摘要:

Short‐term hypertensive and hormonal effects of Captopril were studied in 26 hypertensive patients. Blood pressure (BP) and heart rate were recorded in subjects in the supine position 1 hr before and 3 hr after an oral dose of 1 mg/kg. Urinary, plasma electrolytes, plasma renin activity (PRA), and plasma aldosterone (PA) were determined before and after the test. It was verified, in a preliminary investigation involving 5 patients, that a placebo did not alter the measured parameters. Captopril decreased mean arterial pressure (xABP ± SD) from 128 ± 2.5 to 108.5 ± 2.6 mm Hg (p<0.001); the maximum decrease was between 30 and 180 min. No changes in heart rate or plasma electrolytes were noted. PRA increased after Captopril from 2.29 ± 0.96 to 3.13 ± 1.25 and to 4.11 ± 1.87 at 1 hr and 3 hr (p<0.05). There was a correlation between PRA in standing subjects before Captopril and decrease inxABP (r = 0.59, p<0.01). The best correlation was between the decrease in xABP and the maximum increase in PRA after Captopril (r = 0.69). A good correlation was found betweenxABP and PRA 3 hr after Captopril (r = 0.62). Correlation coefficients between decrease inxABP and either precaptopril PA or decrease in PA were not significant. In 14 patients, Captopril (5.1 ± 0.61 mg/kg/day) for 4 mo induced the same decrease inxABP that was observed during the test. After short‐ and long‐term Captopril,xABP correlated (r = 0.76, p<0.01).Clinical Pharmacology and Therapeutics(1981)29, 699–704; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.98

年代:1981

数据来源: WILEY

摘要:

The effects of alcohol consumed during an evening party on the metabolism and response of β‐adrenergic blocking drugs were investigated in healthy subjects. The drugs were given 12 hr after the first drink. The plasma clearance rate of propranolol, metabolized in the liver, increased, while that of sotalol, which is eliminated unchanged, was reduced. Plasma propranolol levels, but not those of sotalol, were related to blood alcohol content. The blood pressure–reducing effect of propranolol diminished after alcohol and that of sotalol increased. Both drugs reduced the heart rate after alcohol although they were unable to cancel out entirely the alcohol‐induced increase in the heart rate. The results show that drinking may alter the metabolism of β‐blocking drugs. Drinking habits must be considered in therapy with β‐blocking drugs or when seeking reasons for angina pectoris or arterial hypertension that does not respond to therapy.Clinical Pharmacology and Therapeutics(1981)29, 705–710; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.99

年代:1981

数据来源: WILEY

摘要:

Dose‐response curves for heart rate, cardiac output, arterial blood pressure, and pulmonary artery pressure were obtained in 37 patients with ischemic heart disease after intravenous administration of six increasing doses of propranolol, atenolol, practolol, pindolol, CPEP (1 ‐[2‐cyanophenoxy]‐3β‐[3‐phenylureido]‐ethylamino‐2‐propanol), and BMMP (1‐t‐butylamino‐3‐[2‐N‐methylcarbamoyl‐methoxyphenoxy]propan‐2‐ol‐hydrochloride). The doses were equipotent, as indicated by reduction in exercise‐induced tachycardia. The dose‐response curves for cardiac output and heart rate can be divided into three groups according to the degree of intrinsic sympathomimetic activity. One group without intrinsic sympathomimetic activity included propranolol and atenolol, which reduced cardiac output (about 26% to 28%) and heart rate (about 15% to 17%). A second group with moderate intrinsic sympathomimetic activity, represented by practolol and BMMP, induced less reduction in cardiac output (about 12% to 17%) and heart rate (about 7% to 10%). A third group with pronounced intrinsic sympathomimetic activity, represented by pindolol and CPEP, did not reduce cardiac output and heart rate. Mean systemic blood pressure was essentially unchanged even after the largest dose of any of the drugs. Mean pulmonary artery pressure rose after atenolol, propranolol, and BMMP but not after pindolol, CPEP, and practolol. Atenolol, BMMP, and practolol are beta‐1–selective drugs, it is concluded that the acute hemodynamic response to adrenergic beta receptor blocking drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta‐1 selectivity did not modify the central hemodynamic responses to beta adrenoceptor blockade.Clinical Pharmacology and Therape

