gov - Safety and Efficacy Study of KP-1461 to Treat ART-Experienced HIV+ Patients. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00504452. Accessed 02/13/08.
]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[KP-1461]]></drug:drugname><drug:companyname><![CDATA[Koronis Pharmaceuticals]]></drug:companyname><drug:address1><![CDATA[12277 134th Court NE, Suite 110]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Redmond]]></city><drug:state><![CDATA[WA]]></drug:state><drug:zipcode><![CDATA[98052]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(425) 825-0240]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 13, 2008]]></drug:lastupdated></item><item><title><![CDATA[Racivir]]></title><description><![CDATA[Racivir, also known as RCV, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs work by blocking reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=386]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir, also known as RCV, is an oxothiolane nucleoside reverse transcriptase inhibitor similar to emtricitabine and lamivudine. Racivir is a 50:50 mixture of emtricitabine and its positive enantiomer.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir is an investigational drug that displays potent and selective activity against both HIV-1 and hepatitis B virus (HBV) in cell culture and in animal models. Racivir has been compared to lamivudine, an approved cytosine analog, in clinical trials as part of a triple-agent regimen with stavudine and efavirenz. Racivir is now being studied in phase II/III clinical trials as part of combination therapy for the treatment of HIV-1 infection.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir is active in vitro against HBV.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing racivir 50 mg and 200 mg. Racivir is dosed once daily as part of a combination regimen. Clinical trials have evaluated racivir dosages of 200, 400, and 600 mg once daily for up to 14 days.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Racivir, a 50:50 racemic mixture of the (-)- and (+)-beta-enantiomers of emtricitabine, is being developed for the treatment of HIV infection. The (+)-enantiomer of emtricitabine is approximately 10- to 20-fold less potent than (-)-emtricitabine, but it selects for a different HIV mutation in human lymphocytes.

In a Phase I/II dosing study, racivir was administered to HIV infected, treatment-naive, male volunteers in combination with stavudine and efavirenz for 14 days. Racivir was administered once daily at doses of 200, 400, or 600 mg. The combination regimens resulted in a rapid initial drop in viral load, with mean 10-fold reductions by Day 4. Mean HIV RNA levels continued to drop, though more slowly, through the end of treatment on Day 14, resulting in a greater than 20-fold reduction in viral load. Upon cessation of therapy, HIV RNA levels remained suppressed from all doses for more than 2 weeks. Viral load remained steady through Day 28. By Day 35, HIV RNA levels began to increase but still remained at least 10-fold less than baseline levels.

Racivir displays excellent oral bioavailability in human preclinical studies. In a Phase I/II study of racivir in treatment-naive men, pharmacokinetic parameters were dose proportional across 200, 400, and 600 mg dose levels.

A Phase II, randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, and antiviral effect of a racivir 600 mg dose compared with lamivudine in HIV infected, treatment-experienced participants with the M184V mutation who have been on lamivudine as part of a combination regimen. One group of 16 participants continued on existing therapy with lamivudine, and the second group of 26 participants received racivir in place of lamivudine in existing regimens. Participants received 28 days of blinded therapy followed by 20 weeks of open-label treatment. After 28 days of blinded treatment, the mean viral load rose by 34.9% in the lamivudine group and dropped by 60.2% in the racivir group (p=0.02). A subset analysis of 14 participants in the racivir-treated group revealed that the change in viral load was largely due to a positive antiviral response in participants who had an HIV mutation pattern that included M184V and less than three thymidine analog mutations with or without non-nucleoside reverse transcriptase inhibitor or protease inhibitor mutations. Replacing lamivudine with racivir in their existing therapies caused a mean drop in viral load of 80% (p=0.004) in the second week of treatment.

Racivir has demonstrated antiviral activity in patients harboring HIV with the lamivudine-associated M184V mutation and with less than three thymidine-associated mutations. Because such mutations are consistent with first-line therapy failure, racivir may be useful as part of a combination second-line treatment regimen.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Single and multiple doses of racivir appear well tolerated in early studies, with mild headache and fatigue occurring no more frequently than with placebo. In a 14-day, Phase I/II study conducted in HIV infected men, racivir 200, 400 and 600 mg doses were well tolerated in combination with stavudine and efavirenz.

