Pilot clinical trial of the combination of hydroxyurea and didanosine in HIV-1 infected individuals

Biron, F.; Lucht, F.; Peyramond, D.; Frésard, A.; Vallet, Thierry; Nugier, F.; Grange, J.; Malley, Serge; Hamedi-Sangsari, Farid; Vila, Jorge

doi:10.1016/0166-3542(95)00931-0

Cited by 27 publications

(11 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The narrow therapeutic index of these drugs combined with the high concen- jpet.aspetjournals.org trations required to inhibit HIV suggest that chronic dosing with these agents is unlikely to prove effective or successful against HIV-1 ( Martin et al, 1987). This seems to be confirmed by a study reporting a 1.3 log drop in viral load in treatment naive patients receiving didanosine and hydroxyurea plus hydroxyCQ for 12 weeks, less than the median 1.7 log drop seen with didanosine and hydroxyurea alone (Biron et al, 1996).…”

Section: Discussionsupporting

confidence: 58%

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Owen

Janneh²,

Hartkoorn³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells.Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a Ͼ3-fold and Ͼ2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo.

show abstract

Section: Discussionsupporting

confidence: 58%

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Owen

Janneh²,

Hartkoorn³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…HU, a well-documented drug used in HIV-1 treatment, is known to alter intracellular dNTP pools by inhibiting ribonucleotide reductase, resulting in a depletion of all dNTPs (3,8,9,11,21,31). To determine whether treatment of cells with HU would increase the mutant frequency of HIV-1, the effects of HU postinfection treatment of infected target cells were determined.…”

Section: Resultsmentioning

confidence: 99%

Combination of Drugs and Drug-Resistant Reverse Transcriptase Results in a Multiplicative Increase of Human Immunodeficiency Virus Type 1 Mutant Frequencies

Mansky

Pearl

Gajary

2002

J Virol

View full text Add to dashboard Cite

Replication of drug-resistant human immunodeficiency virus type 1 (HIV-1) in the presence of drug can lead to the failure of antiretroviral drug treatment. Drug failure is associated with the accumulation of drug resistance mutations. Previous studies have shown that 3-azido-3-deoxythymidine (AZT), (؊)2,3-dideoxy-3-thiacytidine (3TC), and AZT-resistant HIV-1 reverse transcriptase (RT) can increase the virus in vivo mutation rate. In this study, the combined effects of drug-resistant RT and antiretroviral drugs on the HIV-1 mutant frequency were determined. In most cases, a multiplicative effect was observed with AZT-resistant or AZT/3TC dually resistant RT and several drugs (i.e., AZT, 3TC, hydroxyurea, and thymidine) and led to increases in the odds of recovering virus mutants to over 20 times that of the HIV-1 mutant frequency in the absence of drug or drug-resistance mutations. This observation indicates that HIV-1 can mutate at a significantly higher rate when drug-resistant virus replicates in the presence of drug. These increased mutant frequencies could have important implications for HIV-1 population dynamics and drug therapy regimens.

show abstract

“…During the first month of treatment the viral load decreases sharply by 1-2 log 10 copies/ml, and several patients had undetectable virus levels after 3 months [5], 4 months [6], or 6 months [7] of treatment. In another study, 1000 mg daily HU treatment added to chronic ddI therapy decreased viral load by approximately 1 log 10 copies/ml and decreased CD4 cell count by 25% [8].…”

Section: Clinical Trialsmentioning

confidence: 99%

“…It is a routinely prescribed cytostatic drug used in the treatment of leukaemia [18] and to kill dividing T cells [19,20]. Although the HU dosage employed in ddI-HU trials should be low enough to avoid haematological side-effects [18], most (but not all [5]) of the HU trials in HIV patients report suppression [8,12,13] or poor recovery [1,3,6] of peripheral blood CD4 cell counts. This negative impact on peripheral blood CD4 cell counts is an important difference between the ddI-HU combination and other forms of antiretroviral therapy.…”

Section: Efficacy Of Ddi-humentioning

confidence: 99%

Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine

Boer

Boucher

Perelson

1998

AIDS

View full text Add to dashboard Cite

Pilot clinical trial of the combination of hydroxyurea and didanosine in HIV-1 infected individuals

Cited by 27 publications

References 4 publications

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Combination of Drugs and Drug-Resistant Reverse Transcriptase Results in a Multiplicative Increase of Human Immunodeficiency Virus Type 1 Mutant Frequencies

Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine

Contact Info

Product

Resources

About