Hepatomegaly with severe steatosis in HIV-seropositive patients

Freiman, Joel; Helfert, Karen E.; Hamrell, Michael R.; Stein, Daniel S.

doi:10.1097/00002030-199303000-00012

Cited by 150 publications

(77 citation statements)

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“…5,6 Hepatic steatosis, lactic acidosis, and ultrastructural abnormalities of mitochondria were similar to those of Reye' s syndrome, in which mitochondrial injury is believed to be a critical factor in pathogenesis. 20,21 Hepatic steatosis and lactic acidosis have been observed in patients treated with other nucleoside analogs including ddC, 22 ddl, 23,24 and AZT, [25][26][27] and multiorgan involvement similar to that associated with FIAU toxicity has been attributed to nucleoside-induced mitochondrial damage. 10,28 The mechanism(s) responsible for FIAU-induced mitochondrial dysfunction and the role of mitochondrial dysfunction in FIAU toxicity are not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

et al. 1998

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Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2Јdeoxy-2Јfluoro-1-␤-Darabinofuranosyl-5-iodo-uracil). In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, FIAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1.5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAUtreated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical toxicological evaluation of other nucleoside analogs before use in patients. (HEPATOLOGY 1998;28:179-191.)

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Section: Discussionmentioning

confidence: 99%

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

et al. 1998

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“…31,35 In humans multi-system toxicity due to nucleoside analogues, affecting slowly proliferating but metabolically active tissues (liver, pancreas, muscle, neuronal tissue), has been described for zidovudine, didanosine and zalcitabine, fialuridine, stavudine and lamivudine. [36][37][38][39] Recently, a clinical trial using fialuridine for the treatment of hepatitis B viral infection failed due to high liver toxicity attributed to generalized mitochondrial injury, which cost the lives of 13 of the 15 patients treated. 40 In line with such a mechanism, light microscopy of livers of Ad.CMV.TK/GCV-treated rats, showed marked accumulation of macro-and micro-vesicular fat, depletion of glycogen, iron precipitation and scant hepatocellular necrosis and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration

et al. 1998

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The use of so-called 'suicide' genes to activate prodrugs approach but reveal that hepatic expression of HSVtk, both has been effective in animal models for several solid tumor in tumor bearing and in tumor-free rats, provokes severe types and is now in phase I and II clinical trials. We have liver dysfunction and mortality upon GCV administration. exploited adenovirus vectors (Ad) for transfer and These data show, that in contrast to the common assumpexpression of the herpes simplex virus thymidine kinase tion, normally non-mitotic tissues too, can be affected by (HSVtk) gene to render rat colorectal liver metastases adenovirus-mediated HSVtk transfer and subsequent GCV sensitive to the anti-herpetic agent ganciclovir (GCV). The treatment. Given the hepatotropic nature of systemically efficacy and toxicity of this enzyme-prodrug combination administered adenovirus type 2-and 5-derived vectors, it were tested after in situ transduction of rat colorectal tumor will be essential to monitor liver functions of patients cells and after intraportal administration of the vector included in all gene therapy trials involving adenoviral vecAd.CMV.TK. Our results demonstrate the validity of the tors with the HSVtk gene.

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“…The accessory subunit provides tighter DNA binding of the complex, thus allowing highly processive DNA synthesis . Dalakas et al, 1990Arnaudo et al, 1991Chattha et al, 1993d'Amati et al, 1992Freiman et al, 1993Herskowitz et al, 1992Jolliet and Widmann, 1990 Kohler and Lewis, 1998Lewis and Dalakas, 1995Lewis et al, 2000Lipshultz et al, 2000Sinnwell et al, 1995 Decreased mtDNA in vitro. Decreased mtDNA, mtRNA, mitochondrial polypeptides, and mitochondrial ultrastructural damage in vivo.…”

Section: Mtdna Dna Polymerase-␥ and Nrti Toxicitymentioning

confidence: 99%

“…Hepatic toxicity from AZT, ddI, and ddC was reported (Chattha et al, 1993;Freiman et al, 1993;Jolliet and Widmann, 1990). It is presumed to relate to toxicity to liver mitochondria.…”

Section: Toxicity From Other Nrtis: Varying Tissue Targetsmentioning

confidence: 99%

“…It is presumed to relate to toxicity to liver mitochondria. Fatal hepatomegaly with severe steatosis (Freiman et al, 1993), severe lactic acidosis (Chattha et al, 1993), and adult Reye's syndrome (Jolliet and Widmann, 1990) in AZT-treated HIV seropositive patients are all pathogenetically linked to AZT-induced hepatotoxicity. Clinical features resemble some of those seen in FIAU toxicity.…”

Section: Toxicity From Other Nrtis: Varying Tissue Targetsmentioning

confidence: 99%

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Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

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2001

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Hepatomegaly with severe steatosis in HIV-seropositive patients

Cited by 150 publications

References 0 publications

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

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