PubMed Health⌕ Search

Biomedical subjects

M R Goldberg

Publications and source records attributed to M R Goldberg.

At least 19 recordsLinked to original sources
PubMed1992

Lipid and apolipoprotein levels during therapy with pinacidil combined with hydrochlorothiazide.

This study determined the effect of pinacidil on the concentration of plasma lipids and apolipoproteins in male patients previously equilibrated with 25 mg hydrochlorothiazide twice daily. Pinacidil therapy given to 52 hypertensives at 25 to 100 mg daily for 8 weeks resulted in a reduction of systolic and diastolic blood pressure concurrently to reductions in plasma cholesterol and triglycerides with no change in low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C). There was an associated decrease in apolipoproteins (Apo)B, C-III and E and elevation in ApoA-I. A parallel placebo group of 44 patients experienced reduction in diastolic blood pressure and an elevation in ApoA-I. These changes indicate that pinacidil will be a useful antihypertensive agent having properties on lipoprotein metabolism which would favor decreased risks of atherosclerosis.

Adult↗
PubMed1991

Assessment of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, with intravenous clonidine.

The activity of MK-467, a new peripherally acting alpha 2-antagonist, was assessed in volunteers by a randomized, double-blind, crossover design. One hour after administration of either 15 mg or 30 mg MK-467 or placebo, 200 micrograms clonidine was given intravenously and observations were made for a further 8 hours. Clonidine reduced plasma norepinephrine levels to 79% +/- 7% of that of control 1 hour after infusion, an effect that was antagonized by low-dose MK-467 (p less than 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of MK-467 (p less than 0.01), although there was no significant difference between the 3 study days in the maximal clonidine-induced decrease in systolic pressure, diastolic pressure, or heart rate. Clonidine induced a peak increase in mean blood glucose of 13%, which was antagonized by both doses of MK-467 (p less than 0.05). Plasma insulin was suppressed by clonidine from 72 +/- 14 to 47 +/- 7 IU.L-1, an effect antagonised by both doses of MK-467 (p less than 0.05 in each case). MK-467 had no effect on clonidine-induced increased drowsiness, xerostomia, or increase in growth hormone secretion, which is consistent with it being a peripherally acting specific alpha 2-antagonist. The small effect of MK-467 on clonidine-induced changes in plasma glucose and insulin suggests that peripheral alpha 2-adrenergic receptors play only a minor role in normal glucose homeostasis.

Administration, Oral↗
PubMed1989

Clinical pharmacokinetics of pinacidil, a potassium channel opener, in hypertension.

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl-N-oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N-oxide and the area under the concentration-time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 micrograms/L (1.02 microM) and N-oxide concentration of 172 micrograms/L (0.65 microM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.

Adult↗
PubMed1989

Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.

To determine dose-effect and concentration-effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together, we conducted a randomized, double-blind, 4 X 3 factorial, modified fixed-dose multicenter trial. Three hundred and eighty-four patients with essential hypertension (supine diastolic blood pressure, 95 to 110 mm Hg) were assigned to one of 12 groups that received all combinations of four doses of pinacidil (0, 12.5, 25, and 37.5 mg, b.i.d.) with three doses of hydrochlorothiazide (0, 12.5, and 25 mg, b.i.d.). Significant dose- and concentration-effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose- and concentration-effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near-maximal effects on blood pressure at both peak and trough. Edema occurred in 47% of those who received 37.5 mg pinacidil monotherapy (19% discontinued). The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety.

Adult↗
PubMed1989

Beneficial effects of pinacidil on blood lipids: comparisons with prazosin and placebo in patients with hypertension. Pinacidil-Prazosin and Pinacidil-Placebo Research Groups, Lilly Research Laboratories.

In two randomized, double-blind clinical trials comparing pinacidil with prazosin and with placebo in patients with hypertension, a number of statistically significant and potentially beneficial effects on blood lipids were detected in the patients taking pinacidil. Patients treated with pinacidil exhibited significant average decrements from baseline in concentrations of total and low-density lipoprotein cholesterol and triglycerides and a significant average increment in high-density lipoprotein cholesterol. The mean effects seen in the pinacidil group were significantly greater than those in the placebo group for both total cholesterol (-9.8 vs +4.2 mg/dl, p less than 0.001) and triglycerides (-21.6 vs +8.6 mg/dl, p less than 0.001). The effects seen in patients given pinacidil were also significantly greater than those seen in the patients treated with prazosin for both high-density lipoprotein cholesterol (+3.6 vs -1.0 mg/dl, p = 0.002) and triglycerides (-14.8 vs +30.3 mg/dl, p less than 0.001). Negative effects of hydrochlorothiazide and propranolol on blood lipids were not apparent in patients given pinacidil. Thus, pinacidil treatment of hypertension is associated with a beneficial effect on blood lipids, which may be of clinical significance.

Antihypertensive Agents↗
PubMed1988

Both alpha- and beta-adrenoreceptors contribute to the central depressor effect of catecholamines.

We compared the effects of alpha 2- and beta-adrenoreceptor blockade on the central actions of catecholamines and metabolites of alpha-methyldihydroxyphenylalanine, epinephrine, alpha-methylnorepinephrine, and alpha-methylepinephrine were studied. I.c.v. and nucleus tractus solitarii (NTS) injections were carried out under anesthesia. Following i.c.v. injection, both epinephrine and methylepinephrine rapidly reduced blood pressure and heart rate, but the effects of methylnorepinephrine occurred somewhat later. Following microinjection into the nucleus of the solitary tract, epinephrine, methylepinephrine, and methylnorepinephrine all caused hypotension and bradycardia. The hypotensive effects of all 3 amines in the NTS were attenuated in additive fashion by yohimbine, an alpha 2 adrenoreceptor antagonist, and timolol, a beta-adrenoreceptor antagonist, whereas only yohimbine attenuated the bradycardia. The combination of yohimbine and timolol abolished the effects of the amines. These data suggest that in the NTS both alpha 2 and beta adrenoreceptor stimulation contribute to the hypotensive effects of these amines, but that only alpha 2 adrenoreceptors are principally involved in the heart rate response.

Animals↗
PubMed1988

Depletion of brainstem epinephrine stores by alpha-methyldopa: possible relation to attenuated sympathetic outflow.

The antihypertensive effect of alpha-methyldopa (MD) is believed to be critically dependent on its ability to deplete endogenous catecholamines or cause the synthesis of false neurotransmitters. We used liquid chromatography with electrochemical detection (LCEC) and negative chemical ionization gas chromatography-mass spectrometry (GC-MS) for quantitation of catecholamines and MD metabolites in rat. MD intraperitoneally (100 mg/kg q12 hr X 12 days), significantly increased alpha-methylnorepinephrine (MNE) in brain (1.02 +/- 0.33 micrograms/g), heart (1.67 +/- 0.57 micrograms/g) and adrenal glands (114.93 +/- 50.47 micrograms/g) Endogenous norepinephrine (NE), epinephrine (E) and dopamine (DA) were reduced. ME levels were 2.19 +/- 0.44 micrograms/g (n = 6) in the adrenal gland but only 99 +/- 26 pg/g (n = 3) in the brainstem. MD-induced endogenous brainstem NE depletion was more than compensated by MNE production, but brainstem E depletion was not compensated for by a stoichiometric production of brainstem ME. We conclude (1) although ME is a metabolite of MD, it is present in extremely low concentrations in brainstem and (2) central epinephrine-containing neurons are depleted of neurotransmitter by MD therapy. If this selective epinephrine depletion occurs in the bulbospinal tract neurons responsible for maintaining sympathetic tone, then this effect could contribute to the antihypertensive effect of MD.

Adrenal Glands↗
PubMed1988

Vasodilator monotherapy in the treatment of hypertension: comparative efficacy and safety of pinacidil, a potassium channel opener, and prazosin.

We compared antihypertensive effects of monotherapy with pinacidil (N = 197) or prazosin (N = 204) in a randomized, parallel, double-blind dose-titration study in which hydrochlorothiazide or propranolol could be added for adverse events or lack of efficacy. Pinacidil (12.5 to 75 mg b.i.d.) was a more potent vasodilator, producing a mean decrease in supine diastolic blood pressure (baseline = 102 to 103 +/- 9 mm Hg) of 18.8 +/- 10.0 (SD) mm Hg compared with 15.5 +/- 9.2 mm Hg with prazosin (1 to 10 mg b.i.d.; p less than 0.001). Patients responding to each drug had similar average blood pressure levels during 12-hour monitoring (137/85 mm Hg). More patients taking pinacidil required hydrochlorothiazide for edema (p = 0.008) and more taking prazosin required hydrochlorothiazide and propranolol for lack of efficacy (p less than 0.001). Tachycardia (15% to 20%) and palpitation (13% to 15%) were frequent events with both drugs. Edema (38.2% vs 22.3%) was more frequent with pinacidil (p less than 0.001) and postural hypotension (4.7% vs 1.0%) and asthenia (20.2% vs 13.2%) were more frequent with prazosin (p = 0.025; 0.062). No significant laboratory toxicity was noted. In conclusion, both pinacidil and prazosin are effective as monotherapy for hypertension. Monotherapy with pinacidil is limited by adverse events related to vasodilatation and monotherapy with prazosin is limited by lack of efficacy.

Adult↗
PubMed1988

Clinical pharmacology of pinacidil, a prototype for drugs that affect potassium channels.

The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed1988

Double-blind comparator trials with pinacidil, a potassium channel opener.

The antihypertensive effects of pinacidil, a potassium channel opener, were studied in 4, dose titration, double-blind trials. Patients had mild to severe hypertension, with supine diastolic arterial pressures between 91 and 150mm Hg during the qualification assessment. Efficacy was assessed using an 'intention-to-treat' analysis. In one study, pinacidil-treated patients had a response rate significantly greater than placebo-treated patients. In another study, the pinacidil group had a response rate significantly greater than the prazosin group (83% vs 75%, respectively). In a third study, the response rate in the pinacidil group was marginally greater than in the hydralazine group (77% vs 73%, respectively). In a 'step 2' trial, pinacidil was as effective as methyldopa and more effective than placebo. Adverse experiences with pinacidil were associated with vasodilatation. Electrocardiographic T wave changes occurred intermittently and may be related to its mechanism of action. These studies suggest that antihypertensive monotherapy with pinacidil was effective and generally well tolerated.

Antihypertensive Agents↗
PubMed1988

Pinacidil with and without hydrochlorothiazide. Dose-response relationships from results of a 4 x 3 factorial design study.

Utilising a modified fixed-dose, 4 x 3 factorial design, the antihypertensive effects of all combinations of 4 doses of pinacidil (0, 12.5, 25 and 37.5 mg bid) with 3 doses of hydrochlorothiazide (0, 12.5 and 25 mg bid) were studied in patients with supine diastolic blood pressure of 95 to 110mm Hg. The decreases in supine diastolic blood pressure from baseline were dose-related for both drugs. The response to the highest monotherapy dose of pinacidil was less in patients with oedema. When given in combination, hydrochlorothiazide blunted the differences among pinacidil doses so that 12.5 mg pinacidil with 12.5mg hydrochlorothiazide administered twice daily produced nearly maximal antihypertensive efficacy. For pinacidil monotherapy, the incidence of oedema was 3%, 26% and 47% at dosages of 12.5, 25, and 37.5mg bid, respectively, with significant attenuation of these effects at both hydrochlorothiazide dosage levels. Based upon these data, low (12.5-25mg bid) doses of pinacidil are effective and safe as monotherapy for hypertension. The optimal combination of pinacidil with hydrochlorothiazide given twice daily for hypertension contains 12.5mg of each drug.

Antihypertensive Agents↗
PubMed1987

Oral yohimbine in human autonomic failure.

Yohimbine is an alpha 2-adrenoreceptor antagonist that acts to enhance sympathetic nervous system discharge and potentiate sympathetically mediated cardiovascular reflex responses. We therefore assessed the ability of yohimbine to increase sympathoadrenal discharge and raise blood pressure (BP) in patients with autonomic failure characterized by profound orthostatic hypotension. Yohimbine 5 mg orally in eight seated patients significantly elevated mean systolic BP by 33 mm Hg from 136 +/- 15 (mean +/- SD) to a maximum of 169 +/- 23 mm Hg (p less than 0.01), mean diastolic BP by 16 mm Hg from 77 +/- 9 to a maximum of 93 +/- 15 mm Hg (p less than 0.01), and mean heart rate (HR) by 10 beats per minute (BPM) from 68 +/- 12 to a maximum of 78 +/- 17 BPM (p less than 0.01). Plasma norepinephrine (NE) increased from 104 +/- 71 to a maximum of 196 +/- 182 pg/ml (p less than 0.05), but plasma epinephrine (E) did not increase significantly (31 +/- 18 versus a maximum of 39 +/- 21 pg/ml). In five patients given yohimbine 2.5 mg orally, BP, HR, NE, and E tended to increase, but the changes were not significant. Plasma yohimbine levels correlated significantly with the changes in mean arterial pressure (r = 0.61, p less than 0.01). Yohimbine raises BP and HR in patients with autonomic failure. These effects are dose- and concentration-dependent and mediated through increased sympathetic discharge. Yohimbine may be useful in the treatment of orthostatic hypotension associated with autonomic failure. It is unique among current modes of therapy for this disorder in that it enhances discharge of the patient's own sympathetic system.