In an ongoing Phase II trial of 42 HIV infected patients comparing racivir to lamivudine as part of a combination regimen, no severe adverse effects attributed to therapy were noted over the 28 days. As open-label dosing of racivir continues in this trial, safety data will be presented.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In previous clinical trials, racivir was administered with stavudine and efavirenz. There was no evidence that coadministration of stavudine and efavirenz had an adverse effect on the pharmacokinetics of racivir.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2',3'-Dideoxy-5-fluoro-3'-thiacytidine]]></drug:casname><drug:casnumber><![CDATA[143491-54-7]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H10-F-N3-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C39.0%, H4.1%, F7.3%, N17.1%, O19.5%, S13.0%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[247.25]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[RCV]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15980356 Herzmann C, Arasteh K, Murphy RL, Schulbin H, Kreckel P, Drauz D, Schinazi RF, Beard A, Cartee L, Otto MJ. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in antiretroviral-naive human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2005 Jul;49(7):2828-33.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15980356&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15351346 Otto MJ. New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr Opin Pharmacol. 2004 Oct;4(5):431-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15351346&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Study Comparing Racivir and Lamivudine in Treatment-Experienced HIV Subjects. Available at: http://www.clinicaltrials.gov/ct/show/NCT00121979. Accessed 05/18/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Racivir]]></drug:drugname><drug:companyname><![CDATA[Pharmasset, Inc.]]></drug:companyname><drug:address1><![CDATA[US Research Operations]]></drug:address1><drug:address2><![CDATA[1860 Montreal Road ]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Tucker]]></city><drug:state><![CDATA[GA]]></drug:state><drug:zipcode><![CDATA[30084]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(678) 395-0035]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 30, 2007]]></drug:lastupdated></item><item><title><![CDATA[Bevirimat]]></title><description><![CDATA[Bevirimat is a type of medicine called a maturation inhibitor. It is the first drug in this class to be studied for the treatment of HIV. Maturation inhibitors work by blocking viral maturation, a late step in HIV development that is needed for the virus to become infectious.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=414]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[be-VEER-ih-mat]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat, also known as PA-457, is a betulinic acid derivative and a first-in-its-class maturation inhibitor. It is in Phase II studies to determine its use as a treatment for HIV and has been assigned fast-track status by the FDA as of January 2005.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat is being evaluated as once-daily monotherapy for activity against HIV-1 in patients who are resistant to available treatments. Bevirimat was assigned fast-track status by the FDA as of January 2005.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Bevirimat has been studied at once-daily doses of 25, 50, 75, 100, 150, 200, 250, 400, 500, and 600 mg.

Both bevirimat 100 and 200 mg oral solutions have been studied in a Phase IIa trial, and a bevirimat 50 mg tablet to be used for 400 mg daily dosing has been studied in a Phase IIb trial. Early clinical bioavailability studies indicated that the tablet had approximately 60% of the oral bioavailability of an oral solution formulation. Thus, plasma concentrations after administration of a single 400 mg dose of bevirimat were expected to be comparable to those after administration of the bevirimat 200 mg oral solution. However, plasma concentrations with bevirimat 400 mg tablet dosing were actually about half what was expected and were more similar to concentrations achieved with bevirimat 100 mg oral solution dosing. Data suggest that the lower plasma concentrations result from properties of the bevirimat 50 mg tablet used in the Phase IIb trial. Phase IIb studies are continuing but are using bevirimat oral liquid formulation in increasing dose cohorts.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat is a first-in-its-class maturation inhibitor with potent activity against wild-type HIV-1 as well as against strains resistant to antiretroviral therapy. Maturation is a late stage in viral reproduction, involving Gag protein processing necessary for further infection of human cells. Bevirimat targets this late step and blocks conversion of the HIV-1 capsid precursor p25 to the mature capsid protein p24 in the CA-SP1 cleavage region. This results in the release of noninfectious viral particles and the termination of viral replication. SP1 is a small spacer peptide separating the CA and NC domains in the Gag polyprotein precursor. Bevirimat is specifically active at the CA-SP1 cleavage site.

