Beta-adrenergic Blocking Drugs Research Articles

Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives.

Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.

Current state of the roles of alcohol septal ablation and surgical myectomy in the treatment of hypertrophic obstructive cardiomyopathy.

Hypertrophic cardiomyopathy is a genetically determined disorder resulting in left ventricular hypertrophy. In a majority of the estimated 20 million people affected worldwide, left ventricular outflow obstruction is present at rest or with provocation. The presence and degree of obstruction influence the symptomatic presentation, treatment strategies and prognosis of affected individuals. Pharmacologic therapy with beta-adrenergic blocking drugs and calcium channel blockers is the principal treatment strategy in symptomatic patients with left ventricular outflow obstruction but is ineffective in many patients. When symptoms of exertional shortness of breath, chest pain and/or syncope prove refractory to medical therapy and there is persisting left ventricular outflow obstruction, or when there is drug intolerance, septal reduction strategies (surgical myectomy and alcohol septal ablation) are quite effective. Selection of the optimal septal reduction strategy for a given patient has become controversial and is determined largely by the medical system providing treatment strategies for the patient. Regretably, there are no randomized trials comparing myectomy and ablation and none are anticipated. The comprehensive Hypertrophic Cardiomyopathy Guideline Statements published in 2011 and 2014 differ significantly with the earlier statement favoring surgical myectomy and the more recent statement giving equal class I status to the two septal reduction strategies in adult patients with drug-refractory symptoms. Recently published studies of long-term follow-up of patients after alcohol septal ablation in Europe, where surgical myectomy is rarely performed, confirm long-term safety and effectiveness with survival free of cardiac events exceeding 96% at 15 years. The lesser degree of discomfort and more rapid recovery associated with the minimally invasive catheter-based alcohol ablation procedure coupled with the recently published long-term safety data favor an increased use of this strategy in symptomatic adult patients with hypertrophic obstructive cardiomyopathy (HOCM).

Hereditary Long Q-T Without Congenital Deafness (Romano-Ward) Syndrome

We report a case o fhereditary long Q-T syndrome without congenital deafness (Romano-Ward syndrome). In four members of a family, a father and his daughters, the Q-T intervals on the EKG were found to be prolonged. There were no other accompanying familial anomalies such as deafness or a tendency to extracellular hypokalemia The youngest daughter which had the longest. Q-T interval had several Adams-Stokes attacks, and died in the last attack at the age of 23 months. Her two older siblings died at the age of 15 and 10 months with the same typical clinical histories. The eldest daughter, a 12-year old girl, has no clinical symptoms at all, while the fourth child, 5-yeltr old girl has several occasions of near fainting attacks. The EKG of the father showed several runs of supraventricular premature contractions that ceased spontaneously, besides evidence of the prolongation of Q-T interval. The beta-adrenergic blocking drug (propranalol) given in a relatively small maintenance dose, proved to be effective in preventing attacks of the father and the fourth child, despite the unchanged prolongation of the Q-T interval.

Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study

Recent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC. To explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not. 153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66-0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34-0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial. In this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB. NCT00703326.

Beta blockers and angiotensin-converting enzyme inhibitors’ purported benefit on breast cancer survival may be explained by aspirin use

Preclinical and epidemiologic evidence supports a possible role for beta-adrenergic blocking drugs (beta-blockers), and angiotensin-converting enzyme inhibitors (ACEIs) in promoting survival after breast cancer. However, these drugs are often used concurrently with aspirin, and there is a growing body of evidence indicating a survival benefit for aspirin. Therefore, we analyzed the use of beta-blockers and ACEIs after a breast cancer diagnosis and their association with breast cancer mortality, both individually, combined with each other, and in combination with aspirin use in the Nurses' Health Study, using updated measures of medication use and Cox proportional hazards models. There were 4,661 women with stages I-III breast cancer included; 292 breast cancer deaths occurred during median follow-up time of 10.5 years. Modeled individually, the multivariable relative risk and 95 % confidence intervals (RR, 95 % CI) for breast cancer death were (0.76, 0.54-1.05) for beta blockers, (0.89, 0.60-1.32) for ACEIs, and (0.46, 0.35-0.60) for aspirin. Modeled simultaneously, the multivariable (RR, 95 % CI) for breast cancer death were (0.83, 0.60-1.16) for beta blockers, (1.00, 0.68-1.46) for ACEIs, and (0.46, 0.35-0.61) for aspirin. We did not see a significant association with beta blockers and survival, but there was a suggestion. Our study was limited in that we could not assess type of beta blocker and the number of events among users was still quite low. We found no evidence of a protective effect for ACEIs. The strong protective association with aspirin use confounds the associations with these other drugs and underscores the importance of considering aspirin use in analyses of breast cancer survival.

