ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02030.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Inherent problems exist in the actual delivery of doses of medications to pediatric patients, particularly with the IV route of drug administration. Standardized policies and procedures for recognized problems with specific routes of drug administration, along with pharmaceutical industry cooperation, are essential for solving drug delivery problems in pediatric therapeutics.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02031.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

To test the relationship between plasma moricizine concentration and the electrocardiogram (ECG) and arrhythmia suppression, 17 symptomatic cardiac patients with 30 or more ventricular premature complexes per hour were studied. Seven patients were mature adults, less than 60 years of age; and ten were elderly adults, more than 60 years of age. During steady‐state moricizine therapy, patients had plasma moricizine concentration determined over a dosing interval, and had standard 12‐lead ECG and a 24‐hour ambulatory ECG recorded. The mean moricizine dose was 215 ± 29 mg every 8 hours; mean maximal moricizine concentration was 1.4 ± 0.84 μg/ml; and mean t1/2βwas 1.5 ± 0.7 hours. Baseline age‐related differences were found, including prolonged electrocardiographic intervals(PR and QRS)(P<.05),increased ventricular arrhythmias(P<.05),and reduction in creatinine clearance(P<.05)in the elderly. Compared with pretreatment values, PR(P<.05)and QRS(P<.05) prolongation was observed, and was more marked in elderly patients.Over a dosing interval, there were dynamic changes on the ECG that paralleled plasma moricizine concentration; that is, peak and nadir intact moricizine concentration occurred simultaneously with ECG changes: QRS and JTc prolonged(P<.05),and PR prolongation approached significance(P =0.09).Suppression of ventricular premature complexes of 80% or more occurred in 15 patients, and ventricular tachycardia was abolished in 10 of 12 patients. Probit analysis revealed that the therapeutic antiarrhythmic concentration ranged from 0.20 to 3.6 μg/ml. After treatment, there was no difference for area under the plasma concentration curve, half life of elimination, or volume of distribution in: (1) mature adults younger than 60 years versus elderly adults 60 years of age or older, nor (2) patients with ejection fraction of 35% or lower versus those with ejection fraction higher than 35%. Intact plasma moricizine concentration accounts for dynamic electrocardiographic and antiarrhythmic effects after use of the drug. Cautious administration of moricizine in older patients is warranted in view of age‐related baseline differences in cardiac conduction, as well as more marked effects on PR and QRS duration; and potential toxicity secondary to diminished

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02032.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Digoxin (D3) metabolism is partially mediated by the gastrointestinal tract via acid hydrolysis of digitoxose sugar moieties and bacterial reduction of the lactone. The hypothesis that hypochlorhydria influences digoxin disposition was tested in six normochlorhydric (NC) and four hypochlorhydric (HC) subjects. D3 tablets were administered daily for 19 to 28 days, and quantitative urine and fecal samples were collected over the last 3 days (steady state). Samples were analyzed for D3 and its extractable metabolites by fluorescence‐derivatization HPLC. Excretion of D3 in urine increased from 37% of the dose in NC to 46% in HC, whereas excretion of D3 in feces decreased from 29 to 14%. These changes were statistically significant(P<.05)and consistent with decreased hydrolysis of D3 by stomach acid and increased intestinal metabolism in HC. In each subject, D3 was added to anaerobic cultures of both feces and jejunal fluid. Digoxin was reduced in all but two of the fecal incubates, and was not reduced in any jejunal fluid incubates. Because dihydrodigoxin (DHD3) was found in only two hypochlorhydric subjects, in vitro measures of bacterial reduction of D3 were not predictive of in vivo excretion of reduced metabolites. Sugar‐hydrolyzed, reduced metabolites were not found in any subjects. It is concluded that D3 disposition is altered by hypochlorhydria, and that an understanding of the metabolic mechanisms requires further st

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02033.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Central nervous system (CNS)‐related symptoms and quality of life during treatment with controlled‐release (CR) metoprolol and a standard formulation of atenolol were compared in a double‐blind crossover study in 60 patients with mild to moderate hypertension. After a 4‐week placebo run‐in period, each β1‐adrenoceptor blocker was administered at a dosage of 100 mg once daily for 6 weeks. Quality of life was assessed regularly during the active treatment phases by use of two standardized self‐administered questionnaires, the minor symptom evaluation (MSE) profile, and the psychologic general well‐being (PGWB) index. Both questionnaires have previously been shown to be effective in detecting CNS symptoms and changes in well being produced by β‐blockers. Blood pressure and heart rate were monitored to assess the antihypertensive efficacy of the two drugs. Metoprolol CR and atenolol produced equivalent, clinically effective reductions in systolic and diastolic blood pressures measured 24 hours after administration. The drugs were found to exert similar effects on general well being, as assessed by the PGWB index, and there were no significant differences between the two treatments with regard to the three dimensions of the MSE profile, contentment, vitality, and sleep. Thus, at equivalent antihypertensive dosages, metoprolol CR and atenolol are clinically comparable with regard to the degree of CNS‐related symptoms produced and effects on general well being. Because these agents differ markedly in lipophilicity, other factors, such as β1‐selectivity/nonselectivity, may be more important determinants of whether these subjective symptoms occur during