Amino acid residues in CA-SP1 Gag domains are critical for drug activity; thus, determinants that confer resistance map to this Gag domain. An adenine (A) to valine (V) change at the first or third residues at the N-terminus of SP1 (A1V or A3V) resulted in a resistant phenotype. However, genetic analysis of available patients showed no development of resistance, and bevirimat retained potency in patients with existing extensive mutations.

Oral bevirimat is rapidly absorbed in animal models and in humans and has a half-life of nearly three days (60.3 hrs). A 10-day, multiple-dose trial in healthy males evaluated daily doses of 25, 50, and 100 mg bevirimat. Peak plasma concentrations (Cmax) at Day 10 were 7.98, 15.58, and 31.58 mcg/ml, respectively. Drug plasma levels accumulated approximately three- to fivefold from baseline. Areas under the concentration-time curve (AUC) at Day 10 were 156.5, 303.1, and 599.5 hr(mcg)/ml, respectively. The target minimum therapeutic concentration (Cmin) of bevirimat was determined to be 2.3 mcg/ml and was achieved with single daily doses of 25 mg; tenfold target Cmin concentrations were safely achieved with single daily doses of 100 mg. Bevirimat demonstrated dose-related antiviral activity in a single-dose pharmacokinetic and -dynamic model and in a multiple-dose evaluation.

Bevirimat was nonteratogenic when administered orally in rats and rabbits. No developmental toxicity was observed up to the highest tested dosages of 900 mg/kg/day in the rat and 300 mg/kg/day in the rabbit. These dosages are approximately 44 and 29 times greater, respectively, than the potential human dosage for bevirimat of 200 mg/day. Bevirimat is not oxidatively metabolized by the cytochrome P 450 (CYP) liver enzyme system. Testing of CYP enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 showed no inhibition in human livers by the drug. Bevirimat is glucuronidated primarily by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A3 and weakly inhibits glucuronidation by some UGT isoforms. Bevirimat displayed linear clearance in a three-cohort study of single 75, 150, or 250 mg doses.

When tested against a panel of resistant HIV strains, bevirimat retained wild-type activity, whereas approved antiretroviral medications exhibited decreases in activity that ranged from several-fold to more than 100-fold. Viral resistance to bevirimat was also examined in vitro, and five amino acid changes were identified that independently confer resistance: H226Y, L231M, and L231F at the C-terminus of CA; and A1V and A3V at SP1. The A3V/G225S mutant was fully drug resistant. The clustering of bevirimat resistance mutations at the CA/SP1 junction confirms that this region is the major target of bevirimat activity. Drug dependence observed for A3V mutations suggests multiple mechanisms of resistance. Viral resistance was not detected in vivo during a 10-day, multi-dose study that used standard genotyping methods. Further resistance studies conducted in vitro have confirmed that mutations that confer resistance to bevirimat are found only at or near the site of the drug's mechanism of action: the capsid-SP1 cleavage site in the HIV Gag protein. The six in vitro mutations that induce resistance are CA-H226Y, L231M, and L231F, and SP1-A1V, A3V, and A3T. Bevirimat resistance may develop in the presence of pre-existing protease inhibitor mutations; however, a recent study suggests that PI-resistant mutants may be less likely than wild-type isolates to develop PA-457 resistance.

In a Phase I dose-evaluation trial, twenty-four healthy men received a single oral dose of bevirimat 25, 50, 100, or 250 mg. In each group, six men received active drug, and two men received placebo. Doses of bevirimat 50 mg or greater exceeded target plasma concentrations for more than 24 hours, establishing the possibility of once-daily therapeutic dosing.

