Mg Of Pravastatin Research Articles

Short-term effects of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor on cholesterol and bile acid synthesis in humans.

Competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase improve hypercholesterolemia. However, reports about the effects of these agents on bile acid synthesis, the metabolic pathway of cholesterol, are conflicting. We studied the short-term effect on one of these agents, pravastatin, on bile acid synthesis. Six male volunteers were given 40 mg of pravastatin. Plasma mevalonate level (which reflects cholesterol synthesis) and 7 alpha-hydroxy-4-cholesten-3-one level (which reflects bile acid synthesis) were measured every 2 h for 8 h. These plasma levels were compared to those of the same volunteers without pravastatin. Plasma mevalonate level after 2 h was lower than control (3.0 +/- 1.1 ng/mL vs. 6.7 +/- 2.5, mean +/- SD; P < 0.05). This decrease continued for 8 h (2.5 +/- 0.8 vs. 5.2 +/- 1.5; P < 0.05). On the other hand, plasma 7 alpha-hydroxy-4-cholesten-3-one level did not change until after 6 h; then at 8 h it was lower than control (15.7 +/- 11.8 ng/mL vs. 24.7 +/- 16.9; P < 0.05). According to three-way layout analysis of variance, mevalonate level was influenced by both pravastatin treatment (P < 0.01) and time-course (P < 0.01). On the other hand, the 7 alpha-hydroxy-4-cholesten-3-one level was affected by both individual difference (P < 0.01) and time course (P < 0.01), but pravastatin treatment did not influence this compound. This indicates that bile acid synthesis was influenced by pravastatin, although cholesterol synthesis was inhibited. The short-term inhibition of cholesterol synthesis did not affect bile acid synthesis.

The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients.

Initial trials hint that HMG-CoA reductase inhibitors may have a role in preventing or retarding the progression of AGAS. Whether the potential of HMG-CoA reductase inhibitors to prevent AGAS is due to their lipid-lowering effect, immunomodulating properties, or a combination of both is also not completely known at present. Further study is needed to fully identify their mode of preventing AGAS and, more important, to determine their usefulness and role in preventing AGAS, especially since concurrent HMG-CoA reductase inhibitor use with cyclosporine is not innocuous. Potential for a pharmacokinetic drug interaction, which results in an elevation of HMG-CoA reductase inhibitor concentrations, exists when these two agents are used together, thus increasing the potential for the HMG-CoA reductase inhibitor to cause musculoskeletal complications. When such combination therapy is used, the likelihood of this interaction can be reduced by prescribing the HMG-CoA reductase inhibitor conservatively--using the smallest effective dose and increasing the daily dosage slowly. Although the risk of musculoskeletal toxicity exists at any HMG-CoA reductase inhibitor dosage, most patients should be able to tolerate daily dosages of up to 20 mg of lovastatin, 10 mg of simvastatin, and 40 mg of pravastatin. Patients also need to be made aware of and monitored for musculoskeletal symptoms suggestive of myositis and/or myalgias. In addition, the avoidance of elevated cyclosporine concentrations and when practical, monitoring of HMG-CoA reductase inhibitor concentrations are recommended.

Long-term Treatment With Pravastatin Alone and in Combination With Gemfibrozil in Familial Type IIB Hyperlipoproteinemia or Combined Hyperlipidemia.

BACKGROUND: Pravastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It prevents mevalonate synthesis, reducing endogenous cholesterol production, and reduces cholesterol content in the liver, thus resulting in a down-regulation of low-density lipoprotein receptor production. Gemfibrozil reduces very low-density lipoprotein production and low-density lipoprotein-cholesterol level and increases very low-density lipoprotein catabolism. Therefore, it was suggested that combination therapy with both drugs could effect greater reduction of cholesterol levels as compared to pravastatin alone. The present study was carried out to evaluate the efficacy and safety of pravastatin as a monotherapy or in combination with gemfibrozil in the treatment of patients with familial type IIb hyperlipoproteinemia or familial combined hyperlipidemia. METHODS AND RESULTS: Forty-one patients were included in the study. All patients initially followed 6 weeks of hypolipidemic diet; subsequently they were randomized and received either 20 mg once daily of pravastatin alone (n = 13) or 20 mg of pravastatin together with 600 mg of gemfibrozil twice daily (n = 14). As a control, 14 patients were treated with diet only. The treatment lasted 24 months and clinical evaluation and laboratory tests were done at given time points. Both groups of treated patients showed an early reduction (3 months) of total (about 30% P <.01 vs controls), low-density lipoprotein (about 35%, P <.01 vs controls) and very low-density lipoprotein cholesterol levels (about 18%, P = NS). In contrast, high-density lipoprotein cholesterol levels increased significantly in patients treated with pravastatin and gemfibrozil (about 20%, P <.05 vs controls). Pravastatin treatment alone reduced the level of serum triglycerides as efficiently as in combination with gemfibrozil. Data showed a sustained normalization of lipid profile until 24 months. However, this effect was achieved in patients that had rather low levels of triglycerides. During the treatment we did not observe any difference in the incidence of possible drug-related side effects. Severe myopathy or rhabdomyolysis was not observed at the doses of the drugs used in our study. CONCLUSIONS: Therapy with pravastatin and in combination with gemfibrozil resulted in significant and sustained normalization of lipid profile in high-risk patients with familial type IIb hyperlipoproteinemia or familial combined hyperlipidemia.

Measurement of mevalonic acid in human urine by bench top gas chromatography-mass spectrometry

Urinary excretion of mevalonate was reported to be correlated with endogenous cholesterol biosynthesis. A method is described whereby mevalonate (MVA) concentration in urine is determined by bench top gas chromatography-mass spectrometry after extraction as mevalonolactone (MVL) and conversion to mevalonolactone mono-TMS derivative. Within- and between-assay coefficients of variation were 4.02% and 8%, respectively. The mean concentration of MVA in 24-h urine collections from ten normolipidemic urinary subjects was 203 ± 49.6 ng/ml (range: 44–576 ng/ml). Administration of 40 mg of Pravastatin (an HMG-CoA reductase inhibitor) significantly decreased (≈ 50%) the night concentration of MVA in five healthy volunteers. This assay could be useful for investigation of endogenous cholesterol synthesis rate in various dyslipidemias and in response to drug treatment.

The effectiveness and safety of low dose pravastatin in elderly hypertensive hypercholesterolemic subjects on antihypertensive therapy

To evaluate the efficacy and safety of low dose (10 mg) pravastatin in hypercholesterolemic, hypertensive elderly subjects undergoing antihypertensive treatment, a randomized, double-blind, placebo-controlled 6-month trial was conducted. The subjects had a total plasma cholesterol of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid-lowering diet (American Heart Association Step 1 Diet). Sixty elderly hypertensive patients randomly received placebo (n = 30) or pravastatin (n = 30) treatment. The dosage consisted of 10 mg of pravastatin daily during the 6-month trial. Over that period, in the pravastatin group, plasma levels of total cholesterol and LDL-cholesterol significantly (P < .01) dropped (-20% and -25%, respectively) compared to the placebo group. The plasma level of HDL-cholesterol increased (+5%) while triglycerides slightly decreased (-8%) (P < .05). No serious side effects occurred, and pravastatin was generally tolerated. Fasting hyperinsulinemia (11.0 +/- 0.8 v 9.3 +/- 0.7 microU/mL; P = .06) also improved, although not significantly, after 6 months of pravastatin therapy. Results from this study confirmed that a low dose (10 mg) of pravastatin daily is a safe and effective method of reducing plasma total and LDL-cholesterol in hypercholesterolemic, hypertensive elderly patients who are on concurrent antihypertensive drug therapy.

Comparison of fluvastatin versus pravastatin treatment of primary hypercholesterolemia

Following a 6-week placebo period, 134 patients with low density lipoprotein cholesterol (LDL-C) ≥160 mg/dL and plasma triglyceride ≤400 mg/dL, despite following a standard lipid-lowering diet, were randomized to double-blind, double-placebo treatment with fluvastatin (22 women, 46 men; age 21–71 years) or pravastatin (25 women, 41 men; age 19–76 years). Fluvastatin at 40 mg and pravastatin at 20 mg were given for the first 4 weeks, both once daily with the evening meal. For the following 12 weeks, fluvastatin at 40 mg twice daily and pravastatin at 40 mg once daily were given with the evening meal. Both drugs were equally effective in lowering LDL-C after 4 weeks of treatment (−24.0% with fluvastatin, −24.1 %with pravastatin) but, after 16 weeks, LDL-C reduction was −30.4% with fluvastatin and −26.6% with pravastatin. This further lowering of LDL-C between week 4 and week 16 was significant (p <0.001) for fluvastatin but not pravastatin. Adverse events were reported by 23 fluvastatin patients and 22 pravastatin patients: 3 patients in each group withdrew from the study because of these. No notable abnormalities in levels of alanine or aspartate aminotronsferose values (defined as >3 times the upper limit of normal on 2 consecutive occasions) or of creatine phosphokinase (defined as >10 times the upper limit of normal on any occasion) were observed in either treatment group. The results of this study show that the lipid-lowering effect of fluvastatin at 40 mg daily is similar to that of pravastatin at 20 mg daily. Doubling the dosage to 80 mg of fluvastatin (40 mg twice daily) or 40 mg of pravastatin leads to a statistically significant further reduction in LDL-C with fluvastatin but not pravastatin. The tolerability of the two regimens is comparable.

