Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.
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PMID:Currently available hypolipidaemic drugs and future therapeutic developments. 859 27

Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides <9 mmol/L [800 mg/dL]) into 3 treatment groups: (1) Niaspan 1,000 mg/day; (2) Niaspan 2,000 mg/day; and (3) placebo. The primary treatment endpoint was LDL-cholesterol level. This endpoint was not significantly affected by placebo (0.2% increase), but Niaspan decreased LDL cholesterol by 5.8% (1,000 mg/day) and 14.6% (2,000 mg/day) (p <0.001). Likewise, with placebo there were significant changes in total cholesterol, triglycerides, lipoprotein(a), and apoprotein B, whereas both Niaspan 1,000 and 2,000 mg/day significantly (p <0.001) decreased these parameters. In addition, both Niaspan groups showed significant (p <0.001) increases in HDL cholesterol (17% and 23%, respectively), including HDL subfractions. With respect to flushing, 20% of the placebo group reported at least 1 episode, whereas 88% and 83% of the Niaspon 1,000- and 2,000-mg/day groups, respectively, reported episodes. There was no hepatotoxicity as liver enzyme levels remained within clinically accepted limits in all treatment groups. However, Niaspan 2,000 mg/day showed a significant increase in aspartate aminotransferase compared with baseline and placebo. This trial demonstrated a cholesterol-modifying effect of Niaspan consistent with those reported for niacin, but demonstrated a better tolerance for flushing. Moreover, in contrast to sustained-release formulations, Niaspan showed relatively mild hepatic effects.
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PMID:A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. 991 60

Combination therapy is increasingly recommended for patients with multiple lipid disorders, especially those at high risk for coronary events. We investigated the long-term safety and effectiveness of a new drug formulation containing once-daily extended-release niacin and lovastatin. A total of 814 men and women (mean age 59 years) with dyslipidemia were enrolled in a 52-week multicenter, open-label study. We used 4 escalating doses (niacin/lovastatin in milligrams): 500/10 for the first month, 1,000/20 for the second, 1,500/30 for the third, and 2,000/40 for the fourth month through week 52. Dose-dependent effects were observed for all major lipid parameters. At week 16, mean low-density lipoprotein (LDL) cholesterol and triglycerides were reduced by 47% and 41%, respectively; mean high-density lipoprotein (HDL) cholesterol was increased by 30% (all p <0.001). LDL/HDL cholesterol and total/HDL cholesterol ratios were also decreased by 58% and 48%, respectively. These effects persisted through week 52, except for the mean increase in HDL cholesterol, which had increased to 41% at 1 year. Lipoprotein (a) and C-reactive protein also decreased in a dose-related manner (by 25% and 24%, respectively, on 2,000/40 mg; p <0.01 vs baseline). Treatment was generally well tolerated. The most common adverse event was flushing, which caused 10% of patients to withdraw. Other adverse events included gastrointestinal upset, pruritus, rash, and headache. Drug-induced myopathy did not occur in any patient. The incidence of elevated liver enzymes to >3 times the upper limit of normal was 0.5%. Once-daily niacin/lovastatin exhibits substantial effects on multiple lipid risk factors and represents a significant new treatment option in the management of dyslipidemia.
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PMID:Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. 1189 8

Asian Indian dyslipidemia is characterized by: borderline high low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B; high triglycerides, low high-density lipoprotein (HDL) cholesterol and apoA1; and high lipoprotein(a) (lp[a]). We performed a controlled multicentric trial in India to evaluate the efficacy and safety of a fixed dose combination of lovastatin and niacin extended release (niacin(ER)) formulation in patients with moderate to severe dyslipidemia. Consecutive subjects that satisfied the selection criteria, agreed to an informed consent, and with no baseline presence of liver/renal disease or heart failure were enrolled in the study. After a 4-week run-in period there were 142 patients with LDL levels > or = 130 mg/dL. Eleven patients were excluded because of uncontrolled hyperglycemia and 131 patients were recruited. After baseline evaluation of clinical and biochemical parameters all subjects were administered lovastatin (20 mg) and niacin(ER) (500 mg) combination once daily. Dose escalation was done on basis of lipid parameters at 8 weeks and in 11 patients increased to lovastatin (20 mg) and niacin(ER) (1000 mg). An intention-to-treat analysis was performed and data was analyzed using nonparametric Wilcoxon signed rank test. Thirteen patients (10%) were lost to follow-up and 4 (3%) withdrew because of dermatological adverse effects: flushing, pruritus, and rash. The mean values of various lipid parameters (mg/dL) at baseline, and at weeks 4, 12, and 24 respectively were: total cholesterol 233.9 +/- 27, 206.3 +/- 27, 189.8 +/- 31, and 174.9 +/- 27 mg/dL; LDL cholesterol 153.4 +/- 22, 127.3 +/- 21, 109.2 +/- 27, and 95.1 +/- 23 mg/dL; triglycerides 171.1 +/- 72, 159.5 +/- 75, 149.2 +/- 45, and 135.2 +/- 40 mg/dL; HDL cholesterol 45.6 +/- 7, 48.9 +/- 7, 51.6 +/- 9, and 53.9 +/- 10 mg/dL; lp(a) 48.5 +/- 26, 40.1 +/- 21, 35.4 +/- 21, and 26.9 +/- 19 mg/dL; and apoA1/apoB ratio 0.96 +/- 0.7, 1.04 +/- 0.4, 1.17 +/- 0.5, and 1.45 +/- 0.5 (p < 0.01). The percentage of decline in various lipids at 4, 12, and 24 weeks was: total cholesterol 11.8%, 18.8%, and 25.2%; LDL cholesterol 17.0%, 28.8%, and 38.0%; triglyceride 6.8%, 12.8%, and 21.0%; lp(a) 17.5%, 26.9%, and 44.5% respectively (p < 0.01). HDL cholesterol and apoA1/apoB increased by 7.2%, 13.1%, and 18.2%; and 7.9%, 21.9%, and 51.6% respectively (p < 0.01). Target LDL levels (< 100 mg/dL in subjects with manifest coronary heart disease or diabetes; < 130 mg/dL in subjects with > 2 risk factors) were achieved in 92 (80.7%) patients. No significant changes were observed in systolic or diastolic blood pressure, blood creatinine, transaminases, or creatine kinase. A fixed dose combination of lovastatin and niacin(ER) significantly improved cholesterol lipoprotein lipids as well as lp(a) and apoA1/apoB levels in Asian Indian dyslipidemic patients. Satisfactory safety and tolerability profile in this population was also demonstrated.
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PMID:Evaluation of efficacy and safety of fixed dose lovastatin and niacin(ER) combination in asian Indian dyslipidemic patients: a multicentric study. 1731 73

No appropriate pharmaceutical therapy has been established for dyslipidemia with cholestasis in progressive familial intrahepatic cholestasis (PFIC)-1. We evaluated the efficacy of bezafibrate in PFIC-1. We monitored the clinical presentation and lipoprotein metabolism of 3 patients, aged 3, 4, and 8 years, with FIC1 deficiency, manifesting PFIC-1, over 12 months of bezafibrate therapy. Pruritus was substantially alleviated in the 3 patients after initiation of bezafibrate. Cholestasis was alleviated in 2 of them. Serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol increased 1.6- to 2.0-fold and 1.1- to 1.2-fold, respectively; but the values remained low and normal, respectively. Serum lipoprotein X, which was at normal levels before treatment, was elevated to levels above the upper limit of the reference range. High serum triglyceride levels decreased by 15% to 30%, to normal levels, after treatment initiation. The activities of lipoprotein lipase and hepatic triglyceride lipase were increased, but those of high-density lipoprotein regulators remained unchanged. Liver expression of multidrug resistance protein-3, which regulates lipoprotein X synthesis, was enhanced by bezafibrate therapy. Bezafibrate treatment favorably affected pruritus, dyslipidemia, and cholestasis in PFIC-1.
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PMID:Effects of bezafibrate on dyslipidemia with cholestasis in children with familial intrahepatic cholestasis-1 deficiency manifesting progressive familial intrahepatic cholestasis. 1905 30

A 75 year old woman presented with long-lasting pruritus and elevation of serum levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT). Potentially hepatotoxic drugs were stopped; an abdominal ultra-sonography was normal. Antimitochondrial antibodies were elevated and are the serologic hallmark of primary biliary cirrhosis. The disease can progress from an asymptomatic inflammation to a cirrhosis. The disease-modifying treatment consists in ursodeoxycholic acid 13-15 mg/kg per day. Concomitant to the primary biliary cirrhosis hypothyroidism, osteoporosis, malabsorption and dyslipidemia can occur.
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PMID:[No complaints, but constantly elevated cholestatic serum liver tests]. 2173 1

Intrahepatic Cholestasis of Pregnancy (ICP) constitutes the most common, reversible liver disease closely connected with pregnancy and spontaneously resolving in puerperium. ICP usually reoccurs in consecutive pregnancies (45-90%), often in a more intensified form. Many compounds (hormones, cytokines, medicines, endotoxins) can impair transport in the hepatocyte, disturb the intracellular transport and increase the permeability of the intercellular connections. As a result, the elements of bile may appear in the peripheral blood. Gestational cholestasis constitutes a classic example of intrahepatic cholestasis. The etiology of ICP is multifactorial with hormonal, genetic and environmental factors participating in the process. The diagnosis is based on the presence of pruritus, elevated values of bile acids in the blood serum and of aminotransferases (aspartic, aminopropionic and gamma-glutamylotranspeptydase (AspAt, AlAt, GGTP)), as well as spontaneous remission in the second or third week after childbirth, of lack of other illnesses causing pruritus and icterus. Clinical and biochemical symptoms of ICP include: pruritus without skin rash (usually after 30 weeks of gestation), mild icterus, steatorrhea etc. Abnormalities in the laboratory tests of the LFT (liver function tests) encompass: an increase in the serum concentration of fatty acids (BA) which can be the first and only laboratory abnormality. Concentrations surpassing 10 micromol/l are considered to be abnormal. Concentration of BA higher than 40 micromol/l allows to recognize a case of severe ICP, connected with the risk of premature delivery presence of the meconium liquor, surgical means of delivery and low APGAR score of the newborn (< 7 pt). In about 80% of pregnant women with ICP, the BA concentration ranges between 10-40 micromol/l, but perinatal results are comparable with uncomplicated pregnancies. Some authors are of the opinion that abnormal AlAt value is the most sensitive test, other authors consider the abnormal values of alkaline phosphatase and bilirubin to be the most pathognomonic factors. Other abnormal tests include: higher activity of alpha-hydroxybutyric dehydrogenase correlated with an increase of the alkaline phosphatase and bilirubin; mild metabolic acidosis; dyslipidemia with elevated concentrations of the total lipids, total cholesterol and free LDL cholesterol and apolipoprotein; abnormal glucose tolerance test. ICP constitutes a medical problem that carries a considerable risk for the fetus, resulting from an increased flow of bile acids to the fetal blood circulation (elevated level in the amniotic fluid, in the umbilical blood serum and meconium). The risk of adverse effects for the fetus correlates with the rise of BA concentration in maternal blood serum. Cholestasis increases the risk of premature labor, presence of meconium in the amniotic fluid, fetal bradycardia, intrauterine asphyxia and stillbirth, particularly when the concentration of serum bile acids on an empty stomach is above 40 micromol/l. However, maternal clinical signs and symptoms do not correlate with the fetal outcome. Aspiration of bile acids or their accumulation in the fetal blood circulation are responsible for the increased frequency of RDS appearing in ICP. The aim of the obstetric management of ICP is to reduce maternal symptoms and biochemical disorders and to minimize the risk of premature delivery fetal distress and sudden death. ICP management should include: bed regime, light, low-fat diet, no stress, upper abdomen ultrasound examination, LFT tests and thrombotic tests once a week, monitoring of the fetal well-being with the available biophysical methods, pharmacotherapy and therapeutic termination of pregnancy in case of serious illness and/or the fetal distress. Ursodeoxycholic acid (UDCA) is the basis of the pharmacological treatment of pregnant women and currently constitutes the most promising treatment option of ICP. UDCA is administered orally in the dosage of 10-16 mg/kg/24, what in practice means 250-300 mg/2-3 times a day.
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PMID:[Clinical practice guidelines of the Team of Experts of the Polish Gynecological Society: management of the intrahepatic cholestasis of pregnancy]. 2334 3

Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren's syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva substitutes, cholinergic agents, and scrupulous oral and dental care. Complications of cirrhosis from advanced PBC include esophageal varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatoma formation.
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PMID:Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy. 2595 76

Uremic pruritus (UP) is a frequent and bothersome symptom in hemodialysis patients. Its etiology is not fully understood and that is why there is no specific treatment. The endocannabinoid system plays a role in many pathological conditions. There is reliable evidence on the association between cannabinoid system and pruritus. In our study, we aimed to evaluate whether genetic variations in the endocannabinoid receptor 1 (CNR1) gene can affect UP. The rs12720071, rs806368, rs1049353, rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms of the CNR1 gene were genotyped in 159 hemodialysis patients and 150 healthy controls using two multiplex polymerase chain reactions and the minisequencing technique. No statistically significant relationship was found in any of the evaluated genotypes between patients with and without UP, even after excluding patients with diabetes and dyslipidemia. There were no differences between patients with UP and the control group. However, in the group of all HD patients, a significantly higher incidence of GA genotype and lower incidence in GG genotype in the polymorphism rs806381s were revealed versus the control group (p = 0.04). It seems that polymorphisms of the CNR1 gene are not associated with uremic pruritus.
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PMID:Uremic Pruritus Is Not Associated with Endocannabinoid Receptor 1 Gene Polymorphisms. 2703 34

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder which typically commences in the late second or third trimester and resolves within 48 hours after delivery. It is characterized by mild to severe pruritus, without any specific dermatologic features, elevated liver enzymes and increased serum bile acids (BA). The etiology of ICP is still not completely explicit. Pathogenesis includes a combination of hormonal and environmental factors superimposing on a genetic predisposition. During recent years increasingly ICP is recognized to be associated with an abnormal metabolic profile, including glucose intolerance and dyslipidemia, although it is considered to be secondary to maternal aberrant BA homeostasis. This article reviews the recent literature data and current concepts for ICP, with emphasis on a possibility of metabolic disorders being primary causative factors in ICP pathogenesis.
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PMID:The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy. 3060 68


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