allopurinol and Muscular-Diseases

Several reports have suggested an association between febuxostat and muscle injury. The purpose of this study was to determine whether febuxostat increases the risk of muscle injury. This study included an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and a systematic review/meta-analysis of randomized controlled trials.. First, evaluation of the FAERS data included a disproportionality analysis that compared patients with and without rhabdomyolysis according to whether they were receiving febuxostat or allopurinol. Second, a systematic review/meta-analysis was performed to assess the risk of rhabdomyolysis and muscle injury in patients who used febuxostat or allopurinol.. Analysis of the FAERS data revealed disproportionality for increasing rhabdomyolysis in patients who received febuxostat (reporting odds ratio 4.49, 95% confidence interval [CI] 3.72-5.38, P < .01) and allopurinol (reporting odds ratio 2.49, 95% CI 2.25-2.75, P < .01). Nineteen studies were eligible for inclusion in the systematic review/meta-analysis. Rhabdomyolysis was reported in only 1 study. The risk of any type of muscle damage was not significantly increased with febuxostat compared with placebo (risk ratio 0.92, 95% CI 0.73-1.17, P = .52, I. Febuxostat does not seem to affect the risk of muscle injury. However, the findings of this meta-analysis indicate a need for further high-quality observational studies with long-term follow-up.

Topics: Allopurinol; Febuxostat; Gout; Gout Suppressants; Humans; Muscles; Muscular Diseases; Randomized Controlled Trials as Topic; Rhabdomyolysis

Intensive muscular activity can trigger oxidative stress, and free radicals may hence be generated by working skeletal muscle. The role of the enzyme xanthine oxidase as a generating source of free radicals is well documented and therefore is involved in the skeletal muscle damage as well as in the potential transient cardiovascular damage induced by high-intensity physical exercise. Allopurinol is a purine hypoxanthine-based structural analog and a well-known inhibitor of xanthine oxidase. The administration of the xanthine oxidase inhibitor allopurinol may hence be regarded as promising, safe, and an economic strategy to decrease transient skeletal muscle damage (as well as heart damage, when occurring) in top-level athletes when administered before a competition or a particularly high-intensity training session. Although continuous administration of allopurinol in high-level athletes is not recommended due to its possible role in hampering training-induced adaptations, the drug might be useful in non-athletes. Exertional rhabdomyolysis is the most common form of rhabdomyolysis and affects individuals participating in a type of intense exercise to which they are not accustomed. This condition can cause exercise-related myoglobinuria, thus increasing the risk of acute renal failure and is also associated with sickle cell trait. In this manuscript, we have reviewed the recent evidence about the effects of allopurinol on exercise-induced muscle damage. More research is needed to determine whether allopurinol may be useful for preventing not only exertional rhabdomyolysis and acute renal damage but also skeletal muscle wasting in critical illness as well as in immobilized, bedridden, sarcopenic or cachectic patients.

Topics: Acute Kidney Injury; Allopurinol; Biomarkers; Exercise; Free Radicals; Humans; Muscle, Skeletal; Muscular Diseases; Xanthine Oxidase

Topics: alpha-Glucosidases; AMP Deaminase; Carnitine; Carnitine O-Palmitoyltransferase; Glucan 1,4-alpha-Glucosidase; Glycolysis; Humans; Metabolism, Inborn Errors; Mitochondria, Muscle; Muscular Diseases; Phosphofructokinase-1; Phosphorylases; Triglycerides; Xanthine Oxidase

To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels.. A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped.. AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism.. It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

Topics: Adult; Azathioprine; Drug Interactions; Enzyme Inhibitors; Febuxostat; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Mercaptopurine; Muscular Diseases; Thiazoles; Thionucleotides; Xanthine Oxidase

We have used an in vitro model of oxidative stress by exposing rat muscle to 2:4 dinitrophenol. This causes an efflux of creatine kinase (CK) and prostaglandin E2 (PGE2) commonly used as indicators of muscle cell damage. We then investigated compounds with a putative cell protective effect in the system. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor 1 all prevent the release of PGE2 and CK. To the extent that these indicators may reflect cell damage, the results might support the investigation of the therapeutic potential of these compounds in muscle disease.

