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Annalene Nel - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic assessment of dapivirine Vaginal Microbicide gel in healthy hiv negative women
AIDS Research and Human Retroviruses, 2010Co-Authors: Annalene Nel, Mark Mitchnick, Paul Coplan, Shanique C Smythe, Karen Mccord, Paulina E Kaptur, Joseph RomanoAbstract:Abstract To assess the pharmacokinetics of dapivirine in plasma and dapivirine concentrations in cervicoVaginal fluids (CVF) and cervicoVaginal tissues following Vaginal administration of dapivirine Microbicide gel in healthy, HIV-negative women for 10 days. A randomized, double-blind, phase I study was conducted at a single research center in South Africa. A total of 18 women used dapivirine gel (0.001%, 0.005%, or 0.02%) once daily on Days 1 and 10 and twice daily on Days 2–9. Pharmacokinetics of dapivirine were assessed in plasma on Days 1 and 10. Dapivirine concentrations were measured in CVF on Days 1 and 10 and in cervicoVaginal tissues on Day 10. Safety was evaluated through laboratory tests (hematology, clinical chemistry, and urinalysis), physical examinations, and assessment of adverse events. Plasma concentrations of dapivirine increased over time with gel dose and were greater on Day 10 (Cmax 31 to 471 pg/ml) than Day 1 (Cmax 23 to 80 pg/ml). Tmax was 10–12 h on Day 1, and 9 h on Day 10. Conce...
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pharmacokinetics of 2 dapivirine Vaginal Microbicide gels and their safety vs hydroxyethyl cellulose based universal placebo gel
Journal of Acquired Immune Deficiency Syndromes, 2010Co-Authors: Annalene Nel, Shanique C Smythe, Paulina E Kaptur, Sepideh Habibi, Joseph W. RomanoAbstract:Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is in development as a Microbicide for the protection of women against HIV infection. A randomized, double-blind, phase 1 trial was conducted in 36 healthy HIV-negative women to compare the pharmacokinetics of 2 dapivirine Vaginal gel formulations (0.05% each) and their safety with the hydroxyethyl cellulose-based universal placebo gel. Gel was self-administered once daily for a total of 11 days. Blood and Vaginal fluid samples were collected sequentially over 24 days for pharmacokinetic analysis. Safety was evaluated by pelvic examination, colposcopy, adverse events, and clinical laboratory assessments. Adverse event profiles were similar for the 3 gels. Most events were mild and not related to study gel. Headache and Vaginal hemorrhage (any Vaginal bleeding) were most common. Plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Steady-state conditions were reached within approximately 10 days. Dapivirine concentrations in Vaginal fluids were slightly higher for Gel 4789, but C max values on days 1 and 14 were not significantly different. Terminal half-life was 72-73 hours in plasma and 15-17 hours in Vaginal fluids. Both formulations of dapivirine gel were safe and well tolerated. Dapivirine was delivered to the lower genital tract at concentrations at least 5 logs greater than in vitro inhibitory concentrations.
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safety tolerability and systemic absorption of dapivirine Vaginal Microbicide gel in healthy hiv negative women
AIDS, 2009Co-Authors: Annalene Nel, Janneke Van De Wijgert, Paul Coplan, Saidi Kapiga, Claire Von Mollendorf, Eveline Geubbels, Joseph Vyankandondera, Helen Rees, Gileard Masenga, Ireen KiweluAbstract:Objectives: To assess the local and systemic safety of dapivirine Vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Methods: Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.021%,), and 28 used placebo gel twice daily for 42 clays. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Results: Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02%. gel group on clay 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Conclusion: Twice daily administration of dapivirine Vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women Suggesting that continued development is warranted. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
Ronald S Veazey - One of the best experts on this subject based on the ideXlab platform.
