mercaptopurine and Muscular-Diseases

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

Controlled mechanical ventilation (CMV) has been shown to result in elevated diaphragmatic proteolysis and atrophy together with diaphragmatic contractile dysfunction.. To test whether administration of leupeptin, an inhibitor of lysosomal proteases and calpain, concomitantly with 24 hours of CMV, would protect the diaphragm from the deleterious effects of mechanical ventilation.. Rats were assigned to either a control group or 24 hours of CMV; animals in the ventilation group received either a single intramuscular injection of saline or 15 mg/kg of the protease inhibitor, leupeptin.. Compared with control animals, mechanical ventilation resulted in a significant reduction of the in vitro diaphragm-specific force production at all stimulation frequencies. Leupeptin completely prevented this reduction in force generation. Atrophy of type IIx/b fibers was present after CMV, but not after treatment with leupeptin. Cathepsin B and calpain activities were significantly higher after CMV compared with the other groups; this was abolished by treatment with leupeptin. Significant inverse correlations were found between diaphragmatic force generation and cathepsin B and calpain activity, and illustrate the deleterious role of proteolysis in diminishing diaphragmatic force production after prolonged CMV.. Administration of the protease inhibitor leupeptin concomitantly with mechanical ventilation completely prevented ventilation-induced diaphragmatic contractile dysfunction and atrophy.

Topics: Animals; Blotting, Western; Calpain; Cathepsin B; Diaphragm; Disease Models, Animal; Fluorometry; Male; Mercaptopurine; Muscle Contraction; Muscular Diseases; Nucleic Acid Synthesis Inhibitors; Rats; Rats, Wistar; Respiration, Artificial; Treatment Outcome

Topics: Aging; Animals; Animals, Newborn; Female; Male; Mercaptopurine; Muscles; Muscular Diseases; Rats

6-Mercaptopurine (6-MP) is an adenine antagonist which has been shown to cause skeletal muscle atrophy in neonatal rats. To investigate the effects of 6-MP on developing muscles, pure populations of myoblasts and myotubes in vitro were treated with 6-MP (5-50 micrograms/ml). The viability and protein content of myotubes, but not myoblasts, was decreased by 6-MP. Microscopic examination of the 6-MP-treated (50 micrograms/ml) myotubes demonstrated that severe degenerative changes had occurred, including extensive necrosis, inhibition of myotube formation, and the appearance of intracellular vacuoles. However, 6-MP treatment decreased the incorporation of radiolabeled leucine and thymidine by myoblasts, but not myotubes. These findings indicate that 6-MP exerted a selective toxicity on myotubes but not myoblasts.

Topics: Animals; Cell Survival; Chick Embryo; DNA; In Vitro Techniques; Leucine; Mercaptopurine; Microtubules; Muscle Proteins; Muscles; Muscular Diseases; Thymidine

Topics: Anemia, Aplastic; Antibodies, Antinuclear; Azathioprine; Bone Marrow; Cyclophosphamide; Erythropoiesis; Heme; Humans; Immunosuppressive Agents; In Vitro Techniques; Male; Mercaptopurine; Middle Aged; Muscular Diseases; Prednisone; Splenectomy; Thymectomy; Thymoma