Effects Of Carvedilol Research Articles

Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB

Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.

Efficacy and safety of carvedilol in combination with bronchodilators in patients with CHF of ischemic origin and COPD.

Objective. To study the effectiveness of carvedilol, tiotropium bromide and indacaterol in complex therapy on clinical and functional parameters in patients with CHF of ischemic origin in combination with COPD.
 Material and methods. The study included 98 patients aged 45–75 years, suffering from CHF II–III FC with post-infarction cardiosclerosis, LV ejection fraction less than 45% and COPD of 2–3 degrees (GOLD). In addition to basic therapy all patients received carvedilol and were divided into 3 groups: tiotropium was administered in the 1st (36 people), indacaterol in the 2nd (32 people), and a combination of tiotropium and indacaterol in the 3rd (30 people). At baseline and after 6 months of follow-up, the clinical condition, exercise tolerance were assessed, the quality of life was assessed using the clinical state rating scale (SHOX) and MRC dyspnea scale, questionnaires of University of Minnesota (MLHFQ) and St. George’s Hospital (SGRQ). EchoCG, 24-hour blood pressure monitoring with simultaneous ECG recording, and spirometry test were performed.
 Results. The use of carvedilol in combination with tiotropium and indacaterol (both in mono and in combination) as part of complex therapy of CHF II–III FC of ischemic genesis with COPD is safe and effective: the clinical condition of patients improved, quality of life, frequency and duration of ischemia episodes decreased significantly, significantly increased LVEF, decreased pulmonary hypertension, improved condition of the bronchopulmonary system.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Carvedilol and thyroid hormones co-administration mitigates oxidative stress and improves cardiac function after acute myocardial infarction

After acute myocardial infarction (AMI), reactive oxygen species and oxidative stress have important roles in the progression to heart failure. As a therapeutic alternative, thyroid hormones (TH) revealed cardioprotective effects after AMI, including decreasing oxidative stress. Carvedilol beta-blocker, already used in the clinical treatment of AMI, also mitigate cardiac pathological remodelling. This study assessed the effects of post-AMI carvedilol and TH co-administration on oxidative stress and cardiac function as well as whether those effects were synergistic. Male Wistar rats were divided into five groups: sham-operated (SHAM), infarcted (MI), infarcted + TH (MI + TH), infarcted + carvedilol (MI + C) and infarcted + C + TH (MI + C + TH). Two days post-surgery, the SHAM and MI groups received saline, and treated groups received their respective treatments by gavage for 12 days. The animals were submitted to echocardiographic evaluation, ventricular catheterization and euthanized for heart collection to perform oxidative stress analysis. Treated groups improved for ejection fraction compared to the MI group. Carvedilol decreased the positive chronotropic TH effects in the MI + C + TH group. The MI and MI + C groups had increased reactive oxygen species and reduced sulfhydryl levels. Carvedilol and TH co-administration showed synergic effects in the MI + C + TH group, reducing reactive oxygen species levels and improving GSH/GSSG ratio. Moreover, co-treatment attenuated NADPH oxidase activity in the MI group. Therefore, this study showed for the first time that carvedilol and TH co-administration may improve redox balance and cardiac function after AMI. Such co-administration could represent a therapeutic strategy capable of preventing cardiac dysfunction and redox unbalance after AMI.

Carvedilol Repurposing in Orofacial Pain: Preclinical Findings in Adult Zebrafish

Carvedilol is a non‐selective β‐adrenergic antagonist that is used in the treatment of heart diseases. β‐blockers are known to have an anti‐inflammatory effect that contributes to its analgesic effect. Here we show the acute orofacial antinociceptive effect of carvedilol in adult zebrafish (Danio rerio). Acute nociception was induced by capsaicin (4.93 μM; TRPV1 agonist), formalin (0.1 %; TRPA1 agonist) or menthol (1.2 μM; TRPM8 agonist) into in the upper lip (5.0 μL) of adult wild (short‐fin phenotype) zebrafish. Corneal nociception was induced with hypertonic saline (TRPV1 agonist; 5.0 M NaCl; 5.0 μL) applied into the surface of the right or left eye of the fishes. Then, animals (n=6/group) were placed in a glass Petri dish (10 × 15 cm), divided into quadrants, and the nociceptive response was registered after capsaicin (10 – 20 min), formalin (0 – 5 and 15 – 30 min), menthol (0 – 10 min) or hypertonic saline (0 – 5 min) application. Zebrafish were pretreated by gavage (20 μL) with vehicle (Control; 3 % Tween 80) or carvedilol (0.03; 0.1 or 0.3 mg/mL) 60 min before induction. The effect of carvedilol on zebrafish locomotor behavior was evaluated with the open field test (0 – 5 min). Naive groups (n=6) were included. The interaction between carvedilol and TRPV1 was analyzed using molecular docking. The HEX software was used for molecular docking calculations and the direct action of carvedilol on TRPV1 was viewed using PyMOL v1.4.7. The experimental protocols followed the ethical guidelines of CONCEA (Brazilian Council for the Control of Animal Experimentation) and were approved by the UECE Animal Research Ethics Committee (#7210149/2016). Pre‐treatment with carvedilol (0.03 and 0.1 mg/mL) was associated with a reduction in nociceptive behavior induced by capsaicin and hypertonic saline (TRPV1 agonists; (*p<0.05 vs Control), but not by formalin, or menthol. Carvedilol per se promoted no alteration on the locomotor activity of zebrafish. In the docking experiments, the interaction between carvedilol and the TRPV1 channel showed high reproducibility. It was possible to observe a direct action of carvedilol on TRPV1 amino acids (Asn687, Asn687, Asn687, Asn687, Ala680 and Gly683). The results indicate the potential clinical application of carvedilol an inhibitor of orofacial nociception and that this effect may be due to the modulation of TRPV1 channel.Support or Funding InformationNational Council for Scientific and Technological Development ‐ CNPqCoordination for the Improvement of Higher Education Personnel ‐ CapesResearch Support Foundation of Ceará State ‐ FuncapEdson Queiroz Foundation ‐ FEQThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparative study of carvedilol and quinidine for inhibiting hKv4.3 channel stably expressed in HEK 293 cells

The inhibition of transient outward potassium current (Ito) is the major ionic mechanism for quinidine to treat Brugada syndrome; however, quinidine is inaccessible in many countries. The present study compared the inhibitory effect of the nonselective β-adrenergic blocker carvedilol with quinidine on human Kv4.3 (hKv4.3, encoding for Ito) channel and action potential notch using a whole-cell patch technique in HEK 293 cell line expressing KCND3 as well as in ventricular epicardial myocytes of rabbit hearts. It was found that carvedilol and quinidine inhibited hKv4.3 current in a concentration-dependent manner. The IC50 of carvedilol was 1.2 μM for inhibiting hKv4.3 charge area, while the IC50 of quinidine was 2.9 μM (0.2 Hz). Both carvedilol and quinidine showed typical open channel blocking properties (i.e. decreasing the time to peak of activation and increasing the inactivation of hKv4.3), negatively shifted the V1/2 of activation and inactivation, and slowed the recovery from inactivation of the channel. Although carvedilol had weaker in use- and rate-dependent inhibition of hKv4.3 peak current than quinidine, its reduction of the charge area was more than quinidine at all frequencies (0.2–3.3 Hz). Moreover, the inhibitory effect of carvedilol on action potential notch was greater than quinidine. These results provide the novel information that carvedilol, like quinidine, significantly inhibits hKv4.3 and action potential notch, suggesting that carvedilol is likely an alternative drug for preventing malignant ventricular arrhythmias in patients with Brugada syndrome in countries where quinidine is unavailable.

MicroRNA‑1 downregulation induced by carvedilol protects cardiomyocytes against apoptosis by targeting heat shock protein 60.

Myocardial infarction (MI) is the most common event in cardiovascular disease. Carvedilol, a β-blocker with multiple pleiotropic actions, is widely used for the treatment cardiovascular diseases. However, the underlying mechanisms of carvedilol on alleviating MI are not fully understood. The aim of the present study was to investigate whether the beneficial effects of carvedilol were associated with regulation of microRNA-1 (miR-1). It was demonstrated that carvedilol ameliorated impaired cardiac function and decreased infarct size in a rat model of MI induced by coronary artery occlusion. Similarly, carvedilol reversed the H2O2-induced decrease in cardiomyocyte viability in a dose-dependent manner. The in vivo and in vitro models demonstrated the downregulation of miR-1 following treatment with carvedilol. Overexpression of miR-1, a known pro-apoptotic miRNA, decreased cell viability and induced cell apoptosis. Transfection of miR-1 abolished the beneficial effects of carvedilol. The expression of heat shock protein 60 (HSP60), a direct target of miR-1, was identified to be decreased in MI and H2O2-induced apoptosis, which was associated with a decrease in Bcl-2 and an increase in Bax; expression was restored following treatment with carvedilol. It was concluded that carvedilol partially exhibited its beneficial effects by downregulating miR-1 and increasing HSP60 expression. miR-1 has become a member of the group of carvedilol-responsive miRNAs. Future studies are required to fully elucidate the potential overlapping or compensatory effects of known carvedilol-responsive miRNAs and their underlying mechanisms of action in the pathophysiology of cardiovascular diseases.

Acute effects of intravenous carvedilol versus metoprolol on baroreflex-mediated sympathetic circulatory regulation in rats

AimsTo compare the effects of metoprolol and carvedilol on baroreflex-mediated sympathetic circulatory regulation. MethodsIn anesthetized Wistar–Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA), arterial pressure (AP), heart rate (HR), and aortic flow (AoF) in response to a staircase-wise pressure input were examined before (control) and after intravenous injection of low-dose metoprolol (2 mg/kg), high-dose metoprolol (10 mg/kg), or carvedilol (0.67 mg/kg) (n = 6 each). Peripheral vascular resistance (PVR) was calculated from mean AP divided by mean AoF. ResultsLow-dose metoprolol had limited effect on sympathetic AP regulation compared to control [operating-point AP (drug vs. control): 88.7 ± 7.1 vs. 98.3 ± 3.3 mm Hg, not significant] despite a significant bradycardic effect. Although high-dose metoprolol showed central sympathoinhibition, it increased PVR at a given SNA as a peripheral effect. Consequently, high-dose metoprolol decreased the operating-point AP slightly (96.1 ± 2.7 vs. 101.9 ± 2.7 mm Hg, P < 0.01). Carvedilol showed no significant central sympathoinhibition at the dose examined in this study, but significantly reduced PVR at a given SNA, leading to a marked reduction in the operating-point AP (71.9 ± 8.2 vs. 112.6 ± 7.6 mm Hg, P < 0.05). ConclusionLow-dose metoprolol has limited hypotensive effect despite blockade of sympathetic HR regulation. Although high-dose metoprolol induces central sympathoinhibition, it also induces peripheral vasoconstriction that antagonizes the hypotensive effect. In contrast, carvedilol exhibits hypotensive effect mainly through peripheral vasodilation. Although carvedilol is frequently classified as a β-blocker, its vasodilatory effect via α1-adrenergic blockade plays an important role in AP reduction or heart failure treatment.

Interrelation of liver vascularity to non-alcoholic fatty liver through a comparative study of the vasodilator effect of carvedilol or nicorandil in rats

AimAn experimental study of the effect of two vasodilators, carvedilol (B blocker with alpha-antagonist) and nicorandil (NO donor) on nonalcoholic fatty liver (NAFLD) induced by hypercholesterolemia and fatty diet in rats through studying the possible anti-inflammatory and antioxidant mechanisms. Main methodsThe rats were divided into 4 groups (6 rats each): The first (negative control group). The second, third and fourth groups were fed with cholesterol and fat- enriched diet for one month that stopped and continued on the standard diet for another month without treatment in the second group but treated with carvedilol and nicorandil in the third and fourth group respectively. Key findingsThey revealed that both improved NAFLD especially nicorandil treated proved by the reduction of liver enzymes (AST, ALT), the fatty infiltration determined histologically and biochemically (decrease liver triglycerides). This may be due to either being antioxidants (reduced malondialdehyde and elevated reduced glutathione) or anti-inflammatory (decreased of TNF-α) together with the reduction of insulin resistance and adiponectin elevation or gene expression (increased liver NF-κB and decreased eNOS expression) and finally maybe by their obvious effect on improvements of lipid parameters. SignificanceCarvedilol and nicorandil improved NAFLD through the interrelationship between inflammatory cytokines, antioxidants and insulin resistance.

Effect of carvedilol versus propranolol on acute and chronic liver toxicity in rats

Non-selective β-blockers have largely been used for prophylaxis of bleeding from gastroesophageal varices, but their hepatic effects and their influence on the development of varices has yet to be clarified. This study examined whether carvedilol would reduce acute and chronic liver injury in rats in comparison to propranolol. Experiment (1) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) administered daily for 7 days by gavage on paracetamol (1500 mg/kg i.p.) -induced acute liver injury in rats. Experiment (2) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) by gavage daily for 8 weeks on CCl4 -induced chronic liver injury in rats. Biochemical markers and histopathology of the livers were studied. Liver perfusion studies were carried out on CCl4 treated rats. Experiment (1) Carvedilol significantly improved the functional state of the liver in paracetamol-induced acute toxic hepatitis to a greater extent than propranolol. This was evidenced by a greater reduction in elevated serum levels of ALT and AST, hepatic MDA and TNF-α, attenuation of the paracetamol-induced decrease in GSH, together with improvement in the histological architecture of the liver. Experiment (2) Carvedilol was superior to propranolol against CCl4-induced hepatic injury and fibrogenesis. It suppressed hepatic inflammation, attenuated hepatic oxidative stress, and inhibited HSC activation. Carvedilol also decreased portal perfusion pressure. These results suggest that carvedilol might be a therapeutic anti-fibrogenic candidate against hepatic fibrosis, protecting the liver from acute and chronic toxic injury, in addition to lowering portal pressure.

Carvedilol attenuates experimentally induced silicosis in rats via modulation of P-AKT/mTOR/TGFβ1 signaling

Silicosis is a well acknowledged occupational lung disorder with considerable negative impact on the patients' quality of life. Various signaling pathways have been reported to interplay in the pathogenesis of pulmonary fibro-proliferative disorders; of which, P-AKT/mTOR signaling pathway. The current study highlights the potential pulmonary protective effect of carvedilol; a non-selective α/β blocker against experimental silicosis-induced in rats by the intranasal installation of silica (50 mg/rat, 1 ml 0.9% NaCl). Carvedilol (20 mg/kg, orally) was administered for 8 weeks post intranasal silica installation. Carvedilol significantly attenuated silica-induced pulmonary damage on all the investigated scales. Inflammatory, oxidative/anti-oxidative and fibrotic incidences significantly improved with a significant histopathological restoration of lung architecture and attenuation of inflammatory and fibrotic biomarkers expression. Carvedilol significantly reduced lung contents of P-AKT and mTOR which, appears to be the main mechanism underlying the pulmonary protective effect of carvedilol. In conclusion; carvedilol attenuated silica-induced pulmonary fibrosis by modulating P-AKT/mTOR/TGFβ1 signaling and underlying inflammatory and fibrotic sequel.

Preventive use of carvedilol for anthracycline-induced cardiotoxicity: asystematic review and meta-analysis of randomized controlled trials.

Clinical or subclinical cardiotoxicity is aconcern for cancer patients receiving anthracycline-based chemotherapy. Carvedilol is promising for preventing anthracycline-induced cardiotoxicity (AIC). This review appraised the preventive effects of carvedilol against AIC based on randomized controlled trials (RCTs). The Cochrane Collaboration Central Register of Controlled Trials, PubMed, and Embase databases were searched from inception to March27, 2018. RCTs using carvedilol for the prevention of AIC were selected. Risk of bias and methodological quality were assessed. Meta-analysis was conducted, when applicable, for the trial endpoints; otherwise the data were analyzed descriptively. Nine RCTs comprising 717 patients were selected. The risk of bias was unclear and the methodological quality differed substantially. Data pooling of five eligible studies indicated no decreased mortality in patients receiving carvedilol (risk difference = -0.02, 95% CI: -0.07-0.04, p = 0.57, I2 = 44%). The impact on the incidence of left ventricular systolic dysfunction (LVSD) was inconsistently reported but meta-analysis was not applicable due to discordant LVSD definitions. Data pooling of eightstudies and asubgroup analysis indicated ahigher left ventricular ejection fraction (LVEF) with substantial heterogeneity in the carvedilol group (mean difference [MD] = 5.23, 95% CI: 2.20-8.27, p = 0.0007, I2 = 95%, and MD = 4.65, 95% CI: 0.67-8.64, p = 0.02, I2 = 90%, respectively). Further analysis of echocardiographic parameters and biomarkers showed weak evidence of improvement in diastolic function and troponinI level by carvedilol administration. Preventive use of carvedilol in patients undergoing anthracycline-based chemotherapy may be associated with areduced incidence of LVSD, higher LVEF value, better diastolic function, and lower troponinI level. RCTs with larger sample size and longer follow-up are needed to verify these findings.

Effect of carvedilol on heart rate response to cardiopulmonary exercise up to the anaerobic threshold in patients with subacute myocardial infarction.

Resting heart rate (HR) plus 20 or 30 beats per minute (bpm), i.e., a simplified substitute for HR at the anaerobic threshold (AT), is used as a tool for exercise prescription without cardiopulmonary exercise testing data. While resting HR plus 20bpm is recommended for patients undergoing beta-blocker therapy, the effects of specific beta blockers on HR response to exercise up to the AT (ΔAT HR) in patients with subacute myocardial infarction (MI) are unclear. This study examined whether carvedilol treatment affects ΔAT HR in subacute MI patients. MI patients were divided into two age- and sex-matched groups [carvedilol (+), n = 66; carvedilol (-), n = 66]. All patients underwent cardiopulmonary exercise testing at 1month after MI onset. ΔAT HR was calculated by subtracting resting HR from HR at AT. ΔAT HR did not differ significantly between the carvedilol (+) and carvedilol (-) groups (35.64 ± 9.65 vs. 34.67 ± 11.68, P = 0.604). Multiple regression analysis revealed that old age and heart failure after MI were significant predictors of lower ΔAT HR (P = 0.039 and P = 0.013, respectively), but not carvedilol treatment. Our results indicate that carvedilol treatment does not affect ΔAT HR in subacute MI patients. Therefore, exercise prescription based on HR plus 30bpm may be feasible in this patient population, regardless of carvedilol use, without gas-exchange analysis data.

Venlafaxine and carvedilol ameliorate testicular impairment and disrupted spermatogenesis in rheumatoid arthritis by targeting AMPK/ERK and PI3K/AKT/mTOR pathways

Testicular impairment has been commonly described in long-standing rheumatoid arthritis (RA) patients. Since depression and cardiovascular disorders are the most disturbing co-morbidities of RA, investigating the efficacy of the anti-depressant venlafaxine or the beta-blocker carvedilol in RA-associated testicular dysfunction may add to their clinical utility for RA patients. Previously, both agents have demonstrated significant in vivo anti-oxidant and anti-inflammatory actions. In the current study, venlafaxine (50 mg/kg/day) and carvedilol (10 mg/kg/day) were orally administered to adjuvant arthritic rats for 20 days. Interestingly, venlafaxine and carvedilol effectively suppressed paw edema and mitigated the testicular histopathological aberrations and the disrupted spermatogenesis. Both drugs enhanced testicular steroidogenesis through upregulation of 3β-HSD, 17β-HSD and StAR gene expression with concomitant augmentation of serum testosterone. They also blunted the inflammatory burden via attenuation of myeloperoxidase, TNF-α and the protein expression of NF-κBp65 along with elevation of IL-10. They attenuated testicular oxidative perturbations via lowering lipid peroxides and nitric oxide and boosting glutathione levels. With regard to apoptosis, the two agents lowered the protein expression of caspase-3, cleaved caspase-3, cleaved PARP, Bax and p53, promoting germ cell survival. They also modulated the AMPK/ERK signaling via lowering of p-AMPK and upregulation of p-ERK1/2 along with PI3K/AKT/mTOR transduction by enhancing the PI3Kp110α, p-AKT and p-mTOR protein expression. Together, the present work demonstrates the beneficial effects of venlafaxine and carvedilol in RA testicular dysfunction and impaired spermatogenesis via modulation of AMPK/ERK and PI3K/AKT/mTOR signaling and intervention with the testicular oxidative stress, inflammation and apoptosis.

Lowering hepatic venous pressure agent carvedilol versus variceal banding ligation for clinical outcomes of cirrhotic portal hypertension.

ObjectiveCarvedilol is nonselective beta-blocker with a mild anti-alpha-1-adrenergic effect. Several studies proposed improved hemodynamic effects of carvedilol compared with propanolol. Our study was to perform a systematic review and meta-analysis of randomized control trials comparing carvedilol with variceal banding ligation (VBL).MethodsStudies were searched on online databases MEDLINE, EMBASE(Ovid), the Cochrane Library, Chinese Wanfang Database, and China National Knowledge Infrastructure between January 2000 and May 2018. Incidence of bleeding and mortality were main outcome measures. Subgroup analysis and sensitivity analysis were conducted to ensure the robustness of pooled estimates.ResultsTen randomized control trials including 1,269 cirrhotic patients were chosen. Compared with VBL, carvedilol showed similar preventive efficacy of risk ratios (RRs) in variceal bleeding, and bleeding-related mortality over different follow-up periods from 6 months to 24 months. Also, significant differences between carvedilol and VBL in overall mortality and other causes of mortality were failed to be found. Carvedilol achieved a lower incidence of portal hypertension gastropathy in both 6 months (RR=0.49, 95% CI: 0.38–0.64, P<0.00001) and 12 months (RR=0.35, 95% CI: 0.26–0.47, P<0.00001). Two trials compared combination of carvedilol and VBL with VBL alone; however, the results failed to find an improved preventive efficacy of bleeding (RR=0.71, 95% CI: 0.15–3.30, P=0.67).ConclusionCarvedilol is equivalent to invasive VBL for variceal bleeding prevention. It can be well tolerated and may be of benefit to portal hypertension gastropathy. However, available data during 24 months follow-up did not support a potential advantage of carvedilol for prognosis as a lowering hepatic venous pressure agent.

Transdermal ethosomal gel nanocarriers; a promising strategy for enhancement of anti-hypertensive effect of carvedilol

The current study was conducted to develop vesicular ethosomal gel (ethogel) systems for upgrading the transdermal delivery of anti-hypertensive carvedilol. Ethosomes composed of Phospholipon 100 H, cholesterol, ethanol, and Transcutol P at different ratios, were prepared by thin-film hydration method with sonication. Carvedilol-loaded ethosomes were characterized by microscopic examinations followed by other in-vitro assessments. Selected ethosomal formulation (E10) was incorporated into different concentrations of gelling agents to prepare the ethogel formulations. Ethogels were subjected to physicochemical characterization, compatibility, and in-vitro drug release studies. Ex-vivo skin permeation and retention studies were performed followed by in-vivo studies in induced hypertensive rats. The smooth ethosomes demonstrated vesicular size of 201.55–398.55 nm, entrapment efficiency of 30.00–90.66% and loading capacity of 7.64–43.04% with zeta potential range of −30.30 to −44.90 mV. The homogeneous ethogels exhibited appropriate results of pH and drug content measurements. Spreadability was observed as a function of viscosity as the latter increased, the former decreased. The ethogel formulation (G2) manifested satisfactory physical appearance, spreadability, viscosity, and in-vitro release. In comparison to pure carvedilol gel, tested formulations (E10 and G2) developed high ex-vivo permeation, steady-state flux and drug retention through skin layers. The in-vivo study of G2 formulation revealed a significant gradual decline (p < 0.01) in the mean arterial pressure of rats at the second hour of experiment (146.11 mmHg) with continuous significant decrease (p < 0.001) after 6 h (98.88 mmHg). In conclusion, ethogels as promising lipid carriers proved their potential to enhance skin permeation with extended anti-hypertensive action of carvedilol.

Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats.

BackgroundCarvedilol is the first-line drug for the primary prophylaxis of variceal bleeding due to portal hypertension (PHT) in liver cirrhosis. This study aimed to investigate the effects of carvedilol on intrahepatic angiogenesis and sinusoidal remodeling in cirrhotic rats and explore the underlying mechanisms of carvedilol in PHT.Materials/MethodsFor in vivo experiments, carbon tetrachloride was used to induce liver cirrhosis in rats, and carvedilol was simultaneously administered by gavage. The portal pressure was measured in rats, and liver tissues were examined by immunohistochemistry. Sinusoidal remodeling was observed by transmission electron microscopy. For in vitro experiments, the effects of carvedilol on fibronectin (FN) synthesis in human umbilical vein endothelial cells (HUVECs) were explored by quantitative real-time polymerase chain reaction and western blot analysis.ResultsPortal vein pressure measurements showed that carvedilol reduced portal pressure in cirrhotic rats. Immunohistochemistry assays indicated that carvedilol ameliorated intrahepatic angiogenesis. Transmission electron microscopy examination demonstrated that carvedilol improved sinusoidal remodeling. In the in vitro experiments, carvedilol suppressed transforming growth factor β1 (TGFβ1)-induced FN synthesis in HUVECs by inhibition of the TGFβ1/Smads pathway.ConclusionsCarvedilol ameliorated intrahepatic angiogenesis, sinusoidal remodeling and portal pressure in cirrhotic rats. Carvedilol improved sinusoidal remodeling by suppressing FN synthesis in endothelial cells. Carvedilol has potential utility for treating early-stage liver cirrhosis.

Beta1-Adrenergic Receptor Regulation Revisited.

The actions and regulation of cardiomyocyte β1ARs differ in several respects from the properties described for the prototypical β2AR subtype; a mechanism to explain the unique properties of the β1AR subtype has never been obvious. This viewpoint summarizes recent studies that identify a novel signaling paradigm for the β1AR, implicating the N-terminus as a molecular determinant of β1AR responsiveness.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Formulation and Characterization of Carvedilol Leciplex for Glaucoma Treatment: In-Vitro, Ex-Vivo and In-Vivo Study.

This study evaluated the efficacy of cationic nanoparticle (leciplex) to deliver carvedilol to ocular surface for glaucoma treatment as recent studies pointed out the effect of topical carvedilol on intraocular pressure, therefore carvedilol loaded leciplex formulae were prepared using soy phosphatidyl choline (SPC) and cationic surfactant (CTAB/DDAB) and characterized for morphology, entrapment efficiency, particle size, zeta potential and ex-vivo corneal permeation. Then the selected formula was evaluated via in-vivo studies in comparison with carvedilol solution. Leciplex nanoparticles appeared spherical in shape with entrapment efficiency exceeded 95% in all formulae. Leciplex formula composed of SPC and DDAB in (1:1) molar ratio showed the smallest particle size (16.04 ± 1.2 nm), highest zeta potential value (53.9 ± 0.91 mv) and highest apparent corneal permeability coefficient (0.1157 cm/h). Carvedilol leciplex reduced intraocular pressure (IOP) to normal range in ocular hypertensive rabbits after 30 min and duration of action lasted for 24 h, while carvedilol solution reduced IOP to normal value after 60 min and duration of action lasted for 6 h. Furthermore, histological examination of eyeballs of rabbits treated with carvedilol leciplex showed improvement of retinal atrophy of glaucomatous eyes. This study concluded that leciplex improve transcorneal permeation and bioavailability of carvedilol.