Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.

OBJECTIVE: Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. METHODS: Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. RESULTS: Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. CONCLUSIONS: Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.

Efficacy and safety of zidovudine and zalcitabine combined with a combination of herbs in the treatment of HIV-infected Thai patients.

A randomized double blind placebo controlled trial to determine the efficacy and safety of combined-herbs (SH) given with zidovudine (ZDV) and zalcitabine (ddC) for the treatment of HIV infection in Thai adults was conducted in 3 hospitals in northern Thailand during 2002 to 2003. The eligible subjects were HIV-infected Thai adults who had never received anti-retrovirals, had a Karnofski Performance Score (KPS) of > or = 70, and had no opportunistic infections. The subjects were randomized to receive either a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and SH 2.5 g three times per day or a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and placebo 2.5 g three times per day for 24 weeks. The main outcome measures were HIV-RNA, CD4 cells, and blood chemistry profiles prior to the treatment and then every 4 weeks for 24 weeks. The baseline characteristics of 60 evaluable subjects, 40 in the SH group and 20 in the placebo group, were not significantly different. HIV RNA at week 4 and thereafter was significantly decreased from the baseline value in both groups (p<0.001). However, the decline in HIV RNA in the SH group was significantly more than that in the placebo group. The CD4 cells in the SH group at week 12 and thereafter were significantly increased from the baseline value. Serious adverse events in the two groups were not observed. It is concluded that an addition of SH herbs to two nucleoside reverse transcriptase inhibitors has greater antiviral activity than antiretrovirals only. The SH herbs may be an alternative for the third anti-retroviral agent in the triple drug regimen for the treatment of HIV infected patients in countries with limited resources.

Synthesis and evaluation of novel prodrugs of foscarnet and dideoxycytidine with a universal carrier compound comprising a chemiluminescent and a photochromic conjugate.

To facilitate intracellular delivery of hydrophilic drugs, a general lipophilic carrier molecule was designed and synthesized. The carrier comprised a chemiluminescent-photochromic conjugate that potentiates diffusion across cell membranes to enhance intracellular uptake of the drug. The designed mechanism involves activation of the chemiluminescent moiety by intracellular oxygen free radicals and intermolecular energy transfer of the excited state energy to the photochromic moiety to result in release of the drug to allow the desired pharmacological effect to occur. Prodrugs of foscarnet and dideoxycytidine with several carriers caused suppression of a human immunodeficiency virus infection in human cultured macrophages that was up to five times more effective than the drug alone. Successful in vivo efficacy testing of prodrug has been accomplished by demonstrating the suppression of a retroviral infection of Friend leukemia virus in mice. Acute toxicity studies of the carrier indicated that it was nontoxic.

The impact of ethanol and Marinol/marijuana usage on HIV+/AIDS patients undergoing azidothymidine, azidothymidine/dideoxycytidine, or dideoxyinosine therapy.

Therapeutic observations suggest that azidothymidine (AZT)-resistant HIV+/AIDS patients are frequently offered AZT/dideoxycytidine (DDC) or dideoxyinosine (DDI) therapy. The latter therapies have been associated with the development of acute pancreatitis. During the initial portion of this study, when patients reported limiting ethanol consumption, an increase in CD4+, a decrease in amylase, and a decrease in lipase was observed in patients on DDI monotherapy. Marinol/marijuana usage was associated with depressed CD4+ counts and elevated amylase levels within the DDI subgroup. The purpose of this study was to follow these patients over 1 year and compare clinical indicators of pancreatitis and HIV progression. After 1 year, the remaining 56 patients were reexamined in the follow-up portion for clinical indicators of HIV disease progression and pancreatoxic/hepatotoxic effects. Those in the AZT group, who remained on this therapy throughout the year, had significantly increased amylase values from 55.3 to 69.3 IU/liter (p < 0.05). In the AZT/DDC group, those who remained on combination therapy throughout the year, 4 of the 5 clinical indicators of disease progression changed. Amylase, ALT, and AST all increased significantly from 55.2 to 77.8 IU/liter (p < 0.01), from 38.0 to 92.3 IU/liter (p < 0.05), and from 55.2 to 97.0 IU/liter (p < 0.05), respectively. Lipase levels decreased significantly (106.0 to 74.6 IU/liter, p < 0.05). The most remarkable changes occurred in the AZT/DDC group (who reduced ethanol consumption), wherein clinical indicators of pancreatitis and liver dysfunction declined, including amylase (65.0 to 20.0 IU/liter, p < 0.05), ALT (350.0 to 100.0 IU/liter, p < 0.01), and AST (240.0 to 95.0 IU/liter, p < 0.01). No significant changes were noted in the DDI or AZT groups. Marinol/marijuana use was associated with declining health status in both the AZT and AZT/DDC groups. In contrast, all clinical indicators of pancreatitis improved in the DDI patients who utilized Marinol/marijuana, including amylase (-34%), lipase (-30.8%), ALT (-21.4%), and AST (-20.1%). This paired follow-up study suggests that HIV+/AIDS patients on antiretroviral therapies should restrict their ethanol consumption. In HIV+/AIDS patients with the lowest CD4+ counts (those on DDI monotherapy), utilization of Marinol/marijuana does not seem to have a deleterious impact.

High-level resistance to zidovudine but not to zalcitabine or didanosine in human immunodeficiency virus from children receiving antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) isolates from children receiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resistance to zidovudine, zalcitabine, and didanosine, and for mutations known to be associated with zidovudine or didanosine resistance. HIV-1 from four of six patients receiving zidovudine with zalcitabine developed high-level resistance to zidovudine. A mutation in the HIV-1 reverse transcriptase that is highly associated with zidovudine resistance was identified in all four zidovudine-resistant posttherapy isolates. In contrast, none of the HIV-1 isolates from the seven patients receiving didanosine developed high-level resistance to this agent, despite the identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didanosine were observed. These results indicate that nucleoside analog-associated mutations in HIV-1 occur frequently in children receiving long-term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They also suggest that there may be differences in the degree of resistance conferred by mutations that result from therapy with different nucleoside analogs. These findings underscore the need for studies to define the clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.