Increased Serum Creatine Phosphokinase Research Articles

Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury

We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R = 26 +/- 10.2 U/ml; MI/R = 213 +/- 19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1 +/- 0.4 U x 10(-3)/g tissue and 6.7 +/- 0.9 U x 10(-3)/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.

G619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, reduces myocardial damage and polymorphonuclear leukocyte accumulation following coronary artery occlusion and reperfusion in rats.

We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TxA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 +/- 12 U/ml; MI/R = 205 +/- 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 +/- 0.5 and 6.6 +/- 0.9 U x 10(-3)/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.

Evaluation of the effects of felodipine, verapamil and hydralazine on the survival rate of rats subjected to lethal effects of oxygen free radicals.

Intravenous administration of xanthine (X: 0.225 mg/kg, i.v.) plus xanthine oxidase (XO: 3.0 units/kg, i.v.) to anesthetized rats resulted in a rapid fall in the arterial pressure and a mortality rate of over 80% during 120 min observation period. Pretreatment of the rats with superoxide dismutase (SOD) or SOD plus catalase significantly enhanced survival rate to 60% confirming that the toxicity after [X + XO] administration is due to the generation of oxygen free radicals. Pretreatment of the rats with either felodipine, a dihydropyridine calcium antagonist or verapamil, a structurally different Ca(2+)-channel blocker was most effective in promoting survival rate to 90%; in contrast, hydralazine, an arteriolar dilator but not a calcium antagonist, was ineffective in significantly enhancing survival. In the vehicle treated groups, mortality of the rats after [X + XO] administration was associated with significant increases in serum creatine phosphokinase (CPK) levels; both the calcium antagonists as well as hydralazine prevented any significant changes in CPK levels. Since only the calcium antagonists but not hydralazine were effective in providing significant protection against mortality, the data suggests that CPK may not be a reliable indicator to predict prevention of lethal toxicity induced by free radicals. Hence, the observation that calcium antagonists can promote survival would suggest that calcium overload may be the ultimate mediator of tissue toxicity. These observations can account for the remarkable efficacy of various calcium antagonists in preventing ischemia-reperfusion induced damage to organs, such as heart and kidneys, in which a role for free radicals has been postulated.

5 Thyroid emergencies

Thyroid storm is a rapid decompensation of severe hyperthyroidism which can best be described by the three criteria of hyperthermia, tachycardia and altered mental state with severe agitation. There has to be a precipitating factor such as infection, iodine contamination, surgery or even I-131 treatment. Severe hyperthyroidism not fulfilling the criteria of thyroid storm can also be an indication for emergency treatment, particularly in the elderly with heart disease. Suppressed serum TSH and elevated free T4 levels are essential to confirm the diagnosis. When rapidly available, radioiodine uptake of the thyroid can be useful. Therapy aims at rapidly reducing the active circulating hormone pool, hypermetabolic state, tachycardia, and finally hormone synthesis. Thyroid secretion can be blocked by ioipanoic acid or ipodate while hypermetabolic state can be reduced with β-blockers or calcium channel-blockers. Treatment of hyperthyroidism in patients with iodine contamination is a real therapeutic challenge. Myxoedema coma, a complication of severe hypothyroidism, is defined by hypothermia (rectal temperature less than 36°C), bradycardia, slow mentation, precipitating factor such as infection or drug overdose, and increased serum creatine phosphokinase levels. Diagnosis of severe hypothyroidism should be confirmed by serum measurements of TSH and free T4. Treatment consists of general supporting measures including rewarming, correction of serum electrolyte disturbances, and adequate alimentation. Thyroid hormone treatment should initially be aggressive using either 300–400 μg of T4 or 20–40 μg of T3 intravenously. Cortisone therapy may be added. Patients should be under close monitoring as arrhythmias and myocardial infarction are frequent complications of myxoedema coma and/or its treatment with thyroid hormones.

