摘要:

A method is proposed for the design of dosage regimens using two consecutive constant‐rate intravenous infusions to rapidly achieve and maintain plasma drug levels within a predetermined range. By this method, the plasma level will rise to a predetermined maximum at the end of the loading infusion, decrease rapidly to a chosen fraction of the ultimate steady‐state level, and then slowly rise to the steady‐state level. The method may be particularly useful for drugs exhibiting extensive “multi‐compartment” kinetics. Compared with other methods, this approach allows either or both a shorter loading infusion and a lower peak plasma level. Application of this method to clomethiazole therapy for the sedation of pregnant women at term is also discussed.Clinical Pharmacology and Therapeutics(1980)28,289–295; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1980.164

年代:1980

数据来源: WILEY

摘要:

Acebutolol (ABL) and hydrochlorothiazide (HCT) were compared in patients with mild to moderate essential hypertension and low or normal peripheral renin activity. ABL reduced mean supine blood pressure from 151/97 to 140/87 mm Hg and HCT reduced the mean supine blood pressure from 153/98 to 143/92 mm Hg. ABL reduced heart rate from 73 to 67 beats/min; during HCT therapy it rose from 74 to 77 beats/min. Although the same proportion of patients achieved normal diastolic pressures with ABL (11/19) and with HCT (10/19), tension‐time indices were lower during ABL than during HCT therapy. The average daily dose was 621 mg of ABL and 168 mg of HCT. Stimulated peripheral renin activity increased with HCT and was the same or lower with ABL. ABL did not induce adverse effects on serum potassium or uric acid. ABL was as effective in lowering blood pressure HCT but induced larger reductions in tension‐time index as a result of the lowered heart rate.Clinical Pharmacology and Therapeutics(1980)28,296–301; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.165

年代:1980

数据来源: WILEY

摘要:

Blood and urine levels of atenolol were measured in 12 subjects—2 anephric and 10 with creatinine clearances ranging from 0 to 122 ml/min/1.73 m2. In a single‐dose study subjects were given atenolol 100 mg by mouth, and blood and urine levels were measured during the subsequent 72 hr. In a repeated‐dose study 10 subjects were given atenolol 100 mg for 20 days, and blood and urine levels were measured before and for 72 hr after the final dose on day 21. In the single‐dose study the peak blood level occurred later and the 24‐hr plasma concentrations increased as creatinine clearance decreased. The range in peak blood level was sixfold throughout this range of creatinine clearance. The blood atenolol half‐life (t½) increased from about 6 hr to more than 100 hr with progressive renal failure and there was a corresponding decrease in elimination rate constant and increase in area under the curve. In the repeated‐dose study there was good correlation between predose blood level of atenolol and both logarithm creatinine clearance and serum creatinine, and the elimination rate constant correlated with creatinine clearance and the logarithm of serum creatinine. In the single‐dose study minimum heart rates were observed just after the peak atenolol level. Blood pressure response did not correlate closely with serum atenolol levels. Dosing recommendations are suggested for patients with renal failure to take account of the effects of renal function on atenolol kinetics.Clinical Pharmacology and Therapeutics(1980)28,302–309; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1980.166

年代:1980

数据来源: WILEY

摘要:

Dose‐response curves of blood pressure and of the biochemical components of the renin‐angiotensin‐aldosterone system were determined during long‐term treatment with captopril in 21 hypertensive patients. Captopril was given in biweekly, doubling doses starting with 25 mg 3 times a day until control of blood pressure was achieved or a total daily dosage of 600 mg was reached. Recumbent and standing systolic and diastolic blood pressure fell on 75 mg captopril daily. Increasing the captopril dose did not induce further significant hypotensive effects. The pretreatment level of plasma renin activity (PRA) was a poor predictor of the hypotensive effect of captopril. The rises in PRA and plasma angiotensin I level (PA I) and the decrease in plasma angiotensin II level (PA II) and plasma aldosterone level (PAC) provide biochemical evidence for angiotensin‐converting enzyme (ACE) inhibition in vivo. These effects were present on daily doses of 75 to 150 mg captopril.Clinical Pharmacology and Therapeutics(1980)28,310–315; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.167

年代:1980

数据来源: WILEY

摘要:

Captopril was given for treatment of hypertension alone or in combination with diuretics to 32 patients for 1‐ to 4‐mo periods. The decrement of mean blood pressure after 1 and 2 mo correlated with pretreatment plasma renin activity (PRA) and the response of blood pressure to infusion of an angiotensin II antagonist. These correlations were no longer apparent after 4 mo of treatment. When subjects with a decrement of mean blood pressure that exceeded 13 mm Hg were compared with nonresponders, responders not only had higher control PRA and higher PRA at 1 mo of treatment, but also had decreased plasma aldosterone levels, decreased urinary aldosterone excretion, and increased serum postassium levels that persisted over the 4 mo of observation. The reduction of plasma aldosterone correlated with the fall of mean blood pressure. Urinary kallikrein, catecholamines, electrolytes, and endogenous creatinine clearance did not change in response to treatment. These findings indicate that the antihypertensive activity of captopril on long‐term administration probably depends in part on the blockade of angiotensin II, but other mechanisms cannot be excluded.Clinical Pharmacology and Therapeutics(1980)28,316–323; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.168

年代:1980

数据来源: WILEY

摘要:

Butopamine is chemically similar to dobutamine but, unlike dobutamine, it is not a catecholamine. Preclinical studies on dogs show that butopamine is inotropic intravenously and orally. We gave butopamine intravenously to eight patients with congestive heart failure using a progressive dose‐response protocol ranging from 0.02 to 0.17 mcg/kg/min. The mean cardiac index and stroke volume index increased at doses ≥ 0.06 mcg/kg/min; there was also an increase in heart rate at ≥0.06 mcg/kg/min. At ≥0.08 mcg/kg/min the augmented stroke volume tended to plateau so that additional increases in the cardiac index were secondary to the elevated heart rate. Improved ventricular performance, measured by systolic time intervals, left ventricular stroke work index, and the calculated mean rate of left ventricular pressure development during isovolumetric contraction (ΔP/Δt/PCWP), was noted at ≥0.06 mcg/kg/min. Systemic systolic blood pressure increased at ≥0.04 mcg/kg/min but diastolic and mean arterial pressures and pulmonary artery and pulmonary capillary wedge pressures did not change. The progressive increase in cardiac output was accompanied by a reduction in pulmonary and systemic vascular resistances. Although mean premature ventricular contractions per minute did not change, two patients experienced a substantial increase in ventricular ectopy at 0.10 and 0.12 mcg/kg/min. Butopamine induces a positive inotropic response in patients with congestive heart failure but for equal increments in cardiac output, butopamine increases heart rate more than dobutamine.Clinical Pharmacology and Therapeutics(1980)28,324–334; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1980.169

年代:1980

数据来源: WILEY

摘要:

Prazosin improves hemodynamics promptly in patients with congestive heart failure (CHF), but tolerance to repeated doses may develop rapidly. To determine if the kidneys play a role in this attenuation of effect, we studied renal responses in nine CHF patients treated with prazosin (5 mg three times a day for 3 days) preceded and followed by 3 days of placebo. Prazosin decreased mean arterial blood pressure from 87.0 ± 2.2 (x̄ ± SEM) to 84.0 ± 2.0 mm Hg (p<0.05) with no change in heart rate (73.1 ± 3.3 bpm on placebo and 73.6 ± 3.5 bpm on prazosin). The change in creatinine clearance from 81.6 ± 8.7 to 96.3 ± 10.4 ml/min with prazosin was not statistically significant, but the slight increase in urine volume from 2.33 ± 0.22 to 2.51 ± 0.23 1/24 hr was (p<0.01). There were no significant changes in serum sodium, potassium, chloride, CO2, blood urea nitrogen, osmolality or glucose, urinary excretion of sodium or potassium, or sodium balance. The data were analyzed for changes within each period but there were no significant changes from day to day. Plasma renin activity rose from 3.93 ± 0.69 to 4.96 ± 0.84 ng/ml/hr during prazosin (p<0.02). Significant alterations in renal function are not likely when patients with CHF are treated with prazosin, and any attenuation of effect of prazosin after repeated doses is not likely due to mechanisms involving alterations in renal function.Clinical Pharmacology and Therapeutics(1980)28,335–339; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1980.170

年代:1980

数据来源: WILEY

摘要:

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across‐dose kinetic profile was determined for each subject. After a 6‐mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single‐ and multiple‐dose trials were as follows: elimination half‐life (t½), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = −0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t½, 40.9 and 37.9 hr (r = −0.14). Mean observed and predicted predose steady‐state serum concentrations were 0.59 and 0.79 ng/ml (r = −0.02). Mean values of accumulation and elimination t½ were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = −0.64). Multiple‐dose digoxin therapy leads to no systematic change in digoxin clearance. Single‐dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple‐dose therapy.Clinical Pharmacology and Therapeutics(1980)28,340

ISSN:0009-9236    

DOI:10.1038/clpt.1980.171

年代:1980

数据来源: WILEY

摘要:

To investigate the possibility of altered digoxin receptor binding properties in neonates, we compared digoxin binding with erythrocytes from neonates and adults. Neonatal erythrocytes had two and a half times as many digoxin binding sites as adult erythrocytes. The neonatal “receptors” also had dissociation constants for digoxin that were twice the adult value. These findings suggest that differences in binding properties may explain the clinical observation of decreased sensitivity to digoxin in neonates and infants.Clinical Pharmacology and Therapeutics(1980)28,346–349; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.172

年代:1980

数据来源: WILEY

摘要:

The acetylation of hydralazine has been studied in hypertensive patients undergoing maintenance therapy with the drug. The patients were acetylator phenotyped with sulfamethazine. Using gas‐liquid chromatography and high‐pressure liquid chromatography, hydralazine and two of its acetylated metabolites, methyltriazolophthalazine (MTP) and 3‐hydroxymethyltriazolophthalazine (HOMTP), have been determined in the 0‐ to 24‐hr urine. The excretion of hydralazine and HOMTP but not MTP was found to be related to the acetylator phenotype. The metabolic ratio HOMTP: hydralazine showed a bimodal distribution and the average ratio for slow acetylators (1.6) was lower than the ratio in rapid acetylators (14.9). It is concluded that hydralazine is polymorphically acetylated in man. The acetylated metabolite HOMTP was not, however, the major metabolite reported previously.Clinical Pharmacology and Therapeutics(1980)28,350–355; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.173

年代:1980

数据来源: WILEY