A single-dose, double-blind, placebo-controlled trial in twenty-four HIV infected patients with CD4 counts of 200 cells/ml or greater and viral loads of 5,000 to 250,000 copies/ml compared 75, 150, and 250 mg doses of bevirimat to placebo. All groups showed sustained decreases in viral load after 10 days. Viral load decreases appeared dose-dependent: approximately 70% reduction was achieved with bevirimat 250 mg; nearly 60% reduction with bevirimat 150 mg; and nearly 50% reduction with bevirimat 75 mg.

A Phase IIa, double-blind, placebo-controlled trial examined daily doses of bevirimat 25, 50, 100, or 200 mg in HIV infected patients who were treatment-naive for at least 12 weeks prior to the trial. Six patients received active drug in each dose group, and eight patients received placebo; all groups were treated for 10 days. The primary endpoint of demonstrated antiviral activity was evaluated on Day 11. Steady-state plasma concentrations were reached after approximately seven days of therapy. Bevirimat displayed dose-proportional pharmacokinetics: the 200 mg dose achieved a minimum serum concentration double that of the 100 mg dose. After a mild initial increase, viral load decreased significantly in the 100 and 200 mg dose groups compared with placebo. Day 11 median reductions were nearly threefold and approximately tenfold, respectively. In patients whose baseline viral loads were less than 100,000 copies/ml, median reductions with 100 and 200 mg doses were approximately threefold and 33-fold, respectively. Twenty-one of thirty-three patients showed no resistance to bevirimat.

A Phase IIb study was initiated in 2006 to study bevirimat in HIV infected patients who were failing current antiretroviral therapy. The primary endpoints included reduction in viral load after 14 days and after 3 months. In the first cohort, patients were administered bevirimat or placebo once daily for 3 months in combination with background antiretroviral therapy. A second, dose-escalation, cohort planned to enroll 12 treatment patients plus four placebo patients in three bevirimat once-daily dosage groups: 400, 500, and 600 mg. Results from the first cohort showed an antiviral effect of bevirimat after 14 days of 400 mg daily dosing. At Day 15, the mean viral load reduction was approximately 60% in patients treated with 400 mg bevirimat. Two of 12 patients with drug-resistant HIV and treated with bevirimat achieved undetectable virus levels (HIV viral load less than 400 copies/ml), and one additional patient achieved viral load reduction of more than 90%. The overall plasma concentrations, and thus antiviral response, in the first cohort of bevirimat 400 mg was lower than expected, based on earlier bioavailability studies predicting concentrations similar to those seen in the Phase IIa study that used bevirimat oral liquid formulation. Data suggest the lower plasma concentrations resulted from the tablet formulation properties. In March 2007, the manufacturer received FDA approval to continue revised dose-escalation cohorts in this study with the oral liquid formulation of bevirimat. In the first cohort, patients are being administered 14 days of bevirimat 250 mg monotherapy (eight patients) or placebo (two patients) once daily in the first cohort; primary endpoints are safety and efficacy (i.e., viral load reduction) of bevirimat at Day 15. Dose escalations of 50 mg are ongoing after completion of the first cohort. In the 250 mg cohort, addition of bevirimat to failing background regimens reduced viral load by mean 0.68log on Day 15 and by .5log or greater in 71% of patients. Efficacy as measured by viral load reduction was greater than with the 400 mg tablet cohort, which had a mean viral load reduction of .036log. Mean steady state plasma concentrations were greater than those seen in earlier studies with the liquid formulation and were approximately double those seen with the tablet formulation of bevirimat 400 mg. A 300 mg cohort was initiated, and eight patients received bevirimat. Mean viral load reduction was greater than in the 250 mg cohort at 1.02log; 75% of patients had greater than 0.5log and 63% had greater than 1log reduction on Day 15. A bevirimat 350 mg cohort was initiated, in which nine patients received bevirimat and two received placebo. On Day 15, mean viral load was reduced 0.62log; 33% had greater than .5log reduction and were all greater than 1log. The area under the concentration-time curve and the steady state mean trough levels were similar in the 300 mg and 350 mg cohorts. The manufacturer intends to continue this Phase IIb trial with a 400 mg cohort.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat was safe and well tolerated in a 10-day, double-blind, placebo-controlled trial in HIV infected patients. Six patients were assigned to each dose level (25, 50, 100, and 200 mg), and eight patients were assigned to the placebo group. Adverse effects were mild to moderate; diarrhea with altered bowel habits was reported by one to six patients in each dose group and in five of eight patients in the placebo group. Grade 2 increases in triglyceride levels occurred in one patient on Day 5 but returned to baseline. No treatment-emergent drug-related Grade 3 or 4 adverse effects were seen. One patient with a 5-year history of poorly controlled hypertension experienced a probable transient lacunar cerebrovascular accident (CVA); this serious adverse event may not have been related to bevirimat administration. Two patients experienced mild adverse effects in the 300 mg cohort of an ongoing Phase IIb trial; bevirimat oral liquid formulation was well tolerated in both the 300 mg and 350 mg cohorts.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Bevirimat does not inhibit the CYP liver enzyme system or interact with human p-glycoprotein.

