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Lack of muscle toxicity with didanosine (ddI). Clinical and experimental studies
E Pedrol1, F Masanés, J Fernández-Solá
1Department of Internal Medicine, Hospital Clínic, University of Barcelona, Spain.
Abstract:
Currently, 2',3'-dideoxyinosine (ddI) is used in AIDS therapy. To investigate the possible myotoxicity of ddI in patients infected with human immunodeficiency virus (HIV), we examined the effect of ddI in vitro in tissue cultures of skeletal muscles of rats exposed to ddI at doses equivalent to plasma ddI levels obtained in the treatment of HIV patients. Control cultures were exposed to normal saline and zidovudine (AZT). After 4 weeks no changes were noted in the ddI and normal saline cultures, but AZT cultures showed abnormal accumulation of mitochondria. The creatine kinase values in culture supernatants were all normal. We also reviewed the clinical, nutritional and biological parameters, AZT and ddI dosage, and histochemical findings in muscle specimens of 14 HIV patients receiving ddI therapy. All patients had previously received AZT. The mean cumulative dose of ddI was 91.6 gm. Two patients had myalgia, 9 muscle atrophy, and 13 weakness. All patients were malnourished. Five patients had mitochondrial myopathy related to AZT, 4 had ddI-associated neuropathy and 2 patients had only selective type 2 fiber atrophy. One patient had necrotizing vasculitis, one had scattered necrotic fibers and type 2 fiber atrophy and 2 had a normal muscle biopsy. On the basis of the results, we have been unable to implicate ddI as a cause of skeletal myopathy.
Insights
This study investigated the skeletal muscle toxicity of 2
Area of Science:
- * Virology
- * Toxicology
- * Neurology
Background:
- * 2',3'-dideoxyinosine (ddI) is a medication used in acquired immunodeficiency syndrome (AIDS) therapy.
- * Zidovudine (AZT) is another antiretroviral medication previously used by patients in this study.
- * Skeletal myotoxicity is a potential concern with antiretroviral therapies.
Purpose of the Study:
- * To determine if ddI causes skeletal myotoxicity in human immunodeficiency virus (HIV)-infected patients.
- * To evaluate the in vitro effects of ddI on rat skeletal muscle tissue cultures.
- * To review clinical and histopathological data from HIV patients undergoing ddI therapy.
Main Methods:
- * In vitro study using rat skeletal muscle tissue cultures exposed to ddI and AZT.
- * Analysis of creatine kinase levels in culture supernatants.
- * Review of clinical data, nutritional status, and muscle biopsy findings in 14 HIV patients on ddI therapy.
Main Results:
- * In vitro ddI and saline cultures showed no changes; AZT cultures exhibited mitochondrial abnormalities.
- * Normal creatine kinase levels were observed in all cultures.
- * In patients, myalgia, muscle atrophy, and weakness were reported; however, mitochondrial myopathy was linked to AZT, and neuropathy to ddI, with no definitive link established for ddI-induced myopathy.
Conclusions:
- * The study could not establish ddI as a direct cause of skeletal myopathy.
- * Mitochondrial myopathy was associated with prior AZT use.
- * Further research may be needed to fully understand the neurological effects of ddI.