Hydroxyurea Enhances the Activities of Didanosine, 9-[2-(Phosphonylmethoxy)ethyl]adenine, and 9-[2-(Phosphonylmethoxy)propyl]adenine against Drug-Susceptible and Drug-Resistant Human Immunodeficiency Virus Isolates

Palmer, Sarah; Shafer, Robert W.; Merigan, Thomas C.

doi:10.1128/aac.43.8.2046

Cited by 29 publications

(8 citation statements)

References 36 publications

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“…The addition of 50µM hydroxyurea decreased the IC 50 of didanosine for both didanosine resistant clones to levels comparable to those obtained with wild type strains in the absence of hydroxyurea. Similar results were obtained by an independent group [31]. Thus, decreasing the level of dATP, the cellular competitor of didanosine, favored the incorporation of didanosine even though the viral reverse transcriptase was resistant to this nucleoside analog.…”

Section: Profile Of Hydroxyurea-didanosine Combinationsupporting

confidence: 87%

Virostatics: A New Class of Anti-HIV Drugs

Friedman¹,

Foli²,

Kelly³

et al. 2007

CMC

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In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

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Section: Profile Of Hydroxyurea-didanosine Combinationsupporting

confidence: 87%

Virostatics: A New Class of Anti-HIV Drugs

Friedman¹,

Foli²,

Kelly³

et al. 2007

CMC

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“…In fact, for HSV-1, the potentiating effect of hydroxyurea on PMEA was relatively weak. In a recent study, Palmer and colleagues (26) demonstrated that PMEA and hydroxyurea synergistically inhibit the replication of wild-type and drug-resistant HIV. We do not yet have an explanation of why the antiherpesvirus activity of PMEA is less potentiated by hydroxyurea than those of other nucleoside analogs, the active metabolites of which do not, unlike PMEA, compete with dATP in the (viral) DNA polymerization process.…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxyurea has been used for many years for the treatment of a variety of neoplasms (10) and appears, in addition, to offer clinical benefit for the treatment of sickle cell anemia (4). Hydroxyurea has been shown to inhibit the replication of human immunodeficiency virus (HIV) type 1 (HIV-1) (16) and to potentiate the anti-HIV activities of several 2Ј,3Ј-dideoxynucleoside analogs, in particular, didanosine (ddI) (12-14, 18, 25), as well as those of the nucleoside phosphonate analogs adefovir [9-(2phosphonylmethoxyethyl)adenine (PMEA)] and tenofovir [9-(2-phosphonymethoxypropyl)adenine (PMPA)] (26). The precise mechanism responsible for this potentiation has not been elucidated, but it is conceivable that the depletion of the intracellular 2Ј-deoxynucleoside 5Ј-triphosphate (dNTP) pools induced by hydroxyurea results in a decreased competition of the triphosphate metabolites of the antivirally active nucleoside analogs with the natural dNTP substrate at the level of the reverse transcriptase of HIV.…”

mentioning

confidence: 99%

Hydroxyurea Potentiates the Antiherpesvirus Activities of Purine and Pyrimidine Nucleoside and Nucleoside Phosphonate Analogs

Neyts

Clercq

1999

Antimicrob Agents Chemother

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Hydroxyurea has been shown to potentiate the anti-human immunodeficiency virus activities of 2′,3′-dideoxynucleoside analogs such as didanosine. We have now evaluated in vitro the effect of hydroxyurea on the antiherpesvirus activities of several nucleoside analogs (acyclovir [ACV], ganciclovir [GCV], penciclovir [PCV], lobucavir [LBV], (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [H2G], and brivudin and nucleoside phosphonate analogs (cidofovir [CDV] and adefovir [ADV]). When evaluated in cytopathic effect (CPE) reduction assays, hydroxyurea by itself had little effect on CPE progression and potentiated in a subsynergistic (herpes simplex virus type 1 [HSV-1]) to synergistic (HSV-2) fashion the antiviral activities of ACV, GCV, PCV, LBV, H2G, ADV, and CDV. Hydroxyurea also caused marked increases in the activities of ACV, GCV, PCV, LBV, and H2G (compounds that depend for their activation on a virus-encoded thymidine kinase [TK]) against TK-deficient (TK−) HSV-1. In fact, in combination with hydroxyurea the 50% effective concentrations of these compounds for inhibition of TK−HSV-1-induced CPE decreased from values of 20 to ≥100 μg/ml (in the absence of hydroxyurea) to values of 1 to 5 μg/ml (in the presence of hydroxyurea at 25 to 100 μg/ml). When evaluated in a single-cycle virus yield reduction assay, hydroxyurea at a concentration of 100 μg/ml inhibited progeny virus production by 60 to 90% but had little effect on virus yield at a concentration of 25 μg/ml. Under these assay conditions hydroxyurea still elicited a marked potentiating effect on the antiherpesvirus activities of GCV and CDV, but this effect was less pronounced than that in the CPE reduction assay. It is conceivable that the potentiating effect of hydroxyurea stems from a depletion of the intracellular deoxynucleoside triphosphate pools, thus favoring the triphosphates of the nucleoside analogues (or the diphosphates of the nucleoside phosphonate analogues) in their competition with the natural nucleotides at the viral DNA polymerase level. The possible clinical implications of these findings are discussed.

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“…In vitro, concentrations of hydroxyurea similar to those attained in vivo decreased the IC 50 of tenofovir in several recombinant HIV isolates, including those with the K65R mutation. 60 However, in a substudy of study 901, hydroxyurea 500 mg twice/day did not significantly enhance the antiviral activity of low-dose (i.e., 75 mg) tenofovir relative to tenofovir monotherapy. 61 Furthermore, the initial optimism surrounding hydroxyurea as a means of augmenting the activity of didanosine and overcoming didanosine resistance was tempered by later results suggesting a lack of virologic gain with hydroxyurea relative to placebo at the expense of greater toxicity (i.e., pancreatitis, peripheral neuropathy).…”

Section: Pharmacodynamicsmentioning

confidence: 95%

Tenofovir: A Nucleotide Analog for The Management of Human Immunodeficiency Virus Infection

2003

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Tenofovir disoproxil fumarate, an acyclic nucleotide analog of adenosine monophosphate, is the most recent addition to the antiretroviral arsenal. After conversion to tenofovir by diester hydrolysis, subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate is necessary for antiretroviral activity. Preliminary data suggest that tenofovir is as safe and efficacious as stavudine when given in combination with lamivudine and efavirenz for the treatment of antiretroviral-naïve patients. In antiretroviral-experienced patients, the addition of tenofovir to stable background antiretroviral therapy resulted in approximately a 0.6 log10 copies/ml reduction in viral load relative to placebo. Extended follow-up suggests that such virologic gains may be durable. In vitro, recombinant human immunodeficiency virus (HIV) expressing the K65R mutation showed a 3-4-fold increase in the 50% inhibitory concentrations of tenofovir when compared with wild type. In vivo, this mutation thus far appears to occur infrequently and is associated with variable virologic responses. Response rates to tenofovir vary with the number and pattern of thymidine analog mutations present before starting treatment with this agent. Tenofovir appears to be a well-tolerated agent in patients who are heavily pretreated and who have advanced disease. The main adverse effects appear to be gastrointestinal in nature and include nausea, vomiting, and diarrhea. In animals, osteomalacia and nephrotoxicity have occurred with tenofovir at exposures much higher than those observed in humans. Although no patient had to discontinue therapy as a result of elevated creatinine levels or hypophosphatemia through 58 weeks of treatment, the toxicities associated with long-term tenofovir therapy in humans are unknown. Concomitant administration of tenofovir and didanosine increases the area under the concentration-time curve of the latter by 44-60%; monitoring for signs and symptoms of didanosine toxicity is recommended. The approved dosage of tenofovir is 300 mg (one tablet) once/day with meals. Given the ease of administration and relative safety from the perspectives of adverse effects and drug interactions, tenofovir has the potential to assume a large role in the treatment of patients with HIV infection.

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Hydroxyurea Enhances the Activities of Didanosine, 9-[2-(Phosphonylmethoxy)ethyl]adenine, and 9-[2-(Phosphonylmethoxy)propyl]adenine against Drug-Susceptible and Drug-Resistant Human Immunodeficiency Virus Isolates

Cited by 29 publications

References 36 publications

Virostatics: A New Class of Anti-HIV Drugs

Virostatics: A New Class of Anti-HIV Drugs

Hydroxyurea Potentiates the Antiherpesvirus Activities of Purine and Pyrimidine Nucleoside and Nucleoside Phosphonate Analogs

Tenofovir: A Nucleotide Analog for The Management of Human Immunodeficiency Virus Infection

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