When tested with representative reverse transcriptase, protease, and fusion inhibitors, bevirimat exhibited nearly additive to strongly synergistic activity with each at 90% inhibitory concentrations against a panel of resistant viral strains.

Because both bevirimat and atazanavir interact with the liver's UGT enzymes---bevirimat as a UGT substrate and weak inhibitor and atazanavir as an inhibitor---the combination was studied to determine possible pharmacokinetic interactions. Bevirimat and atazanavir serum concentrations appeared unaffected by concomitant administration, and bevirimat did not increase the hyperbilirubinemia that occurs with atazanavir because of its effect on the UGT system.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[3-O-(3',3'-dimethylsuccinyl)betulinic acid]]></drug:casname><drug:casnumber><![CDATA[]]></drug:casnumber><drug:molecularformula><![CDATA[C36-H53-O6]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C77.1%,H8.1%,O14.7%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[653]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[BVM]]></drug:othername><drug:othername><![CDATA[PA-457]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/16956950 Adamson CS; Ablan SD; Boeras I; Goila-Gaur R; Soheilian F; Nagashima K; Li F; Salzwedel K; Sakalian M; Wild CT; Freed EO. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J Virol.  2006; 80(22):10957-71.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16956950&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17254209 Allaway GP. Development of Bevirimat (PA-457): first-in-class HIV maturation inhibitor. Retrovirology.  2006; 3 Suppl 1:S8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17254209&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16955688 Temesgen Z; Feinberg JE. Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor. Curr Opin Investig Drugs.  2006; 7(8):759-65.

]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16955688&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17151190 Wen Z; Martin DE; Bullock P; Lee KH; Smith PC. Glucuronidation of Anti-HIV Drug Candidate Bevirimat: Identification of Human UDP-glucuronosyltransferases and Species Differences. Drug Metab Dispos.  2007; 35(3):440-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17151190&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Bevirimat]]></drug:drugname><drug:companyname><![CDATA[Panacos Pharmaceuticals, Inc.]]></drug:companyname><drug:address1><![CDATA[Corporate Headquarters]]></drug:address1><drug:address2><![CDATA[134 Coolidge Avenue]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Watertown]]></city><drug:state><![CDATA[MA]]></drug:state><drug:zipcode><![CDATA[02472]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(617) 926-1551]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[March 10, 2008]]></drug:lastupdated></item><item><title><![CDATA[Poly(I)-Poly(C12U)]]></title><description><![CDATA[Poly(I)-poly(C12U), also known as Ampligen, is a type of antiviral drug called a biological response modifier. These types of drugs appear to restart human immune defenses against viruses and tumors.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=402]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-Poly(C12U)]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Ampligen]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-Poly(C12U)]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly (C12U), a specifically mismatched doublestranded RNA (dsRNA) nucleic compound, is a biological response modifier with anti-HIV activity.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly(C12U) is in Phase IIb studies for the treatment of HIV as monotherapy or as an addition to failing regimens of highly active antiretroviral therapy (HAART). Poly(I)-poly(C12U) is also being evaluated for its role in lengthening the duration of structured treatment interruptions (STIs) of HAART therapy.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly(C12U) has widespread antiviral activity, including activity against West Nile virus and other flaviviruses. Poly(I)-poly(C12U) is also being studied for the treatment of hepatitis B and C infection, renal cell carcinoma, and malignant melanoma. Phase III studies evaluating the drug for treatment of chronic fatigue syndrome have recently been completed as well.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous.]]></drug:modeofdelivery><drug:dosageform><![CDATA[In clinical trials, poly(I)-poly(C12U) 400 mg is administered intravenously twice weekly.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly(C12U) provides broad activity by activating otherwise dormant cellular defenses against viruses and tumors. Specifically, poly(I)-poly(C12U) activates intracellular antiviral mediators 2-5A synthetase/RNase. The drug's cell-mediated immunomodulatory properties produce a delayed hypersensitivity response, which may delay viral rebound during STIs of HAART.

STI is based on the premise that immune function may recover in stable HIV infected patients by temporarily withdrawing HAART, allowing viral rebound to stimulate the immune response. However, efforts to date have produced conflicting results. When given during the interruption period, poly(I)-poly(C12U) appears to stabilize patients and allows a longer duration of interrupted therapy.

In a Phase IIb study of poly(I)-poly(C12U) for treatment of HIV during STI, 22 patients with viral loads less than 50 copies/ml and CD4 counts of at least 400 cells/mm3 were randomized to receive poly(I)-poly(C12U) 400 mg IV twice weekly or no treatment during STIs over 64 weeks. STIs continued until the viral load rebounded to at least 5,000 copies/ml for 3 consecutive weeks or 50,000 copies/ml at least once. After 9 months, therapy with poly(I)-poly(C12U) significantly prolonged the duration of STI from a mean 13 weeks without treatment to a mean 27 weeks with the drug. Additionally, the number of CD8 cells significantly increased in patients receiving poly(I)-poly(C12U), destroying additional cells infected with the virus.

During in vitro testing, poly(I)-poly(C12U) was equally active against wild-type HIV and HIV resistant to the following: nevirapine, protease inhibitors, or nucleoside analogue reverse transcriptase inhibitors.

Ampligen 400 mg currently is being studied in AMP 720, an open-label randomized trial, for its use prolonging the structured treatment interruption of existing highly active antiretroviral therapy in HIV infected adults with plasma HIV RNA levels less than 50 copies/ml and CD4 counts of at least 400 cells/mm3.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly(C12U) appears generally well tolerated as monotherapy or as concomitant anti-HIV therapy in clinical studies. In a 9-month trial of poly(I)-poly(C12U) in HIV infected patients, adverse effects were primarily mild and self-limiting. To date, lactic acidosis, insulin resistance, and hyperlipidemia have not been noted in relation to poly(I)-poly(C12U) therapy.