Administration, Oral↗
PubMed1987

Postjunctional vascular smooth muscle alpha-2 adrenoreceptors in human autonomic failure.

Animal studies have suggested that vasoconstrictor alpha-2 adrenoreceptors exist on vascular smooth muscle cells. We tested this hypothesis in a patient with severe autonomic failure who demonstrated a pressor response to oral clonidine (a selective alpha-2 adrenoreceptor partial agonist). After clonidine 0.8 mg orally, mean arterial pressure rose by 54 mm Hg. After pretreatment with prazosin (a selective alpha-1 adrenoreceptor antagonist) and confirmation of alpha-1 blockade, clonidine 0.8 mg still raised mean arterial pressure by 43 mm Hg. After pretreatment with yohimbine (a selective alpha-2 adrenoreceptor antagonist), clonidine 0.8 mg elevated mean arterial pressure by 13 mm Hg. Since alpha-1 antagonism does not block, and alpha-2 antagonism does not block the pressor effect of clonidine, we conclude that clonidine raised blood pressure in this severely affected autonomic failure patient by vascular alpha-2 adrenoreceptor stimulation. Thus, this provides pharmacological evidence that postjunctional vascular smooth muscle alpha-2 adrenoreceptors exist in man and can modulate blood pressure.

Aged↗
PubMed1986

Influence of yohimbine on release of anterior pituitary hormones.

We used a double-blind crossover design to study the effects of alpha 2 adrenoreceptor blockade with yohimbine on levels of anterior pituitary hormones. A dose of yohimbine was used which raised plasma norepinephrine from 379 +/- 74 (S.E.) to 730 +/- 143 pg/ml and mean arterial pressure from 83 +/- 4 to 92 +/- 5 torr (p less than 0.025). This dose (125 micrograms/kg, then 1 microgram/kg/min) also altered mood when compared to saline infusion. In spite of these changes, when prolactin, cortisol, ACTH, beta-endorphin, TSH and growth hormone were measured after 45 minutes of yohimbine infusion, no changes from baseline were noted. These data suggest that in normal man, at rest, alpha 2 adrenoreceptors in the hypothalamus, adenohypophysis or other brain areas do not tonically modulate release of these hormones into the blood.

Adrenocorticotropic Hormone↗
PubMed1986

Management of chronic orthostatic hypotension.

Chronic orthostatic hypotension is characterized by recurrent symptoms of cerebral hypoperfusion due to low upright blood pressure levels. The initial approach should be to identify and correct reversible causes. Persistence of orthostatic hypotension suggests autonomic failure. The goal of management is to minimize symptoms and maximize functional capacity; therefore the magnitude of blood pressure fall is not as important as the advent of symptoms. Therapy is based upon the underlying pathophysiology and the risk/benefit ratio of interventions. Patient education and nondrug measures form the cornerstone of management. Drug therapy is often limited by unacceptable supine hypertension. Rational drug use can be governed by individualized trials of therapy. Patients with moderate or severe orthostatic hypotension are difficult to treat, but can be helped toward resumption of a normal life.

Activities of Daily Living↗
PubMed1986

Reduction of liver plasma flow by caffeine and theophylline.

Caffeine and theophylline block the vasodilating effects of adenosine and may act to enhance sympathoadrenal discharge and activate the renin-angiotensin system. To determine if these methylxanthines might thereby have effects on regional blood flow, we studied the influence of caffeine and theophylline on apparent liver plasma flow (LPF) in normal subjects as assessed by indocyanine green clearance. Oral caffeine, 250 mg, reduced LPF by 19% from 630 +/- 150 to 510 +/- 120 ml/min (P less than 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 +/- 50 to 470 +/- 90 ml/min (P less than 0.05). These methylxanthine-induced falls in LPF may alter the disposition of concomitantly administered drugs. Because of their widespread use in Western society, caffeine and theophylline may be major determinants of liver blood flow in the general population. They may therefore prolong the t1/2 and increase steady-state levels of hepatically eliminated drugs.

Adenosine↗
PubMed1986

Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system.

We studied the effects of clonidine, an alpha 2-adrenoreceptor agonist, and yohimbine, an alpha 2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18 +/- 3 torr in six subjects and raised it 5 +/- 1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P less than 0.05). Yohimbine (4-64 micrograms/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P less than 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree of autonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.

Adult↗