Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HMG-CoA reductase inhibitors have been shown to cause marked reduction of cholesterol and offer a new and effective approach to treatment of hyperlipoproteinemia. Three agents, pravastatin (P), lovastatin (L) and simvastatin (S), have been studied with reference to long-term lipid-lowering effect, tolerance and clinical safety. Following a dietary lead-in period of at least 6 weeks in every case, patients with primary hypercholesterolemia were enrolled from participants of short-term controlled studies which after completion were extended as open studies. Treatment was administered over 6 months with 20 mg S (84 patients), L (42 patients) or P (23 patients) twice daily. Total cholesterol was decreased with S by 30.2% of basal, with L by 25.5%, and with P by 28.2%. The decrease in apolipoprotein B was 28.4%, of basal, with S 16.4% and in P 19.2%. Triglycerides were lowered by 19.6% of basal with S by 17.4%, with L, and by 6.4% with HDL-cholesterol increased in the S group by 23% of basal, by 9.7% in the L group, and by 8.0% in the P group. No serious clinical or laboratory abnormalities were observed. In the S group headache (3.6% of patients), abdominal discomfort (2.4%), sleeping disturbances (3.6%), and muscle pain (2.4%) were reported. In the L group headache (7.1%), abdominal discomfort (4.8%), sleep disorders (4.8%), and muscle pain (4.8%) were observed. In the P group one patient complained of abdominal discomfort (8.7%) and one of sleep disorders (8.7%). Increases in CPK were observed in the S group (4.8% of patients) and in the L group (11.9%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of different HMG-CoA reductase inhibitors. 190 57

Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has been administered to approximately 2,400 patients with primary hypercholesterolemia with a mean follow-up of 1 year in controlled clinical studies and their open extensions. Approximately 10% of this population received simvastatin for a period of greater than or equal to 2 years. The population on whom this safety analysis is based had a mean age of 50 years; 62% were men and approximately 27% had preexisting coronary artery disease. Simvastatin was titrated to the maximal daily dose of 40 mg each evening in 56% of the study population (last recorded dose). The most frequently reported drug-related clinical adverse experiences were constipation (2.5%), abdominal pain (2.2%), flatulence (2.0%) and headaches (1%). Persistent elevations of serum transaminase levels greater than 3 times the upper limit of normal were observed in only 1% of this cohort with only 0.1% of the total population requiring discontinuation of therapy. There were no clinically apparent episodes of hepatitis. Discontinuation of therapy due to myopathy was extremely rare (0.08%). Only minimal increases in the frequency of lens opacities (1%) were observed from baseline to the last lens examination during follow-up, consistent with the expected increase in lens opacity development due to normal aging. Patients who were greater than or equal to 65 years old had a clinical and laboratory safety profile comparable to the nonelderly population.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term safety and efficacy profile of simvastatin. 195 Oct 69

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.
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PMID:Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study. 212 37

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and adverse effects of lovastatin are reviewed. Lovastatin is the first agent marketed in a new class of pharmacologic compounds called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. By competitively inhibiting HMG CoA reductase, the drug disrupts the biosynthesis of cholesterol in hepatic and peripheral cells. This increases the synthesis of low-density-lipoprotein (LDL) receptors and thereby increases the uptake of LDL cholesterol from the plasma. In doses of 20 to 80 mg daily, lovastatin decreases total and LDL cholesterol concentrations 25 to 45%. It also substantially reduces concentrations of triglycerides, very-low-density-lipoprotein (VLDL) cholesterol, and apolipoprotein B and slightly increases high-density-lipoprotein (HDL) cholesterol concentrations. Lovastatin is effective in patients with heterozygous familial and nonfamilial (polygenic) hypercholesterolemia but is ineffective in patients with homozygous familial hypercholesterolemia. It is also effective in combination with bile acid sequestrants, nicotinic acid, and gemfibrozil. Administration of lovastatin once daily in the evening (to enhance compliance) or twice daily is recommended to maximize the drug's cholesterol-lowering effects. Headache and gastrointestinal complaints are the most common adverse effects. Treatment has been withdrawn from 1.9% of patients receiving the drug because of elevated aminotransferase concentrations. The relationship of lovastatin to the development of lens opacities requires further evaluation. Lovastatin is highly effective in the treatment of primary hypercholesterolemia and represents an important therapeutic advance. Safety with long-term use and effect on coronary heart disease remain to be established.
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PMID:Lovastatin: a new cholesterol-lowering agent. 327 32

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical implications of the biopharmaceutical properties of fluvastatin. 819 18

Clinical experience with fluvastatin in > 1,800 North American patients treated for an average of 61 weeks has shown it to be safe and well tolerated. Frequencies of transaminase and creatine kinase elevations compare favorably with those observed during long-term administration of other 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Further, whereas frank rhabdomyolysis has been encountered with treatment with all other HMG-CoA reductase inhibitors, this syndrome has not been observed to date with fluvastatin in studies here or abroad; a single case of myopathy, which was probably related to physical exertion, was reported in a patient receiving fluvastatin. Although dyspepsia was observed more commonly in fluvastatin patients the incidence, along with that of other adverse events (e.g., headache), and the number of treatment discontinuations proved statistically indistinguishable from those of placebo controls. Whether the favorable safety profile of fluvastatin is related to this synthetic agent's unique biopharmaceutical profile is a matter of ongoing long-term inquiry.
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PMID:Updated clinical safety experience with fluvastatin. 819 19

Tolerance and pharmacokinetics after single-dose administration of atorvastatin, an investigational inhibitor of HMG-CoA reductase, were examined in 22 healthy volunteers in a three-period, partially-blinded study. Participants received capsule and solution doses of atorvastatin (0.5 to 120 mg) and placebo at weekly intervals. Atorvastatin was well tolerated at doses as high as 80 mg. The adverse event profile was similar after administration of atorvastatin capsules and placebo. Atorvastatin solution was slightly less well tolerated. The most common side effect after administration of capsules and solution was headache, followed by sporadic reports of diarrhea, flatulence, and nausea. At the 120-mg solution dose, one participant experienced mild, transient restlessness, euphoria, and mental confusion that were considered to be dose-limiting side effects. Mean concentrations of atorvastatin, maximum concentration (Cmax), and area under the concentration-time curve from time 0 to the time of the last detectable concentration (AUCo-tldc) increased with increasing dose. Plasma elimination half-life (t1/2) ranged from 14.7 to 57.6 hours. The bioavailability of atorvastatin capsules was similar to that of solution. These results suggest that atorvastatin is well tolerated after single doses as high as 80 mg, and may require administration only once daily.
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PMID:Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects. 887 77

A 46-yr-old airline captain with many exposures to altitude chamber, fighter, and airliner flight developed migraine-type headaches after exposure to cabin altitudes above 6,000 feet. He had no prior history of chronic headaches or migraine. Symptoms began within days of starting pravastatin for hypercholesterolemia, but had not occurred during 4 yr of treatment with lovastatin. Headache intensity related directly to increasing pressure altitudes above 6,000 ft for periods of time greater than 45 min. Descent below 5,000 ft cabin altitudes relieved headaches. Exposure to barometric pressure changes has been associated with migraine headache. Vascular headaches are also a prominent feature of acute mountain sickness. Although the HMG-CoA reductase inhibitors are reported to be associated with increased occurrence of headache, the mechanism is poorly understood. Migraine headaches may be triggered in previously asymptomatic individuals by unique combinations of trigger factors. However, there have been no prior reports of migraine headaches triggered by the combined exposure to pravastatin and reduced barometric pressure.
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PMID:Altitude-induced migraine headache secondary to pravastatin: case report. 964 8

The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0.2 mg on mean plasma digoxin levels and the effect of digoxin on the single-dose pharmacokinetics of cerivastatin were assessed in 20 healthy normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After a 2-day washout period, subjects were given a loading dose of digoxin 0.5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1-digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic variables for cerivastatin, including area under the curve (AUC(0-24)), peak concentration (C(max)), time to peak concentration (T(max)), and elimination half-life (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.
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PMID:Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers. 1050 51

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.
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PMID:Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults. 1131 78


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