摘要:

Clinical Pharmacology and Therapeutics(1993)54,235–241; doi:10.1038/clpt.1993.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.142

年代:1993

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1993)54,242–244; doi:10.1038/clpt.1993.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.143

年代:1993

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1993)54,245–251; doi:10.1038/clpt.1993.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.144

年代:1993

数据来源: WILEY

摘要:

We assessed rates of hip fracture before and after the institution of the triplicate prescription policy for benzodiazepines in New York State. All patients 55 years of age or older who had a diagnosis of hip fracture between January 1, 1986, and June 30, 1991, were considered for the study. Patients with severe trauma, neoplasm, arthritis, or second admission were excluded. Rates of hip fracture were calculated for each quarter by age and gender. Benzodiazepine prescribing began to decline immediately after the triplicate prescription regulation went into effect on January 1, 1989. However, yearly rates of hip fracture for women (men) ≥75 years of age per 1000 people adjusted for New York population changes remained stable at 13.8 (6.5), 12.6 (5.7), 14.7 (6.7), 14.8 (6.4), 14.4 (6.3), and 14.4 (6.7), from 1986 through the first two quarters of 1991. Regression analyses showed no before or after regulation trend in the rate of hip fracture. We conclude that no dramatic declines in the rate of hip fractures among people older than 55 years of age have been observed in association with the benzodiazepine regulations and decreased benzodiazepine prescribing.Clinical Pharmacology and Therapeutics(1993)54,252–256; doi:10.1038/clpt.1993

ISSN:0009-9236    

DOI:10.1038/clpt.1993.145

年代:1993

数据来源: WILEY

摘要:

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan‐phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9‐hydroxyrisperidone, exhibited CYP2D6‐related polymorphism. The plasma area under the concentration—time curve from time zero to infinity ratio of 9‐hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half‐life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9‐hydroxyrisperidone) varied little among subjects (mean terminal half‐life, 20 ± 21/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.Clinical Pharmacology and Therapeutics(1993)54,257–268; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.146

年代:1993

数据来源: WILEY

摘要:

ObjectiveTo find a dose of fluconazole for very low birth weight infants during an outbreak ofCandida parapsilosis.MethodsTwelve premature infants (mean gestational age, 27.4 weeks; mean birth weight, 912 gm) receiving fluconazole prophylactically from the first day of life were enrolled in an open phase I‐II pharmacokinetics, safety, and tolerance trial. Up to 5 doses of 6 mg/kg were administered intravenously every 72 hours during the first 2 weeks of life. Pharmacokinetic characteristics of fluconazole were determined after the first, third, and fifth doses.ResultsThe mean peak and trough concentrations after the 3 doses were 5.5 and 2.6 μg/ml, 12.8 and 4.3 μg/ml, and 10.0 and 2.9 μg/ml (p= 0.0002 andp= 0.07), respectively. The mean fluconazole half‐lives were 88.6 hours (n= 7), 67.5 hours (n= 9), and 55.2 hours (n= 4;p= 0.3). The mean total clearance corrected for weight (CL/kg) was 0.18 ml/min/kg (n= 7), 0.33 ml/min/kg (n= 7), and 0.52 ml/min/kg (n= 4;p= 0.02), and the mean volume of distribution 1.18 L/kg (n= 7), 1.84 L/kg (n= 7), and 2.25 L/kg (n= 4;p= 0.05). Weight‐corrected clearance increased with postnatal age (r= 0.61;p= 0.007).ConclusionsWith the used fluconazole dose (6 mg/kg every 3 days), the mean serum peak and trough concentrations increased during the first week but decreased during the second week. After the first week we suggest a dose of 6 mg/kg every 2 days, or even daily.Clinical Pharmacology and Therapeutics(1993)54,269–277; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1993.147

年代:1993

数据来源: WILEY

摘要:

The effects of age and gender on the pharmacokinetics of verapamil stereoisomers were examined. Eighty milligrams of racemic verapamil was given orally to 12 young and 12 elderly healthy subjects, half of whom were women. The area under the plasma concentration—time curves (AUC) of (S)‐ and (R)‐verapamil were greater in the elderly group than in the young group [(S)‐/(R)‐verapamil (mean ± SD), 214.4 ± 123.0/1582.2 ± 763.0 and 50.4 ± 36.5/584.9 ± 252.4 ng · hr/ml for the elderly and young groups, respectively (p<0.001/p<0.001)]. Conversely, the apparent oral clearance values of (S)‐and (R)‐verapamil were significantly smaller in the elderly group than in the young group [(S)‐/(R)‐verapamil (mean ± SD), 4.8 ± 3.0/0.53 ± 0.21 and 22.5 ± 21.3/1.30 ± 0.67 L/hr/kg for the elderly and young groups, respectively (p<0.01/p<0.001)]. The ratio of apparent oral clearance of (S)‐ to (R)‐verapamil was significantly smaller in the elderly group than in the young group. As a consequence, the negative chronotropic and dromotropic effect of verapamil was observed in the elderly group. This study suggests that the effect of age on metabolism was greater for (S)‐verapamil than for (R)‐verapamil.Clinical Pharmacology and Therapeutics(1993)

ISSN:0009-9236    

DOI:10.1038/clpt.1993.148

年代:1993

数据来源: WILEY

摘要:

Morphine‐6‐glucuronide is a metabolite of morphine that shows significant analgesic effects in animals and humans. To evaluate route‐specific differences in the potential contribution of morphine‐6‐glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, morphine‐6‐glucuronide, and morphine‐3‐glucuronide after oral and rectal administration of morphine sulfate in a six‐subject randomized, single‐dose, two‐way crossover evaluation. The mean area under the plasma concentration‐time curve (AUC) molar ratios of morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) to morphine (M) were greater after oral morphine administration compared with rectal morphine administration (M6G/M ratio, 2.7:1 versus 1.3:1,p= 0.025; M3G/M ratio, 18.3:1 versus 9.3:1,p= 0.002). Systemic bioavailability and peak plasma concentrations of morphine‐6‐glucuronide and morphine‐3‐glucuronide were significantly greater after oral morphine administration compared with the rectal route (AUC: M6G, 377.1 ± 124.2 versus 236.2 ± 133.7 nmol · hr/L,p= 0.05; M3G, 2610.1 ± 446.4 versus 1650.2 ± 309.0 nmol · hr/L,p= 0.004; maximum concentration: M6G, 110.9 ± 37.5 versus 64.6 ± 28.8 nmol/L,p= 0.002; M3G, 576.9 ± 155.8 versus 266.8 ± 110.5 nmol/L,p= 0.007). Conversely, the systemic availability of morphine was lower after oral administration, although this difference failed to achieve statistical significance (142.3 ± 17.1 versus 176.6 ± 69.4 nmol · hr/L,p= 0.14). These data suggest that rectal administration of morphine is associated with significant avoidance of hepatic biotransformation, and they provide a convincing argument for the evaluation of morphine‐6‐glucuronide concentrations in pharmacokinetic and pharmacodynamic comparisons involving different routes of morphine administration.Clinical Pharmacology

ISSN:0009-9236    

DOI:10.1038/clpt.1993.149

年代:1993

数据来源: WILEY

摘要:

To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half‐maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n= 6) and control subjects (n= 6). Each subject received three consecutive constant‐rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 21/2 hours each) simultaneously with a constant‐rate (30 mg/kg/hr) infusion of inulin. Urine samples were collected at 1/2‐hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high‐performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady‐state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50was significantly lower (p0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.Clinical Pharmacology and Therapeutics(1993)54,293–302; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.150

年代:1993

数据来源: WILEY

摘要:

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half‐life, are presumed to translate directly to a prolonged duration of action, but the concentration‐effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic‐pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo‐corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was − 3.1 ± 0.9 mm Hg/ng/ml. By characterizing the concentration‐effect relationships in individual patients, this study has confirmed that the plasma concentration–time profile is an appropriate index of the effect‐time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough‐to‐peak variability.Clinical Pharmacology and Therapeutics(1993)54,303–310; do

ISSN:0009-9236    

DOI:10.1038/clpt.1993.151

年代:1993

数据来源: WILEY