Efectos cardioprotectores de implantes subcutáneos de liberación crónica de carvedilol en ratas espontáneamente hipertensas / Cardioprotective Effects of Chronic Release Formulations of Subcutaneous Implants of Carvedilol in Spontaneously Hypertensive Rats

RESUMEN Introducción: En nuestro laboratorio hemos desarrollado implantes subcutáneos de carvedilol capaces de mantener niveles plasmáticos sostenidos del β-bloqueante durante 3 semanas. Objetivo: Evaluación de la liberación in vivo y la eficacia cardioprotectora de implantes subcutáneos de carvedilol desarrollados con poliepsilon- caprolactona (PCL) y Soluplus (SP) en ratas espontáneamente hipertensas (REH). Materiales y métodos: Se utilizaron 12 REH macho (250-300 g), a las cuales se colocó un implante subcutáneo cada 3 semanas de PCL: SP 100:50 mg (control, n = 6) o carvedilol: PCL:SP (100mg:100mg:50mg) (carvedilol, n = 6). Se evaluó el perfil plasmático y el efecto sobre la presión arterial sistólica (PAS) durante 62 días. Al final del tratamiento, se realizaron determinaciones ecocardiográficas y la medición de la PAS y. la presión arterial media (PAM) directas. Resultados: El grupo que recibió el implante conteniendo 100 mg de carvedilol presentó concentraciones plasmáticas del fármaco en el rango de 100- 500 ng/mL a lo largo de 62 días de tratamiento, luego del cual la PAS fue 20 mmHg menor que en el grupo control (217 ± 3 mmHg vs. 237 ± 6 mmHg; p <0,05). Las PAS y PAM directas fueron significativamente menores el grupo tratado que en el control. El implante de carvedilol 100 mg redujo la variabilidad de la presión arterial (VPA) de corto plazo en comparación con el control. Parámetros ecocardiográficos como la fracción de eyección del ventrículo izquierdo (FEVI), fracción de acortamiento, y relación E/A fueron significativamente mayores en las ratas tratadas. El peso del VI fue menor en las ratas que recibieron el implante con carvedilol. Conclusión: Los implantes conteniendo CAR/PCL/SP (100:100:50) mg aportan niveles plasmáticos terapéuticos de carvedilol y estables durante el transcurso del tratamiento, los cuales se correlacionan con una disminución significativa y sostenida de los valores de PA indirecta. El tratamiento con los implantes de carvedilol logró atenuar los valores de PA directa y su variabilidad en las REH. Se demostró que el tratamiento con los implantes ejerció un efecto cardioprotector evidenciado en el ecocardiograma y por una reducción de la hipertrofia ventricular izquierda.

ABSTRACT Background: In our laboratory, we have developed subcutaneous implants of carvedilol capable of maintaining stable concentrations of the β-blocker during 3 weeks. Objective: The aim of this study was to evaluate the in vivo release and the cardioprotective efficacy of subcutaneous implants of carvedilol developed with poly-epsilon-caprolactone (PCL) and Soluplus (SP) polymers in spontaneously hypertensive rats (SHR). Methods: Twelve spontaneously hypertensive male rats (250-300 g) underwent placement of subcutaneous implant of PCL:SP 100:50 mg (control group, n=6) or carvedilol:PCL:SP (100mg:100mg:50mg) (carvedilol group, n=6), every 3 weeks. The plasma profile of each implant and its effect on systolic blood pressure (SBP) was evaluated for 62 days. At the end of treatment, echocardiographic parameters were determined, and direct SBP and direct mean arterial pressure (MAP) were measured. Results: The group that received the implant containing 100 mg of carvedilol presented plasma concentrations of the drug in the range of 100- 500 ng/mL throughout 62 days of treatment, after which the SBP was 20 mmHg lower than in the control group (217±3 mm Hg vs. 237±6 mm Hg; p <0.05). Direct SBP and MAP were significantly lower in the treated group than in the control group. The implant loaded with carvedilol 100 mg reduced short-term blood pressure variability (BPV) in SHR compared with the control group. Echocardiographic parameters as left ventricular ejection fraction (LVEF), shortening fraction and E/A ratio were significantly greater in treated rats. Left ventricular weight was lower in the rats with carvedilol implant. Conclusion: Implants containing CAR/PCL/SP (100:100:50) mg provide therapeutic and stable plasma levels of carvedilol during treatment, which correlate with a significant and sustained decrease in indirect BP values. Treatment with carvedilol implants attenuated dirct BP values and blood pressure variability in SHR. Treatment with implant produced cardioprotective effects evidenced in the echocardiogram by a reduction in left ventricular hypertrophy.

