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Biomedical subjects

U Thadani

Publications and source records attributed to U Thadani.

At least 19 recordsLinked to original sources
PubMed1992

Efficacy of isosorbide mononitrate in angina pectoris.

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 A.M. and 3 P.M., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.

Angina Pectoris↗
PubMed1992

Role of nitrates in angina pectoris.

Nitrates are used extensively for the treatment of angina pectoris. However, continuous therapy with either oral nitrates or nitroglycerin patches leads to rapid development of tolerance, with loss or diminution of antianginal and anti-ischemic effects. The only practical way to avoid the development of tolerance is to use intermittent daily therapy with nitrates. Nitroglycerin patches applied for 10-12 hours during the day increase exercise duration for 8-12 hours, but a rebound increase in anginal attacks during the nitrate-free interval may occur. Oral isosorbide-5-mononitrate, 20 mg twice a day, with the first dose administered in the morning and the second dose 7 hours later, increases exercise duration for at least 12 hours without the development of tolerance to either the morning or afternoon dose. This dosing regimen has been shown not to produce a rebound phenomenon during the periods of low nitrate levels at night and early hours of the morning. Isosorbide dinitrate (30 mg) prescribed at 7 AM and 1 PM does not produce tolerance to the 7 AM dose, but effects of the afternoon dose have not been evaluated. Recent data suggest that isosorbide dinitrate given 3 or 4 times daily produces tolerance and this dosing schedule is inadequate for antianginal prophylaxis. It should be recognized that intermittent oral or patch therapy with nitrates during the day leaves the patient unprotected at night and early hours of the morning. If this is of concern, additional therapy with another class of antianginal agent, preferably a long-acting beta blocker or a long-acting calcium antagonist should be instituted.

Angina Pectoris↗
PubMed1992

Effects of 8:00 a.m. and 2:00 p.m. doses of isosorbide-5-mononitrate during twice-daily therapy in stable angina pectoris.

"Trough" plasma concentrations of isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, of less than 95 ng/ml are considered necessary to prevent development of tolerance to isosorbide dinitrate and IS-5-MN. In a double-blind, crossover, placebo-controlled study, the effects of IS-5-MN during twice daily eccentric therapy were evaluated in 18 patients with reproducible exercise-induced angina who were nitrate responders. In a random order, patients received either placebo or IS-5-MN (20 mg) at 8 a.m. and 2 p.m. for 1 week each. Average trough plasma IS-5-MN concentrations before the 8 a.m. and 2 p.m. doses were 67 and 226 ng/ml, respectively, and increased to 382 and 488 ng/ml 2 hours after the 8 a.m. and 2 p.m. doses, respectively. Despite a more than threefold higher trough plasma IS-5-MN concentration before the 2 p.m. dose than before the 8 a.m. dose, the increase in exercise duration 2 hours after the doses was similar (1.21 minutes [21%] after 8 a.m. dose, and 1.08 minutes [19%] after 2 p.m. dose). These increases in exercise duration after IS-5-MN were significantly (p less than 0.01) greater than those observed after placebo (0.17 minutes [3%] after 8 a.m. dose, and -0.05 minute [-0.5%] after 2 p.m. dose). Reduction in standing systolic blood pressure at 2 hours after the doses was also nearly identical after the 8 a.m. and 2 p.m. doses of IS-5-MN (21 [15%] and 19 [14%] mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Evaluation of a prolonged infusion of recombinant tissue-type plasminogen activator (Duteplase) in preventing reocclusion following successful thrombolysis in acute myocardial infarction.

The hypothesis that an infusion of recombinant tissue-type plasminogen activator (rt-PA) maintained for up to 24 hours could prevent reocclusion after early coronary patency had been established was evaluated in patients with acute myocardial infarction. The rt-PA studied was an investigational double chain rt-PA (Duteplase, Burroughs Wellcome Co.), administered according to body weight. Coronary patency was documented in 139 of 213 patients who had 90-minute angiograms recorded after an initial lytic dose of rt-PA. In these responders a further 90-minute infusion at one third the initial lytic dose was given before assignment to 1 of 4 maintenance dose rates (0.012, 0.024, 0.036, 0.048 MIU/kg/hour) which were continued for the subsequent 9 to 21 hours. The principal end point was the status of the infarct-related coronary artery 12 to 24 hours after the start of therapy, and before termination of rt-PA, in patients with initially patent vessels at 90 minutes. Of the 103 responders with repeat angiograms after a 9 to 21 hour maintenance infusion of rt-PA, a total of 17 (16.5%) patients reoccluded across all doses administered. There was no significant relationship between the maintenance dose rate and the incidence of reocclusion. However, there was strong association between total dose of rt-PA administered and the incidence (16%) of serious or life-threatening bleeding exclusive of surgery. Other factors associated with serious bleeding included low body weight, female gender, and total duration of rt-PA infusion. Reocclusion was independent of the 90-minute Thrombolysis in Myocardial Infarction trial perfusion grade and diameter of infarct vessel. Rethrombosis after establishment of early patency after rt-PA remains a significant problem that is unaffected by sustained rt-PA infusion in doses that can be tolerated.

Female↗
PubMed1992

Nitrate tolerance. How to prevent it or minimize its effect.

Continuous therapy with nitrates rapidly produces tolerance along with loss or diminution of circulatory, antianginal, and anti-ischemic effects. Development of tolerance can be avoided by various approaches. In patients with stable angina, intermittent use of nitrates with long nitrate-free intervals, use of transdermal nitroglycerin during the day or oral isosorbide dinitrate or isosorbide-5-mononitrate twice daily in the morning and early afternoon, and intermittent use of nitrates in combination with another class of antianginal agent are appropriate. In patients with unstable angina, continuous therapy with intravenous nitroglycerin is recommended during the acute phase of angina. Despite development of partial tolerance, oral isosorbide dinitrate, 30 to 60 mg four times a day, plus hydralazine may be useful for patients with congestive heart failure who cannot tolerate angiotensin-converting enzyme inhibitors. Concomitant use of sulfhydryl donors or angiotensin-converting enzyme inhibitors, agents that might theoretically prevent nitrate tolerance, is not recommended. Data on these agents are conflicting, and added costs and adverse effects are likely to preclude their use in the future.

Angina Pectoris↗
PubMed1991

Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris.

BACKGROUND: Nisoldipine is a potent 1:4 dihydropyridine calcium channel antagonist, and doses of 5 or 10 mg administered either once or twice daily have been claimed to exert antianginal effects. There is, however, little information regarding the dose-response relation and whether the drug exerts any consistent effects throughout the dosing interval. In this placebo-controlled, parallel-design study, the dose-response relation of monotherapy with nisoldipine administered twice daily was studied in patients with stable angina pectoris. METHODS AND RESULTS: Two hundred thirty-one patients received single-blind placebo for 2 weeks; of these, 185 patients who reproducibly stopped treadmill exercise because of angina of moderate severity and had greater than or equal to 1 mm ST segment depression during exercise and experienced an average of three episodes of anginal attacks per week were randomized in a double-blind manner to one of the four treatment groups: placebo (n = 48), nisoldipine 2.5 mg (n = 47), nisoldipine 5 mg (n = 44), or nisoldipine 10 mg (n = 46). Nisoldipine or placebo was administered twice daily for 4 weeks and symptom-limited exercise tests were repeated at 2 and 10-14 hours after the double-blind medication. One hundred sixty-eight patients completed the study and 181 patients were valid for efficacy analysis. Compared with double-blind placebo, there were marginally significant trends toward increases for time to onset of angina for the 10-mg-b.i.d. group (83 versus 108 seconds, p = 0.08), time to 1 mm ST segment depression for the 5-mg-b.i.d. group (54 versus 83 seconds, p = 0.08), and total exercise time for the 5- (30 versus 50 seconds, p = 0.10) and 10-mg-b.i.d. (30 versus 58 seconds, p = 0.06) groups at 2 hours after the dose (peak effect) after 4 weeks of therapy. At 10-14 hours after the dose (trough effect), no differences between placebo and any of the nisoldipine doses on any of the exercise parameters were found after 4 weeks of therapy. A subset analysis of patients who stopped exercise within 10 minutes because of angina of moderate severity during single-blind placebo therapy (n = 123) revealed significant increase in total exercise duration and time to 1 mm ST segment depression at 2 hours after the dose in the 5- and 10-mg-b.i.d. dose groups compared with double-blind placebo (p less than 0.04). No significant trough effects, however, were observed even in this subgroup after any of the doses of nisoldipine. The frequency of anginal attacks decreased by 44%, 41%, 30%, and 41% after twice-daily therapy with 2.5 mg, 5 mg, 10 mg nisoldipine, and placebo groups, respectively (p = NS, nisoldipine versus placebo). The incidence of adverse events (minor and major) was 43.8% in the placebo group and 42.6%, 45.5%, and 56.5% in the nisoldipine 2.5-, 5-, and 10-mg-b.i.d. groups, respectively (p = NS compared with placebo). However, four patients developed unstable angina while on nisoldipine therapy (two in the 2.5-mg, one in the 5-mg, and one in the 10-mg-b.i.d. group) and two patients died suddenly in the nisoldipine 10-mg-b.i.d. group. CONCLUSIONS: Monotherapy with 2.5, 5, and 10 mg nisoldipine twice a day was not superior to placebo therapy in treating patients with angina pectoris, and the 10-mg-b.i.d. therapy resulted in a statistically insignificant but clinically important increase in the incidence of serious adverse events.

Adult↗
PubMed1991

Medical therapy of stable angina pectoris.

This article discusses the three major classes of drugs with somewhat different mechanisms of action that are available for the treatment of angina pectoris. This include nitrates, beta-adrenoreceptor blockers, and calcium-channel blockers.

Adrenergic beta-Antagonists↗
PubMed1990

A multicenter comparison of isradipine and prazosin for treatment of essential hypertension.

Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

Adult↗
PubMed1988

Long-term bepridil monotherapy for angina pectoris.

The long-term efficacy of bepridil as once-a-day monotherapy was studied in 19 men with stable angina pectoris. After 2 weeks of single-blind placebo therapy and a 12-week parallel placebo-controlled, dose-response study, each patient received open-label bepridil. After a dose-titration period of 3 months, patients received bepridil (100 to 400 mg once a day, mean 290 mg) for 24 months. The response to treatment was assessed by patient diaries and serial treadmill exercise testing 24 hours after dose administration, every 3 months. Only 2 patients were released from the study due to therapeutic failure. Compared with placebo, 3 months of bepridil therapy resulted in a significant reduction in the weekly frequency of angina from 10.3 +/- 9.1 to 1.8 +/- 3.5 (p less than 0.002) and nitroglycerin consumption from 5.0 +/- 5.4 to 1.4 +/- 2.3 (p less than 0.01). In addition, there was a simultaneous significant increase in the walking time to angina from 5.2 +/- 2.3 to 7.9 +/- 2.6 minutes (p less than 0.001) and total exercise time from 7.1 +/- 2.2 to 8.8 +/- 1.9 minutes (p less than 0.001). These favorable effects were sustained throughout the 24 months of the study. Although resting QTc interval was prolonged by 36 to 42 ms (p less than 0.001) during bepridil therapy, ventricular dysrhythmias were not observed immediately before or during exercise testing and were not manifested by symptoms. Neurologic and gastrointestinal side effects of mild to moderate severity were observed, but none required discontinuation of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Noninvasive evaluation of aortic stenosis severity utilizing Doppler ultrasound and electrical bioimpedance.

Aortic valve area was calculated noninvasively in 30 patients with aortic stenosis undergoing cardiac catheterization. Continuous wave Doppler ultrasound was employed to estimate the mean transvalvular pressure gradient. The mean left ventricular outflow tract flow velocity and cross-sectional area were determined from pulsed Doppler and two-dimensional ultrasound recordings. Electrical transthoracic bioimpedance cardiography performed simultaneously with the ultrasonic study and repeated at the time of catheterization measured heart rate, systolic ejection period and cardiac output. These noninvasive data permitted calculation of aortic valve area using the Gorlin equation (range 0.21 to 1.75 cm2) and the continuity equation (range 0.25 to 1.9 cm2). Subsequent cardiac catheterization showed valve area to range from 0.21 to 1.75 cm2. The mean Doppler pressure gradient estimate was highly predictive of the gradient measured at catheterization (r = +0.92, SEE = 10). Bioimpedance cardiac output measurements agreed with the average of Fick and indicator dye estimates (r = +0.90, SEE = 0.52). Valve area estimates utilizing continuous wave Doppler ultrasound and electrical bioimpedance were superior (r = +0.91, SEE = 0.12) to estimates obtained utilizing the continuity equation (r = +0.76, SEE = 0.29) and were more reliable in the detection of patients with severe aortic stenosis (9 of 11 versus 6 of 11). These data show that 1) electrical bioimpedance methods accurately estimate cardiac output in the presence of aortic stenosis; 2) the hybridized bioimpedance-Doppler ultrasound method yields accurate estimates of aortic stenosis area; and 3) the speed, accuracy and cost-effectiveness of aortic stenosis evaluation may be improved by this hybridized approach.

Adult↗
PubMed1988

Effects of 1-epinephrine on hemodynamics and cardiac function in coronary disease: dose-response studies.

To assess the effects of elevated epinephrine levels on cardiovascular performance in patients with coronary artery disease (CAD), epinephrine was infused intravenously into eight patients with normal coronary anatomy and 22 patients with CAD at dose rates of 0.06, 0.12, 0.18, and 0.24 micrograms/kg/min. Hemodynamic responses to epinephrine were not significantly different between the two groups. However, contractility increased significantly more (P less than 0.05) and end-systolic volume decreased significantly more (P less than 0.025) in normal subjects than in those with CAD. Plasma norepinephrine concentrations increased significantly (P less than 0.05) at 0.24 micrograms/kg/min epinephrine, indicating activation of sympathetic nervous system. Epinephrine ischemic thresholds ranged from 652 to 3362 pg/ml. Patients with CAD compared with normal subjects had more frequent ventricular arrhythmias (55% vs. 25%), chest pain (50% vs. 13%), and ischemic ECG changes (73% vs. 13%). These results indicate that although epinephrine induced myocardial ischemia in CAD, hemodynamics and ventricular pump function were maintained.

Adult↗
PubMed1988

Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates.

Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate are, in various formulations, available for clinical use. The pharmacokinetics of glyceryl trinitrate are complex and only 1% of the drug administered orally can be detected in the plasma due to a pronounced arteriovenous concentration gradient, hydrolysis in the blood, and rapid denitration in the liver. There is a poor and usually transient correlation between plasma concentrations and therapeutic effects, due in part to the complex pharmacokinetics of glyceryl trinitrate, but primarily due to development of tolerance during continuous administration, either via the intravenous or cutaneous route. Isosorbide dinitrate kinetics are complicated by its extensive metabolism into 2- and 5-mononitrates, which are pharmacologically active, and which also accumulate more than the parent drug during long term treatment. These facts, combined with development of tolerance during long term therapy, preclude the establishment of a concentration-response relationship. Isosorbide-5-mononitrate has ideal and dose-linear kinetics and is nearly 100% bioavailable after oral administration. However, tolerance develops during long term therapy, and therefore a relationship between plasma concentrations and clinical effects cannot be established. On the basis of available data, plasma concentrations of various nitrates do not reliably predict clinical effects.

Angina Pectoris↗
PubMed1987

Usefulness of twice-daily isosorbide-5-mononitrate in preventing development of tolerance in angina pectoris.

Development of tolerance to nitrates during long-term therapy is a major concern. It has been suggested that isosorbide-5-mononitrate (IS-5MN), an active metabolite of isosorbide dinitrate, administered twice daily 12 hours apart does not lead to development of tolerance. The duration of effects of IS-5MN at a dose of 20 and 40 mg and of placebo was studied in patients with angina pectoris who responded to nitrates after the first dose (n = 12) and after 1 week of twice-daily therapy (n = 9). The study was double-blind, randomized and crossover in design. Compared with placebo values, after the first dose of 20 and 40 mg IS-5MN, exercise duration was higher at 2 hours (p less than 0.001) and 6 hours (p less than 0.02). After 1 week of twice-daily therapy at these doses, exercise duration increased at 2 hours (p less than 0.05) but not at 6 or 10 hours after the dose. After the first dose of 20 and 40 mg IS-5MN, standing systolic blood pressure decreased at 2 hours (p less than 0.02). Blood pressure did not change significantly after chronic therapy. Tolerance to antianginal effects during twice-daily therapy with 20 and 40 mg of IS-5MN developed despite higher plasma IS-5MN concentrations at 2 and 6 hours during twice-daily therapy than after the first dose. The tolerance during twice-daily therapy with IS-5MN was characterized by a reduced peak effect at 2 hours and shortened duration of action compared with first-dose effects.

Aged↗