Topics: Animals; Brain-Derived Neurotrophic Factor; Ciliary Neurotrophic Factor; Creatine Kinase; Dinitrophenols; Dinoprostone; Hypoxanthine; In Vitro Techniques; Insulin-Like Growth Factor I; Male; Muscle, Skeletal; Muscular Diseases; Nerve Growth Factors; Nerve Tissue Proteins; Oxidative Stress; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

1. The present study tested the hypothesis that the level of xanthine oxidase is elevated in injured human skeletal muscle in association with inflammatory events. Seven male subjects performed five bouts of strenuous one-legged eccentric exercise. Muscle biopsies from both the exercised and the control leg, together with venous blood samples, were obtained prior to exercise and at 45 min, 24, 48 and 96 h after exercise. The time courses of xanthine oxidase immunoreactivity and indicators of muscle damage and inflammation were examined. 2. The number of xanthine oxidase structures observed by immunohistological methods in the exercised muscle was up to eightfold higher than control from day 1 to day 4 after exercise (P < 0.05). The increase was attributed to an enhanced expression of xanthine oxidase in microvascular endothelial cells and an invasion of leucocytes containing xanthine oxidase. 3. The concentration of plasma interleukin-6 was significantly higher 90 min after exercise than before exercise (P < 0.05) and remained higher than pre-exercise levels throughout the 4 days. On day 4 the plasma creatine kinase activity was approximately 150-fold higher (P < 0.05) than resting levels. 4. Despite the increase in xanthine oxidase in the muscle there were no detectable changes in the levels of muscle malondialdehyde or in plasma antioxidant capacity up to 4 days post-exercise. 5. It is concluded that eccentric exercise leads to an increased level of xanthine oxidase in human muscle and that the increase is associated with secondary inflammatory processes. The increase in xanthine oxidase in the muscle occurs mainly in microvascular endothelial cells, but occurs also via infiltrating leucocytes containing xanthine oxidase. A role for leucocytes in xanthine oxidase induction in endothelium is proposed.

Topics: Adult; Exercise; Humans; Immunohistochemistry; Inflammation; Male; Muscle, Skeletal; Muscular Diseases; Xanthine Oxidase

Topics: Aged; Allopurinol; Captopril; Drug Synergism; Fever; Humans; Joint Diseases; Male; Muscular Diseases; Pain; Proline

The hypothesis is presented that lipid peroxidation is responsible for the damage in skeletal and cardiac muscle of chronic alcoholic subjects. The enhanced lipid peroxidation is caused by the accumulation of oxygen radicals. Both excessive production and decreased disposal of oxygen radicals can arise from the acetaldehyde formed in the oxidation of ethanol. Although acetaldehyde from hepatic sources may contribute, muscle itself can generate significant amounts of acetaldehyde through the action of muscle catalase. The effects of alcohol on other tissues, and its known long-term effects on membranes lend support to this hypothesis. The ultrastructural features of the alcoholic myopathies provide further support. The resemblance between vitamin E-deficiency myopathy and the alcoholic myopathies is strong additional evidence in favor of this hypothesis.

Topics: Acetaldehyde; Alcohol Oxidoreductases; Alcoholism; Animals; Cardiomyopathy, Alcoholic; Catalase; Ethanol; Free Radicals; Glutathione Peroxidase; Humans; Lipid Peroxides; Liver; Liver Diseases, Alcoholic; Muscles; Muscular Diseases; Oxygen; Superoxide Dismutase; Xanthine Oxidase

Non-steroidal analgesic and anti-inflammatory drugs (NSAID) are potent inhibitors of prostaglandin synthesis in vivo at commonly achieved concentrations of these drugs. Prostaglandins of the E-series are released by exercising muscles, and their release is inhibited by indomethacin. The consequences, with respect to exercise performance, are unknown. Drugs used for hyperuricemia and gout such as colchicine, allopurinol, probenecid, and sulphinpyrazone have not been implicated in affecting exercise performance. The uricosuric drugs probenecid and sulphinpyrazone may be contraindicated in individuals who exercise heavily because of the increased danger of precipitating uric acid crystals in the kidney tubules. Muscle relaxants do not cause measurable muscle relaxation following usual oral dosage regimens. They are, however, sedatives and this property could influence exercise performance.

Topics: Allopurinol; Analgesics; Anti-Inflammatory Agents; Bone Diseases; Colchicine; Gout; Humans; Muscle Relaxants, Central; Muscular Diseases; Physical Exertion; Probenecid; Prostaglandins; Uric Acid

Topics: Allopurinol; Drug Evaluation; Gout; Humans; Muscular Diseases

Topics: Allopurinol; Animals; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Haplorhini; Hematologic Diseases; Humans; Kidney Diseases; Muscular Diseases; Neuritis

Topics: Adult; Allopurinol; Aminohippuric Acids; Electromyography; Humans; Hypoxanthines; Kidney Function Tests; Male; Metabolism, Inborn Errors; Muscles; Muscular Diseases; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Adult; Birefringence; Calculi; Crystallography; Female; Humans; Hypoxanthines; Male; Microscopy, Polarization; Muscles; Muscular Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Xanthine Oxidase; Xanthines

Topics: Adolescent; Adult; Allopurinol; Electromyography; Fatigue; Female; Humans; Kidney; Kidney Failure, Chronic; Knee; Male; Median Nerve; Methods; Middle Aged; Muscle Contraction; Muscle Denervation; Muscles; Muscular Atrophy; Muscular Diseases; Neural Conduction; Neurologic Manifestations; Tracheotomy; Uremia