Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia.

Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.

Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group.

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. HYPOTHESIS: Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. METHODS: Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. RESULTS: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. CONCLUSIONS: Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.

Lipid-altering efficacy and safety of simvastatin 80 mg/day: worldwide long-term experience in patients with hypercholesterolemia.

BACKGROUND AND AIM: Clinical data suggesting that larger decreases in low density lipoprotein cholesterol (LDL-C) result in greater reductions in coronary heart disease events have led to the establishment of aggressive LDL-C targets for the treatment of hypercholesterolemia. In view of this, the efficacy and safety of a new maximum dose of simvastatin, 80 mg, were evaluated in 9 studies involving 2819 hypercholesterolemic patients. This report focuses on the combined results from the 4 main or Pivotal studies in which a total of 1936 patients received simvastatin 40 or 80 mg for 36 to 48 weeks. METHODS AND RESULTS: The Pivotal studies had similar randomized, multicenter, controlled, double-blind, parallel-group designs. Their combined results demonstrated a significant advantage in the LDL-C-lowering effect for the 80 mg dose. At week 24, the mean percentage reductions (95% confidence intervals) from baseline in LDL-C for the 40 and 80 mg groups were -39.8% (-40.9, -38.7) and -45.7% (-46.5, -45.0) respectively (p < 0.001, between groups), and larger reductions in total cholesterol and triglycerides were also observed in the 80 mg group. Both doses were well tolerated. No new or unexpected adverse events were observed and the overall clinical event profiles were similar in the two groups. Clinically significant hepatic transaminase increases (> 3 times the upper limit of normal/ULN) and myopathy (muscle symptoms plus creatine kinase increase > 10 times ULN) occurred infrequently with both doses. Simvastatin 80 mg had a comparable efficacy and safety profile in women and men as well as in non-elderly and elderly patients. CONCLUSIONS: Simvastatin 80 mg provides additional LDL-C and triglyceride reductions compared to the 40 mg dose and has an excellent safety and tolerability profile.

Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

OBJECTIVE: To evaluate the effect of regular-strength grapefruit juice, a cytochrome P4503A4 (CYP3A4) inhibitor, on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin. METHODS: In a randomized crossover study, 16 healthy subjects received a single 40 mg dose of lovastatin in the evening after each consumed an 8-ounce glass of regular-strength grapefruit juice or water with breakfast for 3 consecutive days. The effect of the same grapefruit juice and water regimen on the pharmacokinetics of midazolam (2 mg oral dose given 1 hour after the third day of grapefruit juice and water) was used as a positive control in the same subjects. Plasma concentrations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were determined by an enzyme inhibition assay, and concentrations of lovastatin, lovastatin acid, and midazolam were determined by liquid chromatography-tandem mass spectrometry. RESULTS: The area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors increased slightly (-30% for each) after consumption of grapefruit juice. Similar effects on AUC and Cmax (approximately 40% increase for each) were noted after analysis of samples of hydrolyzed plasma (which converts inactive lactones to active hydroxy acid species). The AUC and Cmax values for lovastatin approximately doubled in the presence of grapefruit juice, whereas the same parameters for lovastatin acid increased 1.6-fold. Grapefruit juice caused the AUC for midazolam to increase by a factor of approximately 2.4. CONCLUSIONS: Daily consumption of a glass of regular-strength grapefruit juice has a minimal effect on plasma concentrations of HMG-CoA reductase inhibitors (approximately 30% to 40% increase) after a 40 mg evening dose of lovastatin.

Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers.

AIMS: The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied. METHODS: In a randomized, crossover study with four periods, twenty-four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1-4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively. RESULTS: The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15-mg rizatriptan were 16, 33, 72, and 127 ng ml-1 h, respectively, in males; and 19, 42, 97, and 161 ng ml-1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was approximately 40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min-1, respectively, in males; and 821 and 174 ml min-1, respectively, in females. CONCLUSIONS: The disposition kinetics of oral rizatriptan were linear for doses of 2. 5-10 mg in males, and for doses of 2.5-5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.

Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group.

This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (-40 to -36) and 46% (-47 to -45) for the 40- and 80-mg groups, respectively (p <0.001 between groups). One third of patients on the 40- and 80-mg doses achieved an LDL cholesterol reduction of 46% and > or = 53%, respectively. Decreases in apolipoprotein B, total cholesterol, and triglycerides were also significantly greater among patients receiving 80 mg/day. Simvastatin was well tolerated in both groups. Two patients (0.6%) in the 80-mg group developed myopathy. Consecutive, clinically significant hepatic transaminase elevations occurred in 3 (1.0%) and 6 (1.9%) patients in the 40- and 80-mg groups, respectively (p= 0.486). In conclusion, simvastatin 80 mg/day provided substantial reductions in LDL cholesterol, allowing most patients to reach their NCEP target levels; it also had an excellent safety and tolerability profile.

Some statistical methods for multiple endpoints in clinical trials.

This paper summarizes, defines, and discusses multiple endpoints comparison procedures, concepts, and methodologies for applications to clinical trials. We address the more widely used methods of alpha-level, p-value, and critical value adjustments. We examine global assessment measures such as O'Brien's test and Simes' procedure and contrast them with the alpha-adjustment procedures of Bonferroni and Holm. We propose a global assessment procedure based on categorization of the individual endpoints to form an overall composite endpoint. Additionally, we discuss a new weighting scheme for Holm's sequentially rejective alpha-adjustment procedure. Investigation of the correlation between endpoints is examined in relation to adjustment of the alpha-level. In the context of a clinical trial, the above multiplicity procedures are applied and compared. Finally, some comments concerning ease of use and relevance are summarized for the above methods.

Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist.

AIMS: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. METHODS: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion. RESULTS: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness. CONCLUSIONS: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.

Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease.

The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.

Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia.

PURPOSE: A randomized, double-blind, dose-ranging study of single-dose intravenous (IV) therapy with alendronate sodium (aminohydroxybutylidene bisphosphonate) was performed in patients with cancer-associated hypercalcemia. PATIENTS AND METHODS: Patients with hypercalcemia who had not received antitumor therapy in the preceding 7 days were treated with 48 hours of IV hydration. Patients with persistent hypercalcemia (albumin-corrected serum calcium concentration [CSCC] > or = 11.5 mg/dL) were randomly assigned to receive 2.5, 5, 10, or 15 mg of alendronate infused over 2 hours, or 10 mg of alendronate infused over 24 hours. Fifty-nine patients were treated and 50 patients were assessable for the dose-response relationship. RESULTS: Normalization of CSCC (< or = 10.5 mg/dL) was achieved in 22%, 82%, 75%, and 90% of assessable patients in the 2.5-, 5-, 10- (2- and 24-hour groups pooled), and 15-mg dose groups, respectively, within 8 days of therapy. Doses > or = 5 mg were significantly superior to the 2.5-mg dose level (P < .05). There was no significant difference in the minimum CSCC achieved between the 2- and 24-hour infusions of the 10-mg dose. Based on an intent-to-treat analysis of all randomized patients, the overall complete response rate was 74% for dose levels greater than 2.5 mg. For assessable patients who responded to > or = 5 mg of alendronate, the estimated median duration of normocalcemia was 10 days (range, 1 to 25). The estimated median time to relapse (CSCC > 11.5 mg/dL) was 15 days from initial treatment and 12 days from initial response, respectively. Adverse events included a transient febrile response in 34% of patients and eight episodes of reversible elevations in serum transaminase levels among treated patients. CONCLUSION: While a statistically significant dose-response relationship was not clearly evident at doses greater than 5 mg, single doses of > or = 5 mg alendronate sodium effectively lowered serum calcium concentrations and were well tolerated in the treatment of cancer-associated hypercalcemia.