Cardiologists are more willing to prescribe β‐blockers than respiratory physicians: an Australasian clinical scenario survey

Recent data show great benefit from beta adrenergic blocking drug (β-blocker) use in heart failure and has resulted in increased use of these established agents. Older data caution against their use in patients with reversible airways disease because of risks of bronchoconstriction. Anecdotally, we noted a difference in willingness to prescribe β-blockers by cardiologists and respiratory physicians, especially for patients with coexisting airways disease. We sought to test this difference. Nine clinical scenarios were created, tested and emailed to all members of the Cardiac and Thoracic societies of Australasia. Scenarios combined varying degrees of benefit and risk (bronchoconstriction). An inducement to return questionnaires was applied. Cardiologists and respiratory physicians were similarly willing to prescribe β-blockers for patients at little risk of bronchoconstriction, irrespective of potential benefit. Cardiologists were more willing to prescribe β-blockers than respiratory physicians for patients at greater risk of bronchoconstriction, particularly when the potential therapeutic benefit was greater. Our perception that cardiologists were more willing to prescribe β-blockers than respiratory physicians was confirmed. This probably results from a difference in focus (namely focus on benefit by cardiologists vs focus on risk by respiratory physicians), although other factors including awareness of limitations of pulmonary function testing by respiratory physicians may have been involved. Until better tests are available (that discriminate between patients who are likely to suffer bronchoconstriction from those who are not), it is likely that this difference between the specialties will remain.

Psychophysiologic Remodeling of the Failing Human Heart

Autonomic imbalance is a therapeutic target in heart failure patients. Overactivation of the sympathetic branch of the autonomic nervous system has for years been treated with beta-adrenergic blocking drugs, although it cannot be long before invasive therapies such as renal sympathetic denervation, currently being tested for resistant hypertension, make their way to the heart failure arena. Insufficient parasympathetic input to the heart is already being augmented with implanted vagal nerve stimulators. It is our contention that biofeedback training could provide much of the same benefit as these more invasive therapies in improving autonomic imbalance, with the added advantage of increasing patient self-efficacy. This article describes a pilot study of biofeedback training in patients with end-stage heart failure awaiting heart transplantation. It was our goal to show not only that patients would appreciate this training and benefit from it but also that patient-controlled autonomic modulation could actually reverse the cellular and molecular markers of heart failure, or remodel the failing heart, similar to what we had previously shown for other types of heart failure therapy such as the left ventricular assist device. To our knowledge, this is the first study to demonstrate changes in the biology of the failing heart in response to a psychophysiologic intervention.

Bisoprolol: A Nçw Cardioselective Beta Blocker In Hypertensive Patients

Introduction: During sixth decade of this century Beta adrenoceptor antagonists were developed for the treatment of cardiac arrhythmias and angina pectoris. It was discovered later on that long term treatment with beta blockers caused decrease in arterial blood pressure. Beta adrenergic blocking drugs can be characterized by their pharmacokinetic properties. One property is lipophilic or hydrophilic. Bisoprolol takes an intermediate position between lipophilic and hydrophilic properties of beta blockers. It is readily Conclusion: This placebo controlled single blind study of drug monotherapy for patients with uncomplicated mild to moderate essential hypertension demonstrates that Bisoprolol is an effective, well tolerated and safe means of achieving blood pressure in patients with mild to moderate hypertension who have tolerated the drug well with a dose range of 5 to 10 mg. Adverse effects were mostly mild and discontinuation of Bisoprolol therapy was necessary in only 2 (10%) of patients. Patients had good compliance of drug. Therapy because of single drug regimen.

The C57BL/6 genetic background confers cardioprotection in iron-overloaded mice.

Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart. Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods. As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1 ± 0.1 mm to 3.5 ± 0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group. These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.

Carvedilol suppresses fatty acid oxidation and stimulates glycolysis in C2C12 cells

Beta adrenergic receptor blocking drugs (β-blockers) are used chronically in many cardiovascular diseases such as hypertension, ischemic heart disease, arrhythmia, and heart failure. Beneficial effects are associated with the inhibition of symphathetic nervous system hyperactivity, reduction of heart rate, and remodeling by blocking the mitogenic activity of catecholamines. A possible effect of β-blockers on substrate metabolism has also been suggested. The direct effects of β-blockers on mouse C2C12 cells were investigated in this study. C2C12 cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and differentiated into myotubes in the same medium that contained 1% FBS. Palmitic acid oxidation and glycolysis were measured by using [9,10-(3)H]palmitate and [5-(3)H]glucose, respectively. The amount of (3)H(2)O was measured as an indicator of substrate usage. Carvedilol (100 µmol/L) inhibited palmitate oxidation and increased glycolysis by nearly 50%. Prazosin altered substrate metabolism in a similar fashion as carvedilol, whereas propranolol or bisoprolol were devoid of metabolic effects. When added to mimic sympathetic activation, epinephrine stimulated glycolysis but did not alter fatty acid oxidation. Based on these results, carvedilol appears to have direct effects on substrate metabolism that are related to the blockade of α1 adrenergic receptors.

The human sympathetic nervous system: its relevance in hypertension and heart failure

Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is at different stages of development with regard to the two disorders. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to the introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on the demonstration of activation of the renal sympathetic outflow. Additional evidence in this regard is provided by the results of pilot studies exploring the possibility to reduce blood pressure in resistant hypertensives through electrical stimulation of the area of carotid baroreceptors. Despite the general importance of the sympathetic nervous system in blood pressure regulation, and the specific demonstration that the blood pressure elevation in essential hypertension is commonly initiated and sustained by sympathetic nervous activation, drugs antagonizing this system are currently underutilized in the care of patients with hypertension. Use of beta-adrenergic blocking drugs is waning, given the propensity of this drug class to have adverse metabolic effects, including predisposition to diabetes development. The blood pressure lowering achieved with carotid baroreceptor stimulation and with the renal denervation device affirms the importance of the sympathetic nervous system in hypertension pathogenesis, and perhaps suggests a wider role for anti-adrenergic antihypertensives, such as the imidazoline drug class (moxonidine, rilmenidine) which act within the CNS to inhibit central sympathetic outflow, although the lack of large-scale outcome trials with this drug class remains a very material deficiency.

The role of self‐regulation in modulating the heart‐brain connection

Cardiovascular disease is characterized by autonomic imbalance. The sympathetic nervous system is activated in order to compensate for declining cardiac function, but the increased activation actually has deleterious effects over time. Mortality in end‐stage heart failure is predicted by elevated plasma norepinephrine levels and a decrease in overall heart rate variability. Beta adrenergic blocking drugs are increasingly used to prevent the cardiac remodeling which follows myocardial infarction or other stresses to the myocardium. Together with sympathetic overdrive, the parasympathetic branch of the autonomic nervous system is correspondingly down‐regulated, and it is now clear that decreased parasympathetic input to the cardiovascular system may be equally harmful, promoting a pro‐inflammatory state which further exacerbates disease. Biofeedback‐mediated stress management is a method for training individuals to control the balance of sympathetic and parasympathetic nervous system activation. Such training can be used to increase parasympathetic and decrease sympathetic activation, with corresponding effects on remodeling and disease progression. Work in our research program focuses on testing the hypothesis that patients with cardiovascular disease can be taught to improve autonomic balance, and that this improvement will result in decreased symptoms, improved quality of life, and possibly even disease reversal. Patient populations which are currently being studied and which will be discussed include those with end‐stage heart failure awaiting transplantation and those with documented coronary artery disease.

Beta-adrenergic blocking drugs in breast cancer: a perspective review

The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signalling can inhibit multiple cellular processes involved in breast cancer progression and metastasis, including extracellular matrix invasion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses. This has led to the hypothesis that the commonly prescribed class of β-AR antagonist drugs (β-blockers) may favourably impact cancer progression. A number of recent pharmacoepidemiological studies have examined the association between β-blocker exposure and breast cancer progression. The results from these studies have suggested a potential role for targeting the β-AR pathway in breast cancer patients. Larger observational studies are, however, required to confirm these results. Questions regarding the type of β-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy must also be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with breast cancer.

Other complications and associated conditions with diabetes in children and adolescents

aChildren’s Hospital auf der Bult, Hannover, Germany; bthe Children’s Hospital at Westmead, NSW, Australia; cUniversity of Helsinki, Finland; dMedical University Vienna, Austria; eUniversity of Genova, Italy; fUniversitat Ulm, Uni West, Germany; gUniversity of Sydney, Australia Corresponding author: Prof. Dr. med. Olga Kordonouri Diabetes Center for Children and Adolescents Children’s Hospital auf der Bult Hannover, Germany Tel: +49 511/8115-3340; fax: +49 511/8115-3334; e-mail: kordonouri@hka.de

