摘要:

Clinical Pharmacology and Therapeutics(1986)39,1–4; doi:10.1038/clpt.1986

ISSN:0009-9236    

DOI:10.1038/clpt.1986.1

年代:1986

数据来源: WILEY

摘要:

Celiprolol is a cardioselective β‐adrenoceptor antagonist with attributed cardiostimulant properties. Its hemodynamic profile was compared in a dose‐response study with that of metoprolol, which is also cardioselective but lacks cardiostimulatory activity. In 24 patients with angiographically proved coronary artery disease, simultaneous hemodynamic and left ventricular ejection fraction (EF) values were determined at rest in the control (drug‐free) state and repeated 3 to 5 minutes after each of four intravenous boluses of Celiprolol, 1, 1, 2, and 4 mg, or equivalent β‐blocking doses of metoprolol, 1.25, 1.25, 2.5, and 5.0 mg. The effects of each drug on hemodynamics during exercise‐induced angina were determined by exercise testing in the control state and after the maximum cumulative dose of each drug. At rest, metoprolol reduced heart rate, cardiac index, and the left ventricular EF and increased pulmonary artery occluded pressure (PAOP), systemic vascular resistance, and left ventricular end‐systolic and end‐diastolic volumes. Celiprolol increased cardiac and stroke volume indices and the EF; the PAOP was reduced without change in other measured variables. During exercise, metoprolol significantly increased the PAOP, which was unchanged by Celiprolol. At exercise both drugs reduced cardiac index and heart rate, but neither altered the EF. The cardiac function curve demonstrated greater depression at rest after metoprolol than after Celiprolol; these differences were attenuated during dynamic exercise. The lesser adverse impact of Celiprolol on cardiac function may be attributable to ancillary cardiac stimulatory properties offsetting the cardiac depression after β‐adrenoceptor blockade.Clinical Pharmacology and Therapeutics(1986)39,5–14; do

ISSN:0009-9236    

DOI:10.1038/clpt.1986.2

年代:1986

数据来源: WILEY

摘要:

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:112C‐R(+) and13C‐S(−)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of14C‐warfarin, was carried out in one of the subjects by monitoring14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of(S)‐warfarin, and increased clearance of(R)‐warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin‐related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P‐450–mediated oxidation of(S)‐warfarin, the biologically more potent enantiomer. The increased clearance of(R)‐warfarin results not from induction, but from its selective displacement from plasma protein binding sites.Clinical Pharmacology and Therapeutics(1986)39,15–24;

ISSN:0009-9236    

DOI:10.1038/clpt.1986.3

年代:1986

数据来源: WILEY

摘要:

The oral absorption of digoxin in tablet form has been reported to be reduced after cancer chemotherapy and radiation therapy because of cancer treatment—induced damage to the intestinal epithelium. We investigated possible differences in the effects of high‐dose cancer chemotherapy on the relative bioavailability of digoxin administered in tablet form (Lanoxin; Burroughs Wellcome Co.) and in solution‐in‐capsule form (Lanoxicaps; Burroughs Wellcome Co.). Each subject received a single oral dose of either 0.5 mg Lanoxin (six subjects) or 0.4 mg Lanoxicaps (seven subjects) both before and after chemotherapy. For Lanoxin, there was a significant reduction in the AUC after chemotherapy to 54.4% ± 35.5% (X̄± SD) of the value before chemotherapy (P = 0.02), whereas for Lanoxicaps there was an insignificant reduction in AUC to 85.1% ± 42.7% of the value before chemotherapy. These findings show that changes in the oral dosage formulation of digoxin from a tablet to a solution‐in‐capsule form can overcome the adverse effects of high‐dose cancer chemotherapy on drug absorption, and suggest that a similar approach may be successful for other drugs.Clinical Pharmacology and Therapeutics(1986)39,25–28; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1986.4

年代:1986

数据来源: WILEY

摘要:

The effects on standing heart rate and respiratory function of two relatively selective β1‐adrenoceptor antagonists, metoprolol and bevantolol, were compared in a double‐blind, randomized, crossover study of 16 patients with asthma. After control observations on 2 separate days, the patients received approximately equivalent cardiac β‐adrenoceptor antagonist doses of metoprolol, 12.5, 25, 50, and 100 mg, and bevantolol, 18.75, 37.5, 75 and 150 mg, at intervals of 2 hours. Dosing was stopped if symptoms warranted or if there was a fall of ≥20% in the forced expiratory volume in 1 second. In general, the cumulative dosing regimen proved a safe and effective means of assessing bronchial responsiveness to these β‐blockers in asthma, but one patient had to be dropped from the study because of severe bronchoconstriction after the first dose. Of the 15 patients studied who were taking both drugs, seven patients were withdrawn prematurely. In these seven patients, the average maximum tolerated cumulative doses were 45.5 mg bevantolol and 26.8 mg metoprolol, doses that are much lower than those usually required for therapeutic activity. The respiratory response to either drug could not be predicted.Clinical Pharmacology and Therapeutics(1986)39,29–34; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.5

