Pravastatin experience in elderly and non-elderly patients

Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering cholesterol concentrations to reduce morbidity and mortality from CHD. Pravastatin, a well tolerated HMG CoA reductase inhibitor with a convenient once-daily dosing regimen, has been shown to effectively lower total and low density lipoprotein (LDL) cholesterol. Individual data from more than 1800 hypercholesterolemic patients enrolled in six double-blind, randomized, multicenter studies were pooled and then analyzed to compare the safety and efficacy of pravastatin in the elderly (i.e., patients at least 65 years old) and the non-elderly. In short-term studies (8-16 weeks), response was dose-related and similar in elderly and non-elderly subjects. Pravastatin 20 or 40 mg daily lowered total cholesterol 19-25%, LDL-cholesterol 25-33%, and triglycerides 14-23%; high density lipoprotein (HDL) cholesterol increased 5-10%. During long-term studies, improvements were sustained for more than 24 months in both the non-elderly and elderly. The incidences of adverse drug events and laboratory abnormalities were similar in the elderly and non-elderly patients in all groups (active treatment control with resin, pravastatin alone, or combination therapy). In short-term studies, treatment was discontinued because of adverse events in < 1% of all patients treated with pravastatin (all doses) or placebo. The frequency and profile of adverse events were similar among patients treated with pravastatin or placebo. In long-term studies, treatment was discontinued in 0.4% of patients in the pravastatin group and in 0.3% of the patients in the bile-acid-binding resin group. If drug therapy is warranted, pravastatin appears to be safe and effective for long-term use in elderly patients with hypercholesterolemia.     

Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators

BACKGROUND: Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels. METHODS AND RESULTS: The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides--were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (P=0.05) and 23% (P<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (P=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, -50%, P=0.05 for nonfatal MI). CONCLUSIONS: Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.     

Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein a

Lipoprotein a [Lp(a)] has emerged as a critical factor in the assessment of cardiovascular risk. In the study reported here, Lp(a) concentrations were monitored in patients taking pravastatin, a new hydrophilic, HMG-CoA reductase inhibitor. A cohort of patients with frozen plasma aliquots at baseline, week 12 of the double-blind therapy, and week 48 of open-label therapy (1 years' treatment) was selected from 306 participants in a phase 2 dose-ranging study of pravastatin. The 125 men and women in the cohort had mean low-density lipoprotein cholesterol (LDL-C) concentrations of at least 150 mg/dL (3.88 mmol/L), and mean plasma triglyceride concentrations less than 250 mg/dL (2.82 mmol/L) during the baseline diet phase. During the double-blind phase, 46 patients received placebo, and 79 received pravastatin 10, 20, or 40 mg daily. Only the 79 pravastatin-treated patients in the cohort continued in the 48-week open-label study of pravastatin. During the double-blind phase, Lp(a) decreased 4.6% in patients taking placebo, and 0.4% in patients taking pravastatin. Net change was not significant. At week 48, in the patients taking pravastatin, Lp(a) had increased 2.4%, a difference that again was not statistically significant. Low-density lipoprotein cholesterol (-33.6%), total cholesterol (-25.6%), triglycerides (-19.9%), high-density lipoprotein cholesterol (HDL-C) (+7.0%), apolipoprotein A-I (+13.3%), and apolipoprotein B (-33.0%) changed significantly (P < .01). Among 19 patients with baseline Lp(a) levels greater than 30 mg/dL, Lp(a) decreased insignificantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized controlled trial of pelvic floor muscle exercises to treat postnatal urinary incontinence

