ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03708.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03709.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03710.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses—the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead‐in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P<.05) in a dose‐related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hyperte

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03711.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Guanfacine, an alpha‐2 adrenoceptor agonist, was compared with methyldopa as step‐2 therapy for patients with mild‐to‐moderate essential hypertension in a 12‐week, double‐blind, randomized, parallel evaluation of efficacy and safety. The study consisted of a 2‐week screening/weaning period (phase I), a 3‐week treatment period with a diuretic (phase II), and a 12‐week treatment period with a diuretic plus methyldopa or guanfacine (phase III). Patients were weaned from prior anti‐hypertensive medication during the screening/weaning period and began receiving chlorthalidone 25 mg every morning. Patients received only 25 mg of chlorthalidone each morning during the phase II period. Those who had an average seated diastolic blood pressure (BP) of 95–114 mm Hg at the end of the phase II period were eligible to enter the phase III period and were randomly assigned to chlorthalidone plus guanfacine, 1 mg every night, or methyldopa, 250 mg tid. Seated and standing systolic and diastolic BP and pulses were measured biweekly for 12 weeks after randomization. Of the 112 patients who were randomly assigned to guanfacine or methyldopa, 87% completed the entire study. The mean seated systolic and diastolic BP were reduced 13/13 mm Hg by guanfacine administration and 15/13 mm Hg by methyldopa administration. No significant changes in seated pulse were seen in either group. Similar changes occurred in the standing position. Very few adverse effects were reported during the study, the most prevalent side effect was xerostomia (13% guanfacine, 9% methyldopa). No significant differences were observed between treatment groups for the incidence of cardiac arrhythmias after methyldopa or guanfacine administration was stopped. No significant effects of these agents were seen on a set of memory function tests. Thus, guanfacine (1 mg each night) and methyldopa (250 mg tid) were equi‐effective in reducing systolic and diastolic BP in combination with diuretic in patients with mild‐to‐mode

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03712.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24‐hour blood pressure profiles monitored by using one of two automatic, non‐invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24‐hour period, with no clinically significant difference between

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03713.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double‐blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol‐pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertens

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03714.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

AICA‐riboside (5‐amino‐4‐imidazole carboxamide ribonucleoside) is a novel adenosine‐regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo‐controlled, double‐blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1‐week wash‐out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post‐infusion plasma concentrations of AICA‐riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean tt/2β of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady‐state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5′‐monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA‐riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P>.05) in the mean estimates of t1/2β, CL, CLR, MRTIVand VSSassociated with dose. The drug was poorly bioavailable (<5%) when

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03715.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

One of the effects of antiarrhythmic drugs is the reduction of conduction velocity. Cable theory predicts that there is a nonlinear relationship between conduction velocity and upstroke velocity (V̇max) of action potential. By using conventional microelectrode techniques, aprindine‐induced reduction of V̇maxof action potential and conduction velocity in guinea‐pig papillary muscles were measured. Aprindine‐produced, use‐dependent, and concentration‐dependent changes in conduction velocity and the decline of square of conduction velocity was well fit by a single exponential. Time constants for square of conduction velocity were comparable to simultaneously measured time constants for effects of V̇max. At a concentration of 1 to 10 μM aprindine, onset changes between V̇maxand conduction velocity had a log‐linear relationship in a predicted fashion. Whereas, in the recovery process from aprindine‐induced depression, slow recovery time course of conduction velocity was observed. In conclusion, in the presence of aprindine, only onset block of conduction velocity can be analyzed quantitatively in the relationship to observation on V̇maxin vitro. These results suggested that in the presence of aprindine, the recovery of internal conductance may be slower

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03716.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two‐way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained‐release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2β, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline‐mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0–24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03717.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY