Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis--and, consequently, DNA synthesis--by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus-type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages, as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS). The antiviral effect was achieved at nontoxic doses of hydroxyurea, lower than those currently used in human therapy. Combination of hydroxyurea with the nucleoside analog didanosine (2',3'-dideoxyinosine, or ddl) generated a synergistic inhibitory effect without increasing toxicity. In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possible candidate for AIDS therapy.
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PMID:Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. 797 34

Human immunodeficiency virus type 1 (HIV-1) replication is shown to be sensitive to the intracellular concentration of deoxynucleoside triphosphate substrates. Addition of thymidine to established cell lines resulted in a dramatic reduction of virus production. The effect could be substantially alleviated by addition of deoxycytidine, which, alone, enhanced viral titers by a factor of 2 to 3. Hydroxyurea treatment abolished HIV-1 replication in peripheral blood mononuclear cells and could be reversed by deoxyadenosine. These data show that HIV-1 replication occurs under suboptimal DNA precursor conditions.
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PMID:Restriction and enhancement of human immunodeficiency virus type 1 replication by modulation of intracellular deoxynucleoside triphosphate pools. 825 68

In a prospective, randomized, controlled, three-arm study, the pharmacokinetics of hydroxyurea administered as an antiviral agent in patients infected with human immunodeficiency virus type 1 (HIV-1) were evaluated. The three arms of the study consisted of azidothymidine (AZT) 250 mg twice daily, hydroxyurea 500 mg twice daily, or a combination of the two. Nine patients receiving hydroxyurea in monotherapy (n = 4) or in combination with AZT (n = 5) agreed to undergo multiple venipunctures for pharmacokinetic analysis. Sample collection was performed at steady-state conditions and serum concentration-time data for hydroxyurea were fitted using a one-compartment model. Mean (+/- standard deviation) peak concentration (Cmax) was 0.135 +/- 0.06 mmol/L and mean trough level (Cmin) was 0.0085 +/- 0.003 mmol/L. Mean concentration at steady state was 0.045 +/- 0.006 mmol/L. Apparent clearance (Cl/F) was 0.18 +/- 0.005 L/hr/kg, and half-life (t1/2) was 2.5 +/- 0.5 hours. Hydroxyurea given orally to patients infected with HIV-1 was well absorbed from the gastrointestinal tract, with a tmax of 0.85 to 0.96 hours after ingestion. Serum levels of hydroxyurea ranged from 0.01 to 0.13 mmol/L. These values are similar to the concentrations (between 0.01 and 0.1 mmol/L) demonstrated to inhibit HIV-1 in vitro. Our data show that hydroxyurea given at a dosage of 500 mg twice daily is sufficient to yield serum concentrations potentially useful for in vivo inhibition of HIV-1.
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PMID:Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type I. 885 87

Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection. Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms. Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics. Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination. The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies.
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PMID:Pharmacokinetics and pharmacodynamics of hydroxyurea. 959 19

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.
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PMID:Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters. 1051 48

Hydroxyurea has been a compound of scientific and clinical interest for over 100 years. A small molecule with many biological properties, hydroxyurea is used in a number of myeloproliferative, neoplastic, and non-hematological diseases. Recently, the agent has been investigated for use in the treatment of Human Immunodeficiency Virus (HIV) disease. Hydroxyurea is associated with dose related bone marrow suppression, crosses the placenta, and is excreted in breast milk. Toxicity is often managed through dose titration. Although adequate attention must be paid to the drug's use in pregnancy and during breast feeding, hydroxyurea's ease of administration, multiplicity of clinical effects, and low cost ensure the drug a place in therapy for years to come.
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PMID:Hydroxyurea: an overview. 1056 Jul 51

Virus life cycles depend on cellular factors. Therefore, targeting cellular in combination with viral enzymes could be an effective control in virus replication. In contrast to viral proteins, cellular proteins are not prone to mutations; therefore, viral escape is not expected from drugs inhibiting cellular factors. Hydroxyurea inhibits the cellular enzyme ribonucleotide reductase, thus reducing DNA synthesis. Furthermore, this drug potentiates the activity of nucleoside analogues, inhibits the escape of A-analogue resistant mutants, and increases the phosphorylation of T-analogues. Besides its antiviral activity, hydroxyurea effects the immune system by decreasing immune activation, inhibiting the expansion of CD8 cells and the depletion of CD4 cells. Hydroxyurea has been used in medicine for 40 years, is well tolerated, and it is the least expensive available anti-HIV-1 drug. These characteristics make hydroxyurea a primary candidate for use in combination therapies for the treatment of HIV-1 infection.
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PMID:Mechanisms of human immunodeficiency virus type 1 inhibition by hydroxyurea. 1056 Jul 52

Hydroxyurea has been used in numerous clinical trials for the treatment of HIV-1 infection, almost always in combination with didanosine with or without other antiretrovirals. Due to its inhibition of DNA synthesis, the main side effect of hydroxyurea is myelosuppression. When administered at the dosage of 1000 mg/day in asymptomatic, moderately-immunosuppressed HIV-1 infected patients, its tolerability profile appears to be quite favourable, with rare, reversible episodes of peripheral blood cytopenia that seldom require therapy discontinuation. Higher dosages of hydroxyurea and its use in advanced, heavily-pretreated patients may increase the likelihood of more severe side effects or newer toxicities developing. So far hydroxyurea-containing long therapy courses, up to 3 years, have not elicited any significant toxicity and appear to be safe as in onco-hematologic patients.
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PMID:Hydroxyurea in the treatment of HIV-1 infection: toxicity and side effects. 1056 Jul 53

Emerging drug resistance and side effects complicate the clinical care of HIV-infected patients. Accumulating data from basic science and clinical studies suggest that hydroxyurea-based regimens are effective treatment options for patients at various stages of disease. Review of the clinical studies confirms that hydroxyurea-based regimens produce potent and sustained viral suppression, with an unexpected high degree of tolerability, in patients with primary and chronic HIV infection. Hydroxyurea, the first antiretroviral drug targeting a cellular factor, represents a novel and inexpensive approach to combination therapy for HIV infection. Hydroxyurea is not prone to resistance while impeding resistance to reverse transcriptase inhibitors. The cytostatic properties of hydroxyurea may contribute to its immunomodulatory effects while reducing activated HIV target cells. These characteristics make hydroxyurea a good candidate for long-term treatment of HIV infected individuals. Future studies including those that evaluate optimal dosing a long-term use will continue to define the role for this agent in the treatment of HIV infection.
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PMID:Clinical use of hydroxyurea in HIV-1 infected patients. 1056 Jul 54

Hydroxyurea inhibits cellular ribonucleotide reductase, resulting in decreased pools of dNTPs and thus inhibition of DNA synthesis. Studies in vitro have shown that hydroxyurea reduces dNTP pools in cells infected with human immunodeficiency virus type 1 (HIV-1), inhibiting HIV-1 DNA synthesis in infected quiescent and activated primary human lymphocytes and macrophages. Hydroxyurea also potentiates the activity of nucleoside reverse transcriptase inhibitors (NRTIs): the activated triphosphate forms of NRTIs compete with naturally occurring dNTPs for incorporation into nascent viral DNA during reverse transcription. A synergistic effect is observed between hydroxyurea and didanosine (2',3'-dideoxyinosine; DDI). This combination exerts persistent suppression of HIV-1 replication without evidence of viral rebound for over 1 year in HIV-1-infected patients. Didanosine-resistant HIV-1 mutants retain sensitivity to didanosine in the presence of hydroxyurea. The incorporation of didanosine triphosphate by resistant reverse transcriptase is increased in the context of the hydroxyurea-induced depletion of dATP. Although hydroxyurea has a reduced effect on dNTPs competing with the triphosphate forms of pyrimidine NRTIs, it appears to augment the anti-HIV-1 activity of these agents by increasing their intracellular phosphorylation; this may be of particular interest for salvage strategies given recent data indicating disruption of NRTI phosphorylation with specific NRTI treatment regimens. Finally, by exerting a cytostatic effect on CD4 and CD8 T lymphocytes, hydroxyurea may (i) reduce HIV-1 replication by decreasing CD4 T cell proliferation; and (ii) prevent the exhaustion of CD8 T cell populations that may occur as a result of excessive activation in the context of HIV-1 infection.
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PMID:Hydroxyurea: mechanisms of HIV-1 inhibition. 1072 6


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