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The emergence of multidrug-resistant strains of Candida albicans has become a global threat mostly due to co-infection with immune-compromised patients leading to invasive candidiasis. The life-threatening form of the disease can be managed quickly and effectively by drug repurposing. Thus, the study used in silico approaches to evaluate Food and Drug Administration (FDA) approved drugs against three drug targets-TRR1, TOM40, and YHB1. The tertiary structures of three drug targets were modeled, refined, and evaluated for their structural integrity based on PROCHECK, ERRAT, and PROSA. High-throughput virtual screening of FDA-approved drugs (8815), interaction analysis, and energy profiles had revealed that DB01102 (Arbutamine), DB01611 (Hydroxychloroquine), and DB09319 (Carindacillin) exhibited better binding affinity with TRR1, TOM40, and YHB1, respectively. Notably, the molecular dynamic simulation explored that Gln45, Thr119, and Asp288 of TRR1; Thr107 and Ser121 of TOM40; Arg193, Glu213, and Ser228 of YHB1 are crucial residues for stable drug-target interaction. Additionally, it also prioritized Arbutamine-TRR1 as the best drug-target complex based on MM-PBSA (-52.72 kcal/mol), RMSD (2.43 A), and radius of gyration (-21.49 A) analysis. In-depth, PCA results supported the findings of molecular dynamic simulations. Interestingly, the conserved region (>70%) among the TRR1 sequences from pathogenic Candida species indicated the effectiveness of Arbutamine against multiple species of Candida as well. Thus, the study dispenses new insight and enriches the understanding of developing an advanced technique to consider potential antifungals against C. albicans. Nonetheless, a detailed experimental validation is needed to investigate the efficacy of Arbutamin against life-threatening candidiasis.

Nuclear radiology is valuable in assessing pathophysiology of a variety of organ systems. Pharmacologic interventions are often employed in radionuclide imaging to monitor the physiologic changes, which in turn facilitate the diagnosis. Metoclopramide, erythromycin, and cisapride have been used for gastric emptying studies. To overcome false-negative results, cimetidine, pentagastrin, and glucagon have been used in imaging of Meckel diverticula. Pharmacologic intervention with either cholecystokinin-8 or morphine is used primarily for the assessment of diseases of the gallbladder, common bile duct, and sphincter of Oddi. Pharmacologic interventions performed during renography include diuretic administration, angiotensin-converting enzyme inhibition, and aspirin renography. Recombinant thyrotropin can be used in patients with previously treated thyroid carcinoma who require lifelong follow-up for recurrent disease. Cardiac pharmacologic stress agents fall into two categories: coronary vasodilating agents, such as dipyridamole and adenosine, and cardiac positive inotropic agents, such as dobutamine and arbutamine. Measurement of hemodynamic responses to pharmacologic flow augmentation with carbon dioxide or acetazolamide is valuable in cerebrovascular perfusion studies.

OBJECTIVE This study sought to evaluate the safety and efficacy of arbutamine echocardiography in identifying contractile reserve and predicting functional improvement early after acute myocardial infarction (AMI). METHODS AND RESULTS Seventeen patients with first AMI underwent arbutamine echocardiography 48 to 96 hours after AMI. Arbutamine was infused by a closed-loop delivery device. The heart rate slope was 4 beats/min and the heart rate target was 20 beats/min above baseline heart rate. A follow-up echocardiogram was obtained one month later. N-13 ammonia and F-18 FDG positron emission tomographic (PET) imaging were performed 6 +/- 2 days after AMI, before coronary angiography. Mean duration of arbutamine infusion was 6 +/- 2 min. There was no complication and there were no major side effects. Myocardial viability was identified with PET in 15 of the 17 patients. Contractile reserve was observed in 10 patients during arbutamine infusion. Functional recovery was identified in 12 patients. Sensitivity, specificity and accuracy of PET and arbutamine echocardiography for predicting functional recovery were 100%, 40%, 76% and 67%, 80%, 84%, respectively. CONCLUSIONS Low-dose arbutamine stress testing is safe early after AMI. Contractile reserve can be rapidly identified by echocardiography and is specific, but moderately sensitive for predicting reversible dysfunction.

We evaluated the use of adenosine, dobutamine and arbutamine with 99m Tc-tetrofosmin myocardial perfusion imaging. Forty patients under investigation for suspected coronary artery disease were recruited. Each had a resting scan and two separate stress scans on different days, in a randomized cross-over study. Resultant images were blindly reported in 13 segments per scan as normal, reversible or fixed defects. A score was given (0-3) for segmental defect severity. Haemodynamic responses were as expected for each agent. Subjective side effect scores did not differ overall between agents. Adenosine caused a significantly higher incidence of abnormal taste (54%) than dobutamine and arbutamine (both 23%) and a lower incidence of palpitations (25% vs 69% and 54%, respectively), all P < 0.05. Arbutamine caused significantly more chest pain than adenosine (77% vs 46%) though less flushing (35% vs 68%), both P < 0.05. Comparison of the results obtained showed highly significant levels of segmental agreement for visual and semi-quantitative analysis between adenosine and arbutamine, K value and correlation coefficient of 0.78 and 0.86, respectively, dobutamine and adenosine 0.69 and 0.78, and arbutamine and dobutamine 0.75 and 0.78, all P < 0.0001. Adenosine, arbutamine and dobutamine differ in their haemodynamic response and side effect profile but provide highly comparable results during 99m Tc SPECT imaging.

