Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027121 (myositis)
 4,538 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 25 patients with primary dyslipoproteinemias and severe premature atherosclerosis, during an average combined Lopid-Mevacor treatment span of 12.5 months per patient, our specific aim was to assess safety and efficacy of open-label therapy with diet, gemfibrozil (Lopid), and lovastatin (Mevacor). Because targeted lipid values were not reached on diet alone (low-density lipoprotein cholesterol [LDLC] less than 120 mg/dl, high-density lipoprotein cholesterol [HDLC] greater than 35 mg/dl or total cholesterol [TC]/HDLC less than 4.5), the patients received Lopid, 1.2 gm/day as their initial lipid-lowering drug. Because targeted lipid levels were not reached with Lopid treatment alone after 3 or more months, Mevacor was added, with 17 subjects receiving 20 mg/day, five receiving 40 mg, two receiving 60 mg, and one receiving 80 mg. Outpatient visits were repeated during combined therapy every 6 to 8 weeks, with an average of 6.4 visits per subject, 162 measurements of fasting lipids and liver function tests, and 127 measurements of creatine phosphokinase (CPK). By selection, all patients had normal liver function (gamma-glutamyltransferase, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) levels) and normal CPK levels at baseline. No gamma-glutamyltransferase levels were high during combined therapy. Of the 162 liver function test measurements, five (3.1%) SGOT levels and three (1.9%) SGPT levels were high. Of 127 CPK measurements, three (2.4%) were high; one subject had a high CPK measurement, and one subject had two high measurements for CPK. No symptomatic myositis or myalgias developed in the subjects; none had palpable skeletal muscle tenderness.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Safety and efficacy of combined gemfibrozil-lovastatin therapy for primary dyslipoproteinemias. 234 62

Calcification and ossification of soft tissues occurs as a response to a variety of injuries such as atherosclerosis, myositis ossificans, and caseous necrosis. These injuries and others have as a unifying characteristic persistent necrotic tissue elements. Normal tissues may calcify under conditions of hypercalcemia or hyperphosphatemia. The initial mobilization of Ca and P following injury is rapid, as observed in calcergy. The mitochondria of cells, normally a storehouse of Ca, become preferential sites of precipitated Ca when cells are irreversibly injured, and act as foci of progressive calcification. Collagen fibers undergo calcification directly, principally when they are located within devitalized sites such as prosthetic heart valves, and direct calcification of collagen may predominate generally in dystrophic calcification. VArious porous sponges act as foci for calcification and ossification, and the utilization of porous implants may provide for the development of therapeutically useful calcifying and ossifying biomaterials.
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PMID:Mineralization of connective tissue surrounding implanted devices. 733 Nov 58

Both the European Atherosclerosis Society and the US National Cholesterol Education Program have issued revised guidelines for the prevention of coronary heart disease (CHD), based on a multitude of recent epidemiological and angiographic studies. Both authorities agree that a target plasma low-density lipoprotein cholesterol (LDL-C) level is the single most important parameter, this target level being different for primary and secondary prevention. The introduction of statins for the treatment of hypercholesterolaemia provides an important tool to enable target LDL-C levels to be reached in most cases of primary prevention. For secondary prevention, however, the target LDL-C levels--2.6 mmol/l (100 mg/dl)--may be achieved in only a fraction of cases. Others may require the concomitant administration of other cholesterol-lowering drugs, such as bile-acid sequestrants (resins) and/or derivatives of fibric acid (fibrates). The use of statin-fibrate combinations has been discouraged since the report by the US Food and Drug Administration of 12 sporadic cases of myositis or rhabdomyolysis. During the past 7 years, however, 21 clinical trials have examined the efficacy and safety of statin-fibrate combinations in a total of 486 patients with a variety of dyslipidaemias. Overall, the combinations were proven to be effective and safe, and the incidence of abnormalities in liver function tests and levels of creatine kinase (CK) was low. A double-blind study has been carried out at the Hadassah University Hospital to examine the efficacy and safety of fluvastatin when combined with either cholestyramine (group 1) or bezafibrate (group 2) for the treatment of 38 patients with heterozygous familial hypercholesterolaemia (FH). Patients in group 2 showed a reduction in plasma LDL-C levels of 35% and in LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio of 45% compared with 32% and 38% respectively in group 1. Both cholestyramine and bezafibrate produced an additional benefit of a 13% reduction in LDL-C levels in comparison with fluvastatin as monotherapy. An open-label ongoing study on a larger cohort of FH patients reveals that a decrease in plasma LDL-C levels of up to 38.5% may be achieved with a combination of fluvastatin 80 mg/day and bezafibrate 400 mg/day. In both studies, biochemical safety analyses revealed no notable abnormalities in liver function tests or levels of CK. It was concluded that fluvastatin-bezafibrate is a very effective synergistic therapy for heterozygous FH and is superior to a fluvastatin-cholestyramine combination.
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PMID:The patient at risk: who should we be treating? 1949 69