Intoxicación por beta bloqueadores / Beta Blockers Intoxication

La intoxicación por betabloqueadores es una situación clínica de poca frecuencia, estrechamente relacionada con trastornos depresivos mayores, con una prevalencia mayor en mujeres. Los episodios de gravedad relacio- nados a toxicidad por betabloqueadores son clasificados como episodios de moderados a severos. En el caso del carvedilol con un umbral tóxico de 50mg. Caso Clínico: Paciente de 16 años con historia de ingesta de carvedilol en niveles tóxicos y único antecedente depresión ma- yor. Discusión: Los betabloqueadores antagonizan los receptores betaadrenérgicos, la sintomatología relacio- nada con bradicardia e hipotensión es frecuente y puede generar afección a nivel del sistema nervioso central. El tratamiento de emergencia sí se capta al paciente en la primera hora consiste en realizar un lavado gástrico y aplicar carbón activado. Se propone el uso de crista- loides y el uso de epinefrina o norepinefrina como ma- nejo de primera línea, en caso de bradicardias sosteni- das debe considerarse el uso de atropina. Los pacientes asintomáticos deben ser vigilados durante seis horas...(AU)

The Design And Development Of Carvedilol Gastroretentive Floating Drug Delivery Systems Using Hydrophilic Polymers And In Vitro Characterization

Objective: The primary aim of the present examination was to create carvedilol phosphate floating tablets using factorial designs and for retention in the upper portion of the gastrointestinal (GI) tract to sustain the dissolution where the solubility of carvedilol phosphate is more in an acidic medium. Methods: The floating tablets of carvedilol phosphate were ready to employ different concentrations and a combination of these polymers of Na-alginate, Carbopol 934P, and sodium carboxymethyl cellulose (NaCMC) with lubricants magnesium stearate by direct compression technique. In the present experiment, involved sodium bicarbonate and citric acid as a gas-producing agent. Fifteen formulations structured and judged for pre-compression components like the angle of repose, bulk and tapped density, Hausner’s ratio, compressibility index, and post-compression factors are weight uniformity, hardness, drug content, friability, in vitro buoyancy, dissolution studies, and Fourier transforms infrared spectroscopy (FTIR). Results: The drug released 90.02% in 12 h by combining NaCMC (7.5 mg) and Na-alginate (7.5 mg) in the formulation F14 towards the achievement of sustained release. Batch F14 selected as optimized, as provided desired zero-order release profile as well as floating lag time 20 s and total floating time>12 h, and the mechanism of drug release observed (n = 1.098, super case-II transport). Conclusion: From the results fulfilled that all the preparation found to be within the pharmacopeia limits and was the best dosage form to treat moderate heart failure and hypertension. The in vitro dissolution profiles of all formulations placed into various kinetic models, the statistical parameters like slope, regression coefficient and intercept determined. The gastro-retentive dosage form to maintain the sustain drug delivery, which would improve the maximum therapeutic efficacy and patient compliance.

Carvedilol As A Potential Addition To The Covid-19 Therapeutic Arsenal

No single therapeutic agent has been recognized so far as the ultimate treatment for COVID-19 and many treatment strategies rely on associating different medications with proven or hypothetical anti-viral effects. Carvedilol is a third-generation beta-blocker displaying potential inhibitory properties on several key enzymatic processes and pathways involved in SARS-CoV-2 or other coronaviruses replication, in addition to the modulatory effect on several inflammatory messengers of COVID-19. These data could provide a reasonable hypothetical background for further investigating specific anti-SARS-CoV-2 effects and could pave the way for further clinical verification.

Desarrollo de implantes subcutáneos de liberación controlada de Carvedilol para la reducción sostenida de la presión arterial en modelos experimentales de hipertensión arterial / Development of Subcutaneous Implants of Controlled Release Formulations of Carvedilol for Sustained Blood Pressure Reduction in Experimental Models of Hypertension