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02034.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetics and safety of CL 275,838, a new potential memory‐enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double‐blind, placebo‐controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple‐dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmaxand AUC of the parent compound and its two metabolites were dose related. Mean wash‐out t1/2was 18 to 20 hours for the parent compound, 22–23 hours for metabolite II, and 28–33 hours for metabolite IV; these elimination t1/2are comparable for the two doses, and are similar to those observed in single‐dose studies. For the 50‐mg‐dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly. However, for the 100‐mg‐dose group, observed Css of CL 275,838 and its main metabolite, the desbenzyl derivative II, were slightly higher than those predicted from the single‐dose study, indicating a deviation from linearity after repeated higher oral doses. No major adverse drug reaction was detected at either dosage, and there was no evidence of CL 275,838‐induced changes in hepatic parameters. Mild headache occurred in three of the ten subjects given active treatment, without any clear relation with the dose. At 100 mg, a significant improvement of attention was observed. This is a preliminary, but encouraging, finding that indicates the usefulness of studying the safety and efficacy in an app

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02035.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady‐state pharmacokinetics of valproate after multiple 250‐mg oral and intravenous infusion doses after an intravenous 750‐mg loading dose. Multiple blood samples were collected throughout each 168‐hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within‐regimen comparisons indicated statistically significant differences for mean steady‐state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐versus‐time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed‐release tablet preparation. Between‐regimen steady‐state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax(Tmax), Cmax, Cmin, AUC, and total body clearance for respective day‐4 dosing intervals, but not for the entire day 4, except for Cminand Tmax. Mean elimination rate constant and half‐life did not significantly differ between the regimens. The regimens were bio‐equivalent at steady state, as assessed by 90% confidence intervals (two one‐sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation {(Cmax‐Cmin)/Caverage}. Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady‐state plasma concentration‐versus‐time profile was well maintained by both regimens within the accepted

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02036.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor that may be useful for the treatment of complications of diabetes, have been investigated using oral doses ranging from 50 to 1200 mg administered to healthy male volunteers. In a single‐dose study, Cmax, AUC(0–48), and urinary elimination of zopolrestat increased linearly with increasing dose. The amount of zopolrestat excreted unchanged in the urine within 48 hours ranged from 34 to 45% of the administered dose. Renal clearance ranged from 2.6 to 5.6 mL/min, and appeared to decrease as the dose was increased. In a 2‐week multiple dose study, the mean steady‐state minimum and maximum plasma concentrations, Cminand Cmax, were 91.5 and 196 μg/mL for subjects administered 800 mg/day, and 131 and 281 μg/mL for subjects administered 1200 mg/day. Steady‐state AUC(0–24) was also dose proportional. The mean steady state half life of about 30.3 hours was consistent with the observed 2.2‐fold accumulation in plasma. Apparent oral clearance (Clpo) was 5.2 mL/min, and apparent volume of distribution (Vdss/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was excreted into the urine at steady state. There was no effect of food consumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration‐dependent binding of zopolrestat to plasma proteins was observed. These data indicate that once‐daily dosing of zopolrestat will provide suitable exposure in the treatment of dia

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02037.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The effect of a typical 5‐day chemotherapy treatment with cisplatin (20–40 mg/m2per day) and 5‐fluorouracil (5‐FU, 1 gm/m2per day) on the pharmacokinetics of ondansetron was investigated. Twenty cancer patients received 8 mg of ondansetron in three periods, including an oral tablet on day 1, an intravenous infusion on day 4, and an oral tablet on day 5. Absolute bioavailability after the oral dosing on day 1 was 87.5 ± 31.3%, and on day 5 was 85.2 ± 22.1%(P>.05).Mean values of AUC, Cmax, Tmax, and half life on days 1 and 5 were 399 ± 275 and 381 ± 222 ng · hour/mL, 53.3 ± 26.8 and 43.6 ± 21.7 ng/mL, 1.9 ± 1.4 and 2± 1.4 hours, and 5.21 ± 1.78 and 6.19 ± 1.99 hours, respectively. These values were not significantly different(P>.05).In summary, this study showed that cisplatin and 5‐FU did not significantly alter the pharmacokinetics of oral ondansetron in cancer patients during the 5 days of chemotherapy. Oral bioavailability of ondansetron appeared to be greater in cancer patients than

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02038.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The influence of age on the pharmacokinetics of cefpodoxime was evaluated in 12 elderly (ages 65–85 years) and 12 weight‐ and sex‐matched young (ages 20–33 years) subjects, each of whom received two cefpodoxime proxetil 200‐mg tablets every 12 hours for 14.5 days. Serial blood samples and urine were collected after the first dose on day 1, after the morning dose on day 8, and after the last (morning) dose on day 15. Plasma and urine samples were assayed for cefpodoxime concentrations using HPLC methods. Within each age group, mean pharmacokinetic parameters determined on day 1 were similar to corresponding values on days 8 and 15, indicating that cefpodoxime does not accumulate after twice‐daily dosing of cefpodoxime proxetil. Based on this result, parameters were pooled across days in each age group. No significant differences were observed between healthy and elderly volunteers in area under the plasma concentration‐time curve for the 12‐hour dosing interval, peak plasma concentration, or time to peak concentration. Mean urinary excretion and renal clearance of cefpodoxime were significantly lower in elderly subjects. Differences in renal clearance were attributed to the corresponding age‐related reduction that was noted in creatinine clearance values, whereas the lower urinary excretion of cefpodoxime probably reflected slightly reduced systemic drug absorption in the elderly. Differences in these parameters between groups were less than 30%, and were unlikely to be of clinical importance. The data indicate that dose adjustment of cefpodoxime in elderly subjects having normal (age‐adjusted) creatinine clearance val

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02039.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY