Mg Of Carvedilol Research Articles

Cardioprotective Effects of Chronic Release Formulations of Subcutaneous Implants of Carvedilol in Spontaneously Hypertensive Rats

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 direct 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.

A Hemodynamic Study to assess response, tolerance and dose optimization of Carvedilol in Child Class A patients with Portal Hypertension

Background: Carvedilol has an established role in Chronic Liver disease (CLD) associated Portal Hypertension, however its role in specific subclasses of CLD has not been studied, neither the factors leading to non-response thereby predisposing such patients to variceal bleed with empiric therapy.
 Aims and Objectives: The purpose of this study was. 1. To evaluate the hemodynamic response to Carvedilol and optimum dosage in patients of CTP Class A Cirrhosis. 2. To determine any clinical variables that would help in differentiating responders from non-responders.
 Materials and Methods: In forty-three consecutive patients of chronic liver disease Child Turcotte Pugh (CTP) Class A with esophageal varices, Hepatic Venous Pressure Gradient (HVPG) was measured at baseline, 90 minutes after initial administration of 12.5 mg of Carvedilol and after 3 months of dose optimization.
 Results: Twenty-one (48.8%) patients demonstrated Acute Response and after dose optimization Chronic Response was seen in 29 (67.4%) patients with additional 8 (18.6%) patients responding to dose optimization. Fourteen (32.55%) patients failed to show any response. Low pre-drug Cardiac Output (CO), High pre-drug mean arterial pressure (MAP), more than 2.5mmHg drop in HVPG acutely, higher dose toleration of more than 18.5mg and lower change in HR predicted response.
 Conclusion: Patients with CTP Class A Cirrhosis with Portal Hypertension and Esophageal Varices tolerate Carvedilol well and nearly two-thirds show hemodynamic response when dose is optimized over a period of time, including patients who initially show no acute response. Nearly one-third of patients show no response even after dose optimization.

Towards the Elucidation of the Role of the Chloride Anion in Arterial Hypertension: Its Link with Oxidative Damage in the Kidney

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 blood pressure (MBP) 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 MNP 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. The echocardiographic parameters as left ventricular ejection fraction (LVEF), shortening

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. 
 Objectives: To find efficacy of low dose oral carvedilol in attenuating the hemodynamic responses to direct laryngoscopy and endotracheal intubation. 
 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. 
 Results: Both groups were well matched for their demographic data. There was a statistically significant difference (P< 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. 
 Conclusion: Low dose carvedilol has statistically significant effect in attenuating the heart rate response to direct laryngoscopy and endotracheal intubation.

SAT-576 Possible Involvement of Thyroid Function in PCSK9 Inhibitor Therapy

INTRODUCTIONProprotein convertase subtilisin kexin type 9 (PCSK9) inhibition is an effective strategy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol lowering ability of statins. PCSK9, a serine protease that binds to the LDL receptor promoting its degradation, is an important regulator of LDL metabolism. In addition, LDL-cholesterol is also controlled by TSH and thyroid hormones via PCSK9. TSH has received increasing attention as being closely associated with increased LDL-cholesterol level and higher atherosclerotic risks. In vitro study, the effects of TSH on hepatic PCSK9 expression in HepG2 cells were reported (1). I here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. This case highlights the involvement of thyroid function in PCSK9 Inhibitor therapy.CLINICAL CASEA 65-year-old man had a weight loss of 6 kg (13 lbs.) in 4 months, accompanied with fatigue. He had a past history of myocardial infarction and his LDL was 83 mg/dL by 2.5mg of rosuvastatin and heart rate was controlled by 10mg of carvedilol. Six months ago, he started a PCSK9 Inhibitor therapy with 140mg of evolocumab every 2 weeks for 6 weeks. He had no preceding viral illness and denied anterior neck pain or tenderness. His height was 1.53 m, weight 52.6 kg (115 lbs.), and body mass index (BMI) 22.46 kg/m2. His thyroid was not enlarged and non-tender without clear palpable thyroid nodules or neck lymph nodes. Hyperthyroidism was suspected and confirmed by thyroid function tests: TSH was less than 0.0005 μIU/mL (normal 0.35–4.94), and free T4 1.830 ng/dL (0.70–1.48). Graves’ disease was considered, and thyroid antibody tests performed. Thyroid peroxidase (TPO) antibody titer was less than 9 IU/mL (<9), and TSI 141% (<120%). To confirm the diagnosis of this hyperthyroid patient, Technetium-99m uptake and scan was done which showed uptake of 0.8% (0.5–7%). After careful observation for 2 months with 5mg of carvedilol, he turned asymptomatic and free T4 lowered to 1.480 ng/dL and TSH remained less than 0.0005 μIU/mL.CLINICAL LESSONSI here report a case of transient hyperthyroidism secondary to PCSK9 inhibitor therapy. There has been no report of hyperthyroidism induced by PCSK9 inhibitors. Immunological influence of anti-PCSK9 therapy on thyroid is unknown. In this case, the decrease of TSH due to hyperthyroidism was considered to reduce hepatic PCSK9 expression, leading to additive effect to PCSK9 inhibitor. PCSK9 inhibitors may modify the effects of hyperlipidemia treatment by causing changes in thyroid function. When using PCSK9 inhibitors, follow-up of thyroid function should be considered. This case highlights the involvement of thyroid function in PCSK9 inhibitor therapy.Reference(1) Gong, Y., Ma, Y., et al. Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression. Metabolism. 2017;76;32–41

Complementary and Integrative Therapies in Psychiatry

Complementary and Integrative Therapies in Psychiatry

Effects of Carvedilol Compared to Nebivolol on Insulin Resistance and Lipid Profile in Patients With Essential Hypertension.

Beta-blockers have unfavorable effects on metabolic parameters in hypertensive treatment. New generation beta-blockers with vasodilatory capabilities are superior to traditional beta-blockers, but studies examining their effects on metabolic parameters are still lacking. This study aimed to compare the effects of 2 new generation beta-blockers, carvedilol and nebivolol, on insulin resistance (IR) and lipid profiles in patients with essential hypertension. This was a prospective, randomized, open-label, single-center clinical trial. A total of 80 patients were randomized into 2 groups: the carvedilol group (n = 40, 25 mg of carvedilol daily) and the nebivolol group (n = 40, 5 mg of nebivolol daily). Follow-up was performed for 4 months. Fasting plasma glucose, insulin levels, and the lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol, triglyceride, apolipoprotein AI, and apolipoprotein B levels) were measured and IR was calculated by the homeostasis model assessment (HOMA) index. These variables were compared before and 4 months after treatment. Blood pressure and heart rate were significantly and similarly reduced in the carvedilol and nebivolol groups after treatment compared to those before treatment (both P < .001). Serum glucose ( P < .001), insulin ( P < .01), HOMA-IR (P < .01), HDL ( P < .001), LDL ( P < .001), total cholesterol ( P < .001), and apolipoprotein B ( P < .05) levels decreased in a similar manner in the carvedilol and nebivolol groups after treatment compared to those before treatment. Serum triglyceride and apolipoprotein AI levels did not change after treatment with both drugs. New generation beta-blockers, carvedilol and nebivolol, efficiently and similarly decrease blood pressure. They have similar favorable effects on glucose, insulin, IR, and the lipid profile.

Does acute response to safe dose of carvedilol vary across different child class of liver disease: A large cohort hemodynamic study

Background: Carvedilol is a nonselective beta-blocker with an additional alpha 1 adrenoceptor blocking action, causing a much greater decrease in portal pressure as compared to propranolol. Materials and Methods: One hundred two consecutive patients of cirrhosis of the liver with significant portal hypertension were included, and hepatic venous pressure gradient (HVPG) was measured at the baseline and after 90 min of administration of 12.5 mg carvedilol. Results: A total of 102 patients with mean age of 58.3 ± 6.6 years were included. A total of 42.2%, 31.9%, and 26.6% patients had child Class A, child Class B, and Child Class C cirrhosis, respectively. Mean baseline HVPG was 16.75 ± 2.12 mmHg that dropped to 13.07 ± 2.32 mmHg, after 90 min of administration of 12.5 mg of carvedilol. The mean drop of HVPG was 4.5 ± 2.2 mmHg and 2.4 ± 1.9 mmHg between responders and nonresponders, respectively. Overall, 52 patients (51%) showed acute response while 50 (49%) were nonresponders. Baseline low cardiac output (CO) and high mean arterial pressure (MAP) were significant predictors of acute response on univariate analysis. On multivariate analysis, low baseline CO was found as an independent predictor. Conclusion: Carvedilol is a drug of choice among beta-blockers for primary prophylaxis of variceal bleed. Hemodynamic parameters like baseline low CO high MAP are significantly predicting acute response while as etiology, child class, and variceal size are not significantly associated with acute response to a safe dose of carvedilol.

Impact of Beta Blockers on Left Ventricular Reverse Remodeling Following Primary Coronary Intervention for ST-elevation Myocardial Infarction

Background. Benefits of beta-adrenergic receptor blockers (BB) following ST-elevation myocardial infarction (STEMI) are based on data before primary percutaneous coronary intervention (PCI) became the therapeutic first choice. This study examined the relationship between BB dose and magnitude of left ventricular ejection fraction (LVEF) improvement in STEMI following primary PCI. Methods and Findings. A total of 235 STEMI patients following primary PCI who underwent echocardiography during the acute phase and over 6 months from onset were studied retrospectively. Serial LVEFs were assessed for three groups: no BB (n=33), carvedilol (n=163), and bisoprolol (n=42). Left ventricular reverse remodeling (RR) was defined as LVEF improvement ≥10%. All patients received fixed doses of BB and renin-angiotensin system inhibitor during observation. The median interval between echocardiographs was 526 days. The mean LVEF change was +2.6% (acute: 53.9±9.9%, chronic: 56.4±10.6%). Carvedilol and bisoprolol groups showed LVEF improvement, but none was seen in the no BB group (+3.7±6.5%, +3.8±6.9%, -4.2±5.0%, P<0.0001, respectively). The LVEF improvement effect was BB dose dependent. Therapy with BBs had a high rate of RR (no BB 0%, carvedilol 19.4%, bisoprolol 16.7%, P=0.0225, respectively). Multivariate analysis showed the following predictors of RR: baseline LVEF <50% and regular dose of BB, ≥10 mg of carvedilol or ≥1.25 mg of bisoprolol (Odds ratio 2.35, 95% Confidence Interval [CI] 1.12-5.02, P=0.0242; Odds ratio 4.45, 95% CI 2.06-10.27, P=0.0001). Conclusions. Immediate BB administration following primary PCI for STEMI provided a dose-dependent LVEF improvement. A LVEF <50% and regular dose of BB are predictors of RR.

Tracking of crystalline-amorphous transition of carvedilol in rotary spun microfibers and their formulation to orodispersible tablets for in vitro dissolution enhancement

Physicochemical characterization of microfibers including powder X-ray diffraction, differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, and positron annihilation spectroscopy were used to track the crystalline-amorphous transition of carvedilol during formulation and stability testing. The applied methods unanimously indicated the amorphous transition of carvedilol in the course of rotary spinning, furthermore a supramolecular ordering of chains of polymer matrix was revealed out by positron annihilation spectroscopy. The accelerated stability study (40±2°C/75±5% RH, for 4 weeks) indicated a large stress tolerance capacity of fibers, since only a partial crystallization of the active compound was observable at the last sampling point. To demonstrate possible utilization of microfibers, orodispersible tablets containing 10mg of carvedilol were successfully prepared by direct compression applying common tableting excipients. All of the investigated tablet parameters (hardness, friability, in vitro disintegration time) complied with the pharmacopoeial requirements. The performed dissolution (pH 1.0 and 6.8) study indicated that the drug dissolution from the microfiber based formula was rapid, complete and independent from the pH of the applied media, while the dissolution from the control tablets, containing crystalline carvedilol was incomplete and was strongly influenced by the pH of the applied media.

Effect of different beta blockers on penile vascular velocities in hypertensive males

BackgroundBeta blockers are very commonly used as antihypertensive medications in young active individuals. This class has been accused of erectile dysfunction in patients taking them. Problems with erectile function can raise a concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. AimThe aim was to assess the effect of different beta blockers: nebivolol, atenolol, bisoprolol, and carvedilol on the penile arterial duplex velocities in hypertensive males. Methods and results108 non-smoking, non-diabetic, recently diagnosed hypertensive men, otherwise healthy, participated in the study. The patients were divided into four groups: Group 1 (24 patients) who were taking 5mg of nebivolol, Group 2 (28 patients) who took 100mg of atenolol, Group 3 (29 patients) who were taking 10mg of bisoprolol, and Group 4 (27 patients) who were on 25mg of carvedilol. The penile vascular velocities were measured before treatment and after a treatment phase of eight to twelve weeks of beta blocker antihypertensive treatment. We obtained a statistically significant diminish of the stimulated PSV with atenolol (P=0.03), bisoprolol (P=0.05), and carvedilol (P=0.02), while, with nebivolol the PSV did not show a significant change (P=0.7). There was also a significant decrease of the stimulated EDV with nebivolol (0.04) with no change with the other beta blockers. ConclusionNebivolol is a unique member of the beta blocker family showing neutral effects on the penile vascular velocities as compared to other beta blockers in hypertensive males.

A Haemodynamic Analysis to Assess the Safe Dose of Carvedilol across Different Child Class of Liver Disease

Background: Literature regarding safe dose of carvedilol is limited and also safe dose across different child classes of chronic liver disease is not very clear. Aim: We aimed primarily to study, the effect of reasonably safe dose (12.5 mg) of carvedilol in acute reduction of portal pressure and compared it with chronic reduction of portal pressure, after Original Research Article Wani et al.; BJMMR, 7(5): 355-368, 2015; Article no.BJMMR.2015.342 356 proper optimization of dose of carvedilol. Second aim of our study was to define predictors of response for acute and chronic reduction of portal pressure and to assess difference in dose tolerated and response across different child class on chronic basis. Methods: One hundred two consecutive patients of cirrhosis of liver with significant portal hypertension were included and hepatic venous pressure gradient was measured at the base line and after 90 minutes of administration of 12.5 mg carvedilol. After proper dose optimization of carvedilol, hepatic venous pressure gradient was again measured after 3 months to assess the chronic response. Results: The mean age of study population was 58.3±6.6 years. A total of 42.2%, 31.9% and 26.6% patients had child class A, child class B and Child class C cirrhosis, respectively. Mean pre-drug hepatic venous pressure gradient was 16.75±2.12 mmHg which dropped to 13.07±2.32 mmHg after 90 minutes of administration of 12.5 mg of carvedilol. The mean drop of hepatic venous pressure gradient was 4.5±2.2 mmHg and 2.4±1.9 mmHg among responders and non-responders, respectively. Overall, 51% showed acute response while 49% were nonresponders. Low cardiac output and high mean arterial pressure were significantly predicting the acute response, while, low baseline cardiac output was found as an independent predictor. After dose optimization, number of responders increased from 52 to 62. Mean dose of carvedilol was higher in non–responders as compared to responders, though statistically insignificant (p>0.05). Mean reduction of hepatic venous pressure gradient from baseline and after 3 months was 5.5±1.7 mmHg and 2.8±1.6 mmHg among responders and non responders on chronic basis, respectively (p<0.001). Absence of any adverse events (OR 11.3, 95% CI; 1.9-67.8), and more than 2.5 mmHg fall in hepatic venous pressure gradient during acute response (OR 8.7, 95% CI; 3.1-25.3) were found as independent predictors of chronic response (p<0.05). Univariate analysis found that no adverse events, no ascites, low baseline cardiac output, more than 2.5 mmHg fall in hepatic venous pressure gradient during acute response, as predictors of chronic response. However, etiology, child class, variceal size (large vs small) and gender were not significantly associated with chronic response Conclusion: At safe dose and with proper optimization of dose, carvedilol may achieve greater response with minimum side effects among different child classes of liver disease.

A vivid example of angioedema

Case reportA 68-year-old hypertensive woman, who had been using25 mg of carvedilol daily for the past 5 years, woke up withedema of the tongue and dyspnea. At the admission to therural hospital, 5 mg of hydrocortisone and 5 mg of dex-chlorpheniramine were given intravenously, and the patientwas sent to our department. It was learned from relatives ofthe patient that she had been given sublingual captopril inanother hospital where she had been treated the day beforefor hypertension. Additionally, it was reported that thepatient hadalsosufferedfromtongueedema intheprioryearafter using the same medication, sublingual captopril. Onphysical examination, she was alert, with vital signs: bloodpressure 130/80 mmHg, pulse rate 94 beats per minute,respiration rate 14 breathes per minute (Fig. 1). Inspiratorystridor was heard on auscultation, and the patient was notable to speak. She was breathing supplemental oxygen,placed on a cardiac monitor, and intravenous lines wereestablished. Therapy was commenced with 0.3 mg of a1:10,000 epinephrine subcutaneously, 40 mg methylpred-nisolone, 50 mg diphenhydramine administered intra-venously. Over the following 10 min, subcutaneous 0.3 mgof a 1:10,000 epinephrine was repeated a single time. Thetongue of the patient decreased in size and she became ableto speak. The patient stayed in the observation unit for 24 hand was discharged without any further problems.DiscussionAngiotensin-converting enzyme (ACE) inhibitors are fre-quently used in the treatment of hypertension. Side effectprofiles vary from minor allergic reactions to anaphylactic

Preparation and evaluation of controlled release tablets of carvedilol

The objective of the present investigation is to design and evaluate controlled release tablets of carvedilol, employing synthetic polymers like polyethylene oxides, of different molecular weights as release retarding materials and to select the optimized formulation based on the pharmacokinetics of carvedilol. Matrix tablets each containing 80 mg of carvedilol were formulated employing PEO N60 K, PEO 301, and PEO 303 as release-retarding polymers and β Cyclodextrin and HP β cyclodextrin as release modulators from the matrix. Carvedilol release from the formulated tablets was very slow. Hence the release was modulated with the use of cyclodextrins. The dissolution from the matrix tablets was spread over more than 24 hours and depended on the type of polymer, its concentration and the type of cyclodextrin used. All the matrix tablets prepared using polyethylene oxides showed very good controlled release over more than 24 hours.The matrix tablets prepared using HP β cyclodextrin showed a higher dissolution rate and gave a dissolution profile that was comparable to the theoretical sustained release needed for once-a-day administration of carvedilol. The drug release mechanism from the matrix tablets was found to be quasi Fickian mechanism.

73-Year-Old Woman With Fever and Mental Status Changes

A 73-year-old right-handed woman from Wisconsin presented to her local hospital in early March with sharp central chest pain, epigastric discomfort, and painful swallowing. Findings on a work-up for intra-abdominal pathology and cardiac ischemia (including extensive blood work, serial electrocardiograms, and a computed tomographic [CT] scan of the abdomen and pelvis were unremarkable, and the patient was given a presumptive diagnosis of gastroesophageal reflux disease. Before discharge, however, the patient developed recurrent fevers ranging as high as 39.4oC and had difficulty with speaking. Over the next day, her mental status and speech continued to worsen, prompting transfer to Mayo Clinic in Rochester, Minn. The patient’s medical history was notable for nonischemic dilated cardiomyopathy with frequent ventricular ectopy, polymyalgia, and hypothyroidism. Her surgical history included excision of 2 parathyroid glands for hyperparathyroidism. She had traveled only within the upper Midwest. Her medications were all oral and included 81 mg/d of aspirin, 12.5 mg of carvedilol twice daily, 50 mg/d of losartan, 40 mg/d of furosemide, 400 mg/d of amiodarone, 20 mg/d of prednisone (as part of a slow taper after an initial dosage of 30 mg/d started 4 months earlier), and 125 μg/d of levothyroxine. On physical examination, the patient had a temperature of 38.4°C, a heart rate of 92 beats/min, a regular blood pressure of 140/60 mm Hg, a respiratory rate of 24/min, and an oxygen saturation rate of 94% while breathing room air. Her mucous membranes were dry, and 2 shallow bleeding ulcers were noted on her upper palate and tongue. Findings on examination of the lungs, abdomen, extremities, and skin were normal. However, cardiac examination revealed a grade 2/6 systolic ejection murmur. Neurologic examination revealed that the patient was somnolent, opening her eyes and maintaining arousal only when verbally stimulated. She was unable to follow even simple 1-step commands and answered “yes” to most questions. Her speech was otherwise unintelligible. The patient was able to track with her eyes and blinked to threat bilaterally. Her optic discs were flat, and her face was symmetric. She had strong spontaneous movements of the upper and lower extremities and localized to pain throughout. Reflexes on the right were slightly stronger than those on the left. The right plantar response was extensor, whereas the left was flexor. No nuchal rigidity was observed.

