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Biomedical subjects

M B Murphy

Publications and source records attributed to M B Murphy.

At least 91 records · Page 5Linked to original sources
PubMed1988

Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients.

1 The pharmacokinetic properties of intravenous fenoldopam, a selective dopamine1-receptor agonist, were studied in 10 patients with essential hypertension. 2 Reduction in blood pressure was linearly related to the log fenoldopam plasma concentration (r = 0.69) and the log fenoldopam infusion rate (r = 0.71). 3 The mean elimination half-life (+/- s. e. mean) was 9.8 +/- 1.0 min. The total body clearance was 30.3 +/- 2.3 ml kg-1 min-1 and the volume of distribution was 582 +/- 62 ml kg-1. 4 The rapid onset of action, short elimination half-life, linear dose-response relationship, and ease of administration suggest that fenoldopam may have a role where parenteral treatment of hypertension is required.

Adult↗
PubMed1988

Renal effects of atrial natriuretic factor are independent of dopamine1 receptors.

This study examined whether the renal effects of atrial natriuretic factor (ANF) are mediated by dopamine1 (DA1) receptor activation. Intravenous infusion of low-dose ANF (0.0025 micrograms.kg-1.min-1) in euvolemic, pentobarbital sodium-anesthetized male mongrel dogs enhanced urine flow (V) by 71 +/- 14% (mean +/- SE) and urinary sodium excretion (UNaV) by 457 +/- 172% (P less than 0.05). Renal blood flow (RBF) was unchanged. Administration of pharmacological doses of ANF (0.1 microgram.kg-1.min-1) into the renal artery in volume-expanded dogs increased RBF by 26 +/- 6, V by 56 +/- 15, and UNaV by 101 +/- 42%. The selective DA1 receptor antagonist SCH-23390 (0.5 microgram.kg-1.min-1 iv) did not affect the response to ANF at either dose. The selective DA1 agonist, fenoldopam, increased RBF by 45 +/- 3, V by 94 +/- 27, and UNaV by 61 +/- 15% in volume-expanded dogs. With SCH-23390, fenoldopam increased RBF by only 16 +/- 6% whereas V and UNaV decreased by 16 +/- 10 and 17 +/- 10%, respectively. Accordingly, the failure of DA1 receptor-blocking doses of SCH-23390 to antagonize the response to ANF, at pharmacological or physiological doses, indicates that the renal effects of ANF, in the dog, are independent of DA1 receptor activation.

Animals↗
PubMed1988

Comparison of the effects of dopamine and fenoldopam, a selective dopamine-1 agonist, on parathyroid hormone release in man.

Dopamine has been reported to transiently increase parathyroid hormone (PTH) secretion in man; however, the mechanism is unclear. To test the hypothesis that selective dopamine-1 receptor (DA1) stimulation increases PTH secretion, we compared the effects of fenoldopam, a novel selective DA1 receptor agonist, as well as dopamine on serum PTH secretion and total serum calcium concentration in seven normal human subjects. Dopamine was infused at 1 and 3 micrograms/kg/min, each for 10 minutes, and 5 micrograms/kg/min for 25 min. Fenoldopam was infused at 0.1 and 0.3 micrograms/kg/min, each for 10 min. and thereafter at 0.5 micrograms/kg/min for 25 min. The infusions were given at least 1 week apart. Blood samples for PTH, calcium and dopamine or fenoldopam concentrations were drawn prior to and at the 25th minute of each drug infusion. PTH concentrations increased in all subjects at the 25th minute of dopamine but not fenoldopam infusion. Serum calcium was not significantly affected. The plasma concentrations of both dopamine (83.6 +/- 7.1 ng/ml) and fenoldopam (13.0 +/- 3.4 ng/ml) were in the range known to cause equivalent DA1 receptor stimulation. Since dopamine but not fenoldopam increased PTH secretion in man, we conclude that selective DA1 receptor stimulation alone does not increase PTH release and the effects of dopamine must be mediated through some other mechanism.

Adolescent↗
PubMed1987

Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam.

Activation of dopamine1 (DA1) receptors relaxes vascular smooth muscle, especially in the renal vascular bed. Fenoldopam, the first selective DA1-receptor agonist that can be administered to man, was infused intravenously in 17 patients with essential hypertension (mean blood pressure 152/101 mm Hg). It reduced blood pressure in a dose-dependent fashion at doses between 0.025 and 0.5 microgram/kg/min and the antihypertensive effect was sustained during 2 hr infusions. In 10 patients studied during free-water diuresis, fenoldopam increased renal plasma flow by 42%, glomerular filtration rate by 6%, and sodium excretion by 202%, while lowering mean arterial pressure by 12% (all p less than .05). Similar promotion of sodium excretion was observed during blood pressure reduction in six additional patients studied without water loading. Pronounced enhancement of renal function in spite of blood pressure reduction suggests that fenoldopam might have a special role in the treatment of patients with hypertension and renal impairment.

Adult↗
PubMed1987

Potential use of DA1 and DA2 receptor agonists in the treatment of hypertension.

Will dopamine (DA) agonists have a role in the treatment of hypertension? Recent advances of medicinal chemistry and receptor pharmacology have suggested a positive answer. First, the division of DA receptors into two subtypes, DA1 and DA2, and the differentiation of these receptors from other receptors have resulted in the synthesis of relatively selective agonists and antagonists. Second, agonists of DA1 and DA2 receptors have been shown to decrease blood pressure in experimental animals and hypertensive patients. Review of clinical data with DA1, DA2, and combination of DA1 and DA2 agonists not only has demonstrated efficacy, but has revealed problems in the use of these compounds. Finally, possible solutions of these problems will be discussed.

Animals↗
PubMed1986

Bicarbonate therapy in severe diabetic ketoacidosis.

Twenty-one adult patients with severe diabetic ketoacidosis entered a randomized prospective protocol in which variable doses of sodium bicarbonate, based on initial arterial pH (6.9 to 7.14), were administered to 10 patients (treatment group) and were withheld from 11 patients (control group). During treatment, there were no significant differences in the rate of decline of glucose or ketone levels or in the rate of increase in pH or bicarbonate levels in the blood or cerebrospinal fluid in either group. Similarly, there were no significant differences in the time required for the plasma glucose level to reach 250 mg/dL, blood pH to reach 7.3, or bicarbonate level to reach 15 meq/L. We conclude that in severe diabetic ketoacidosis (arterial pH 6.9 to 7.14), the administration of bicarbonate does not affect recovery outcome variables as compared with those in a control group.

Adult↗
PubMed1985

The effects of nifedipine on platelet aggregation and plasma 6-keto-PGF1 alpha, and its interaction with indomethacin.

Pre-incubation of human platelets with nifedipine in vitro or treatment of normal volunteers with nifedipine, 30 mg daily for one week, did not alter ADP induced aggregation measured by whole blood aggregometry. 6-oxo-Prostaglandin F1 alpha remained undetectable in plasma following oral administration of nifedipine to normal volunteers. The hypotensive response to intravenous nifedipine administration was similar in spontaneously hypertensive rats pretreated with indomethacin or placebo. These results conflict with previous reports that nifedipine alters platelet aggregation and prostaglandin metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Treatment of hypertension with calcium antagonists.

Calcium antagonists are the latest addition to the antihypertensive armamentarium. The evidence available suggests that they lower blood pressure at least as effectively as diuretics, beta-receptor blockers and other vasodilators. Nifedipine is as effective as hydralazine as a third-line drug. Both nifedipine and verapamil may be used alone as first-line therapy, but they are more expensive and probably cause more symptomatic side-effects than diuretics or beta-receptor blockers.

Adrenergic beta-Antagonists↗
PubMed1984

Role of nifedipine in the treatment of resistant hypertension. Comparison with hydralazine in hospital outpatients.

