ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In an open-label, randomized trial using a 3 × 3 Latin square design, single doses of 24 mg of the ACE inhibitor spirapril, or 50 mg hydrochlorothiazide, or their combination were given to 18 healthy male volunteers. No alteration in the area under plasma drug concentration curve (AUC), peak plasma level, time to peak level, or elimination half-life was detected for hydrochlorothiazide, spirapril, or its active metabolite, spiraprilat, during combination therapy. It was concluded that there was no significant effect of spirapril on single-dose kinetics of hydrochlorothiazide, nor of hydrochlorothiazide on single-dose kinetics of spirapril. Significant reductions in systolic blood pressure were noted 2–6 h after either spirapril or combination treatment, but no evidence of any synergistic effect of single-dose effects on blood pressure was seen during combination therapy.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Cromakalim, a benzopyran derivative, is a member of a novel class of antihypertensive agents that increase membrane K+ conductance through ATP-sensitive K+channels. The effects of glybenclamide and N;a'-L-arginine methyl ester (L-NAME), a specific inhibitor of nitric oxide synthesis from L-arginine were investigated on the vasodilator response to cromakalim in the hindlimb vascular bed in the male rat, as well as the combination glybenclamide and L-NAME. Thirty male Sprague-Dawley rats (350–450 g) were studied. Cromakalim in three doses (10, 30, 100 μg) injected into the hindlimb through a catheter induced a significant dose-dependent decrease in both mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP). These responses were significantly modified by either glybenclamide or L-NAME. The role of a combination of glybenclamide and L-NAME on the vasodilator responses to cromakalim, acetylcholine, and nitroglycerin were also investigated. Three doses of either acetylcholine, nitroglycerin, or cromakalim caused dose-dependent reduction in HPP of the rats. The responses to acetylcholine were significantly blocked by L-NAME, but the responses to nitroglycerin were not. The vasodilation induced by cromakalim was not only partly blocked by glybenclamide but also by L-NAME. This blockade was significantly augmented when both glybenclamide and L-NAME were infused. These results suggest that nitric oxide may play an important role in regulating hindlimb vascular tone under physiologic conditions. The data also suggest that nitric oxide may be an additional mediator for cromakalim vasodilation as well as KAPT+channel activation in the hindlimb vascular bed of the male rat.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of15N-labeled nitroglycerin (15N-NTG) solution. The total amount of NTG transdermally absorbed (AUC ± CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 ± 3.3 versus 8.1 ± 2.6 mg;p= 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 ± 3.1 versus 10.8 ± 3.1 mg;p= 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 ± 0.21 mg h-1at 1 h for the experimental system and 0.41 ± 0.15 mg h-1at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and15N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of15N-NTG for all participating subjects. The momentary changes of clearance, estimated from15N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The serum and urine kinetics of tiracizine, a new class I antiarrhythmic agent, and three of its metabolites were assessed in eight healthy extensive metabolizers after a single oral administration of 100 mg tiracizine in fasted state and after a standard breakfast. Additionally, ECG changes caused by tiracizine were compared between the two states. With food, the mean A0-xvalue of the parent compound was significantly increased (560.7 versus 419.0 ng h ml-1). The amount excreted unchanged in urine (percentage of the dose) rose significantly (2.43% versus 1.78%). However, mean AUC0–32hand Cmaxas well as urinary excretion of the 3-amino-5-methylamino-acetyl-iminodibenzyl metabolite were decreased (1152.8 versus 1328.0 ng h ml-1, 43.6 versus 56.1 ng ml-1, and 8.59 versus 11.95%, respectively). Total urine recovery (sum of individual tiracizine and metabolite excretion) tended to decrease (31.1% versus 36.1%).Serum and urine metabolite kinetics indicate that food-induced enhancement of tiracizine bioavailability is caused by an alteration in hepatic first-pass metabolism. ReducedN-demethylation is considered to be the limiting step. Tiracizine-induced PQ and QRS prolongations in the ECG tended to be more pronounced with food. Due to the serum concentration dependence of these ECG alterations, food intake might alter the antiarrhythmic efficacy of tiracizine at higher doses. Therefore, patients should be advised to take tiracizine in a constant relationship to food to assure consistent bioavailability.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A comparative study was made of the utilization of cardiovascular drugs in a long-term-care facility for the aged for 1987 and 1992 during which the age and sex distributions and incidence of usage were similar.There were statistically significant declines in the usage of diuretics and potassium supplementation, digoxin, antihypertensives, antiarrhythmics, and beta blockers and a rise in the use of calcium-channel blockers. There was a slight fall in the use of antianginal drugs. The ACE inhibitors introduced after 1987 were taken by 6.1%.The dosages of digoxin and diuretics decreased as management was adequate and toxicity avoided and usage of digoxin reduced in accordance with the concept that digoxin is useful in failure only when left ventricular output is impaired.