Carvedilol versus Metoprolol for the Prevention of Atrial Fibrillation After Off-Pump Coronary Bypass Surgery: Rationale and Design of the Carvedilol or Metoprolol Post-Revascularization Atrial Fibrillation Controlled Trial (COMPACT)

Postoperative new-onset atrial fibrillation (AF) remains the most common complication of coronary artery bypass graft surgery. Postoperative AF carries the risk of hemodynamic instability, increases the risk of thromboembolic events, and has a significant economic impact. Current guidelines recommend treatment with beta-blockers to prevent AF; information, however, is limited regarding the relative efficacy of beta-blocking agents. Carvedilol is a non-selective adrenergic blocker with anti-inflammatory, antioxidant, and multiple cationic channel blocking properties. These unique properties of carvedilol have generated interest in its use as a prophylaxis for postoperative AF. We hypothesize that carvedilol will be more effective than metoprolol, a conventional beta(1)-selective antagonist, in suppressing newly developed AF following off-pump coronary artery bypass (OPCAB) surgery. We have designed the Carvedilol or Metoprolol Post-Revascularization Atrial Fibrillation Controlled Trial (COMPACT) to test our hypothesis in a multi-center, open-label, randomized, and controlled trial. A total of at least 650 patients will be randomized to receive an initial oral dose of either 5 mg of carvedilol twice per day or 20 mg of metoprolol tartrate three times per day following surgery. The dose of each beta-blocker will be increased to the maximum tolerated dose. The primary endpoint is the incidence of new-onset AF during the first 7 days after surgery. The COMPACT is the first multi-center, randomized, controlled trial to directly compare two different beta-blockers in patients following surgical coronary revascularization. Results of this trial will help to guide physicians in choosing appropriate medications following OPCAB surgery.

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

The aim of this study was to evaluate the pharmacogenetic variability in the disposition of carvedilol in the Japanese population. Five or 10 mg of carvedilol was orally administered to 54 healthy Japanese subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A5, UGT2B7, and MDR1 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. We then examined the effect of the genetic polymorphisms on the variability in the pharmacokinetics of carvedilol using a multiple regression analysis. The oral clearance (CL/F) and also apparent volume of distribution (V/F) of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than those with the CYP2D6*1/*1, *1/*2, or *2/*2 genotype, confirming our previous finding that the bioavailability (F) and systemic clearance (CL) of R- and S-carvedilol in the liver is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, and MDR1 C3435T did not significantly affect the pharmacokinetics of carvedilol in Japanese subjects.

O-50. The expression of apoptosis-regulating proteins in usual ductal hyperplasia with known outcome

β-Blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the β1-blocker metoprolol tartrate and the β1-, β2-, and α1-blocker carvedilol.In a randomized double-blind design, 3029 patients with chronic congestive heart failure requiring diuretic therapy and with left ventricular dysfunction were randomized to treatment with carvedilol (n = 1511) or metoprolol tartrate (n = 1518) and titrated to target doses of 25 mg of carvedilol twice daily or 50 mg of metoprolol tartrate twice daily. The main outcome measures were total mortality and the combination of mortality or hospitalization for any cause. Secondary end points were cardiovascular death, combinations of morbidity and mortality, New York Heart Association class, worsening of heart failure, hospitalizations, and discontinuation of study therapy.A total of 512 and 600 patients in the carvedilol group and metoprolol group, respectively, died (hazard ratio [HR] 0.83, 95% CI 0.74-0.93, P = .0017). Cardiovascular death was reduced by carvedilol (HR 0.80, 95% CI 0.70-0.90, P = .0004). There were fewer sudden deaths and deaths caused by circulatory failure or by stroke in the carvedilol group. There was no difference in all-cause hospitalizations or in worsening heart failure between treatment groups. The incidence of fatal or nonfatal acute myocardial infarction was significantly lower in the carvedilol group (HR 0.71, 95% CI 0.52-0.97, P = .03). Discontinuations of study therapy were similar in the 2 groups.Compared with metoprolol tartrate, carvedilol reduced cardiovascular mortality, sudden death, death caused by circulatory failure, death caused by stroke, as well as fatal and nonfatal myocardial infarctions.

