The influence of the BGE composition, including the addition of a single-isomer sulfated beta-CD derivative, on the ionization performance of the model compound carvedilol in NACE-ESI-MS was studied using an alternative infusion method. This approach employs voltage-induced infusion of the BGE containing the analyte, and takes into account the effects of variations in EOF and effective analyte mobility on the ESI-MS intensity. First, the optimal composition of the sheath liquid for CE-MS in terms of signal abundance and stability was determined. The BGE ammonium formate, acetate, and camphorsulfonate were found to have similar effects on analyte ionization. Addition of single-isomer sulfated beta-CD derivatives (available as sodium salt) to the BGE revealed that the anionic CD derivatives did not give rise to the same ionization suppression effect. This result can be attributed to differences in the dissociation state of these sodium salts. Finally, it is shown that information about chiral selectivity can also be obtained with the applied infusion method.

The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. The microspheres were prepared by emulsification-cross-linking method and evaluated for size, shape, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The mucoadhesive properties were also evaluated by Freundlich and Langmuir adsorption isotherms. In vivo tests were carried out in rabbits. The microspheres were spherical with size of 20-50 microm, which is favorable for intranasal absorption. The EE was observed from 42% to 68% while percentage mucoadhesion was from 74% to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining adsorption with electrostatic interaction. The microspheres released around 75% of drug in 8 h. DSC and XRD studies revealed that CRV was molecularly dispersed. The absorption rate was rapid and the absolute bioavailability was high, 72.29%. The gamma scintigraphy indicated that the microspheres cleared slowly from the nasal cavity. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability.

The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number, BrDU-LI, cAMP levels and spheroid volume. Carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. Carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.

A simple, specific, sensitive, inexpensive and rapid HPLC method for enantioselective quantification of carvedilol in human plasma was developed in this study. S(-)- and R(+)-carvedilol and R(+)-propranolol as the internal standard were extracted from human plasma by liquid-liquid extraction using methyl tert-butyl ether. Enantioseparation was performed on a reverse-phase C18 Phenomenex Luna 5micron 150mmx2mm column after chiral derivatization with 2,3,4,6-tetra-O-acetyl-beta-d-glucopyranosyl isothiocyanate. The mobile phase was a mixture of water and acetonitrile. The peaks were detected using a fluorescence detector, where the excitation and emission wavelengths were set at 242 and 344nm, respectively. The limits of quantification for the S(-)- and R(+)-carvedilol enantiomers were both 0.5ng/ml. Combined intra- and inter-day variations for both enantiomers were less than 8.3%. The combined accuracy for both enantiomers ranged from 91.7 to 104.7%. This method was used to assay the carvedilol enantiomers in human plasma samples obtained from heavily medicated heart failure patients within the framework of a clinical trial.

Unique stereochemistry of the third-generation beta-adrenoblockers is a basis of advantages of the new drugs such as carvedilol. Data on the stereochemistry beta-adrenoblockers and the influence of their optical activity on the pharmacological effects of related drugs are presented. Main steps in the practical invest gation of carvedilol stereoisomers are reviewed. Clinical aspects of the use of carvedilol, representing a racemic mixture of two enantiomers, in the treatment chronic heart failure, arterial hypertension, and coronary heart disease are considered.

This study has evaluated whether candesartan prevent the recurrence of atrial fibrillation (AF) and decrease type III procollagen-N-peptide (PIIINP) levels. A total of 153 patients with AF were enrolled in this study. Three groups of patients were compared; candesartan group was treated with candesartan plus bepridil (n=52); and carvedilol group with carvedilol plus bepridil (n=51); and bepridil group with bepridil alone (n=50). The primary end point was length of time to the recurrence of AF and all patients were ultimately followed-up for 730 days. Serum levels of the biomarkers were measured at baseline and after 24 months. Maintenance of sinus rhythm was achieved in 25 (50%) patients in bepridil group, 37 (73%) in candesartan group, and 34 (67%) in carvedilol group, giving a bepridil group / candesartan group hazard ratio of 0.36 (95% CI 0.21 to 0.63; P = 0.03). Candesartan significantly decreased PIIINP levels at 24 months than at baseline in sinus rhythm group (0.57+/-0.02 u/ml versus 0.64+/-0.05 u/ml, P=0.04) and did not decrease PIIINP levels in the recurrence group. In conclusions, PIIINP might be related to the possibility of the atrial fibrosis for AF. However, further studies are needed to clarify the relationship between PIIINP and AF.

BACKGROUND AND OBJECTIVE: The safety of rapid carvedilol up-titration in patients with depressed left ventricular ejection fraction (LVEF) is unknown. The aim of the present work was to assess whether carvedilol can be used safely and rapidly up-titrated before hospital discharge in patients with left ventricular systolic dysfunction, with or without heart failure symptoms. METHODS: We studied 611 patients with LVEF less than 0.4 in whom carvedilol was used during hospital admission. RESULTS: Mean age was 66 years, 23% were women and 372 had symptoms of heart failure. Carvedilol was initiated 3 days after admission (median); 594 patients (97%) were discharged alive, 27 (5%) without beta-blockers. Carvedilol up-titration during admission was performed in 65%. The mean time of up-titration was 1 week, with a mean increase of 16 mg/day. The discharge dose was higher in younger patients and in those weighing more than 70 kg. Only 30 patients (5%) were re-admitted during the first month after discharge. At the end of follow-up (mean 2.3 years), 497 patients were alive and transplant-free (81%). Carvedilol mean daily dose at the end of follow-up was 32.4 +/- 22.2 mg and was related to the discharge dose. The absence of beta-blocker treatment at discharge was the most important independent predictor of long-term mortality (hazard ratio 3.1, 95% confidence interval 1.5-6.2, P = 0.002). CONCLUSION: Carvedilol up-titration is well tolerated in patients hospitalized with depressed LVEF, with or without heart failure, with a high compliance rate at discharge and in the long term.

The purpose of this study was to formulate a superporous hydrogel (SPH) containing carvedilol self-nanoemulsifying drug delivery system. Effects of formulation parameters (amount of SPH and 0.1 N HCl used during drug loading) were studied in 3(2) factorial design. Response surface plots showed significant effect of the parameters on hydrogel swelling, carvedilol content, and carvedilol in vitro release. Regression equations were generated to calculate the desirable responses.

OBJECTIVE: To report a case of takotsubo cardiomyopathy, also known as apical ballooning syndrome or stress cardiomyopathy. CASE SUMMARY: A 68-year-old female with a history of hypertension, hyperlipidemia, and anxiety presented with symptoms that mimicked acute coronary syndrome (ACS); the chief symptom was chest tightness. An electrocardiogram showed normal sinus rhythm, with minimal ST elevation in the anterior leads. The patient was initially treated for ST-segment elevation myocardial infarction and symptoms resolved. Coronary angiography ruled out ACS and confirmed a diagnosis of takotsubo cardiomyopathy. DISCUSSION: Takotsubo cardiomyopathy is commonly triggered by severe emotional or psychological stress and occurs primarily in postmenopausal women. A reversible contractility abnormality of the left ventricle causes the ventricle to take on a balloon-like appearance; hence the name of tako-tsubo, a Japanese octopus fishing pot that has a narrow neck and a wide midsection. Signs and symptoms of takotsubo cardiomyopathy mimic those of ACS. Takotsubo cardiomyopathy is best diagnosed with coronary angiography, which can rule out blockage. Treatment usually consists of carvedilol and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocking agent if left ventricular ejection fraction is less than 40%. The syndrome is usually spontaneously reversible and cardiovascular function returns to normal after a few weeks. CONCLUSIONS: Takotsubo cardiomyopathy causes a reversible left ventricle dysfunction which occurs most commonly in postmenopausal women with or without cardiovascular disease. Recognition is detected with coronary angiography. It is thought to primarily be due to an abnormally high sympathetic stimulation after emotional or psychological stress. Treatment consists of an angiotensin converting enzyme inhibitor and/or beta blocker if needed for left ventricular dysfunction and possibly an anxiolytic agent.

In neurodegenerative diseases, progressive oxidative stress is a major event that precedes neuronal death. Oxidative stress is characterized by an imbalance between oxidants and antioxidants. This imbalance induced oxidative molecular and cell damage, reducing cellular viability. 3-Nitropropionic acid (3NP) causes oxidative stress and other molecular and cellular changes similar to those observed in neurons of patients with Huntington's disease. Since carvedilol and melatonin act as free-radical scavengers, this study examined the effect of carvedilol (10(-5) M) and melatonin (10(-5) M) on oxidative and cell damage induced by 3NP in N1E-115 neuroblastoma cells. Carvedilol and melatonin prevented the increases in lipid peroxidation and total LDH activity, as well as the depletion of reduced glutathione (GSH) and the reduction of antioxidative enzymes activities in N1E-115 cells incubated with 100 mM 3NP. All these carvedilol and melatonin effects were more intense when the drugs were added before rather than after inducing the damage by 3NP. These results also provided evidence supporting the hypothesis that carvedilol and melatonin can be useful for treating neurodegenerative diseases, such as Huntington's disease.

We present a patient without primary heart disease in whom subclinical hyperthyroidism was accompanied by manifestations of dilated cardiomyopathy, as evaluated by echocardiography, coronary angiography, and radionuclide ventriculography. His condition was reversed 6 months after conventional treatment (furosemide, carvedilol, angiotensin-converting-enzyme inhibitor and thiamazole administration). This patient represents an exceptional case, as overt congestive heart failure with left ventricular dilatation and depressed ventricular ejection fraction is not a common finding in patients with hyperthyroidism, let alone patients with subclinical hyperthyroidism and no underlying heart disease.

OBJECTIVES: The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy. BACKGROUND: The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking. METHODS: We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF) </=45% due to AC-CMP. Enalapril and, when possible, carvedilol were promptly initiated after detection of LVEF impairment. LVEF was measured at enrollment, every month for the first 3 months, every 3 months during the first 2 following years, and every 6 months afterward (mean follow-up 36 +/- 27 months). Patients were considered responders, partial responders, or nonresponders according to complete, partial, or no recovery in LVEF, respectively. Major adverse cardiac events during follow-up were also evaluated. RESULTS: Eighty-five patients (42%) were responders; 26 patients (13%) were partial responders, and 90 patients (45%) were nonresponders. The percentage of responders progressively decreased as the time from the end of chemotherapy to the start of HF treatment increased; no complete recovery of LVEF was observed after 6 months. Responders showed a lower rate of cumulative cardiac events than partial and nonresponders (5%, 31%, and 29%, respectively; p < 0.001). CONCLUSIONS: In cancer patients developing AC-CMP, LVEF recovery and cardiac event reduction may be achieved when cardiac dysfunction is detected early and a modern HF treatment is promptly initiated.

Here we examine the effect of adding carvedilol (CVD) to University of Wisconsin (UW) solution on the preservation of steatotic and nonsteatotic livers during cold ischemia and after normothermic reperfusion. We used an isolated perfused rat liver model. The following protocols were evaluated. Protocol 1 concerned the effect of CVD after cold ischemia. Steatotic and nonsteatotic livers were preserved for 24 hours in UW solution alone or with CVD. Livers without cold ischemia were used as controls. Transaminases were evaluated in the flushing effluent. Protocol 2 involved the effect of CVD after reperfusion. Both liver types were preserved for 24 hours in UW solution alone or with CVD and then perfused ex vivo for 2 hours at 37 degrees C. Livers flushed and perfused without ischemia were used as controls. Hepatic injury and functionality [transaminases, bile production, and hepatic clearance of sulfobromophthalein (BSP)] were evaluated after reperfusion. In addition, factors potentially involved in hepatic ischemia-reperfusion injury, including oxidative stress (malondialdehyde and superoxide anion levels), mitochondrial damage (glutamate dehydrogenase activity), microcirculatory disorders (flow rate and vascular resistance), and adenosine triphosphate (ATP) depletion, were evaluated after reperfusion. After cold ischemia, steatotic livers preserved in UW solution showed higher transaminase levels than nonsteatotic livers. After reperfusion, steatotic livers preserved in UW solution showed higher transaminase levels and lower bile production and BSP clearance than nonsteatotic livers. Alterations in the perfusion flow rate and vascular resistance, mitochondrial damage, and reduced ATP content were more evident in steatotic livers preserved in UW solution. The addition of CVD to UW solution reduced hepatic injury, obstructed its mechanisms, and improved hepatic functionality in both liver types. We conclude that CVD is a useful additive for UW solution that improves the preservation of steatotic and nonsteatotic livers subjected to prolonged cold ischemia. Liver Transpl 16:163-171, 2010. (c) 2010 AASLD.

Carvedilol is a potent noncardioselective beta-blocker, with weak vasodilating properties because of alpha 1 blockade. A reduction in both intrahepatic and portocollateral resistance contribute to enhanced effects on portal pressure. There are 10 published hemodynamic studies involving 168 patients investigating the role of carvedilol in portal hypertension. A reduction in the hepatic venous pressure gradient of up to 43% (range 10-43%) has been reported, particularly after chronic administration. However, tolerability at doses greater than 12.5 mg/day was comprised because of a fall in mean arterial pressure (MAP), particularly in ascitic patients. Carvedilol was more effective than propranolol in reducing hepatic venous pressure gradient in two of three studies, albeit with a greater decrease in MAP. One study showed deterioration of pre-existing ascites with carvedilol. The addition of nitrates to propranolol was less effective than carvedilol monotherapy in another study. A large multicentre, randomized controlled trial comparing carvedilol with variceal band ligation for the prevention of variceal bleeding has been published. Carvedilol resulted in fewer episodes of bleeding, although there was no difference in survival. Carvedilol was well tolerated. Carvedilol is a promising agent, and seems to be more effective than propranolol in hemodynamic studies. The efficacy in primary prevention of variceal bleeding suggests that carvedilol has a role in the management of clinically significant portal hypertension.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the American Heart Association held in Orlando, Florida in 2009. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. Patients with heart failure randomized to high-dose losartan treatment (150 mg) in the HEAAL study had a reduced risk of death or heart failure hospitalization compared with patients in the low-dose (50 mg) group. In FAIR-HF, patients with heart failure and concomitant iron deficiency but without severe anaemia who received iron supplementation therapy demonstrated an improvement in symptoms at 24 weeks compared with placebo. The J-CHF study was too small and was stopped too early to provide definitive evidence about the optimal dose of carvedilol for Japanese patients with heart failure. Results from the HeartMate II study suggest that continuous-flow left ventricular assist devices may offer benefits over pulsatile-flow devices for long-term support in patients with advanced heart failure. In the PACE study, atrial synchronized right ventricular pacing induced adverse effects on left ventricular function compared with atrial synchronized biventricular pacing in patients with standard pacing indications and a normal ejection fraction.

ABSTRACT: BACKGROUND: After coronary artery bypass grafting ischemia/reperfusion injury inducing cardiomyocyte apoptosis may occur. This surgery-related inflammatory reaction appears to be of extreme complexity with regard to its molecular, cellular and tissue mechanisms and many studies have been performed on animal models. However, finding retrieved from animal studies were only partially confirmed in humans. To investigate this phenomenon and to evaluate possible therapies in vitro, adequate human cardiomyocyte models are required. We established a tissue model of human cardiomyocytes preserving the complex tissue environment. To our knowledge human cardiac tissue has not been investigated in an experimental setup mimicking extracorporeal circulation just in accordance to clinical routine, yet. METHODS: Cardiac biopsies were retrieved from the right auricle of patients undergoing elective coronary artery bypass grafting before cardiopulmonary bypass. The extracorporeal circulation was simulated by submitting the biopsies to varied conditions simulating cardioplegia (cp) and reperfusion (rep) in a microperfusion chamber. Cp/rep time sets were 20/7, 40/13 and 60/20 min. For analyses of the calcium homoeostasis the fluorescent calcium ion indicator FURA-2 and for apoptosis detection PARP-1 cleavage immunostaining were employed. Further the anti-apoptotic effect of carvedilol [10 uM] was investigated by adding into the perfusate. RESULTS: Viable cardiomyocytes presented an intact calcium homoeostasis under physiologic conditions. Following cardioplegia and reperfusion a time-dependent elevation of cytosolic calcium as a sign of disarrangement of the calcium homoeostasis occurred. PARP-1 cleavage also showed a time-dependence whereas reperfusion had the highest impact on apoptosis. Cardioplegia and carvedilol could reduce apoptosis significantly, lowering it between 60-70% (p < 0.05). CONCLUSIONS: Our human cardiac preparation served as a reliable cellular model tool to study apoptosis in vitro. Decisively cardiac tissue from the right auricle can be easily obtained at nearly every cardiac operation avoiding biopsying of the myocardium or even experiments on animals. The apoptotic damage induced by the ischemia/reperfusion stimulus could be significantly reduced by the cold crystalloid cardioplegia. The additional treatment of cardiomyocytes with a non-selective beta-blocker, carvedilol had even a significantly higher reduction of apoptotis.

BACKGROUND: The loss of cardiac myocytes is one of the mechanisms involved in acute myocardial infarction (AMI)-related heart failure. Autophagy is a common biological process in eukaryote cells. The relationship between cardiac myocyte loss and autophagy after AMI is still unclear. Carvedilol, a non-selective alpha1- and beta-receptor blocker, also suppresses cardiac myocyte necrosis and apoptosis induced by ischemia. However, the association between the therapeutic effects of carvedilol and autophagy is still not well understood. The aim of the present study was to establish a rat model of AMI and observe changes in autophagy in different zones of the myocardium and the effects of carvedilol on autophagy in AMI rats. METHODS: The animals were randomly assigned to a sham group, an AMI group, a chloroquine intervention group and a carvedilol group. The AMI rat model was established by ligating the left anterior descending coronary artery. The hearts were harvested at 40 minutes, 2 hours, 24 hours and 2 weeks after ligation in the AMI group, at 40 minutes in the chloroquine intervention group and at 2 weeks in other groups. Presence of autophagic vacuoles (AV) in the myocytes was observed by electron microscopy. The expression of autophagy-, anti-apoptotic- and apoptotic-related proteins, MAPLC-3, Beclin-1, Bcl-xl and Bax, were detected by immunohistochemical staining and Western blotting. RESULTS: AVs were not observed in necrotic regions of the myocardium 40 minutes after ligation of the coronary artery. A large number of AVs were found in the region bordering the infarction. Compared with the infarction region and the normal region, the formation of AV was significantly increased in the region bordering the infarction (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the region bordering the infarction. Meanwhile, the expression of apoptotic-related proteins was significantly increased in the infarction region. In the chloroquine intervention group, a large number of initiated AVs (AVis) were found in the necrotic myocardial region. At 2 weeks after AMI, AVs were frequently observed in myocardial cells in the AMI group, the carvedilol group and the sham group, and the number of AVs was significantly increased in the carvedilol group compared with both the AMI group and the sham group (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the carvedilol group compared with that in the AMI group, and the positive expression located in the infarction region and the region bordering the infarction. CONCLUSIONS: AMI induces the formation of AV in the myocardium. The expression of anti-apoptosis-related proteins increases in response to upregulation of autophagy. Carvedilol increases the formation of AVs and upregulates autophagy and anti-apoptosis of the cardiac myocytes after AMI.

BACKGROUND: Erectile dysfunction (ED) is a multifactorial disease related to age, vascular disease, psychological disorders, or medical treatments. Beta-blockade agents are the recommended treatment for hypertensive patients with some specific organ damage but have been outlined as one of leading causes of drug-related ED, although differences between beta-blockade agents have not been assessed. METHODS: Cross-sectional and observational study of hypertensive male subjects treated with any beta-blockade agent for at least 6 months. ED dysfunction was assessed by the International Index of Erectile Dysfunction (IIEF). RESULTS: 1.007 patients, mean age 57.9 (10.59) years, were included. The prevalence of any category of ED was 71.0% (38.1% mild ED; 16.8% moderate ED; 16.1% severe ED). Patients with ED had longer time since the diagnosis of hypertension and higher prevalence of risk factors and comorbidities. The prevalence of ED increased linearly with age. ED patients received more medications and were more frequently treated with carvedilol and less frequently with nebivolol. Patients treated with nebivolol obtained higher scores in every parameter of the IIEF questionnaire. The multivariate analysis identified independent associations between ED and coronary heart disease (OR: 1.57), depression (OR: 2.25), diabetes (OR: 2.27), atrial fibrillation (OR: 2.59), and dyhidopiridines calcium channel blockers (OR: 1.76); treatment with nebivolol was associated to lower prevalence of ED (OR: 0.27). CONCLUSION: ED is highly prevalent in hypertensive patients treated with beta-blockade agents. The presence of ED is associated with more extended organ damage and not to cardiovascular treatments, except for the lower prevalence in nebivolol-treated patients.