In clinical trials of poly(l)-poly(C12U) for various treatments, a low level of clinical toxicity has been observed. An infusion rate-related mild flushing reaction, at time accompanied by tachycardia, shortness of breath, or anxiety, has occurred in approximately 15% of patients. Other adverse effects noted in trials include diarrhea, itching, rash, hypotension, anemia, elevation of kidney function tests, dizziness, and confusion. Mild flu-like symptoms, such as chills, fever, nausea, vomiting, headache, and fatigue, have also been reported but appear to resolve within several months of treatment initiation.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Poly(I)-poly(C12U) is synergistic with zidovudine in decreasing CD4 counts in patients receiving combination therapy for more than a year. Poly(I)-poly(C12U) also appears to resensitize zidovudine-resistant HIV when given concomitantly. In addition, in vitro studies have demonstrated poly(I)-poly(C12U) synergy with the following antiretroviral medications: abacavir, amprenavir, didanosine, efavirenz, indinavir, ritonavir, nelfinavir, stavudine, zalcitabine, and zidovudine.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)]]></drug:casname><drug:casnumber><![CDATA[38640-92-5]]></drug:casnumber><drug:molecularformula><![CDATA[(C10-H13-N4-O8-P)x-.(C9-H14-N3-O8-P.C9-H13-N2-O9-P)x-]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[]]></drug:molecularweight><drug:physicaldescription><![CDATA[]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15357629 Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. PMID: 15357629]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15357629&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Safety and Efficacy of Ampligen in the Treament of HIV Patients Failing HAART. Available at: http://www.clinicaltrials.gov/ct/show/NCT00035581. Accessed 02/24/06.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART. Available at: http://www.clinicaltrials.gov/ct/show/NCT00035893. Accessed 02/24/06.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Poly(I)-Poly(C12U)]]></drug:drugname><drug:companyname><![CDATA[Hemispherx Biopharma, Inc]]></drug:companyname><drug:address1><![CDATA[One Penn Ctr]]></drug:address1><drug:address2><![CDATA[1617 JFK Blvd, 6th Floor]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Philadelphia]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[19103]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(215) 988-0080]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Ampligen]]></drug:drugname><drug:companyname><![CDATA[Hemispherx Biopharma, Inc]]></drug:companyname><drug:address1><![CDATA[One Penn Ctr]]></drug:address1><drug:address2><![CDATA[1617 JFK Blvd, 6th Floor]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Philadelphia]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[19103]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(215) 988-0080]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 14, 2008]]></drug:lastupdated></item><item><title><![CDATA[Valproic acid]]></title><description><![CDATA[Valproic acid, also known as Depakene, is a type of medicine normally used to treat seizures and other nervous system problems. Valproic acid works against HIV by releasing the virus from resting cells so other anti-HIV medicines can attack it.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=417]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[val-PROE-ic A-cid]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Depakene]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid is a carboxylic acid that increases gamma-amino butyric acid (GABA) levels in the central nervous system and inhibits the enzyme histone deacetylase 1 (HDAC1).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid is being studied for use in the treatment of HIV infection by reducing the number of dormant, infected T cells, making the virus more accessible to attack by other antiretrovirals.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid is an anticonvulsant indicated for use as monotherapy and adjunctive therapy in the treatment of simple or complex absence seizures. Valproic acid has been studied in the treatment of manic episodes associated with bipolar disorder and in migraine headache prophylaxis, although it has not been approved by the FDA for these disorders.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.

Intravenous. ]]></drug:modeofdelivery><drug:dosageform><![CDATA[Orange-colored, soft gelatin capsules containing valproic acid 250 mg.  

Red-colored syrup containing valproic acid 250 mg as a sodium salt per 5 ml.

Dosages of 500 to 750 mg twice daily have been tested for use in combination with enfuvirtide and as part of certain antiretroviral regimens.]]></drug:dosageform><drug:storage><![CDATA[Store capsules at 15 C to 25 C (59 F to 77 F). Store syrup below 30 C (86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid, a histone deacetylase (HDAC)-1 inhibitor, stimulates the release of HIV from latent T cells, allowing antiretrovirals to attack the re-emerged virus. HDAC-1 inhibition may also suppress HIV promoter activity in latent T cells infected with the virus. 

In a small proof-of-concept study, valproic acid administered to HIV infected adults for three months with enfuvirtide accelerated the clearance of HIV from latent T cells and decreased the frequency of latent cell infection significantly in three of four patients. These findings suggest valproic acid may be useful in decreasing the HIV reservoir and eliminating more of the virus from infected cells.

Valproic acid dissociates to the active valproate ion in the gastrointestinal (GI) tract. Absorption from the GI tract varies with dosage regimens and formulations, but the variances are unlikely to have a clinical effect. 

Valproic acid is protein bound in a concentration-dependent manner; the free fraction increases from 10% to nearly 20% at 40 mcg/ml and 130 mcg/ml concentrations, respectively. Cerebrospinal fluid concentrations approximate the unbound plasma concentrations at 10%. Protein binding is saturable; unbound valproic acid pharmacokinetic measurements are linear. Mean terminal half-life ranges from 9 to 16 hours.

