摘要:

Dilevalol is the R‐R' optical isomer of labetalol and differs pharmacologically from the racemic mixture in the following ways: it is seven‐fold more potent as a selective beta‐2 agonist; it is four times more potent as a nonselective beta antagonist; it has no clinically significant alpha antagonist property. Dilevalol is a vasodilator and reduces blood pressure by reducing systemic vascular resistance. It has a half‐life of 15–18 hours, and is demonstrated to he effective as an antihypertensive agent for 24–30 hours. Hemodynamic studies in humans show that following administration of dilevalol either orally or intravenously, blood pressure falls as a consequence of a decrease in systemic vascular resistance. Cardiac index is unchanged and heart rate decreases slightly. Dilevalol is shown to cause regression of left ventricular hypertrophy in younger individuals, to improve left ventricular performance and to have no effect on parameters of renal function. Prospective double‐blinded clinical trials in comparison with placebo, propranolol, metoprolol and atenolol were conducted and demonstrate dilevalol to be an effective antihypertensive agent with a favorable side effect profile with a particularly low incidence of central nervous system

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03280.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03281.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

In 14 patients with congestive heart failure (CHF) of various grade (NYHA class 2–4) the effects of zofenopril calcium (SQ 26,991) on blood pressure and forearm circulation were studied by venous occlusion pletismography. Changes in plasma renin activity (PRA), aldosterone, Atrial natriuretic factor (ANF) and arginine‐vasopressin (AVP) were also measured. Two hours after oral administration of 7.5 mg of zofenopril we observed a decrease in blood pressure, heart rate, and forearm vascular resistance along with an increase in venous distensibility. Zofenopril also decreased ANP levels in a manner directly related to peripheral venodilatation (r = .64; P<.05) and modified arginine‐vasopressin (AVP) proportionally to the fall in blood pressure observed in response to drug administration (%SBP/%AVP: r = .64, P<.05; % DBP/%AVP: r = .67, P<.05). Hemodynamic and humoral responses to zofenopril occurred without any significant unwanted adverse reaction, even in patients with greater pressor reduction. We conclude that oral acute zofenopril administration, in patients with congestive heart failure, causes an arterial and venous forearm vasodilatation which is probably involved in the acute changes in plasma levels of ANF and AVP observed after drug administr

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03282.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58–74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P<.01) change in serum digoxin concentrations. Significant (P<.01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t‐test with Bonferroni correction. A weak correlation (r = 0.74, r2= 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations. Failure to consider the activity level of the patient at the time that digoxin blood samples are drawn could result in inappropriate dosage adjustme

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03283.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(–) DP) and racemic disopyramide (equimolar mixture of R(–) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind crossover randomized trial was achieved, at steady‐state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(–) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P<.01), and QTc interval (+9.2% and +7%, respectively, P<.001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(–) DP (157 ml/min), (P<.001). The mean total plasma clearance of R(–) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(–) DP, due to the presence of S(+) DP, which is known to be a potent displac

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03284.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

The safety and efficacy of using continuous high‐dose transcutaneous nitroglycerin in doses up to 100 mg/24 hours in chronic stable angina was assessed in 20 patients using serial treadmill testing. Patients had first to show a response to sublingual nitroglycerin with a 20% improvement in exercise time. All patients were then titrated with 20 mg (40 cm2), 60 mg (120 cm2), 80 mg (160 cm2) or 100 mg (200 cm2) patches, until intolerable headache in association with a 10 mmHg reduction in blood pressure and a ten‐beat increment in heart rate. Drug was then discontinued for 2 days and patients underwent three repeat stress tests to reestablish a consistent drug‐free baseline. Patients were then randomized in double‐blind fashion to receive either active patch (N = 11) in previous titration dose or placebo patch (N = 9), with treadmill tests performed at 0 (1 hour after previous patch removal), 4, and 24 hours after patch application at baseline and at weeks 1 and 2. Venous blood was obtained for measurement of plasma nitroglycerin levels. After the first 24 hours of active patch therapy, there was a significant reduction in systolic blood pressure (P = .05), a significant increase in heart rate (P = .01), and a minor increase in exercise tolerance (P = .06) compared to placebo. At weeks 1 and 2, there was an attenuation of drug effect in all of these parameters. Plasma nitroglycerin levels demonstrated consistently high plasma levels over each 24‐hour dosing interval, on day 1, week 1, and week 2. Headache was the most common side effect, and with the 1‐hour treatment withdrawal there was no evidence of angina rebound. High‐dose continuous nitroglycerin patch therapy is well tolerated in patients, and there is some evidence of antianginal efficacy during the first 24 hours of therapy. However, despite the high plasma nitroglycerin drug levels seen with continued use of high‐dose therapy, there is an attenuation of hemodynamic and antianginal effects, suggesting the development of pharmacolo