At low doses, dobutamine has potent inotropic, but limited chronotropic, effects—properties that may be necessary for detection of hibernating myocardium. The efficacy of other catecholamines, which have more closely coupled inotropic and chronotropic effects, for the detection of viable myocardium is unknown. This study evaluated the efficacy of arbutamine, a catecholamine with potent chrono-tropic effects, for the detection of viable myocardium in a canine model of hibernating myocardium. Contractile reserve was assessed during stepwise arbutamine infusion (dosages of 2.5, 5, 10, 50, and 100 ng/kg/min) at 3 days (early) and 4 weeks (late) after coronary ligation. Segment shortening, wall thickening, and segmental wall motion were assessed by sonomicrometry and echocardiography. After 4 weeks of occlusion, functional recovery was assessed after revascularization. During the early arbutamine study, the sensitivity for predicting functional recovery was highest at a dosage of 50 ng/kg/min, which also produced tachycardia. The sensitivity was 50% for segment shortening, 20% for wall thickening, and 75% for wall motion score. The late arbutamine study had improved sensitivity. The sensitivity was 100% for segment shortening, 80% for wall thickening, and 90% for wall motion score at a dosage of 50 ng/kg/min. At the late arbutamine study, myocardial perfusion reserve in the ischemic zone of dogs with functional recovery was only mildly reduced (2.0 versus 2.6 in nonischemic zones, P =.53). After coronary occlusion, viable myocardium can be detected with high doses of arbutamine that produce tachycardia. However, the sensitivity of arbutamine stimulation for predicting functional recovery is low early after occlusion, but it is improved by 4 weeks after occlusion with adequate perfusion reserve. (J Am Soc Echocardiogr 2001;14:138-48.)

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols.The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO2 [35.1 (S.D. 3.1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (VD/VT) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml·min-1·beat-1; exercise, 4.7 (1.4) to 16.1 (4.6) ml·min-1·beat-1 (P < 0.0001 compared with baseline); difference between peak responses: P < 0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.

Stress echocardiography is composed of a family of examinations in which various forms of cardiovascular stress are combined with echocardiographic imaging to assist in the diagnosis of coronary artery disease. The various forms of stress that can be employed in conjunction with echocardiography include physical exercise as well as pharmacologic and other nonexercise forms of stress (most common techniques in bold). Exercise Immediate post-treadmill exercise Supine bicycle exercise Upright bicycle exercise Isometric stress Nonexercise Pharmacologic Dobutamine infusion Dipyridamole Adenosine Arbutamine (no longer commercially available) Ergonovine (for evaluation of coronary vasospasm) Nonpharmacologic Direct atrial pacing Esophageal atrial pacing Mental stress Cold pressor Hyperventilation (for evaluation of coronary vasospasm) Each of these modalities has distinct advantages and disadvantages, as is subsequently discussed. The first demonstration of the feasibility of stress echocardiography was in combination with bicycle exercise. 113 Subsequent to the demonstration of feasibility with supine bicycle exercise, several investigators began performing echocardiographic imaging immediately after treadmill exercise. 2,13,56,95 There then followed a literal explosion of studies validating the accuracy of stress echocardiography and more recently highly specialized studies evaluating prognostic factors. Stress echocardiography has now evolved into a successful multimodality technique that is competitive with the more established nuclear medicine techniques and provides distinct advantages and disadvantages. Much of the subsequent growth in stress echocardiography and its clinical acceptance has occurred because of advancements in both imaging technology and digital acquisition systems that allow rapid comparison of rest and stress images in a side-by-side format. The rationale for using echocardiographic imaging at the time of cardiovascular stress is quite simple and relies on the occurrence of ischemia when a threshold of supply-demand mismatch has been reached during cardiovascular stress. When this threshold has been reached, the wall motion abnormalities that develop are then detected with echocardiography. It should be obvious that unless cardiovascular stress is sufficient to provoke ischemia, abnormalities will not become apparent with echocardiographic imaging.

Pharmacologic stress testing has emerged as an important diagnostic tool in the evaluation and management of patients with known or suspected coronary artery disease (CAD) who are unable to adequately perform physical exercise. In addition, pharmacologic stress testing has become an important adjunct in the assessment of selected patients prior to noncardiac surgery and in the evaluation of myocardial viability, hibernation, and valvular heart disease. Unlike exercise stress testing utilizing treadmill or bicycle stress, in which cardiac imaging is not always a necessary adjunct to the stress ECG, the use of a pharmacologic agent to stress the heart usually requires the use of some form of cardiac imaging to detect evidence of myocardial ischemia. Pharmacologic stress testing with vasodilators (dipyridamole and more recently adenosine) has been used extensively in conjunction with nuclear perfusion imaging. 64 More recently, pharmacologic stress echocardiography has become an accepted alternative to exercise testing and to pharmacologic stress testing with nuclear imaging. Many pharmacologic agents have been used for stress testing. Dipyridamole and adenosine are commonly used in Europe in combination with echocardiographic imaging. In the United States, dobutamine is the pharmacologic agent of choice for use with echocardiography. More recently, arbutamine (a synthetic catecholamine developed specifically as a pharmacologic stress agent) has been evaluated in combination with either nuclear perfusion or echocardiographic imaging and has received Food and Drug Administration approval as a pharmacologic stress agent.

Closed-loop arbutamine stress echocardiography has been shown to be safe and effective for detecting coronary artery disease (CAD) using a standardized infusion protocol and centralized core laboratory analyses. However, the accuracy of arbutamine stress echocardiography using local test interpretation has not been previously tested in a large population. The present study reports the safety, sensitivity, and specificity of arbutamine stress echocardiography in a multicenter trial allowing user-defined, nonstandardized protocols and local test interpretation. In all, 1,070 patients underwent arbutamine stress testing at 81 sites. Heart rate increased from 73 ± 13 to 124 ± 15 beats/min, systolic blood pressure from 144 ± 24 to 174 ± 25 mm Hg, and pressure rate product × 10 3 from 10.5 ± 2.8 to 19.6 ± 3.9. Among 1,070 patients, there were only 2 (0.2%) significant adverse events related to arbutamine, both of which resolved completely with appropriate therapy. There were no incidents of ventricular fibrillation, sustained ventricular tachycardia, or death related to testing. Among 242 patients who underwent arbutamine stress echocardiography and diagnostic coronary angiography within 12 weeks, sensitivity and specificity for detection of CAD were 71% (95% confidence interval 64% to 77%) and 67% (95% confidence interval 52% to 80%), respectively. Closed-loop arbutamine stress echocardiography is a safe and effective method for evaluating CAD in clinical practice.

