A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy,normotensive volunteers

Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system. Received: 24 January 1995/Accepted in revised form: 18 September 1995     

Desipramine pharmacokinetics in Chinese and Caucasian volunteers

In order to better define the role of pharmacokinetic variation in reported cross-ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics of the tricyclic antidepressant desipramine (DMI) were studied in 14 Chinese and 16 Caucasian healthy volunteers. DMI and 2-OH-DMI concentrations were assayed with h.p.l.c. in serial plasma and 24 h urine samples over 5 days following an oral 100 mg dose of DMI. Mean total clearance of DMI ( CLDMI ) from plasma was significantly (P less than 0.05) higher in the Caucasians (123 +/- 57 l/h) than in the Chinese (73.5 +/- 38.8 l/h). There was no significant difference in the apparent clearance of DMI by hydroxylation, fraction of dose metabolized to the hydroxy metabolite, DMI t1/2 or plasma protein binding between the two groups. Trimodal distribution of CLDMI was found, with 4/14 (29%) Chinese demonstrating slow CL (less than 33 l/h) and 4/16 (25%) Caucasians rapid CL (greater than 195 l/h). Correcting CL values for the greater mean weight of the Caucasians did not alter the pattern of distribution. CLDMI did not correlate with body weight. Although environmental factors cannot be ruled out, these results are consistent with genetically based differences in hepatic metabolism, probably affecting pathways in addition to hydroxylation, and suggest that 30% of Orientals would be at risk for toxicity from routine doses of tricyclics or similarly metabolized drugs.     

Interaction between nifedipine and atenolol: pharmacokinetics and pharmacodynamics in normotensive volunteers

The cardiovascular effects of single oral doses of nifedipine (20 mg), atenolol (50 mg), or of their combination were compared with placebo in a double-blind randomized cross-over study in 10 normotensive volunteers. After subjects rested for 2 h, before drug administration, heart rate, blood pressure, stroke volume index, and cardiac index were measured noninvasively. These cardiovascular parameters were then determined prior to and after exercise periods (160 W, 10 min, bicycle ergometry) which were performed 40, 70, 130, 190, 310 min, and 22 h after drug intake. Nifedipine decreased resting diastolic blood pressure (p less than or equal to 0.05) after 2 h, whereas systolic blood pressure remained unchanged and heart rate significantly increased at rest and after exercise. Stroke volume index and cardiac index were unaffected. Atenolol significantly decreased systolic and diastolic blood pressure as well as heart rate; stroke volume index following exercise increased significantly, and cardiac index was unchanged. Administration of the combination caused a significantly more pronounced fall of systolic and diastolic blood pressure as compared with either drug alone, whereas the negative chronotropic effect was not different from that of atenolol. As did atenolol, the combination increased stroke volume index after exercise with no change in cardiac index. Maximum plasma concentrations of nifedipine (37.1 +/- 16.7 ng/ml) and atenolol (276.3 +/- 107.2 ng/ml) and terminal half-life of atenolol (9.9 +/- 2.6 h) were not altered by combined administration of the drugs.     

Comparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P<10(-4) and intravenously: 15.0+/-2.4 versus 5.1+/-0.6 hr, P<10(-4)). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0-->24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.     

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.     

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.     

The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers

The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing.The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l^–1 and t1/2_z increased to 4.0 h (NS).There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.     

The pharmacokinetics of single oral doses of feprazone in healthy volunteers and elderly patients.

1. The pharmacokinetics of feprazone were studied in nine healthy volunteers and 10 elderly patients. 2. The mean elimination half-life of feprazone after a single oral dose in the healthy volunteers was 22.3 h, the mean apparent clearance 0.0051 1/h per kg and the mean volume of distribution 0.1681/kg. Corresponding values for the elderly patients were 22.6 h, 0.00561/h per kg and 0.1651/kg, which are not different from those for the volunteers. Thus, we were unable to detect any changes in feprazone pharmacokinetics which are related to age, or to the concurrent use of chronic medications, such as digoxin, diuretics, or hormones.     

Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

Aim:

To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects.

Methods:

Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction-corrected visual predictive check (pcVPC) approaches.

Results:

The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment (V₁), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment (V₂) were 0.323 L·h^-1·kg^-1, 0.086 L/kg, 0.0957 L·h^-1·kg^-1, and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E_max model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC^*), had a significant effect on the EC₅₀ value. The typical PD population values of maximum effect (E_max), EC₅₀, baseline ACT value (E₀) and the coefficient of RBC^* on EC₅₀ were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E_max, EC₅₀, and E₀ were 6.80%, 46.4%, and 4.10%, respectively.

Conclusion:

Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.     

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.     

The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.     

Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers.

The pharmacokinetics and pharmacodynamics of prochlorperazine were studied in healthy volunteers using a recently developed h.p.l.c. assay. Eight subjects received 12.5 mg and 6.25 mg i.v. doses of prochlorperazine, a 25 mg oral dose and placebo in random order. Plasma half-life (t1/2) of prochlorperazine was 6.8 +/- 0.7 h and 6.9 +/- 0.8 h for the 12.5 mg and 6.25 mg i.v. doses respectively. Apparent volume of distribution and plasma clearance were high and the kinetics did not appear to be dose-related. Absorption of oral prochlorperazine appeared to be slow and bioavailability was very low. A metabolite, possibly prochlorperazine sulphoxide, was noted after oral dosing. Mild sedation was common after i.v. prochlorperazine, but cardiovascular effects were minimal. The main adverse effect was akathisia which was reported by five out of eight subjects after the higher i.v. dose. These results provide preliminary information on the pharmacokinetics of i.v. prochlorperazine which were previously unknown.     

Effects of ursodeoxycholic acid on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam in healthy volunteers

Animal and in vitro studies suggest that ursodeoxycholic acid (UDCA) can induce cytochrome P450 3A (CYP3A) expression and enhance its activities. On the other hand, Becquemont et al. demonstrated that UDCA had no influence on intestinal CYP3A activities. The aim of this study was to investigate the effects of UDCA on the intestinal and hepatic CYP3A activities by administration of midazolam (MDZ), as a specific probe for CYP3A activity, in humans. This was a randomized, open-label, crossover study with two phases in 14 healthy volunteers. The volunteers received UDCA (300 mg/day) or placebo orally for 9 days. The pharmacokinetics and pharmacodynamics of intravenous MDZ (5 mug/kg) and oral MDZ (15 mug/kg) were assessed on days 8 and 9, respectively. The pharmacodynamics of MDZ was estimated by measuring peak saccadic velocity, postural away length, critical fusion flicker frequency, and visual analogue scale. UDCA did not affect the pharmacokinetic and pharmacodynamic parameters of intravenous and oral MDZ administrations. Our study suggests that the clinical dosage of UDCA could not affect both hepatic and intestinal CYP3A activities and that the drug interaction between UDCA and substrates for CYP3A is unlikely in humans.     

Pharmacodynamics and pharmacokinetics of pinacidil in normotensive volunteers after repeated doses of a new slow-release tablet formulation

Pinacidil (CAS 85371-64-8) is an antihypertensive drug of the class of agents called "potassium channel openers". The pharmacokinetics of were studied after repeated oral administration of a new slow release tablet formulation (Pindac) as compared with the standard slow release capsule formulation in healthy volunteers. Eighteen healthy volunteers (3 males and 15 females), aged from 22 to 48 years, and 49 to 95 kg in weight, were given a 12.5 mg dose of each formulation every 12 h for 7 days on two occasions, in a randomized, cross-over trial with at least two weeks interval between trials. Blood samples were drawn immediately before drug administration on the morning of days 1, 2, 3, 4, 5, 6, and 7 and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 h after the last drug administration. Blood pressure, heart rate, and respiratory function were assessed at admission and on the morning of day 0 (baseline), 2 and 7, before drug administration, and at 4, 24 and 36 h after the final administration. Pinacidil plasma levels were determined by an HPLC method. Both formulations elicited similar reductions of systolic and diastolic pressures from 4 h after administration, but did not change heart rate. The main model-independent pharmacokinetic parameters of pinacidil (Cmax, Tmax, AUC, MRT), as well as the absorption and elimination half-lives were similar with the two formulations. During the study there were no complaints of side-effects with either of the formulations. One advantage of the new formulation as compared to the capsules is that the tablets can be cut easily and the dosage adapted to a patient's needs.     

Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers

OBJECTIVE: To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method. DESIGN: Open, randomised, four-way cross-over trial. PARTICIPANTS: 24 healthy male and female volunteers, aged 18-46 years. METHODS: Lacidipine was administered as single doses of 2, 4, 6 and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic evaluations were performed on study days 1 and 8. Plasma concentrations of lacidipine were determined by a validated high-performance liquid chromatography-radioimmunoassay method. The ratios of dose-normalised peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) were calculated and then compared across dose groups by analysis of variance to assess dose linearity against a 4 mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity. RESULTS: After repeated 2, 4 and 6 mg doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46-2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57-6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the administration interval at steady state (AUC(tau)), respectively. Mean half-life ranged between 13.2 hours and 18.7 hours. Precision of these estimates was limited by the small number of sampling timepoints collected in the final part of the curve. After administration of single doses, no statistically significant deviation from linearity was found except for the 8 mg dose, but a trend of greater than proportional exposure was evident with increasing dose. Following repeated administration, dose linearity over the therapeutic range was observed. No statistically significant difference was observed between AUC to infinity (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of pharmacokinetics. CONCLUSIONS: Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2-6 mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8 mg dose, which is outside the recommended therapeutic range, resulted in greater than predicted exposure. After low doses, the analytical method still does not allow complete characterisation of kinetics. Time-invariance of lacidipine kinetics is suggested.     

The pharmacokinetics of single oral doses of feprazone in healthy volunteers and elderly patients

1. The pharmacokinetics of feprazone were studied in nine healthy volunteers and 10 elderly patients.

2. The mean elimination half-life of feprazone after a single oral dose in the healthy volunteers was 22.3?h, the mean apparent clearance 0.00511/h per kg and the mean volume of distribution 0.1681/kg. Corresponding values for the elderly patients were 22.6?h, 0.00561/h per kg and 0.1651/kg, which are not different from those for the volunteers. Thus, we were unable to detect any changes in feprazone pharmacokinetics which are related to age, or to the concurrent use of chronic medications, such as digoxin, diuretics, or hormones.     

Effect of moricizine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single-dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics; and plasma protein binding were examined in 12 healthy male volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.     

Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers.

1. The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg was investigated in twelve healthy volunteers. 2. Co-administration of nicardipine significantly increased the AUC and the mean Cmax of propranolol. 3. Blood pressure and heart rate tended to decrease more when propranolol and nicardipine were administered together than when propranolol was given alone, but differences are of doubtful significance. 4. The results indicate that nicardipine alters the pharmacokinetics of propranolol by impaired hepatic 'first-pass' clearance, but pharmacodynamics were little affected.     

短效重组人胰岛素在人体内的药动学及药效学研究

目的 采用正常血糖-高胰岛素钳夹技术评估短效重组人胰岛素在健康人体内的药动学及药效学.方法采用单中心、随机、双肓、平行交叉研究,22名健康志愿者在正常血糖—高胰岛素钳夹平台基础上,分别前后接受皮下注射短效重组人胰岛素和优泌林R两次10 h钳夹试验,于给药前120、90、60、30 min及给药后0、10、20、30、4...     

Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly.

The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers. No difference between the groups in peak plasma concentration (Cmax) or in the time to peak (tmax) was found, but the elimination half-life t1/2,z and area under the plasma concentration-time curve (AUC) were significantly greater in the elderly group. The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT] and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.