Biomedical subjects

J Kuhlmann

Publications and source records attributed to J Kuhlmann.

At least 55 records · Page 3Linked to original sources

PubMed1997

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form.

OBJECTIVE: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. METHODS: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. RESULTS: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. CONCLUSION: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

Adult↗

PubMed1997

Improved cytosolic free calcium mobilization and superoxide production in bicarbonate-based peritoneal dialysis solution.

BACKGROUND: Intraperitoneal phagocytes play an important role in local host defence to prevent CAPD peritonitis. The intracellular calcium [Ca2+]i is thought to be involved in the regulation of various cell functions. This study therefore investigates the effect of lactate-based dialysis solution (LBDS) and bicarbonate-based dialysis solution (BBDS) on cytosolic free calcium mobilization and superoxide production (SP) as important steps in signal transduction and bacterial killing. METHODS: We studied changes in [Ca2+]i and SP following stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP) in polymorphonuclear neutrophils (PMNs) incubated in either LBDS-pH 5.2, LBDS adjusted to pH 7.4, 1:10 diluted spent and fresh LBDS or BBDS-pH 7.4 with different glucose concentrations, comparing the data with cells treated with Hanks buffer (HBSS) pH 7.4 as control. To elucidate the effect of glucose and lactate PMNs were additionally incubated in HBSS-pH 7.4, containing glucose (HBSS-Glu-pH 7.4) or lactate (HBSS-Lact-pH 7.4) in the same concentrations as contained in CAPD solutions and tested as above. PMNs were isolated from healthy blood donors and incubated with dialysis solution 10 min prior to stimulation with fMLP. RESULTS: [Ca2+]i mobilization and SP were completely inhibited in PMNs incubated in LBDS pH 5.2. pH adjustment of LBDS to 7.4 and 1:10 dilution of spent and fresh LBDS corrected some of the suppression of the calcium influx and superoxide production. BBDS pH 7.4, however, preserved physiological cell function significantly better at low (1.5 and 2.3%) glucose concentrations. CONCLUSION: In comparison to conventional lactate-based dialysis solution, pH adjusted and 1:10 diluted LBDS, bicarbonate-based dialysis solution is more biocompatible since it preserves significantly better neutrophil cell functions.

Bicarbonates↗

PubMed1997

Influence of cholestyramine on the pharmacokinetics of cerivastatin.

The possible influence of the bile acid sequestering agent cholestyramine, a basic comedication in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated. When both drugs were administered concomitantly in the morning under fasting conditions, a decrease in relative bioavailability by 21% could be observed, possibly due to irreversible adsorption of the statin to the resin. In addition, the delay in absorption led to a 41% decrease in cerivastatin mean maximum plasma concentration which also occurred at later time. A second study addressed in detail the question of time interval required between both treatments to minimize the influence of cholestyramine pretreatment on cerivastatin bioavailability: dosing of cerivastatin at dinner (6 p.m.) or bed time (10 p.m.) with cholestyramine pretreatment 1 hour before meal (5 p.m.) in both treatments. The decrease in mean AUC was now approximately 8-16% depending on the time of pretreatment (1-hour-interval: 16%, 5-hour-interval: 8%), and Cmax decreased by approximately 32%, irrespective of the time of pretreatment. Tmax was increased in both treatments, whereas t1/2 was not changed. The presented data support the conclusion that when administered concomitantly, the bioavailability of cerivastatin is moderately reduced by adsorption to cholestyramine. Following, however, the dosing instructions of both cholestyramine (1 hour before meal) and cerivastatin (once-daily in the evening at dinner or at bed time), i.e. administering both drugs several hours (at least 1 hour) apart, the observed effects on rate and extent of absorption of cerivastatin are unlikely to be of clinical relevance.

Absorption↗

PubMed1997

Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin.

To determine the absolute bioavailability of the HMG-CoA reductase inhibitor cerivastatin, 12 healthy young male volunteers received single doses of either 100 micrograms as a 1-minute bolus infusion or 200 micrograms orally as tablets in a controlled, randomized crossover study. In addition, 8 of the 12 subjects participated in a third treatment period in which 200 micrograms cerivastatin were administered as an oral solution as reference for determining the relative bioavailability of the tablet drug formulation. Plasma samples were analyzed for cerivastatin by a specific HPLC assay with fluorescence detection after post-column irradiation of the eluate, with a limit of quantification of 0.1 microgram/l. Following all treatments, cerivastatin was well tolerated and no clinically relevant adverse events or changes in laboratory parameters were observed. Vital signs and ECG remained unchanged. Plasma concentration/time profiles of cerivastatin following intravenous bolus could be described by a 2-compartment model with a distribution half-life of 3-5 min and an elimination half-life of 1.5-2.4 h. For the 2 oral administrations a 1-compartmental pharmacokinetic model with a first-order absorption process was best to describe the plasma concentration/time data. Based on the AUCnorm values of the 7 subjects, valid for complete pharmacokinetic evaluation, the absolute bioavailability of tablet and oral solution was 60.0 and 59.6% (90% confidence intervals 53-68%), respectively. The relative bioavailability of tablet compared with solution was 100.7% (90% confidence interval 89-114%), with tablet and oral solution showing nearly identical in vivo absorption characteristics and almost superimposable plasma concentration/time curves. The tablet formulation, therefore, can be regarded as an optimal oral formulation with respect to galenic aspects.

Administration, Oral↗

PubMed1997

Influence of the antacid Maalox and the H2-antagonist cimetidine on the pharmacokinetics of cerivastatin.

The possible influence of Maalox 70, an antacid based on magnesium-aluminum hydroxide, and the H2-antagonist cimetidine, both commonly prescribed in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated in 2 separate studies in 8 healthy young male subjects each. Cerivastatin plasma concentration/time profiles were assessed by a specific HPLC assay; in addition, total immunoreactive drug (cerivastatin plus metabolites) was determined by RIA. Single oral doses of 200 micrograms cerivastatin were administered under fasting conditions without or with 10 ml Maalox 70 suspension. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.92 (0.73-1.15) and 0.89 (0.72-1.10) for the HPLC data, and 0.99 (0.85-1.14) and 1.03 (0.82-1.30) for the RIA data, respectively. Thus, no interaction of the simultaneous administration of Maalox 70 on the pharmacokinetics of cerivastatin was observed. In a similar controlled, randomized nonblind 2-way crossover design the influence of the H2- antagonist and well-known cytochrome P450 enzyme inhibitor cimetidine was investigated. Eight healthy young male volunteers received single oral doses of 200 micrograms cerivastatin alone or on the fourth day of a 4-day cimetidine 400 mg b.i.d. pretreatment. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.98 (0.90-1.08) and 0.91 (0.78-1.07) for the RIA data, and 0.89 (0.82-0.96) and 0.93 (0.80-1.09) for the HPLC data, respectively, clearly indicating that cimetidine and cerivastatin did not interact pharmacokinetically. These results do not only reflect the apparent insensitivity of cerivastatin absorption to possible changes in gastric pH, but demonstrate that the metabolic pathways of cerivastatin, involved in its first-pass metabolism and elimination, are rather insensitive to cytochrome P450 enzyme inhibition induced by cimetidine.

Administration, Oral↗

PubMed1997

Test-retest reliability and influence of practice effects on performance in a multi-user computerized psychometric test system for use in clinical pharmacological studies.

Fifty naive drug-free healthy young male or female volunteers performed psychometric tests on 6 sessions with 3- to 4-days intervals, using a new multi-user computerized test system for use in clinical pharmacology. Tests of simple reaction time, complex reaction time, concentration, motor coordination, and short-term memory (word pairs or figures) were performed. Clear practice effects were shown for almost every psychometric variable recorded. The magnitude differed considerably between tests. The magnitude of practice effects was most evident (46.5-55.0%) for the concentration test, the coordination test, and the Vienna reaction test. Intermediate practice effects (20.8-31.0%) were observed with the complex reaction test (percent correct reactions) and both short-term memory tests (test duration). Only small practice effects (5.1-14.3%) were observed with the reaction times of the simple and the complex reaction test, and the percent correct responses in the short-term memory tests. After 3 test sessions, significant further improvements could not be shown for most tests, but for the reaction times in the simple and the complex reaction test this was true from the first or the second test session, respectively. For the concentration test and the coordination test, significant practice effects could be shown even after 5 training sessions. It is recommended to perform at least one training session before the start of clinical pharmacological studies with psychometric testing. Test-retest-reliability, as determined from session 5 to session 6 by Spearman's rank correlation coefficient (R8), was very good (> or = 0.95) for the concentration test (percent correct responses) and the coordination test (mean steering time). Most other variables showed intermediate (0.44-0.68) reliability (reaction times in the simple and complex reaction test, percent correct reactions in the complex reaction test, percent errors in the concentration test, test duration of the short-term memory tests). The percent correct answers, which is the primary variable in both short-term memory tests, had a relatively poor reliability (0.14-0.18).

Adult↗

PubMed1997

Pharmacokinetics of the controlled-release nisoldipine coat-core tablet formulation.

UNLABELLED: The pharmacokinetics, safety, and tolerability of the novel once-daily "coat-core" formulation of the calcium antagonist nisoldipine were investigated in 4 randomized nonblind studies A-D in 52 healthy volunteers. Immediate-release or intravenous formulations were administered as reference in 3 studies. The objective of the present studies was to select the optimum controlled-release formulation (A), compare it to the immediate-release tablet at steady-state (B), determine the absolute bioavailability (C), and investigate bioequivalence after a small change in composition (D). Comparative pharmacokinetic properties: Mean residence time and apparent terminal half-life of nisoldipine in the coat-core formulation were significantly increased in comparison to administration via the intravenous route or the oral immediate-release formulation. Concentration profiles could be described with a 3-segment input model. Steady-state conditions were established with the second dose of nisoldipine coat-core and accumulation from first dose to steady-state accounted for 46% as expected due to the contribution of AUC beyond 24 h. At steady-state the coat-core formulation produced a plateau-shaped profile of nisoldipine plasma concentrations throughout the 24 h dosing interval and the peak-trough fluctuation was reduced by approximately 4-fold, compared to the immediate-release tablet in a b.i.d. regimen. While the absolute bioavailability of the drug in the coat-core tablet was 5.5%, its relative bioavailability was greater by 1.5-fold compared to the immediate-release tablet. This can be attributed to release of drug in the colon where the contribution of the gut wall to presystemic metabolism is reduced resulting in an increase in bioavailability as compared to stomach and small intestine. The intersubject variability of nisoldipine coat-core pharmacokinetics was comparable to that of the immediate-release tablet. The within-subject (intraindividual) variability was considerably smaller. Based on its pharmacokinetic profile the side chain-hydroxylated metabolite M 9 is not expected to contribute significantly to the antihypertensive effect of nisoldipine coat-core. In vitro/in vivo correlation: There was a rank order correlation between in vitro release rate of 3 different nisoldipine coat-core formulations and their noncompartmental pharmacokinetic parameters, a decrease in dissolution rate leading to increased bioavailability in vivo. Likewise, the mean dissolution times in vitro and in vivo were correlated in rank order. A linear (level A) correlation could be established within approximately 0-6 hours (in vitro) corresponding to 0-12 hours in vivo. The change in slope of the correlation curve after approximately 12 hours (in vivo) most likely reflects changes in both rate and extent of nisoldipine absorption in different sections of the gastrointestinal tract. SAFETY: In the present studies the drug was safe and well tolerated, adverse events related to peripheral vasodilatation being less frequent with the coat-core tablet compared to intravenous or immediate-release formulations.

Adult↗

PubMed1997

Drug research: from the idea to the product.

The path of a new drug from the idea to product may be divided into 2 phases, namely drug discovery and drug development. In drug discovery a dramatic change is taking place. Due to a remarkable progress in understanding and explaining the underlying cause of many diseases by identifying and sequencing the genes encoded within DNA, it has become possible with new methods, like molecular biology or gene technology, to develop simple test assays by which a large number of compounds may be tested in regard to their biological efficacy. Automation of these test systems utilizing computer-controlled robotic systems has made it possible to evaluate up to 1 million substances per robot per year on their biological effect. While the classical medicinal chemistry cannot produce such a large number of new compounds, combinatorial chemistry may offer the opportunity to screen large numbers of novel compounds rapidly and to reduce the time taken to identify drug candidates substantially. Overall, it is estimated that combinatorial chemistry techniques have resulted in a reduction in the time taken to identify drug candidates of between 18-24 months. In drug development 2 partly overlapping phases can be differentiated, namely the preclinical and clinical phase. During the first part of drug development necessary requirements for first use in man are met by performing preclinical pharmacological, toxicological, and pharmacokinetic investigations in the animal and in in vitro testing. These investigations are playing a central part for the benefit/risk evaluation of new drugs. Only if the risks connected to the clinical study are medically justifiable in relation to the likely therapeutic benefit of the compound, the clinical trial may basically take place under consideration of the legal requirements of the country in which the study is carried out. In drug research clinical pharmacology is the connecting link between preclinical and clinical research. Clinical pharmacology produces the necessary basis for the clinical trial of a new substance in the patient with the target indication. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial and the probable effective dose range and dosing interval is made, the aim of phase II-IV is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Only with a very careful drug investigation during phase I-IV it is really possible to register the therapeutic risk and benefit of a new drug and to control resulting serious problems. An analysis of registered drugs during the last years shows that despite enhanced efforts and dramatically rising development costs the innovation potential of the classical approach is steadily decreasing. Therefore, it is absolutely necessary to develop new innovative drugs with the help of new technologies like molecular and cell biology, gene technology, or immunology as well as combinatorial chemistry and robot supported substance screening.

Animals↗

PubMed1996

Defective interactions between TCR chains and CD3 heterodimers prevent membrane expression of TCR-alpha beta in human T cells.

The human TCR complex is composed of two clonotypic polypeptide chains, TCR-alpha and TCR-beta (or TCR-gamma and TCR-delta) associated with CD3 gamma-, delta-, and epsilon-chains and zeta 2 homodimers. All six polypeptide chains are indispensable for TCR membrane expression and signaling function. In the present paper is described the analysis of a new TCR membrane-negative Jurkat T cell variant: E6.R3. The defect in this variant bears on the interaction between TCR and CD3 chains. E6.R3 cells have deleted three nucleotides in the TCR-alpha transmembrane (TM) region, which consequently lacks a leucine. This defect causes 1) lack of association between TCR alpha-chains and CD delta epsilon heterodimers; 2) lack of formation of disulphide-linked, fully glycosylated TCR-alpha beta heterodimers; and 3) lack of interaction between TCR-alpha beta/CD3 complexes and zeta-chains. Despite these defective interactions, TCR alpha-chains appear to become fully glycosylated, i.e., they are not retained in the endoplasmic reticulum but are further processed in the Golgi apparatus without such interactions. The defect may be due to the observation that in the E6.R3 TCR alpha- chains TM region, the two charged amino acids are situated on the same side of the alpha-helix; these two amino acids are exposed on opposite faces of the TM alpha-helix in normal TCR alpha-chains, possibly allowing TCR alpha-chains to interact with both CD3 delta- and CD3 epsilon-chains. Further possible consequences of the leucine deletion in the E6.R3 TCR-alpha TM region are discussed.

Amino Acid Sequence↗

PubMed1996

Pharmacodynamics and pharmacokinetics of BAY x 7195 aerosol, a new and selective receptor antagonist of cysteinyl-leukotrienes, in normal volunteers.

1. The safety, tolerability and pharmacokinetics of BAY x 7195 aerosol, a new selective receptor antagonist of cysteinyl-leukotrienes, were investigated in healthy male volunteers in two observational studies (1 and 2 mg; n = 5 each) and two double blind, placebo-controlled two way crossover studies (4 and 8 mg; n = 6 each) using the commercially available Inhaler Ingelheim M. 2. The pharmacodynamic effect was assessed by testing the ability of BAY x 7195 aerosol to inhibit leukotriene-D4 (LTD4) induced bronchoconstriction in healthy volunteers. Using a double-blind, placebo-controlled three way crossover design, volunteers received 2 and 4 mg of BAY x 7195 by means of a newly developed metered dose dry powder inhaler. Bronchoprovocation with nebulized LTD4 was performed 20 min and 8 h (n = 6 each) after drug administration. Specific airways of conductance (SGaw) served to assess the airway's response. 3. BAY x 7195 aerosol was safe and well tolerated. Inhalation of the aerosol had no effect on baseline lung function. Only one volunteer reported cough following the inhalation of the 8 mg dose. 4. The pharmacokinetics of unchanged drug following the administration of BAY x 7195 aerosol were linear in the investigated range of doses and in general very similar to a previously investigated tablet formulation. Plasma-concentration vs time courses followed a two-compartment body model. Compared with oral administration of the tablet formulation absorption tended to be more rapid with the aerosol formulation. 5. Compared with placebo, 2 and 4 mg BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 20 min after drug administration by a mean (geometric) of 14.2 and 29.7 fold, respectively. For both doses only three volunteers showed a protective effect against LTD4 induced bronchoconstriction 8 h after drug administration. Individual shifts in the concentration-response curve ranged between 0.4 and 7.2 fold. 6. In conclusion, the present results suggest that BAY x 7195 aerosol is a safe and potent but short acting receptor antagonist of cysteinyl leukotrienes in man.

Administration, Inhalation↗

PubMed1996

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Administration, Oral↗

PubMed1996

The influence of age on the pharmacokinetics of nimodipine.

Single and multiple dose pharmacokinetics and absolute bioavailability of the calcium antagonist nimodipine (Nimotop) were investigated in 24 young (age: 22 - 40 years) and 24 elderly (age: 59 - 79 years) healthy subjects. There were no significant changes in blood pressure, heart rate, and ECG-parameters in both age groups, and no increase in frequency of adverse events was observed in the elderly. Following a single intravenous infusion of 15 micrograms/kg for 1 hour, there were no significant differences in nimodipine pharmacokinetics between young and elderly volunteers. Oral administration (single dose of 30 mg, 30 mg t.i.d. for 6 days), however, resulted in pronounced differences in AUC and Cmax between elderly and young subjects when the same doses were given. Under steady-state conditions the elderly reached significantly higher Cmax (g.mean/SD: 23.3/1.62 micrograms/l) and AUC-values (47.5/1.62 micrograms*h/l) than the young volunteers (13.5/2.03 micrograms/l, and 25.7/1.73 micrograms*h/l, respectively). The absolute bioavailability was 10.6/1.60% in the elderly and 5.4/2.11% in young subjects. The observed pharmacokinetic differences in the study most likely reflect the reduced metabolic clearance of nimodipine in the elderly.

Adult↗

PubMed1996

No interethnic differences in stereoselective disposition of oral nimodipine between Caucasian and Japanese subjects.

Using stereospecific assays plasma samples of 4 clinical-pharmacological studies have been analyzed to obtain enantioselective data on the pharmacokinetics of the calcium channel blocker nimodipine in healthy young and elderly Caucasians as well as in healthy young Japanese subjects. Basic pharmacokinetics (AUC, C(max), t(max), t1/2) and dose-proportionality based on racemic nimodipine plasma concentrations after oral single doses of 30, 60, and 90 mg were comparable in Caucasian and Japanese subjects. Stereoselective disposition of nimodipine could be observed in all cases investigated, resulting in pronounced differences in AUC and C(max) values favoring the (R)-(+)-isomer in respect of higher oral bioavailability: After single doses of 60 mg nimodipine, for instance, (R)/(S)-ratios for AUC were ranging from 5.5 - 10.0 (g.mean/SD: 7.4/1.3) in young Caucasians, for C(max) from 4.4 - 7.7 (g.mean/SD: 5.9/1.3). Corresponding ranges of 4.7 - 5.5 (g.mean/SD: 5.0/1.1) and 4.5 - 6.5 (g.mean/SD: 5.0/1.2), respectively, were calculated for Japanese subjects. The mean (R)/(S)-ratios for AUC and C(max) of all 4 studies were quite comparable between the 2 ethnic groups. The available data suggest that there are neither any differences in racemic nimodipine pharmacokinetics in Caucasians and Japanese subjects nor interethnic differences in its stereoselective disposition after oral therapeutic doses.

Administration, Oral↗

PubMed1996

Effect of educational level, gender and age on the performance in a multi-user computerized psychometric test system for use in clinical pharmacological studies.

197 native, drug-free healthy young volunteers performed psychometric tests on a single occasion, using a new multi-user computerized test system which consists of tests of simple reaction time, complex reaction time, vigilance, concentration, motor coordination, short-term memory (word pairs or figures) and abstract language-free reasoning (2 versions). Normality of distribution of all psychometric variables was checked. For the reasoning tests and the memory tests, internal consistency and parallel test reliability were determined. Cross-correlations between the variables and factor analysis were done to evaluate whether different tests measure different brain functions. Multivariate variance analysis was carried out to test the effect of the independent factors school education, gender and age on the performance in the psychometric tests. Subjects with a lower school education level performed worse in the reasoning tests, the concentration test and the memory tests. Females were slower in the coordination test and made fewer correct solutions in the concentration test. Older subjects performed worse in the reasoning tests and had a longer working time in the memory tests than younger ones. The results show the necessity of psychometric screening of volunteers before recruitment for clinical pharmacological psychometric studies in order to reduce-individual variability.

Adolescent↗

PubMed1995

Nimodipine. Potential for drug-drug interactions in the elderly.

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

Aged↗

PubMed1995

Pharmacokinetic development of quinolone antibiotics.

A prerequisite for the pharmacokinetic development of quinolone antibiotics is a sensitive and accurate method for the quantification of the drug in biological fluids. Both, a drug specific (e.g. HPLC) and a drug non-specific but effect related assay (e.g. bioassay) should be used during early clinical development to detect major active metabolites. The basic pharmacokinetic behavior of the drug is investigated as part of the early phase I program, where single and multiple ascending dose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studies are performed to describe the absolute bioavailability, dose proportionality, pharmacokinetics in young and elderly, male and female volunteers. The suitability of the clinical dosage from must be evaluated in comparison to an oral solution and by quantification of the effect of food on bioavailability. The characterization of the absorption in different parts of the gastrointestinal tract may be valuable for dosage form optimization. In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine, theophylline and warfarin has to be evaluated. This can be done by in vitro and in vivo preclinical experiments, before formal clinical-pharmacology studies are performed. Further pharmacokinetic characterization (e.g. studies in special subpopulation, extended interaction studies, total recovery using 14C-labelled compound, blister fluid penetration) will be done parallel to the phase II/III development program. During these efficacy and safety trials blood samples should be obtained and PK-parameters can be calculated using sparse data analysis methods like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.

4-Quinolones↗

PubMed1995

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.

Aged↗

PubMed1995

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.

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