Low-dose Carvedilol Research Articles

Comparing Low-Dose Carvedilol Continuous Manufacturing by Solid and Liquid Feeding in Self-Emulsifying Delivery Systems via Hot Melt EXtrusion (SEDEX)

Background/Objectives: This study compared two pilot scale continuous manufacturing methods of solid self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME). Methods: A model poorly water-soluble drug carvedilol in low dose (0.5–1.0% w/w) was processed in HME either in a conventional powder form or pre-dissolved in the liquid SEDDS. Results: HME yielded a processable final product with up to 20% w/w SEDDS. Addition of carvedilol powder resulted in a non-homogeneous drug distribution in the extrudates, whereas a homogeneous drug distribution was observed in pre-dissolved carvedilol. SEDDSs were shown to have a plasticizing effect, reducing the HME process torque up to 50%. Compatibility between excipients and carvedilol in the studied ratios after HME was confirmed via DSC and WAXS, demonstrating their amorphous form. Solid SEDDSs with Kollidon® VA64 self-emulsified in aqueous medium within 15 min with mean droplet sizes 150–200 nm and were independent of the medium temperature, whereas reconstitution of Soluplus® took over 60 min and mean droplet size increased 2-fold from 70 nm to 150 nm after temperature increased from 25 °C to 37 °C, indicating emulsion phase inversion at cloud point. Conclusions: In conclusion, using Kollidon® VA64 and pre-dissolved carvedilol in SEDDS has shown to yield a stabile HME process with a homogenous carvedilol content in the extrudate.

Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial

Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Carvedilol for prevention of heart failure in anthracycline-exposed survivors of childhood cancer: Results from COG ALTE1621.

10013 Background: Carvedilol improves cardiac function in patients with heart failure (HF), but remains untested as cardioprotective therapy in long-term childhood cancer survivors at risk for HF due to high-dose anthracycline exposure. We hypothesized that low-dose carvedilol would be safe and efficacious in reducing anthracycline-related heart failure risk in long-term survivors without evidence of HF. Methods: This was a randomized, double-blind, placebo-controlled phase 2B trial (NCT02717507) conducted at 28 sites. Eligibility included ≥250 mg/m2 cumulative anthracycline exposure by age 21 years (y), ≥2y from completion of cancer treatment, and preserved systolic function (ejection fraction [EF] ≥55% and/or fractional shortening [FS] ≥28%) at enrollment. Patients were randomized 1:1 to take low-dose carvedilol (12.5 mg/day) or placebo for 2y; dose up-titration started at 3.125 mg/day. The primary objective was to determine the impact of carvedilol on echocardiographic indices of HF risk: standardized left ventricular (LV) wall thickness/dimension ratio (LVWT/Dz; primary endpoint), LV end-systolic wall stress (ESWS), LV chamber diameters, systolic and diastolic function. These indices were obtained every 6 months and measured centrally in a blinded fashion. Common Terminology Criteria for Adverse Events (CTCAE v4.0) was used to assess toxicity. Cardiac event was defined as relative EF/FS decline < 20% from baseline or both < 55% [EF] and < 28% [FS]. Treatment effects were analyzed using the Generalized Estimating Equation for normally distributed data, assuming linear time-trend. Group differences were evaluated by treatment*time interaction. Results: Of 196 participants enrolled, 182 were eligible and randomized. Characteristics (median, range): age at enrollment, 24.7y (10.4-53.9); time from cancer diagnosis, 13.4y (2.9-43.6); anthracycline dose, 374 mg/m2 (250-1760); 19% had received chest-directed radiotherapy. There were no group differences in baseline participant demographics, cardiotoxic treatment exposure, or cardiac endpoints. LVWT/Dz was similar (+0.053, p = 0.15) between arms at 2y. However, treatment effects varied by time since diagnosis (p = 0.008) suggesting greater efficacy among longer-term survivors. Compared to placebo, carvedilol arm participants had significantly better LV end-diastolic diameter (-0.16 cm, p = 0.005) and LVESWS (-7.53, p = 0.027) at 2y. There were no CTCAE grade ≥3 events; all except 2 participants tolerated full dose escalation. Six out of eight cardiac events occurred on the placebo arm; longer-term follow-up of study participants is ongoing. Conclusions: In this randomized trial of long-term survivors of childhood cancer treated with high-dose anthracyclines, low-dose carvedilol was safe and effective in reducing established biomarkers of HF risk and could serve as a risk reduction strategy. Clinical trial information: NCT02717507 .

ACUTE REVERSAL OF SYSTOLIC HEART FAILURE IN A CASE OF COXSACKIEVIRUS MYOCARDITIS

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Viral Myocarditis is generally a self-limiting condition. Patients usually recover from viral myocarditis within a few weeks to months. Some patients can develop hemodynamic instability and may require critical care management. We present a unique case of acute systolic heart failure secondary to Coxsackievirus myocarditis which recovered within a few days. CASE PRESENTATION: A 19-year-old male came to ER for vomiting and abdominal pain for five days. Initial vitals were Temperature of 98 F, BP of 80/47 mm Hg HR of 124/min, and oxygen saturation of 93% on room air. EKG showed sinus tachycardia without ischemic changes. Initial labs were creatinine-2.6 mg/dl, troponin-2.15 ng/ml. CT of abdomen was unremarkable. CT of chest showed bilateral pulmonary edema and pleural effusion. Lung perfusion scan showed no perfusion defect. He did not respond to intravenous(IV) fluid. Initially it required IV vasopressor support- norepinephrine, phenylephrine, and dobutamine. Echocardiogram showed ejection fraction(EF) of 20-24% with severe global hypokinesis. COVID-19 PCR was negative. The pleural fluid study revealed transudative in nature. On day 3, he was weaned off from vasopressors. Acute kidney injury also resolved. Cytomegalovirus, HIV, autoimmune panel, and respiratory virus panel were negative. Coxsackievirus antibody came back positive. It was consistent with viral myocarditis. Patient showed clinical improvement, and we decided to repeat echocardiogram before discharge. On day 6, repeat echocardiogram showed significant improvement of EF to 54%. The patient was discharged on low dose carvedilol and lisinopril. Clinic follow up showed the patient's significant clinical recovery within a few weeks. DISCUSSION: In case of severe cardiomyopathy secondary to viral myocarditis, patient generally recovers within a few weeks to months. However, in our case, the patient developed acute systolic heart failure from Coxsackievirus myocarditis recovered within a few days after aggressive hemodynamic support. Repeat echocardiogram on the same admission also showed significant improvement in ejection fraction from 24% to 54%. It is a rapid recovery as per our knowledge and published data. CONCLUSIONS: Our case highlights that viral myocarditis has the potency to recover quickly, even from severe systolic dysfunction. This case also emphasizes the importance of repeating an echocardiogram on the same admission rather than waiting for a couple of months to ensure cardiac function recovery, particularly with very low ejection fraction on presentation. REFERENCE #1: Tschöpe, C., Cooper, L., Torre-Amione, G., & Van Linthout, S. (2019). Management of Myocarditis-Related Cardiomyopathy in Adults. Circulation Research, 124(11), 1568-1583. https://doi.org/10.1161/circresaha.118.313578 REFERENCE #2: 3. Schultz J, Hilliard A, Cooper L, Rihal C. Diagnosis and Treatment of Viral Myocarditis. Mayo Clin Proc. 2009;84(11):1001-1009. doi:10.4065/84.11.1001 DISCLOSURES: No relevant relationships by Gnananandh Jayaraman, source=Web Response No relevant relationships by Ramesh Babu Kesavan, source=Web Response No relevant relationships by Tusharkumar Pansuriya, source=Web Response No relevant relationships by Hytham Rashid, source=Web Response No relevant relationships by Sivatej Sarva, source=Web Response No relevant relationships by Aswin Srinivasan, source=Web Response No relevant relationships by BRANDEN WILSON, source=Web Response

Rosuvastatin and low-dose carvedilol combination protects against isoprenaline-induced myocardial infarction in rats: Role of PI3K/Akt/Nrf2/HO-1 signalling.

Rosuvastatin has been shown to activate PI3K/Akt/Nrf2/HO-1 pathway, which promotes cell survival in the myocardium. This study investigated the therapeutic benefit of adding rosuvastatin to low-dose carvedilol in protection against myocardial infarction (MI). Rosuvastatin (RSV) and carvedilol (CAR) were given for 7 consecutive days with concurrent administration of two doses of isoprenaline (ISP) on 6th and 7th days to induce MI. Isoprenaline injections caused detrimental alterations in the myocardial architecture and electrocardiogram (ECG) pattern and significantly increased the infarct size, heart index and serum levels of cardiotoxicity markers compared to the control group. ISP induced oxidative damage, inflammatory and apoptotic events and downregulated PI3K/Akt/Nrf2/HO-1signalling pathway compared to the control values. Treatment with low-dose CAR and/or RSV prevented the ECG and histopathological alterations induced by ISP, and also reduced the infarct size, heart index, serum creatine kinase-MB, cardiac troponin-I and C-reactive protein levels compared to ISP group. CAR and/or RSV treatment restored the activity of superoxide dismutase and total antioxidant capacity with a consequent reduction in lipid peroxides level. Further, they decreased the expression of nuclear factor (NF)-κB (p65) and increased the phosphorylated PI3K and Akt, which may activate the anti-apoptotic signalling as evidenced by the decreased active caspase 3level. The combination therapy has a more significant effect in the most studied parameters than their monotherapy, which may be because of the activation of PI3K/Akt Nrf2/HO-1 pro-survival signalling pathway. This study highlights the potential benefits of combining RSV with low-dose CAR in case of MI.

Extended-Release Carvedilol in the Treatment of Hypertension: A Double-Blind, Randomized, Placebo-Controlled Trial.

Immediate-release carvedilol requires twice-daily dosing and may have low treatment compliance. We assessed the efficacy of a new formulation of once-daily extended-release carvedilol (carvedilol ER) on systolic blood pressure (SBP) and diastolic blood pressure (DBP) among patients with hypertension in this double-blind, randomized, placebo-controlled trial. A total of 134 patients with untreated or uncontrolled hypertension were randomly assigned in a 1:1:1 ratio to receive placebo, low-dose carvedilol ER, or high-dose carvedilol ER for 8 weeks. The primary endpoint was the reduction in office SBP at 8 weeks. Secondary endpoints included the reduction in office DBP and the proportion of patients with blood pressure (BP) < 140/90 mm Hg. In the intention-to-treat population, placebo-adjusted changes in SBP/DBP were -2.9 mm Hg [95% confidence interval (CI), -9.6 to 3.7]/-1.7 mm Hg (95% CI, -5.6 to 2.3) and -4.9 mm Hg (95% CI, -11.5 to 1.7)/-3.4 mm Hg (95% CI, -7.3 to 0.5) for low-dose carvedilol ER and high-dose carvedilol ER, respectively. In the per-protocol population, high-dose carvedilol ER was associated with a significant DBP reduction [placebo-adjusted difference, -4.7 mm Hg (95% CI, -8.8 to -0.5); adjusted p = 0.026]. There was a gradational improvement in BP control with carvedilol ER (25%, 37%, and 48% for placebo, low-dose carvedilol ER, and high-dose carvedilol ER, respectively; linear-by-linear association p = 0.028). There were no differences in safety among the three groups. Carvedilol ER, though well tolerated, did not result in a greater reduction in either SBP or DBP compared with placebo.

The effects of carvedilol, metoprolol and propranolol on cisplatin-induced kidney injury

The β-adrenoceptor blockers may have anti-oxidant properties or induce β-arrestin recruitment beyond classical desensitization of receptor/G protein coupling, offering potential therapeutic benefits. Here, we investigated the effects of carvedilol, metoprolol and propranolol in an animal model of cisplatin-induced nephrotoxicity. Rats received the β-blockers (3 or 12 mg/kg/day) with or without cisplatin, and kidney function was investigated using renal scintigraphy, histopathology, and serum variables. Metoprolol and propranolol as well as low-dose carvedilol did not alter kidney function, per se. Meanwhile, high-dose carvedilol reduced renal accumulation of Technetium-99m (99mTc)–labeled dimercaptosuccinic acid (99mTc-DMSA) without significant effect on other variables. Furthermore, low-dose carvedilol prevented cisplatin-induced reduction of tracer uptake, but high-dose of this drug aggravated the situation. In this regard, both low and high -doses of carvedilol significantly inhibited cisplatin effects on kidney histology, BUN and creatinine levels. Also, high-dose propranolol inhibited cisplatin adverse effects on radiotracer uptake, histological manifestations, BUN and creatinine levels, while metoprolol failed to cause a notable effect. Taken together, carvedilol and high-dose propranolol may offer potential benefits in cisplatin nephrotoxicity.

Efficacy of Oral Carvedilol Premedication in Attenuating the Hemodynamic Response to Direct Laryngoscopy and Endotracheal Intubation

Introduction: Laryngoscopy and endotracheal intubation is associated with significant hemodynamic changes. Though these changes are well tolerated in healthy patients, they are undesirable in patients with comorbidities like coronary artery disease, systemic hypertension, myocardial insufficiency and intracranial hypertension. Various drugs have been tried in an effort to attenuate adverse hemodynamic responses to intubation, but so far none is ideal. &#x0D; Objectives: To find efficacy of low dose oral carvedilol in attenuating the hemodynamic responses to direct laryngoscopy and endotracheal intubation. &#x0D; Methodology: In this randomized, prospective, double-blind placebocontrolled study 80 patients of either sex aged between 18 and 60 years of age, belonging to the American Society of Anesthesiologists (ASA) health status Classes I and II, undergoing elective surgery requiring general anesthesia with endotracheal intubation were included. Patients were randomly divided into two groups. Group A: given 3.125 mg of Carvedilol orally and Group B: given a placebo (Vitamin B capsule) orally one hour before intubation with sips of water. Hemodynamic parameters were noted before and then 1, 2, 5, 10, 15 min after intubation. Any adverse effects associated with drugs were noted. &#x0D; Results: Both groups were well matched for their demographic data. There was a statistically significant difference (P&lt; 0.05) between carvedilol and placebo in heart rate at all points of measurement after tracheal intubation. The systolic blood pressure was significantly lower in carvedilol group only at 5min after intubation. Diastolic and mean blood pressures were comparable in every points of measurement. None of the patients had any adverse effects. &#x0D; Conclusion: Low dose carvedilol has statistically significant effect in attenuating the heart rate response to direct laryngoscopy and endotracheal intubation.

Effects of Carvedilol on the Expression of TLR4 and its Downstream Signaling Pathway in the Liver Tissues of Rats with Cholestatic Liver Fibrosis.

This study was designed to investigate the effects of carvedilol on the expression of TLR4 and its downstream signaling pathway in the liver tissues of rats with cholestatic liver fibrosis and provide experimental evidence for clinical treatment of liver fibrosis with carvedilol. A total of fifty male Sprague Dawley rats were randomly divided into five groups (10 rats per group): sham operation (SHAM) control group, bile duct ligation (BDL) model group, low-dose carvedilol treatment group (0.1mg·kg-1·d-1), medium-dose carvedilol treatment group (1mg·kg-1·d-1), and high-dose carvedilol treatment group (10mg·kg-1·d-1). Rat hepatic fibrosis model was established by applying BDL. Forty-eight hours after the operation, carvedilol was administered twice a day. The blood and liver were simultaneously collected under the aseptic condition for further detection in two weeks after the operation. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (Alb) in serum were measured. HE and Masson staining were used to determine hepatic fibrosis degree. Hydroxyproline assay was employed to detect liver collagen synthesis. Western Blot was used to measure the expression of TLR4, NF-κB p65 and β-arrestin2 protein. Quantitative analysis of TLR4, MyD88, TNF-α and IL-6 mRNA was performed by Realtime-PCR. Compared with the SHAM group, the BDL group showed obvious liver injury, increased levels of inflammatory factors, and continued progression of liver fibrosis. The above changes in the BDL group were alleviated in the carvedilol treatment groups. The improvement effects augmented as dosages increased. In addition, compared with the BDL group, the reduction of the expressions of TLR4, MyD88 and NF-κB p65 in liver tissues and the increase of the expression of β -arrestin2 in the high-dose carvedilol group were more significant. Carvedilol can reduce the release of inflammatory mediators by downregulating TLR4 expression and inhibiting its downstream signaling pathway, thus playing a potential therapeutic role in cholestatic liver fibrosis.

WITHDRAWN: Effects of carvedilol on expression of TLR4 and its downstream signaling pathway in liver tissue of rats with cholestatic liver fibrosisjaundice.

This study was designed to investigate the effects of carvedilol on the expression of TLR4 and its downstream signaling pathway in liver tissue of rats with cholestatic liver fibrosis, and provided experimental evidence for clinical treatment of liver fibrosis with carvedilol.? A total of fifty male Sprague Dawley rats were randomly divided into five groups (10 rats per group): sham surgery control group, bile duct ligation (BDL) model group, low-dose carvedilol treatment group (0.1mgkg-1d-1), medium-dose carvedilol treatment group (1mgkg-1d-1), high-dose carvedilol treatment group (10mgkg-1d-1). Rat hepatic fibrosis model was established by applying BDL. Forty-eight hours after the operation, carvedilol was administered twice a day. The blood and liver were simultaneously collected under the aseptic condition for further detection in two weeks after operation.? Compared with the sham group, the BDL group showed obvious liver injury, increased levels of inflammatory factors, and continued progression of liver fibrosis. Carvedilol could alleviate the above changes. The improvement effects were augmenting as dosages increasing. In addition, compared with the BDL group, carvedilol can reduce the expressions of TLR4, MyD88 and NF-?B p65 in liver tissue and increase the expression of ?-arrestin2, and the effect in the high dose group was more obvious. Carvedilol can reduce the release of inflammatory mediators by down-regulating TLR4 expression and inhibiting its downstream signaling pathway, thus playing a therapeutic role in cholestatic liver fibrosis.

Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension.

Background: The therapeutic benefits of β-blockers are well established in left heart failure. The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure [PAHTCH] study showed safety and possible benefit of carvedilol in pulmonary arterial hypertension (PAH) associated right heart failure over 6 months. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy.Methods: Thirty patients with pulmonary hypertension (PH) received low dose carvedilol (3.125 mg twice daily) for 1 week prior to randomization to placebo, low-dose, or dose-escalating carvedilol therapy. Echocardiography was performed at baseline and 1 week. Exercise capacity was assessed by 6 min walk distance (6MWD). The L-arginine/nitric oxide pathway and other biological markers of endothelial function were measured.Results: All participants tolerated 1 week of carvedilol without adverse effects. After 1 week of carvedilol, 6MWD and heart rate at peak exercise did not vary (both p > 0.1). Heart rate at rest and 1 min post walk dropped significantly (both p < 0.05) with a trend for increase in heart rate recovery (p = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg (p = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders (n = 17), and those with a lesser drop as non-responders (n = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol (p = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both p < 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders (p = 0.03 and p = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate (p = 0.04). Responders treated with carvedilol had a sustained drop in RVSP and PVR after 6 months of carvedilol with no change in cardiac output.Conclusions: Low-dose carvedilol for 1 week can potentially identify a PH responder phenotype that may benefit from β-blockers that is associated with less endothelial dysfunction.Clinical Trial Registration: http://www.clinicaltrials.gov. identifier: NCT01586156.

Rationale and design of the Children's Oncology Group (COG) study ALTE1621: a randomized, placebo-controlled trial to determine if low-dose carvedilol can prevent anthracycline-related left ventricular remodeling in childhood cancer survivors at high risk for developing heart failure.

BackgroundAnthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population.Methods/DesignThe primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m2) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability.DiscussionWhen completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF.Trial registrationClinicalTrials.gov; NCT02717507

Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy

BackgroundThe left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood. MethodsWe reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study. ResultsDCM onset ranged from 8 to 16 months. Initial treatment of their acute heart failure was successful in all 5 but 4 patients relapsed despite the usual dose of carvedilol (induction 0.02–maintenance 0.4mg/kg/day), and developed worsening heart failure. Brain natriuretic peptide (BNP) levels which increased again after the acute treatment had fallen subsequent to discontinuing or decreasing carvedilol. Over 24 months, LVFS had increased from 11±2% (mean±SD) to 34±5% (p<0.05), and %LVDd decreased from 149±27% to 108±11% (p<0.05). ConclusionsLVRR was found at 2 years after the onset of DCM. Usual dose induction of carvedilol therapy can sometimes worsen heart failure after successful initial conventional treatment for the acute heart failure in DCM. Close control of carvedilol treatment may determine the prognosis of infantile DCM around 12 months old. It is prudent to increase low-dose carvedilol slowly corresponding with the BNP level.

Identifying Synergistic Interactions Between the Rexinoid and Adrenergic Signaling Pathways

The RXR‐selective retinoid bexarotene is a potent anti‐proliferative agent that effectively suppresses mammary tumorigenesis, yet chronic treatment at effective doses is associated with adverse effects. To identify compounds that synergistically enhance the anti‐proliferative activity of bexarotene, we conducted high throughput screens using a library of clinically tested drugs and small molecules in premalignant human breast epithelial cells. The dual b/a1‐adrenergic receptor antagonist carvedilol showed strong synergy with bexarotene in both anchorage‐dependent and colony formation assays. Long‐term treatment of MMTV‐ErbB2 mice with low‐dose carvedilol (20 mg/kg/d) and bexarotene (20 mg/kg/d) as single agents delayed de novo tumor formation, while their combination effectively inhibited the development of ER‐negative breast cancer. Carvedilol administration was also associated with slower tumor growth compared to control mice.Most beta‐blockers tested had no effect on cell growth, and did not enhance the anti‐proliferative effect of bexarotene in vitro. However, another antagonist with a beta‐arrestin bias, alprenolol, was also synergistic with bexarotene, suggesting that long‐term modulation of downstream MAPK signaling pathways may play a role in the cancer preventive action of the combination of carvedilol and bexarotene.Carvedilol's favorable toxicity profile makes it a promising candidate for drug 'repurposing' as an anti‐cancer agent.Supported by the Duncan Family Institute Seed Funding Research Program and RO3 CA180550 (to I.P.U.).

Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases.

Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor-alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis.

The Effect of Low‐Dose Carvedilol, Nebivolol, and Metoprolol on Central Arterial Pressure and Its Determinants: A Randomized Clinical Trial

In this prospective, open-label, randomized, controlled clinical trial the effects of low-dose carvedilol, nebivolol, and metoprolol on central arterial pressure and augmentation index (AIx) and its heart rate-corrected value (AIx@75) were assessed. The authors randomized 75 hypertensive patients (18-70years) to carvedilol 12.5/25mg, metoprolol 50/100mg, or nebivolol 2.5/5mg daily and followed them up for 3months. Central arterial pressure and AIx were measured with applanation tonometry at baseline and at the end of follow-up. Analyses were restricted to 60 completers. Central systolic pressure decreased equally in all 3 treatment arms. AIx remained unchanged, while AIx@75 decreased significantly by 5.4%±2.5% in the nebivolol group. According to general linear models, individual change in heart rate was a strong predictor of change in AIx in the carvedilol group (r(2) =0.23, P=.03) although no similar association was found in the nebivolol group (r(2) =0.09). The impact of β-blockers with vasodilator effects on pressure augmentation seems to be different with nebivolol having the largest potential of decreasing AIx@75. While AIx changes associated with carvedilol treatment are strongly driven by heart rate changes, those associated with nebivolol treatment seem to be the result of other mechanisms.

Smad3 Inactivation and MiR-29b Upregulation Mediate the Effect of Carvedilol on Attenuating the Acute Myocardium Infarction-Induced Myocardial Fibrosis in Rat

Carvedilol, a nonselective β-adrenoreceptor antagonist, protects against myocardial injury induced by acute myocardium infarction (AMI). The mechanisms underlying the anti-fibrotic effects of carvedilol are unknown. Recent studies have revealed the critical role of microRNAs (miRNAs) in a variety of cardiovascular diseases. This study investigated whether miR-29b is involved in the cardioprotective effect of carvedilol against AMI-induced myocardial fibrosis. Male SD rats were randomized into several groups: the sham surgery control, left anterior descending (LAD) surgery-AMI model, AMI plus low-dose carvedilol treatment (1 mg/kg per day, CAR-L), AMI plus medium-dose carvedilol treatment (5 mg/kg per day, CAR-M) and AMI plus high-dose carvedilol treatment (10 mg/kg per day, CAR-H). Cardiac remodeling and impaired heart function were observed 4 weeks after LAD surgery treatment; the observed cardiac remodeling, decreased ejection fraction, and fractional shortening were rescued in the CAR-M and CAR-H groups. The upregulated expression of Col1a1, Col3a1, and α-SMA mRNA was significantly reduced in the CAR-M and CAR-H groups. Moreover, the downregulated miR-29b was elevated in the CAR-M and CAR-H groups. The in vitro study showed that Col1a1, Col3a1, and α-SMA were downregulated and miR-29b was upregulated by carvedilol in a dose-dependent manner in rat cardiac fibroblasts. Inhibition of ROS-induced Smad3 activation by carvedilol resulted in downregulation of Col1a1, Col3a1, and α-SMA and upregulation of miR-29b derived from the miR-29b-2 precursor. Enforced expression of miR-29b significantly suppressed Col1a1, Col3a1, and α-SMA expression. Taken together, we found that smad3 inactivation and miR-29b upregulation contributed to the cardioprotective activity of carvedilol against AMI-induced myocardial fibrosis.

Preventive effect of low-dose carvedilol combined with candesartan on the cardiotoxicity of anthracycline drugs in the adjuvant chemotherapy of breast cancer

To investigate the effect of low-dose carvedilol combined with candesartan in the prevention of acute and chronic cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer. Forty patients were randomly divided into two groups: the experimental group with chemotherapy plus low-dose carvedilol combined with candesartan (20 cases) and control group with chemotherapy alone (20 cases). The same chemotherapy was given to the two groups. All the 40 patients had no contraindication for carvedilol and candesartan. Patients of the experimental group received low-dose carvedilol from 2.5 mg orally twice a day at first cycle to 5 mg twice a day gradually if no side reactions, and candesartan 2.5 mg orally once a day. Electrocardiogram, ultrasonic cardiogram, arrhythmia, troponin and non-hematologic toxicity were recorded and compared after the second, forth and sixth cycle of chemotherapy. Each cycle included 21 days. LVEF was decreased along with the prolongation of chemotherapy in the experimental group and control group. LVEDD and LVESD showed no significant changes in the experimental group, but gradually increased in the control group. After four and six cycles of chemotherapy, LVEF were (57.00 ± 5.13)% and (45.95 ± 3.68)%, respectively, in the control group, significantly lower than that of (67.00 ± 5.13)% and (57.50 ± 2.57)%, respectively, in the experimental group (P < 0.05). After six cycles of chemotherapy, LVEDD and LVESD were (50.00 ± 10.48) mm and (35.01 ± 2.99) mm, respectively, in the control group, significantly higher than those before chemotherapy (P < 0.05) and experimental group (P < 0.001). The rate of ST segment and T wave abnormalities was 80.0% in the control group after six cycles of chemotherapy, significantly higher than that of 25.0% after four cycles of chemotherapy (P = 0.001) and 10.0% after two cycles of chemotherapy (P < 0.001). The reduction of QRS voltage, arrhythmia and abnormal troponin were 55.0%, 45.0% and 45.0%, respectively, in the control group, significantly higher than those in the experimental group (20.0%, P < 0.05), (10.0%, P = 0.010) and (10.0%, P < 0.05), respectively. The rate of abnormal expression of troponin was 45.0% in the control group, significantly higher than the 10.0% in the experimental group (P < 0.05). The use of low-dose carvedilol combined with candesartan can reduce the acute and chronic cardiotoxicity of anthracycline drugs, and with tolerable toxicities. This may provide a new approach to prevent cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer.

Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol

Several studies have demonstrated the improvement of left ventricular ejection fraction (LVEF) in heart failure patients after the long-term treatment with beta blockers [ [1] Hori M. Sasayama S. Kitabatake A. et al. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial. Am Heart J. 2004; 147: 324-330 Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar ], although, not all patients have similar results. To date, it has not been fully investigated that patients with systolic heart failure respond uniformly to this therapy. Myocardial fibrosis triggers impaired cardiac systolic function and has an association with adverse cardiovascular events [ 2 Wu K.C. Weiss R.G. Thiemann D.R. et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol. 2008; 51: 2414-2421 Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar , 3 Cho J.R. Park S. Choi B.W. et al. Delayed enhancement magnetic resonance imaging is a significant prognostic factor in patients with non-ischemic cardiomyopathy. Circ J. 2010; 74: 476-483 Crossref PubMed Scopus (25) Google Scholar ]. Nowadays, late gadolinium enhancement (LGE) on cardiac magnetic resonance images (CMR) is widely used to assess myocardial tissue viability [ 4 Schalla S. Bekkers S.C. Dennert R. et al. Replacement and reactive myocardial fibrosis in idiopathic dilated cardiomyopathy: comparison of magnetic resonance imaging with right ventricular biopsy. Eur J Heart Fail. 2010; 12: 227-231 Crossref PubMed Scopus (60) Google Scholar , 5 Park S. Choi B.W. Rim S.J. et al. Delayed hyperenhancement magnetic resonance imaging is useful in predicting functional recovery of nonischemic left ventricular systolic dysfunction. J Card Fail. 2006; 12: 93-99 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ]. This study was designed to investigate whether myocardial fibrosis determined by LGE on CMR would be useful to assess left ventricular reverse remodeling (LVRR) in patients with nonischemic cardiomyopathy (NICM) treated with beta blockers.

Tolerability of Low-dose Carvedilol in Elderly Patients

Tolerability of Low-dose Carvedilol in Elderly Patients