BACKGROUND: The enzyme lecithin-cholesterol acyl transferase (LCAT) esterifies free cholesterol on high-density lipoprotein (HDL) and the cholesteryl ester transfer protein (CETP) transfers cholesteryl ester to very-low-density lipoprotein (VLDL) and low-density lipoproteins (LDL). Using statins, contradictory findings have been made regarding CETP activity in normolipidemic individuals and in those with familial dysbetalipoproteinemia. In contrast, LCAT activity appears to be unaffected by simvastatin. Antioxidants have also been proposed for the use of anti-atherosclerotic treatment, because the oxidation of LDL may have a key role in the pathophysiology of atherogenesis. OBJECTIVE: To investigate, in hypercholesterolemic patients, whether a combination of pravastatin with the antioxidant, vitamin E, has greater effects on the activity of CETP and of LCAT than does pravastatin alone. METHODS: This placebo-diet-controlled multicenter trial included 220 hypercholesterolemic patients who were assigned randomly to groups to receive: diet and 20-40 mg pravastatin (n = 52), diet and alpha-tocopherol (n = 60), or diet associated with placebo (n = 52). Plasma LCAT activity was determined using excess exogenous substrate, containing [3H]cholesterol. Plasma CETP activity was measured in the supernatant fraction after precipitation of endogenous apo B-containing lipoproteins with phosphotungstate-Mg2+. The exchange of cholesteryl esters between [14C]cholesteryl ester-labeled LDL and unlabeled HDL was measured during a 16-h incubation, while LCAT was inhibited. RESULTS: The addition of pravastatin to the diet induced a significant decrease in plasma CETP activity (P < 0.05); this effect was less evident in the group cotreated with vitamin E. For the first time, it was shown that CETP concentrations increased significantly after vitamin E alone (P < 0.05). No significant differences in the plasma activity of LCAT were observed among the groups. CONCLUSIONS: Pravastatin reduced CETP activity, but not that of LCAT. Addition of vitamin E prevented the decrease in CETP activity and had no effect on LCAT activity. The mechanism responsible for these effects is unknown, but could involve the prevention of radical-induced damage to CETP by vitamin E.     

Effectiveness, tolerance and safety of simvastatin in comparison with bezafibrate in treatment of hypercholesterolemia

The efficacy, tolerability and safety of simvastatin was compared to that of bezafibrate in a randomized placebo controlled double-blind trial including 64 patients with primary hypercholesterolemia with total cholesterol levels above 240 mg/dl and low-density lipoprotein (LDL) cholesterol above 195 mg/dl. During a placebo period of four weeks patients were counselled for a diet low in cholesterol (< 300 mg/day) and saturated fat (< 10% of calories). This period was also used for randomization of the individuals into the bezafibrate and simvastatin group, respectively. Patients assigned to bezafibrate treatment took bezafibrate at 600 mg/day throughout the entire 12 weeks of active treatment. Patients assigned to simvastatin took simvastatin at 10 mg/day when LDL-cholesterol was below 195 mg/dl, and at 20 mg/day when LDL-cholesterol was above 195 mg. To compare the lipid lowering effect of both substances total cholesterol, LDL- and high-density lipoprotein (HDL)-cholesterol were measured as well as triglycerides, very low density lipoprotein (VLDL)-cholesterol and the concentrations of apolipoproteins (apo)-AI, apo-AII and apo-B, respectively. These variables were compared between the two study groups with respect to the percentage change from baseline levels obtained during the placebo period. After a 12 week treatment period mean percent reduction of total cholesterol in the simvastatin group was 24% and that of LDL-cholesterol was 36%, both more pronounced than the respective reductions (14% and 17%) observed in the bezafibrate group. The mean percent increase in HDL-cholesterol was similar in both treatment groups (simvastation by 20% vs. bezafibrate by 17%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Video laparoscopic adrenalectomy

BACKGROUND: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. OBJECTIVE: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. DESIGN: Subset analysis of a randomized, controlled trial. SETTING: 80 hospitals and affiliates in the United States and Canada. PATIENTS: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). INTERVENTION: Pravastatin, 40 mg/d, or placebo. MEASUREMENTS: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. RESULTS: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. CONCLUSIONS: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.     