年代:1986

数据来源: WILEY

摘要:

The dose‐dependence of the nifedipine‐digoxin interaction was investigated in seven healthy subjects. After an adequate loading dose of digoxin for 2 weeks, 0.25 mg digoxin b.i.d. was given by mouth by itself. Afterwards, 0.25 mg digoxin was given twice a day for three 1‐week periods in combination with capsules of nifedipine, 5, 10, or 20 mg, respectively, given on a thrice‐daily basis. The study ended with a digoxin monotherapy phase lasting 7 days. All three doses of nifedipine significantly increased digoxin plasma concentrations and AUC compared with digoxin monotherapy. Thus, for example, the AUC was 10.16 ± 0.88 ng/ml · hr (X̄ ± SE) when digoxin was given alone and 12.33 ± 1.59 ng/ml · hr with concurrent nifedipine, 5 mg t.i.d. (P<0.05). Nifedipine causes a slight but significant increase (15%) in digoxin plasma concentrations and AUC. This effect did not depend on the nifedipine dose given in the range studied.Clinical Pharmacology and Therapeutics(1986)39,35–39; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.6

年代:1986

数据来源: WILEY

摘要:

This study was a parallel, double‐blind, placebo‐controlled evaluation of acute doses of nifalatide, an enkephalin analog, in subjects with castor oil–induced diarrhea. Seventy‐two subjects completed the study. The time to first stool after castor oil administration was significantly greater after the 16 and 48 mg doses of nifalatide as compared with placebo dosing. The same doses of nifalatide also decreased the overall stool frequency, the frequency of abdominal cramping, and the incidence of nausea and vomiting. There were no clinically significant, drug‐related changes in the physical examination results, ECG, vital signs, or clinical laboratory parameters. The only increased adverse experiences that appeared to be related to the drug were dizziness and mild dry mouth.Clinical Pharmacology and Therapeutics(1986)39,40–42; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1986.7

年代:1986

数据来源: WILEY

摘要:

To assess the effect of potent vasodilator therapy in patients with severe or resistant hypertension, 10 patients underwent therapy with Captopril and nifedipine alone and in combination. Blood pressure (BP), heart rate, and blood chemistry values were monitored for 4 weeks during Captopril monotherapy and after 8 weeks during combination therapy with Captopril and nifedipine. Compared with baseline, the BP decreased during Captopril monotherapy (180 ± 11/98 ± 7 vs. 209 ± 16/118 ± 12 mm Hg; P<0.005). After the addition of nifedipine, the BP was further reduced (148 ± 23/85 ± 16 mm Hg), but there was no change in heart rate. In three patients not achieving the diastolic BP goal during combination therapy with dosing every 8 hours, automatic 24‐hour ambulatory BP monitoring demonstrated lack of antihypertensive control for only the last 2 to 3 hours of the dosing interval. These data demonstrate that combination therapy with Captopril and nifedipine is effective in patients with severe hypertension, but frequent dosing intervals are necessary for adequate antihypertensive control.Clinical Pharmacology and Therapeutics(1986)39,43–48; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1986.8

年代:1986

数据来源: WILEY

摘要:

In a placebo‐controlled, double‐blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration‐time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose‐normalized mean kinetic parameters such as clearance, steady‐state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.Clinical Pharmacology and Therapeutics(1986)39,49–53; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1986.9

年代:1986

数据来源: WILEY

摘要:

The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 ± 21.8 mg for instant coffee (14‐fold range), 80.1 ± 19.2 mg for brewed coffee (2.8‐fold range), and 28.8 ± 13.7 mg for tea (5.5‐fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2= 0.42). Caffeine intake correlated poorly with the 24‐hour average caffeine concentration (r2= 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24‐hour average concentration (r2= 0.94). The same was true for paraxanthine (r2= 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 ± 0.3 ml/min/ kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2= 0.07), even when adjusted for caffeine intake (r2= 0.21).Clinical Pharmacology and Therapeutics(1986)39,54–59; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.10

年代:1986

数据来源: WILEY