RESUMEN Objetivo: El objetivo del presente estudio fue el desarrollo y la evaluación farmacocinética y farmacodinámica de la liberación in vivo de implantes subcutáneos de carvedilol capaces de aportar niveles tisulares estables en modelos experimentales de hipertensión arterial. La incorporación del polímero hidrofílico SoluPlus (SP) en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol dado que aporta concentraciones plasmáticas en el rango de 100-200 ng/mL durante 2 semanas, lo que tiene como resultado una reducción sostenida de la presión arterial sistólica indirecta en animales SHR. Material y métodos: Se prepararon implantes subcutáneos de poli (epsilon-caprolactona) (PCL) con diferentes proporciones del polímero hidrofílico SoluPlus (300:0; 250:50; 150:150 y 50:250 mg) cargados con 100 mg de carvedilol. Se evaluó el perfil plasmático y el efecto sobre la presión arterial sistólica (PAS) luego del implante de cada formulación en el tejido subcutáneo de ratas espontáneamente hipertensas (REH) macho. Resultados: Las formulaciones PCL:SP 50:250 y 150:150 aportaron niveles en el rango de 100-200 ng/mL. Las formulaciones PCL:SP 250:50 y 300:0 aportaron concentraciones inferiores de carvedilol comprendidas en el rango de los 0-100 ng/mL durante el transcurso del tratamiento. Los animales espontáneamente hipertensos tratados con PCL:SP 50:250 y 150:150 experimentaron un descenso significativo de la presión arterial sistólica (PCL:SP 50:250: DPAS: -36,6 ± 2,0 mmHg; PCL:SP150:150: 35,7 ± 2,2 mmHg; p <0,05 vs. basal). Conclusiones: La incorporación del polímero hidrofílico SoluPlus en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol, ya que aporta concentraciones plasmáticas del β-bloqueante que aseguran una reducción sostenida de la PAS indirecta en animales espontáneamente hipertensos.

ABSTRACT Objective: The aim of this study was the development and pharmacokinetic/pharmacodynamic evaluation of the in vivo release of subcutaneous implants of carvedilol capable of providing stable tissue levels in experimental models of hypertension. Methods: The subcutaneous implants were prepared with poly (epsilon-caprolactone) (PCL) and different proportions of the SoluPlus (SP) hydrophilic polymer (300:0; 250:50; 150:150 and 50:250 mg) loaded with 100 mg carvedilol. The plasma profile and the effect on systolic blood pressure (SBP) after subcutaneous implantation of each formulation was evaluated in male spontaneously hypertensive rats (SHR). Results: The PCL:SP 50:250 and 150:150 formulations provided levels ranging from 100 to 200 ng/mL and the PCL:SP 250:50 and 300:0 formulations provided lower concentrations of carvedilol ranging from 0 to 100 ng/mL during the treatment period. Spontaneously hypertensive animals treated with the PCL:SP 50:250 y 150:150 implants presented a significant decrease in SBP (PCL:SP 50:250: DPAS: -36.6 ± 2.0 mm Hg; PCL:SP150:150: -35.7 ± 2.2 mmHg; p <0.05 vs. baseline values) Conclusions: The incorporation of the SoluPlus hydrophilic polymer in PC:SP 150:150 and 50:250 implants increases the release of carvedilol, since it provides plasma concentrations ranging from 100 to 200 ng/ml, resulting in a sustained reduction of indirect SBP in SHR.

Risk of dementia in patients taking beta blocker as antihypertensive treatment: a cross sectional study

Background: Hypertension is considered to be the third most important disease in the list of diseases in the south Asian region. Several trials have shown active treatment of hypertension reduced the incidence of dementia. This study was adopted to understand the cognitive status of patients using beta blockers for hypertension for a period of more than 5 years.Methods: The study was done during the period of August 2018 and September 2018. Patients taking beta blockers for atleast 5 years were included and was made to take the MMSE test which is scored out of 30 marks containing 11 questions, each of varying marks.Results: In the study, 54 patients were included, 8 out of 54 patients taking beta blockers obtained a score of 30 which is 15% of the study population taking beta blockers, 15 out of 54 patients taking beta blockers obtained a score of 29 which corresponds to 28% of the study population, 21 out of 54 individuals taking beta blockers obtained a score of 28 which is 39% of the population taking it, 7 patients taking beta blockers obtained a score of 27 pertaining to 13% of the population. One patient obtained a score of 26 and two patients scored 25 out of 30. The average score obtained was 28.2963.Conclusions: About 18.5% of the study population had scores below the average value of 28 in this study. This population is at higher risk of developing dementia in the future and need follow up.

Carvedilol solid dispersion for enhanced oral bioavailability using rat model

The objective of the present study was to develop a solid dispersion formulation to improve oral bioavailability of poorly water-soluble drug carvedilol. Several solid dispersions were prepared by fusion-solvent method mixing different concentrations of Gelucire 44/14 and Gelucire 50/13. To the resultant solid dispersions, microcrystalline cellulose and amorphous fumed silica were added to obtain a free-flowing powder. The dissolution of carvedilol was evaluated using an USP Type-II dissolution apparatus. Solid dispersion with Gelucire 44/14 showed, in general, a lower extent of drug release when compared to Gelucire 50/13 at the same concentrations. Gelucire 50/13 in a ratio of 1 to 1.75 (drug: Gelucire) achieved a drug release of 83% in 4 hours, a 5-fold increase compared to pure carvedilol. When incorporating 10% D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS/ TPGS) a higher drug release was observed (88%). Parallel artificial membrane permeability assay was used to evaluate the in vitro diffusion. GelucireTPGS solid dispersion showed a higher permeability coefficient compared to pure drug. After oral administration to Sprague-Dawley rats, a significant increase in the oral bioavailability of carvedilol was observed when administered as a solid dispersion in combination with Gelucire-TPGS, 169% higher compared to pure drug suspension.

Comparison of protective effects of carvedilol and ?-tocopherol on doxorubicin-induced cardiotoxocity

Background: Doxorubicin, an effective anticancer drug used to treat multiple solid tumours and childhood malignancies since many decades but its cardiac adverse effects limits its use in full therapeutic dose. The mechanism involved in cardiotoxicity is apoptosis of cardiomyocytes due to reactive oxidative stress. The study was conducted to compare the cardioprotective effects of carvedilol and ?-Tocopherol and to detect myocardial injury at early stage.Methods: Cardiotoxicity was produced in a group of rabbits by single intravenous injection of doxorubicin; control group was treated with normal saline only. Third and fourth groups were pretreated with carvedilol 30 mg/kg bodyweight and ?-Tocopherol 200 mg/kg bodyweight respectively for ten days before injection of doxorubicin.Results: Doxorubicin produced marked cardiotoxicity represented by raised levels of serum biomarkers (cTnI, LDH and CK-MB) and severe necrosis of cardiomyocytes on microscopic examination. Carvedilol and ?-tocopherol pretreatment resulted in decreased serum levels of biomarkers and improved the histological picture of heart tissue.Conclusions: The outcome of doxorubicin chemotherapy can be made successful with the concurrent use of carvedilol or ?-tocopherol. Although carvedilol has more pronounced cardioprotective effects perhaps due to its antioxidant activity in addition to antiapoptotic, antiproliferative and anti-inflammatory effects. Furthermore the quantitative cTnI estimation for detection of cardiotoxicity at early stage can lead to significant economic impact in management of cancer.

Evaluation of Cardioprotective activity of Asparagus racemosus against Doxorubicin induced cardiotoxicity in albino rats: an experimental study

Background: Cardiotoxicity is one of the most feared side effects of anticancer agents like Doxorubicin. Asparagus racemosus is a widely used medicinal plant in Indian system of medicine known for its antioxidant activity. In certain studies ethanol extract of Asparagus racemosus has shown to possess cardioprotective activity in experimental animals while in some other studies cardioprotective potential of Asparagus racemosus has not been demonstrated. Therefore, due to the controversial action, the present study was designed to explore the cardioprotective effect of aqueous effect of Asparagus racemosus against doxorubicin induced cardiotoxity.Methods: Following approval from Institutional Animal Ethics Committee of L.L.R.M Medical College registered under CPCSEA, India, this study was conducted in which 30 rats were randomized into five groups of six rats each. Group I received 2 ml/kg b.w. normal saline p.o for 21 days, group II apart from receiving pellet diet and normal saline for 21 days were treated with Doxorubicin in a single dose of 20 mg/kg intraperitoneally on the 21st day, group III and group IV received aqueous extract of Asparagus racemosus in doses of 250 mg/kg/day and 500 mg/kg/day respectively p.o. for 21 days followed by administration of Doxorubicin (20 mg/kg i.p.) on the 21st day, Group V received Carvedilol in doses of 30 mg/kg/day p.o. for 21 days followed by administration of Doxorubicin (20mg/kg i.p) on the 21st day. Then they were anaesthetized and blood sample was collected from abdominal aorta for performing blood test i.e. Creatinine kinase MB fraction (CK-MB), Lactate dehydrogenase (LDH), Serum glutamate oxaloacetate transaminase (SGOT), Serum glutamate pyruvate transaminase (SGPT). After blood collection the animals were sacrificed and heart was dissected out for histopathological study. The data obtained was organized and analysed by suitable statistical methods i.e. ANOVA followed by Post Hoc test.Results: CK-MB, LDH, SGOT and SGPT levels were found to be significantly raised (p<0.001) in Doxorubicin treated group. Asparagus racemosus pretreated groups exhibited significant limitation (p<0.001) in rise in levels of CK-MB,LDH,SGOT and SGPT levels in a dose dependent manner following Doxorubicin administration which were comparable to the group treated with the standard cardioprotective drug Carvedilol. Histopathological changes further corroborated cardioprotective potential of Asparagus racemosus.Conclusions: The present study concluded that aqueous extract of Asparagus racemosus possess cardioprotective potential against Doxorubicin induced cardiotoxicity.