Myopathy Associated With Ketoconazole Treatment

Sir .—Ketoconazole is an imidazole-derivative, broad-spectrum antimycotic agent, with relatively limited toxicity compared with other antifungal medications. However, gastrointestinal disturbances, hepatotoxicity, impaired adrenal steroidogenesis, gynecomastia, and immune hemolytic anemia have been reported in association with ketoconazole treatment. 1,2 We noticed myopathy with a significant increase of serum creatine phosphokinase during ketoconazole treatment, indicating a possible drug-induced myositis. To our knowledge, there has been no fully documented report of myopathy associated with the use of this drug, although myalgia has been reported in two patients 3 and muscular weakness in one patient. 4 Patient Report .—A 17-year-old boy afflicted with autoimmune polyglandular syndrome type I presented with hypoparathyroidism, Addison's disease, alopecia universalis, and mucocutaneous candidiasis was treated with ketoconazole (200 mg/d) because of worsening oral candidiasis. Within a week, doctors noticed clinical improvement of the oral lesions, but concomitantly, the patient developed significant weakness and diffuse myalgia, particularly of the shoulder

Comparative study of three phospholipase A 2s from the venom of Vipera aspis

1. 1. Three phospholipase A 2s, PLA 2-I, PLA 2-II and PLA 2-III, were isolated from Vipera aspis venom by gel filtration and ion exchange chromatography. 2. 2. Purified PLA 2-I, -II and -III have mol. wts of 30,200, 16,000 and 13,500, and isoelectric points of 9.45, 7.65 and <4.1, respectively. 3. 3. PLA 2-I consists of an acidic subunit (mol. wt 13,700, pI: <3.5) and a basic subunit (mol. wt 16,500, pI: 10.6), which can be separated under highly acidic conditions. 4. 4. PLA 2-I possessed lethal activity and LD 50 for this preparation was estimated to be 0.288 (0.209–0.397) μg/g, while lethality was not observed when PLA 2-II, -III or each subunit of PLA 2-I were administered. 5. 5. Capillary permeability-increasing activity was found in the samples which possessed basic isoelectric points. Additionally, PLA 2-I and its basic subunit drastically prolonged activated partial thromboplastin time of platelet rich plasma. 6. 6. Intramuscular injections of PLA 2-I, -II and -III increased serum creatine phosphokinase activity in mice, indicating that damage in muscle was caused by these enzymes. 7. 7. NH 2-terminal sequences of the three PLA 2-s were compared with other phospholipase A 2s from snake venoms. Furthermore, antigenicities were tested using antiserum prepared against each sample.

Preclinical toxicology studies with the lipid-regulating agent gemcadiol

Gemcadiol is a medium-length diol moiety with lipid-regulating properties in animals and man. The compound was not toxic when single doses were administered to rodents with the lethal dose greater than 7000 mg/kg in rats and mice. Rats treated for 13 or 52 weeks with 30 to 300 mg/kg had reversible food intake suppression and weight gain inhibition, decreased blood cholesterol, slight anemia, and generally dose-related but reversible decreases in glucose, and increases in alkaline phosphatase and blood urea nitrogen. Liver weights were increased, and there was accompanying hypertrophy and increased cytoplasmic eosinophilia of hepatocytes with associated peroxisome proliferation. Rats treated for 52 weeks also had mild renal tubular dilatation. Dogs given 25 to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compound better than rats. Effects related to compound administration were elevated serum alanine aminotransferase activity in female animals only, and microscopic cytoplasmic vacuolation and hyaline body formation in both sexes. Monkeys given 25 to 300 mg/kg gemcadiol for 13 weeks had slightly decreased serum cholesterol and slightly increased serum creatine phosphokinase. Teratology studies in rats or rabbits indicated no teratogenic response. Gemcadiol affects principally the liver, and the hepatic alterations seen in rats and dogs may reflect compensatory manifestations of altered metabolism related to the lipid-regulating activity of the compound.

Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs

Three families of English springer spaniel dogs with phosphofructokinase (PFK) deficiency causing haemolysis were studied. Four male dogs and one female dog with chronic haemolysis and haemolytic crises were found to have markedly reduced PFK activity in erythrocytes (8-20% of control English springer spaniels). PFK-deficient erythrocytes exhibited an extreme alkaline and sucrose lysis. The oxygen dissociation curve of erythrocyte suspensions was shifted to the left with a 50% saturation of haemoglobin at a partial oxygen pressure of 16-17 mmHg (normal 26-31 mmHg). Muscle wasting and mildly increased serum creatine phosphokinase activity were also noted. Six clinically normal first degree relatives of affected dogs had erythrocyte PFK activities that were 38-51% of controls. In these family members, there was an erythrocytosis and mild reticulocytosis probably due to a mildly enhanced haemoglobin-oxygen affinity but no increase in serum creatine phosphokinase. These studies confirm the familial nature of muscle-type PFK deficiency in English springer spaniels and support the conclusion that this animal model of the human glycogen storage disease type VII is inherited as an autosomal recessive trait.

Preclinical Toxicology Studies with the Lipid-Regulating Agent Gemcadiol

Preclinical Toxicology Studies with the Lipid-Regulating Agent Gemcadiol. FITZGERALD, J. E., PETRERE, J. A., MCGUIRE, E. J., AND DE LA IGLESIA, F. A. (1986). Fundam. Appl. Toxicol. 6,520–531. Gemcadiol is a medium-length diol moiety with lipid-regulating properties in animals and man. The compound was not toxic when single doses were administered to rodents with the lethal dose greater than 7000 mg/kg in rats and mice. Rats treated for 13 or 52 weeks with 30 to 300 mg/kg had reversible food intake suppression and weight gain inhibition, decreased blood cholesterol, slight anemia, and generally dose-related but reversible decreases in glucose, and increases in alkaline phosphatase and blood urea nitrogen. Liver weights were increased, and there was accompanying hypertrophy and increased cytoplasmic eosinophilia of hepatocytes with associated peroxisome proliferation. Rats treated for 52 weeks also had mild renal tubular dilatation. Dogs given 25 to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compound better than rats. Effects related to compound administration were elevated serum alanine aminotransferase activity in female animals only, and microscopic cytoplasmic vacuolation and hyaline body formation in both sexes. Monkeys given 25 to 300 mg/kg gemcadiol for 13 weeks had slightly decreased serum cholesterol and slightly increased serum creatine phosphokinase. Teratology studies in rats or rabbits indicated no teratogenic response. Gemcadiol affects principally the liver, and the hepatic alterations seen in rats and dogs may reflect compensatory manifestations of altered metabolism related to the lipid-regulating activity of the compound.

SUXAMETHONIUM-INDUCED CHANGES IN SERUM CREATINE PHOSPHOKINASE

In sixty patients undergoing minor surgical procedures with minimal involvement of muscle, there was a significant increase in serum creatine phosphokinase induced by suxamethonium. The increase was significantly reduced by prior administration of tubocurarine 3 mg and by pretreatment with suxamethonium 10 mg.

Effect of tetracycline on adriamycin cardiotoxicity

Male rats were treated with either adriamycin (2 mg/kg, i.v. weekly) or adriamycin and tetracycline (10 mg/kg, i.p., daily) for 8 weeks. Serum creatine phosphokinase (CPK) activity was measured after 8 weeks as an index of cardiotoxicity. Serum CPK was significantly elevated in the adriamycin-treated rats. Tetracycline failed to inhibit the adriamycin-induced increase in serum CPK. These results indicated that tetracycline does not prevent adriamycin-induced cardiotoxicity.

