Stability of dobutamine in continuous ambulatory delivery devices.

WHAT IS KNOWN AND OBJECTIVE: Continuous infusion of dobutamine plays an important role in the management of patients with end-stage heart failure. Home infusion of dobutamine using a continuous ambulatory delivery device (CADD) facilitates the management of patients in their home, avoiding complications associated with long-term hospitalization. However, the stability of dobutamine in CADD is currently unknown. Therefore, this study investigated the physicochemical stability of dobutamine in CADDs at three different temperatures over various time points. METHODS: Six CADDs (three containing dobutamine 10 mg/mL in 0.9% sodium chloride and three containing dobutamine 10 mg/mL in 5% glucose) were prepared and stored at 4°C for 7 days, followed by 12 hours at 35°C and then for another 12 hours at 25°C. An aliquot (n = 3) was withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144 and 168 hours when stored at 4°C, and at 0, 6 and 12 hours when stored at the other two temperatures. Each sample was analysed for dobutamine concentration using a stability-indicating high-performance liquid chromatography. All the samples were also evaluated for change in pH, colour and for particle content. RESULTS AND DISCUSSION: No evidence of particle formation, colour or pH change was observed throughout the study period. Dobutamine, when admixed with 0.9% sodium chloride or 5% glucose, was found to be chemically stable for at least 168 hours at 4°C and for another 12 hours at 35°C and for another 12 hours at 25°C. WHAT IS NEW AND CONCLUSIONS: Our findings will allow health professionals to provide a weekly supply of dobutamine-containing CADDs to patients for home infusions. Continuous infusion over a 24-hour period using one CADD per day will also decrease the number of exchanges required and thus reduce the risk of catheter-related bloodstream infections.

Cardiac stress imaging for the prediction of very long-term outcomes: Dobutamine stress echocardiography or dobutamine 99mTc-sestamibi SPECT?

BACKGROUND: Both dobutamine stress echocardiography (DSE) and myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) are frequently used for cardiac risk stratification. The long-term relative prognostic value of these modalities has not been studied. Therefore, this study evaluated the long-term prognostic value of DSE compared to MPI in patients unable to perform exercise testing. METHODS: This prospective, single center study included 301 patients (mean age 59 ± 12 years, 56% men) unable to perform exercise tests who underwent DSE and dobutamine stress 99mTc-sestamibi MPI. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction (MI). Univariable and multivariable Cox proportional hazards regression models were used to identify independent predictors of outcome. The probability of survival was calculated using the Kaplan-Meier method. RESULTS: A total of 182 patients (60%) had an abnormal DSE and 198 (66%) patients had an abnormal MPI. The agreement between DSE and MPI was 82% (κ = 0.62). During a median follow-up of 14 years (range 5-18), 172 deaths (57%) occurred, of which 72 (24%) were due to cardiac causes. Nonfatal MI occurred in 46 patients (15%). The multivariable analysis demonstrated that an abnormal DSE was a significant predictor of cardiac mortality (HR 2.35, 95% CI [1.17-4.73]) and hard cardiac events (HR 2.11, 95% CI [1.25-3.57]). Also, an abnormal MPI result was a significant predictor of cardiac mortality (HR 3.03, 95% CI [1.33-6.95]) and hard cardiac events (HR 2.06, 95% CI [1.12-3.79]). CONCLUSIONS: DSE and MPI are comparable in predicting long-term cardiac mortality and hard cardiac events in patients unable to perform exercise testing.

Functional selectivity of GPCR-directed drug action through location bias.

G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The ß2-adrenergic GPCR can activate Gs-linked cyclic AMP (Gs-cAMP) signaling from endosomes. We show here that the homologous human ß1-adrenergic receptor initiates an internal Gs-cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that ß-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose 'location bias' as a new principle for achieving functional selectivity of GPCR-directed drug action.

Mapping of intracellular pH in the in vivo rodent heart using hyperpolarized [1-13C]pyruvate.

PURPOSE: To demonstrate the feasibility of mapping intracellular pH within the in vivo rodent heart. Alterations in cardiac acid-base balance can lead to acute contractile depression and alterations in Ca2+ signaling. The transient reduction in adenosine triphosphate (ATP) consumption and cardiac contractility may be initially beneficial; however, sustained pH changes can be maladaptive, leading to myocardial damage and electrical arrhythmias. METHODS: Spectrally selective radiofrequency (RF) pulses were used to excite the HCO3- and CO2 resonances individually while preserving signal from the injected hyperpolarized [1-13 C]pyruvate. The large flip angle pulses were placed within a three-dimensional (3D) imaging acquisition, which exploited CA-mediated label exchange between HCO3- and CO2 . Images at 4.5 × 4.5 × 5 mm3 resolution were obtained in the in vivo rodent heart. The technique was evaluated in healthy rodents scanned at baseline and during high cardiac workload induced by dobutamine infusion. RESULTS: The intracellular pH was measured to be 7.15 ± 0.04 at baseline, and decreased to 6.90 ± 0.06 following 15 min of continuous ß-adrenergic stimulation. CONCLUSIONS: Volumetric maps of intracellular pH can be obtained following an injection of hyperpolarized [1-13 C]pyruvate. The new method is anticipated to enable assessment of stress-inducible ischemia and potential ventricular arrythmogenic substrates within the ischemic heart. Magn Reson Med 77:1810-1817, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Adiposity Is Associated with Gender-Specific Reductions in Left Ventricular Myocardial Perfusion during Dobutamine Stress.

BACKGROUND: Obesity and visceral adiposity are increasingly recognized risk factors for cardiovascular disease. Visceral fat may reduce myocardial perfusion by impairing vascular endothelial function. Women experience more anginal symptoms compared to men despite less severe coronary artery stenosis, as assessed by angiography. Women and men have different fat storage patterns which may account for the observed differences in cardiovascular disease. Therefore, our objective was to evaluate the relationship between visceral adipose tissue distributions and myocardial perfusion in men and women. METHODS: Visceral and subcutaneous fat distributions and myocardial perfusion were measured in 69 men and women without coronary artery disease using magnetic resonance imaging techniques. Myocardial perfusion index was quantified after first-pass perfusion with gadolinium contrast at peak dose dobutamine stress. RESULTS: We observed inverse relationships between female gender (r = -0.35, p = 0.003), pericardial fat (r = -0.36, p = 0.03), intraperitoneal fat (r = -0.37, p = 0.001), and retroperitoneal fat (r = -0.36, p = 0.002) and myocardial perfusion index. Visceral fat depots were not associated with reduced myocardial perfusion at peak dose dobutamine in men. However, in women, BMI (r = -0.33, p = 0.04), pericardial fat (r = -0.53, p = 0.02), subcutaneous fat (r = -0.39, p = 0.01) and intraperitoneal fat (r = -0.30, p = 0.05) were associated with reduced myocardial perfusion during dobutamine stress. CONCLUSIONS: Higher visceral fat volumes are associated with reduced left ventricular myocardial perfusion at peak dose dobutamine stress in women but not in men. These findings suggest that visceral fat may contribute to abnormal microcirculatory coronary artery perfusion syndromes, explaining why some women exhibit more anginal symptoms despite typically lower grade epicardial coronary artery stenoses than men.

Na+-induced Ca2+ influx through reverse mode of Na+-Ca2+ exchanger in mouse ventricular cardiomyocyte.

BACKGROUND: Dobutamine is commonly used for clinical management of heart failure and its pharmacological effects have long been investigated as inotropics via ß-receptor activation. However, there is no electrophysiological evidence if dobutamine contributes inotropic action due at least partially to the reverse mode of Na+-Ca2+ exchanger (NCX) activation. METHODS: Action potential (AP), voltage-gated Na+ (INa), Ca2+ (ICa), and K+ (Ito and IK1) currents were observed using whole-cell patch technique before and after dobutamine in ventricular cardiomyocytes isolated from adult mouse hearts. Another sets of observation were also performed with Kb-r7943 or in the solution without [Ca2+]o. RESULTS: Dobutamine (0.1-1.0 µM) significantly enhanced the AP depolarization with prolongation of AP duration (APD) in a concentration-dependent fashion. The density of INa was also increased concentration-dependently without alternation of voltage-dependent steady-status of activation and inactivation, reactivation as well. Whereas, the activities for ICa, Ito, and IK1 were not changed by dobutamine. Intriguingly, the dobutamine-mediated changes in AP repolarization were abolished by 3 µM Kb-r7943 pretreatment or by simply removing [Ca2+]o without affecting accelerated depolarization. Additionally, the ratio of APD50/APD90 was not significantly altered in the presence of dobutamine, implying that effective refractory period was remain unchanged. CONCLUSIONS: This novel finding provides evidence that dobutamine upregulates of voltage-gated Na+ channel function and Na+ influx-induced activation of the reverse mode of NCX, suggesting that dobutamine may not only accelerate ventricular contraction via fast depolarization but also cause Ca2+ influx, which contributes its positive inotropic effect synergistically with ß-receptor activation without increasing the arrhythmogenetic risk.

High-dose dobutamine stress steady-state free precession (SSFP) cine MRI at 3T with patient adaptive local radiofrequency (RF) shimming using dual-source RF transmission.

PURPOSE: To prospectively assess the feasibility, image quality, and diagnostic accuracy of high-dose dobutamine stress magnetic resonance imaging (DSMR) using steady-state free precession (SSFP) cine imaging at 3T applying a dual-source radiofrequency (RF) excitation magnetic resonance imaging (MRI) system with parallel transmission and patient adaptive local RF shimming. MATERIALS AND METHODS: DSMR using SSFP cine imaging was performed in 44 patients at 3T scheduled for a clinically indicated coronary angiography. The effect of conventional versus dual-source RF transmission was assessed regarding homogeneity of the B1 field, contrast-to-noise ratios (CNRs) at rest, image quality, and diagnostic accuracy of DSMR using long and short axis. RESULTS: The mean percentage of the intended flip angle within the heart increased from 88 ± 9.1% with single-source to 103 ± 5.6% (P < 0.001) dual-source RF transmission. CNR increased for dual-source particularly at the apex (63.4 ± 24.2 vs. 36.5 ± 16.5, P < 0.001) but also at the base of the left ventricle (LV) (50.1 ± 14.8 vs. 39.3 ± 15.8, P < 0.001). Image quality of dual-source was higher both at rest (2.8 ± 0.5 vs. 2.6 ± 0.7, P < 0.001) and stress (2.5 ± 0.7 vs. 2.0 ± 1.0, P < 0.001). The number of segments with severe artifacts or nondiagnostic image quality at stress was lower with dual-source RF transmission (8% vs. 27%, P < 0.001). The diagnostic accuracy of DSMR in coronary territories using dual-source RF transmission was significantly higher (77% vs. 65%, P = 0.04). CONCLUSION: Patient adaptive local RF shimming using dual-source RF transmission provided significantly improved image quality and higher diagnostic accuracy of SSFP during DSMR at 3T compared to conventional RF transmission.

Prediction of 14-year outcomes in patients with a limited exercise capacity: Utility of dobutamine myocardial perfusion imaging in a high-risk population.

OBJECTIVE: Despite multiple studies on the diagnostic and prognostic use of dobutamine myocardial perfusion imaging (MPI), information on its long-term prognostic value is scarce. The aim of this study was to assess the value of this technique for the prediction of very long-term outcome. METHODS: A total of 721 patients with limited exercise capacity underwent dobutamine MPI for the evaluation of suspected or known coronary artery disease. 719 of 721 patients attended follow-up (99.7%). Twenty-eight patients who underwent early coronary revascularization were excluded from analysis. Endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival curves were constructed, and univariate and multivariate analyses were performed to identify predictors of long-term outcome. RESULTS: The mean age of patients was 60 ± 11 years, and 61% were male. Myocardial perfusion abnormalities were present in 381 patients (55%) and included fixed defects in 190 patients (27%) and reversible defects in 191 patients (28%). During a median follow-up time of 14 years (range 0-16), 295 deaths occurred (43%), of which 158 were cardiac deaths (23%). Nonfatal myocardial infarction occurred in 35 (5%), and late coronary revascularization was performed on 133 patients (19%). An abnormal dobutamine MPI provided significant prognostic information for prediction of cardiac death, hard cardiac events, and MACE, after adjustment for significant clinical variables and stress test variables. CONCLUSIONS: Dobutamine MPI provides incremental prognostic information for the prediction of cardiovascular outcomes in patients with limited exercise capacity. The long-term prognosis of patients with limited exercise capacity who have an abnormal dobutamine MPI is significantly worse than those with a normal MPI.

The effects of cardiac output and pulmonary arterial hypertension on volumetric capnography derived-variables during normoxia and hypoxia.

The aim of this study was to test the effect of cardiac output (CO) and pulmonary artery hypertension (PHT) on volumetric capnography (VCap) derived-variables. Nine pigs were mechanically ventilated using fixed ventilatory settings. Two steps of PHT were induced by IV infusion of a thromboxane analogue: PHT25 [mean pulmonary arterial pressure (MPAP) of 25 mmHg] and PHT40 (MPAP of 40 mmHg). CO was increased by 50% from baseline (COup) with an infusion of dobutamine≥5 µg kg(-1) min(-1) and decreased by 40% from baseline (COdown) infusing sodium nitroglycerine≥30 µg kg(-1) min(-1) plus esmolol 500 µg kg(-1) min(-1). Another state of PHT and COdown was induced by severe hypoxemia (FiO2 0.07). Invasive hemodynamic data and VCap were recorded and compared before and after each step using a mixed random effects model. Compared to baseline, the normalized slope of phase III (SnIII) increased by 32% in PHT25 and by 22% in PHT40. SnIII decreased non-significantly by 4% with COdown. A combination of PHT and COdown associated with severe hypoxemia increased SnIII by 28% compared to baseline. The elimination of CO2 per breath decreased by 7% in PHT40 and by 12% in COdown but increased only slightly with COup. Dead space variables did not change significantly along the protocol. At constant ventilation and body metabolism, pulmonary artery hypertension and decreases in CO had the biggest effects on the SnIII of the volumetric capnogram and on the elimination of CO2.

Lipophilicity of amine neurotransmitter precursors, metabolites and related drugs estimated on various TLC plates.

The retention behavior for a series of amine neurotransmitters, their precursors, metabolites and structurally related drugs has been investigated in reversed-phase thin-layer chromatography using RP-18, RP-8, RP-2, CN and Diol stationary phases and mixtures of phosphate buffer and methanol as mobile phase. According to the computed lipophilicity of the neutral form of the investigated compounds, the most lipophilic compound is dobutamine (log P(N) = 3.78), while the less lipophilic is norepinephrine (log P(N) = -0.14). The experimental results also show dobutamine as the most lipophilic compound in the case of RP-18 and CN stationary phases (RM0(RP-18) = 1.58 and RM(CN) = 1.21), while RP-8 indicates norepinephrine as the less lipophilic one (RM0(RP8) = -0.70). Both the theoretical computation and the experimental data revealed that only one ionic form of the compounds prevails in the used chromatographic conditions. In addition, the evaluation of the experimental results showed that a similar chromatographic behavior could be assumed in the case of RP-18, RP-8 and CN stationary phases. Moreover, the mRM (mean of the RM values) and PC1/RM (scores of the first principal component) experimental lipophilicity indices showed a high correlation with the computed lipophilicity indices.

The structural basis for agonist and partial agonist action on a ß(1)-adrenergic receptor.

ß-adrenergic receptors (ßARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit ßARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) ß(1)-adrenergic receptor (ß(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

"The ß1-selective adrenoceptor agonist dobutamine": a fallacy being perpetuated.

Dobutamine is a cardiotonic agent, developed as a racemate more than 30 years ago. The compound soon got the label "the ß(1)-selective adrenoceptor agonist". However, a closer examination of the enantiomers showed that (+)-dobutamine is predominantly a ß(1)- and ß(2)-adrenoceptor agonist with modest selectivity whereas (-)-dobutamine is predominantly an α(1)-adrenoceptor agonist. Nevertheless, rac dobutamine is still frequently used as a tool for classification of ß-adrenoceptors. This ignorance of chirality may lead to erroneous conclusions and consolidate false labels.

Potencial hidrogeniônico de soluções de cloridrato de dobutamina expostas a condições ambientais de unidades de cuidados intensivos neonatais / Hydrogen-ion potential of dobutamine hydrochloride solutions exposed to environmental conditions of neonatal intensive care units