Temperature and eluent composition effects on enantiomer separation of carvedilol by high-performance liquid chromatography on immobilized amylose-based chiral stationary phases / 药物分析学报

Carvedilol is a chiral drug with potent antihypertensive and antianginal activities. Although it is clinically used as a racemic mixture, its enantiomers show different pharmacokinetic and pharmacodynamic profiles. Here, the direct chiral separation of racemic drug by high performance liquid chromatography using two immobilized-type amylose-based chiral stationary phases is presented. Some chromato-graphic parameters, such as retention and selectivity, were determined under multimodal eluent con-ditions and different temperatures. A temperature-dependent inversion of the elution order of enantiomers was observed in the operative temperature range of chiral chromatographic support. Finally, an effective direct enantioselective method was successfully applied to the separation of the enantiomers of carvedilol on a semipreparative scale.

Mechanism and current status of carvedilol in treatment of cirrhotic portal hypertension / 临床肝胆病杂志

The formation of cirrhotic portal hypertension depends on the increase in intrahepatic vascular resistance and the state of hyperdynamic circulation. The specific effect of carvedilol in reducing intrahepatic vascular resistance has a better effect in alleviating portal hypertension in theory. This article summarizes the known and possible mechanisms of carvedilol in reducing portal hypertension and reviews the latest research advances in the role of carvedilol in the treatment of cirrhotic portal hypertension. It is pointed out that carvedilol is expected to become the core drug in the treatment of cirrhotic portal hypertension, and statins may be their best partner.

Evaluation of cardioprotective effect of Aegle marmelos on doxorubicin induced cardiotoxicity: an experimental study

Background: Aegle marmelos (A. marmelos), a medicinal herb, is widely used in the Indian system of medicine for treatment of various ailments. The methanolic extract of A. marmelos leaves had shown antioxidant effect. However, so far aqueous extract of A. marmelos is not scientifically evaluated for its cardio protective potential. Hence the present study was designed to find out cardio protective role of A. marmelos against doxorubicin induced cardiotoxicity.Methods: Thirty rats were randomized into five major groups (n=6). Group I received only 2ml/100g/day normal saline p.o., group II received 2ml/100g/day of normal saline p.o. followed by doxorubicin on 21st day, group III received carvedilol 30 mg/kg/day p.o., Group IV received A. marmelos 250mg/kg/day p.o. and Group V received A. marmelos 500mg/kg/day p.o. for 21days. Doxorubicin 20mg/kg i.p. single dose was given to induce cardiotoxicity in rats of group II, III, IV and V respectively on last day of experiment. Animals were sacrificed 48 hours after doxorubicin administration. Cardiac serum markers creatinine phosphokinase MB, lactate dehydrogenase, serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase were analysed biochemically. Histopathological changes were studied under light microscope.Results: All cardiac serum marker levels were found significantly (p<0.001) increased in doxorubicin group while A. marmelos pre-treated group displayed significant (p<0.001) reduction in rise of these parameters in a dose dependent manner indicating cardio protection. Histological observations further correlated the cardio protective effect of A. marmelos.Conclusions: The present study concluded that aqueous extract of A. marmelos possesses cardio protective potential against doxorubicin induced cardiotoxicity.

Protective effect of carvedilol against anthracycline-induced cardiomyopathy on patients with breast cancer and lymphoma

Background:Anthracycline antibiotics are potent antineoplastic agents. Unfortunately, despite its broad effectiveness, anthracycline therapy is associated with irreversible dilated cardiomyopathy. Toxic effect may occur at any stage of anthracycline treatment. When it takes place, medical therapy is mostly insufficient. Therefore, prevention of cardiomyopathy has great clinical importance. This study aimed at evaluating the protective effect of carvedilol against anthracycline-induced cardiomyopathy on patients with breast cancer and lymphoma.Methods: In a randomized clinical trial, 66 patients with breast cancer or lymphoma selected for chemotherapy in Tabriz city hospital. These patients randomized in three groups; the first group (control) received placebo; the second group (A) received carvedilol 6.25mg/d and the third group (B) received carvedilol 12.5mg/d for 4months. Conventional echocardiography and tissue Doppler study were employed for evaluating the patients on the baseline and at the end of survey.Results:At the end of 4 months of follow-up, 1 (4.5%) patient in group B, 2 (9.1%) patients in group A and 4 (18.2%) patients of the control group had died. Clinical systolic dysfunction was encountered in 5 (27.8%), 5 (25%) and 1 (4.8%) patients in the control, A and B groups, respectively. A distinctive clinical diastolic dysfunction was encountered in 5 (27.8%), 3 (15%) and 3 (14.3%) patients in the control, A and B groups, respectively. Carvedilol with a dose of 6.25mg/d prohibited the diastolic dysfunction at the end of study without a significant effect on the prevention of diastolic dysfunction. Carvedilol with a dose of 12.5mg/d effectively prevented both the systolic and diastolic dysfunctions at the end of study.Conclusions:The current study showed that prophylactic administration of carvedilol with a dose of 12.5 mg/d might significantly prevent the systolic and diastolic dysfunction of the left ventricle in patients receiving chemotherapy with anthracycline

Influence of CYP2D6 Polymorphism on the Pharmacokinetic/Pharmacodynamic Characteristics of Carvedilol in Healthy Korean Volunteers

BACKGROUND: Carvedilol is commonly used to treat hypertension as a β- and α1-adrenoreceptor blocker, but it is metabolized by CYP2D6, and CYP2D6*10 allele is dominant in Asian population. The objective of this study was to assess the influence of CYP2D6 polymorphisms on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of carvedilol in healthy Korean volunteers. METHODS: A PK/PD study for a single and multiple dosing of carvedilol were conducted. All volunteers in 3 genotypic groups received single oral dose of carvedilol 12.5 mg for 3 days, then 25 mg QD for 5 days, and 12.5 mg QD for another 3 days. PK parameters for carvedilol and its three metabolites were determined using non-compartmental analysis. For PD properties, blood pressure, heart rate, and the chronotropic dose 25 (CD25) value were obtained. RESULTS: The IM_2 group with two *10 alleles (intermediate metabolizers) exhibited lower clearance of carvedilol as well as higher area under the curve (AUC) for O-desmethyl carvedilol. The ratio of CD25 to baseline at multiple dosing was significantly higher in the combined IM group (IM_1 and IM_2) than in the EM group, however, the ratio of CD25 after single and multiple dosing and the other PD markers were not significantly different between the 3 genotypic groups compared with the baseline. CONCLUSION: These findings showed that CYP2D6 genotype influenced the PK characteristics of carvedilol and no differences in PD response were observed in Korean healthy volunteers. Registered at the ClinicalTrials.gov, NCT02286934.

The B-blocker carvedilol and the benznidazole modulate the cardiac immune response in the acute infection induced by Colombian strain of the Trypanosoma cruzi

BACKGROUND The infection led by Trypanosoma cruzi persists in mammalian tissues causing an inflammatory imbalance. Carvedilol (Cv), a non-selective beta blocker drug indicated to treat heart failure and antihypertensive has shown to promote antioxidant and immunomodulatory properties which might improve the inflammation induced by T. cruzi. OBJECTIVES Evaluate the role of Cv on the inflammatory response of C57BL/6 mice acutely infected with the Colombian strain of T. cruzi. METHODS Animals were infected with the Colombian strain of T. cruzi and treated with Cv (25 mg/kg/day), benznidazole (Bz) (100 mg/kg/day) or their combination. On the 28th day of infection and 23 days of treatment, the euthanasia occurred, and the heart preserved for histopathological, oxidative stress (SOD, catalase, TBARs, carbonylated proteins) and plasma (CCL2, CCL5, TNF, IL-10) analyses. Parasitaemia and survival were assessed along the infection. FINDINGS Cv decreased TBARs, but increased the mortality rate, the parasitaemia and the levels of CCL2, CCL5, catalase and the inflammatory infiltrate in the cardiac tissue. Bz led the reduction of the inflammatory infiltrate and circulating levels of oxidative stress and inflammatory mediators in the infected mice. MAIN CONCLUSIONS Our data suggest that Cv, in this experimental model using the Colombian strain of T. cruzi, caused damage to the host.

Augmented cytotoxic, mutagenic and genotoxic response triggered by carvedilol and celecoxib combinations

It is understood that drugs regardless of their order of administration can exhibit drug interactions. Established on the fact that treatment of hypertension may last for decades and prolong usage of multiple drug regimen may induce substantial pathophysiological changes. Hence, This study was designed to evaluate the possible synergistic toxic effects of anti-hypertensive (carvedilol), and anti-inflammatory drug (celecoxib) alone and in combinations. Well-established MTT assay, Single Cell Gel Electrophoresis (SCGE) and Ames assay were employed to evaluate the toxicity at cellular level. Results from MTT assay on Vero cell line revealed that drug combinations have more pronounced anti-proliferative activity with combine IC50 value of 13.7:47.8 µg/mL. Likewise, exposure of peripheral blood mononuclear cells with drug combinations revealed significant (P<0.05) DNA damage (Class 3) in a dose dependent manner at concentrations ≥ 0.78: 2.34 µg/mL. However, carvedilol and celecoxib were non mutagenic against either mutant strain (TA 100 and TA 98) and combinations have also shown mild to moderate mutagenic potential. Nevertheless, upon addition of metabolic activation enzyme, concentration <12.5:37.5 µg/plate exhibited significant (P<0.05) mutagenicity against both tester strains. In conclusion, this study provides additional genotoxicity and mutagenicity data that could be used in considering options for formulating regimens with reduced mutagenic potential

Mechanism of carvedilol against myocardial ischemia/reperfusion injury / 医学研究生学报

Objective Carvedilol (Cvd) has a potential cardioprotective effect against myocardial ischemia/reperfusion (I/R) injury but its molecular mechanism is not yet clarified. The present study aimed to investigate whether the mechanism of Cvd against myocardial I/R injury-induced cardiomyocyte apoptosis is associated with its protection of the myocardium by modulating the unfolded protein response (UPR).Methods Forty male SD rats were randomly divided into five groups of equal number, sham operation, I/R, I/R + UPR agonist dithiothreitol (I/R+DTT), I/R + DTT with Cvd pretreatment at 5 mg/kg (I/R+DTT+Cvd), and I/R with Cvd pretreatment at 5 mg/kg (I/R+Cvd). The myocardial infarct size (infarct area / area-at-risk, IA/AAR) was measured by TCC & Evans blue double staining, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) detected by echocardiography, the apoptosis of the myocardiocytes determined by TUNEL staining, the activation of the UPR signaling pathway and the expressions of Caspase-12 and Casoase-3 detected by Western blot, and the concentrations of LDH and CK-MB assayed with the detection kit, followed by a comprehensive evaluation of the effects of Cvd on myocardial I/R injury.Results Myocardial IA/AAR was significantly increased in the I/R+DTT group as compared with the sham operation control (\[54.1±3.28\] % vs \[24.25±3.19\] %, P<0.05), higher in the I/R+DTT and I/R+DTT+Cvd (P<0.05) but lower in the I/R+Cvd than in the I/R group (P<0.05), and lower in the I/R+DTT+Cvd than in the I/R+DTT group (P<0.05). In comparison with the sham operation control, all the other four groups showed significantly decreased LVEF and LVFS (P<0.05), both remarkably lower in the I/R+DTT (\[44.5±1.56\] % and \[19.2±2.23\] %) than in the I/R group (\[61.5±2.63\] % and \[28.4±1.42\] %) (P<0.05), but higher in the I/R+DTT+Cvd and I/R+Cvd groups (P<0.05). The apoptosis rate of the cardiomyocytes was markedly increased in the I/R, I/R+DTT, I/R+DTT+Cvd, and I/R+Cvd groups as compared with that in the sham operation control (\[24.4±2.65\]%, \[48.3±1.62\]%, \[32.6±1.28\] % and \[13.2±2.21\]% vs \[6.2±1.27\]%, P<0.05), higher in the I/R+DTT and I/R+DTT+Cvd (P<0.05) but lower in the I/R+Cvd than in the I/R group (P<0.05). Compared with the sham operation control, the other four groups exhibited significantly elevated levels of expressions of the GRP78, CHOP and ATF6 proteins (P<0.05), all markedly higher in the I/R+DTT (P<0.05) but lower in the I/R+Cvd (P<0.05) and that of GRP78 lower in the I/R+DTT+Cvd than in in the I/R group (P<0.05), and all lower in the I/R+DTT+Cvd than in the I/R+DTT group (P<0.05).Conclusion Carvedilol can significantly alleviate the apoptosis of cardiomyocytes, and its molecular mechanism is related to its inhibitory effect on the UPR pathway.

