Stampidine Is a Potent Inhibitor of Zidovudine- and Nucleoside Analog Reverse Transcriptase Inhibitor-Resistant Primary Clinical Human Immunodeficiency Virus Type 1 Isolates with Thymidine Analog Mutations

Uckun, Fatih M.; Pendergrass, Sharon; Venkatachalam, T. K.; Qazi, Sanjive; Richman, Douglas D.

doi:10.1128/aac.46.11.3613-3616.2002

Cited by 43 publications

(46 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relative contributions of intestinal wall metabolism versus liver first-pass metabolism to the observed metabolism of stampidine after oral administration will be the subject of future studies. Notably, stampidine inhibits the replication of primary clinical HIV-1 isolates with subnanomolar to nanomolar IC 50 values (Uckun et al, 2002c). Our results provided direct evidence that plasma concentrations of stampidine Ͼ4 logs higher than its IC 50 value can be achieved in both dogs and cats after its p.o administration at a 100-mg/kg dose level.…”

Section: Involvement Of Liver Enzymes In Metabolism Of Stampidinesupporting

confidence: 53%

“…Importantly, stampidine was active against phenotypically and/or genotypically nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV with low nanomolar to subnanomolar IC 50 values (Uckun et al, 2002c). Similarly, stampidine inhibited the replication of laboratory HIV-1 strains and primary clinical HIV-1 isolates with non-nucleoside reverse transcriptase inhibitors binding site mutations (K103N, V106N, Y179I, Y181C, and Y188L) and/or a phenotypically non-nucleoside reverse transcriptase inhibitor-resistant profile with low nanomolar to subnanomolar IC 50 values.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Metabolism of Stavudine-5′-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats

Chen

Yu²,

Venkatachalam³

et al. 2002

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:We examined the pharmacokinetics and metabolism of the experimental nucleoside reverse transcriptase inhibitor compound stampidine in mice, dogs, and cats. Also reported is the identification of p-bromophenyl sulfate (p-Br-Ph-S) as a major in vivo phase II metabolite of stampidine. Liver cytosol was shown to take part in the hydrolysis of stampidine to form alaninyl-STV-monophosphate (Ala-STV-MP), 2,3-didehydro-3-deoxythymidine (STV), and p-bromophenol; p-bromophenol was further sulfonated by sulfotransferase to form p-Br-Ph-S. Notably, plasma concentrations of stampidine >4 logs higher than its IC 50 value can be achieved in both dogs and cats after its p.o administration at a 100-mg/kg dose level. In dogs as well as cats, stampidine was metabolized to yield micromolar concentrations of the active metabolites ala-STV-MP and STV, which is similar to the metabolism of stampidine in mice. These findings encourage the further development of this new antiviral agent for possible clinical use in human immunodeficiency virusinfected patients.

show abstract

Section: Involvement Of Liver Enzymes In Metabolism Of Stampidinesupporting

confidence: 53%

mentioning

confidence: 99%

Metabolism of Stavudine-5′-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats

Chen

Yu²,

Venkatachalam³

et al. 2002

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

show abstract

“…In preliminary studies, we found that STAMP is substantially more potent than STV at inhibiting HIV-1 replication in thymidine kinase-deficient T cells (23). STAMP was a much more potent anti-HIV agent than STV, and it was active against phenotypically and/or genotypically NRTI-resistant HIV strains for which the 50% inhibitory concentrations (IC 50 s) are in the low nanomolar-to-subnanomolar range (21). Similarly, STAMP inhibited the replication of laboratory HIV-1 strains and primary clinical HIV-1 isolates with non-NRTI (NNRTI) (1) binding site mutations and NNRTI-resistant phenotypes for which the IC 50 s are in the low nanomolar-to-subnanomolar range (21).…”

mentioning

confidence: 99%

“…STAMP was a much more potent anti-HIV agent than STV, and it was active against phenotypically and/or genotypically NRTI-resistant HIV strains for which the 50% inhibitory concentrations (IC 50 s) are in the low nanomolar-to-subnanomolar range (21). Similarly, STAMP inhibited the replication of laboratory HIV-1 strains and primary clinical HIV-1 isolates with non-NRTI (NNRTI) (1) binding site mutations and NNRTI-resistant phenotypes for which the IC 50 s are in the low nanomolar-to-subnanomolar range (21). STAMP was very well tolerated by rodent species, with no detectable acute or subacute toxicity at single intraperitoneal or oral bolus dose levels as high as 500 mg/kg (19).…”

mentioning

confidence: 99%

In Vivo Antiretroviral Activity of Stampidine in Chronically Feline Immunodeficiency Virus-Infected Cats

