Selection Of Pharmacologic Agents Research Articles

Guidelines for obesity clinic consultations in primary healthcare clinics

Background: The prevalence of obesity and its public health implications underscore the necessity for prioritizing its prevention and care in primary healthcare clinics.Current Concepts: The establishment of dedicated obesity clinics requires a comprehensive initial assessment of patients, ideally facilitated by a pre-consultation questionnaire. The initial assessment of patients includes a detailed patient interview, thorough physical examination, body composition analysis, and evaluation of visceral adiposity. Identifying potential causes of secondary obesity, particularly drug-induced obesity, is imperative before the initiation of treatment. The primary goal of obesity management transcends weight reduction alone and should encompass the improvement of overall health status, addressing concurrent comorbidities. Individualized treatment goals are established after a thorough assessment. Although the cornerstone of obesity management is the promotion of a healthier lifestyle, personalized approaches tailored to the circumstances of each patient are advocated for long term sustainability. Dietary and exercise recommendations should be personalized and introduced progressively. Pharmacotherapy can significantly potentiate lifestyle modification efforts for weight reduction. However, the selection of pharmacological agents must be reasonable, considering factors as comorbid conditions, severity of obesity, previous weight gain history, and economic constraints related to treatment. Dosing regimens should be meticulously calibrated and adjusted as necessary, with vigilant monitoring of the therapeutic efficacy and potential adverse reactions.Discussion and Conclusion: Effective obesity management in primary healthcare clinics involves thorough assessment, goal setting, recommendation of individualized lifestyle modifications, and careful implementation of suitable pharmacotherapy.

Convection-Enhanced Delivery in Children: Techniques and Applications.

Since its first description in 1994, convection-enhanced delivery (CED) has become a reliable method of administering drugs directly into the brain parenchyma. More predictable and effective than simple diffusion, CED bypasses the challenging boundary of the blood brain barrier, which has frustrated many attempts at delivering large molecules or polymers into the brain parenchyma. Although most of the clinical work with CED has been carried out on adults with incurable neoplasms, principally glioblastoma multiforme, an increasing number of studies have recognized its potential for paediatric applications, which now include treatment of currently incurable brain tumours such as diffuse intrinsic pontine glioma (DIPG), as well as metabolic and neurotransmitter diseases. The roadmap for the development of hardware and use of pharmacological agents in CED has been well-established, and some neurosurgical centres throughout the world have successfully undertaken clinical trials, admittedly mostly early phase, on the basis of in vitro, small animal and large animal pre-clinical foundations. However, the clinical efficacy of CED, although theoretically logical, has yet to be unequivocally demonstrated in a clinical trial; this applies particularly to neuro-oncology.This review aims to provide a broad description of the current knowledge of CED as applied to children. It reviews published studies of paediatric CED in the context of its wider history and developments and underlines the challenges related to the development of hardware, the selection of pharmacological agents, and gene therapy. It also reviews the difficulties related to the development of clinical trials involving CED and looks towards its potential disease-modifying opportunities in the future.

A novel assay based on pre-equilibrium titration curves for the determination of enzyme inhibitor binding kinetics

Selection of pharmacological agents based on potency measurements performed at equilibrium fail to incorporate the kinetic aspects of the drug–target interaction. Here we describe a method for screening or characterization of enzyme inhibitors that allows the concomitant determination of the equilibrium inhibition constant in unison with rates of complex formation and dissociation. The assay is distinct from conventional enzymatic assays and is based on the analysis of inhibition curves recorded prior to full equilibration of the system. The methodology is illustrated using bicyclic peptide inhibitors of the serine protease plasma kallikrein.

Bipolar depression: Managing patients with second generation antipsychotics.

Bipolar affective disorder is a debilitating illness that manifests as cyclical episodes of mood elevation and depression, but the treatment of the depressive episodes (i.e., bipolar depression) differs considerably from the treatment of major depressive disorder. In bipolar affective disorder, it is well known that patients spend a significantly greater amount of time in depressive episodes than manic or hypomanic episodes, yet there are currently just three Food and Drug Administration-approved agents for the treatment of bipolar depression: (1) olanzapine/fluoxetine combination (2) quetiapine, both immediate- and extended-release, and (3) lurasidone. The literature review presented here focuses on the clinical trials that led to the Food and Drug Administration-approval of these second generation antipsychotics in the treatment of bipolar depression. The discussion highlights key considerations regarding overall treatment strategies to aid clinicians in the selection of pharmacologic agents. Recommended monitoring parameters, potential adverse effects, and pertinent counseling points for second generation antipsychotics used in bipolar depression are included.

Direct photocapture of bromodomains using tropolone chemical probes

Tropolone probes directly photoaffinity label bromodomains.

SY04-4 * NEW DEVELOPMENTS IN THE TREATMENT OF GAMBLING DISORDER

Background. Although there are no medications with indications for pathological gambling or gambling disorder, multiple pharmacotherapies and behavioral therapies have received empirical support in the treatment of pathological gambling or gambling disorder. Methods. Data from clinical trials will be reviewed, with an emphasis on findings from placebo-controlled, randomized clinical trials. Results. Both behavioral and pharmacological therapies appear efficacious in the treatment of gambling disorder. Behavioral therapies with varying degrees of empirical support include different forms of cognitive behavioral therapies, imaginal desensitization, motivational interviewing and brief interventions. Pharmacological therapies with varying degrees of support include opioid antagonists like naltrexone, mood stabilizers like lithium, serotonin reuptake inhibitors like paroxetine, and nutraceuticals like n-acetyl-cysteine. Recent data suggest that combinations of behavioral and pharmacological approaches hold promise and that co-occurring disorders may be used to guide selection of pharmacological agents. Conclusions. Although no medication currently has a formal indication for gambling disorder, multiple therapies have empirical support in the treatment of gambling disorder.

ACE Inhibitors and ARBs for Obesity-Related Hypertension

Multiple abnormalities in hemodynamics, endocrine factors and adipocytokines are involved in pressor mechanisms of obesity-related hypertension. These abnormalities induce insulin resistance, which plays a central role in the mechanism leading to blood pressure elevation. Thus, in addition to body weight control, selection of pharmacological agents that improve insulin resistance is important for treatment of patients with obesity and hypertension. Although angiotensin receptor antagonists (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), α-adrenoceptor blockers, and Ca2+-channel antagonists have been shown to improve insulin sensitivity in hypertensives, ARBs and ACEIs are mainly selected for this purpose. Beneficial effects of ARBs in obesity-related hypertension have recently been confirmed in Japanese subjects by the CASE-J trial. Keywords: Insulin resistance, adipocytokine, TNF-α, obesity-related hypertension, angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, a-adrenoceptor blockers, Ca2+-channel, systolic blood pressure, diastolic blood pressure, Obesity, dyslipidemia, hemodynamic responses, renin angiotensinaldosterone system, plasma norepinephrine, pancreatic b-cells, hyperinsulinemia, leptin, Tumor necrotic factor-a, cytokine, plasma adiponectin, amlodipine

Update on Pharmacologic Options for Smoking Cessation Treatment

Although the proportion of the adult population in the United States that smokes has decreased steadily, the rate of successful quit attempts is still low. Smokers develop nicotine dependence that resembles other addictions, and may require multiple attempts and long-term treatment to sustain abstinence. Currently available first-line agents for smoking cessation therapy include nicotine replacement therapy, which is available in several formulations, including transdermal patch, gum, nasal spray, inhaler, and lozenge; bupropion, an atypical antidepressant; and varenicline, a partial agonist of the α 4β 2 nicotinic acetylcholine receptor that was recently developed and approved specifically for smoking cessation therapy. Second-line agents are nortriptyline, a tricyclic antidepressant agent, and clonidine, an antihypertensive drug. With the exception of varenicline, which has been shown to offer significant improvement in abstinence rates over bupropion, all of the available treatments appear similarly effective. However, the adverse event profiles of nortriptyline and clonidine make them more appropriate for second-line therapy, when first-line treatments have failed or are not tolerated. Rimonabant, a cannabinoid-1 receptor antagonist that was being developed for smoking cessation, received a nonapprovable letter from the FDA in 2006 and there is no further information as to whether development for this indication is continuing for this agent. Nicotine vaccines are under investigation and offer promise, especially for relapse prevention. Ultimately, selection of pharmacologic agent should be based on the patient’s comorbidities and preferences, as well as on the agent’s adverse event profile.

