Search PubMed⌕ Search

Biomedical subjects

R K Ferguson

Publications and source records attributed to R K Ferguson.

At least 91 records · Page 5Linked to original sources
PubMed1981

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Adult↗
PubMed1981

Adrenocortical function after chronic inhalation of fluocortinbutyl and beclomethasone dipropionate.

Fluocortinbutyl (FCB) is a C-21 ester, topically active corticosteroid; no adrenal suppression has been noted after large doses. We compared safety and effects on adrenocortical function of orally inhaled FCB (40 mg/day), beclomethasone dipropionate (BDP) (2 mg/day), and placebo administered in four monitored divided doses for 4 wk by three groups of five healthy men. Circadian plasma cortisol concentration and daily urinary free cortisol excretion were determined before and after 3- and 4-wk exposure. Although pretreatment mean area under the curve (micrograms . hr . dl-1) for plasma cortisol did not differ among groups, mean values after weeks 3 and 4 of treatment were lower (p less than 0.05) in the BDP group (95.1 and 83) than in the FCB (155.8 and 153.7) and placebo (141 and 135.8) groups. Mean urinary cortisol excretion after week 4 for the BDP group (29 micrograms) was less (p less than 0.05) than in the FCB (59 micrograms) and the placebo (69 micrograms) groups. Slopes of individual regression lines noting time trends in plasma and urinary cortisol in the BDP group were negative and less (p less than 0.05) than those of the other groups. A cosyntropin test given intravenously after 4 wk of exposure resulted in similar plasma cortisol responses among groups. No serious adverse effects were noted. Thus after long-term high-dose treatment BDP but not FCB suppressed basal adrenocortical function, but neither suppressed the adrenocortical response to cosyntropin.

Adolescent↗
PubMed1981

Captopril withdrawal after chronic therapy.

Sudden symptomatic increases in blood pressure may result from withdrawal of antihypertensive drug therapy. Captopril, an orally active angiotensin converting enzyme inhibitor, was abruptly withdrawn from the antihypertensive regimen of 6 patients (5 males; aged 31 to 58) with moderate to severe hypertension. The patients had received captopril (50-450 mg/day), diuretics, and in 2 cases, propranolol for 3-13 months; all drugs other than captopril were continued during the study. Blood pressure increased gradually in all patients from a mean (+/- SEM) of 135/92 +/- 5/2 mm Hg to 164/111 +/- 8/3 mm Hg in the 14 to 156 hours following captopril withdrawal, without the occurrence of symptoms. No "rebound" increase in blood pressure was noted. Plasma renin activity decreased, plasma aldosterone and serum angiotensin II concentrations increased and plasma catecholamine concentrations did not change during this time. These changes are consistent with the cessation of angiotensin converting enzyme inhibition. Reinstitution of captopril reduced blood pressure to the previous nadir suggesting a lack of tolerance to its effects after chronic therapy.

Adult↗
PubMed1981

Angiotensin converting enzyme activity in human serum: relationship to enzyme inhibitor in vivo and in vitro.

Quantitative relationships between angiotensin converting enzyme activity in human serum and concentration of an enzyme inhibitor, the active diacid metabolite of MK-421 [N-(S-1-carbethoxy-3-phenylpropyl)-S-alanyl-S-proline maleate], were defined. Dose-response curves were generated in vitro by adding the diacid metabolite (DM) to serum (ID50 = to 6x10-9 M); l0-15% of initial activity was nonsuppressible. DM an converting enzyme activity were also measured in serum from hypertensive subjects receiving oral MK-421. The dose-response curve for serum samples following single doses of MK-421 (ID50 = 6x10-9M), was similar to curves generated in vitro while the curve for sample following chronic therapy suggested a small decrease in inhibitory potency.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1980

Captopril in diuretic-treated hypertensive patients.

Eight hypertensive patients with normal renal function and receiving diuretic therapy for at least 28 days received captopril in small increasing doses (6.25, 12.5, and 25 mg). Supine and standing blood pressure (BP) and pulse rate, plasma renin activity (PRA), and plasma aldosterone concentration (PAC) were measured before and after captopril administration. The mean (+/- SEM) maximal decline in BP was 38/18 +/- 3/2, 34/18 +/- 4/2, and 25/17 +/- 3/2 mm Hg and occurred within 70 minutes of each of the three doses. In contrast, the duration of a 10 mm Hg or greater decrease in BP was prolonged markedly (103 +/- 5, 175 +/- 15, and 287 +/- 10 minutes) after each dose increment. After captopril, mean PRA levels increased while PAC levels fell. Transient dizziness on standing occurred in two patients, but captopril was otherwise well tolerated. Evaluation of the response to initial doses of captopril appears to be helpful in predicting maintenance requirements.

