摘要:

Clinical Pharmacology and Therapeutics(1982)31,285–289; doi:10.1038/clpt.1982.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.34

年代:1982

数据来源: WILEY

摘要:

Although postload‐reducing drugs are effective vasodilators in chronic congestive heart failure, the clinical application of the approach to ambulatory patient management remains difficult. We compared the hemodynamic effects of the new oral systemic vasodilator trimazosin (TZ) with those of nitroprusside (NP). Both TZ (172 mg) and NP (46 µg/min) decreased mean blood pressure modestly (P<0.001), while causing considerable decline in elevated left ventricular filling pressure (TZ from 30 to 24 mm Hg; NP from 31 to 20 mm Hg; both P<0.001). TZ also raised the low cardiac index (Cl) of 2.02 to 2.59 l/min/M2(P<0.001), whereas NP elevated Cl from 2.16 to 2.96 l/min/M2(P<0.001). Both drugs lowered (P<0.05) total systemic vascular resistance and pressure time /minute while enhancing (P<0.01) stroke work index. The drugs diminished forearm venous tone (P<0.02) and forearm vascular resistance (P<0.01) concomitantly with elevation of forearm blood flow (P<0.05). Thus, TZ induced qualitatively similar marked augmentation of cardiac function to that by NP. These encouraging hemodynamic findings indicate that TZ may be beneficial to patients undergoing ambulatory vasodilator therapy of severe chronic congestive heart failure.Clinical Pharmacology and Therapeutics(1982)31,290–296; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1982.35

年代:1982

数据来源: WILEY

摘要:

Cimetidine has been shown to impair elimination of a number of drugs metabolized by the hepatic mixed‐function oxidase enzymes. It is uncertain whether this is related to its histamine H2‐receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2‐receptor antagonist and has a completely different structure. Cimetidine (1 gm/day for 7 days) induced a 23% and 35% fall in mean systemic clearance of antipyrine and theophylline, whereas ranitidine (300 mg/day for 7 days) had no significant effect on the clearance of either drug. Our data suggest that the inhibition of drug metabolism by cimetidine is not related to histamine H2‐receptor antagonism.Clinical Pharmacology and Therapeutics(1982)31,297–300; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1982.36

年代:1982

数据来源: WILEY

摘要:

Michaelis‐Menten parameters for rate of drug metabolism (Vmax) and the serum concentration at which metabolism is half of Vmax(Km) were determined in 92 adult epileptic patients taking phenytoin who were 21 to 78 yr old. The patients received no known inhibitors or inducers of phenytoin metabolism. Results of physical examinations and tests of liver function and total bilirubin and albumin concentration were normal. Divided into age groups, Vmaxvalues were 7.5 ± 2.2, 6.6 ± 1.8, and 6.0 ± 1.9 mg/kg/day for the 20‐ to 39‐, 40‐ to 59‐, and 60‐ to 79‐yr‐old subjects, respectively. Values for those in the 60‐ to 79‐yr‐old group were substantially less than those for the youngest subjects (20‐ to 39‐yr‐olds; P<0.05). Linear regression analysis indicated a decline in Vmaxwith age (r = −0.518). Km values did not appear to be influenced by age; means ranged from 5.4 to 5.8 µg/ml. As a result of these changes, the 60‐ to 79‐yr‐old group would require, on the average, 21% less phenytoin per day than the 20‐ to 39‐year‐olds to maintain a steady‐state concentration of 15 µg/ml. First doses can be based on these data and maintenance doses arrived at based on clinical response.Clinical Pharmacology and Thera

ISSN:0009-9236    

DOI:10.1038/clpt.1982.37

年代:1982

数据来源: WILEY

摘要:

The humoral and hemodynamic effects of converting enzyme inhibition with captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (±SEM) plasma renin activity (PRA) rose from 5.0 ± 1.4 to 35.3 ± 5.3 ng/ml/hr (P<0.001) and mean (±SEM) plasma aldosterone (PA) declined from 25.8 ± 2.9 to 15.1 ± 1.9 ng/ml (P<0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone‐producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive.Clinical Pharmacology and Therapeutics(1982)31,305–311; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1982.38

年代:1982

数据来源: WILEY

摘要:

The clinical kinetics of 1,4‐dihydroxy‐5,8‐bis[[2‐[(2‐hydroxyethyl)amino]ethyl]amino]‐9,10‐anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half‐life (t½) of 13.7 min and a terminal t½ of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 ±2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.Clinical Pharmacology and Therapeutics(1982)31,312–316; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1982.39

年代:1982

数据来源: WILEY

摘要:

The overnight urine electrolyte and plasma potassium responses to spironolactone (25, 50, 100, and 200 mg daily) at steady state were investigated in 11 healthy subjects after fludrocortisone challenge. For sodium excretion and urine log1010 Na/K, log dose‐response relationships were defined (P<0.001 in each case), but there was little evidence of dose‐related influences on potassium excretion or plasma potassium. The findings confirm the limitations of the fludrocortisone model in evaluating the potassium‐sparing properties of aldosterone antagonists at steady state and of the urine sodium:potassium ratio as an overall index of renal antimineralocorticoid activity.Clinical Pharmacology and Therapeutics(1982)31,317–323; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1982.40

年代:1982

数据来源: WILEY

摘要:

The effects of short‐term beta blockade with the nonselective antagonist propranolol and with the cardioselective antagonist metoprolol on arterial blood pressure, heart rate, serum renin activity, plasma thromboxane (Tx) B2(the stable metabolite of TxA2), and plasma and urinary prostaglandin (PG) E2and F2αlevels were examined in 11 normal subjects. After propranolol (160 mg by mouth), supine and standing mean arterial pressure (MAP) fell from 82 ± 2 and 88 ±4 mm Hg to 71 ± 3 (P<0.001) and 78 ± 3 mm Hg (P<0.01) within 13 hr. MAP fell from 78 ±2 and 88 ± 3 mm Hg to 72 ± 2 (P<0.025) and 80 ± 2 mm Hg (P<0.01) after metoprolol (200 mg by mouth). These blood pressure effects were associated with beta blockade; both drugs induced reductions in heart rate and serum renin activity and the reductions were of the same order. Propranolol and metoprolol also reduced plasma TxB2levels by 33% (P<0.005) and 46% (P<0.05), but plasma and urinary PGE2and PGF2αlevels were not changed by either drug. These findings suggest that changes in PGE2or PGF2αlevels are unlikely to contribute to the short‐term hypotensive effects of propranolol or metoprolol in normal subjects. Alterations in the synthesis or metabolism of the potent vasoconstrictor and proaggregatory drug TxA2, however, may be involved in the hypotensive, cardioprotective, and antiplatelet effects of beta‐adrenergic antagonists.Clinical Pharmacology and Therapeutics(1982)31,324–329; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1982.41

年代:1982

数据来源: WILEY

摘要:

The kinetics of the antiplatelet drug dipyridamole were studied in six normal subjects (three men and three women) who were ages 22 to 34 yr old. Each received 20 mg IV and four also took a 50‐mg oral dose. Blood samples were collected after each dose for a period of 3 days and concentrations of dipyridamole were measured by a sensitive and specific high‐performance liquid Chromatographic assay. Concentrations after the intravenous dose showed a triexponential decline with a terminal half‐life of 11.6 ±2.2 hr (x̄ ± SD). Total plasma clearance was 8.27 ± 1.82 l/hr and the apparent volume of distribution was 141 ± 51 l. Concentrations rose 6 to 10 hr after intravenous dipyridamole in each female subject, but not in the male subjects. Dipyridamole blood/plasma concentration ratio changed from an average of 0.7 over the first hour to 1.2 after 5 hr after the intravenous dose. There was an absorption lag time ranging from 34 to 75 min after the oral dose; concentrations peaked at about 2 to 2.5 hr after the dose. The percentage of unbound drug in plasma was 0.88 ± 0.24%. Systemic availability of the oral dose was 43 ± 13%. These results suggest widely varying concentrations in patients receiving the drug, and raise questions about the current clinical practice of using empirical dosage schedules.Clinical Pharmacology and Therapeutics(1982)31,330–338; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1982.42

年代:1982

数据来源: WILEY

摘要:

Piretanide, a new potent diuretic, was given to 18 healthy male subjects to determine its effect on serum, total body (TBK), and red cell potassium (RCP). TBK and RCP were measured before treatment to establish baseline values, after which all subjects received 6 mg piretanide a day for 14 days. After this period subjects were divided into two groups; group 1 received 6 mg/day piretanide for 14 more days and group 2 received the same dose of piretanide with 0.5 mg digoxin daily during the remaining 14 days. All treatments were terminated after 28 days, but subjects remained under observation for another 14 days. Serum potassium, TBK, and RCP were measured weekly during the 42‐day period. Piretanide in a dose of 6 mg daily for a period of 6 wk did not induce a fall in serum potassium, TBK, or RCP. The addition of digoxin for 2 wk after piretanide alone for 2 wk did not decrease serum potassium and TBK, but RCP fell under the influence of piretanide with digoxin.Clinical Pharmacology and Therapeutics(1982)31,339–342; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1982.43

年代:1982

数据来源: WILEY