Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.01, 0.1, 1.0, and 10.0 mg/kg i.v. was compared in 30 normal and 30 salt-depleted, anesthetized monkeys (n = 5/dose). Baseline mean arterial pressure (MAP) was similar among all groups, but baseline PRA was elevated in salt-depleted monkeys. A-64662 induced a comparable dose-related fall in MAP, affecting the magnitude and duration of action, accompanied by inhibition of PRA, the duration of which was dose-related in both the normal and salt-depleted groups. However, the minimum effective doses required to reduce MAP by approximately 10% were 0.01 mg/kg for the salt-depleted monkeys and 0.1 mg/kg for the normal monkeys. In a second study, three consecutive boluses of vehicle or A-64662 at 0.1, 1.0, and 10.0 mg/kg were administered to anephric monkeys, human renin-infused anephric monkeys, and normal monkeys (n = 4/group). A dose of 0.1 mg/kg was ineffective, but the 1.0 mg/kg dose lowered MAP by 11 +/- 3% (mean +/- SE) in the anephric monkeys. The infusion of renin into anephric monkeys restored the efficacy of A-64662 at the 0.1 and 1.0 mg/kg doses to responses comparable to those of the normal monkeys. A-64662 at 10.0 mg/kg caused a similar fall in MAP of 50 to 60% in anephric, renin-infused anephric, and normal monkeys in the absence of detectable PRA.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

Effects of renin inhibition in systemic hypertension.

The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour, p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml, p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly, but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.

Toxicity of uricosuric diuretics in rat hepatocyte culture.

Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of the uricosuric properties of some of them. This study was designed to test the utility of the hepatocyte monolayer culture as a model for studying these compounds. In addition, an attempt was made to define the structural components that are common to hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid and A-49816, an investigational compound, were found to be toxic in hepatocyte cultures; thus, with the exception of indacrinone, paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chemical structure. A-56234, an investigational uricosuric, was also found to be toxic in cultures but has not been demonstrated to be hepatotoxic in humans in limited clinical experience. It does not possess the ketodichlorophenoxyacetic acid structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the ketodichlorophenoxyacetic acid structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is ketodichlorophenoxyacetic acid or a closely related compound. The hepatocyte monolayer system appears to be a good model for demonstrating toxicity and, perhaps, for predicting toxicity of new compounds under development.

Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury.

Accumulation of calcium following experimental traumatic brain injury (TBI) has been demonstrated to be a prominent pathophysiological component that can compromise mitochondrial functioning and threaten cell survival. The omega-conopeptide SNX-111, also known as Ziconotide, is a potent antagonist of the voltage-gated N-type calcium channel and has demonstrated significant neuroprotective effects against ischemia-induced neuronal injury. To determine whether this compound would be effective in reducing calcium accumulation associated with TBI, SNX-111 was administered intravenously to rats 1 hour following a moderate (2.2 to 2.75 atm) lateral fluid-percussion injury (or sham) at doses of 1 (n = 30), 3 (n = 31), or 5 (n = 30) mg/kg; another group received 0.9% saline solution (n = 35). Brains were processed for calcium 45 (45Ca) autoradiography at 6, 12, 24, 48, and 96 hours following insult. Optical density measurements of 20 cortical and subcortical regions were analyzed. Injured animals administered saline solution exhibited a significant increase in 45Ca uptake within 12 regions ipsilateral to the site of injury. The most prominent increases were evident throughout the ipsilateral cerebral cortex. SNX-111 reduced the injury-induced calcium accumulation within the ipsilateral cortex in a dose-response fashion when measured at 6, 12, and 48 hours after insult. These drug-induced reductions in calcium accumulation were as high as 75% in the ipsilateral cerebral cortex, and up to 50% in other ipsilateral regions (including thalamus and hippocampus). Consequently, the results suggest that posttraumatic blocking of the voltage-gated N-type calcium channel after injury reduces prolonged, trauma-induced calcium accumulation.

New perspectives on selective alpha 1 blockade.

Selective alpha 1 adrenergic receptor blocking agents lower blood pressure by reducing the increased peripheral vascular resistance that characterizes essential hypertension. Prazosin and terazosin have been shown to be well tolerated in clinical practice and seldom cause impotence or metabolic abnormalities. The most common adverse effects--dizziness, headache, and asthenia--are generally well tolerated and infrequently lead to discontinuation of therapy. First-dose syncope can usually be avoided by initiating therapy with low doses administered at bedtime. Finally, the alpha 1 receptor antagonists do not adversely affect such cardiovascular risk factors as hypokalemia, serum lipid profile, and left ventricular hypertrophy. In fact, alpha 1 antagonists reduce total cholesterol and low-density-lipoprotein plus very-low-density-lipoprotein cholesterol and thus may contribute to the overall management of cardiovascular risk by blood pressure reduction and improvement of the serum lipid profile. Since the goal of treating chronic essential hypertension is to improve morbidity and mortality, the choice of therapy should be influenced by the agent's ability to modify as many risk factors as possible. Alpha 1 adrenoreceptor antagonists beneficially impact several cardiovascular risk factors and thus merit consideration as first-line antihypertensive therapy.

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.

Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the management of perioperative hypertension and hypertensive crises.

A panel of clinicians from anesthesiology, surgery, nephrology, hypertension, cardiology, and pharmacology was convened to discuss pharmacologic therapeutics in the management of hypertensive crisis and perioperative hypertension. The panel discussed the advantages and limitations of currently available parenteral drugs, and assessed the potential use of fenoldopam mesylate, a drug in clinical development since 1981, and recently approved by the U.S. Food and Drug Administration (FDA). Fenoldopam is a dopamine receptor (DA1 selective) agonist that is a systemic and renal vasodilator. It was concluded that fenoldopam offers significant advantages as a parenterally administered agent for the management of blood pressure in both hypertensive emergencies and in the perioperative setting.

Prolonged fenoldopam infusions in patients with mild to moderate hypertension: pharmacodynamic and pharmacokinetic effects.

Thirty-three patients with mild-to-moderate essential hypertension received either placebo or fenoldopam, a selective dopamine-1 agonist, by intravenous infusion at a fixed infusion rate ranging from 0.1 to 0.8 microg/kg/min for 48 h during a double-blind, placebo-controlled, randomized inpatient clinical trial. Blood pressure and heart rate were measured every 15 min for 24 h before, during, and 24 h after the 48-h drug infusion. Plasma concentrations of racemic fenoldopam were measured at frequent intervals during and for 24 h after fenoldopam infusion. In the 26 patients who received fenoldopam, there were dose-dependent reductions in systolic and diastolic blood pressure, which usually reached a nadir within 2 h of beginning infusion and were significant even at the lowest dose studied (-9 and -9 mm Hg for systolic and diastolic blood pressure, respectively, at 24 h for the dose of 0.04 microg/kg/min, P < .05). There were associated increases in heart rate that were greater in the first than in the last 24 h of drug infusion. Compared to the average 24-h control blood pressure, maximum mean reductions in systolic and diastolic blood pressures of 33 and 21 mm Hg, respectively, were noted in patients receiving fenoldopam at 0.8 microg/kg/min and occurred 4 and 1 h, respectively, after beginning infusion. Tolerance to the blood pressure lowering effects of the drug developed slowly during the 48 h of drug infusion; the half-life for this effect was 60 h. No serious adverse clinical effects were noted in any patient. These results demonstrate that fenoldopam is effective in reducing blood pressure of patients with mild-to-moderate hypertension at doses as low as 0.04 microg/kg/min, is well tolerated at doses up to 0.8 microg/kg/min, maintains most of its antihypertensive efficacy throughout 48 h of continuous, constant rate infusion, and produces neither prolonged pharmacodynamic effects nor rebound hypertension when discontinued. The pharmacodynamic effects of the drug are best predicted by pharmacokinetics of racemic and R-fenoldopam.

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)

Pharmacologic effects of A-56234, a new high-ceiling diuretic.

The pharmacokinetic characteristics, the diuretic, saluretic, and uricosuric properties, and the safety of single, rising, oral doses of A-56234, a new high-ceiling diuretic, were evaluated in this double-blind, placebo-controlled, cross-over study. Each of three groups of eight subjects received placebo and three different single doses of the diuretic at 1-week intervals. Doses ranged from 0.5 to 80 mg. Significant, dose-related increases in urine volume and in urinary excretion of sodium and chloride were produced during the 24 hours after administration of 20, 40, 60, and 80 mg of the drug. Uricosuria was not observed at any dose. The drug was rapidly absorbed and displayed linear pharmacokinetics within the dose range studied. The elimination-phase plasma half-life was approximately 6 hours. Hepatic clearance was the main route of excretion in humans; only 2 to 10% of the parent drug was excreted in the urine. The drug was well tolerated and no clinically important adverse events were noted.

Sustained hemodynamic effects of the selective dopamine-1 agonist, fenoldopam, during 48-hour infusions in hypertensive patients: a dose-tolerability study.

Eight patients with stage I-II hypertension received a continuous IV infusion of the selective dopamine-1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 micrograms/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24-hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 microgram/kg/min and 1.9 micrograms/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 microgram/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I-II hypertension for up to 48 hours, but fixed-dose infusion rates above 0.8 microgram/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.

Pharmacologic effects of A-49816, a new high-ceiling diuretic.

The pharmacologic effects of A-49816, a high-ceiling, loop diuretic, were evaluated in a single-blind, placebo-controlled, randomized trial. Eighteen (18) normal volunteers aged 19 to 40 years were divided into three groups. The subjects in each group received either placebo or three increasing doses of A-49816 with at least a one-week washout between doses. Nine doses of A-49816 (0.5 to 20 mg) were administered during the entire study. Urine volume and excretion of electrolytes were measured at timed intervals following dosing. A-49816 increased urine volume and excretion of sodium and chloride. Significant saluresis, chloruresis and diuresis were seen in most time periods following administration of the highest doses (12.5, 15 and 20 mg) of A-49816. Kaluresis was not consistently seen at any dose. The mean rates of urine output and sodium and chloride excretion were increased relative to placebo within 2 hours of drug administration. The mean rates of urine formation and sodium and chloride excretion peaked at 2-4 hours and often remained elevated at the 6-12 hour interval.

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.

Selective blockade of N-type voltage-sensitive calcium channels protects against brain injury after transient focal cerebral ischemia in rats.

The neuroprotective efficacy of the selective N-type voltage-sensitive calcium channel blocker, SNX-111, was evaluated in spontaneously hypertensive rats subjected to 60 min of focal cerebral ischemia by permanent ligation of the right common carotid artery and temporary occlusion of the right middle cerebral artery. Intravenous infusion of 167 microg/kg per min SNX-111 for 30 min (5 mg/kg), initiated immediately after reperfusion, significantly reduced cortical infarct volumes measured 24 h after the ischemic insult.

Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers.

The ability of a series of synthetic analogues of omega-conopeptides MVIIA (SNX-111) and TVIA (SNX-185) to prevent electrically-evoked norepinephrine release from rat tail artery and hippocampal slice preparations was determined in an effort to identify voltage-sensitive calcium channel (VSCC) blockers that selectively target N-type VSCCs in central nervous system tissue. Electrical field stimulation (3 Hz, 1 ms in duration. 80 V for 1 min) caused a high and consistent tritium outflow from rat tail artery and hippocampal slice preparations preloaded with [3H]-norepinephrine. All conopeptides, chosen for their selective affinities for high-affinity SNX-111 binding sites (i.e., N-type VSCCs) over high-affinity omega-conopeptides MVIIC (SNX-230) binding sites (i.e., P/Q-type VSCCs), produced a concentration-dependent inhibition of calcium dependent electrically-evoked tritium outflow from both tail arteries and hippocampal slices: IC50s ranged from 1.2 nM to 1.2 microM. Blocking potencies (IC50s) in the tail artery assay were significantly correlated with those measured in the hippocampal slice preparation (r = 0.91, P = 0.00000012). There was a significant correlation between IC50s for blockade of hippocampal norepinephrine release and the inhibition of high-affinity [125I]-SNX-I11 binding in rat brain synaptosomes (r = 0.76, P = 0.00028). Blockade of hippocampal norepinephrine release was not significantly correlated with the inhibition of high-affinity SNX-230 binding (r = 0.46, P = 0.056). Maximum inhibition of tritium outflow in the tail artery assay was 22+/-1.4% of control, approximating the value (20.9+/-16.0% of control) obtained in the absence of extracellular Ca2+. In contrast, the maximum inhibition of tritium release from hippocampal slices was 36.8+/-2.5% of control (P < 0.05, compared to that of the tail artery assay). These results suggest that (1) N-type VSCCs alone mediate low frequency electrical stimulation-evoked neurotransmitter release from peripheral sympathetic efferents (tail artery) while both N-type and non-N type(s) mediate neurotransmitter release from CNS neurons (hippocampus); and (2) analogues of omega-conopeptides MVIIA and TVIA do not differentiate between N-type VSCCs mediating norepinephrine release from central and peripheral neural tissues.

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.