Efficacy and safety of 300 micrograms and 400 micrograms cerivastatin once daily in patients with primary hypercholesterolaemia: a multicentre, randomized, double-blind, placebo-controlled study.

This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance.

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.

Steady-state pharmacokinetics of nimodipine during chronic administration of indometacin in elderly healthy volunteers.

The possible influence of chronic indometacin (CAS 53-86-1) medication on nimodipine (CAS 66085-59-4) pharmacokinetics was investigated in 24 elderly healthy subjects. Both drugs were orally administered in a non-blinded, randomized, twofold crossover design. The study periods with a 5-day treatment each were separated by a 2-week washout period. The Css,max of nimodipine was increased after the combined administration of nimodipine (30 mg t.i.d.) and indometacin (25 mg b.i.d.) as compared with those after nimodipine monotherapy: 24.2 +/- 14.7 micrograms/l vs. 19.7 +/- 10.3 micrograms/l. This increase, however, was not of an order to become clinically relevant. Nimodipine AUCss slightly increased under indometacin co-medication from 57.9 +/- 27.5 micrograms.h.l-1 to 62.8 +/- 26.6 micrograms.h.l-1, resulting in a mean relative bioavailability of nimodipine of 111% with a 90%-confidence interval of 96-128% for the combined medication. There was no evidence of any clinically relevant difference in hemodynamics and other findings between both treatments. The overall frequency of side effects was low after both medication regimens. The findings of this study indicate that a combined treatment with both compounds should not be associated with a clinically relevant interaction.

Chronic administration of nimodipine and propranolol in elderly normotensive subjects--an interaction study.

Nimodipine (30 mg t.i.d.) and propranolol (40 mg t.i.d.) were given orally to 24 healthy elderly subjects in a randomized, un-blinded, threefold crossover study. Each of the study periods lasted 8 days with a 5-day treatment phase separated by 2-week washout phases. Mean peak nimodipine plasma concentration was decreased after combined administration of the two drugs (16.1 +/- 8.1 micrograms/l vs. 12.4 +/- 9.5 micrograms/l). Nimodipine AUCss slightly decreased under propranolol co-medication from 44.9 +/- 15.1 micrograms x l/l to 38.8 +/- 22.5 micrograms x h/l, resulting in an AUC ratio of 88.8 +/- 44.5%. The relative bioavailability of propranolol was 104.1 +/- 38.3% after the combined propranolol and nimodipine medication, all other pharmacokinetic parameters remained unchanged. The pharmacological effects on the cardiovascular system were negligible after nimodipine alone. The reductions in blood pressure and pulse rate and the prolongations of typical ECG times observed after propranolol monotherapy and after the combination therapy were of similar size and were almost solely attributed to the action of the beta-blocker. The findings of this study indicate that chronic treatment with nimodipine together with propranolol should not be associated with a clinically relevant interaction.

The influence of nimodipine on hemodynamic parameters and peak and trough plasma concentrations of nifedipine chronically administered to elderly hypertensive patients.

Possible drug interactions between the two calcium channel blockers nimodipine and nifedipine were investigated in 12 elderly patients with stable mild to moderate hypertension. Their individually adjusted nifedipine treatment had been unchanged for at least 5 weeks. There was no evidence of significant changes in nifedipine efficacy as seen from blood pressure and heart rate after a 7-day comedication of 30 mg nimodipine t.i.d. as compared with the findings after combined administration of nifedipine and placebo. Nifedipine steady-state trough and peak concentrations were not significantly altered by concomitant nimodipine administration. On the other hand, nifedipine did not affect nimodipine trough and peak concentrations when compared with published data. Differences in clinical chemistry or tolerance between both treatment regimens did not occur or were marginal, respectively. In conclusion, a clinically relevant drug interaction between nifedipine and nimodipine which might be potentially harmful for patients with hypertension was not observed in this study.

Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects.

1. Nimodipine (30 mg three times daily) and diazepam (10 mg once daily), were given orally to 24 elderly healthy subjects in a randomized, non-blinded, threefold-crossover study. Each of the three treatment periods lasted 5 days separated by 2 week washout phases. 2. Plasma concentrations of nimodipine and diazepam were not affected by the combined treatment. 3. No clinically relevant changes in haemodynamics, ECG recordings, clinical chemistry or haematology were observed after all of the three treatments. The overall frequency of side effects was lowest during monotherapy with nimodipine and highest during diazepam monotherapy. 4. In the test of subjective rating of tiredness (VAS) and the Pauli calculation test, diazepam, alone and with nimodipine co-medication, produced an increase in tiredness and a clear reduction in performance and endurance. After nimodipine monotherapy an improvement was observed only in the Pauli test. Using the critical flicker fusion frequency test (CFF) significant decrements in performance were found after diazepam monotherapy only. 5. In summary, there was no evidence that either nimodipine or diazepam affected the pharmacokinetics, safety and tolerance of each other. However, the CNS-effects of diazepam were compensated partially by nimodipine.

Global rating, symptoms, behavior, and cognitive performance as indicators of efficacy in clinical studies with nimodipine in elderly patients with cognitive impairment syndromes.

Nimodipine is a calcium antagonist which improves learning and memory in brain-lesioned or aged animals (LeVere & Sandin, 1989; Schuurman & Traber, 1989). It also accelerates the recovery of experimentally damaged sciatic nerves (van der Zee et al., 1987) and reduces age-associated gait abnormalities in aging rats (Schuurman et al., 1987). Selective action on cerebral vessels has also been proven. Vasoconstriction was prevented or reduced with nimodipine under experimental conditions (Toward, 1981) and cerebral blood flow could be increased (Kazda et al., 1982). The drug has been tested in subarachnoid hemorrhage, stroke, severe head injury, cerebral resuscitation after cardiac arrest, impaired brain function in old age, and dementia. Methodological aspects of clinical studies with this agent are examined in this paper.

Uso de la nimodipina (Nimotop) en psicogeriatría / Use of the nimodipine (Nimotop) in psychogeriatric

La nimodipina (Nimotop) es una droga prometedora para el anciano demente y para pacientes no dementes. Varios estudios doble ciego han demostrado que la droga puede ser efectiva para los déficit cognitivos, rendimiento, afectividad e integración social. Las conclusiones derivadas de los resultados de varios experimentos sobre conducta en animales son significativos para predecir los efectos clínicos de la nimodipina (Nimotop)