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non aqueous silicone elastomer gels as a Vaginal Microbicide delivery system for the hiv 1 entry inhibitor maraviroc
Journal of Controlled Release, 2011Co-Authors: Claire J Forbes, Deborah Lowry, Leslie Geer, Ronald S Veazey, Per Johan Klasse, Mark Mitchnick, Laurie Goldman, Laura A Doyle, Brendan C O MuldoonAbstract:Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in Vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for Vaginal HIV Microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for Vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose Vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in Vaginal fluid, Vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent Vaginal HIV Microbicides.
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protection of rhesus macaques from Vaginal infection by Vaginally delivered maraviroc an inhibitor of hiv 1 entry via the ccr5 co receptor
The Journal of Infectious Diseases, 2010Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Linda C Green, Jason Dufour, Terri Moroneyrasmussen, John P MooreAbstract:An effective Vaginal Microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among Microbicide candidates in clinical development is Maraviroc (MVC), a small molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected people, but its ability to prevent transmission is untested. We have now evaluated MVC as a Vaginal Microbicide, using a stringent model involving challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/ml). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (T1/2 ~ 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated post-infection viremia. These findings validate MVC development as a Vaginal Microbicide for women, and should guide clinical programs.
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protection of rhesus macaques from Vaginal infection by Vaginally delivered maraviroc an inhibitor of hiv 1 entry via the ccr5 co receptor
The Journal of Infectious Diseases, 2010Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Linda C Green, Jason Dufour, Terri Moroneyrasmussen, John P MooreAbstract:An effective Vaginal Microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among Microbicide candidates in clinical development is Maraviroc (MVC), a small-molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected individuals, but its ability to prevent transmission is untested. We have now evaluated MVC as a Vaginal Microbicide with use of a stringent model that involves challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/mL). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (half life of approximately 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated postinfection viremia. These findings validate MVC development as a Vaginal Microbicide for women and should guide clinical programs.
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tropism independent protection of macaques against Vaginal transmission of three shivs by the hiv 1 fusion inhibitor t 1249
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Donna K Davison, Morgan L Singletary, Linda C Green, Michael L Greenberg, John P MooreAbstract:We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a Vaginal Microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of ≈40–130 μM, whereas complete protection was observed at 0.1–2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 μM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC50 values typically clustered in a 10-fold range ≈10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination Microbicide to prevent the sexual transmission of diverse HIV-1 variants.
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protection of macaques from Vaginal shiv challenge by Vaginally delivered inhibitors of virus cell fusion
Nature, 2005Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Susan M Schader, Qinxue Hu, Min Lu, Preston A Marx, Jason Dufour, Richard J Colonno, Robin J ShattockAbstract:A trial of three inhibitors of HIV-1 entry into target cells, administered Vaginally in macaque monkeys prior to intercourse, shows that they can protect against infection by a simian-human immunodeficiency virus. One molecule, the antiviral CMPD 167, is particularly potent, providing protection when applied 6 hours before challenge. The macaque model is a proven test of AIDS prevention strategies, so these findings bode well for the prospects of similar compounds in humans. Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available1. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a Vaginal Microbicide: the application of inhibitory compounds before intercourse2. Here, we have evaluated the Microbicide concept using the rhesus macaque ‘high dose’ Vaginal transmission model with a CCR5-receptor-using simian–human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus–cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors3,4, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association5, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion6. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.
Quarraisha Abdool Karim - One of the best experts on this subject based on the ideXlab platform.
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Safety of coitally administered tenofovir 1% gel, a Vaginal Microbicide, in chronic hepatitis B virus carriers: results from the CAPRISA 004 trial.
Antiviral research, 2013Co-Authors: Cheryl Baxter, Quarraisha Abdool Karim, Nonhlanhla Yende-zuma, Phindile Tshabalala, Salim S. Abdool KarimAbstract:Abstract Tenofovir disoproxil fumarate, a licensed oral treatment for both HIV and Hepatitis B virus (HBV) infections, has been associated with severe rebound hepatic flares when treatment is interrupted. A gel formulation of tenofovir is currently being assessed as a Microbicide against HIV. If licensed, it is possible that tenofovir gel could be used either intentionally or unintentionally by HBV carriers. The purpose of this study was to establish the safety of tenofovir gel use in this patient group participating in the CAPRISA 004 tenofovir gel trial. HBV infection status was assessed at enrolment and study exit. Liver function testing was performed at enrolment, study months 3, 12, 24, study exit, and 2 months after exiting the study. At enrolment, 34 women were identified as being HBV carriers and 22 women acquired HBV infections during follow-up; 14 and 8 in the tenofovir and placebo gel arms, respectively ( p = 0.21). Intermittent tenofovir gel use did not cause an increase in hepatic flares or impact on viral load suppression in women with HBV infection. There were 2 hepatic flares in each gel arm during follow-up and none 2 months after cessation of gel at study exit. The mean HBV DNA levels were similar at enrolment and exit in both study arms. Tenofovir gel, when used intermittently, was safe to use in women with HBV infection.
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Safety of tenofovir gel, a Vaginal Microbicide, in South African women: results of the CAPRISA 004 Trial.
Antiviral therapy, 2012Co-Authors: David C. Sokal, Quarraisha Abdool Karim, Janet A. Frohlich, Cheryl Baxter, Sengeziwe Sibeko, Leila E Mansoor, Ayesha B. M. Kharsany, Anna Christina. Grobler, Nonhlanhla. Yende Zuma, Nomsa. MiyaAbstract:BACKGROUND Tenofovir gel, used Vaginally before and after coitus, reduced women's acquisition of HIV by 39%. This is a safety assessment of tenofovir gel, including renal, bone, gastrointestinal, genital and haematological parameters. METHODS In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, a double-blind, randomized placebo-controlled trial, 445 of the 889 eligibly enrolled women were assigned to tenofovir gel. All participants were advised to use the gel Vaginally only, with one dose of gel within 12 h before and a second dose as soon as possible after sex, with no more than two doses in 24 h. Clinical and laboratory safety data were collected at monthly and quarterly visits, respectively. Genital assessments were undertaken at enrolment and quarterly thereafter, or as indicated. RESULTS Women assigned to tenofovir gel were exposed to an average monthly Vaginal dose of 240 mg of tenofovir (six applications). In total, six women, three in each group, had mild creatinine elevations, all of which occurred in July/August 2008. The incidence of anaemia was 3.5 and 3.8 per 100 women-years in tenofovir and placebo groups, respectively (P=0.80). Of the six women (four tenofovir and two placebo) experiencing bone fractures, none were associated with abnormal phosphate or calcium values. The proportion of women with diarrhoea was higher in the tenofovir gel group (17% versus 11%; P=0.026). There was no significant increase of any genital adverse event in the tenofovir group. CONCLUSIONS No significant renal, haematological, genital or bone effects were associated with the use of tenofovir gel. Aside from a puzzling increase in diarrhoea, tenofovir gel has an excellent safety profile.
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Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir Microbicide gel.
The Journal of infectious diseases, 2012Co-Authors: Vivek Naranbhai, Quarraisha Abdool Karim, Sengeziwe Sibeko, Salim S. Abdool Karim, Natasha Samsunder, Marcus Altfeld, Raveshni Durgiah, William H. CarrAbstract:The antiretroviral agent, tenofovir, formulated as a Vaginal Microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral Microbicides.
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Preservation HIV-1-specific IFNγ+ CD4+ T-cell responses in breakthrough infections after exposure to tenofovir gel in the CAPRISA 004 Microbicide trial.
Journal of acquired immune deficiency syndromes (1999), 2012Co-Authors: Marianne W. Mureithi, Quarraisha Abdool Karim, Sengeziwe Sibeko, Salim S. Abdool Karim, Lise. Werner, Vivek Naranbhai, Danielle Poole, Shabashini Reddy, Nompumelelo Mkhwanazi, Thumbi NdungʼuAbstract:The Centre for the AIDS Program of Research in South Africa 004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a Vaginal Microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing Microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of Microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 although using tenofovir gel showed significantly higher (P = 0.01) Gag-specific IFNγ+ CD4+ T-cell responses. The use of tenofovir-containing gel around the time of infection can modulate HIV-1 immunity, and these immunological changes need to be considered in future trials combining vaccines and Microbicides.