Therapeutic options for cardiogenic shock

To the Editor: The recently published report describing a case of cardiogenic shock following nasal septoplasty1 helps to raise our awareness of the issue and suggests that beta blockade can be ineffective and, at times, harmful in that situation. Unfortunately, the authors fail to discuss other therapeutic options which may have been appropriate and should have been considered. Since, as a rule, the effects of single injections of epinephrine are transient, should the ensuing hypertension and tachycardia simply be ignored, or should definitive alpha blockade, either alone or in combination with a beta adrenergic blocking drug, be considered? This case report also raises the question as to what are the most appropriate resuscitative measures to assume when faced with a cardiac arrest in this scenario. The problem is already postulated to be excess alpha stimulation in the presence of beta blockade; therefore, administering additional epinephrine in this case may not have been ideal. Should the use of beta stimulants (e.g., isoproterenol) to achieve a positive chronotropic effect be considered? The answers to these questions may not be straightforward; however, the authors might have considered discussing the additional treatment options.

Le blues du méthylène : prévenir les réactions indésirables aux médicaments non anesthésiques

NE of the main focuses in the training of anesthesiologists is the art of applied clinical pharmacology. The many and diverse drugs that we use daily have near instantaneous actions, satisfying the need for “immediate gratification” that attracted many of us to this field. We are also well trained in anticipating and treating the unintended effects of our pharmacologic armamentarium. These range from common side effects such as hypotension or hypoventilation, to sporadic reactions such as anaphylaxis. To complicate matters, the incidence of adverse drug reactions is influenced by factors such as age, ethnicity, pre-existing medical conditions and concurrent drug therapy. For example, we can predict that elderly, diabetic or hypertensive patients may have an exaggerated blood pressure response to induction agents, or that angiotensin converting enzyme inhibitor and beta adrenergic blocking drugs may alter the hemodynamic response to anesthetics. In this way, we constantly anticipate reactions and tailor our anesthetic techniques to account for these factors. Similarly, many patients present with a history of allergic reactions to medications; these drugs can easily be avoided. We can also predict a higher incidence of such reactions in patients with other known sensitivities, such as the increased incidence of reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in patients with allergy to aspirin, 1 or an alteration in response to meperidine in patients receiving monoamine oxidase inhibitors. 2 A family history of malignant hyperthermia or cholinesterase deficiency prompts special precautions due to the known genetic transmission of these traits. Frequently, it is not the drug compound that is responsible for reactions, but rather preservatives in the preparations, such as local anesthetics with the preservatives methylparaben in patients with a history of sunscreen allergy, and sodium metabisulfite in patients with sulfite allergy. 3 There is, however, an increasing demand on the anesthesiologist to administer (and thereby assume responsibility for) a variety of non-anesthetic drugs. In addition, drugs, or other potential allergens such as disinfectant preparations, are frequently administered by surgeons and nurses, with the expectation that the “resuscitation expert” at the head of the table will deal with any potential reactions. A list of commonly used agents that fall into this category is provided in the Table; this list is not comprehensive, and there are new drugs with potential reactions being added almost daily.

Cardiogenic shock following nasal septoplasty: a case report and review of the literature

Nasal septoplasty is a surgical procedure offered to patients with chronic snoring secondary to nasal obstruction. We describe a case of cardiogenic shock following the administration of metoprolol to treat hypertension, (likely) induced by systemic absorption of topical epinephrine used during a routine nasal septoplasty. A 29-yr-old male, with no significant medical history, was scheduled for nasal septoplasty for mild nasal obstruction. Following routine anesthetic induction, cotton balls, soaked with epinephrine (1:1000), were applied to the nasal mucosa. The patient became hypertensive with a blood pressure of 207/123 mmHg. Intravenous metoprolol was administered. Severe pulmonary edema ensued, with resulting hypoxic respiratory failure and cardiogenic shock. The patient was transferred to a tertiary care facility for percutaneous cardiopulmonary bypass. After five days of cardiopulmonary bypass support and six weeks of intensive care monitoring, the patient's cardiac status returned to normal limits. A hypertensive response, following systemically absorbed topical vasoconstrictors, including both phenylephrine and epinephrine, can be associated with dire consequences when treated with a beta-adrenergic blocking drug and, possibly, calcium channel blockers. To prevent severe complications including; pulmonary edema, cardiogenic shock, cardiac arrest, and, possibly, death, these drug interactions need to be appreciated.

