Sodium-glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice.     

Medications for treating alcohol dependence

Medications for treating alcohol dependence primarily have been adjunctive interventions, and only three medications--disulfiram, naltrexone, and acamprosate--are approved for this indication by the U.S. Food and Drug Administration. Disulfiram, an aversive agent that has been used for more than 40 years, has significant adverse effects and compliance difficulties with no clear evidence that it increases abstinence rates, decreases relapse rates, or reduces cravings. In contrast, naltrexone, an anticraving agent, reduces relapse rates and cravings and increases abstinence rates. Acamprosate also reduces relapse rates and increases abstinence rates. Serotonergic and anticonvulsant agents promise to play more of a role in the treatment of alcohol dependence. Although not approved by the U.S. Food and Drug Administration for this indication, the anticonvulsant topiramate and several serotonergic agents (e.g., fluoxetine, ondansetron) have been shown in recent studies to increase abstinence rates and decrease drinking.     

Challenges in the adoption of new pharmacotherapeutics for addiction to alcohol and other drugs

The adoption of pharmacotherapies for the treatment of alcohol and drug use disorders has progressed slowly despite the approval of new and effective medications. This paper begins with overviews of the prevalence of alcohol and drug abuse and dependence, the costs of addiction to the nation, and the value of treatment services. The role of pharmacotherapy in the treatment of addictive diseases is examined, and factors that affect the adoption and use of medications for alcohol and drug treatment are identified and discussed. Investigations that tested the effectiveness of buprenorphine for treatment of opioid dependence in new settings illustrate physician and counselor training and mentorship strategies that may promote the adoption of medications in the treatment of alcohol and drug use disorders. The paper concludes with a discussion of barriers and ways to surmount the barriers and to foster greater use of medications in alcohol and drug treatment.     

Baclofen: a new drug for the treatment of alcohol dependence

Recent preclinical and clinical studies have suggested that baclofen, the prototypic gamma-aminobutyric acid B (GABA(B)) receptor agonist, is a promising pharmacological compound for use in the treatment of alcohol dependence. In particular, baclofen has been found to suppress symptoms of alcohol withdrawal syndrome with an efficacy comparable with that of the 'gold standard' diazepam. Moreover, baclofen has proven effective in the prevention of relapse due to its ability to reduce alcohol intake and craving in alcoholic patients. Baclofen proved to be manageable, producing no significant side effects and displaying no addictive properties. The efficacy of the drug in the management of both alcohol withdrawal syndrome and relapse prevention should entail a vastly simplified pharmacotherapy of alcohol dependence.     

Neurobiology of relapse to alcohol in rats

Relapse to alcohol use after prolonged withdrawal periods is the major problem in the treatment of alcohol dependence in humans. However, until recently, relatively few preclinical studies concentrated on the elucidation of the neurochemical events underlying relapse to alcohol. In this article we will review recent data from studies in which alcohol-deprivation and reinstatement models were used to determine the mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies, which used these preclinical models, on the effect of specific pharmacological agents on relapse to alcohol seeking induced by re-exposure to alcohol and to alcohol-associated cues and by exposure to stress. Subsequently, we will describe potential neuronal circuits that may underlie relapse to alcohol. Finally, future directions and clinical implications of the study of relapse to alcohol in laboratory animals will be discussed briefly.     

Potential of buprenorphine/naltrexone in treating polydrug addiction and co-occurring psychiatric disorders

In recent years, we have seen regulatory approval being given for several new pharmacotherapies in the treatment of drug addiction disorders. Within the United States, the most noteworthy development has been the approval of buprenorphine in the treatment of opioid dependence, and its availability for prescribing in an office-based setting has resulted in thousands of additional patients going into treatment. Although approved medications for the treatment of cocaine and methamphetamine dependence are still lacking, the National Institute on Drug Abuse has devoted substantial effort toward meeting these clinical needs. Recent studies of modafinil for the treatment of cocaine dependence have been especially encouraging. Looking to the future, the looming challenge is polydrug addiction, a situation that is often complicated by co-occurring psychiatric disorders. As we strive to address the needs of these complicated patients, studies of buprenorphine/naltrexone may hold the key to a major advance.     

Treatment of nicotine dependence

Nicotine dependence is characterized by periods of relapse and remission. Health care workers can have a pivotal role in the treatment of nicotine dependence. Smokers should be identified and categorized based on their readiness to change. Smokers who are preparing to stop smoking should be given multicomponent therapy in a step-care approach using behavioral treatment, addiction treatment, pharmacotherapy, and techniques of relapse prevention. Pharmacotherapies approved by the Food and Drug Administration for smoking interventions include sustained-release bupropion, nicotine gum, the nicotine inhaler, nicotine nasal spray, and nicotine patches.     

The role of anticonvulsants in preventive migraine therapy

The mainstay of migraine treatment is pharmacotherapy. There have been numerous medications used to prevent migraine headaches, including β-blockers, calcium-channel blockers, anticonvulsants, and nonsteroidal anti-inflammatory drugs. Sodium valproate is the only antiepileptic drug approved by the Food and Drug Administration for migraine prevention. Newer antiepileptics, including gabapentin and topiramate, are being evaluated for their role in preventive therapy. The mechanism of action of antiepileptics is not fully understood, but they all share a common role in enhancing gamma-aminobutyric acid-mediated inhibition. This article reviews the role of anticonvulsants in preventive migraine therapy.     

Overview of transplantation immunology and the pharmacotherapy of adult solid organ transplant recipients: focus on immunosuppression

A review of transplantation immunology is discussed with emphasis on alloantigen presentation, T-lymphocyte activation and proliferation, and the immune effector mechanisms responsible for allograft rejection. Immunosuppressive pharmacology is introduced beginning with conventional medications (cyclosporine, azathioprine, and corticosteroids) followed by a discussion of drugs recently approved by the US Food and Drug Administration (mycophenolate mofetil, tacrolimus, and the interleukin-2 receptor antagonists). In addition, drugs that are used in the treatment of transplant rejection or as rescue therapy are discussed (muromonab-CD3, antithymocyte globulin, mycophenolate mofetil, tacrolimus, and corticosteroids). Throughout, implications for nurses involved in the pharmacotherapy of transplant recipients are discussed.     

Some Recent Concepts Concerning the Mechanisms of Action of Antiarrhythmic Drugs

The administration of antiarrhythmic drugs is determined largely on the basis of empiricism, and the experience of individual physicians and the results of clinical studies are probably the two major factors determining the approach to treatment. Although much effort has been expended in learning the mechanisms of action of antiarrhythmic drugs, the applicability to clinical treatment of the knowledge attained has been limited. Nonetheless, recent advances in our understanding of the biology of the cardiac cell, of the factors that predispose to arrhythmias and of drug-receptor interactions, have not only provided new insights into the mechanisms whereby specific drugs exert their effects, but promise to provide means for designing and testing compounds whose actions will be more specific and more predictable than is presently the case. This paper will review some of the advances that have been made and will consider some of their implications.     

Drug adjuncts for treating alcohol dependence

Three drugs are approved by the US Food and Drug Administration for treating alcoholism: disulfiram, naltrexone, and acamprosate. Drugs approved for other indications that are being used experimentally or "off-label" include nalmafene, topiramate, and ondansetron. As we learn more about the pathophysiologic basis of alcoholism, it is hoped that novel drugs can be developed to help people with alcohol dependence achieve abstinence, and as a result, curb alcohol-related morbidity.     

Treatment of major depressive disorder--method and selection of the treatment

There are many ways of treatment for depression. Among them the most popular and effective treatment is pharmacotherapy. In the acute phase, pharmacotherapy with antidepressants, certain forms of psychotherapy, the combination of pharmacotherapy plus psychotherapy, and electroconvulsive treatment have clearly proven to be efficacious in most types of unipolar depressive disorders. The common augmenting agents probably are lithium, thyroid hormone, dopaminergic agents, and mood stabilizers. Certain treatments may be more effective in specific subtypes; for example, light therapy is useful for seasonal affective disorder. During the 16-24 weeks following remission, patients with antidepressant medications in the acute phase should be maintained on these agents to prevent relapse. For patient pharmacotherapy or psychotherapy has not been effective, the use of ECT may be useful. Following the continuation phase, maintenance-phase treatment should be considered for patients who have many depressive episodes to prevent recurrences of major depressive disorder.     

