Lactic Acidosis and Hepatic Steatosis Associated with Use of Stavudine: Report of Four Cases

Miller, Kirk D.; Cameron, Miriam L.; Wood, Lauren V.; Dalakas, Marinos C.; Kovacs, Joseph A.

doi:10.7326/0003-4819-133-3-200008010-00010

Cited by 192 publications

(97 citation statements)

References 19 publications

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“…Lactic acidosis is one of the most serious complications induced by prolonged therapy with NRTIs. When diagnosed, it often requires intensive care (32) and can be fatal in some patients (43). Therefore, lactic acid production is considered an important marker for characterization of NRTI-induced mitochondrial dysfunction.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that ddC can cause mitochondrial alterations in Schwann cells in a rabbit model of ddC-induced neuropathy (1). Didanosine (ddI) and stavudine (d4T) therapy can induce adverse effects such as hepatic steatosis and lactic acidosis, which are presumably also a consequence of drug-associated mitochondrial toxicity (5,32). In contrast, the etiology of abacavir-associated adverse effects such as hypersensitivity does not seem to involve mitochondrial toxicity (21,22).…”

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confidence: 99%

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Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Birkuš

Hitchcock

Cihlář

2002

Antimicrob Agents Chemother

393

252

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Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 M) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine ‫؍‬ abacavir ‫؍‬ tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 M tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 M ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 M) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 M) is not associated with mitochondrial toxicity.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Birkuš

Hitchcock

Cihlář

2002

Antimicrob Agents Chemother

393

252

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“…During the development of nucleoside analogues for FDA approval, it was determined that fialuridine, zidovudine, stavudine, and 2 0 ,3 0 -dideoxyinosine lead to hepatotoxicity. [47][48][49][50] Examination of liver biopsy specimens revealed microvascular steatosis signifying mitochondrial damage that was later confirmed in experimental models. 12 The FDA approves approximately 20 to 40 new drugs per year, and many-fold more start the approval process but fail during phase 1 to 3 clinical trials.…”

Section: Histologic Patterns Of Liver Injurymentioning

confidence: 99%

Drug-Induced Liver Injury

Fisher¹,

Vuppalanchi²,

Saxena

2015

Archives of Pathology &Amp; Laboratory Medicine

161

116

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Context Drug-induced liver injury (DILI) represents a diverse set of responses following exposure to any manufactured or naturally occurring chemical compound. Drug-induced liver injury is of major concern owing to the ever increasing number of compounds introduced into the market for treatment of various diseases as well as the increasing popularity of herbals, which lend themselves to self-medication but are not rigorously regulated. Objective To provide an overview of the prevalence, classification, and diagnosis of DILI with emphasis on pathogenesis and the role of a liver biopsy. To focus on the most common, emerging, and herbal agents that cause DILI with emphasis on the histologic pattern of injury observed. Data Sources A review of the literature was drawn from the PubMed (US National Library of Medicine) repository, textbooks, and online databases. All figures were taken from cases seen at our tertiary referral center, which is 1 of 12 participating sites in the National Institutes of Health–funded Drug-Induced Liver Injury Network. Conclusions Drug-induced liver injury due to prescription, over-the-counter, and herbal products is a major cause of liver disease in the United States and around the world. Diagnosis of DILI is challenging because there is no single clinical, laboratory, or histologic feature specific to DILI. Accurate diagnosis requires establishing a causal relationship with the suspected agent and excluding competing causes of liver injury. The liver biopsy is an essential component in the management of DILI by offering clues to the underlying pathogenesis, providing prognostic information, and guiding therapy.

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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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Lactic Acidosis and Hepatic Steatosis Associated with Use of Stavudine: Report of Four Cases

Abstract: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine.

Cited by 192 publications

References 19 publications

Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Drug-Induced Liver Injury

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

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