Protocol implementation in anesthesia: beta-blockade in non-cardiac surgery patients

An audit of intensive care unit (ICU) patients with perioperative myocardial ischemia and/or infarction (PMI/I) suggested under-use of prophylactic beta-adrenergic blocking drugs (ABDs). A multidisciplinary team developed an institutional protocol to identify at-risk patients, to standardize and facilitate prophylactic beta-adrenergic blockade, and to improve management of such patients. We report a retrospective assessment of the efficiency of program implementation. Eligible preanesthesia assessment unit patients received metoprolol for one to four weeks prior to surgery, intraoperatively, and postoperatively. Patients with PMI/I requiring ICU admission were tracked from January 2002 to December 2004. The protocol was implemented in May 2003. The efficiency of program implementation was evaluated during two months of normal operating room activity (September 2003 and February 2004). The use of ABDs increased during the audit. Preoperative use increased from 31% in September 2003 to 39% of eligible patients in February 2004, with a stable surgical population. The incidence of patients with PMI/I admitted to ICU decreased from 2.6/1,000 surgical cases pre-implementation to 1.6/1,000 surgical cases post-implementation (P=0.025). For the whole hospital, implementation was associated with a decrease in PMI/I incidence from 5.9 to 2.0/1,000 surgical cases (P<0.001). Heightened awareness and standardization of perioperative beta-blockade coincided with an increase in metoprolol use in at-risk patients and reduction in PMI/I. There was an increase in at-risk patients receiving prophylactic ABDs, a reduction in PMI/I diagnoses throughout the hospital, and reduced ICU patient admissions with PMI/I.

Stereoselective Metabolism of Racemic Carvedilol by UGT1A1 and UGT2B7, and Effects of Mutation of these Enzymes on Glucuronidation Activity

Carvedilol, an alpha- and beta-adrenergic blocking drug, is mainly metabolized by CYP2D6, UGT1A1, UGT2B4 and UGT2B7. This drug is administered orally as a racemic mixture of R(+)- and S(-)-enantiomers. It has been reported that CYP2D6 prefers metabolizing S-carvedilol to R-carvedilol stereoselectively. On the other hand, stereoselective metabolism of carvedilol by UGTs is still unclear. Moreover, we have reported that patients with chronic heart failure who had polymorphism in CYP2D6, UGT1A1 and/or UGT2B7 had lower metabolic activity and oral clearance than did patients with no polymorphism. The aim of this study was to clarify stereoselective metabolism of carvedilol by UGT1A1 and UGT2B7 and to determine by using a recombinant enzyme-introduced mutation whether genetic mutation in UGT1A1 and UGT2B7 causes reduction in metabolic activity for carvedilol. A glucuronidation assay using human liver microsomes and recombinant UGT1A1 and UGT2B7 expressed in HeLa cells demonstrated that UGT1A1 prefers metabolizing R-carvedilol to S-carvedilol. On the other hand, UGT2B7 prefers metabolizing S-carvedilol to R-carvedilol. Moreover, G71R mutation of UGT1A1 reduced both affinity and capacity but did not affect stereoselective metabolism. On the other hand, both A71S and H268Y mutations of UGT2B7 reduced capacity but did not affect affinity and, as a result, the efficiency of metabolism was remarkably reduced. However, as in the case of UGT1A1, neither of the mutations affected stereoselective metabolism.

Novel therapeutic approaches to treating chronic angina in the setting of chronic ischemic heart disease.

Pharmacologic therapy to alleviate symptoms in chronic angina has been enhanced by the recent approval of several novel compounds that complement the traditional approach using beta-adrenergic blocking drugs, calcium antagonists, and long-acting nitrates. In the United States, ranolazine, a drug that inhibits late I(Na), was approved for patients with chronic angina that remain symptomatic on beta-blockers, calcium antagonists, or long-acting nitrates, on the basis of an acceptable safety profile and efficacy in several randomized placebo controlled studies. A slight increase in the QT interval is observed (<10 ms on average) at the maximum approved dose of 1,000 mg twice daily. Therefore, an ECG should be acquired at baseline and during follow-up, and the drug should not be used in patients with QT prolongation or those who are on QT prolonging drugs unless longer term randomized outcome data demonstrates no excess risk. The MERLIN trial of non-ST-elevation acute coronary syndrome (NSTE ACS) randomized 6,560 patients to assess the potential benefit of ranolazine in reducing the composite endpoint of cardiovascular death, myocardial infarction, and recurrent ischemia, with results expected in 2007. In Europe, ivabradine, a drug that inhibits the hyperpolarization-activated mixed sodium/potassium inward I(f) current, which slows the rest and exercise heart rate, was approved in 2005. Ivabradine at a dose of 10 mg twice daily has been shown to have similar efficacy to amlodipine 10 mg once daily or atenolol 100 mg once daily in alleviating chronic angina symptoms. In this review, several other novel investigational approaches are presented and patient selection considerations for the most recent approved drugs for chronic angina are discussed.