摘要:

Clinical Pharmacology and Therapeutics(1984)35,131–140; doi:10.1038/clpt.1984.

ISSN:0009-9236    

DOI:10.1038/clpt.1984.18

年代:1984

数据来源: WILEY

摘要:

The kinetic and clinical profile of betaxolol—α β1‐selective blocker with 80% to 90% bioavailability and a 16 to 20 hr t½—were studied in ten children aged 5 to 13 yr with chronic renal hypertension and mild to severe renal failure. An IV dose of 20 mg of betaxolol per 1.73 m2body surface area (BSA) was followed by six daily oral doses. Six patients were maintained on combination therapy and four on betaxolol alone; two of these were newly treated. After the intravenous dose, t½ (mean ± SE) was 19.9 ± 1.7 hr, total clearance 0.30 ± 0.03 l/kg/hr, and volume of distribution 8.2 ±0.7 l/kg. Clearance adjusted for BSA was 7.9 ± 0.6 l/hr. The t½ correlated linearly to serum creatinine levels. After the last dose, peak concentration was 97.4 ± 7.6 ng/ml, and t½ 19.4 ± 2.7 hr. Betaxolol 24‐hr blood levels were twice as high as after the first dose. Blood pressure was reduced in two newly treated patients and two patients on combination therapy; previous responses were maintained in the others. The maximum effect was reached after the first dose and was maintained throughout the study week. Our results indicate that betaxolol disposition in children aged 5 to 13 yr with different degrees of renal failure is of the same order as that in young healthy adults, implying that there may be a higher rate of non‐renal clearance. Renal failure‐induced modification led to a doubling of the t½ in the most severe cases, again as in adult renal patients. There is an antihypertensive effect.Clinical Pharmacology and Therapeutics(1984)35,141–1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.19

年代:1984

数据来源: WILEY

摘要:

The effects of intravenous propranolol infusion for 24 hr was compared with those of zero‐order rectal administration by an osmotic delivery system in six healthy subjects. In plasma and urine, levels of propranolol, 4‐OH‐propranolol (4‐OH‐P), and conjugates were determined just before and at 6 hr and at 20 hr during drug administration. With the rectally applied osmotic delivery system providing zero‐order release, fairly constant steady‐state levels of propranolol in plasma were produced within 12 to 15 hr (four to five times elimination t½). The mean steady‐state levels were 25 ng/ml after 1.1 µg/min/kg rectally and 60 ng/ml after 0.8 µg/min/kg IV. The mean rectal systemic availability was 33%; the elimination t½s for the two routes did not differ. The results of analysis of plasma for metabolites indicate that after rectal propranolol different metabolic pathways are followed and that there is partial avoidance of first‐pass elimination. The isoproterenol challenge resulted in a reproducible assessment of β‐receptor blockade that was closely related to the propranolol concentration in plasma in all subjects and for both routes of administration. With rate‐controlled release of propranolol from an osmotic delivery device, the rectal route provides an alternative to intravenous infusion to achieve constant steady‐state propranolol concentrations. This may be useful for research purposes or during the perioperative period in surgical patients.Clinical Pharmacology and Therapeutics(1984)35,148

ISSN:0009-9236    

DOI:10.1038/clpt.1984.20

年代:1984

数据来源: WILEY

摘要:

Oral and intravenous trimazosin, a quinazoline derivative, resulted in a significant reduction in blood pressure of normal subjects, particularly when the subjects rose from a supine position to standing. This hypotensive effect was maximal between 4 and 6 hr after dosing and was accompanied by a significant increase in heart rate. The responses to intravenous infusions of phenylephrine indicated that trimazosin had significant, selective, peripheral α1‐antagonist properties. Kinetic analysis showed oral bioavailability of 63%, a clearance rate of 66 ml/min, and a terminal elimination t½ of approximately 3 hr. The correlation between drug levels and hypotensive effect was significantly improved by inclusion of the concentrations of trimazosin's major metabolite, 1 ‐hydroxy‐trimazosin (CP 23445), particularly for the period of maximum effect. Our data show that acute administration of trimazosin is associated with a fall in blood pressure, an increase in heart rate, and a significant degree of α1‐antagonism and that the overall hypotensive effect may in part be mediated by an active metabolite. It seems 1‐hydroxy‐trimazosin is a likely candidate for this role, but it is not clear whether this metabolite also has significant α‐adrenoceptor antagonist properties.Clinical Pharmacology and Therapeutics(1984)35,156–160; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1984.21

年代:1984

数据来源: WILEY

摘要:

Ten healthy subjects were fed three diets for 10 days each: a control diet, a cabbage and brussels sprouts–containing diet, and the control diet a second time. Oxazepam was taken on day 7 and acetaminophen on day 10 of each dietary regimen. The test diet stimulated the metabolism of acetaminophen, at least in part by enhanced glucuronidation, as evidenced by a 16% decrease in mean plasma AUC, a 17% increase in mean metabolic clearance rate, an increased ratio of acetaminophen glucuronide to acetaminophen in plasma from 1 to 11 hr after drug and an 8% increase in mean 24‐hr urinary recovery of acetaminophen glucuronide, which returned toward control when the subjects were fed the control diet a second time. There were no comparable changes in the metabolism of acetaminophen to acetaminophen sulfate. When the subjects ate the test diet, 24‐hr urinary recovery of the cysteine conjugate and of 3‐methoxyacetaminophen sulfate, end‐products of minor oxidative pathways, the former involving a toxic intermediate, decreased 13% and 22%. Cabbage and brussels sprouts induced a 17% decrease in mean plasma AUC and a 19% increase in mean metabolic clearance rate for oxazepam, but there was no change in mean plasma t½ for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.Clinical Pharmacology and Therapeutics(1984)35,161–169; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1984.22

年代:1984

数据来源: WILEY

摘要:

Variation of theophylline metabolism in 54 healthy, nonmedicated adults (13 monozygotic [MZ] twin pairs, 11 dizygotic [DZ]twin pairs, and 6 single individuals) was assessed by kinetic study. Elimination rate constant, clearance (CI), t½, and apparent volume of distribution, as well as urine excretion of unchanged theophylline and of the three major metabolites (1‐methyluric acid, 3‐methyl‐xanthine, and 1,3‐dimethyluric acid) were studied. Smokers and men had increased theophylline elimination rates compared to nonsmokers and women. Identical (MZ) twins resembled each other more closely than nonidentical (DZ) twins in the various kinetic parameters, but mean intrapair differences between MZ and DZ twins for all but one of the serum and urinary parameters examined (including t½) were not statistically significant. Correspondingly, estimates of heritability and of intrapair correlation coefficients showed a smaller contribution of genetic factors to variation in theophylline metabolism than had been reported for other drugs investigated by twin studies. Nevertheless, in the family of the individual with the longest theophylline t½, the operation of a rare major gene retarding theophylline metabolism could not be excluded. A father and two out of four children had very slow Cls. This finding would be consistent with, but does not prove, monogenic inheritance.Clinical Pharmacology and Therapeutics(1984)35,170–182; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1984.23

年代:1984

数据来源: WILEY

摘要:

The interaction between Cimetidine and two tricyclic antidepressants was examined in healthy subjects. One tricyclic, imipramine, is primarily metabolized to a demethylated active metabolite, desipramine. The other, nortriptyline, is largely metabolized to a 10‐hydroxylated metabolite. It was assumed that pretreatment with Cimetidine, because of its inhibition of metabolic pathways of both demethylation and hydroxylation as well as its ability to reduce hepatic extraction of these drugs, would increase bioavailability and decrease clearance of both drugs. Such was the case with imipramine, but the bioavailability of nortriptyline was not increased. Further, the bioavailability of the 10‐hydroxy metabolite of nortriptyline was increased rather than decreased. The degree of change in these kinetic variables varied widely between individuals. Thus it is not possible to predict which subjects might develop evidence of toxicity to tricyclics when Cimetidine is added to the treatment program. The monitoring of tricyclic plasma concentrations is probably desirable in such circumstances.Clinical Pharmacology and Therapeutics(1984)35,183–187; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.24

年代:1984

数据来源: WILEY

摘要:

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwie drug‐free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t½ between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t½ (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t½ (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike Cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.Clinical Pharmacology and Therapeutics(1984)35,188–192; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1984.25

年代:1984

数据来源: WILEY

摘要:

Clofilium, a new quaternary ammonium antiarrhythmic without apparent ganglion‐blocking effect, was evaluated in 25 patients, 22 with a history of ventricular arrhythmias and three with paroxysmal supraventricular arrhythmias. The study, including programmed atrial and ventricular stimulation, was carried out before and after infusion of 20 to 240 µg/kg IV as a single dose. Continuous Holter monitoring was carried out the day before the study through the fourth day after study, and laboratory parameters were monitored for up to 2 wk. There were no changes in intra‐atrial and intraventricular conduction times or in AH or HV intervals. There were increases in QT interval, atrial effective refractory period, and ventricular refractory period. The atrioventricular nodal effective refractory period was unchanged. No side effects were noted, nor were changes in blood pressure or laboratory parameters. Monitoring revealed no change in frequency of premature ventricular complexes between the 24 hr before drug infusion and the 96 hr thereafter. In one patient refractoriness of the His‐Purkinje system was increased and in two patients atrial fibrillation converted to sinus rhythm after clofilium. Three patients had sustained ventricular tachycardia with programmed stimulation before clofilium infusion; none had more than three repetitive ventricular responses after it. Clofilium increases atrial and ventricular effective refractory period without changing conduction time and, despite no apparent change in premature ventricular complex frequency, it can abolish the ability to induce ventricular tachycardia by programmed stimulation and is also well tolerated.Clinical Pharmacology and Therapeutics(1984)35,193–202; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1984.26

年代:1984

数据来源: WILEY

摘要:

We compared the effect of oral and intravenous ranitidine, a new H2‐receptor antagonist, with that of Cimetidine on pentagastrin‐stimulated gastric acid secretion in normal subjects. Ranitidine in intravenous doses of 20, 60, and 100 mg and oral doses of 100, 150, and 200 mg inhibited acid secretion. Only the 100 mg iv ranitidine dose was substantially more effective than Cimetidine. Comparable dose‐related decreases in gastric secretory volume were observed. Acid inhibition correlated strongly (r = 0.90) with plasma ranitidine concentration, with the estimated plasma concentration producing 50% inhibition (IC50) being 95 nglml. Maximal acid inhibition achieved was 87.3%. We conclude that ranitidine is a potent inhibitor of gastric acid secretion and should be a valuable addition to the medical treatment of acid‐peptic disease.Clinical Pharmacology and Therapeutics(1984)35,203–207; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1984.27

年代:1984

数据来源: WILEY