Metabolic studies in patients with nadolol: oral and intravenous administration.

Nadolol-14C, 2,3-cis-5-(3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-naphthalenediol, a nonselective beta-adrenergic blocking agent, was administered orally and intravenously at 2-mg doses to patients with mild cases of essential hypertension. Terminal plasma half-times after oral and intravenous doses were an average of 12.2 and 9.8 hours, respectively. After oral doses, an average of 24.6 and 76.9 per cent of the dose was excreted in urine and feces, respectively, whereas, after intravenous doses, an average of 72.9 and 23.3 per cent of the dose was excreted by the same routes. Calculations of absorption, based on urinary excretion and on areas under the plasma concentration-versus-time curves, indicated that oral doses of nadolol-14C were absorbed to the extent of 33.6+/-2.4 per cent (+/- S.E.). The average overall volume of distribution after intravenous administration was 2.09+/-0.51 1./kg (+/- S.E.), and the average volume of the central compartment was 0.30+/-0.04 1./kg. Only unchanged nadolol-14C was excreted in the urine and feces of patients after either oral or intravenous administration of the drug.

Endocrine and cardiovascular consequences of angiotensin converting enzyme inhibition.

One of several novel peptidic inhibitors of angiotensin converting enzyme (CEI) has been studied intravenously both in normal male volunteers and severely hypertensive patients without any clinically significant adversity or intolerance. Hypertensive patients experienced a significant yet gradual reduction in resting arterial pressure without hypotension. The addition of a diuretic agent was observed to potentiate this antihypertensive effect. Normal, sodium replete volunteers received this nonapeptide intravenously in doses up to 2-0 mg/kg without any significant cardiovascular effect. Both patients and normal subjects exhibited reversible dose related increases in angiotensin I and renin levels after receiving the peptide. The plasma renin response to tilting was also potentiated by CEI. These findings suggest that intravenous CEI may be of value in the treatment of severely elevated hypertension and as a tool to evaluate vasoconstrictor and volume factors in hypertension.

Prepartion of 16alpha-alkoxy and 16alpha-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids and determination of their vasoconstrictor activities in humans.

A number of number of 16alpha-alkoxy and 16alpha-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids have been prepared. The synthetic routes used were (a) reaction of the 16alpha,17-disubstituted 21-mesylate with lithium chloride and (b) reaction of the 16alpha-substituted 17,21-cyclic ortho ester with triphenylmethyl chloride. The vasoconstrictor activities in humans exhibited by these compounds were significantly lower than that of a 16beta-methyl analogue.

Sex differences in the intramuscular absorption and bioavailability of cephradine.

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the alpha phase was observed to be 1.16 +/- 0.17 hr(-1) for females and 2.70 +/- 0.34 hr(-1) for males. Total area under the mean serum concentration-time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.