Aged↗
PubMed1980

Comparison of oral indacrinone with furosemide.

The oral dose response and time course of action of indacrinone was compared with that of furosemide in six healthy men on a sodium and potassium-controlled diet. The single doses were 5, 10, 20, 40, and 80 mg indacrinone and 20, 40, and 80 mg furosemide. Diuretic, natriuretic, and kaliuretic effects revealed that indacrinone was more potent, had a longer duration of action, and induced a greater sodium for equivalent potassium loss during its period of peak activity than furosemide. During the 8 hr after drug, all doses of indacrinone decreased serum uric acid levels and increased uric acid clearance while furosemide generally increased serum uric acid and decreased uric acid clearance. After 24 hr, serum uric acid and uric acid clearance were the same for the two drugs. A rise in plasma renin activity was observed 2 hr after an 80-mg dose of furosemide but not after indacrinone.

Adult↗
PubMed1980

Effect of orally administered probenecid on the pharmacokinetics of cefoxitin.

To characterize the effect of orally administered probenecid on the pharmacokinetics of cefoxitin in healthy male volunteers, we administered to one group of six subjects 2 g of cefoxitin by intravenous (i.v.) bolus either alone, with 1 g of probenecid concomitantly, or when 1 g of probenecid was administered 1 h previously by using a crossover design. Likewise, we administered to a second group of six subjects 2 g of cefoxitin intramuscularly (i.m.) together with 1 and 2 g of probenecid. Probenecid increased the mean terminal half-life and the area under the serum cefoxitin concentration-time curve (AUC0-24) and decreased renal clearance, but did not alter the volume of the central compartment or the total urinary recovery of i.v.-administered cefoxitin; pretreatment with probenecid produced a greater increase in cefoxitin AUC0-24 and a constant decrease in renal clearance compared to concomitant probenecid. The AUC0-24 after i.m.-administered cefoxitin was greater after 2 g than 1 g of probenecid; the AUC0-24 after i.v.-and i.m.-administered cefoxitin was similar after 1 g of probenecid was given concomitantly. Cefoxitin AUC0-24 was increased further when 1 g of probenecid was given before i.v.-administered cefoxitin or when 2 g of probenecid was given with i.m.-administered cefoxitin. The effect of probenecid was related to both timing and dose.

Administration, Oral↗
PubMed1978

[Long-term minoxidil therapy: renin, aldosterone, noradrenaline and the need for beta blockers].

Minoxidil-induced sequential changes in plasma renin activity, urinary aldosterone and norepinephrine excretion were assessed in 11 patients with severe hypertension receiving propranolol or oxprenolol, chlorthalidone and spironolactone. Blood pressure with this treatment alone averaged 175 +/- 7/114+/-4 mm Hg (mean +/- SEM). Addition of minoxidil in a dose of 5 to 35 mg/day (mean 16 mg/day) reduced blood pressure within one week to 125+/-5/87+/-3 mm Hg. Plasma renin, urinary aldosterone and norepinephrine increased two- to threefold initially, but returned to baseline within two weeks and remained unchanged during a mean follow-up of 6.8 months. In 6 patients beta-blocking drugs were then progressively reduced and withdrawn without adverse effects, though blood pressure and heart rate increased slightly in 5 patients who required readministration of minimal doses of beta-blockers. Neither renin nor urinary aldosterone or norepinephrine excretion changed significantly after discontinuation of beta-blockade. Thus, the stimulating effect of minoxidil on renin, aldosterone and norepinephrine secretion lasts less than 3 weeks. With long-term minoxidil treatment the need for beta-blockade is markedly reduced, and these drugs may even become unnecessary in some patients.

Adult↗
PubMed1978

Need for beta-blockade in hypertension reduced with long-term minoxidil.

Sequential changes in plasma renin activity and urinary aldosterone and noradrenaline were assessed in eight patients with severe hypertension after minoxidil had been added to their treatment. Doses of 2.5--27.5 (mean 12.5) mg/day reduced the mean blood pressure from 166/113 +/-6/2 mm Hg to 124/88+/-4/2 mm Hg in one week. Plasma renin activity and urinary aldosterone and noradrenaline increased twofold to threefold initially but returned to baseline values within two to three weeks and remained unchanged during a mean follow-up of 5.1 months. Beta-blocking drugs were then withdrawn slowly in six patients without adverse effects, though blood pressure and heart rate increased in three patients, who required minimal doses of beta-blockers. Plasma renin activity and urinary aldosterone and noradrenaline did not change significantly after beta-blockade had been stopped. We conclude that the need for beta-blockade is greatly reduced with long-term minoxidil treatment and that it may be unnecessary in some patients.