Prevention of restenosis after percutaneous transluminal coronary angioplasty by reducing lipoprotein (a) levels with low-density lipoprotein apheresis

This study was designed to test the hypothesis that high plasma lipoprotein (a) (Lp[a]) levels are associated with an increase incidence of restenosis after angioplasty. Elective transluminal coronary angioplasty was performed in 66 patients (58 men and 8 women) aged 57 ± 9 years (mean ± SD). Two days before and 5 days after angioplasty, all patients underwent low-density lipoprotein (LDL) apheresis with a dextran sulfate cellulose column as an Lp(a) absorbent; 39 patients also received 10 mg of pravastatin and 1,500 mg of niacin daily. Restenosis was defined as a recurrent luminal stenosis of ≥ 50% in a previously dilated segment. Median Lp(a) levels were reduced from 23.3 mg/dl before apheresis to 10.9 mg/dl after apheresis (p < 0.0001). Angiography performed 2 to 9 months after angioplasty revealed restenosis in at least 1 site in 38% of the 137 control patients and in 32% of the 66 patients who underwent apheresis. Restenosis also occurred in 37% of the patients who underwent apheresis alone and in 28% of the patients who also received pravastatin and niacin in combination with LDL apheresis. The restenosis rate was 21% in the 42 patients whose Lp(a) levels were significantly reduced ≥ 50%, and in 50% of the 24 patients whose Lp(a) levels were significantly reduced < 50% (p < 0.05). Among the patients who received pravastatin and niacin in combination with LDL apheresis, the restenosis rate was 12.5% in the 24 patients whose Lp(a) levels were acutely lowered ≥ 50 and 53% in the 15 patients whose acute reductions of Lp(a) levels were < 50% (p < 0.05). Results indicate that reducing Lp(a) levels can prevent restenosis after angioplasty in some patients, particularly when combined with lipid-lowering drugs.

Epidemiology of hyperlipidemia and the efficacy of pravastatin therapy

To evaluate the effectiveness of pravastatin, a 3-hydroxy, 3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, as a cholesterol-reducing agent in typical general-practice use, data from 313 patients with primary type-II hyperlipidemia were analyzed in terms of epidemiologic factors, efficacy, and safety. Patients were to have had at least 4 weeks of diet therapy before beginning the study medication. The mean duration of therapy with pravastatin for all patients was 6 weeks. Of the 134 previously untreated patients, 67 received 10 mg of pravastatin daily and 67 received 20 mg. Patients in the 10-mg group showed mean percent changes of −23.1% in total cholesterol (TC) and −27.2% in low-density lipoprotein cholesterol (LDL-C) levels ( P < 0.0001). The corresponding changes in the 32 evaluable patients taking 20 mg of pravastatin daily were −28.1% and −34.9%, respectively ( P < 0.0001). Patients who had been previously treated with other antihyperlipidemic agents also showed significant percent reductions in the various lipid indices, albeit from lower baseline levels. The 13 evaluable patients in the 10-mg group showed reductions of −13.8% in TC and −20.3% in LDL-C, while the 36 evaluable patients taking 20-mg daily doses showed changes of −15.6% for TC and −19.3% for LDL-C ( P < 0.01). All these patients were switched directly to pravastatin with no washout period. The incidence of side effects was low, the most common being gastrointestinal disturbances. There was no significant difference in the incidence or the distribution of adverse effects between the total intent-to-treat patient population and the previously untreated patients. Dosage administered also had no significant bearing on the nature or incidence of adverse effects. Fewer than 50% of reported side effects were evaluated by the investigator as being definitely related to pravastatin therapy. We conclude that pravastatin in “real world” use yields results similar to those of the developmental studies and other HMG-CoA reductase inhibitors.

Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Pravastatin Multicenter Study Group II

Treatment of severe hypercholesterolemia often requires high-dose therapy with a hydroxymethylglutaryl-coenzyme A reductase inhibitor alone or in combination with bile acid-binding resin. We evaluated the efficacy and safety of pravastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor with hydrophilic selectivity, alone and in combination with cholestyramine. Pravastatin was studied at doses of 20 or 40 mg twice daily alone or 20 mg twice daily with cholestyramine, 12 g twice daily, vs placebo in a randomized, double-blind multicenter study of 311 patients for 8 weeks and in continued therapy through 24 weeks. After 8 weeks of therapy, pravastatin in a dosage of 20 mg twice daily reduced low-density lipoprotein cholesterol levels by 31%, whereas a dosage of 40 mg twice daily reduced low-density lipoprotein cholesterol levels by 38%. Cholestyramine, 24 g daily alone, reduced low-density lipoprotein cholesterol levels by 32%. Cholestyramine combined with 40 mg of pravastatin reduced the level by 51%. Pravastatin, 40 or 80 mg daily, reduced the triglyceride level by 13% to 19%, resin alone increased the triglyceride level by 21%, and no change was seen with combined therapy. High-density lipoprotein cholesterol levels increased by about 5% regardless of regimen. Similar effects were seen at 24 weeks. Symptoms reported were indistinguishable among placebo and pravastatin users and were less than with cholestyramine alone or cholestyramine in combination with pravastatin. Elevations of liver enzyme levels were small in all groups, indistinguishable between resin and pravastatin, and were highest when the two drugs were combined. Plasma creatine kinase levels did not increase in any treatment group. Pravastatin treatment of hypercholesterolemia is highly effective and well tolerated alone and in combination with bile acid-binding resin and shows no tendency to increase muscle enzyme levels.

The Effect of Pravastatin on Plasma Lipoprotein and Apolipoprotein Levels in Primary Hypercholesterolemia

Pravastatin is a metabolic product of mevastatin and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It was investigated for its cholesterol-lowering properties in a double-blind, placebo-controlled, multicenter study of 82 patients with primary hypercholesterolemia. Following a 6- to 8-week dietary lead-in period, patients were randomized to twice-daily placebo or active drug for 16 weeks. Patients receiving 10 mg of pravastatin twice a day for 8 weeks experienced mean total cholesterol and low-density lipoprotein cholesterol (LDL-C) level reductions of 20% (6.85 vs 5.48 mmol/L [265 vs 212 mg/dL]) and 28% (5.17 vs 3.75 mmol/L [200 vs 145 mg/dL]), respectively. At 20 mg twice a day for an additional 8 weeks, pravastatin reduced plasma total cholesterol, LDL-C, and apolipoprotein B-100 levels by 23% (6.85 vs 5.30 mmol/L [265 vs 205 mg/dL]), 31% (5.17 vs 3.59 mmol/L [200 vs 139 mg/dL]), and 23% (118 vs 91 mg/dL), respectively. Highdensity lipoprotein cholesterol (HDL-C), HDL_b-C, HDL and apolipoprotein A-I plasma concentrations increased by 11%, 60%, 7%, and 10%. Plasma triglyceride concentrations decreased in both the pravastatin- and placebo-treated patients. Pravastatin was generally well tolerated and an effective agent for the treatment of primary hypercholesterolemia. (<i>Arch Intern Med</i>. 1991;151:2234-2240)

The effect of pravastatin on plasma lipoprotein and apolipoprotein levels in primary hypercholesterolemia. The Southeastern Michigan Collaborative Group

Pravastatin is a metabolic product of mevastatin and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It was investigated for its cholesterol-lowering properties in a double-blind, placebo-controlled, multicenter study of 82 patients with primary hypercholesterolemia. Following a 6- to 8-week dietary lead-in period, patients were randomized to twice-daily placebo or active drug for 16 weeks. Patients receiving 10 mg of pravastatin twice a day for 8 weeks experienced mean total cholesterol and low-density lipoprotein cholesterol (LDL-C) level reductions of 20% (6.85 vs 5.48 mmol/L [265 vs 212 mg/dL]) and 28% (5.17 vs 3.75 mmol/L [200 vs 145 mg/dL]), respectively. At 20 mg twice a day for an additional 8 weeks, pravastatin reduced plasma total cholesterol, LDL-C, and apolipoprotein B-100 levels by 23% (6.85 vs 5.30 mmol/L [265 vs 205 mg/dL]), 31% (5.17 vs 3.59 mmol/L [200 vs 139 mg/dL]), and 23% (118 vs 91 mg/dL), respectively. High-density lipoprotein cholesterol (HDL-C), HDLb-C, HDLb-C, and apolipoprotein A-I plasma concentrations increased by 11%, 60%, 7%, and 10%. Plasma triglyceride concentrations decreased in both the pravastatin- and placebo-treated patients. Pravastatin was generally well tolerated and an effective agent for the treatment of primary hypercholesterolemia.