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Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial
Trials, 2011Co-Authors: Quarraisha Abdool Karim, Janet A. Frohlich, Cheryl Baxter, Koleka P. Mlisana, Leila E Mansoor, Ayesha B. M. Kharsany, Silvia Maarschalk, Nonhlanhla Yende, Natasha Arulappan, Anneke GroblerAbstract:Background: Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose: This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the Vaginal Microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods: This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results: HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001). Conclusion: The populations selected provide suitable diverse target groups for HIV prevention intervention studies. Trial registration: ClinicalTrials.gov: NCT 00441298 Background
David F Katz - One of the best experts on this subject based on the ideXlab platform.
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sensitivity analysis of a pharmacokinetic model of Vaginal anti hiv Microbicide drug delivery
Journal of Pharmaceutical Sciences, 2016Co-Authors: Angela M Jarrett, Yajing Gao, Yousuff M Hussaini, N G Cogan, David F KatzAbstract:Uncertainties in parameter values in Microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the Vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient Vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by Vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of Vaginal Microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization.
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analysis of Vaginal Microbicide film hydration kinetics by quantitative imaging refractometry
PLOS ONE, 2014Co-Authors: Matthew T Rinehart, Sheila Grab, Lisa C. Rohan, David F KatzAbstract:We have developed a quantitative imaging refractometry technique, based on holographic phase microscopy, as a tool for investigating microscopic structural changes in water-soluble polymeric materials. Here we apply the approach to analyze the structural degradation of Vaginal topical Microbicide films due to water uptake. We implemented transmission imaging of 1-mm diameter film samples loaded into a flow chamber with a 1.5×2 mm field of view. After water was flooded into the chamber, interference images were captured and analyzed to obtain high resolution maps of the local refractive index and subsequently the volume fraction and mass density of film material at each spatial location. Here, we compare the hydration dynamics of a panel of films with varying thicknesses and polymer compositions, demonstrating that quantitative imaging refractometry can be an effective tool for evaluating and characterizing the performance of candidate Microbicide film designs for anti-HIV drug delivery.
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design of a semisolid Vaginal Microbicide gel by relating composition to properties and performance
Pharmaceutical Research, 2010Co-Authors: Alamelu Mahalingam, David F Katz, Meredith R. Clark, Judit Fabian, David R. Friend, Eric Smith, Festo Damian, Jennifer J Peters, Patrick F. KiserAbstract:Purpose Develop a preclinical in vitro algorithm enabling de novo design of semisolid Vaginal drug delivery gels, by using biomechanical modeling of gel spreading in the Vaginal canal and empirically relating gel composition to mechanical properties and predicted performance.
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design of a semisolid Vaginal Microbicide gel by relating composition to properties and performance
Pharmaceutical Research, 2010Co-Authors: Alamelu Mahalingam, David F Katz, Meredith R. Clark, Judit Fabian, David R. Friend, Eric Smith, Festo Damian, Jennifer J Peters, Patrick F. KiserAbstract:Develop a preclinical in vitro algorithm enabling de novo design of semisolid Vaginal drug delivery gels, by using biomechanical modeling of gel spreading in the Vaginal canal and empirically relating gel composition to mechanical properties and predicted performance. Gel performance was defined through a multivariate objective function constructed from gels’ mechanical properties and selected performance criteria for gel spreading within the Vaginal canal. Mixture design of experiment was used to establish a semi-empirical relationship linking composition-property and property-performance relationships for gels with varying concentrations of hydroxyethylcellulose and Carbopol 974P. This permits definition of a local optimum for gel composition and volume of administration, within a defined gel composition space. Rheological behavior and, consequently, the value of the objective function varied broadly with composition. The algorithm indicated a 3.0 wt% HEC gel as the near optimal composition for a 3.5 mL applied volume for gels designed to spread throughout the vagina. The algorithm introduced herein is a novel tool that facilitates an understanding of the composition-property-performance relationship for Vaginal semisolid drug delivery gels. This approach has promise as a scientific methodology for evaluation and optimization of Vaginal gels prior to in vivo investigations.
Per Johan Klasse - One of the best experts on this subject based on the ideXlab platform.
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non aqueous silicone elastomer gels as a Vaginal Microbicide delivery system for the hiv 1 entry inhibitor maraviroc
Journal of Controlled Release, 2011Co-Authors: Claire J Forbes, Deborah Lowry, Leslie Geer, Ronald S Veazey, Per Johan Klasse, Mark Mitchnick, Laurie Goldman, Laura A Doyle, Brendan C O MuldoonAbstract:Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in Vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for Vaginal HIV Microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for Vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose Vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in Vaginal fluid, Vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent Vaginal HIV Microbicides.
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protection of rhesus macaques from Vaginal infection by Vaginally delivered maraviroc an inhibitor of hiv 1 entry via the ccr5 co receptor
The Journal of Infectious Diseases, 2010Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Linda C Green, Jason Dufour, Terri Moroneyrasmussen, John P MooreAbstract:An effective Vaginal Microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among Microbicide candidates in clinical development is Maraviroc (MVC), a small molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected people, but its ability to prevent transmission is untested. We have now evaluated MVC as a Vaginal Microbicide, using a stringent model involving challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/ml). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (T1/2 ~ 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated post-infection viremia. These findings validate MVC development as a Vaginal Microbicide for women, and should guide clinical programs.
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protection of rhesus macaques from Vaginal infection by Vaginally delivered maraviroc an inhibitor of hiv 1 entry via the ccr5 co receptor
The Journal of Infectious Diseases, 2010Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Linda C Green, Jason Dufour, Terri Moroneyrasmussen, John P MooreAbstract:An effective Vaginal Microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among Microbicide candidates in clinical development is Maraviroc (MVC), a small-molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected individuals, but its ability to prevent transmission is untested. We have now evaluated MVC as a Vaginal Microbicide with use of a stringent model that involves challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/mL). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (half life of approximately 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated postinfection viremia. These findings validate MVC development as a Vaginal Microbicide for women and should guide clinical programs.
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tropism independent protection of macaques against Vaginal transmission of three shivs by the hiv 1 fusion inhibitor t 1249
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Donna K Davison, Morgan L Singletary, Linda C Green, Michael L Greenberg, John P MooreAbstract:We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a Vaginal Microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of ≈40–130 μM, whereas complete protection was observed at 0.1–2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 μM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC50 values typically clustered in a 10-fold range ≈10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination Microbicide to prevent the sexual transmission of diverse HIV-1 variants.
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protection of macaques from Vaginal shiv challenge by Vaginally delivered inhibitors of virus cell fusion
Nature, 2005Co-Authors: Ronald S Veazey, Per Johan Klasse, Thomas A Ketas, Susan M Schader, Qinxue Hu, Min Lu, Preston A Marx, Jason Dufour, Richard J Colonno, Robin J ShattockAbstract:A trial of three inhibitors of HIV-1 entry into target cells, administered Vaginally in macaque monkeys prior to intercourse, shows that they can protect against infection by a simian-human immunodeficiency virus. One molecule, the antiviral CMPD 167, is particularly potent, providing protection when applied 6 hours before challenge. The macaque model is a proven test of AIDS prevention strategies, so these findings bode well for the prospects of similar compounds in humans. Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available1. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a Vaginal Microbicide: the application of inhibitory compounds before intercourse2. Here, we have evaluated the Microbicide concept using the rhesus macaque ‘high dose’ Vaginal transmission model with a CCR5-receptor-using simian–human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus–cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors3,4, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association5, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion6. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.