Influence of valsartan combined carvedilol on heart function and myocardial remodeling in patients with heart failure with preserved ejection fraction / 心血管康复医学杂志

Objective: To study therapeutic effect of valsartan combined carvedilol on patients with heart failure with preserved ejection fraction (HFPEF) and its influence on heart function and myocardial remodeling. Methods: A total of 92 aged HFPEF patients treated in our hospital were selected. They were randomly and equally divided into routine treatment group and combined treatment group (received valsartan combined carvedilol based on routine treatment), and both groups were treated for six months. Therapeutic effect, heart function, myocardial remodeling indexes and adverse reactions were compared between two groups after six months. Results: Total effective rate of combined treatment group was significantly higher than that of routine treatment group (93. 48％ vs. 78. 26％, P=0. 036). Compared with routine treatment group after treatment, there were significant reductions in blood pressure [(120. 26±9. 17) / (73. 56±5. 86) mmHg vs. (115. 68±10. 31) / (67. 24±4. 92) mmHg], heart rate [(74. 35±8. 53) beats/min vs. (68. 48±7. 17) beats/min]and BNP level [(299. 86±19. 43) pg/ml vs. (231. 71± 20. 15) pg/ml], significant rise in E/A [(1. 02±0. 09) vs. (1. 26±0. 07)] and LVEF [(53. 14±1. 60) ％ vs. (57. 02±1. 51) ％]; and significant reductions in IVRT [(119. 45±14. 23) ms vs. (102. 17±11. 53) ms], LAVI [(35. 82±7. 15) ml/m2 vs. (30. 17±6. 48) ml/m2], LVEDd [(57. 22±7. 24) mm vs. (50. 61±6. 35) mm]and LVESd [(50. 14±5. 06) mm vs. (44. 93±5. 82) mm]in combined treatment group, P＜0. 05 or＜0. 01. During treatment, no obvious adverse reactions occurred in two groups. Conclusion: Valsartan combined carvedilol can significantly increase effective rate, improve heart function and myocardial construction in HFPEF patients. Which is worth extending.

Advances in the effect of carvedilol in prevention and treatment of esophageal variceal bleeding in patients with cirrhosis / 临床肝胆病杂志

Carvedilol is a new non-selective beta blocker, and studies have proven that the effect of carvedilol in receptor blocking is 2-4 times that of propranolol. Carvedilol is widely used in the treatment of heart failure. However, there are still controversies over its effect in reducing portal pressure and preventing esophageal variceal bleeding. This article analyzes and compares the clinical application of carvedilol, propranolol, and endoscopic variceal ligation in the prevention and treatment of bleeding and summarizes the pharmacological action, clinical effect, dose, and adverse reactions of carvedilol. It is pointed out that carvedilol can significantly improve hemodynamic disorder caused by portal hypertension and thus may become a new drug for the prevention and treatment of esophageal variceal bleeding.

Effects of Bisoprolol Are Comparable with Carvedilol in Secondary Prevention of Acute Myocardial Infarction in Patients Undergoing Percutaneous Coronary Intervention / 전남의대학술지

Although the benefits of carvedilol have been demonstrated in the era of percutaneous coronary intervention (PCI), very few studies have evaluated the efficacy of bisoprolol in the secondary prevention of acute myocardial infarction (MI) in patients treated with PCI. We hypothesized that the effect of bisoprolol would not be different from carvedilol in post-MI patients. A total of 13,813 patients who underwent PCI were treated either with carvedilol or bisoprolol at the time of discharge. They were enrolled from the Korean Acute MI Registry (KAMIR). After 1:2 propensity score matching, 1,806 patients were enrolled in the bisoprolol group and 3,612 patients in the carvedilol group. The primary end point was the composite of major adverse cardiac events (MACEs), which was defined as cardiac death, nonfatal MI, target vessel revascularization, and coronary artery bypass surgery. The secondary end point was defined as all-cause mortality, cardiac death, nonfatal MI, any revascularization, or target vessel revascularization. After adjustment for differences in baseline characteristics by propensity score matching, the MACE-free survival rate was not different between the groups (HR=0.815, 95% CI:0.614–1.081, p=0.156). In the subgroup analysis, the cumulative incidence of MACEs was lower in the bisoprolol group in patients having a Killip class of III or IV than in the carvedilol group (HR=0.512, 95% CI: 0.263–0.998, p=0.049). The incidence of secondary end points was similar between the two beta-blocker groups. In conclusion, the benefits of bisoprolol were comparable with those of carvedilol in the secondary prevention of acute MI.