scholarly journals Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

2007 ◽  
Vol 51 (7) ◽  
pp. 2424-2429 ◽  
Author(s):  
Ghazia Asif ◽  
Selwyn J. Hurwitz ◽  
Aleksandr Obikhod ◽  
David Delinsky ◽  
Janarthanan Narayanasamy ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Pharmacokinetic Profile ◽  
Preclinical Development ◽  
Immunodeficiency Virus ◽  
Oral Pharmacokinetics ◽  
Average Serum ◽  
Median Effective Concentration ◽  
Further Development

ABSTRACT β-d-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h−1; fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

scholarly journals In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5′-(p-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice

2002 ◽  
Vol 46 (11) ◽  
pp. 3428-3436 ◽  
Author(s):  
Fatih M. Uckun ◽  
Sanjive Qazi ◽  
Sharon Pendergrass ◽  
Elizabeth Lisowski ◽  
Barbara Waurzyniak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Peripheral Blood ◽  
Pharmacokinetic Profile ◽  
Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Dose Levels ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT 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.

scholarly journals Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Didehydro-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys

1999 ◽  
Vol 43 (2) ◽  
pp. 381-384 ◽  
Author(s):  
Li Ma ◽  
Selwyn J. Hurwitz ◽  
Junxing Shi ◽  
Jeffrey J. McAtee ◽  
Dennis C. Liotta ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Rhesus Monkeys ◽  
Antiviral Agent ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Administration Route ◽  
Two Compartment Model ◽  
Immunodeficiency Virus ◽  
Median Effective Concentration

ABSTRACT The values of the pharmacokinetic parameters of the nucleoside antiretroviral agent β-d-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC) in rhesus monkeys were determined with a two-compartment model after the administration of a single dose. The average values for the terminal half-life, renal clearance, and total systemic clearance for the intravenous administration route were 3.6 h and 0.31 and 0.43 liter · kg−1 · h−1, respectively. The oral bioavailability of D-D4FC averaged 41%. For the intravenous administration route, 76% of the compound was recovered intact in the urine within 8 h, indicating that D-D4FC was eliminated mainly by renal excretion. D-D4FC was detected in the cerebrospinal fluid (CSF) at similar concentrations after administration by both the intravenous and oral routes. D-D4FC levels in plasma and CSF were higher than the median effective concentration for human immunodeficiency virus type 1 in vitro.

scholarly journals In Vitro Anti-Human Immunodeficiency Virus Activities ofZ- and E-Methylenecyclopropane Nucleoside Analogues and Their Phosphoro-l-Alaninate Diesters

1999 ◽  
Vol 43 (6) ◽  
pp. 1487-1490 ◽  
Author(s):  
Hiroyuki Uchida ◽  
Eiichi N. Kodama ◽  
Kazuhisa Yoshimura ◽  
Yosuke Maeda ◽  
Pope Kosalaraksa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nucleoside Analogues ◽  
Infectious Clones ◽  
Immunodeficiency Virus ◽  
Further Development ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Methyl Phenyl

ABSTRACT Nucleoside analogues with a Z- or anE-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-l-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 μM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

scholarly journals Polyethylene Glycol 40-Modified Peptide with High Therapeutic Efficacy in Simian-Human Immunodeficiency Virus-Acutely Infected Rhesus Monkeys

2020 ◽  
Vol 94 (14) ◽  
Author(s):  
Mingli Li ◽  
Shuihong Cheng ◽  
Yibo Ding ◽  
Chen Wang ◽  
Yong Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Half Life ◽  
Rhesus Monkeys ◽  
Glycosylation Site ◽  
Control Treatment ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Anti-human immunodeficiency virus type 1 (anti-HIV-1) fusion peptides have been studied for nearly 2 decades, but few candidates have found useful clinical applications. One factor underlying the failure of such agents to reach the clinic is their poor pharmacokinetic properties, and many efforts have been made to overcome this problem. In this study, we modified C34, a peptide inhibitor of HIV-1 fusion, at its conserved glycosylation site using polyethylene glycols (PEGs) of different molecular weights. PEG40-NC, a conjugate of C34 and branched PEG 40 kDa (PEG40), which has been previously shown to improve the pharmacokinetic profiles of proteins, showed a significantly extended half-life (t1/2; 10.39 h in rats), which compensated for decreased in vitro activity (50% effective concentration [EC50] of 18.51 nM). PEG40-NC also showed a mechanism of action similar to that of C34. PEG40-NC monotherapy in acutely simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys significantly suppressed viral load compared with a control treatment. Efficacy was linked to the extended half-life and lymphatic exposure conferred by attached PEG40. These results highlight the potential of further clinical investigations of PEG40-NC in combination with antiretroviral therapy or other anti-HIV agents. IMPORTANCE Poor pharmacokinetics have severely hindered the clinical use of anti-HIV peptides. Different small molecules, such as lipid, cholesterol, and small PEG, were designed to modify peptides to improve their pharmacokinetics. In this study, we incorporated large branched PEG to anti-HIV peptide and obtained a conjugate with extended half-life and improved in vivo efficacy. The strategy we developed in this study can also be applicable for the development of other peptide candidates.

DEVELOPMENT OF APPROACHES FOR DETECTION OF GENOME-INTEGRATED PROVIRAL DNA OF THE HUMAN IMMUNODEFICIENCY VIRUS (HIV-1) IN ULTRA LOW CONCENTRATIONS USING THE CRISPR/CAS SYSTEM

2020 ◽  
Author(s):  
M.A. Tyumentseva ◽  
◽  
A.I. Tyumentsev ◽  
V.G. Akimkin ◽  
◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Health Monitoring ◽  
Biological Samples ◽  
Proviral Dna ◽  
Guide Rnas ◽  
Ribonucleoprotein Complexes ◽  
Low Concentrations ◽  
Immunodeficiency Virus ◽  
Hiv 1

For the effective functioning of supervisory and health monitoring services, it is necessary to introduce modern molecular technologies into their practice. Therefore, the task of developing new effective methods for detecting pathogen, for example HIV, based on CRISPR/CAS genome editing systems, remains urgent. In the present work, guide RNAs and specific oligonucleotides were developed for preliminary amplification of highly conserved regions of the HIV-1 genome. The developed guide RNAs make it possible to detect single copies of HIV-1 proviral DNA in vitro as part of CRISPR/CAS ribonucleoprotein complexes in biological samples after preliminary amplification.

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