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03285.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03286.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

CGS 13080, a selective thromboxane synthetase inhibitor, was given intravenously (0.6 mg/kg over 6 hours) to eight hypertensive (diastolic 95–115 mm Hg) euvolemic caucasian females on their customary salt intake (24 hour urine Na: 142.9 ± 14.8 meq). No change occurred in blood pressure or glomerular filtration rate (GFR): 95.2 ± 7.2, control versus 95.0 ± 9.0, CGS 13080 (ml/min); or renal plasma flow (RPF): 363.2 ± 34.2, control, versus 373.2 ± 31.2, CGS 13080, (ml/min). Prostaglandin production was altered: platelet generation of thromboxane B283.3 ± 10.9, control, versus 5.4 ± 1.8, CGS 13080 (ng/hr) (P<.001); urinary prostaglandin E (PGE) 249.0 ± 56.3, control, versus 443.9 ± 79.8, CGS 13080 (ng/6 hr) (P = .06); urinary 6‐ketoprostaglandin F1a(6‐ketoPGF1a) 188.6 ± 23.4, control, versus 287.9 ± 21.8, CGS 13080 (ng/6 hr) (P = .01); urinary thromboxane B254.8 ± 12.9, control, versus 58.6 ± 20.3 CGS 13080 (ng/6 hr) (P = NS). Serum levels of renin, angiotensin II and aldosterone were not altered by CGS 13080. Captopril when dosed to lower diastolic blood pressure 5–7 mm Hg did not significantly affect GFR, RPF or RVR. Nor did it affect platelet generation of thromboxane B2or urine concentrations of PGE, 6‐keto‐PGF1aor thromboxane B2. Captopril did increase renin levels 1.2 ± 0.2, control, versus 2.9 ± 1.1, captopril (ng/ml/hr) (P = NS), but did not statistically change angiotensin II, or aldosterone levels. To see if the angiotensin converting enzyme inhibitor, captopril, would unmask a hypotensive effect of CGS 13080, the same experiments were repeated with captopril being dosed for 2 weeks prior to treatment with CGS 13080. The blood pressure decrease seen with captopril was not augmented by CGS 13080. The two drugs when dosed together did not affect GFR or RPF, nor did they significantly affect urinary prostaglandin excretion. Our preliminary observations suggest that CGS 13080 as acutely dosed in this study inhibited serum thromboxane A2production and increased vasodilator prostaglandins breakdown products in the urine (PGE, 6‐ketoPGF1a), yet did not augment the hyp

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03287.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Some features of hyperthyroidism mimic sympathetic nervous system overactivity. We have compared the clinical (scored on the Wayne Therapeutic Index), hemodynamic (blood pressure and heart rate) and biochemical (plasma epinephrine, norepinephrine, glucose, free fatty acids, insulin, growth hormone and free thyroxine index) effects of clonidine (α2‐agonist, which reduces plasma catecholamine levels) with those of nadolol (non‐selective beta adrenergic receptor antagonist) in ten female hyperthyroid patients. Each patient received nadolol for 1 week followed by clonidine for 1 week in a single‐blind manner. All measurements were made before treatment and then repeated at the end of the nadolol and clonidine treatment periods. Thyroid function remained unaltered during the study. Both agents caused significant clinical improvement— the mean Wayne Index score was 18 pretreatment, 2 on nadolol and 6 on clonidine (P<.003 for each). Heart rate was reduced by both drugs, but blood pressure was unchanged. Side effects occurred in eight out of ten patients while on clonidine. Nadolol increased plasma concentrations of epinephrine from 47 ± 18 pg/mL to 87 ± 24 pg/mL, and norepinephrine from 241 ± 154 pg/mL to 338 ± 224 pg/mL (P<.001 for each). In contrast, clonidine depressed norepinephrine levels from 241 ± 154 pg/mL to 110 ± 49 pg/mL (P<.001) without lowering plasma epinephrine significantly. Plasma free fatty acids tended to fall on both agents compared to pretreatment levels. The blood glucose, insulin and growth hormone concentrations were unaffected by either drug. We conclude that, despite the similar clinical effects of nadolol and clonidine, these drugs have contrasting effects on plasma catecholamine concentrations. Beta‐adrenergic receptor antagonists remain the drugs of choice for the symptomatic relief of hyperthyroidism, because of the high incidence of side effects caused by clonidine. However, clonidine could be considered for patients with conditions in which beta‐adrenergic antagonists a

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03288.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax(range 2.0–2.5 hours), Cmax(385–465 μg/l), and t1/2(4.0–4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, CI, Vgs and Vareawere not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp(0.83%) than either of the two elderly groups (0.55–0.64%), but Clintdid not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to t

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03289.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY