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Biomedical subjects

S M Mohiuddin

Publications and source records attributed to S M Mohiuddin.

At least 37 records · Page 2Linked to original sources

Randomized, controlled trial of transdermal clonidine for smoking cessation.

OBJECTIVE: To determine the efficacy and safety of clonidine versus placebo in smoking cessation. DESIGN: Single-center, randomized, double-blind, parallel-design comparison of transdermal clonidine with behavior modification, transdermal clonidine without behavior modification, placebo with behavior modification, and placebo without behavior modification. SETTING: Outpatient, university-based ambulatory care facility. PATIENTS: One hundred fifty generally healthy, highly nicotine-dependent cigarette smokers. INTERVENTION: Clonidine was given as the transdermal patch initiated 72 hours prior to smoking-cessation attempts and continued for six weeks thereafter. Clonidine was given at a dose of 0.2 mg/d for patients weighing more than 150 pounds (> 67.5 kg) and at a dose of 0.1 mg/d for patients weighing less than 150 pounds (< 67.5 kg). Behavior modification consisted of a total of 12 one-hour structured group training sessions. Patients not receiving behavior modification received printed material, which included the "Help Quit Kit" and the "I Quit Kit" from the American Cancer Society. MAIN OUTCOME MEASURES: Smoking-cessation rates were assessed at 6, 12, 24, and 52 weeks of follow-up. In addition, adverse reactions to clonidine or placebo were evaluated. RESULTS: Clonidine with behavior modification was statistically superior to the other three treatment groups but only at 6 weeks of follow-up. There were no differences in smoking-cessation rates among any of the treatment groups at any other follow-up intervals. Patients receiving behavior modification, regardless of whether they received clonidine, had better quit rates than patients not receiving behavior modification at all follow-up times except 52 weeks. Women receiving clonidine had significantly better quit rates than men receiving clonidine at all follow-up visits. Clonidine was associated with a significantly higher incidence of adverse effects than placebo (52 vs. 11 percent). However, the number of smokers withdrawing from the study was not greater with clonidine compared with placebo (9 vs. 7 percent, respectively). CONCLUSIONS: Clonidine is probably not effective as a pharmacologic adjunct to behavior modification in smoking cessation. It may have a potential role in women smokers who do not respond to or cannot tolerate more traditional smoking-cessation therapies.

Administration, Cutaneous↗

Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias.

Sematilide, a close structural analog of N-acetylprocainamide, prolongs cardiac action potentials in vitro, whereas it does not depress maximum action potential upstroke slope, a "class III" action. This report outlines an evaluation of the clinical pharmacologic actions of sematilide in 14 patients with chronic high-frequency nonsustained ventricular arrhythmias. In all, 36 intravenous infusions (range 0.15 to 1.5 mg/kg over 15 minutes) were administered in a dose-ranging, placebo-controlled study design. Sematilide prolonged rate-corrected QT (QTc) in a dose- and concentration-related fashion, did not alter PR or QRS, and slowed heart rate at high concentrations (greater than or equal to 2 micrograms/ml). The relations between dose and total area under the time-concentration curve, dose and peak plasma concentration, and peak plasma concentration and increase in QTc were linear (r = 0.66 to 0.92; p less than 0.001). QTc increases of approximately equal to 25% were seen at plasma concentrations of approximately equal to 2.0 micrograms/ml. The mean elimination half-life (+/- SD) was 3.6 +/- 0.8 hours, and most of a dose (77 +/- 13%) was recovered unchanged in the urine. Plasma concentrations greater than or equal to 0.8 micrograms/ml suppressed arrhythmias (5 patients) or aggravated them (3), including 1 patient who needed cardioversion for an episode of torsades de pointes (2.7 micrograms/ml). Thus, sematilide exerts class III actions in patients. Further studies to evaluate the role of this antiarrhythmic mode of action should be conducted at doses designed to limit QTc increases.

Anti-Arrhythmia Agents↗

Impact of chronic oral H2-antagonist therapy on left ventricular systolic function and exercise capacity.

It has been suggested that H2-antagonists may adversely affect left ventricular systolic function. To assess the effects of cimetidine, famotidine, and ranitidine on exercise capacity and left ventricular systolic function, the authors conducted a randomized, double-blind, four-way crossover study in 15 healthy male volunteers with placebo control. Each subject underwent a maximal upright treadmill exercise test, aerobic metabolic assessment, and two-dimensional stress echocardiography on six separate occasions. The initial two treadmill exercise tests with aerobic metabolic assessment and stress echocardiography were performed to minimize the learning effect. In the final four evaluations, subjects were randomized to receive 7 days of oral treatment with cimetidine 400 mg twice daily, famotidine 40 mg daily, ranitidine 150 mg twice daily, and placebo. A comparison of exercise tests, aerobic metabolic assessment, and stress echocardiography results found no significant differences between any of the H2-antagonists and placebo. In addition, there were no significant differences in test results between cimetidine, famotidine, and ranitidine. Specifically, exercise treadmill time, maximal oxygen consumption, respiratory quotient, maximal exercise systolic and diastolic blood pressure, maximal exercise heart rate, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and ejection fraction were not different between treatments. The authors conclude that 7 days of oral treatment with cimetidine, famotidine, or ranitidine has no deleterious effect on exercise capacity or left ventricular systolic function in healthy subjects.

Administration, Oral↗

Impact of food on the bioavailability of encainide.

The bioavailability of drugs that undergo extensive presystemic hepatic metabolism may be increased by concomitant ingestion with food. The effect of food on the bioavailability of encainide, a class IC antiarrhythmic agent, was evaluated in 14 healthy subjects in this randomized crossover study. The subjects received encainide 35 mg every 8 hours for 7 days and were randomized to receive their test dose of encainide with food or after an overnight fast. Encainide area-under-the-concentration versus time curve (AUCs) were detectable in 3 of 14 subjects after fasting and in 7 of 14 after feeding. Although food increased the mean encainide AUC by more than threefold, this increase did not reach statistical significance because of the large number of subjects with indeterminate encainide AUCs. Food did significantly increase the AUC of O-demethyl-encainide (ODE), but not the AUC of methoxy-O-demethyl-encainide (MODE). Despite the increase in ODE AUC, no significant effect on the surface electrocardiogram 2 hours after dose administration could be detected. Food may increase the bioavailability of encainide and one of its active metabolites (ODE). The clinical relevance of this pharmacodynamic effect warrants further evaluation.

Adult↗

Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism.

There is no universally accepted approach to the initiation of systemic anticoagulant therapy. In an open, randomized study, two anticoagulant regimens that differed only in the timing of warfarin therapy after the start of heparin were compared. We randomized 119 patients with acute thromboembolic events to receive warfarin either within 48 hours of the start of heparin (early group, n = 63) or 96 hours or later after the start of heparin (late group, n = 56). Heparin was given as a 5000 IU bolus as a constant infusion titrated to maintain the activated partial thromboplastin time at 1.5 to 2 times control values. Warfarin was started at 10 mg daily for 3 days and the dose was titrated to maintain the prothrombin time at 1.2 to 1.5 times control values. There were no significant differences between the early and late warfarin groups with regard to age, sex, indication for anticoagulation, heparin dose, mean activated partial thromboplastin time during heparin, warfarin dose at discharge, length of warfarin therapy before discharge, bleeding, recurrent thromboembolic events, or mortality rates. Time to the start of warfarin after heparin was 31 hours and 108 hours in the early and late groups, respectively. Length of hospitalization, hospital costs, and the incidence of heparin-induced infusion phlebitis and thrombocytopenia were significantly less in the early group compared with the late group. Early initiation of warfarin after heparin is safer, less expensive, and as effective as the late initiation of warfarin.

Aged↗

Comparison of adenosine and exercise thallium-201 single-photon emission computed tomography (SPECT) myocardial perfusion imaging. The GE SPECT Multicenter Adenosine Study Group.

Pharmacologic stress with dipyridamole has provided useful diagnostic, as well as prognostic, information in patients undergoing thallium-201 myocardial perfusion imaging. With its ultrashort half-life and a potent and consistent vasodilator effect, adenosine may be the coronary vasodilator of choice with myocardial perfusion imaging. Fifty-one healthy subjects and 93 patients with suspected coronary artery disease constituted the study group. In this multicenter study the comparative safety and diagnostic efficacy of single-photon emission computed tomography (SPECT) thallium imaging during adenosine-induced coronary hyperemia was compared with exercise treadmill stress. There was a mean increase in heart rate of 37% and a mean decrease in diastolic blood pressure of 5% during the adenosine infusion of 140 micrograms/kg per min for 6 min. Adenosine infusion was well tolerated in 95% of the subjects. Side effects requiring intervention occurred in seven subjects (5%). None of the subjects experienced a life-threatening complication. The sensitivity, specificity and predictive accuracy for detection of coronary artery disease with use of quantitative analysis was 83%, 87% and 84% for adenosine SPECT and 82%, 80% and 81% for exercise SPECT studies, respectively. Most false negative results with adenosine, as well as exercise SPECT studies, occurred in patients with single-vessel disease. The first-order concordance (no defect vs. defect) and second-order concordance (no defect vs. irreversible vs. reversible defect) was 89% and 78% between the two studies, respectively. Thus, the results of adenosine SPECT imaging are highly concordant with exercise SPECT thallium imaging. Adenosine SPECT thallium imaging provides a safe and highly accurate imaging mode for the detection of coronary artery disease.

Adenosine↗

Comparative pharmacodynamics of intravenous lidocaine in patients with acute and chronic ventricular arrhythmias.

OBJECTIVE: To evaluate the pharmacodynamics of intravenous lidocaine in patients with acute-onset and chronic ventricular arrhythmias. DESIGN: Open-label, pharmacodynamic evaluation. SETTING: Private, university-affiliated, hospital coronary-care unit. PATIENTS: Twenty cardiac patients with acute-onset ventricular ectopy and 20 with chronic ventricular ectopy. INTERVENTIONS: Intravenous lidocaine was administered to all patients as a 1-mg/kg bolus, a 0.5-mg/kg bolus, and a 2.8-mg/min constant infusion for 48 hours. MAIN OUTCOME MEASURES: Changes in ventricular premature beat (VPB) frequency against total treatment period frequency and by an hour-to-hour assessment of changes in VPB frequency compared with total baseline frequencies. Response was defined as greater than or equal to 80 percent total VPB reduction, greater than or equal to 90 percent paired VPB reduction, and total abolition of nonsustained ventricular tachycardia events. RESULTS: A statistically significant difference in the pharmacodynamic effects of lidocaine were observed during the first eight hours of treatment in patients with acute-onset and chronic VPBs. The number of patients with acute-onset VPBs who responded to lidocaine in the first hour of treatment did not change significantly over the remaining hours of treatment. Response to lidocaine was less in patients with chronic VPBs than in patients with acute-onset VPBs. The response rate to lidocaine was significantly less during the first eight hours in patients with chronic VPBs than in patients with acute-onset VPBs. Following eight hours of treatment, the response rates between acute-onset and chronic VPB patients were not significantly different. Mean lidocaine plasma concentrations were not different between the groups. In addition, there were no significant differences in the incidence of adverse effects between the two groups. CONCLUSIONS: The onset of antiarrhythmic effect as measured by suppression of ventricular ectopy is delayed in patients with chronic VPBs compared with patients with acute-onset VPBs. Decisions about lidocaine response in patients with chronic VPBs cannot be made accurately in the first eight hours of therapy.

Acute Disease↗

Thallium-201 myocardial imaging in patients with coronary artery disease: comparison of intravenous adenosine and oral dipyridamole.

OBJECTIVE: To compare thallium-201 (201Tl) myocardial perfusion imaging following intravenous adenosine and oral dipyridamole. DESIGN: Open-label, randomized, comparison. SETTING: Outpatient, university-affiliated clinic. PATIENTS: Fifteen patients with angiographically documented coronary artery disease. INTERVENTIONS: Planar 201Tl myocardial perfusion imaging following both intravenous adenosine 140 micrograms/kg/min for six minutes and oral dipyridamole suspension 300 mg. MAIN OUTCOME MEASURES: A comparison between adenosine and dipyridamole was made in the following areas: concordance in interpretation of 201Tl scintigrams, cardiac and noncardiac 201Tl uptake and clearance, hemodynamic and electrocardiographic changes, and adverse effects. RESULTS: The scintigraphic studies showed perfusion defects in 13 patients (87 percent) after dipyridamole and in 15 patients (100 percent) after adenosine. 201Tl uptake and clearance were quantitated in nine myocardial segments and in four extracardiac segments in each patient. 201Tl uptake was not significantly different between adenosine and dipyridamole studies in most cardiac regions. Extracardiac 201Tl uptake was significantly less in the liver and splanchnic regions following adenosine compared with dipyridamole. 201Tl clearance was not significantly different following adenosine and dipyridamole except in the anterolateral region in the anterior view. Hemodynamic changes following administration of intravenous adenosine and oral dipyridamole were not significantly different. Adverse effects were more common with adenosine than with dipyridamole. Adverse effects with adenosine were transient; however, adverse effects with dipyridamole were prolonged and required reversal with aminophylline in 2 patients. No patients required termination of the adenosine infusion or administration of aminophylline. CONCLUSIONS: These preliminary data suggest that adenosine 201Tl imaging may be a useful alternative to dipyridamole 201Tl imaging. Although adenosine produces more frequent adverse effects, they are generally better tolerated than those associated with dipyridamole.

Adenosine↗

Effect of buspirone on withdrawal symptoms associated with smoking cessation.

BACKGROUND: Preliminary information suggests that buspirone hydrochloride ameliorates symptoms of nicotine withdrawal. In a double-blind, randomized, placebo-controlled trial, we determined the effects of buspirone on the withdrawal symptoms associated with smoking cessation in 40 long-term cigarette smokers. METHODS: Subjects were randomized to 4 weeks of treatment with either buspirone (n = 20) or placebo (n = 20). Subjects were instructed to maintain their usual cigarette intake during the first 21 days of treatment and to cease smoking on day 22 of treatment. Withdrawal symptoms were subjectively rated before and during smoking cessation. RESULTS: Before smoking cessation, there were no significant differences in the intensity of any withdrawal symptom between the buspirone- and placebo-treated subjects, with the exception of a significantly higher rating for drowsiness in the buspirone group. During the smoking cessation period, the ratings for craving, anxiety, irritability, restlessness, and sadness were significantly lower in the buspirone group than the placebo group. There were no significant differences between the groups in their ratings for hunger, inability to concentrate, or drowsiness. Fifteen buspirone-treated subjects and nine placebo-treated subjects were able to abstain from cigarettes during the entire 7-day smoking cessation period. No subject dropped out of the study for perceived drug side effects. Eight buspirone-treated subjects and five placebo-treated subjects reported side effects, all of which were mild. CONCLUSIONS: Buspirone ameliorated most of the short-term withdrawal symptoms associated with smoking cessation. Further controlled studies will be needed to define the benefit in smoking cessation.

Adult↗

Effect of digoxin on ST-segment changes detected by ambulatory electrocardiographic monitoring in healthy subjects.

Digoxin causes false-positive ST depression during exercise stress testing, but it is unknown if digoxin produces ST depression during ambulatory electrocardiographic monitoring. Fifty healthy volunteers underwent both exercise stress testing and ambulatory electrocardiographic monitoring before and after 14 days of digoxin (0.25 mg/day) administration. Significant ST depression was defined as greater than or equal to 1 mm of horizontal or downsloping ST depression 80 ms after the J point lasting for greater than or equal to 60 seconds. During therapy, 13 subjects (26%) had at least 1 episode of ST depression and 5 subjects (10%) had multiple episodes of ST depression detected by ambulatory monitoring. Ten subjects (20%) had ST depression that occurred during exercise that was detected by both stress test and ambulatory monitoring. Three subjects (6%) had ST depression that was detected on the ambulatory recording only at times other than during the stress test. Stratification of demographic and clinical variables did not predict digoxin-induced ST depression. Thus, digoxin causes false-positive ST depression detected by ambulatory monitoring. The incidence is similar to that observed during stress testing, but also occurs at heart rates lower than that achieved during stress tests. Ambulatory electrocardiographic monitoring will be less useful in the noninvasive assessment of coronary artery disease in patients receiving digoxin.

Adult↗

Influence of mexiletine on the pharmacokinetics of theophylline in healthy volunteers.

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two-way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained-release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2 beta, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline-mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0-24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine therapy.

Adult↗

Pharmacokinetic and tolerance evaluation of actisomide, a new antiarrhythmic agent, in healthy volunteers.

The pharmacokinetics and tolerance of actisomide (SC-36602) were determined following intravenous doses of 2.1, 4.2, and 8.4 mg/kg infused over five hours. Plasma concentrations observed in the low-dose group (2.1 mg/kg) were below the assay's limit of detection and were not included in the pharmacokinetic analysis. The following pharmacokinetic parameters were obtained in the medium-dose (4.2 mg/kg) and high-dose (8.4 mg/kg) groups, respectively: peak plasma concentration 4.25 +/- 0.26 and 7.81 +/- 0.31 micrograms/mL; area under the plasma concentration versus time curve 19.79 +/- 2.96 and 39.81 +/- 7.05 h.micrograms/mL; elimination rate constant of the beta phase 0.105 +/- 0.77 and 0.093 +/- 0.009 h(-1), and half-life 8.85 +/- 4.61 and 7.51 +/- 0.69 h. Left ventricular ejection fraction decreased by 10, 11, and 16 percent in the low-, medium-, and high-dose groups, respectively. Heart rate was not altered during the low-dose infusion. At the medium- and high-dose levels, resting peak heart rate increased by 18 and 27 percent, respectively. Systolic and diastolic blood pressures were not significantly changed in any of the dose groups. Changes in electrocardiographic intervals for the three dose groups were not significant except at the highest dose where an average 20 percent increase in the QRS interval was seen. Mild subjective adverse effects (dizziness, taste perversion, and circumoral paresthesia) which did not necessitate discontinuing the infusion occurred in the highest dosage group. Further studies are warranted to more fully characterize the pharmacokinetic profile and therapeutic potential of actisomide.

Adult↗

Changing strategies in the management of chronic congestive heart failure.

Recent studies have more clearly defined the role of drug therapy in patients with chronic congestive heart failure (CHF). Treatment of patients with asymptomatic left ventricular dysfunction (New York Heart Association [NYHA] class I) cannot be recommended at this time. The benefit of prophylactic treatment with angiotensin-converting enzyme inhibitors (ACEIs) or vasodilators in patients at high risk for developing symptomatic CHF is currently being evaluated. Treatment of patients with symptomatic CHF (NYHA class II-IV) should be initiated with a combination of a diuretic, digoxin, and an ACEI. This combination has been shown to reduce the mortality rate in patients with NYHA class II-IV CHF. Patients who remain symptomatic despite treatment with this combination may benefit from the addition of the direct-acting, nonspecific vasodilators--hydralazine and a nitrate. The addition of the nonspecific vasodilators to an ACEI has not been tested in controlled trials. In patients who remain symptomatic despite treatment with diuretics, digoxin, ACEIs, and nonspecific vasodilators, treatment options are not clear. The use of beta-agonists, phosphodiesterase inhibitors, and intermittent fixed-dose, fixed-interval dobutamine should be avoided as these agents are associated with a high mortality rate. Heart transplantation should be considered early in the course of CHF to allow for preservation of other vital organ systems. Unfortunately, heart transplantation is available to only a very small minority of potential transplant candidates.

Angiotensin-Converting Enzyme Inhibitors↗

Efficacy and tolerance of high-dose intravenous amiodarone for recurrent, refractory ventricular tachycardia.

High-dose intravenous amiodarone was given to 35 patients with recurrent life-threatening ventricular tachycardia (VT) refractory to conventional antiarrhythmic agents. Intravenous amiodarone was given as a 5 mg/kg dose over 30 minutes followed by 20 to 30 mg/kg/day as a constant infusion for 5 days. Twenty-two (63%) patients responded to intravenous amiodarone. All 22 responders received oral amiodarone. Thirteen (59%) continue to receive oral amiodarone after an average follow-up of 19 months, 4 (18%) had sudden cardiac death on oral amiodarone, 2 (9%) died while receiving amiodarone, secondary to left ventricular failure, and 3 (14%) discontinued amiodarone because of side effects. Of the 13 (37%) nonresponders, 10 died in the hospital while receiving intravenous amiodarone, secondary to lethal arrhythmia. Three nonresponders were discharged from the hospital; 2 with automatic cardioverter/defibrillators and 1 receiving a combination of antiarrhythmic agents. Serious adverse events occurred in 13 (37%) patients during intravenous amiodarone therapy. These included hypotension in 8 patients, symptomatic bradycardia in 4 patients and sinus arrest with bradycardia and hypotension in 1 patient. Minor side effects occurred in 23 (66%) patients. In conclusion, high dose intravenous amiodarone is effective in most patients with recurrent, sustained VT but is associated with an unacceptably high incidence of serious adverse events. The optimal dose and duration of intravenous amiodarone for patients with recurrent, refractory sustained VT remain unknown.

Administration, Oral↗

Ten-year results with the St. Jude Medical prosthesis.

Although the hemodynamic characteristics and durability of the St. Jude valve prosthesis have been reported, the need for and the degree of anticoagulation in patients who receive these valves remain uncertain. Our 10-year experience with 165 patients (100 men and 65 women, mean age of 58 +/- 13 years), who underwent valve replacement with St. Jude prostheses, is reported. Of the 165 patients, 147 were treated with warfarin. A prothrombin time 1.3 to 1.8 times control (range 15 to 20 seconds) was maintained in 134 patients with single valve and 1.8 to 2 times control (range 20 to 25 seconds) in 13 patients with double valve prostheses. The 10-year actuarial event-free incidence from thromboembolic and hemorrhagic complications was 84 and 95%, respectively. Of the 8 patients receiving antiplatelet therapy alone, 4 had thromboembolic events. Of the 10 patients on neither warfarin nor antiplatelet therapy, 3 had thromboembolic events. The 10-year actuarial event-free incidence from valve failure was 95%. The 10-year actuarial patient survival was 55%. Thus, the St. Jude valve is a safe and reliable prosthesis with acceptable overall long-term performance in patients given a modest anticoagulation regimen. Patients who receive St. Jude prosthetic valves without anticoagulants have a high incidence of thromboembolic events despite therapy with antiplatelet agents.

Adolescent↗

Myocardial uptake and clearance of T1-201 in healthy subjects: comparison of adenosine-induced hyperemia and exercise stress.

Pharmacologic stress testing with dipyridamole is useful in patients undergoing thallium-201 myocardial perfusion scintigraphy who cannot adequately exercise. Because dipyridamole increases coronary blood flow by reducing the metabolism of adenosine, the authors compared the uptake and clearance of T1-201 following exercise stress testing (EST) and resting intravenous infusion of adenosine (AI) in crossover fashion in 20 healthy men. No perfusion defects or areas of redistribution were noted in any of the scans. Mean absolute myocardial T1-201 uptake was 1.3 times greater with AI than with EST. Mean absolute extracardiac uptake was 2.0 times greater with AI. Mean T1-201 myocardial clearance was virtually the same in all AI and EST views. During AI, 70% of the subjects experienced subjective side effects, mean arterial blood pressure decreased by 15%, and heart rate increased by 48%. The effects of adenosine on T1-201 kinetics in the myocardium are similar to those of EST. Adenosine may be useful as a pharmacologic stress agent in patients undergoing T1-201 myocardial perfusion scintigraphy.

Adenosine↗