Valproic acid is almost entirely hepatically metabolized. Nearly 40% of a dose is glucuronidated, and mitochondrial beta-oxidation accounts for more than 40% of the dose.  Other oxidative metabolism accounts for the remaining administered drug. Less than 3% of drug is recovered unchanged. Children between the ages of 3 months and 10 years have 50% higher clearance rates. Elderly clearance rates are reduced by 39% to 44%.

Valproic acid is in FDA Pregnancy Category D.  The drug may be teratogenic in humans. Neural tube defects and other congenital anomalies may occur, and clotting abnormalities may develop in pregnant women.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In the first proof-of-concept study of valproic acid in HIV infected patients, no severe adverse effects occurred. Mild anemia and irritation at injection sites were attributed to concomitant antiretrovirals.

Hepatic failure resulting in fatalities has occurred in people taking valproic acid, usually within the first 6 months of treatment. Hepatotoxicity may be preceded by symptoms of malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Valproic acid should be discontinued immediately in the presence of suspected or apparent hepatic dysfunction; dysfunction may progress despite drug discontinuation.

Adverse effects commonly associated with divalproex sodium, an oral salt dosage form of valproic acid, include headache; asthenia; nausea, vomiting, abdominal pain, and diarrhea; somnolence; dizziness; and tremor. Photosensitivity, Steven-Johnsons Syndrome, and rare cases of toxic epidermal necrosis have occurred. Minor, dose-related elevations of hepatic enzymes occur frequently.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Food does not appear to alter clinical effects of valproic acid, although single dose half-lives appear increased by 4 hours when the drug is administered with food.

Valproic acid may interact with concurrently administered medications capable of hepatic enzyme induction; for example, phenytoin, cyclobenzaprine, and phenobarbital can double valproic acid clearance. Cytochrome P450 (CYP) inhibitors have a smaller effect on valproic acid clearance, because CYP-mediated oxidation of valproic acid is secondary to glucuronidation and beta-oxidation.

Valproic acid is a weak inhibitor of some hepatic enzymes and is able to displace plasma protein-bound drugs.  These effects increase the serum levels of cyclobenzaprine, diazepam, phenobarbital, phenytoin, and some other medications.

Concurrent valproic acid and zidovudine administration results in a 38% decrease in zidovudine clearance but half-life is unaffected.

Coadministration of valproic acid and aspirin results in a fourfold increase in the free fraction of valproic acid, compared to monotherapy due to inhibition of beta-oxidation.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction. Valproic acid is contraindicated in patients with known hypersensitivity to the drug.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2-propylpentanoic acid]]></drug:casname><drug:casnumber><![CDATA[99-66-1]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H16-O2]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C67%, H11%, O22%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[144]]></drug:molecularweight><drug:physicaldescription><![CDATA[Colorless liquid with a characteristic odor.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Slightly soluble in water at 1.3 mg/ml; very soluble in organic solvents.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Depakene Prescribing Information from the FDA web site <A HREF="http://www.fda.gov/cder/foi/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf.">[PDF]</A>. A more current version may be available on the manufacturer's web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16099956 Cohen J. HIV/AIDS. Report of novel treatment aimed at latent HIV raises the 'c word'. Science. 2005 Aug 12;309(5737):999-1000. No abstract available. 
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16099956&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15504860 DiCenzo R, Peterson D, Cruttenden K, Morse G, Riggs G, Gelbard H, Schifitto G.  Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004 Nov;48(11):4328-31.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15504860&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16099290 Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16099290&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16168066 Smith SM. Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology. 2005 Sep 19;2:56.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16168066&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells. Available at: http://clinicaltrials.gov/ct/show/NCT00289952. Accessed 12/11/07]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Valproic acid]]></drug:drugname><drug:companyname><![CDATA[Abbott Laboratories]]></drug:companyname><drug:address1><![CDATA[One Hundred Abbott Park Rd]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Abbott Park]]></city><drug:state><![CDATA[IL]]></drug:state><drug:zipcode><![CDATA[60064-3500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 633-9110]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[December 11, 2007]]></drug:lastupdated></item></channel></rss>