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
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PMID:Chemical toxicity and reactive oxygen species. 911 92

Fibric acid derivatives are a class of hypolipidaemic drugs used in the treatment of patients with hypertriglyceridaemia, mixed hyperlipidaemia and diabetic dyslipidaemia. Fibrate therapy results in a significant decrease in serum triglycerides and an increase in high-density lipoprotein (HDL) cholesterol levels. The latest drugs of this class are also effective in lowering low-density (LDL) cholesterol levels and can change the distribution of LDL towards higher and larger particles. The effects of fibrates on lipid metabolism are mostly mediated through the activation of peroxisome proliferator-activated receptors (PPARalpha). A number of angiographic and clinical trials have confirmed that fibrates can slow the progression of atherosclerotic disease and decrease cardiovascular morbidity and mortality. Recently published data suggest that the ability of fibrates to prevent atherosclerosis is not related only to their hypolipidaemic effects but also to other 'pleiotropic effects', such as their anti-inflammatory, antioxidant and antithrombotic effects, as well as their ability to improve endothelial function. Interestingly, fibrates may favourably influence the thrombotic/fibrinolytic system. In fact, most of these drugs can significantly decrease plasma fibrinogen levels and inhibit tissue factor expression and activity in human monocytes and macrophages. Some studies have shown that fibrates can improve carbohydrate metabolism in patients with dyslipidaemia, including diabetic patients. Among fibrates only fenofibrate can significantly decrease serum uric acid levels by increasing renal urate excretion. Fibrates, with the possible exception of gemfibrozil, can significantly increase serum creatinine and homocysteine levels. Finally, a reduction in serum alkaline phosphatase and gamma glutamyltranspeptidase (gammaGT) activity is a well-documented effect of therapy with fibrates. The fibrates are generally well-tolerated drugs with few side-effects. The most important side-effect is myositis, which is observed in patients with impaired renal function or when statins are given concomitantly.
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PMID:Effects of fibrates on serum metabolic parameters. 1274 Jan 59

The management of dyslipidemia in adults with diabetes is receiving more attention. However, there is a paucity of large, prospective, randomized outcome trials designed for diabetic patients. Diabetic dyslipidemia is characterized by an increase in triglyceride levels, low high-density lipoprotein (HDL) cholesterol concentrations, and small, dense low-density lipoprotein (LDL) particles. The treatment goals include an LDL cholesterol less than 100 mg/dL, triglyceride level less than 150 mg/dL, and an HDL greater than 40 mg/dL for men and more than 50 mg/dL for women. In the Diabetic Atherosclerosis Intervention Study, fenofibrate resulted in a 42% less increase in the percent stenosis, as assessed by quantitative coronary arteriography. The Heart Protection Study documented the unambiguous benefit of simvastatin in reducing all-cause mortality among 5963 diabetic patients. The Lescol Intervention Prevention Study observed a reduction in major adverse cardiac events in diabetics undergoing percutaneous intervention who received fluvastatin. The Veterans Affairs HDL Cholesterol Intervention Trial reported a reduction in major coronary events among 627 diabetic patients with low HDL cholesterol who sustained a myocardial infarction. The Fenofibrate Intervention and Event Lowering in Diabetics (FIELD) Trial (n = 9795), the Action to Control Cardiovascular Risk in Diabetes (ACCORD, n = 10,000), the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non Insulin Dependent Diabetes Mellitus (ASPEN, n = 2421), and the Collaborative Atorvastatin Diabetes Study (CARDS, n = 2140) will provide the prospective outcome data that are needed for the management of patients. Combination drug therapy will be necessary to achieve treatment goals. Careful monitoring will be required to avoid myositis and hepatotoxicity.
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PMID:Clinical trials and lipid guidelines for type II diabetes. 1505 51

The mechanism of the muscle toxicity associated with lipid-lowering therapy remains obscure. Pathological and biochemical findings in patients with statin myotoxicity suggest impaired fatty acid oxidation. Exhaled gas analysis can be used to assess substrate utilization including fatty acid oxidation. In order to determine if muscle toxicity due to lipid-lowering therapy might be related to abnormalities in lipid oxidation, exhaled gas analysis was performed in the fasted state on 11 patients subsequent to statin-associated myositis reactions. Results were compared to those of 16 normal controls who were measured both on and off statin therapy. Post-myositis patients showed a depressed anaerobic threshold (AT) (P=0.009) compared to controls while age-adjusted maximal oxygen consumption (VO2max) and ventilatory efficiency (VE/VCO2) were not significantly different. The fasting respiratory exchange ratio (RER) of post-myositis patients off statins was abnormally increased (P=0.00001) as was their S1-slope (P=0.023). Controls demonstrated a significant increase in their RER while taking statins consistent with decreased lipid oxidation (P <0.00001). These findings suggest that abnormal lipid oxidation in certain patients may predispose them to the myotoxicity caused by lipid-lowering therapies.
Atherosclerosis 2004 Nov
PMID:Statin myotoxicity is associated with changes in the cardiopulmonary function. 1548 82

Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.
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PMID:Ciprofibrate, clofibric acid and respective glycinate derivatives. Effects of a four-week treatment on male lean and obese Zucker rats. 1858 57

Recently,both the European Atherosclerosis Society and the US National Cholesterol Education Program have issued revised guidelines for the prevention of coronary heart disease (CHD), based on a multitude of recent epidemiological and angiographic studies. Both authorities agree that a target plasma low-density lipoprotein cholesterol (LDL-C) level is the single most important parameter, this target level being different for primary and secondary prevention. The introduction of statins for the treatment of hypercholesterolaemia provides an important tool to enable target LDL-C levels to be reached in most cases of primary prevention. For secondary prevention, however, the target LDL-C levels--2.6 mmol/l (100 mg/dl)--may be achieved in only a fraction of cases. Others may require the concomitant administration of other cholesterol-lowering drugs, such as bile-acid sequestrants (resins) and/or derivatives of fibric acid (fibrates). The use of statin-fibrate combinations has been discouraged since the report by the US Food and Drug Administration of 12 sporadic cases of myositis or rhabdomyolysis. During the past 5 years, however, 15 linical trials have examined the efficacy and safety of statin-fibrate combinations in a total of 394 patients with a variety of dyslipidaemias. Overall, the combinations were proven to be effective and safe, and the incidence of abnormalities in liver function tests and levels of creatine kinase (CK) was low. A double-blind study has been carried out at the Hadassah University Hospital to examine the efficacy and safety of fluvastatin when combined with either cholestyramine (group 1) or bezafibrate (group 2) for the treatment of 38 patients with heterozygous familial hypercholesterolaemia (FH). Patients in group 2 showed a reduction in plasma LDL-C levels of 35% and in LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio of 45% compared with 32% and 38% respectively in group 1. Both cholestyramine and bezafibrate produced an additional benefit of a 13% reduction in LDL-C levels in comparison with fluvastatin as monotherapy. Biochemical safety analyses revealed no notable abnormalities in liver function tests or levels of CK. It was concluded that fluvastatin-bezafibrate is a very effective synergistic therapy for heterozygous FH and is superior to a fluvastatin-cholestyramine combination.
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PMID:The patient at risk: who should we be treating? 872 87

Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.
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PMID:Statin-induced myopathies. 2200 73


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