摘要:

Clinical Pharmacology and Therapeutics(1988)43,345–353; doi:10.1038/clpt.1988.

ISSN:0009-9236    

DOI:10.1038/clpt.1988.42

年代:1988

数据来源: WILEY

摘要:

The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11β‐hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 ±1.0 vs. 7.7 ± 1.6 ml/min/kg, mean ± SD; P<0.001) and renal (0.9 ± 0.3 vs. 2.9 ± 0.7ml/min/kg; P<0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6β‐hydroxyprednisolone (reflecting the activity of the 6β‐hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.Clinical Pharmacology and Therapeutics(1988)43,354–362; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.43

年代:1988

数据来源: WILEY

摘要:

In a randomized, double‐blind crossover study, 40 patients with postherpetic neuralgia were given single oral doses of clonidine, 0.2 mg, codeine, 120 mg, ibuprofen, 800 mg, or inert placebo. Pain relief and side effects were recorded for 6 hours. Patients reported significantly more relief after clonidine than after the other three treatments. Codeine and ibuprofen were ineffective. Sedation, dizziness, and other side effects were more frequent after clonidine (74%) or codeine (69%) than after placebo (36%) or ibuprofen (28%). Reported pain relief was greater during trials in which side effects were present. A single, mild side effect was associated with as much additional pain relief as multiple, severe side effects. Clonidine's superiority to codeine, which had a similar incidence of side effects, argues for a specific analgesic effect. In addition, side effects may have contributed to clonidine analgesia, perhaps by suggesting to patients that they had received a potent drug.Clinical Pharmacology and Therapeutics(1988)43,363–371; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1988.44

年代:1988

数据来源: WILEY

摘要:

A young woman with epilepsy had tonic‐clonic seizures during antineoplastic therapy with adriamycin and cisplatin. During two courses of cytostatic drug administration peak and trough plasma levels of phenytoin, carbamazepine, and valproate sodium were measured. Lower plasma levels of carbamazepine and valproate sodium were observed after 2 days of antineoplastic therapy. Normal plasma levels of these drugs were found 2 to 3 days after the last cisplatin dose. Impaired absorption or accelerated elimination might explain these results. Phenytoin levels were reduced to 37% of the original values, although the drug was given intravenously. Changed Michaelis‐Menten parameters suggest that cisplatin increases the metabolic rate of phenytoin. Another explanation for the decreased drug levels might be an increased volume of distribution. Calculation of this volume from peak and trough levels showed an increase of the volume of distribution during and after chemotherapy.Clinical Pharmacology and Therapeutics(1988)43,372–375; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.45

年代:1988

数据来源: WILEY

摘要:

A design is described that uses need for supplemental (rescue) analgesic as a factor predicting effectiveness of a test analgesic. This methodology is especially suited for evaluating long‐acting analgesics given repeatedly. Rescue use is measured over dosing intervals as test drug is titrated from a subanalgesic dose to that requiring no or minimal rescue. This design was used to evaluate oral long‐acting morphine sulfate (MS Contin) given every 12 hours in a crossover study of cancer pain using oral immediate–release morphine sulfate given every 4 hours as reference. Less morphine was required for MS Contin given every 12 hours relative to immediate–release morphine sulfate given every 4 hours (186 ± 22 mg vs. 239 ± 35 mg;p= 0.04). Total daily morphine for both regimens correlated linearly (r = 0.96) with a slope of 1.27 ± 0.11, significantly(p= 0.03) different from equivalence (slope of unity) in favor of MS Contin. This design features assay sensitivity (dose‐response) and provides relative potency estimates for analgesics given at specific regimens.Clinical Pharmacology and Therapeutics(1988)43,376–380; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1988.46

年代:1988

数据来源: WILEY

摘要:

This study examined the effect of two widely used iron treatments on methyldopa absorption, metabolism, and blood pressure control. A 500 mg tablet of methyldopa (2.37 mmol) was taken with and without ferrous sulfate (325 mg) by 12 normal subjects in a randomized crossover trial. When ferrous sulfate was taken with methyldopa there was a decrease in the proportion of methyldopa excreted as “free” methyldopa (49.5% ± 12.4% vs 21.1% ± 4.77%;p<0.01), a significant increase in the proportion excreted as methyldopa sulfate (37.8% ± 12.3% vs 65.8% ± 10.5%;p<0.01), and a decrease in the percentage of methyldopa absorbed (29.1% ± 12.5% vs 7.88% ± 4.14%;p<0.01). These factors resulted in an 88% reduction in the quantity of “free” methyldopa excreted. To determine if an iron preparation without sulfate produced the same effect, the study was repeated with ferrous gluconate (600 mg) with similar results. The clinical consequences of the methyldopa–ferrous sulfate interaction was determined in five hypertensive subjects receiving chronic methyldopa therapy. The subjects took ferrous sulfate for 2 weeks. There was an increase in both systolic and diastolic blood pressure in four patients and a decrease in blood pressure in all patients after ferrous sulfate was discontinued. The increases in blood pressure were substantial in three of the patients.Clinical Pharmacology and Therapeutics(1988)43,381–386; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1988.47