ISSN:0009-9236    

DOI:10.1038/clpt.1981.100

年代:1981

数据来源: WILEY

摘要:

To elucidate the mechanism of action of prazosin in lowering the blood pressure, we studied the vascular pressor responsiveness to the infusion of norepinephrine and angiotensin II before and after prazosin in patients with essential hypertension. After prazosin, the pressor response to the alpha agonist norepinephrine was markedly attenuated, but the vascular reactivity to angiotensin II was unchanged. There was a threefold increment in the dose of norepinephrine required to elicit a 20 mm Hg rise in diastolic blood pressure after prazosin therapy. These results confirm that prazosin induces significant alpha adrenergic blockade during the treatment of essential hypertension.Clinical Pharmacology and Therapeutics(1981)29, 719–722; doi:10.1038/clpt.1981.1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.101

年代:1981

数据来源: WILEY

摘要:

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high‐performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p<0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 µg/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 µg/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p<0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first‐order terminal elimination t½. The t½ as estimated by log‐linear regression ranged from about 3 to 15 hr;x± SEM value was 8.3 (±1.1) hr.Clinical Pharmacology and Therapeutics(1981)29, 723–728; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1981.102

年代:1981

数据来源: WILEY

摘要:

Single‐dose kinetics of mexiletine (MEX) was studied in six healthy subjects after three different formulations. The respective doses were 200 mg (intravenous infusion), 400 mg (two conventional capsules), and 432 mg (sustained‐release dosage forms). By a three‐compartment open model with lag time the kinetic parameters of the drug were calculated from the experimental plasma level data. The mathematical analysis of the processes of distribution and elimination was restricted to the intravenous data only, and the resulting transfer constants were introduced into the evaluations of the oral experiments. With this procedure one common value for the plasma t½ of elimination was obtained (t½γ = 6.34 ± 1.5 hr). Mean values for the total volume of distribution (Vdtot) and the total body clearance (Cltot) were 5.5 l/kg and 10.3 ml/min/kg. After capsules, peak plasma concentrations (Cmax= 0.77 µg/ml) were reached after 2.2 hr, and the sustained‐release form built up a flat maximum of concentration (Cmax= 0.34 µg/ml) after 9.2 hr. Mexiletine is highly bioavailable, almost identical for the two oral formulations: 87.3% (capsule) and 78.7% (slow release). Under physiologic urinary pH17.5% to 9.2% of the dose was excreted unchanged by the kidneys.Clinical Pharmacology and Therapeutics(1981)29, 729–736; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.103

年代:1981

数据来源: WILEY

摘要:

Cimetidine induces reversible dose‐related central nervous system (CNS) toxicity. Trough serum concentrations and the development of CNS toxicity correlate. We compared cimetidine kinetics in 12 healthy subjects and 31 patients. Six of the latter had normal renal and liver function, five had renal disease only, 12 had liver disease only, and eight had both renal and liver disease. Postmortem tissue distribution was assessed in 11 patients, and expressed as tissue : serum ratio. Average cimetidine total clearance (ClB) in milliliters per minute for each group was as follows: patients with renal and liver disease (182 ± 105), renal disease only (193 ± 24), liver disease only (463 ± 145), normal patients (510 ± 93), and healthy subjects (583 ± 140). Renal function was the major determinant of ClB, and the relationship was described by ClB= 4.2(CCr) + 140, r = 0.87, where CCr is creatinine clearance. Cimetidine clearance was affected little by age. Tissue : serum ratios from highest to lowest were as follows: kidney>stomach>liver>bone>brain>fat. Central and steady‐state distribution volumes were not influenced by age or disease. There was enhanced CNS penetration in liver disease patients; their cerebrospinal fluid (CSF) : serum ratio was twice the normal. Our kinetic studies identify patient characteristics likely to result in elevated blood levels, and suggest that the greatest risk of CNS toxicity is in those with liver disease.Clinical Pharmacology and Therapeutics(1981)29, 737–743; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.104

年代:1981

数据来源: WILEY

摘要:

Cimetidine plasma concentration‐response relationships were investigated in six healthy subjects using suppression of gastric acid secretion under continuous pentagastrin stimulation (1.5 µg/kg/hr) as a test model. With the Hill equation the sigmoid was preferable to the linear relationship between plasma concentration and effect, and there were significant correlations with p values under 0.01 in all but one subject. From the individual curves a mean plasma level of 0.78 µg/ml (range 0.54 to 1.04 µg/ml) for 50% inhibition of gastric acid secretion was determined; mean concentration for 90% inhibition was calculated to be 3.9 µg/ml. The model described should allow determination of whether different patient populations (e.g., healthy subjects, patients with ulcers, male and female patients, patients with renal or liver disease) differ from one another in concentration‐response relationships to histamine H2‐receptor antagonists, so that appropriate drug plasma levels should be achieved for specific degrees of inhibition of gastric acid secretion.Clinical Pharmacology and Therapeutics(1981)29, 744–748; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1981.105

年代:1981

数据来源: WILEY

摘要:

Mental and psychomotor effects and diazepam kinetics were studied in Caucasians and Orientals. 12 Caucasian and 13 Oriental young adults received on one of two occasions, separated by 2 weeks, either 0.2–mg/kg diazepam or saline intravenously. Serum diazepam and desmethyldiazepam concentrations were measured by electron–capture gas–liquid chromatography in samples drawn up to 72 hr after injection. Serum protein binding was measured by equilibrium dialysis. Subjects were tested on a battery of psychological tests before and 0.5, 2, and 4 hr after treatment. While the free fraction of diazepam was identical in both races (0.02), volume of distribution at steady state (Vdss) was different when calculated as absolute volume (Vdss= 76.55 ± 9.63 l in Caucasians and 54.96 ± 4.55 l in Orientals, p = 0.04) and marginally significant when corrected for body weight (Vdssl/kg = 1.10 ± 0.11 in Caucasians and 0.88 ± 0.05 in Orientals, p = 0.07). Total body clearance (Cl), but not elimination half‐life (t½), was higher in Caucasians than Orientals (Cl = 0.40 ± 0.03 ml/min/kg in Caucasians and 0.29 ± 0.03 in Orientals, p<0.01; t½ = 37.70 ± 5.53 hr in Caucasians and 41.77 ± 3.80 in Orientals). Desmethyldiazepam levels were higher in Orientals than Caucasians. Mental and psychomotor effects were maximal at the first session (0.5 hr), followed by complete recovery by the 4‐hr session. Effects were similar in both groups. If repeated dosing causes a higher rate of cumulated diazepam serum levels in Orientals, as expected, there might be deeper brain depression in that group.Clinical Pharmacology and Therapeutics(1981)29, 749–756; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1981.106

年代:1981

数据来源: WILEY

摘要:

The effect of high concentrations of desmethyldiazepam (DMDZ), the major metabolite of diazepam (DZ), on parent drug kinetics was evaluated in six healthy young subjects who received a single intravenous dose (10 mg) of DZ on two occasions. The first DZ dose was given in the drug‐free control condition and the second after the subject had ingested clorazepate (CZP), a precursor of DMDZ (15 mg daily for 7 days before DZ and then during the second DZ study). Maximum DMDZ concentration after the first DZ dose did not exceed 66 ng/ml, whereas mean DMDZ levels (derived from CZP) during the second DZ study were 481 ± 61.5 ng/ml (SE) for all subjects. DZ kinetic parameters for all subjects during the first and second studies were: elimination half life (t½). 43.3 ± 5.3 and 44.9 ±9.7 hr; total volume of distribution (Vd), 1.26 ± 0.10 and 1.32 ± 0.10l/kg; unbound Vd, 97.4 ± 9.9 and 94.9 ± 9.9l/kg; clearance, 0.364 ± 0.048 and 0.394 ± 0.055 ml/min/kg; and unbound clearance, 28.3 ± 4.6 and 28.3 ± 5.0 ml/min/kg. Percent unbound DZ was 1.40 ± 0.25% when subject plasma was spiked with DZ alone and 1.47 ± 0.21% when subjects' plasma was spiked with 500 ng/ml DMDZ in addition to DZ. Paired analysis of the two studies in each subject revealed no difference in t½, Vd, unbound Vd, clearance, or DZ protein binding in the absence or presence of DMDZ. Formation and presence of the active metabolite DMDZ had no influence on kinetic behavior of parent DZ.Clinical Pharmacology and Therapeutics(1981)29, 757–761; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.107

年代:1981

数据来源: WILEY