Uckun

Chen

Samuel

et al. 2003

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Here we report the antiretroviral activity of the experimental nucleoside reverse transcriptase inhibitor (NRTI) compound stampidine in cats chronically infected with feline immunodeficiency virus (FIV). Notably, a single oral bolus dose of 50 or 100 mg of stampidine per kg resulted in a transient >1-log decrease in the FIV load of circulating peripheral blood mononuclear cells in five of six FIV-infected cats and no side effects. A 4-week stampidine treatment course with twice-daily administration of hard gelatin capsules containing 25 to 100 mg of stampidine per kg was also very well tolerated by cats at cumulative dose levels as high as 8.4 g/kg and exhibited a dose-dependent antiretroviral effect. One of three cats treated at the 25-mg/kg dose level, three of three cats treated at the 50-mg/kg dose level, and three of three cats treated at the 100-mg/kg dose level (but none of three control cats treated with placebo pills) showed a therapeutic response, as evidenced by a >1-log reduction in the FIV load in peripheral blood mononuclear cells within 2 weeks. The previously documented in vitro and in vivo antiretroviral activity of stampidine against primary clinical human immunodeficiency virus type 1 isolates with genotypic and/or phenotypic NRTI resistance, together with its favorable animal toxicity profile, pharmacokinetics, and in vivo antiretroviral activity in FIV-infected cats, warrants further development of this promising new NRTI compound.Stavudine (STV) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase (RT), as do zidovudine (ZDV), didanosine, zalcitabine, and lamivudine, which make up the family of nucleoside RT inhibitors (NRTIs). The 5Ј triphosphates of these NRTI, which are generated intracellularly by the action of nucleoside and nucleotide kinases, are potent inhibitors of HIV type 1 (HIV-1) RT (13). The rate-limiting step in the generation of the bioactive STV metabolite STV triphosphate is conversion of STV to its monophosphate derivative (3,13,23). To overcome the dependence of STV on intracellular nucleoside kinase activation, we prepared stampidine (STAMP) HI-113, STV-5Ј-(p-bromophenyl methoxyalaninyl phosphate), a novel aryl phosphate derivative of STV (18,23,25). In preliminary studies, we found that STAMP is substantially more potent than STV at inhibiting HIV-1 replication in thymidine kinase-deficient T cells (23). STAMP was a much more potent anti-HIV agent than STV, and it was active against phenotypically and/or genotypically NRTI-resistant HIV strains for which the 50% inhibitory concentrations (IC 50 s) are in the low nanomolar-to-subnanomolar range (21). Similarly, STAMP inhibited the replication of laboratory HIV-1 strains and primary clinical HIV-1 isolates with non-NRTI (NNRTI) (1) binding site mutations and NNRTI-resistant phenotypes for which the IC 50 s are in the low nanomolar-to-subnanomolar range (21).

show abstract

“…They have broad-spectrum in vivo anti-HIV activity, lack of systemic and mucosal toxicity following repeated oral or intravaginal administration, and display favorable in vivo pharmacokinetic profiles. 11,[14][15][16][17][18][19][20] A novel nonspermicidal gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was formulated incorporating these lipophilic drugs. These pharmaceutical excipients were selected because of their safety, physical characteristics, bioadhesive properties, versatile consistencies, and solubility, as well as improved bioavailability of target drugs.…”

Section: Introductionmentioning

confidence: 99%

Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides

2005

Self Cite

View full text Add to dashboard Cite

The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides. Three representative poorly water-soluble novel broad-spectrum anti-HIV microbicides, PHI-113, PHI-346, and PHI-443, were evaluated in 11 different solvent systems. Based on their solubility profiles, a novel nonspermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized. Conceival enhanced the solubility of these poorly water-soluble (<0.001 mg/mL) anti-HIV drugs by at least 150-to 270-fold. Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively. Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group. Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.

show abstract

Stampidine Is a Potent Inhibitor of Zidovudine- and Nucleoside Analog Reverse Transcriptase Inhibitor-Resistant Primary Clinical Human Immunodeficiency Virus Type 1 Isolates with Thymidine Analog Mutations

Cited by 43 publications

References 15 publications

Metabolism of Stavudine-5′-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats

Metabolism of Stavudine-5′-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats

In Vivo Antiretroviral Activity of Stampidine in Chronically Feline Immunodeficiency Virus-Infected Cats

Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides

Contact Info

Product

Resources

About