年代:1988

数据来源: WILEY

摘要:

Methacholine challenges were performed by 10 asthmatic subjects, 2 hours before and 15 minutes after placebo (diluent alone) and 5, 10, 15, 30, and 60 mg inhaled diltiazem given in a single‐blind crossover manner. There was no significant change from placebo in the dose of methacholine required to produce a 20% decrease in forced expiratory volume in the first second (FEV1) (PD20); the fold increase in PD20from baseline was 1.1 ± 0.1 after placebo, 1.4 ± 0.2 after 5 mg, 1.8 ± 0.3 after 10 mg, 1.4 ± 0.2 after 15 mg, 1.6 ± 0.2 after 30 mg, and 1.2 ± 0.1 after 60 mg. There was a 1% chance that we missed a twofold difference between placebo and the 10 mg dose because of inadequate sample size. Fifteen minutes before a standardized exercise challenge, 10 subjects received placebo, 10 mg, and the highest dose tolerated during the methacholine study (20 to 45 mg) in a randomized double‐blind crossover design. The mean ± SE maximum postexercise decrease in FEV1was 28.8% ± 5.7% after placebo, 23.4% ± 4.6% after 10 mg, and 20.8% ± 3.0% after high‐dose diltiazem (P>0.05). There was a 12% chance that we missed a 15% difference between placebo and the high‐dose regimen because of inadequate sample size. We conclude that diltiazem does not attenuate airway reactivity to methacholine or exercise even when high concentrations are delivered to the lungs.Clinical Pharmacology and Therapeutics(1988)43,387–392; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1988.48

年代:1988

数据来源: WILEY

摘要:

The effects of dilevalol, a new β‐adrenergic blocking agent with β‐agonism, on renal function were determined in two groups of patients. Patients in group 1, all with normal renal function, received either dilevalol or atenolol. Patients in group II, all with impaired renal function, received either dilevalol or metoprolol. Parameters of renal function determined before and after chronic oral treatment included glomerular filtration rate (GFR), effective renal plasma flow, filtration fraction, mean arterial pressure (MAP), renal blood flow, and renal vascular resistance. Dilevalol lowered MAP by 14 mm Hg (P<0.005) in group I and 25 mm Hg (P<0.01) in group II but had no effect on other parameters of renal function, at either peak or trough drug levels. Atenolol and metoprolol also lowered MAP by 11 mm Hg (P<0.01) and 15 mm Hg (P<0.05), respectively. Atenolol reduced GFR by 23% at peak drug level, an effect that was partially ameliorated at trough drug level. The effect of atenolol on GFR appeared to vary as a function of baseline renal function in that greater reductions were seen in groups of patients with increasing baseline GFR. Metoprolol significantly decreased renal vascular resistance by 17% (P<0.05). These data suggest that dilevalol effectively lowers blood pressure in hypertensive patients with normal or compromised renal function with no negative impact on parameters of renal function.Clinical Pharmacology and Therapeutics(1988)43,393–399; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1988.49

年代:1988

数据来源: WILEY

摘要:

Four rapid extensive metabolizers (EM), four slow EM, and three poor metabolizers (PM) of sparteine were given single intravenous doses of 50 mg imipramine and desipramine. All subjects had previously taken single oral doses (100 mg) of imipramine and desipramine. The first‐pass metabolism of imipramine and desipramine ranged from 23% to 73% and 0% to 48%, respectively, and was more pronounced for both drugs in EM than in poor metabolizers. The study suggested saturable 2‐hydroxylation of imipramine and desipramine during the first‐pass through the liver, especially in EM.Clinical Pharmacology and Therapeutics(1988)43,400–406; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1988.50

年代:1988

数据来源: WILEY

摘要:

To evaluate the effect of dextran 70 on the kinetics of epidural meperidine, 10 female patients anesthetized with nitrous oxide and halothane were studied. Meperidine, 1 mg· kg−1, was administered epidurally in either 10 ml dextran 70 in saline solution (group I) or 10 ml saline solution (group II, control subjects). Plasma concentration of meperidine was determined for 10 hours after its administration with GC. Meperidine plasma concentration‐time curves could be best resolved into three exponential terms with a lag time in both groups of patients. The disposition kinetics were described adequately by a three‐compartment model. This study demonstrated that apart from a significantly longer lag time and smaller k10(apparent first‐order rate constant for elimination of meperidine from the central compartment), the addition of dextran did not alter significantly the kinetic parameters of epidural meperidine.Clinical Pharmacology and Therapeutics(1988)43,407–411; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1988.51

年代:1988

数据来源: WILEY