Beneficial effects of high doses of growth hormone in the introduction and optimization of medical treatment in decompensated congestive heart failure

Background Optimizing oral therapy in patients with unstable decompensated and/or dobutamine-dependent congestive heart failure (CHF) is a challenge. Methods and results We investigated the effects of high doses of recombinant human growth hormone (GH) in 6 patients with cardiac cachexia and unstable decompensated CHF (5 dobutamine-dependent), including its influence in the optimization of oral CHF treatment. Patients received 8 IU of subcutaneous GH per day for median 26 (range 61) days. GH improved the systolic systemic blood pressure (SSBP, in mm Hg) from median 85 (range 34) to 100 (20) ( p < .01), and the left ventricular (LV) ejection fraction (in %) from median 23 (range 22) (pretreatment) to 28 (18) (posttreatment) and 38 (28) (later) ( p < .007). The NYHA functional class improved from IV to I in 2 patients, from IV to II in 3, and from IV to II–III in one. All patients were discharged from the hospital. It was possible in the hospital to initiate and after discharge to optimize long-term CHF treatment from 37.5 to 50 mg of carvedilol in 5 patients and with higher doses of captopril (from 50 to 150 mg) in all patients. Three patients are alive after 67, 75, and 11 months of follow-up. The remaining 3 patients died from a pulmonary abscess at 9 months, septicemia at 21 months, and progressive heart failure due to unplanned withdrawal of carvedilol at 36 months. Conclusion The use of GH in patients with decompensated CHF and cardiac cachexia provided clinical stability without the need for inotropic drugs permitting introduction of nonpreviously tolerated drugs. This could represent a new option for optimizing long-term CHF therapy and discharging hospitalized patients who are dobutamine-dependent.

Carvedilol Reduces Plasma 8-Hydroxy-2′-Deoxyguanosine in Mild to Moderate Hypertension

The purpose of this pilot study was to test whether carvedilol has a protective effect against oxidative deoxyribonucleic acid (DNA) damage in human hypertension in vivo. Carvedilol's antioxidant effect has mostly focused on lipid or amino acid so far. However, there has been no data that carvedilol reduces DNA damage in human hypertension. Never-treated mild to moderate hypertension patients and age- and sex-matched control subjects volunteered for the study. The hypertension subjects were given 12.5 or 25 mg of carvedilol or hydrochlorothiazide orally for 2 months and controls were not given any. Fasting blood samples were collected before and after carvedilol. Plasma highly sensitive 8-hydroxy-2'-deoxyguanosine (hs8-OHdG) and high-sensitivity C-reactive protein (hsCRP) were checked with the samples. There were no statistical differences in clinical characteristics in 3 groups. The hs8-OHdG declined from 9.07+/-4.23 ng/mL to 5.74+/-3.89 ng/mL (P=0.002) after carvedilol. However, it did not show significant reduction after hydrochlorothiazide (9.01+/-3.89 versus 8.23+/-4.12 ng/mL; P=NS). In the control group, the hs8-OHdG concentration was 3.41+/-2.03 ng/mL and 3.01+/-2.65 ng/mL at baseline and 2 months later, respectively (P=NS). The baseline hs8-OHdG levels were higher in hypertension groups compared with control (P=0.000). The hsCRP had no significant difference before and after the tested drugs in 2 hypertension groups (group A: 0.21+/-0.51 versus 0.19+/-0.37 mg/dL; group B: 0.20+/-0.45 versus 0.18+/-0.42 mg/dL). In conclusion, DNA damage caused by reactive oxygen species occurs more in the hypertension patients than normals. Carvedilol significantly reduces DNA damage in the hypertension patients.