Stress myocardial perfusion imaging has become a mainstay in the noninvasive assessment of patients with known or suspected coronary artery disease for several compelling reasons. Radionuclide myocardial perfusion imaging can be performed using a variety of stressors, including exercise, pharmacologic stress (including dipyridamole, adenosine, dobutamine, and arbutamine), or a combination of exercise and pharmacologic stress. The combination of exercise and pharmacologic stress allows an assessment of the patient's exercise tolerance, to be performed while adequately stressing him or her pharmacologically. Radiopharmaceutical choice has been expanded to include not only thallium-201 but also technetium-based imaging agents such as sestamibi and tetrofosmin. The use of technetium imaging agents has recently been enhanced by the ability to assess ventricular function using gated single-photon emission computed tomography (SPECT) imaging techniques. Finally, the ability to provide prognostic information in the same patients has led to incremental clinical use.

There is a paucity of data comparing the relative merits of inotropic and vasodilator stress Tc-99m sestamibi single-photon emission computed tomography (SPECT) for the detection of coronary artery disease and reversible ischemia. Twenty-seven patients referred for diagnostic coronary arteriography underwent separate day dipyridamole and arbutamine Tc-99m sestamibi SPECT imaging with simultaneous two-dimensional echocardiography. The sensitivity of arbutamine and dipyridamole Tc-99m sestamibi for the detection of coronary artery disease was 100% (21 of 21) and 90% (19 of 21), respectively, with a specificity of 66% (4 of 6) for both. Coronary artery disease was detected in all six patients with single vessel disease by both stress modalities. The sensitivity for prediction of multivessel disease was 66% (10 of 15) for arbutamine and 46% (7 of 15) for dipyridamole stress. Arbutamine stress induced a greater extent and severity of perfusion abnormality at peak stress (peak perfusion score 25±6.2 and 21±5.9 for arbutamine and dipyridamole, respectively, p=0.001) and reversible perfusion defects (difference between peak stress and rest scores 8.8±5.5 and 5.2±4.4 for arbutamine and dipyridamole, respectively, p=0.001). Furthermore a significantly higher percentage of reversible defects induced by arbutamine stress was associated with wall thickening abnormality on simultaneous echocardiography, which is a more specific marker of myocardial ischemia (88% and 24% for arbutamine and dipyridamole, respectively, p=0.002). Inotropic stress may be superior to vasodilators for the determination of the extent and severity of myocardial involvement and reversible ischemia by Tc-99m sestamibi SPECT.

Arbutamine, a new sympathomimetic compound, appears to elicit a more balanced inotropic and chronotropic response than dobutamine, currently used as a pharmacologic stress agent. The present study was performed to compare standard dobutamine stress testing with arbutamine for the detection of myocardial ischemia with technetium (Tc)-99m sestamibi tomographic imaging and 2-dimensional echocardiography in patients with coronary artery disease. Twenty-six patients with evidence of coronary artery disease underwent dobutamine infusion of 5 to 40 microg/kg/min in 3-minute stages. On a separate day, arbutamine was administered by an automated, computerized, closed-loop device monitoring both heart rate and blood pressure. Both infusions were terminated upon achievement of target heart rate, completion of maximal infusion dose (dobutamine), heart rate saturation (arbutamine), or standard clinical end points. Tc-99m sestamibi was injected before termination of both infusions followed by tomographic myocardial perfusion imaging, whereas echocardiography was performed at baseline and throughout the infusions. There were no significant differences in maximal heart rate, blood pressure, and rate-pressure product as well as in the development of anginal symptoms or electrocardiographic changes during both infusions. The location and severity of myocardial perfusion defects and echocardiographic wall motion abnormalities were similar between both agents. It is concluded that arbutamine produces similar imaging results compared with standard dobutamine stress with both Tc-99m sestamibi single-photon emission computed tomographic myocardial perfusion imaging and 2-dimensional echocardiography.

Background Arbutamine is a new synthetic catecholamine developed specifically for pharmacologic stress testing.

The diagnosis of coronary artery disease (CAD) is an important task in the management of cardiology patients. Recently, the use of pharmacological stress testing has become available as an alternative to exercise stress testing (ETT). A new system (device-drug combination) was developed specifically for the diagnosis of coronary artery disease. The system uses a novel catecholamine, arbutamine, which is infused intravenously to increase heart rate (HR) and cardiac contractility in order to evoke signs of ischemia. The development of a closed-loop control algorithm for the delivery of this drug and a pharmacodynamic (PD) model representing the HR response to arbutamine infusions are presented. Model parameters are estimated from clinical data on normal volunteers and patients. Based on this mathematical model, a rule-based control algorithm is designed. The structure of the control algorithm is discussed and testing of the algorithm based on simulations and animal and human trials are summarized. Results from clinical trials shows that the algorithm controls the HR increase according to a selected trajectory. The automated delivery of the drug can provide the cardiologist with an efficient, effective, and safe method for administering a pharmacological stress test.

Zusammenfassung Ziel: Der neue Beta-adrenerge Rezeptoren-Agonist Arbutamin (GenESA®, Gensia Europe Ltd., Berkshire, England) wurde speziell für den pharmakologischen Streß zum Nachweis einer koronaren Herzerkrankung entwickelt und stellt damit auch für die Belastungsmyokardszintigraphie eine Option dar. Die pharmakologische Wirkung kann im Vergleich zum Vasodilatator Dipyridamol anhand der Ganzkörper-Aktivitätsverteilung nach Applikation von Tc-99m-Sestamibi bestimmt werden. Methoden: Untersucht wurden 9 Patienten nach Applikation von Tc-99m-Sestamibi unter Ruhebedingung, nach Steigerung der myokardialen Perfusion durch Infusion von Arbutamin und unter maximaler Vasodilatation durch Infusion von Dipyridamol. Ergebnisse: Nach Gabe von Arbutamin bestand eine szintigraphisch meßbare verminderte Radiotracereinlagerung in der unteren Extremität. Gegenüber Dipyridamol war die myokardiale Akkumulation von Tc-99m-Sestamibi trotzdem vermindert, was sich neben dem relativen Anteil des Herzens an der Ganzkörperaktivität (2,1% ± 0,5% gegenüber 2,4% ± 0,4%, p

Successful scintigraphic imaging of coronary artery stenosis is dependent on detecting regional differences (nonhomogeneous distribution) in coronary blood flow that can be induced by physiologic or pharmacologic stress. Table 1 represents a summary of major pharmacologic responses of the heart to the four agents discussed above. Both adenosine and dipyridamole produce superior coronary vasodilation and tend to be preferred for use in single-photon emission computed tomography, whereas dobutamine and arbutamine provoke a marked ischemic response and tend to be preferred for use in echocardiography. Which agent employed remains a judgment of the physician based on known side effects of these agents, the patient's ability to tolerate these side effects, and the nature of the test desired.

Exercise myocardial perfusion imaging and exercise echocardiography have been applied widely for diagnosis and risk stratification of patients with known or suspected coronary artery disease. The accuracy of these evaluations depends upon the ability of the patient to achieve maximal exercise (>85% of age-predicted maximal heart rate). In patients unable to exercise or with a limited capacity to exercise maximally, pharmacologic stress imaging is a safe and effective alternative to exercise stress imaging. Pharmacologic stress is also indicated in patients with resting or exercise-induced left bundle branch block. Vasodilator stress with dipyridamole or adenosine, as well as catecholamine stimulation with dobutamine or preliminarily with arbutamine, provides diagnostic and prognostic information that appears to be equivalent to that achieved with exercise imaging. In addition, low dose catecholamine infusion during echocardiography to assess inotropic reserve is valuable in identifying viable myocardium in patients with left ventricular dysfunction and appears to assess viability with an accuracy that approaches that of nuclear cardiology methods. Hence, pharmacologic stress imaging, like exercise stress imaging, has important implications regarding patient outcome, patient management, and selection of patients for interventional therapy.

Objectives. This study sought to determine the efficacy and safety of arbutamine echocardiography in inducing myocardial ischemia and detecting coronary artery disease. Background. Exercise and pharmacologic stress echocardiography are clinically accepted techniques for detecting coronary artery disease. Arbutamine is a new synthetic beta-adrenoceptor agonist developed specifically as a stress agent. Arbutamine is delivered by a new computerized drug delivery device that adjusts the rate of drug infusion according to the patient's heart rate response during stress testing. Methods. The sensitivity of arbutamine echocardiography was determined in 143 patients who had coronary artery disease documented by coronary angiography. A subset of these patients (n = 114) also underwent exercise echocardiography. The specificity, or normalcy, of arbutamine echocardiography was determined in 54 patients considered to have a low likelihood of coronary artery disease. Results. Among those patients who had both stress test results, the incidence of inducing myocardial ischemia (new or worsening wall motion abnormalities) was 79% (95% confidence interval [ci]69% to 86%, n = 98) for arbutamine and 77% (95% CI 67% to 85%, n = 98) for exercise echocardiography. The sensitivity of detecting coronary artery disease (ischemia or rest wall motion abnormality) was 87% (95% CI 79% to 93%, n = 101) for arbutamine and 83% (95% CI 74% to 90%, n = 101) for exercise echocardiography. The specificity (normalcy) of arbutamine echocardiography was 96% (95% CI 87% to 100%, n = 52). Arbutamine was well tolerated, and there were no serious adverse events. Conclusions. Arbutamine echocardiography is an effective and safe pharmacologic stress test technique for diagnosing or excluding the presence of coronary artery disease. The ability of arbutamine stress to induce myocardial ischemia, detectable by echocardiography, was comparable to that for exercise.

Objectives. This study sought to evaluate the efficacy and safety of arbutamine when used in conjunction with thallium-201 single-photon emission computed tomography (SPECT) in a multicenter trial and to compare arbutamine stress and treadmill exercise thallium-201 SPECT for diagnostic sensitivity and myocardial perfusion pattern. Background. Arbutamine is a potent beta-agonist developed specifically for pharmacologic stress testing. Methods. Arbutamine was administered by a novel computerized closed-loop device that measures heart rate and adjusts arbutamine infusion to achieve a selected rate of heart rate increase toward a predetermined limit. The cohort included 184 patients who underwent arbutamine stress testing, of whom 122 (catheterization group) had angiographically defined coronary artery disease (≥50% diameter stenosis of a major coronary artery), and 62 had a low pretest likelihood of coronary artery disease (low likelihood group). A subset of 69 patients from the catheterization group underwent both arbutamine and exercise stress testing. Results. Hemodynamic responses during arbutamine and exercise stress testing demonstrated no significant difference in percent increase in heart rate (81% vs. 76%) or systolic blood pressure (26% vs. 30%). The sensitivity for detecting coronary artery disease (≥50% stenosis) using arbutamine thallium-201 SPECT was 87% (95% for detecting ≥70% stenoses), and the normalcy rate in the low likelihood group was 90%. In patients completing both arbutamine and exercise stress testing, thallium-201 SPECT sensitivity for detecting coronary artery disease (≥50% stenosis) was 94% and 97% (p = NS), respectively. Furthermore, SPECT segmental visual score agreement (defect vs. no defect) showed a concordance of 92% between arbutamine and exercise results (kappa 0.80, p Conclusions. Arbutamine, administered by a closed-loop feedback system was shown to be a safe and effective pharmacologic stress agent. Arbutamine stress thallium-201 SPECT appears to be accurate for the diagnosis of coronary artery disease with a diagnostic efficacy similar to that of treadmill exercise thallium-201 studies.

This study evaluated the efficacy of computer-controlled closed-loop delivery of a new synthetic catecholamine, arbutamine, when given to induce myocardial ischemia detected by electrocardiography and echocardiography with a high (10 beats/min/min) and low (6 beats/min/min) rate of increase in heart rate (heart rate slope) in 70 patients with coronary artery disease. The electrocardiographic sensitivity for the detection of myocardial ischemia was 52% for the low slope and 51% for the high slope. The corresponding figures for echocardiographic sensitivity were 83% and 79% for the low and high slopes, respectively. There were no significant differences in changes from baseline to maximum in pharmacodynamic variables, although the mean times to reach maximum heart rate and systolic blood pressure were 1.4 minutes shorter (p = 0.001) and 3.7 minutes shorter (p < 0.05), respectively, for the high-slope regimen. The duration of the infusion was shorter (p < 0.001) for the high slope. In this study, closed-loop arbutamine administration was effective and safe in the detection of coronary artery disease for both heart rate slope regimens.

Arbutamine, 1,2-Benzenediol,4-[1-hydroxy-2-[[4-(4-hydroxyphenyl)butyl[amino]ethyl]rsqb;rsqb; hydrochloride, (R), is a new catecholamine being developed as a pharmacologic stress agent for the diagnosis of coronary artery disease and myocardial ischemia. The pharmacology of arbutamine was studied in vitro using receptor binding assays and functional bioassays of α- and β-adrenoceptor activity, and in vivo using the hemodynamic responses to intravenous infusion in anesthetized and conscious dogs. In isolated membranes, receptor binding studies demonstrated Ki values of 196 ± 12 nM and 147 ± 11 nM for β1- and β2-adrenoceptors, and 265 ± 4 nM and 867 ± 40 nM for α1- and β2-adrenoceptors, suggesting that arbutamine is a mixed β1+2-adrenoceptor agonist with significant affinity for β1-adrenoceptors. This was supported by in vitro bioassay data, where arbutamine increased spontaneous atrial rate (β1-activity, ED50 = 16 ± 6 nM), relaxed isolated tracheal rings (β2-activity, ED50 = 13 ± 5 nM), and contracted aortic rings (α-activity, ED50 = 430 ± 80 nM), indicating 25–30-fold selectivity for β-adrenoceptor activation. In conscious or anethetized dogs, arbutamine elicited dose-dependent increases in heart rate and LV dP/dt with little fall in mean arterial pressure. The data demonstrate that arbutamine exhibits similar degrees of intropic and chronotropic activity, while eliciting less peripheral vasodialation than isoproteronal and less inotropic activity than dobutamine. Moreover, there was rapid termination of the tachycardia, as heart rate resolved to 50% of the maximal effect within 7.2 ± 1.1 min following arbutamine, compared to 5.5 ± 1.0 min following isoproterenol and 5.9 ± 1.4 min following dobutamine. This hemodynamic profile and rapid pharmacodynamic offset makes arbutamine ideally suited for use as a pharmacologic stress agent.

Objectives . The present study was performed to determine the mechanisms for catecholamine-induced wall motion abnormalities and to compare the diagnostic efficacy of two catecholamines: arbutamine and dobutamine. Background . Catecholamine stress echocardiography is used to induce regional wall motion abnormalities for the detection of coronary artery disease, but the mechanism by which these abnormalities occur is unknown. Methods . Ten pigs were instrumented with left circumflex coronary artery ameroid constrictors, sonomicrometers to measure transmural wall thickening in the left circumflex (ischemic) and left anterior descending (control) coronary artery beds and a pressure gauge to measure left ventricular pressure and its first derivative (dP/dt). Myocardial blood flow was measured by microspheres. Results . At 38 ± 6 days (mean ± SEM) after surgery, percent wall thickening was normal at rest in both beds but abnormal in the left circumflex coronary artery bed during atrial pacing. These findings were associated with reduced myocardial blood flow in the ischemic bed during atrial pacing. Dobutamine infusion increased percent wall thickening, with no differences between the two beds (p = 0.63). In contrast, arbutamine infusion increased percent wall thickening only in the nonischemic bed, with no effect on percent wall thickening in the ischemic bed (p s 0.03). Although the endocardial/epicardial blood flow ratio tended to be reduced in the left circumflex artery bed during catecholamine infusion (p = 0.07), both agents were similar in this effect. Despite differences in function between the beds, there was no difference in transmural myocardial blood flow between the two beds during catecholamine infusion. When examined at matched metabolic demands, arbutamine elicited greater differences in percent wall thickening than dobutamine between the two beds (p Conclusions . Arbutamine was able to provoke regional differences in fonction in a manner superior to dobutamine. This occurred independently of altered transmural myocardial blood flow or differences in hemodynamic effects between the agents. Differences in their inotropic properties may be important in explaining their different effects on ischemic myocardium.

Pharmacologic stress testing may be used in the diagnosis of coronary artery disease and risk assessment. The stress agents may be divided into those that produce primary coronary vasodilation (dipyridamole, adenosine, or adenosine triphosphate) and those that produce secondary vasodilation as a result of increase in myocardial oxygen demand (dobutamine and arbutamine). Assessment of myocardial perfusion and function can be made by single-photon imaging, positron emission tomography, two-dimensional echocardiography, magnetic resonance imaging, and contrast angiography. For assessment of myocardial perfusion, either thallium 201-labeled or technetium-labeled perfusion imaging agents may be used. This article will focus on the mechanisms of action, hemodynamic responses, and results of pharmacologic imaging in detecting coronary artery disease. The use of pharmacologic stress testing in risk assessment will be discussed in a separate article.

[reaction: see text] Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported. Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the beta-receptor agonists (-)-denopamine and (-)-arbutamine.

[reaction: see text] Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported. Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the beta-receptor agonists (-)-denopamine and (-)-arbutamine.

The use of the isolated perfused porcine skin flap (IPPSF), an alternative in vitro animal model, to predict the profile of the concentration of arbutamine in plasma samples from humans after transdermal iontophoretic administration of this novel catecholamine is described. The strategy involved administering the drug in the IPPSF (n = 8) and assaying concentrations of drug in the venous efflux versus time (IPPSF venous efflux profile). Intravenous infusion (n = 7) and transdermal studies (n = 32) were also conducted in humans. The IPPSF profile was then used as an input into an intravenous pharmacokinetic model obtained from the human experiments to predict the profile of concentration of drug in plasma versus time (plasma concentration‐time profile) seen after iontophoretic administration. The IPPSF profiles were denormalized according to the parameters used in the human studies (i.e., multiplied by in vivo concentration, electrode area, current, and dosing time). For two different sets of iontophoretic dosing conditions, the concentration‐time profiles that were predicted on the basis of the IPPSF study were compared with those seen after delivery to humans.

Stress echocardiography with dobutamine infusion for detection of coronary artery disease is a potential alternative to exercise stress testing with some theoretic advantages. Fifty patients who were not receiving cardioactive medication were prospectively studied with two-dimensional echocardiography and 12-lead electrocardiography (ECG) during incremental dobutamine infusion (5, 10, 15 and 20 micrograms/kg body weight per min, each dose for 8 min). Images were analyzed by using an 11-segment left ventricular model. All patients underwent correlative exercise ECG and coronary angiography, which revealed normal coronary arteries in 14 and significant disease (greater than or equal to 70% diameter stenosis) in 36. Peak rate-pressure product during dobutamine infusion was 18,845 +/- 4,156 versus 23,740 +/- 6,158 mm Hg/min on exercise (p less than 0.01). Interobserver concordance for wall motion analysis was good (kappa coefficient = 0.77). The use of baseline (n = 14) or reversible (n = 24) regional asynergy to define an abnormal dobutamine echocardiogram resulted in a sensitivity for detecting coronary artery disease of 78% and a specificity of 93%. Corresponding data for the dobutamine ECG were 47% and 71% and for the exercise ECG were 72% and 71%, respectively. The development of new mitral regurgitation on Doppler color flow imaging (n = 4) improved sensitivity to 81% without loss of specificity. Inducible asynergy or new mitral regurgitation was observed in 6 (50%) of 12 patients with single-, 6 (60%) of 10 with double- and 12 (86%) of 14 with triple-vessel disease. The site of transient asynergy provided additional localizing information. Exercise duration and time to diagnostic ST segment shift were shorter in patients with coronary artery disease with versus those without echocardiographic evidence of ischemia (both p less than 0.05). Side effects during dobutamine infusion were mild and short-lived. Dobutamine stress echocardiography is well tolerated, is useful for detection and assessment of coronary artery disease and is applicable to patients unable to exercise.

BACKGROUND Two-dimensional echocardiography performed during dobutamine infusion has been proposed as a potentially useful method for detecting coronary artery disease. However, the safety and diagnostic value of dobutamine stress echocardiography has not been established. METHODS AND RESULTS In this study, echocardiograms were recorded during step-wise infusion of dobutamine to a maximum dose of 30 micrograms/kg/min in 103 patients who also underwent quantitative coronary angiography. The echocardiograms were digitally stored and displayed in a format that allowed simultaneous analysis of rest and stress images. Development of a new abnormality in regional function was used as an early end point for the dobutamine infusion. No patient had a symptomatic arrhythmia or complications from stress-induced ischemia. Significant coronary artery disease (greater than or equal to 50% diameter stenosis) was present in 35 of 55 patients who had normal echocardiograms at rest. The sensitivity and specificity of dobutamine-induced wall motion abnormalities for coronary artery disease was 89% (31 of 35) and 85% (17 of 20), respectively. The sensitivity was 81% (17 of 21) in those with one-vessel disease and 100% (14 of 14) in those with multivessel or left main disease. Forty-one of 48 patients with abnormal echocardiograms at baseline had localized rest wall motion abnormalities. Fifteen had coronary artery disease confined to regions that had abnormal rest wall motion, and 26 had disease remote from these regions. Thirteen of 15 patients (87%) without remote disease did not develop remote stress-induced abnormalities, and 21 of 26 (81%) who had remote disease developed corresponding abnormalities. CONCLUSIONS Echocardiography combined with dobutamine infusion is a safe and accurate method for detecting coronary artery disease and for predicting the extent of disease in those who have localized rest wall motion abnormalities.

Two beta-receptor agonists (-)-denopamine and (-)-arbutamine were prepared in good yields and enantioselectivities by asymmetric hydrogenation of unprotected amino ketones for the first time by using Rh catalysts bearing electron-donating phosphine ligands. A series of alpha-primary and secondary amino ketones were synthesized and hydrogenated to produce various 1,2-amino alcohols in good yields and with good enantioselectivies. This Rh electron-donating phosphine-catalyzed asymmetric hyderogenation represents one of the most promising and convenient approaches towards the asymmetric synthesis of chiral amino alcohols.

Dobutamine stress echocardiography is widely used as a noninvasive method to determine the presence, extent, and prognosis of coronary artery disease. To maximize diagnostic sensitivity, adequate pharmacologic stress has been conventionally defined as achieving 85% of the age-predicted maximum heart rate. 1 Beta-adrenergic blockers, prescribed as antianginal or antihypertensive therapy, may blunt the inotropic and chronotropic response to dobutamine infusion, resulting in: (1) a higher peak dose, 2 (2) a greater incidence of failure to achieve target heart rate, 3 and (3) subsequent prolonged infusion times. Although the administration of atropine attenuates these limiting effects, 4,5 additional side effects may occur. Arbutamine is a synthetic, nonselective b-receptor agonist with mild a-1 activity that has been recently developed and approved for use in stress testing using a dedicated closed-loop delivery system (The GenESA System, Gensia Automedics, Inc., San Diego, California). 6 This drug stimulates both the inotropic and chronotropic adrenergic responses equivalently and in a dose-dependent manner. 7 The delivery system measures the heart rate response and alters the drug infusion rate to achieve a selected rate of increase in heart rate (heart rate slope) towards the desired heart rate goal. Because of the hemodynamic profile of arbutamine and the properites of the closed-loop delivery system, this form of pharmacologic stress testing may be superior to the infusion of dobutamine in fixed-dosing increments in patients taking b blockers. 8 Clinical studies to date using the closed-loop delivery device have excluded patients receiving b blockers. 9,10 We therefore evaluated the ability of the closed-loop arbutamine feedback system to produce adequate pharmacologic stress in patients receiving selective b-1 blockers. ••• To test the effect of b-1 blockade on arbutamine stress, a substudy was formed from the larger study involving a total of 1,070 patients with suspected coronary artery disease who underwent arbutamine stress testing as part of an evaluation of the clinical utility, safety, and tolerability of the GenESA System. Patients were identified as candidates for the trial if they had the usual indications for pharmacologic stress testing (i.e., known or suspected coronary artery disease). Women of childbearing age were excluded. Exclusionary conditions to trial participation included hospitalization for unstable angina within the preceding 3 days, hospitalization for myocardial infarction within the previous 30 days, history of sustained ventricular tachycardia or cardiac arrest, history of other arrhythmias which preclude catecholamine administration, the presence of a pacemaker or implantable cardiodefibrillator, left ventricular outflow tract obstruction, severe valvular aortic stenosis, hypertrophic obstructive cardiomyopathy, decompensated heart failure, uncontrolled hypertension, hypokalemia, and aortic aneurysm or dissection. To test the effect of selective b blockade, 5 experienced centers were al

The use of pharmacologic agents to stress patients who are unsuitable for maximal exercise stress has evolved into an essential clinical tool for the diagnosis of coronary artery disease (CAD) and for noninvasive cardiac risk assessment. The initial administration of a drug to create differential coronary hyperemia (using oral then intravenous dipyridamole), as an adjunct to planar 201Tl myocardial perfusion imaging for the diagnosis of CAD in stable patients, has been extended to include the following: use with single photon and positron nuclear tomography, 2-D echocardiography, and MRI; use with 99mTc-labeled myocardial radiotracers (sestamibi, tetrofosmin, etc.); Food and Drug Administration-approved indication for the definition of the risk of future cardiac events (ie, prognosis); development of short-acting, highly specific hyperemic agents (adenosine and its analogues); use of catecholamine infusion in patients with contraindications to hyperemic agents (dobutamine, arbutamine); protocols combining drug stress with submaximal exercise stress (isometric or dynamic); and safe use early after uncomplicated acute coronary syndromes (unstable angina, myocardial infarction).

A number of pharmaceuticals are employed as diagnostic agents for cardiovascular diseases. Four groups of agents are reviewed here: 1) vasoactive substances employed as adjuncts to physical maneuvers in diagnosis of structural heart disease; 2) vasodilators used to produce heterogeneity of coronary flow; 3) sympathomimetic agents simulating the effects of exercise on the heart for the purpose of detection of coronary artery stenosis; and 4) ultrasonic contrast agents used to enhance myocardial imaging for the assessment of segmental wall motion. In the first group are amyl nitrate, a vasodilator, and methoxamine and phenylephrine, both vasopressors. The vasodilators of the second group are dipyridamole and adenosine. When combined with scintigraphic perfusion imaging or with echocardiographic assessment of segmental wall motion, these agents can detect single- or multiple-vessel coronary artery disease with sensitivity and specificity comparable to submaximal exercise. They are especially useful for preoperative risk assessment before noncardiac surgery. The sympathomimetic agents of the third group, dobutamine and arbutamine, increase myocardial contractility and heart rate, and dilate the peripheral vasculature. As with the vasodilators, when combined with nuclear or echocardiographic techniques they are equivalent to exercise in detection of coronary disease. They are especially useful in patients with bronchospastic disease and for assessment of myocardial viability. Agents from groups 2 and 3 have acceptable side-effect and safety profiles. The last group reviewed includes echocardiographic contrast agents that, in this investigative setting, are employed to enhance detection of segmental wall motion when used with agents from groups 2 and 3.

Ischemic heart disease is the leading cause of death in the developed countries for those older than 65 years of age. In patients suspected to have coronary artery disease a stress test should be performed to identify the vulnerability of the myocardium to ischemia. As a rule of thumb, the evaluation of coronary artery disease is best done by exercise stress test. In patients who are not able to exercise adequately, pharmacological stress agents are used. The commonly used agents are the coronary vasodilators, adenosine and dipyridamole and the catecholamines, dobutamine and arbutamine. These agents are combined with imaging techniques to increase the sensitivity and specificity of the test. These agents have been widely used and have an excellent safety profile. Another advantage in using pharmacological stress agents is that they do not affect the image quality, especially with echocardiography and magnetic resonance imaging. Ongoing developments hold promise for safer and more reliable pharmacological stress agents in the future.

In less than a decade, the use of stress echocardiography has grown dramatically, with both exercise and, for patients unable to exercise adequately, pharmacological stressors, such as dobutamine. A new pharmacological stress agent, arbutamine, administered using a closed-loop computerized feedback system, has recently received approval by the Food and Drug Administration for use with echocardiography and radionuclide myocardial perfusion imaging. This system offers safety and accuracy in echocardiography comparable to the use of dobutamine and promises a number of advantages in terms of ease of use and reductions in personnel and time. A catecholamine specifically designed as a pharmacological stress agent, arbutamine increases heart rate, cardiac contractility, and systolic blood pressure with more balanced chronotropic and inotropic effects than dobutamine. The arbutamine delivery system includes a prefilled syringe of the agent, automatic dosing based on the patient's heart rate response, continuous monitoring of heart rate and blood pressure, a printout of test results, and safety features such as visual and audible warnings and automatic discontinuation of drug after an alarm. The accuracy, safety, convenience, and cost of the arbutamine closed-loop system are likely to make it an attractive agent for echocardiographic diagnosis.

SonoVue is a second-generation ultrasound contrast agent consisting of phospholipid-stabilized microbubbles filled with sulfur hexafluoride, with outstanding stability and resistance to pressure. The efficacy of SonoVue (0.5, 1, 2, 4 mL) was compared with Albunex (doses 0.08 and 0.22 mL/kg) in patients with suspected ischemic disease and suboptimal endocardial-border delineation on unenhanced echocardiography at rest. All the doses resulted in significantly greater increases compared with Albunex in left-ventricular endocardial-border delineation score as well as in the duration of clinically useful contrast effect. The utility of SonoVue in diagnosing ischemic heart disease was also evaluated during pharmacologic stress (arbutamine or dobutamine). SonoVue produced significant increases from baseline in endocardial-border delineation score both at rest and during pharmacologic stress. The possibility of detecting myocardial perfusion defects using SonoVue-enhanced power Doppler and gray-scale harmonic contrast echocardiography associated with continuous and intermittent imaging was assessed in patients with coronary artery disease. The results obtained were comparable with corresponding 99mTc sestamibi single-photon emission computed tomography images. An effective cardiovascular assessment of a patient should also include the evaluation of carotid vessels, intracranial circulation, and renal arteries. SonoVue provided significant improvements in the evaluation of the Doppler signal in terms of diagnosis agreement with reference imaging modality especially for intracranial vessels. The safety profile of SonoVue was evaluated in 1,406 patients. The incidence of adverse events was 10.4%, the great majority of which were of mild intensity and resolved without consequences.

Pharmacological stress in conjunction with radionuclide myocardial perfusion imaging has become a widely used noninvasive method of assessing patients with known or suspected coronary artery disease. In the United States, over one third of perfusion imaging studies are performed with pharmacological stress. Pharmacological stress agents fall into two categories: coronary vasodilating agents such as dipyridamole and adenosine, and cardiac positive inotropic agents such as dobutamine and arbutamine. For both, in the presence of coronary artery disease (CAD), perfusion image abnormalities result from heterogeneity of coronary blood flow reserve. Vasodilating agents work directly on the coronary vessels to increase blood flow, whereas inotropic agents work indirectly by increasing myocardial work load, which then leads to an increase in coronary blood flow. Both classes of agents have high accuracies for diagnosing coronary artery disease, and they have excellent safety records with acceptably low occurrences of side effects. For dipyridamole planar thallium imaging, pooled analysis yields a sensitivity of 85% and a specificity of 87% for diagnosis of coronary disease, but there is a large variation in reported values depending on various factors, such as the extent of postcatheterization referral bias, the type of imaging (planar versus single photon emission computed tomography [SPECT]), the types of patients being studied (single versus multivessel disease, men versus women), and the imaging agent used (thallium versus one of the technetium-based agents). Diagnostic accuracies for adenosine are similar to those of dipyridamole, with reported overall sensitivities ranging from 83% to 97%, and specificities ranging from 38% to 94%. For dobutamine, pooled analyses yield a sensitivity of 82% and a specificity of 75%. There is some concern that dobutamine may interfere with uptake of technetium-99m sestamibi, lowering the sensitivity for detection of disease, and thus the vasdodilating agents are generally preferred. Pharmacological stress testing has high clinical use for risk stratifying patients with known or suspected CAD, in patients after myocardial infarction, and in patients needing noncardiac surgery. Vasodilating agents are particularly advantageous in assessing post-myocardial infarction patients, allowing testing as soon as 2 days after the event. Like patients undergoing exercise stress testing, patients with normal perfusion images by pharmacological stress have a1% annual incidence of cardiac events. The likelihood of an event increases with the extent and severity of perfusion abnormalities. However, it is important to consider clinical variables when using perfusion imaging for risk stratification, particularly in the presurgery patients. As with exercise testing, adjunct markers such as ST segment depression during testing, lung uptake of radiotracer (if thallium is used), and ventricular cavity dilatation add additional prognostic information to that available from the perfusion images alone. The aim of current research is to find better agents that are easier to use and that have fewer side effects. MRE-0470 is an experimental vasodilating agent that is more receptor selective than adenosine and promises a lower incidence of hypotension. Arbutamine more closely simulates exercise than dobutamine, and it can be administered by a closed-loop computerized delivery device. Work is also underway to look at novel uses of pharmacological stress agents, such as acquiring gated SPECT images during dobutamine infusion to enhance detection of myocardial viability. With increasing use of noninvasive testing in elderly patients and in patients with comorbidities that preclude adequate exercise, pharmacological stress testing has become an indispensable tool for radionuclide myocardial perfusion imaging studies. A good understanding of pharmacological stress testing is essential for performing high-quality nuclear cardiology

Purpose: This study evaluated the feasibility, hemodynamic responses, and relation of combined Tc-99m sestamibi SPECT imaging and first-pass radionuclide angiography during the infusion of a new β agonist arbutamine. Methods: Arbutamine was administered to 15 patients and constantly adjusted by a closed-loop computerized system. Rest and arbutamine Tc-99m sestamibi radionuclide angiography was performed with a multicrystal gamma camera followed by SPECT imaging with a rotating triple-head, single-crystal gamma camera. Results: The mean differences (paired t-test) between rest and arbutamine studies for heart rate (HR), end-diastolic volume (EDV), stroke volume (SV), cardiac output (CO), and ejection fraction (EF) were as follows: 55 bpm for HR (P < 0.001), 5 ml for EDV (P = ns), 7.5 ml for SV (P = 0.04), 4.4 I/min for CO (P < 0.001), and 6.4% for EF (P < 0.001), respectively. The results of SPECT studies were abnormal in six patients and normal in nine. Findings of radionuclide angiography were normal in 12 patients and abnormal in three. Interpretation of the perfusion and functional studies were concordant in 10 and discordant in five patients. Conclusions: Simultaneous cardiac radionuclide angiography and SPECT imaging are feasible during arbutamine infusion. This potent β agonist increases cardiac output through a chronotropic effect with no significant changes in EDV. The discordance in SPECT and radionuclide angiography results may represent incremental diagnostic and prognostic information provided by both studies.

This study examined the hemodynamic effects of arbutamine, a synthetic catecholamine, in 12 patients with and 7 patients without coronary artery disease. Arbutamine produced a balanced positive inotropic (increase in left ventricular dp/dt) and chronotropic effect (increase in heart rate).

We have compared our standard stress protocol (adenosine combined with exercise) with the new stress agent arbutamine, for thallium-201 myocardial perfusion imaging (MPI) in order to assess the comparative value of arbutamine. We studied 23 patients referred for MPI, and each patient had two studies (18 males, median age 66 years, five with previous myocardial infarction). Uptake scores were assigned to each of nine segments, and the extent and severity of defects were measured using a polar plot. Haemodynamic changes were greater with arbutamine (rate-pressure product increase 78% vs 51%, P = 0.003). Symptoms were experienced by 21 patients with arbutamine and 16 with adenosine (P = 0.07). Agreement between the techniques for classification of patients as normal or as having reversible, fixed or mixed defects was good (19 of 23 studies, 83%, kappa = 0.76). Agreement for similar classification of segments was also good (82%, kappa = 0.71). Segmental agreement for stress scores was good (86%, kappa = 0.77). However, mean size of stress defect was larger with adenosine (83+/-52 pixels vs 65+/-48 pixels, P0.05), though severity and reversibility were similar (P = NS). We conclude that arbutamine provides comparable results to those obtained with adenosine and exercise and that the observed differences are not clinically significant.