La dépendance aux opiacés. Conséquences pour le traitement de la douleur

Addiction is a chronic disease of the central nervous system. Numerous neuroadaptations occur following chronic exposure to drugs of abuse. The progress in numerous domains, neuroimaging, molecular biology, animal models, allowed these last years to understand better the neurobiological and neurochemical mechanisms of addictions. The activity of the central nervous system is globally regulated by excitatory and inhibitory ligands. The very fine balance which exists between these two groups of neurotransmitters and neuropeptides allows maintaining the equilibrium of the brain. The acute drug exposure is strongly destabilizing this balance. If the exposure is repeated, the brain is going to try to oppose to these effects to maintain the balance. We have neuroadaptations of the brain. These mechanisms, which are mechanisms of re-equilibrium, are relatively stable, and explain the necessity of using pharmacotherapy to help in the abstinence. The maintenance treatments in the management of opioid dependence showed its utility during the last years, with a reduction of the consumption of opiates as well as to a decrease of the rates of morbidity and mortality bound to the taking of drugs. Nevertheless thesemaintenance treatments are opioid agonists (buprenorphine or methadone), with specific pharmacodynamic and pharmacokinetic properties. Adequate treatment of painful conditions is an essential dimension of quality medical care. Physicians will frequently encounter patients receiving agonist therapy treatment with methadone or buprenorphine and who develop acutely or chronically painful conditions, requiring effective treatment strategies.     

Dependent Behavior in Patients with Medication-Overuse Headache

Two thirds of patients with medication-overuse headache (MOH) fulfilled criteria for dependence on acute symptomatic treatments for pain, not exclusive of psychoactive medications, based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Several questionnaires have been used to assess dependent behavior in patients with MOH. Findings regarding underlying psychological profiles of dependence and MOH are not consistent. Nevertheless, several neuroimaging, genetic, and neurobiological studies support the existence of the common pathophysiological features of dependence and MOH and suggest a link between them. This review highlights recent studies on the relationship between dependence and MOH. This issue is important because it implies a treatment strategy in managing patients with MOH by providing the treatment of dependence.     

Denosumab: mechanism of action and clinical outcomes

Aims: To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments. Methods: Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches. Findings: Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high‐risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment. Discussion: Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first‐line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options.     

Advances in Diabetes Pharmacotherapy: An Update for the Emergency Provider

Background

Diabetes mellitus is a disease that affects millions of Americans, and its prevalence is only anticipated to increase in coming years. It is estimated that diabetes-related visits account for 1% of all emergency department (ED) encounters. In recent years, there have been several new categories of medications approved for the treatment of diabetes, including new insulins, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 inhibitors.

ADVANCES IN THE TREATMENT OF SCHIZOPHRENIA

SUMMARY We review advances in the treatment of schizophrenia. We begin with an overview of antipsychotic drug development, focusing on the in vitro and in vivo binding profiles of clozapine and a new generation of D2:5HT antagonists. We then consider the main barriers to effective treatment: non-compliance (and side-effects) of medication, recurrent relapse, ‘treatment resistance’, negative symptoms and neurocognitive deficits. Within this framework, we review the mechanisms of action and clinical uses of the ‘atypical’ antipsychotic drugs. We also show how a variety of psychosocial interventions, particularly those that incorporate cognitive techniques, can be used in combination with pharmacotherapy to overcome the same clinical hurdles.     

Opioid Insights

Opioid analgesics are an irreplaceable component of pharmacotherapy of numerous pain-producing conditions. Clinicians and patients must contend with the imperfect nature of this class of drugs, trying to balance benefits and burdens on a continual basis. New literature related to evidence-based selection of opioids and the neurobiological phenomenon of opioid induced hyperalgesia are reviewed. A matrix describing critical elements in the selection of opioid analgesics, both for initial therapy and for opioid rotation, is presented.     

Opioid insights:opioid-induced hyperalgesia and opioid rotation

Opioid analgesics are an irreplaceable component of pharmacotherapy of numerous pain-producing conditions. Clinicians and patients must contend with the imperfect nature of this class of drugs, trying to balance benefits and burdens on a continual basis. New literature related to evidence-based selection of opioids and the neurobiological phenomenon of opioid induced hyperalgesia are reviewed. A matrix describing critical elements in the selection of opioid analgesics, both for initial therapy and for opioid rotation, is presented.     

Review of calcium-channel blockers

Calcium-channel blocking drugs were introduced to the United States in 1982. The three approved calcium-channel blockers--nifedipine, verapamil and diltiazem--have offered new treatments for angina. This article presents an overview of these drugs with emphasis on their mechanisms of action, clinical use and guidelines for the nurse practitioner in assessing the need for calcium-channel blockers in the management of angina.