L. J. Brannick

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.

Influence of Probenecid and Food on the Bioavailability of Cephradine in Normal Male Subjects

604 The Journal of Clinical Pharmacology C EPHRADINE is a new broad-spectrum semisynthetic cephalosporin antibiotic, 7 [D(-) amino 2 (1,4 c3-clohexadien 1 yl)acctamido 3 methyl8 oxo 5 thia 1 azabicyclo[4.2.0J oct-2-ene-2-carboxylic acid. Cephradine has demonstrated a broad spectrum o antimicrobial activity against both Grampositive and Gram-negative organisms.1 It is the first cephalosporin agent available for oral, intramuscular, and intravenous administration. Cephradine has demonstrated complete and rapid absorption as well as rapid renal elimination when administered to human subjects.1’2 availability of cephradine given either orally or by intramuscular injection.

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.

Effect of Gluco- and Mineralocorticoid Adrenal Steroids on Fluid and Electrolytes of Fasted Adrenalectomized Dogs.

Summary 1) 1-dehydrohydrocortisone induced rapid revival of fasted adrenalectomized dogs from severe insufficiency. Disappearance of symptoms and return of activity and vigor was accompanied by restoration of normal values of arterial pressure and serum electrolytes. Hemodilution was evident and a profuse diuresis occurred with marked renal loss of Na, Cl, K and fluid. Desoxycorticosterone, in doses of 500 mg day was much less effective in restoring activity but sharply increased serum Na and Cl, an increase which in part seemed due to excretion of relatively “salt free” water. There was renal retention of Na and Cl, persistent hemoconcentration and failure of the blood pressure to rise above the low level characteristic of adrenal insufficiency. 2) The fluid and electrolyte changes of the glucocorticoid-treated dogs are presumed to be due to an outflux of Na. Cl. K and water from cells including probably bone and collagenous tissue. Although an apparent correlation exists between the ability of 1-dehydrohydrocortisone to shift fluid and electrolytes and to restore arterial pressure, some of the data suggest that a possible direct effect of this type of steroid on the peripheral vasculature may be of primary importance in revival from insufficiency.

Effect of 2-Methyl-9 Alpha Fluorohydrocortisone on Internal Distribution of Fluid and Electrolytes of Fasted Adrenalectomized Dogs.

Summary 2-methyl-9a-fluorohydrocortisone will revive adrenalectomized dogs from severe insufficiency and restore them to normal health within 48-60 hours even though they are deprived of food and water during recovery. The steroid fully corrects the distorted fluid and electrolyte equilibria of the blood. The lowered arterial pressure, serum Na and Cl increase to normal levels, the elevated serum K and blood urea nitrogen fall, while accompanying these changes, hemodilution occurs along with a diuresis and further loss of fluid, Na and Cl. When adrenal hormones are lacking, water and salt are not only lost in urine and other excretions but perhaps equally important, are immobilized in cells and tissues. Following administration of potent steroid ample fluid and salt are redistributed to the extracellular and intravascular compartment with complete disappearance of symptoms and return of activity and vigor.

A component of substance P active in releasing ACTH.

Summary Substance P. prepared from horses intestine, is rich in a component which is highly active in releasing ACTH from pituitary glands in vitro. This factor is not P itself but is an accompanying material of unknown nature which can be separated from P by strong acid hydrolysis and shown to contain all of the ACTH-releasing activity. The hydrolysate also contains a potent histamine-like substance the activity of which, unlike that of P, is readily abolished by pyribenzamine. The releasing factor, provisionally designated as P1, is apparently identical with the ACTH-releasing agent known to occur in commercial pitressin.

Fractions of Commercial Pitressin which Release ACTH.

Summary Commercial pitressin, hydro-lyzed or nonhydrolyzed, exhibits ACTH-releasing activity when incubated with pitui-taries in Warburg flasks and the incubation fluid infused i.v. into hypophysectomized rats. The ACTH-releasing agent of pitressin can be separated from the pressor component by Craig counter current distribution or by destroying the latter by acid hydrolysis. The hydrolysates when infused i.v. do not deplete the adrenal ascorbic acid of hypophysectomized rats. Unmodified pitressin will release ACTH in vivo from pituitaries of steroid inhibited rats. The histamine-like substance present in acid hydrolysates is not the ACTH-releasing agent and can be separated from it. Histamine added to the Warburg incubation fluid does not induce ACTH release.

A Histamine-Like Component of Commercial Pitressin.∗

Summary Commercial pitressin contains minute amounts of a histamine-like component apparently bound to the polypeptide but which can be concentrated and rendered capable of inducing physiological responses characteristic of histamine when pitressin is subjected to strong acid hydrolysis and the pressor activity destroyed. Extracts of commercial oxytocin contained but one-tenth the vasodepressor activity of pitressin extracts.