Continuous assay for acid phosphatase using 1-naphthyl phosphate as a substrate

The sequential effects of an American Heart Association (AHA) Step 1 diet and subsequent weight loss on lipoprotein lipids in obese [body mass index (in kg/m2) > 27], postmenopausal women (n = 48) were determined. Subjects followed a euenergetic AHA Step 1 diet for 2 mo, followed by a weight-loss diet (deficit of 1.0-1.5 MJ/d) for 6 mo. The AHA diet lowered concentrations of total (7%), low-density-lipoprotein (LDL) (6%), and high-density-lipoprotein (HDL) (14%) cholesterol (P < 0.01). Weight loss (-5.6 +/- 0.7 kg; P < 0.01) increased plasma triacylglycerol concentrations (9%; P < 0.01) and increased HDL-cholesterol concentrations (8%; P < 0.01) compared with changes after the AHA diet, but there were no changes in total or LDL cholesterol. The combined AHA diet and weight-loss interventions lowered triacylglycerol (10%) and total (6%), LDL (6%), and HDL (7%) cholesterol. These changes correlated indirectly with the baseline concentration for each lipid. When the women were divided on the basis of initial LDL-cholesterol concentration, the AHA diet and weight-loss interventions reduced (P < 0.01) triacylglycerol (19%), total cholesterol (13%), and LDL cholesterol (14%) in the women with hypercholesterolemia but not in normocholesterolemic or midly hypercholesterolemic women. Thus, an AHA Step 1 diet and subsequent weight loss improve lipoprotein lipid profiles of obese, postmenopausal women with hypercholesterolemia. However, because it lowers HDL cholesterol, a low-fat diet without substantial weight loss may not be beneficial for improving lipoprotein lipid risk factors for coronary artery disease in obese, postmenopausal women with normal lipid profiles.     

Comparative studies on the substrate specificity of lecithin:cholesterol acyltransferase towards the molecular species of phosphatidylcholine in the plasma of 14 vertebrates

We have studied, in a prospective blinded fashion, the effects of regular and extended-release gemfibrozil on plasma lipoprotein and apolipoprotein (apo) levels in hypercholesterolemic subjects with decreased high density lipoprotein (HDL) cholesterol (C) levels. Study participants were men and women 19 to 80 years of age with baseline plasma low density lipoprotein (LDL) C levels > or = 4.5 mmol/l (175 mg/dl), HDL-C levels < or = 1.2 mmol/l (45 mg/dl), and triglyceride levels < or = 3.4 mmol/L (300 mg/dl). All subjects were stabilized on a diet for eight weeks prior to entry into two different protocols. In the first protocol 229 subjects were randomized to placebo or extended-release gemfibrozil (1200 mg/day) for 3 months (placebo trial). In the second protocol 655 subjects were randomized to regular or extended-release gemfibrozil (1200 mg/day) for 6 months (equivalency trial). Changes in lipids and apos were stratified by baseline HDL-C levels (< 0.9 mmol/l, and 0.9-12.2 mmol/l). In both studies, treatment with gemfibrozil, either regular or extended-release, was associated with significant (P < 0.05) decreases in plasma very low density lipoprotein (VLDL) C and triglyceride levels of 42-45% and 33-37%, respectively, in subjects with HDL-C level < 0.9 mmol/l, and of 38-47% and 32-39%, respectively, in patients with HDL-C levels of 0.9-1.2 mmol/l. Modest reductions from baseline in directly measured LDL-C levels were observed in both groups (3-6% and 8-9%, respectively). These reductions were less than those observed for calculated LDL-C (7-10% and 11%, respectively). For apo B, reductions were 11-14% and 16-17% in the two groups. HDL-C, apo A-I, and apo A-II levels increased by 15-16%, 5-6%, and 21-25%, respectively, in patients with HDL-C < 0.9 mmol/l, and by 6-7%, 2-3%, and 19-22%, respectively, in patients with HDL-C of 0.9-1.2 mmol/l. These differences in HDL-C levels reached statistical significance in the equivalency trial (P < 0.0001) and were independent of baseline triglyceride levels. Our data indicate that gemfibrozil, either regular or extended-release, is highly effective in lowering plasma triglyceride levels and increases HDL-C levels by approximately 15% in hypercholesterolemic patients with low HDL-C levels (< 0.9 mmol/l). Moreover, this agent lowers VLDL-C somewhat more than triglyceride, resulting in an underestimation of calculated VLDL-C reductions and in an overestimation of calculated LDL-C reductions. This agent also raises apo A-II levels much more than apo A-I levels.     