Adrenergic beta-Antagonists↗
PubMed1978

Mechanism of blood pressure reduction by teprotide (SQ 20881) in rats.

The mechanism by which the angiotensin converting enzyme inhibitor, teprotide (SQ 20881), lowers blood pressure was assessed in anesthetized normotensive and spontaneously hypertensive (SHR) rats. Teprotide always was administered at a maximally effective dose of 1 mg/kg. In six normal Wistar rats, teprotide lowered blood pressure only after sodium depletion, an effect which was abolished by bilateral nephrectomy. Saralasin infusion (5 microgram/kg/min) into salt-depleted normal rats induced a blood pressure effect similar to that of teprotide. When administered in addition to saralasin infusion, teprotide did not reduce blood pressure further in normal rats or in SHR. When blood pressure of normal rats was raised by angiotensin II infusion (200 ng/kg/min), teprotide did not affect the induced blood pressure increase. In contrast, the pressure rise induced by angiotensin I infusion (230 ng/kg/min) was reversed by saralasin, but again concomitant administration of teprotide did not induce further blood pressure reduction. Thus, under the particular conditions of the present study, teprotide did not appear to exert its hypotensive effect by any mechanism other than inhibition of the renin-angiotensin system. Furthermore, given at a maximally effective dose to the rat, it produced no greater vasodepressor effect than did saralasin.

Angiotensin I↗
PubMed1978

Congestive heart failure in normotensive man. Haemodynamics, renin, and angiotensin II blockade.

The role of the renin angiotensin system was evaluated in 18 normotensive patients with chronic congestive heart failure and in 5 controls. No correlation was observed between plasma renin activity and cardiac index. There was a significant inverse correlation between renin and pulmonary capillary wedge pressure (r = -0.61, P less than 0.01). Renin values of the patients appeared to be increased when compared with controls with similar left ventricular filling pressure. Specific angiotensin II inhibition by saralasin decreased arterial pressure in 8 out of 14 patients: their renin was significantly higher than that of the remaining 6 patients (P less than 0.01). The 2 patients with the lowest renin levels responded to saralasin with a blood pressure increase. Left ventricular filling pressure decreased in all but these latter 2 patients with either little change or an increase in stroke volume. Thus, renin levels appear to be increased in normotensive patients with congestive heart failure when related to left ventricular filling pressure. Renin via angiotensin II plays a role in the blood pressure control of many patients with congestive heart failure. In some patients angiotensin II blockade appears to improve cardiac function by unloading the left ventricle.

Adult↗
PubMed1978

Glomerulonephritis associated with Hemophilus aphrophilus endocarditis.

A 65 year old man developed endocarditis and septicemia due to Hemophilus aphrophilus, a Gram-negative coccobacillus. Renal rather than cardiac failure was the principal feature of his illness and renal biopsy was compatible with glomerulonephritis secondary to septicemia. Rapid recovery of renal function and improvement of the glomerular lesion followed antibiotic treatment of the septicemia. This case illustrates the renal damage that can occur in association with septicemia due to rarer infectious agents. As with more common organisms, specific antimicrobial therapy leads to rapid improvement of the nephropathy.

Aged↗
PubMed1978

Angiotensin II blockade in congestive heart failure.

Five of 11 normotensive patients with congestive heart failure responded to an infusion of the specific angiotensin II antagonist, saralasin, by reducing systemic vascular resistance from 2274 +/- 418 to 1690 +/- 351 dynes/sec/cm-5 (mean +/- standard error). This decrease was accompanied by a reduction in left ventricular filling pressure from 19.4 +/- 5.9 to 11.6 +/- 4.0 mm Hg, an increase in cardiac index from 2.2 +/- 0.4 to 2.7 +/- 0.4 l/min/m2 and a decrease in mean arterial pressure from 95 +/- 9.8 to 86 /+- 8.6 mm Hg. In the other 6 patients with congestive heart failure and in 4 controls, saralasin produced either no change or slight increases in systemic vascular resistance. Plasma renin activity did not differentiate responders from non-respnders. Specific inhibition of angiotensin may provide a means for reducing inappropriately high peripheral resistance in some patients with congestive heart failure.

Adult↗