OBJETIVO: Verificar o potencial hidrogeniônico (pH) de soluções de cloridrato de dobutamina sob condições ambientais que mimetizam unidades de cuidados intensivos neonatais. MÉTODOS: Analisou-se pH do fármaco em solução glicosada 5 por cento ou NaCl 0,9 por cento segundo temperatura (22 e 37 °C), luz (escuro, lâmpadas fluorescentes ambiente e equipamento de fototerapia) e equipos (incolor e âmbar) em intervalos de tempo (0, 1, 24, 48, 72 e 96 horas). RESULTADOS: Evidenciaram-se valores próximos de pH do fármaco na apresentação comercial e diluído. Obteve-se média de pH de 3,45±0,19 a 22 °C e de 3,55±0,20 a 37 °C. A média de pH das soluções mantidas no escuro foi de 3,62±0,09, na luz ambiente, de 3,63±0,07, e sob fototerapia, de 3,31±0,16. Soluções em equipos incolores tiveram média menor (3,41±0,24) do que em âmbares (3,52±0,15). Obtiveram-se menores valores de pH nas soluções sob fototerapia em equipos incolores (3,17±0,03) do que em âmbares (3,55±0,03). CONCLUSÃO: Sob a luz da fototerapia houve maior variação do pH das soluções, e o emprego de equipos âmbares minimizou tal efeito.

OBJECTIVE: To verify the hydrogen-ion potential (pH) of dobutamine hydrochloride solutions under environmental conditions similar to those of neonatal intensive care units. METHODS: We analyzed the pH of the drug diluted in 5 percent dextrose in water or 0.9 percent NaCl under different conditions of temperature (22 and 37 °C) and light (dark, fluorescent light bulbs, and phototherapy equipment), using colorless and amber intravenous sets at time intervals of 0, 1, 24, 48, 72, and 96 hours. RESULTS: The pH values of the marketed form of the drug and the diluted drug were similar. The pH means were 3.45±0.19 at 22 °C and 3.55±0.20 at 37 °C. The average of the pH according to light conditions were as follows: in the dark = 3.62±0.09, under room light = 3.63±0.07, and exposed to phototherapy = 3.31±0.16. Solutions stored in colorless intravenous sets had a lower mean (3.41±0.24) than those kept in amber intravenous sets (3.52±0.15). We found lower pH values in the solutions exposed to phototherapy using colorless intravenous sets (3.17±0.03) than in those using amber intravenous sets (3.55±0.03). CONCLUSION: There was higher variation in the pH of the solutions exposed to phototherapy, and the use of amber intravenous sets reduced such effect.

Hydrogen-ion potential of dobutamine hydrochloride solutions exposed to environmental conditions of neonatal intensive care units.

OBJECTIVE: To verify the hydrogen-ion potential (pH) of dobutamine hydrochloride solutions under environmental conditions similar to those of neonatal intensive care units. METHODS: We analyzed the pH of the drug diluted in 5% dextrose in water or 0.9% NaCl under different conditions of temperature (22 and 37 degrees C) and light (dark, fluorescent light bulbs, and phototherapy equipment), using colorless and amber intravenous sets at time intervals of 0, 1, 24, 48, 72, and 96 hours. RESULTS: The pH values of the marketed form of the drug and the diluted drug were similar. The pH means were 3.45+/-0.19 at 22 degrees C and 3.55+/-0.20 at 37 degrees C. The average of the pH according to light conditions were as follows: in the dark = 3.62+/-0.09, under room light = 3.63+/-0.07, and exposed to phototherapy = 3.31+/-0.16. Solutions stored in colorless intravenous sets had a lower mean (3.41+/-0.24) than those kept in amber intravenous sets (3.52+/-0.15). We found lower pH values in the solutions exposed to phototherapy using colorless intravenous sets (3.17+/-0.03) than in those using amber intravenous sets (3.55+/-0.03). CONCLUSION: There was higher variation in the pH of the solutions exposed to phototherapy, and the use of amber intravenous sets reduced such effect.

Left ventricular motion reconstruction with a prolate spheroidal B-spline model.

Tagged cardiac magnetic resonance (MR) imaging can non-invasively image deformation of the left ventricular (LV) wall. Three-dimensional (3D) analysis of tag data requires fitting a deformation model to tag lines in the image data. In this paper, we present a 3D myocardial displacement and strain reconstruction method based on a B-spline deformation model defined in prolate spheroidal coordinates, which more closely matches the shape of the LV wall than existing Cartesian or cylindrical coordinate models. The prolate spheroidal B-spline (PSB) deformation model also enforces smoothness across and can compute strain at the apex. The PSB reconstruction algorithm was evaluated on a previously published data set to allow head-to-head comparison of the PSB model with existing LV deformation reconstruction methods. We conclude that the PSB method can accurately reconstruct deformation and strain in the LV wall from tagged MR images and has several advantages relative to existing techniques.