Serum pyruvate-kinase (PK) and creatine-phosphokinase (CPK) in female relatives and patients with X-linked muscular dystrophies (Duchenne and Becker)

Determination of serum creatine phosphokinase (CPK) activity is often used in efforts to detect carriers of X-linked muscular dystrophies. We have recently demonstrated that another serum enzyme, pyruvate-kinase (PK) may also be of use in the diagnosis of patients affected with a variety of neuromuscular disorders. To evaluate the usefulness of this assay for carrier detection, a comparative study of serum PK and CPK activity was performed in 74 female relatives of patients affected with Duchenne (DMD) and Becker (BMD) muscular dystrophies. For obligate carriers of the DMD gene, 10 of 14 had elevated CPK's, 11 of 14 had elevated PK's and 12 of 14 had abnormal results for either of the two enzymes. Three of 16 mothers of isolated cases had increased serum CPK activity and 6 of 16 had increased PK activity (7 had elevation of at least one enzyme). These preliminary data suggest that the use of PK may enhance the capability to discriminate carriers for these X-linked recessive genes.

Acute Myopathy Associated With Influenza A/Texas/1/77 Infection

Influenza A/Texas/1/77 was isolated from a muscle biopsy specimen from a patient with muscle weakness and increased serum creatine phosphokinase level. The patient was seen during an outbreak of influenza A/Texas/1/77 that was associated with myopathy. Isolation of this virus from this patient's muscle specimen suggests that the myopathy associated with influenza may be due to direct infection of skeletal muscle.

Phenothiazine-induced dystonia associated with an increase in serum creatine phosphokinase.

A transient but considerable rise in serum creatine phosphokinase (CPK) levels occurred in six boys aged between 8 and 11 years and suffering from phenothiazine-induced dystonia. In one boy (Case 4), after the CPK level had returned to normal after withdrawal of the drug, its reintroduction orally at lower dosage caused a slight increase in the level of CPK in the absence of any recurrence of the dystonia.

Serum creatine phosphokinase activity in asthma.

Serum creatine phosphokinase activity was measured in 2 groups of asthmatics. The first group consisted of 12 asthmatics followed as outpatients for periods of up to 16 months. Serum creatine phosphokinase activity increased in 8 patients and correlated with the severity of subjective symptoms and objective measurement of airway obstruction, as represented by the forced expiratory volume in 1 second. In the second group, consisting of 5 asthmatic patients studied during hospitalization for acute exacerbations of asthma, serum creatine phosphokinase activity was increased on admission in all the patients and decreased as symptoms and airway obstruction improved and alveolar ventilation decreased. Analysis of creatine phosphokinase isoenzymes showed the increase in every instance to be due entirely to skeletal muscle isoenzyme. The results of additional laboratory tests and further evaluation suggested that the increased serum creatine phosphokinase activity was not derived from the myocardium and was not related to parenteral therapy, specific drugs, hyperthermia, or hyperkalemia. The increase in serum creatine phosphokinase during exacerbations of asthma is probably derived from respiratory muscles, owing to the increased work of breathing.

Increased Erythrocytic Osmotic Fragility in Pseudohypertrophic Muscular Dystrophy

THE DEMONSTRATION by scanning electron microscopy1that erythrocytes in patients with pseudohypertrophic muscular dystrophy (PHMD) have an irregular, crenated-like surface prompted us to investigate the fragility of these erythrocytes, since crenation represents an early stage in the development of osmotic fragility.2Our studies indicate that the susceptibility of erythrocytes to hemolysis in hypotonic saline is increased in 85% of patients with PHMD. Materials and Methods Venous blood (0.1 ml) from 94 patients with PHMD and 19 healthy, aging, and sex-matched controls was added to hypotonic saline for the detection of osmotic fragility of erythrocytes. The concentrations of saline are indicated in the Table. The percent of hemolysis of erythrocytes was determined by spectrophotometry. The diagnosis of PHMD was based in each instance on muscle weakness on recording ergometry, increased calf size, and increased serum creatine phosphokinase levels. In addition, electromyography (41 patients), motor nerve conduction velocity (40 patients),

Serum creatine phosphokinase activity in psychiatrically hospitalized children.