Evaluating The Therapeutic Package for Diabetic Patients: The Whole Exceeds the Sum of Its Parts

A s health professionals treat patients under the Medicare Modernization Act, subtle but important changes in the experience of designing drug treatments for diabetes and related disorders are becoming apparent. The first change to affect providers is a clear rise in the frequency of requests for “prior authorization” of nonformulary prescription agents. This increase was a predicted effect of Medicare D, and its impact on physician work patterns and the costs of rendering care to diabetic patients is not at all welcome.1 The increase in prior-authorization requests may also reflect a greater consumer awareness of insurance coverage for drugs and greater resistance to obtain drugs that are costly but not covered by insurance plans. As physicians are, in some way or another, profiled about the outcomes of the diabetes care they render (“pay-for-performance”), changes in physician prescribing behavior are predicted.2,3 All of the recent and coming influences on providers and patients alike may lead to essential alterations in how both physicians and consumers view drugs that are prescribed for the treatment of individual patients. The composite effects of these trends on prescribing behavior have not been fully assessed. However, there are many reasons to suggest that profound changes may be imminent in how physicians, patients, and pharmaceutical vendors interact over the selection of pharmacological agents and medical devices in the care of diabetic patients. Given the profound impact we are already seeing in the numbers of prior-authorization requests under Medicare D as an index of these coming changes, an assessment of these possible trends may be helpful to diabetes care providers. Experienced physicians know well what has not been clearly stated in the literature until recently: that the customary decision-making processes that are typically used to select treatments for diabetes and the influences used to encourage …

Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.

In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

Pharmacotherapy of Congenital Heart Defects

Congenital cardiovascular defects account for significant morbidity and mortality in the pediatric population. Complications of congenital heart disease are lesion-dependent and may range from mild heart failure with no cyanosis to severe cyanosis and shock. Pharmacotherapy of congenital heart disease is also lesion-dependent and usage may range from palliative agents (e.g., prostaglandin E1 for relaxation of aortic stricture) to corrective agents (e.g., indomethacin for closure of the ductus arteriosus). This review will discuss the aberrant pathophysiology and complications associated with specific congenital heart defects, as well as the selection of pharmacological agents used in the management of these defects.

Stress ulcer prophylaxis in the postoperative period.

The implications of recent studies for guidelines that pertain to stress ulcer prophylaxis in the postoperative period are discussed. The therapeutic guidelines on stress ulcer prophylaxis published by the American Society of Health-System Pharmacists (ASHP) provided clinicians with recommendations regarding appropriate candidates for stress ulcer prophylaxis and selection of a pharmacologic agent. Since these guidelines were published in 1999, additional research has been completed to resolve some of the controversial issues surrounding stress ulcer prophylaxis. The frequency of stress-induced bleeding in recent investigations continues to be highly variable, depending on the definition used to describe bleeding. In general, investigations that evaluate overt bleeding or bleeding without hemodynamic changes or blood transfusion report higher frequencies of bleeding than those that evaluate clinically important bleeding. Similar to that reported in the initial ASHP guidelines, the frequency of clinically important bleeding in recent investigations is low. In addition, the majority of recently published prospective studies and a meta-analysis have been unable to demonstrate a reduction in clinically important bleeding with pharmacologic agents. As a result, some experts have suggested that advances in critical care are more influential in the development of stress-induced bleeding than the use of pharmacologic agents. Recently published investigations support the effectiveness of institution-specific guidelines to help clinicians identify appropriate candidates for stress ulcer prophylaxis. The selection of an optimal pharmacologic agent for stress ulcer prophylaxis continues to be debated. The majority of recent studies have involved the administration of proton-pump inhibitors (PPIs). In general, these studies have demonstrated that PPIs are at least as effective as histamine H2-receptor antagonists at increasing gastric pH, but adequately powered studies investigating the endpoint of clinically important bleeding are needed. Similar to the initial ASHP guidelines, the development of institution-specific guidelines is recommended to identify the most appropriate pharmacologic treatment. The frequency of clinically important bleeding reported in recent studies is low. The majority of recently published prospective studies and meta-analyses found little significant reduction in bleeding with pharmacologic prophylaxis.