Investigation of milk-borne Streptococcus zooepidemicus infection associated with glomerulonephritis in Australia

OBJECTIVES: The aim of this study was to estimate the cost-effectiveness of antihypertensive treatment in elderly people based on the results of the Swedish Trial in Old Patients with Hypertension (STOP Hypertension). DESIGN: The STOP Hypertension study was a randomized trial comparing active antihypertensive treatment with a placebo. The risk of stroke, cardiovascular disease and total mortality was significantly reduced in the actively treated group compared to placebo. SETTING: One hundred and sixteen primary health care centres in Sweden. SUBJECTS: A total of 1627 hypertensive patients aged 70-84. No patient was lost to follow-up. INTERVENTIONS: Antihypertensive treatment with beta blockers and diuretics for a mean follow-up of 25 months. MAIN OUTCOME MEASURE: The cost-effectiveness ratio estimated as the net cost (the treatment cost minus saved costs of reduced cardiovascular morbidity) divided by the number of life-years gained (the increase in life expectancy from treatment). RESULTS: The cost per life-year gained was estimated as SEK 5000 for men and SEK 15,000 for women ($1 = SEK 6; 1 pound = SEK 10). The cost per life-year gained did not exceed SEK 100,000 in any of the sensitivity analyses. CONCLUSIONS: It is concluded that treatment of elderly hypertensive patients with beta blockers and/or diuretics is cost-effective according to the results of the STOP Hypertension study.     

Determining residual urine volumes using a portable ultrasonographic device

To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage. At entry (before placebo), SI was slightly but not significantly lower in group A than B [2.7 vs. 3.6 x 10(-4) ml.microU-4.min-1]; fasting plasma insulin was 13.6 vs. 12.9 microU.ml-1. After 6 weeks on placebo, S1 averaged 3.7 in group A and 4.4 x 10(-4) microU.ml-1.min-1 in group B; fasting plasma insulin was 14.6 vs. 15.1 microU.ml-1, and glucose 5.5 vs. 5.5 mmol.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of a transforming growth factor alpha-like molecule in human seminal plasma

In a double-blind controlled trial, 91 middle-aged and elderly women with mild to moderate hypertension who were not on antihypertensive medication were randomly assigned to treatment with magnesium aspartate-HCl (20 mmol Mg/d) or placebo for 6 mo. Magnesium aspartate-HCl in the given dose was well-tolerated and was not associated with an increased frequency of diarrhea compared with placebo. At the end of the study, systolic blood pressure had fallen by 2.7 mm Hg (95% CI -1.2, 6.7; P = 0.18) and diastolic blood pressure by 3.4 mm Hg (1.3, 5.6; P = 0.003) more in the magnesium group than in the placebo group. Blood pressure response was not associated with baseline magnesium status, as measured by dietary magnesium intake and urinary magnesium excretion. Urinary magnesium excretion in the magnesium group increased by 50% during the intervention period. No changes were seen in other biochemical indexes, including serum concentrations of total and high-density-lipoprotein cholesterol. The findings suggest that oral supplementation with magnesium aspartate-HCl may lower blood pressure in subjects with mild to moderate hypertension.     

Effect of pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary artery disease. Coronary Artery Regression Study (CARS) Group

To evaluate the effect of pravastatin on progression of coronary atherosclerosis in normocholesterolemic patients with coronary artery disease (CAD), 90 patients with CAD and serum cholesterol levels of 160 to 220 mg/dl were randomized into a pravastatin (10 mg/day) group (n = 45) and control group (n = 45) in a 2-year study. The proportions of patients with progression (an increase of > or = 15% in percent stenosis) and regression (a decrease of > or = 15% in percent stenosis) of coronary atherosclerosis were compared between the 2 groups. Of 90 patients, 80 (89%) had a final angiogram: the pravastatin (n = 39) and control group (n = 41). Percent changes in total cholesterol, low-density lipoprotein cholesterol, and apoprotein B levels were significantly greater in the pravastatin group than in the control group (total cholesterol -11 +/- 12% vs 3 +/- 15%, p < 0.01; low-density lipoprotein cholesterol -18 +/- 16% vs 4 +/- 21%, p < 0.01; apoprotein B -5 +/- 20% vs 6 +/- 20%, p < 0.05). The proportion of patients with progression of coronary atherosclerosis was significantly smaller in the pravastatin group than in the control group (21% vs 49%, p < 0.05). The proportion of patients with disease regression did not differ in the 2 groups (3% vs 2%, p = NS). In conclusion, this study indicates that cholesterol-lowering therapy with pravastatin can prevent the progression of coronary atherosclerosis even in normocholesterolemic patients with established CAD.     