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Chronically unstable generalized epilepsy (CUGE) is a disabling disease usually treated by ineffective association of drugs. Authors have devoted attention to calcium-dependent mechanisms of seizures. Calcium channel blockers have been used with success in the control of both experimental and clinical epilepsy. β-Adrenergic blockers, such as propranolol hydrochloride (PR), had been described to be experimentally effective in the control of epilepsy in rats and chicks, due to its receptor-dependent calcium channel blocking and membrane-stabilizing actions. We used PR in this crossover, placebo-controlled, randomized trial. Twelve patients with CUGE were enrolled and treated for 15 days with treatment A (20–40) mg PR bid) and treatment B (20–40) mg placebo); the difference in the total number of seizures in the two periods of treatment was compared. Patients treated with PR showed a 32.9% reduction (p < 0.05) in epileptic manifestations. The authors concluded that PR may be an effective adjunct therapy in CUGE and other forms of generalized epilepsy.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19–38 years) and in 12 geriatric volunteers (65–76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1–3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1–4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The Tmaxfor ceftibuten and ceftibuten-transoccurred at about 2 and 3 h, respectively, in both populations. The Cmaxand AUC(0–12h)ranged from 10.8 to 12.4 μg ml--1and from 47.5 to 55.1 μg h ml-1, respectively, for normal volunteers compared to 12.9–17.5 μg ml-1and 62.3–87.1 μg h ml-1, respectively, for geriatric volunteers. The respective values for ceftibuten-transin normal and geriatric volunteers were 1.3 and 1.3 μg ml-1, respectively, and 6.9–8.2 and 5.9–9.8 μg h ml-1. At steady state, the Cmaxand AUC(0–12h)of ceftibuten-transwere about 10–11% and 13–16% those of ceftibuten in normal volunteers and about 8–9% and 9–11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg-1as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h-1kg-1and volume of distribution was about 1.1 L kg-1. Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC50)of methylprednisolone disappear. The difference in (IC50)for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Previous clinical studies with indapamide, an indoline antihypertensive drug with diuretic and vasodilating activities, have shown a dose relationship associated with potassium loss. Two placebo-controlled, randomized, double-blind, parallel clinical studies were, therefore, done to evaluate the safety and efficacy of a low dose (1.25 mg) of indapamide and to determine if an improved safety profile could be produced while maintaining efficacy with a 1.25-mg dose in patients with mild to moderate essential hypertension.Four hundred seventeen (417) adult patients with mild to moderate essential hypertension (sitting diastolic blood pressure ≥ 95 mmHg and ≤ 110 mmHg) were enrolled in two clinical studies; 209 patients were randomized to indapamide 1.25 mg and 208 patients to placebo. Patients received single-blind placebo for a 4-week washout period followed by an 8-week double-blind treatment period during which patients received either indapamide 1.25 mg or placebo. The primary efficacy endpoint was the mean change from baseline to week 8 in sitting diastolic blood pressure. Secondary efficacy variables were the proportion of patients whose sitting diastolic blood pressure had decreased > 10 mmHg and/or had a sitting diastolic blood pressure of < 90 mmHg (treatment success) at all visits and at endpoint, mean changes from baseline in sitting diastolic blood pressure at designated timepoints and at endpoint, and mean changes from baseline in standing diastolic blood pressure and in sitting and standing systolic blood pressure at all visits and at endpoint.Results of these trials were pooled in order to have a larger patient population in an attempt to detect trends not readily apparent with a smaller sample size. In the primary analysis, indapamide produced statistically significantly (p= 0.0001) greater reductions in sitting diastolic blood pressure than placebo after 8 weeks of therapy. In the secondary analysis, the percentage of indapamide-treated patients who achieved treatment success after 8 weeks of therapy was statistically significantly (p< 0.0001) higher compared to placebo-treated patients. In addition, indapamide produced a statistically significantly (p= 0.0001) superior reduction compared to placebo in sitting systolic and standing systolic and diastolic blood pressure after 8 weeks of therapy. The incidence of drug-related adverse events between patients in the indapamide and placebo groups was similar. There were no clinically meaningful differences in laboratory values, including serum potassium, between the patients in the indapamide and placebo groups.Low-dose (1.25 mg) indapamide proved to be safe and effective in the treatent of mild to moderate hypertension.

ISSN:1075-2765    

出版商:OVID    

年代:1994

数据来源: OVID