Fulminant hepatitis with severe lactate acidosis in HIV‐infected patients on didanosine therapy

Bissuel, F.; Bruneel, Fabrice; Habersetzer, François; Chassard, D.; Cotte, Laurent; Chevallier, M.; Bernuau, Jacques; Lucet, Jean Christophe; Trépo, C

doi:10.1111/j.1365-2796.1994.tb01088.x

Cited by 139 publications

(72 citation statements)

References 15 publications

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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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“…This syndrome has also been reported in patients receiving other antiretroviral nucleoside analogue therapy, including retrovir (AZT) and didanosine (ddI) but in a more reversible form. 36 In vitro and in vivo systems have been devised for assessing mitochondrial injury. These tests include incubation of hepatocyte cultures (primary or transformed) with drug and quantitation of mitochondrial morphology, DNA content, respiratory chain enzymes, and lactate production.…”

Section: J H Hoofnagle B C Tennant W Lewis and R J Sokolmentioning

confidence: 99%

Drug-induced liver injury: Mechanisms and test systems

et al. 2001

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“…In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration 1667 www.chinaphar.com Zeng W et al Acta Pharmacologica Sinica npg zalcitabine (ddC), didanosine (ddI) and stavudine (d4T) [14][15][16] . A study of maternal-fetal exposure to AZT in patas monkeys also showed evidence for mitochondrial dysfunction including respiratory-chain defects and mtDNA reduction [17] .…”

Section: Introductionmentioning

confidence: 99%

In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

et al. 2009

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Aim: To explore the potential mitochondrial toxicities and their severities of intravenously administered metacavir, a nucleoside analog, in rhesus monkeys. Methods: Totally 21 rhesus monkeys were randomly divided into 4 groups: metacavir 120 mg/kg group, metacavir 40 mg/kg group, zidovudine(AZT) 50 mg/kg group, and blank control group. Animals were killed after the completion of dosing or further observed in a 4-week recovery phase. Changes of structure of mitochondria in liver, kidney, skeletal muscles, and cardiac muscles were observed under transmission electron microscope(TEM). Changes of the activities of mitochondrial respiratory chain complexes and mitochondrial DNA were also determined. Results: In metacavir 120 mg/kg group, some mitochondrial injuries were found in skeletal muscle, cardiac muscle, and liver, including that some cristae was broken and became sparse in density in the skeletal muscle, the morphology and size of mitochondria remained unchanged. Metacavir decreased the activities of respiratory chain complexes I and II and the mtDNA contents in three tissues in a dose-dependent manner; however, the extent of such decrease was lower than that in AZT 50 mg/kg group. The mitochondrial injuries in metacavir 40 mg/kg group were mild in each tissue and no obvious change in mitochondrial function was noted. On week 4 in the recovery phase, results showed that all these injuries were reversible after drug withdrawal. Conclusion: These results suggest that metacavir has not a high risk for potential mitochondrial-related effects in rhesus monkeys.

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Fulminant hepatitis with severe lactate acidosis in HIV‐infected patients on didanosine therapy

Cited by 139 publications

References 15 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

Drug-induced liver injury: Mechanisms and test systems

In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

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