摘要:

Clinical Pharmacology and Therapeutics(1991)50,357–362; doi:10.1038/clpt.1991.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.151

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetic and pharmacodynamic interaction between caffeine and phenylpropanolamine has been investigated in six normal subjects in a double‐blind, placebo‐controlled, Latin‐square design study. After 3 days on a 100 mEq sodium, xanthine‐free diet, fasting subjects were placed in a supine position and were given 25 mg phenylpropanolamine and placebo, 250 mg caffeine and placebo, or 25 mg phenylpropanolamine and 250 mg caffeine in random order. Blood pressure, pulse, plasma renin activity, and plasma catecholamine levels were measured before and for 3 hours after drug administration. Plasma and urinary phenylpropanolamine, caffeine, and caffeine metabolite levels were measured serially for 48 hours. Coadministration of caffeine and phenylpropanolamine produced an additive increase in blood pressure. This effect could not be explained by any pharmacokinetic interaction between the two drugs and occurred even though phenylpropanolamine attenuated the epinephrine and renin response to caffeine. These data suggest that a clinically relevant interaction between caffeine and phenylpropanolamine does occur in drug‐free subjects and that this interaction cannot be explained by a mechanism involving the sympathetic or renin‐angiotensin systems.Clinical Pharmacology and Therapeutics(1991)50,363–371; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1991.152

年代:1991

数据来源: WILEY

摘要:

Effects of AF‐DX 116, a cardioselective antagonist, on M cholinergic receptors (M‐ChR) were studied in healthy volunteers. Occupancy of M‐ChR subtypes by drug present in plasma samples (radioreceptor assay) was compared with these effects. After an intravenous dose of AF‐DX 116 saturating greater than 90% of cardiac M2‐ChR, an increase in heart rate by 25 beats/min was observed. This cardiac receptor occupancy and effect wore off with a parallel time course within 10 hours. No inhibition of salivary flow was observed, coinciding with a lack of M3‐ChR blockade in the radioreceptor assay. β‐Adrenergic receptor blockade by propranolol did not affect either of the effects. No indication for active metabolites or stereoselective drug metabolism was found comparing HPLC and receptor assay for drug concentrations in plasma. We conclude that AF‐DX 116 may be a useful drug for the treatment of bradycardia. Its lack of troublesome side effects is the result of its selectivity for cardiac M‐ChR.Clinical Pharmacology and Therapeutics(1991)50,372–378; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1991.153

年代:1991

数据来源: WILEY

摘要:

Duplex ultrasonography was used to measure changes in hepatic blood flow in 13 healthy volunteers after they received single doses of 10 mg oral nifedipine and placebo. Blood flow was measured in the hepatic artery and branches of the portal and hepatic veins at baseline and 0.3, 0.6, 1, 1.5, 2, 3, 4, and 5 hours after drug administration. Cardiac output was also measured at baseline and 1, 2, and 3 hours after dosing. Blood flow initially increased in all three vessels 0.6 hour after administration of nifedipine (29%, 56%, and 31% in the hepatic artery, hepatic vein, and portal vein, respectively) compared with placebo. Flow rapidly returned to baseline in the hepatic artery and hepatic vein, whereas it appeared to remain elevated through 3 hours in the portal vein. Nifedipine administration resulted in an increase in cardiac output of 26%, 22%, and 14% above placebo at 1, 2, and 3 hours, respectively. No significant differences were detected in the systolic, diastolic, or mean arterial blood pressures after nifedipine or placebo. This study demonstrates that nifedipine increases hepatic blood flow in a transient nature and systemic hemodynamic parameters do not necessarily reflect specific organ responses. The nifedipine‐induced change in blood flow should be considered when nifedipine is coadministered with high‐clearance drugs, because systemic availability may be increased.Clinical Pharmacology and Therapeutics(1991)50,379–384; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1991.154

年代:1991

数据来源: WILEY

摘要:

The pharmacodynamics of total and unbound etoposide was studied in 28 adult patients with solid tumors who were receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined by use of an HPLC method, and etoposide plasma protein binding was determined by equilibrium dialysis. Patients with higher systemic exposure experienced greater hematologic toxicity. The sigmoid maximum effect model with unbound systemic exposure performed better (i.e., lower residual sum of squares) than the model using total systemic exposure; in all patients (7043 versus 9755) and in the subset of patients who had not received previous chemotherapy (1986 versus 3664). The model estimates forunboundsystemic exposure were more precisely estimated than fortotalsystemic exposure (e.g., coefficient of variation for the area under the concentration—time curve producing half of the maximal effect = 51% for total drug versus 21% for unbound drug). These findings indicate that the hematologic toxicity of etoposide is better correlated with systemic exposure to unbound drug than total drug, which may be of clinical importance because of the variable plasma protein binding of etoposide.Clinical Pharmacology and Therapeutics(1991)50,385–393; doi:10.1038/clpt.1991

ISSN:0009-9236    

DOI:10.1038/clpt.1991.155

年代:1991

数据来源: WILEY

摘要:

The effects of grapefruit juice (150 ml at −15, −10, ¼, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo‐controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)‐ and (R)‐nitrendipine. There were highly significant differences in the area under the concentration‐time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half‐lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.Clinical Pharmacology and Therapeutics(1991)50,394–403; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.156

年代:1991

数据来源: WILEY

摘要:

The effects of menstrual cycle phases and gender on alprazolam pharmacokinetics were evaluated in normal volunteers. Alprazolam (1 mg) was administered to seven women during the late follicular and luteal phases of the menstrual cycle and to eight men on one occasion. No difference in alprazolam pharmacokinetic parameters was observed during the menstrual cycle phases. Mean alprazolam clearance (±SD) was 0.0037 ± 0.0009 ml/hr during the follicular phase and 0.0036 ± 0.001 ml/hr during the luteal phase (p>0.05, difference not significant). With use of weight as a covariant, there was no difference in alprazolam pharmacokinetic parameters between women and men. Mean alprazolam clearance (±SD) was 0.0036 ± 0.0009 ml/hr in women compared with 0.0041 ± 0.0006 ml/hr in men (p>0.05, difference not significant). Although alprazolam metabolism was similar on the 2 days tested, alterations may occur at other times during the menstrual cycle. Further investigation is needed to understand the effects of menstrual cycle phases and gender on drug metabolism.Clinical Pharmacology and Therapeutics(1991)50,404–409; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.157

年代:1991

数据来源: WILEY

摘要:

The disposition of oxcarbazepine was studied in 12 young and 12 elderly healthy male and 12 young and 12 elderly healthy female volunteers, with emphasis on the influence of age. Oxcarbazepine was administered as a single dose of either 300 mg (men) or 600 mg (women), followed by multiple‐dose (300 mg) administration twice a day for 7 days (men) or 6 days (women). Semilogarithmic plasma concentration—time curves showed an increasing decline at decreasing concentrations. Accumulation of the pharmacologically active metabolite monohydroxycarbamazepine was found to be more than one would anticipate on the basis of linear and unchanged pharmacokinetics. Saturation did not seem to occur at the level of renal excretion. No apparent differences between male and female volunteers were observed. A significant higher maximum concentration, higher area under the curve parameters, and a lower elimination rate constant were observed in the elderly. These observations are in line with a smaller renal clearance of monohydroxycarbamazepine in the elderly group. In a clinical situation, these age‐related differences are not likely to have important implications. In general, treatment with oxcarbazepine was well tolerated.Clinical Pharmacology and Therapeutics(1991)50,410–419; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.158

年代:1991

数据来源: WILEY

摘要:

Measurements were done to determine the plasma concentrations of galanthamine and two of its metabolites, as well as the corresponding inhibition of acetylcholinesterase activity in erythrocytes after applying 5 and 10 mg galanthamine hydrobromide as a constant‐rate intravenous infusion for 30 minutes and single oral doses of 10 mg in eight healthy male volunteers. The data obtained revealed first‐order pharmacokinetics, complete oral bioavailability, and a mean terminal half‐life of 5.68 hours (95% confidence interval, 5.17 to 6.25 hours). Renal clearance accounted for only 25% of the total plasma clearance (CL = 0.34 L · kg−1· hr−1). Only negligible quantities of the putative metabolites, epigalanthamine and galanthaminone, were detected in blood and urine. The inhibition of acetylcholinesterase activity was closely correlated with the pharmacokinetics of galanthamine, a median maximal value of 53% being achieved by applying 10 mg galanthamine intravenously. Analysis of in vitro and ex vivo concentration responses revealed no differences, indicating that no metabolites of galanthamine exert additional inhibition of acetylcholinesterase activity.Clinical Pharmacology and Therapeutics(1991)50,420–428; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1991.159

年代:1991

数据来源: WILEY

摘要:

The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human tissue‐type plasminogen activator and is unglycosylated because of its expression inEscherichia colicells. Pharmacokinetics for activity and hemostatic effects of BM 06.022 were studied in 18 healthy male volunteers after an intravenous bolus injection over 2 minutes. BM 06.022 was administered successively at doses of 0.1125, 0.55, 2.2, 3.3, 4.4, and 5.5 MU to three volunteers. Plasma fibrinogen was unchanged; effects of BM 06.022 were observed on plasminogen only at higher doses, and dose‐dependent effects were seen on α2‐antiplasmin and fibrin D‐dimers. The concentration of plasminogen and α2‐antiplasmin was 87% ± 3% and 79% ± 3%, respectively, of baseline 2 hours after injection of 5.5 MU of BM 06.022. Fibrin D‐dimers were highest with 1147 ± 380 ng/ml at 5.5 MU of BM 06.022. The area under the activity concentration‐time curve (AUC) increased dose‐dependently and linearly. At 5.5 MU of BM 06.022, the AUC was 313 ± 47 IU · hr · ml−1, the total plasma clearance was 306 ± 40 ml/min, and the half‐life was 14.4 ± 1.1 minutes.Clinical Pharmacology and Therapeutics(1991)50,429

ISSN:0009-9236    

DOI:10.1038/clpt.1991.160

年代:1991

数据来源: WILEY