Retinoic acid enhances fibrinolytic activity in-vivo by enhancing tissue type plasminogen activator (t-PA) activity and inhibits venous thrombosis

BACKGROUND: Simvastatin and pravastatin are both competitive inhibitors of the rate limiting enzyme for cholesterol biosynthesis (HMG CoA) reductase, but data from individual clinical trials suggest significant differences in potency for cholesterol reduction between the two drugs. AIM: To assess any differences in efficacy and safety between simvastatin and pravastatin in a direct, comparative study. METHODS: A double-blind, double-dummy, randomised study design was used, involving 48 patients with primary hypercholesterolaemia. Following a 6 week placebo baseline period, patients were randomly allocated to treatment with either simvastatin or pravastatin, commencing at a dose of 10 mg daily. The dose levels were titrated up to the recommended maximum effective dose of 40 mg daily at 6 weekly intervals if LDL cholesterol levels remained > or = 3.4 mmol/L. After 18 weeks of therapy, all patients were transferred to simvastatin therapy for a further 6 weeks, continuing at their week 18 dose level. Patients complied with a standard lipid lowering diet (containing < 30% of energy as total fat) throughout the study period. RESULTS: Over the 18 week direct comparison of the two drugs, there was a significant difference (p < 0.001) in response between simvastatin and pravastatin for reduction in levels of total cholesterol (32% vs 21% respectively), LDL cholesterol (38% vs 27%) and apolipoprotein B levels (34% vs 23%). No significant difference in drug effect was seen for the small reduction in levels of apolipoprotein AI (5% vs 6% respectively), nor for the increased levels of apolipoprotein AII (14% vs 11%) and HDL cholesterol (11% vs 7%). Lp(a) levels remained unchanged. When pravastatin was replaced with simvastatin for the final 6 weeks of the study in the 23 patients initially randomised to pravastatin, there were further reductions (p < 0.01) in total and LDL cholesterol, and apolipoprotein B. These results establish the advantage of simvastatin over pravastatin in terms of efficacy, for the treatment of primary hypercholesterolaemia.     

Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group

BACKGROUND: Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels. METHODS AND RESULTS: In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (2P for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (2P for interaction >.8). CONCLUSIONS: Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up.     

Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.     

Cloning of a mouse smoothened cDNA and expression patterns of hedgehog signalling molecules during chondrogenesis and cartilage differentiation in clonal mouse EC cells, ATDC5

The effects of simvastatin and pravastatin administered alone at initial doses of 5 and 10 mg/day, respectively, on normalization of abnormal lipid metabolism in patients with hypercholesterolemia were evaluated by a crossover method. Patients whose serum levels of total cholesterol (TC) were > or = 220 mg/dl were randomly divided into two groups, and one of the groups (group S-P: 17 patients) was treated with simvastatin first and then with pravastatin whereas the other group (group P-S: 19 patients) was treated with pravastatin first and then with simvastatin. Simvastatin or pravastatin was replaced with the other drug after 8-week administration in each group. These drugs were administered for 8 weeks each. Simvastatin and pravastatin significantly reduced the following serum lipids as compared with the levels in the observation period: TC by 23.2 +/- 8.1% and 18.1 +/- 10.9%, triglyceride (TG) by 13.0 +/- 24.7% and 5.8 +/- 47.1%, and low-density lipoprotein cholesterol (LDL-C) by 31.3 +/- 10.1% and 23.1 +/- 14.3%, respectively. TC and LDL-C levels were significantly (p < 0.001) lower and decreased to significantly (p < 0.001) greater degrees after simvastatin treatment than after pravastatin treatment. TC was normalized in 77.8% of the patients (28 of 36) after simvastatin treatment and in 68.9% of the patients (23 of 36) after pravastatin treatment. LDL-C was normalized in 63.9% of the patients (23 of 36) after simvastatin treatment and in 44.4% of the patients (16 of 36) after pravastatin treatment. The percentage of patients whose LDL-C was normalized by simvastatin was significantly (p < 0.05) higher as compared with pravastatin. Results of this trial, which was conducted by a crossover method, show that the initial dose of simvastatin reduces serum cholesterol and LDL-C more potently than the initial dose of pravastatin in patients with hypercholesterolemia.     

Short-term treatment with low-dose pravastatin attenuates oxidative susceptibility of low-density lipoprotein in hypercholesterolemic patients

The effects of treatment with low-dose 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin on the changes of chemical composition and in vitro oxidative susceptibility of low-density lipoprotein (LDL) were studied in 20 type Ila hyperlipidemic patients with a plasma total cholesterol level > 240 mg/dL at the end of a diet control period for 3 months using the American Heart Association recommended step I diet. Treatment with pravastatin in a dose of 5 mg twice daily for 4 weeks resulted in lowering plasma total and LDL cholesterol levels by 17.0% and 22.9%, respectively. There was no further decline in plasma lipid thereafter. Chemical composition analysis showed that LDL particles did not contain significantly less cholesterol and thiobarbituric acid reactive substances (TBARS) until the end of 8 weeks (130.6 +/- 17.8 vs. 106.6 +/- 37.1 mg/mg protein, P < 0.05 and 0.16 +/- 0.06 vs. 0.08 +/- 0.02 nmol/mg protein, P < 0.005, respectively). Vitamin E, phospholipid, and triglyceride contents remained at the same levels throughout the study. In terms of oxidative kinetics, lag time and time to maximal diene concentration were not prolonged during the treatment period for 12 weeks, while total diene concentration and reaction rate were not significantly reduced until 8 weeks of treatment. Plasma enzyme activity of glutathione reductase and peroxidase, as well as the whole blood level of reduced and oxidized glutathione, remained similar during the study. In conclusion, pravastatin, at the low dose of 5 mg twice daily, produced a significant decline in plasma lipid levels to a steady-state range by 4 weeks; however, 8-weeks treatment is necessary to reduce the cholesterol and TBARS content, as well as to attenuate the oxidative susceptibility of LDL. These effects are not related to the antioxidant glutathione.     

Efficacy and safety of pravastatin in African Americans with primary hypercholesterolemia

BACKGROUND: Coronary artery disease strikes early and may prove particularly severe in persons of African-American descent. Therefore, we studied the lipid-lowering efficacy and safety of pravastatin sodium (20 mg/d), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in 245 African-American patients with primary hypercholesterolemia. METHODS: After 4 weeks on an American Heart Association phase I low-fat diet, patients were randomized in a double-blind manner to either pravastatin or placebo in a 3:1 ratio. RESULTS: After 12 weeks of pravastatin treatment, low-density lipoprotein cholesterol levels declined 25.8%, total cholesterol levels 20.3%, and triglyceride levels 6.2%, while high-density lipoprotein cholesterol levels remained essentially unchanged. Overall, 72% of pravastatin-treated patients achieved reductions in low-density lipoprotein cholesterol level in excess of 20%, and 44% attained declines in excess of 30% (both P < .01 vs placebo). Pravastatin was generally well tolerated in this population, with one patient (0.5%) exhibiting a reversible myopathy with creatine kinase elevations to 10 times the upper limit of normal. No substantial elevations of aminotransferase levels of two to three times the upper limit of normal occurred in either the pravastatin or the placebo group. Drug compliance was high, exceeding 90%. CONCLUSION: Pravastatin appears to be an effective and safe lipid-lowering agent and is the first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to be studied extensively in this underrepresented population.     

Clinical results of the Verapamil inHypertension and Atherosclerosis Study. VHAS Investigators

OBJECTIVE: The Verapamil in Hypertension and Atherosclerosis Study (VHAS) is a prospective randomized study the objective of which was to compare the long-term effects of verapamil and chlorthalidone on the blood pressure, clinical safety, and the progression/regression of carotid wall lesions in members of a large population of hypertensive patients. DESIGN: After a 3-week placebo run-in period, 1414 hypertensive patients [692 men and 722 women, aged 53.2 +/- 7 years, blood pressure 168.9 +/- 10.5/ 102.2 +/- 5.0 mmHg (means +/- SD)] were assigned randomly to be administered either 240 mg sustained-release verapamil (n = 707) or 25 mg chlorthalidone (n = 707) once a day for 2 years. The study design was double blind for the first 6 months and open thereafter. 25-50 mg/day captopril were added to the treatment of non-responding patients; subsequently, patients not responding to combined therapy were switched to any therapy chosen by the treating doctors (free therapy). The blood pressure of the sitting subject, heart rate, and a standard clinical safety profile (electrocardiogram, laboratory tests, adverse events, cardiovascular events, and deaths) were assessed regularly throughout the study. RESULTS: After 2 years the systolic and diastolic blood pressures were reduced significantly in members of both treatment groups (by 16.3/16.6% with verapamil and by 16.9/16.2% with chlorthalidone, both by analysis of variance, P < 0.0001). The patients for whom we added captopril treatment constituted 22.6% of the verapamil and 26.2% of the chlorthalidone group; while 11.6 and 12.2% of patients in these groups, respectively, were administered free therapy. Normalization of the diastolic blood pressure (to < or = 90 mmHg or to < or = 95 mmHg with a > or = 10% decrease) was achieved for 69.3% of the verapamil and 66.9% of the chlorthalidone group. A decrease in heart rate (by 5.8%) occurred in members of the verapamil group only. A decrease in total serum cholesterol (from 223.6 to 216.9 mg/dl, P < 0.01) and in the total cholesterol: high-density lipoprotein cholesterol ratio (from 4.9 to 4.5, P < 0.01) was noted for the verapamil group only, whereas significantly greater rates of hyperuricemia (plasma urate > 7.0 mg/dl; 10.8 versus 3.9%) and hypokalemia (serum K < 3.5 mmol/l; 24.6 versus 4.4%) were observed for the chlorthalidone group (P < 0.01, versus verapamil for both). Adverse events were reported by 32.5% of patients treated with verapamil and by 33.4% of those treated with chlorthalidone. The most frequent adverse events were constipation in members of the verapamil group (13.7%) and asthenia in members of the chlorthalidone group (8.5%). In total 315 dropped out (153 from the verapamil and 162 from the chlorthalidone group). The occurrence of cardiovascular events was similar for both treatments (42 events for verapamil and 43 for chlorthalidone, NS). CONCLUSION: Similar antihypertensive efficacies, tolerabilities and cardiovascular event rates were observed with verapamil and with chlorthalidone. However, treatment with chlorthalidone was associated with significantly higher incidences of hyperuricemia and hypokalemia than was treatment with verapamil.     

Protective role of the free glucocorticoid pool in development of autoimmune hemolytic anemia

OBJECTIVE: Patients with type II diabetes mellitus have an increased risk of coronary he disease. We investigated the efficacy and safety of pravastatin in the treatment of patients with diabetic nephropathy and hypercholesterolemia. METHOD: In this 6-months study, 12 patients (4 men, 8 women, mean age 60.5 +/- 10.8 years), with diabetic nephropathy and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol levels -LDL-C- > 130 mg/dl) received pravastatin 10 mg/day. The dose could be doubled after 4 weeks. Seven patients have chronic renal failure. RESULTS: Significant reductions in LDL-C (-19.1%, p < 0.05), total cholesterol (-16%, p < 0.01), very-low-density lipoprotein cholesterol (-29.2%, p < 0.05), apolipoprotein B (-21.5%, p < 0.05), and triglycerides (-26.0%, p < 0.01) were noted. No changes were found either in high-density-cholesterol or its fractions (HDL2 and HDL3) or in apolipoprotein A plasmatic levels. Pravastatin was well tolerated and no one side effect was detected. No clinically significant changes on the control of diabetes, renal function, as assessed by plasmatic creatinin and creatinin clearance, and proteinuria were seen during the follow-up time. CONCLUSIONS: The results of the study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with diabetic nephropathy and hypercholesterolemia.