In a double-blind, randomized crossover study, the daily administration of 30 to 90 mg of nifedipine lowered blood pressure in a dose-related fashion in 14 patients already taking a beta receptor blocker and diuretic. The duration of the hypotensive response to 20 mg of nifedipine in capsule form, giving as a "step-three" drug to five of these patients, was six to eight hours. A survey of 122 patients with resistant hypertension treated long-term with nifedipine and a control group of 102 similar patients treated with hydralazine revealed that nifedipine at an average dose of 40 mg daily caused a fall in blood pressure similar to that achieved with hydralazine in a dose of 86 mg daily. The side effect profile of both drugs was also similar. Nifedipine may be a useful alternative to existing step-three antihypertensive drugs.

Double-Blind Method↗
PubMed1984

Effects of intravenous infusions of prostaglandin D2 in man.

Prostaglandin D2 (PGD2) was infused intravenously into normal male volunteers. Seven subjects received infusions of 16, 32, 64 ng/kg/min and six of these a further dose of 128 ng/kg/min. Each individual's maximum dose was limited by discomfort caused by intense facial flushing and nasal congestion. At these doses there was no significant effect on systolic or diastolic blood pressure nor on spirometric measurements. There was a small but statistically significant tachycardia at 64 and 128 ng/kg/min. Collagen- and adenosine diphosphate (ADP)-induced platelet aggregation ex vivo was not affected at any of the infusion rates. Infused PGD2 is unlikely to be a useful antithrombotic agent.

Adenosine Diphosphate↗
PubMed1984

Nifedipine and alpha adrenoceptor antagonism.

The effects of nifedipine and placebo on the pressor responses to methoxamine, alpha-methylnorepinephrine, and angiotensin II were compared in normal subjects. Nifedipine shifted the pressor dose-response curves of all three agonists to the right. The dose ratios of the three agonists were of the same order. Thus in contrast to the findings in animals, nifedipine is not a selective alpha 2-adrenergic antagonist in man, although it may lower blood pressure partly by antagonism of norepinephrine and angiotensin II.

Adult↗
PubMed1984

Location of vascular alpha 2-adrenoceptors in man.

To determine whether vascular postsynaptic alpha 2-adrenoceptors are innervated by sympathetic nerves in man, normal volunteers were infused for 90 min with angiotensin II (A II) and the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline (MNA) in a double-blind cross-over study. Whilst systolic blood pressure returned to baseline within 5 min of terminating the A II infusion it remained elevated 40 min after stopping MNA. The prolongation of the pressor response to MNA, a substrate for neuronal uptake, was probably due to activation of alpha 2-adrenoceptors by MNA re-released from contiguous sympathetic nerve endings. The proximity of alpha 2-adrenoceptors to sympathetic nerve terminals suggests that they could contribute to blood pressure regulation in man.

Adult↗
PubMed1984

Effects of short term beta adrenoreceptor blockade on serum lipids and lipoproteins in patients with hypertension or coronary artery disease.

The effects of beta adrenoceptor blockade with propranolol or pindolol on serum total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and its subfractions HDL2 and HDL3, serum triglyceride, and Intralipid clearance were studied in 17 normolipidaemic, non-diabetic patients with hypertension or angina pectoris. Both pindolol and propranolol had similar effects on fasting serum total and lipoprotein cholesterol concentrations. HDL2 cholesterol concentrations were reduced by 9 +/- 29% and HDL3 cholesterol increased by 11 +/- 16%, but there were no significant changes in total or LDL cholesterol in the combined groups after six weeks' treatment. After 12 weeks' treatment total cholesterol concentrations were reduced by 7 +/- 10% mainly owing to a reduction in the LDL fraction of 9 +/- 15%. Concentrations of HDL2 remained low, 8% less than control values. Serum triglyceride concentrations were increased by both drugs at six weeks but had returned to base values in the pindolol group by the twelfth week. Pindolol, but not propranolol, enhanced the rate of clearance of intravenous Intralipid.

Adult↗
PubMed1984

Atopy, immunological changes, and respiratory function in bronchiectasis.

