Biomedical subjects

H N Glassman

Publications and source records attributed to H N Glassman.

At least 19 recordsLinked to original sources

PubMed1995

Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-depleted normotensive subjects.

BACKGROUND: Zankiren HCl (A-72517) is a potent renin inhibitor shown to have substantial bioavailability in several animal species and to produce dose-related reductions in blood pressure, plasma renin activity, and angiotensin II (Ang II) in salt-depleted dogs. The present study was designed to evaluate the hemodynamic effects of oral zankiren HCl administration in healthy volunteers and to characterize the response of the renin-angiotensin system (RAS) to specific blockade by this new renin inhibitor. METHODS AND RESULTS: Twenty-four male volunteers participated in a double-blind randomized, placebo-controlled in-hospital study to evaluate the effects of zankiren HCl (10 to 250 mg). All subjects were pretreated with 40 mg furosemide 12 hours before study drug administration. Blood pressure and heart rate were monitored by an automated oscillometric device, and blood samples were obtained for active renin, total renin, plasma renin activity, angiotensin I (Ang I), Ang II, aldosterone, and plasma zankiren concentration. Satisfactory absorption of zankiren HCl was demonstrated by the results of plasma drug concentration determinations, and renin inhibitory activity was confirmed by dose-related suppression of plasma renin activity, Ang I, Ang II, and aldosterone and increases in plasma active renin concentration. Furthermore, hypotensive activity was readily observed in these normotensive subjects, as evidenced by statistically significant dose-related blood pressure reductions (P < .01). CONCLUSIONS: Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.

Adult↗

PubMed1991

Renin inhibitors in hypertension.

The renin-angiotensin system (RAS) is an important modulator of blood pressure and fluid balance. The clinical success of angiotensin converting enzyme inhibitors (ACEIs) in the treatment of hypertension has stimulated the search for antagonists of renin. Because renin is highly specific for its substrate, angiotensinogen, renin inhibitors may emerge as clinically preferable alternatives to ACEIs, which affect multiple biological systems, including bradykinin and prostaglandin metabolism. Recent advances in renin inhibitor chemistry have produced highly specific and potent, transition-state analogs of angiotensinogen. Several compounds (e.g., enalkiren, ditekiren, CGP 38560A, and RO 42-5892) have been tested in man. These renin inhibitors produce dose-dependent decreases in plasma renin activity (PRA) which are dissociated from the dose-dependent decreases in blood pressure (BP). Potential explanations for this dissociation include methodologic errors in PRA assays and alternate sites or mechanisms of drug action, including inhibition of noncirculating tissue renin. A prolonged hypotensive effect is seen following single doses of enalkiren and RO 42-5892, and repeated dosing with enalkiren results in sustained hypotensive effect without tachyphylaxis. Renin inhibitors can reduce blood pressure irrespective of baseline renin status and sodium balance. However, high-renin patients generally respond more vigorously, and the hypotensive response is enhanced by sodium depletion. In general, renin inhibitors have been safe and well tolerated in limited clinical studies. New generation renin inhibitors with higher potency and greater oral bioavailability may join the antihypertensive armamentarium.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Clinical pharmacology of enalkiren, a novel, dipeptide renin inhibitor.

Enalkiren (A-64662), a potent, dipeptide renin inhibitor, mimics the transition state of the human renin substrate, angiotensinogen. Enalkiren has been shown to produce dose-related suppression of plasma renin activity (PRA) and angiotensin II when administered intravenously. Doses of enalkiren of less than 0.1 mg/kg induced little hemodynamic response in normotensive and hypertensive volunteers despite marked suppression of PRA. However, at doses of 0.3 and 1.2 mg/kg, enalkiren produced significant, dose-related decreases in systolic and diastolic blood pressure (BP) in hypertensive patients, and the BP response was enhanced by pretreatment with hydrochlorothiazide. The effects of enalkiren on PRA and BP are prolonged despite its relatively short elimination phase plasma half-life (1.6 h). Persistent pharmacologic activity without evidence of tachyphylaxis was demonstrated during 1 week of treatment in hypertensive patients. The observed dissociation between suppression of PRA and BP response and the recruitment of dose-related BP decrements, despite complete suppression of PRA, are unexplained phenomena. The results of clinical trials with enalkiren are encouraging, and suggest that renin inhibitors may be safe, useful therapeutic agents in the management of hypertension.

Dipeptides↗

PubMed1990

Assessment of renin dependency of hypertension with a dipeptide renin inhibitor.

To evaluate the participation of the renin-angiotensin system in sustaining hypertension, we administered the specific dipeptide renin inhibitor enalkiren (A-64662) to 18 patients with essential hypertension. Ascending intravenous bolus doses (0.03, 0.1, 0.3, and 1.0 mg/kg) of the inhibitor were each given at 45-minute intervals to patients maintained on an ad libitum sodium diet who were studied while in bed in the semirecumbent posture. Enalkiren produced marked decreases in plasma renin activity (PRA) that were still evident 8 hours after completion of dosing. Systolic and diastolic blood pressures were decreased in a dose-dependent fashion without an effect on heart rate. Repetition of this procedure after patients were subjected to sodium depletion by 1 week of thiazide treatment produced amplified decreases in blood pressure. Despite the short plasma half-life of the inhibitor, these blood pressure-lowering effects were sustained for 4-8 hours when compared with parallel placebo administration in the same patients. Both the baseline PRA and the inhibitor-induced changes in PRA correlated significantly with blood pressure changes during the unstimulated and the sodium-depleted studies. However, effects of the inhibitor on diastolic blood pressure in the latter study correlated most closely with actual increases in renin produced by diuretic pretreatment. Thus, this specific renin inhibitor has demonstrated the dependency of blood pressure on the renin-angiotensin system even during basal conditions in hypertensive patients. Moreover, renin response to sodium depletion appears to be an attribute that additionally characterizes individual hypertensive patients.

Adult↗

PubMed1990

Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension.

The effects of sustained renin inhibition by repeated administration of enalkiren (A-64662), the novel dipeptide renin inhibitor, were evaluated in a randomized, double-blind, placebo-controlled, parallel-group study of 32 inpatients (eight per group) with essential hypertension who were maintained on a diet containing 60 meq/day sodium. Three different dosage regimens of enalkiren were studied: 1) 1.2 mg/kg quotid., 2) 0.3 mg/kg q.i.d., and 3) 0.1 mg/kg q.i.d. Each patient received an intravenous infusion every 6 hours for 1 week. Placebo infusions were used to mimic the 4 times/day dosing schedule. Blood pressure was measured periodically via 24-hour automated monitoring equipment. Mean plasma renin activity in the patient groups ranged from 1.58 to 2.68 ng angiotensin I/ml/hr. Plasma renin activity was promptly suppressed in all groups receiving enalkiren. Prolonged duration of plasma renin activity suppression (greater than or equal to 24 hours) was demonstrated after the administration of 1.2 mg/kg enalkiren. The 0.3 mg/kg q.i.d. and 1.2 mg/kg quotid. regimens produced statistically significant reductions (p less than or equal to 0.05) in systolic and diastolic blood pressures with clear evidence of persistent antihypertensive activity for 12 hours or more when compared with the placebo group. Despite relatively large reductions in mean systolic and diastolic blood pressure, mean pulse rates were essentially unchanged. The prolonged reduction in blood pressure with enalkiren without evidence of tachyphylaxis after 1 week of treatment suggests that renin inhibitors may emerge as useful therapeutic agents for the treatment of hypertension.

Adult↗

PubMed1990

Efficacy of terazosin in the treatment of essential hypertension in blacks.

The antihypertensive effects of the selective alpha 1-adrenoceptor antagonist, terazosin, in black patients with uncomplicated, mild to moderate essential hypertension were examined retrospectively in seven randomized, double-blind, placebo-controlled trials conducted in the United States. Following 4 to 13 weeks of treatment with terazosin (2-40 mg, once daily), supine and standing systolic and diastolic blood pressures were decreased significantly from baseline, and these decreases were significantly greater than those observed in the placebo group (P less than 0.05). Blood pressure changes in the black and white patient subgroups were comparable. Terazosin was generally well tolerated with a low incidence of serious side effects. We conclude that terazosin is a safe and effective antihypertensive agent in black patients with essential hypertension.

Adolescent↗

PubMed1990

Effects of terazosin on serum lipid levels in hypertensive blacks.

The effects of terazosin, a new, selective, alpha 1-adrenoceptor antagonist, on the serum lipid levels were examined in 103 black patients with uncomplicated, mild to moderate essential hypertension in six randomized, double-blind, placebo-controlled trials conducted in the United States. Terazosin produced statistically significant (P less than 0.05) reductions in total serum cholesterol and triglyceride levels and a marginally significant (P = 0.080) reduction in the combined low-density lipoprotein (LDL-C) and very-low-density lipoprotein (VLDL-C) cholesterol fraction when compared with placebo. We conclude that terazosin, unlike thiazide diuretics, has a favourable effect on the serum lipid profiles of hypertensive blacks.

Adolescent↗

PubMed1989

The effects of terazosin and methyclothiazide on blood pressure and serum lipids.

This study compared the antihypertensive efficacy and the effects on serum lipids of terazosin, a new selective alpha 1-adrenergic antagonist, of methyclothiazide (MCTZ), and of the two drugs used as combination therapy. Adult patients with supine diastolic blood pressure ranging from 95 to 120 mm Hg were eligible to enter this double-blind, randomized, parallel-group study. Analyses of the blood pressure data from the 194 evaluable patients revealed that all three treatments produced significant (p less than 0.001) reductions in supine and standing systolic and diastolic blood pressures from baseline values. Moreover, combination therapy resulted in significantly greater mean blood pressure reductions than were observed with either drug used as monotherapy. In the group receiving terazosin monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level fell significantly (median changes of 3.7%, 5.0%, and 16.3%, respectively, p less than 0.05). However, in the group receiving MCTZ monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level increased significantly (4.7%, 7.1%, and 12.5%, respectively, p less than 0.001). In contrast, no significant changes from baseline values were observed for any lipid variable in the group receiving terazosin/MCTZ combination therapy. We conclude that terazosin is effective antihypertensive therapy that has a potentially beneficial effect on the serum lipid profile when used as monotherapy and that it counteracts the negative impact of MCTZ monotherapy on the serum lipid profile when used concurrently with this thiazide diuretic.

Adrenergic alpha-Antagonists↗

PubMed1989

Renin inhibitors: specific modulators of the renin-angiotensin system.

1. Angiotensin II (AII) acts as a potent pressor agent directly, by virtue of its vasoconstrictor activity and indirectly, by the volume expansion resulting from stimulation of aldosterone release from the adrenal cortex, leading to sodium and water retention. Various approaches of interfering with the enzymatic cascade leading to the production of AII have been made in an attempt to define therapeutic agents for the control of hypertension and heart failure. 2. AII receptor antagonists, to date, lack oral activity and have a relatively short duration of action, limiting their clinical usefulness. Inhibitors of angiotensin converting enzyme block AII production, are orally active and have been used successfully in the control of hypertension and in the treatment of congestive heart failure. 3. An ideal approach to the blockade of the renin-angiotensin system (RAS) is the inhibition of renin, an enzyme with only one known substrate (angiotensinogen) which catalyzes the first and rate-limiting step in the RAS. Early attempts to discover a renin inhibitor focused on immunologic inhibitors of renin, fragments of the prorenin sequence and compounds related to pepstatin, a potent pentapeptide inhibitor of pepsin and less potent inhibitor of renin. None of these approaches proved feasible for a variety of reasons including poor absorption, short duration of action and weak activity. 4. Substrate analogs offer the greatest promise for clinically useful renin inhibitors. Most recently, synthesis of compounds mimicking the enzyme transition state, the condition of greatest binding affinity, has resulted in renin inhibitors with potencies in the nanomolar range, which have shown hypotensive activity. These compounds contain at least one peptide bond and have limited oral activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

A comparison of carteolol and nadolol in the treatment of stable angina pectoris.

In a multicenter, dose-ranging, double-blind study, 63 patients diagnosed as having stable angina pectoris were randomly assigned to treatment with carteolol (33 patients) or nadolol (30 patients). Following a 2 to 4-week dose-ranging period, an optimal dose was determined for each patient and treatment with that dose continued for 6 weeks. Data from all 63 patients were analyzed for drug safety; data for 52 patients (27 carteolol and 25 nadolol) were analyzed for drug efficacy. The most commonly chosen dosage levels were 20 mg of carteolol and 80 mg of nadolol. There were no statistically significant differences between the carteolol and nadolol groups in changes in exercise tolerance as reflected by time to onset of angina, end-point of exercise, and onset of 1 mm ST segment change on ECG. Both drugs significantly suppressed tachycardia and double product during treadmill exercise. The nadolol-treated group demonstrated a significantly greater reduction in resting heart rate (18.7 bpm) as compared with the carteolol-treated group (3.1 bpm). Carteolol possesses intrinsic sympathomimetic activity (ISA), which may account for the fact that carteolol effectively reduces exercise-induced tachycardia while producing relatively little effect on resting heart rate. The frequency of anginal attacks and the use of sublingual nitroglycerin were reduced to a similar extent in both treatment groups. The most commonly reported side effect in both treatment groups was asthenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Terazosin, a new selective alpha 1-adrenergic blocking agent. Results of long-term treatment in patients with essential hypertension.

The long-term treatment of essential hypertension with terazosin, a new once-a-day alpha 1-adrenergic blocking agent, was evaluated in 364 hypertensive patients who received total daily doses of 1 to 40 mg for 3 weeks to 56 months. Consistent mean decreases in supine and standing systolic and diastolic blood pressures were observed throughout the study for patients treated with terazosin as monotherapy (supine, 9 to 12/10 to 13 mm Hg; and standing, 12 to 18/11 to 14 mm Hg) or in combination with other antihypertensive agents (supine, 12 to 16/12 to 15 mm Hg; and standing, 16 to 22/13 to 19 mm Hg). The most commonly reported adverse experiences were dizziness, headache, asthenia, cold symptoms, and nasal congestion. Adverse effects and metabolic disorders often associated with diuretics and beta blockers such as sexual dysfunction, hyperglycemia, hyperuricemia, hypokalemia, or adverse lipid effects were seen infrequently during long-term treatment with terazosin as monotherapy. Overall, terazosin was shown to be effective, safe, and well tolerated by most patients.

Adrenergic alpha-Antagonists↗

PubMed1988

Effect of age on the pharmacokinetics of orally and intravenously administered terazosin.

Terazosin, a new long-acting selective alpha 1-receptor antagonist, was studied in a crossover trial to assess the effect of age on oral and intravenous pharmacokinetics. Thirty healthy male and female volunteers between the ages of 23 and 75 years received 1-mg oral and intravenous doses of terazosin. For both routes of administration, the only pharmacokinetic variables significantly correlated with age were terminal elimination rate constant and the area under the plasma concentration-time curve (AUC). However, the differences in half-life and AUC between the youngest and oldest subjects were modest and not of practical clinical significance. There was no evidence of an enhanced pharmacologic or toxic effect in older subjects. From these data, we conclude that the dosage of terazosin does not need to be adjusted on the basis of age alone; the dose of terazosin is titrated in all patients to the lowest effective dose that is well tolerated.

Administration, Oral↗

PubMed1986

Clinical trials with terazosin. General methods.

Terazosin has been studied in a variety of clinical trials conducted in hypertensive patients with supine diastolic blood pressures of 95 mm Hg or greater before treatment. Blood pressure, pulse rate, body weight, clinical laboratory variables, and adverse experience data were evaluated periodically throughout each study. Patients generally were seen at weekly or biweekly intervals. Total daily doses of terazosin ranged from 1 to 40 mg. Terazosin was administered alone and in combination with other antihypertensive agents. Clinical trials consisted of double-blind, controlled studies and long-term, follow-up studies. The controlled clinical trials employed three principal designs: studies in which the dose was titrated according to blood pressure response; studies in which the dose was increased to a fixed level regardless of blood pressure response; and randomized withdrawal studies. Efficacy evaluations were based on mean blood pressure changes from baseline to the final visit and on the distribution of patient responses, which were categorized from excellent to inadequate. Safety evaluations were based principally on comparisons of specific safety parameters before and after the study.

Adolescent↗

PubMed1986

Efficacy of terazosin as an antihypertensive agent.

A total of 713 patients with hypertension were evaluated in eight randomized, double-blind, placebo-controlled trials of terazosin administered in single daily doses ranging from 1 to 40 mg. In three of these studies, terazosin or placebo was added to ongoing antihypertensive drug therapy. Patient response was categorized (from excellent to inadequate) according to the change in supine diastolic blood pressure from baseline and the value at the final visit. The distribution of patients in these response categories differed significantly between patients treated with terazosin and those treated with placebo. Overall, 52 percent of terazosin-treated patients in these eight studies, compared with 30 percent of placebo-treated patients, had good to excellent responses. Subgroup analysis revealed that blood pressure response was not dependent on sex or age, although white patients appeared to achieve better responses to terazosin in comparison with placebo than did black patients. These studies demonstrate that terazosin administered once daily, either as monotherapy or in combination with other antihypertensive agents, effectively controls blood pressure in patients with mild to moderate hypertension.

Adolescent↗

PubMed1986

Overall safety of terazosin as an antihypertensive agent.

The safety of terazosin, an effective agent for the treatment of hypertension, was assessed by analyzing data from 1,006 hypertensive patients who were enrolled in short-term and/or long-term studies. The total experience with terazosin in this article represents 422.5 patient-years. Changes in pulse rate measurements from pretreatment to posttreatment were not significantly different between the terazosin- and placebo-treated patients (-1.0 beat per minute for the terazosin group and -1.0 beat per minute for the placebo group, in the supine position). Dizziness, headache, and asthenia were the most commonly reported adverse experiences among all terazosin-treated patients, although the incidence of headache in placebo-controlled trials was not significantly different between the terazosin and placebo groups. As a whole, patients receiving terazosin had a tendency to gain small amounts of weight (2 pounds). In addition, there was a trend for slight decreases in hemoglobin, hematocrit, white blood cell count, total protein, and albumin levels in those patients who received terazosin, suggesting hemodilution. Overall, terazosin was shown to be safe in patients with mild to moderate essential hypertension.

Adolescent↗

PubMed1986

Long-term treatment of angina pectoris with carteolol: a new beta-adrenergic receptor blocking agent.

Seventy-two patients entered the treatment phase of an open, long-term, dose-ranging trial of carteolol in stable, exercise-induced angina pectoris. Patients were to be treated with progressive doses of carteolol (2.5, 5, 10, 20, 40, and 60 mg), given as a single daily oral dose. Thirty of the patients (42%) completed one year of treatment with carteolol as the sole antianginal therapy. The most frequent final carteolol doses were 20 mg and 40 mg once daily. Statistically significant improvements from baseline in exercise tolerance as reflected in time to onset of angina, time to the endpoint of exercise and time to the onset of 1 mm S-T segment change on ECG were observed in carteolol-treated patients. Exercise-induced increases in heart rate and double-product were significantly suppressed, compared to baseline, throughout the study. Resting heart rate and double-product were modestly decreased. Carteolol was shown to be effective and safe when administered on a long-term basis to patients with angina pectoris.

Adult↗

PubMed1986

Terazosin: a new alpha 1-blocker for the treatment of hypertension: a review of randomized, controlled clinical trials of once-daily administration as monotherapy.

Terazosin, a new selective long-acting alpha1-adrenergic blocking agent, has been shown to be an effective once-daily antihypertensive agent in four of five randomized double-blind placebo-controlled studies of patients with mild to moderate hypertension. In one trial, 24-h monitoring revealed that terazosin produced a sustained blood pressure lowering effect throughout the day. In three fixed-dose trials, steady patterns of blood pressure response during maintenance therapy indicated that tolerance to terazosin did not develop. Favourable changes in the plasma lipid profile were observed, while laboratory data suggested the development of haemodilution. Overall, terazosin was well tolerated. Asthenia, dizziness and peripheral oedema were significantly more common in patients treated with terazosin than with placebo.

Adrenergic alpha-Antagonists↗

PubMed1982

Failure to find electrophysiological correlates of chronic neuroleptic-induced oral dyskinesias in cats: somatosensory and substantia nigra evoked potentials, electroencephalogram, and caudate spindles.

Each of nine cats was prepared with 30 chronically implanted stainless steel gross electrodes in cortex, basal ganglia and other brain structures. Measurements were taken for 0.5-11.5 months of baseline, chronic daily administration of chlorpromazine, and withdrawal. In most cases there was also a second cycle of drug administration and withdrawal. Although we observed dramatic, persistent increases in licking behavior, suggestive of tardive dyskinesia, consistent correlated patterns were not observed in somatosensory or substantia nigra evoked potentials, electroencephalogram, or spindling evoked in cortex by caudate stimulation.

Animals↗