stampidine and HIV-Infections

Pre-exposure prophylaxis (PrEP) is an evolving new approach to prevention of sexually transmitted HIV-1 that employs antiretroviral (ARV) agents prior to potential HIV-1 exposure in an attempt to reduce the likelihood of HIV-1 infection postexposure. The identification of new ARV agents with potent activity against multidrug-resistant HIV remains an unmet and urgent challenge in the field of PrEP.. This article reviews the preclinical and early clinical activity and safety profile of stampidine, a novel antiretroviral (ARV) drug candidate that exhibits remarkable subnanomolar to low nanomolar in vitro antiretroviral potency against genotypically and phenotypically nucleoside reverse transcriptase inhibitor (NRTI)-resistant primary clinical HIV isolates, non-nucleoside RT-resistant HIV-1 isolates. Stampidine has a favorable pharmacokinetic profile in mice, rats, dogs and cats with 25 or 50 mg/kg tolerable dose levels yielding micromolar plasma concentrations that are 1000-fold higher than its in vitro IC(50) value against HIV. Stampidine has a favorable, safety profile in mice, rats, dogs and cats and it showed significant in vivo ARV activity in HIV-infected Hu-PBL-SCID mice as well as FIV-infected domestic cats. Furthermore, it did not cause any maternal toxicity, developmental toxicity or teratogenicity in rabbits treated at 10 - 40 mg/kg/day dose levels. In a recently completed first-in-human Phase I clinical trial, stampidine did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg.. The favorable safety and activity profile of stampidine warrants its further development as a promising next-generation PrEP candidate to prevent the sexual transmission of HIV-1. The discovery of stampidine as a potent antiretroviral agent represents a significant step forward in the development of effective therapeutic as well as preventive strategies against HIV/AIDS.

Topics: Animals; Anti-Retroviral Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Dideoxynucleotides; Drug Evaluation, Preclinical; HIV Infections; HIV-1; Humans; Randomized Controlled Trials as Topic; Stavudine; Thymidine Monophosphate

The most common mode of acquiring HIV-1 is via sexual transmission across the genital mucosa. Topical microbicides are a promising prevention strategy for the protection against HIV infection and may ultimately have an impact on the global AIDS pandemic. The effectiveness of a microbicide to prevent HIV-1 transmission will depend on the evolutionary and genital transmission dynamics of the viral subtypes, and sexual behavioral characteristics. Contemporary antiretroviral therapy has led to virological failure as a result of HIV-1 reverse transcriptase gene mutations. The transmission of these multidrug-resistant HIV-1 variants, and the superinfection with the same or distinct HIV-1 subtypes and recombination is a formidable hindrance inherent to global microbicide development. Consequently, mechanism-based microbicides targeting both the cell-free and cell-associated HIV-1 variants and subtypes can be expected to have superior clinical efficacy and safety profiles compared with polymeric anionic microbicides. This review describes the discovery of potent anti-HIV-1 agents against multidrug-resistant and multitropic HIV-1 variants with implications for global microbicide development. Stampidine and thiourea non-nucleoside reverse transcriptase inhibitors (NNRTIs) have demonstrated highly potent activity against clinically relevant multidrug-resistant and recombinant HIV-1 isolates spanning different subtypes across several continents. Extensive preclinical studies have shown that stampidine and a candidate thiourea NNRTI (HI-443) have clinical potential as a safe combination microbicide to inhibit, prevent or treat mucosal HIV-1 infections.

Topics: Animals; Anti-HIV Agents; Anti-Infective Agents; Dideoxynucleotides; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Pyridines; Stavudine; Thiourea; Thymidine Monophosphate

Topics: Animals; Anti-HIV Agents; Dideoxynucleotides; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine; Thymidine Monophosphate

Stavudine (STV, d4T, 2',3'-didehydro-3'-deoxythymidine, CAS 3056-17-5) is a standard anti-HIV drug. Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) is a novel aryl phosphate derivative of stavudine with more potent anti-HIV activity and more favorable pharmacodynamic features. The remarkable potency of stampidine against clinical HIV-1 isolates with NRTI- or NNRTI-resistance (NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor) warrants the further development of this new anti-HIV agent.

Topics: Anti-HIV Agents; Chemistry, Pharmaceutical; Dideoxynucleotides; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Liver; Reverse Transcriptase Inhibitors; Stavudine; Thymidine Monophosphate

To investigate the in vitro and in vivo mucosal safety of a nonnucleoside reverse transcriptase (RT) inhibitor (PHI-443) and a nucleoside analogue RT inhibitor (stampidine)-based anti-HIV microbicide either alone or in combination.. In vitro and in vivo studies using three-dimensional vaginal epithelia integrating Langerhans cells and 16 New Zealand White rabbits, respectively.. Research laboratory.. Rabbits in groups of four were exposed intravaginally to a gel with and without 1% PHI-443, 1% stampidine, or 1% PHI-443 plus 1% stampidine for 14 days. Cytokine/chemokine release by three-dimensional co-cultures in the presence and absence of PHI-443 or stampidine.. Histologic scoring of vaginal tissue for mucosal toxicity at 24 hours after dosing. Simultaneous evaluation of levels of 10 cytokines (granulocyte-macrophage colony-stimulating factor, interleukin-1 alpha, interleukin-13, macrophage inflammatory protein-1 beta, granulocyte colony-stimulating factor, interleukin-18, tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta, and interferon-gamma) and 6 chemokines (epithelial neutrophil-activating peptide-78, interleukin-8, monocyte/macrophage chemoattractant protein-1, macrophage inflammatory protein-3 alpha, interferon-inducible protein-10, and regulated upon activation of normal T-cell expressed and secreted) in culture media by a multiplexed chemiluminescence-based immunoassay.. In the rabbit model, repeated intravaginal administration of PHI-443 plus stampidine via a gel formulation at concentrations nearly 2,000 and 10,000 times higher than their respective in vitro anti-HIV IC(50) values did not result in vaginal irritation. The levels of proinflammatory cytokines/chemokines secreted by multilayered human genital epithelia integrating Langerhans cells were unaffected by prolonged exposure to PHI-443 or stampidine.. The combination of PHI-443 and stampidine was noncytotoxic to vaginal epithelial cells, nonirritating to vaginal mucosa, and did not induce the secretion of proinflammatory cytokines and chemokines by co-cultures of human genital epithelia and Langerhans cells. These attributes are particularly useful for the clinical development of PHI-443 and stampidine as a combination microbicide and as a prophylactic anti-HIV agent to curb genital transmission of HIV-1 by semen.

Topics: Administration, Intravaginal; Animals; Anti-Infective Agents, Local; Dideoxynucleotides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Mucous Membrane; Pyridines; Rabbits; Stavudine; Thiourea; Thymidine Monophosphate; Vagina

The in vitro activity profile of stampidine (CAS 217178-62-6, STAMP) was examined against clinical isolates of HIV-1. In a side-by-side comparison against 10 zidovudine-sensitive clinical HIV-1 isolates, STAMP was 100-fold more potent than stavudine (CAS 3056-17-5) and twice as effective as zidovudine (CAS 30516-87-1). STAMP was also active against phenotypically and/or genotypically NRTI (nucleoside analog inhibitors of reverse transcriptase) -resistant HIV and inhibited the replication of 20 zidovudine-resistant clinical HIV-1 isolates with low nanomolar to subnanomolar IC50 values. Similarly, STAMP inhibited the replication of 9 genotypically NNRTI (non-nucleoside analog inhibitors of reverse transcriptase)-resistant clinical HIV-1 isolates (n = 9) with an average IC50 value of 11.2 +/- 6.5 nmol/L. The remarkable potency of STAMP against clinical HIV-1 isolates with NRTI- or NNRTI-resistance warrants the further development of this promising new antiviral agent.

Topics: Cells, Cultured; Dideoxynucleotides; Drug Resistance, Viral; Genotype; HIV; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Neutrophils; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Thymidine Monophosphate; Viral Plaque Assay; Zidovudine

We have evaluated the clinical potential of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Biotransformation; Chromatography, High Pressure Liquid; Dideoxynucleotides; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Mice, SCID; Stavudine; Thymidine Monophosphate

We report the antiretroviral activity of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate) (stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, against primary clinical human immunodeficiency virus type 1 (HIV-1) isolates. STAMP inhibited each one of nine clinical HIV-1 isolates of non-B envelope subtype and 20 genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor-resistant HIV-1 isolates at subnanomolar to low-nanomolar concentrations.

Topics: Anti-HIV Agents; Dideoxynucleotides; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Nucleosides; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Structure-Activity Relationship; Thymidine; Thymidine Monophosphate; Zidovudine