Serum creatine phosphokinase (CPK) activity was determined in a series of 101 sequential admissions to the Pritzker Children's Hospital, an inpatient psychiatric facility. Black children had significantly higher serum CPK levels than whites, and males had significantly higher levels than females, as is the case with adults. There was a higher incidence of CPK elevations in children with organic brain pathology than in children with personality disorders or schizoprenia. Children with chronic symptoms of a psychotic nature did not have increased serum CPK activity, which is similar to the findings in adults. There were no children in the sample with acute psychotic symptoms, so it was not possible to determine whether acute psychosis in children is accompanied by increased serum CPK activity, as it frequently is in psychotics over the age of 17.

One‐year trials with halofenate, clofibrate, and placebo

The hypolipidemic as well as other laboratory and clinical effects of halofenate, clofibrate, and placebo were compared in 29 patients with type IV hyperlipoproteinemia in a double-blind, controlled, therapeutic trial of 1 yr duration. Plasma drug levels were obtained to monitor compliance. Clofibrate and halofenate lowered serum triglycerides to a similar extent. The hypotriglyceridemic effect of halofenate was significant only when data from noncompliant patients were discarded. Only clofibrate lowered baseline levels of plasma cholesterol. Very low density lipoproteins were decreased and low density lipoproteins were increased by clofibrate but not by halofenate. Halofenate had a marked hypouricemic effect that was greater than that of clofibrate. The hypouricemic effect of halofenate and clofibrate was paralleled by a concomitant decrease in serum bilirubin. Abnormal increases in serum creatine phosphokinase were observed with both drugs primarily in patients who had abnormal initial levels.

Serum creatine phosphokinase in schizophrenia.

The author notes that increased serum creatine phosphokinase (CPK) activity is found in the majority of hospitalized acutely disturbed schizophrenics and patients with affective psychoses. It is probable that some of these increases do not result from nonspecific factors such as activity, trauma, or stress, which do cause increases in some cases. Those patients who show increased CPK activity have more florid psychopathology and tend to have higher CPK levels in nonacute periods than those without increases. First-degree relatives of psychotic patients with elevated serum CPK have high-normal or slightly increased serum CPK. There is also evidence of other neuromuscular dysfunction in psychotic patients. The author concludes that the investigation of CPK may have considerable heuristic value for the study of schizophrenia and other psychoses.

Metabolic and histopathologic changes in arteriosclerotic versus nonarteriosclerotic rats following isoproterenol-induced myocardial infarction with superimposed diabetes

Male and female, arteriosclerotic and nonarteriosclerotic rats were subjected to acute myocardial infarction by two, subcutaneous injections (spaced 24 hr apart) of isoproterenol. During the immediate postinfarct repair phase all of the experimental animals were made severely diabetic with alloxan. Two weeks later the animals were sacrificed and their blood and pertinent organs analyzed for biochemical and pathologic changes. Females survived the myocardial infarct with superimposed diabetes in significantly greater numbers than males. In addition to marked loss in body weight all of the experimental animals developed marked adrenal hypertrophy and thymus gland involution, cardiac hypertrophy, and unusual increase in ovarian or testicular size and weight. The combined conditions of mhocardial infarction + diabetes led to substantial increases in serum creatine phosphokinase (CPK) and glutamic oxaloacetic transaminase (SGOT) whereas the enzymes glutamic pyruvic transaminase (SGPT) and lactic dehydrogenase (LDH) were reduced. Although serum triglyceride levels were greatly elevated, total cholesterol and free fatty acids were reduced. All of the animals were severely hyperglycemic and had greatly increased B.U.N. levels. Diabetes caused hypercalcemia but diabetes + myocardial infarction was associated with a definite reduction of this hypercalcemia. Despite marked adrenal hypertrophy, circulating Cmpd. B levels were subnormal. The diabetic condition and its attendant hyperlipidemia did not alter the morphologic nature of the arterial lesions in the breeder rats but the diabetes did cause definite impairment of the usual myocardial repair process observed in these rats with a particularly high incidence of left ventricular aneurysms in males.