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 Å), and radius of gyration (-21.49 Å) 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.

Understanding how drugs and diseases are associated in the molecular level is of critical importance to unveil disease mechanisms and treatments. Until recently, few studies attempt end to discover important gene modules shared by both drugs and diseases.

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.

Stress echocardiography is valuable, non-invasive method useful for detection of coronary artery disease. In stress echocardiography myocardial ischemia is most commonly induced by exercise or pharmacological agents like dobutamine, dypiridamole, arbutamine or adenosine. The aim of the study was to compare usefulness of dobutamine-atropine stress echocardiography (DATR) with dobutamine-adenosine stress echocardiography (DADE) in detection of coronary artery disease. Studies were carried out in 23 patients, 11 women and 12 men, with suspected coronary artery disease. Both DATR and DADE were performed in all patients. In DATR left ventricular segmental contractility was estimating during intravenous infusion of dobutamine in increasing doses from 5 to 40 microg/kg/min and after intravenous administration of 1 mg of atropine. In DADE regional left ventricular systolic function was analyzed during intravenous infusion of dobutamine in increasing doses from 5 to 40 microg/kg/min and adenosine in dose of 0.14 mg/kg/min. The sensitivity of DATR in detection of coronary artery disease was 87% and specificity was 85%, whereas DADE 87% and 100% respectively. The sensitivity of DATR and DADE in subgroups of patients with one-vessel and multivessel disease was equal: 83% and 90% respectively. There were no significant differences between DADE and DATR in respect of sensitivity and specificity in detection of coronary artery disease. The results of this study suggest that dobutamine-adenosine stress echocardiography is highly sensitive and specific diagnostic test for detection both one-vessel and multivessel coronary artery disease. Moreover, there is no statistically important difference between dobutamine-adenosine stress echocardiography and dobutamine-atropine echocardiography in respect of sensitivity and specificity in detection of coronary artery disease.

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.

[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.

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.

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.

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, kappa 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.

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.

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.

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.

Within the last decade of this millennium, stress echocardiography has been established for the diagnosis and follow-up of coronary artery disease. The basis is the technical development of the echo machines: first, the improved echocardiographic resolution and, second, the digital image storage of a whole cineloop, which may be interpreted frame-by-frame in an ECG synchronized manner for several exercise levels simultaneously. Myocardial ischemia can be detected much earlier by regional contraction abnormalities of the left ventricular myocardium than in conventional ECG exercise tolerance testing explaining the higher sensitivities. Furthermore, the extent and localization, including the correlation with the stenotic coronary anatomy, is possible. The usage of pharmacological stress agents (dobutamine, arbutamine, dipyridamole, adenosine) or electrical stimulating methods (transesophageal, intracardial) allow the examination of patients unable to exercise in similar accuracy.

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 CO(2) [35.1 (S.D. 3. 1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (V(D)/V(T)) [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.

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 a <1% 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

This study investigated changes in spatial distribution of QT duration in patients with and without coronary artery disease (CAD) using magnetocardiography. Thirty-six-channel magnetocardiograms (MCGs) were registered at rest and under stress in 15 patients with chest pain, seven of whom had significant coronary stenosis. QT dispersion (QTd) was calculated for MCG and 12-lead electrocardiogram (ECG) under both conditions. For MCG, homogeneity of repolarization was measured using a smoothness index (SI). Also, at each registration site, the intraindividual difference between QT at rest and under stress was determined (deltaQT). QTd values as determined by standard 12-lead configurations were not significantly different between groups. MCG QTd values were significantly higher in the CAD group at rest only when all available channels were taken into consideration (P < .05); SI values differed significantly between groups under both conditions (rest, P < .005; stress, P < .01). Good separation between groups was possible using the range of deltaQT (P < .05) and SI (deltaQT) (P < .005). Consideration of the spatial distribution of QTd increases its sensitivity in the detection of CAD, suggesting that CAD involves complex changes in repolarization, not apparent in limited lead sets such as standard 12-lead configurations.

Pharmacologic stress testing is an important noninvasive method for evaluating patients with known or suspected coronary artery disease who are unable to adequately exercise. Pharmacologic stress echocardiography using dobutamine has been developed over the last 10 to 15 years as an alternative to vasodilator stress testing using nuclear perfusion imaging. As experience has grown, digital subtraction echocardiogram has been shown to be a safe, convenient, and reliable method for stress testing in a variety of patient populations. Digital subtraction echocardiogram has comparable sensitivity, specificity, and accuracy when compared to other stress testing methods which employ cardiac imaging and is superior to the exercise echocardiogram. It has certain advantages over nuclear perfusion imaging in terms of cost and convenience. The recent addition of arbutamine echocardiography (which has been shown to be comparable to digital subtraction echocardiogram) provides another alternative method for pharmacologic stress testing. Continued improvement in echocardiographic image quality and the development of new technologies such as tissue harmonic imaging and contrast echocardiography will hopefully improve the echocardiographic evaluation of wall motion therefore increasing the diagnostic accuracy of echocardiographic stress testing.

A review of the most important findings published during 1997 in cardiovascular papers is presented: Chlamydia pneumoniae was recognised as a potential risk factor for coronary artery disease (CAD) and possible pathogenic agent for valvular aortic stenosis. Valvular changes similar to the valvular disease reported after ergotamine and methylsergide were also detected in obese women treated with a combination of phentermine and fenfluramine. In CAD, several new laboratory methods were introduced for early diagnosis, such as serum troponin levels, and arbutamine and adenosine stress echocardiography. Laser transmyocardial revascularisation can be performed in patients unsuitable for PTCA and CABG. In patients with end-stage heart failure, implantable ventricular-assist devices can be used, and dynamic cardiomyoplasty or partial ventriculectomy may be useful temporary measures until a suitable heart donor is available. In pharmacotherapy, fluvastatin was registered as an antiatherosclerotic agent, and mibefradil and moxonidin in hypertension and angina. Digoxin was shown to reduce the number of hospitalisations in patients with CHF but still in sinus rhythm. In the future, several improvements in anti-thrombotic therapy are expected: antithrombins, platelet glycoprotein IIb/IIIa receptor blockers and tissue factor inhibitors are all potentially more potent than presently available drugs. Also, efforts are under way to introduce genes directly into the cells of the vascular wall to prevent atherosclerosis and restenosis, as well as to transform cardiac mesenchymal cells into the cardiac myocytes of hearts that have suffered large infarctions.

Arbutamine stress echocardiography was performed in 81 patients with suspected coronary artery disease. Arbutamine infusion, using a dedicated closed-loop delivery device, provided comparable myocardial stress in patients receiving beta-1 blockers versus those who were not.

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, P<0.05), 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.