Creatine kinase activation

Dinovo, E. C. Miyada, D. S. and Nakamura, R. H. Evaluation of direct and indirect compled enzyme assay systems for measurements of creatine kinase activity. 

Table 11.2 Release of creatine kinase activity from isoiated rat soieus muscies of different vitamin E status...

Swanson, J. R., and Wilkinson, J. H., Measurement of creatine kinase activity in serum. Stand. Methods Clin. Chem. 7, 33-42 (1972). 

T6. Tummistor, T., and Airaksinen, M. N., Increase of creatine kinase activity in serum caused by intermittently administered suxamethonium. Brit. J. Anaesth. 38, 510 (1966). 

W9. Wilkinson, J. H., and Steciw, B., Evaluation of a new procedure for measuring creatine kinase activity. Clin. Chen. 16, 370-374 (1970). 

Creatine kinase activity should be measured in patients receiving potentially interacting drug combinations. In all patients, CK should be measured at baseline. If muscle pain, tenderness, or weakness appears, CK should be measured immediately and the drug discontinued if activity is elevated significantly over baseline. The myopathy usually reverses promptly upon cessation of therapy. If the association is unclear, the patient can be rechallenged under close surveillance. Myopathy in the absence of elevated CK has been reported. Rarely, hypersensitivity syndromes have been reported that include a lupus-like disorder and peripheral neuropathy. 

It is possible that the combination of rosiglitazone with fenofibrate was responsible for the severe myopathy, although the possibility of a single drug cannot be excluded. Raised creatine kinase activity has been reported with troglitazone, and there has been a report of rhabdomyolysis in a patient with type 2 diabetes taking pioglitazone when fenofibrate was added. 

A 59-year-old man took troglitazone 400 mg/day for 6 months and alcohol about 40 g/day. He developed weakness and muscle pain. He had mild liver damage. His HbAic concentration was 9.0%. All his muscles were tender, his creatine kinase activity was 10 570 IU/ml, and his myoglobin, aldolase, and aspartate transaminase were raised. Troglitazone was withdrawn. He improved biochemically and clinically. 

In one study of 133 patients there was myalgia in 3% of those taking atorvastatin, but no patient had persistent increases in creatine kinase activity above 10 times the top of the reference range (21). 

A 51-year-old white woman developed severe weakness, near syncope, shortness of breath, and chest pain. She had complete heart block. The creatine kinase activity was over 7000 U/l. She had taken atorvastatin... 

In other respects, the adverse effects of cerivastatin are similar to those of other statins (3), and a pooled analysis of studies of cerivastatin 100-400 micrograms/day taken for at least 8 weeks showed no differences in drug-related adverse events between cerivastatin and placebo (4). There was no association between plasma transaminase or creatine kinase activities and cerivastatin dosages. 

Creatine kinase activity increased in five out of 1213 patients taking beclobrate (21). Myopathy during treatment has been reported with gemfibrozil (49) and ciprofi-brate (50,51). 

Combination therapy with fluvastatin and bezafibrate 400 mg/day in 71 patients with persistent hypertriglyceridemia resulted in no significant increase in creatine kinase activity or in the frequency of myalgia (76). 

In a pooled analysis of a large population of patients with hypercholesterolemia taking fluvastatin 20 mg/day, 40 mg/day, and fluvastatin modified-release 80 mg/day, the frequency of significant rises in creatine kinase activity was low and not different from placebo (5). This applied to men and women both above and below the age of 65 years. There were no increases in the frequency of rises in creatine kinase activity with higher doses of fluvastatin. 

In four patients with muscle symptoms while taking statins, creatine kinase activity was normal, but they were subsequently able to distinguish from their symptoms whether they were taking drug or placebo muscle biopsies showed evidence of mitochondrial dysfunction (45). 

Exercise-induced muscle pain, without myopathy and a rise in creatine kinase activity, can probably be caused by statins. This has been described in seven patients with heterozygous familial hypercholesterolemia and consisted of pain during exercise and cramps in the following hours (54). 

Symptomatic rises in creatine kinase activity to over 10 times the upper end of the reference range occurred in 0,1, and 0.9% of patients taking placebo, cerivastatin 0.4 mg, or cerivastatin 0.8 mg respectively (55), and rhabdomyolysis has been described in patients taking cerivastatin (56,57). However, in a review of the pharmacological properties and therapeutic efficacy of cerivastatin in hypercholesterolemia, it was stated that cerivastatin only infrequently causes rhabdomyolysis when given alone (58). 

A 56-year-old man taking simvastatin was given clarithromycin and amiodarone for pneumonia and a supraventricular tachycardia. He found it difficult to move and complained of general weakness and muscle pain. The blood creatine kinase activity was over 20 000 IU/... 

Lovastatin in combination with gemfibrozil caused a rise in creatine kinase activity 234 000 U/l, with complete remission after both drugs had been withdrawn (15). 

In a placebo-controlled study of 1142 hypercholestero-lemic patients treated with pravastatin for 8-16 weeks, the numbers of adverse drug experiences were similar in the treated and untreated individuals (1). Rash was the only adverse clinical event that was different (4.0 versus 1.1%). However, in the same patients withdrawal of therapy during follow-up was thought to be necessary in 3.2% of those given pravastatin alone. Myopathy was observed in one instance only, and increases in creatine kinase activity in those taking pravastatin did not differ significantly from controls. There were marked persistent increases in transaminases in 1.1%, with no cases of symptomatic hepatitis. Pravastatin is believed to have a particularly low potential for nervous system-related adverse effects, as it has not been shown to enter the cerebrospinal fluid, and clinical experience suggests that muscle toxicity occurs less often with pravastatin than with lovastatin (2). 

Rhabdomyolysis has been reported in patients taking simvastatin (28,29). Of 66 patients who took simvastatin for 1 year, two had myalgia and weakness with creatine kinase activity above 3000 (normally less than 100) (30). 

A 63-year-old white man with insulin-dependent diabetes and recent coronary artery bypass surgery developed diffuse muscle pain with generalized muscular weakness after taking amiodarone 1 g/day for 10 days then 200 mg/ day plus simvastatin 40 mg/day (37). He had a significant increase in creatine kinase activity, peaking at 40 392 U/l. 

A 64-year-old African-American man developed worsening renal insufficiency, raised creatine kinase activity, diffuse muscle pain, and severe muscle weakness. He had been taking simvastatin for about 6 months and clarithromycin for sinusitis for about 3 weeks. He was treated aggressively with intravenous hydration, sodium bicarbonate, and hemodialysis. A muscle biopsy showed necrotizing myopathy secondary to a toxin. He continued to receive intermittent hemodialysis until he died from infectious complications 3 months after admission. 

Creatine Kinase Activity of Scaleless Chickens (Milliunits/ml plasma)... 

Cadoux-Hudson, T.A., Blackledge, M.J., Radda, G.K. (1989). Imaging of human brain creatine kinase activity in vivo. FASEB J. 3,2660-2666. 

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