and NPI-2358 Plinabulin relatively low manufacturing cost, dapivirine ring 004, if safe and effective against HIV, would be suitable for use in developing countries, especially in sub Saharan Africa where HIV incidence in women is high. Randomised, placebo controlled studies to determine efficacy and long term safety of dapivirine ring 004 in about 5000 women are planned to begin in several countries in sub Saharan Africa in early 2012. Additional studies evaluating safety in adolescents and perimenopausal and post menopausal women are also planned. Dapivirine film Dapivirine has also been formulated into small fast dissolving films, designed to release drug following dissolution by vaginal fluids.41 Flexible, translucent polyvinyl alcohol based vaginal films containing 1.
25 mg dapivirine per film were designed to dissolve rapidly upon exposure to an aqueous environment with greater than 50% of the loaded dapivirine being released from the film within 10 mins. In addition, dapivirinewas shown to permeate target tissue in vitro and inactivate HIV 1 in exvivo models using human cervical WZ4002 EGFR inhibitor explant tissue.41 The advantages of vaginal films as a microbicidedosage form include the potential for improved drug stability compared with water based gels, especially for hydrophobic drugs such as dapivirine. As a result of their small size, vaginal films may also have economic advantages over vaginal rings and gels in manufacturing, storage and shipping costs. Vaginal leakage observed with frequent use of microbicide gels may also be eliminated by vaginal films that do not require exogenous fluids for dissolution.
3,18 Acceptability of vaginal films as a contraceptive dosage form has been evaluated in several MGCD-265 studies that reported similar levels of satisfaction for vaginal films compared with contraceptive gels, foams and suppositories.42,43 Women have also reported acceptability of vaginal films for microbicide delivery.4,44 46 Maraviroc Maraviroc, belongs to a pharmacological class of antiretroviral agents known as CCR5 antagonists, marketed as Selzentry for treatment of CCR5 tropic HIV 1 infection, which acts by blocking the CCR5 co receptor on human cellular targets to prevent infection of the cell by HIV 1.47,48 As CCR5 is the primary co receptor involved in sexual transmission of HIV, blocking CCR5 has the potential to prevent the establishment of infection in individuals exposed to the virus.
49 Maraviroc has demonstrated efficacy in vitro against a wide range of CCR5 tropic clinical isolates from multiple clades of HIV 1, as well as those resistant to other classes of antiretroviral medicinal products.47 Maraviroc delivered vaginally has been shown in non human primates to prevent transmission of simian human immunodeficiency virus infection when delivered within a few hours before infection.50 Maraviroc and maraviroc dapivirine vaginal rings Maraviroc,s short duration of effect in NHP suggests that vaginal rings would be a suitable dosage form for maraviroc based microbicides. Pre clinically, maraviroc has been shown to be safe after topical gel application for 4 weeks in rabbit vaginal irritation studies. Vaginal rings containing maraviroc, and a combination of maraviroc and dapivirine, are currently being tested in a phase I safety and pharmacokinetics study. Althou