Cystic fibrosis has been reported to be associated with an increased prevalence of atopy and reversible airways obstruction. To determine whether such features can also result from other chronic suppurative lung infections, we studied 23 patients with proved bronchiectasis, and 23 age and sex matched normal controls. A personal or family history of atopy was reported with equal frequency in the two groups. Although the groups displayed a similar prevalence of positive immediate hypersensitivity skinprick test responses, the positive patients reacted to more antigens (p less than 0.05) and had larger weal diameters (p less than 0.01) than the positive controls. Other indices, such as blood eosinophil counts and serum IgE, did not differ significantly. Serum concentrations of immunoglobulins G, A, and M and of the four IgG subclasses tended to be higher in patients than controls, but only in the case of IgA (p less than 0.01) was this difference significant. No case of IgG subclass deficiency was noted. The patients displayed significant airflow obstruction, the mean basal one second forced expiratory volume (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEFR) being 67%, 77%, and 67% of their predicted values. There was evidence of a significant reversible obstructive component in that FEV1 or PEFR or both increased by 15% or more in nine of the 23 patients after inhalation of fenoterol, the mean increases in FEV1, FVC, and PEFR for the whole group being 9.5%, 11%, and 16.9%. These results indicate that while bronchiectasis provokes a hyperimmune response it differs from cystic fibrosis in that there is no significant increase in the prevalence of atopy. The finding of reversible airways obstruction, however, suggests that bronchodilators may be useful adjuncts to treatment.

Adolescent↗
PubMed1984

Evidence for a peripheral component in the sympatholytic actions of clonidine and guanfacine in man.

The time courses of the changes in plasma growth hormone and noradrenaline concentrations in response to 15 min infusions of clonidine 0.2 mgs and guanfacine 2 mgs, were studied in six normal volunteers, in a double-blind, randomised, cross-over study. Plasma noradrenaline fell within 15 min of the commencement of drug administration, by 36 +/- 14% after clonidine (p less than 0.05) and by 32 +/- 11% (p less than 0.05) after guanfacine. Plasma growth hormone was not significantly elevated until the 30th minute to 12.0 +/- 4.7 lU/ml (p less than 0.05) after clonidine and 14.7 +/- 11.5 lU/ml (p less than 0.05) after guanfacine, having been undetectable prior to both drugs. The reduction in plasma noradrenaline by these alpha 2-adrenergic agonists, prior to activation of central adrenoceptors as detected by changes in plasma growth hormone, is evidence for a peripheral component in their sympatholytic effect.

Adult↗
PubMed1983

Hypokalemia from beta2-receptor stimulation by circulating epinephrine.

To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation, and whether hypokalemia can occur at physiologic concentrations of the agonist, epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute. The circulating epinephrine concentration was increased to 1.74 +/- 0.65 ng per milliliter, plasma potassium was reduced by 0.82 +/- 0.19 meq per liter, plasma insulin fell by 12 +/- 4 mU per liter, plasma renin activity was elevated, and tachycardia occurred. Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia (25 beats per minute) and elevation in plasma renin activity (6.0 to 6.5 ng per milliliter per hour), but no hypokalemia. The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine. This hypothesis was tested in six subjects given infusions of epinephrine (0.05 micrograms per kilogram per minute) after administration of either 2.5 or 5 mg of ICI 118551--a selective beta2-receptor antagonist--or placebo. After placebo, epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium; hypokalemia was prevented by the beta2-antagonist. This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals; there was no tachycardia. Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine. This phenomenon may be of physiologic importance after severe myocardial infarction, when similar increases in plasma epinephrine have occurred.

Adult↗
PubMed1983

Role of nifedipine in treatment of hypertension.

The efficacy of nifedipine in the treatment of hypertension was assessed in 15 patients whose hypertension continued while being treated with atenolol 100 mg and bendrofluazide 5 mg daily. Nifedipine was added in doses of 10, 20, and 30 mg three times daily in a placebo controlled, double blind trial. One patient was withdrawn from the trial because of severe postural hypotension with the highest dose. Erect and supine blood pressure in the remaining 14 patients were significantly reduced by all doses of nifedipine. The drug was well tolerated but plasma potassium fell by 0.3 mmol(mEq)/1 during treatment (p less than 0.05). Nifedipine is thus effective in the treatment of hypertension but should probably be used in combination with a potassium sparing diuretic.

Adult↗