The Impact of Opioids on Cardiac Electrophysiology

Synthetic opioid agents have been used in modern medicine for over a century and for opioid addiction treatment for over a half-century. Liberal use of opioids in the United States has been attended by an extraordinary increase in opioid-related mortality, with over 16,000 deaths in 2012. As there have been advances in opioid agents for pain and addiction, so have there been advances in our understanding of the cardiac effects of these agents. In the last 10 years, significant data regarding electrophysiologic effects of these agents have been collected. We aim in this review to discuss the effects on cardiac electrophysiology of the various opioid agents currently in use and the evidence that these effects are contributing to the rise in opioid-related mortality.     

口服降糖药与胰岛素对妊娠糖尿病患者分娩方式及新生儿影响的荟萃分析

目的评价口服降糖药与胰岛素对妊娠糖尿病患者分娩方式及新生儿的影响。方法检索1990年1月～2011年2月发表的有关口服降糖药与胰岛素对妊娠糖尿病患者剖宫产率、新生儿低血糖、新生儿出生体重、大于胎龄儿出生率影响的随机对照试验。结果纳入荟萃分析的文献共8篇,包含1538个研究对象。口服降糖药组与注射胰岛素组剖宫产发生率、新生儿低血糖、新生儿出生体重及大于胎龄儿出生率比较差异无统计学意义（P〉0．05）。结论口服降糖药与胰岛素对妊娠糖尿病患者分娩方式及新生儿影响无显著性差异。     

On the future of thrombolytic therapy for acute myocardial infarction

The beneficial effects of thrombolytic therapy in acute ischemic coronary syndromes, and particularly in acute myocardial infarction, are now well established. The limited efficacy and potentially life-threatening side effects of currently available thrombolytic agents, however, remain a problem. Available evidence suggests that the efficacy of coronary thrombolysis could be augmented either by shortening the time to treatment, by improvement of the potency and specificity of fibrin-dissolving agents, by optimized conjunctive treatment with anticoagulant and antiplatelet agents, or by a combination of all 3. These objectives can be pursued by intensified education of the public, paramedical personnel, and physicians; development of novel thrombolytic agents; and further elucidation of pathophysiologic determinants of recanalization and its maintenance. Although it is clear that compounds with antithrombin or antiplatelet properties may enhance and sustain the action of thrombolytic agents, their optimal use and potential hemorrhagic side effects remain to be further explored. Optimized thrombolytic therapy eventually will most likely consist of administration of potent specific plasminogen activators in combination with conjunctive targeted anticoagulant and/or antiplatelet agents.     

A review of metabolic and cardiovascular effects of oral antidiabetic agents: beyond glucose-level lowering.

It has become evident that cardiovascular disease is the major cause of morbidity and mortality in type 2 diabetes mellitus. This raises the possibility that glucose lowering agents with other nonglucose-lowering effects, might have added benefits. In this review, we focus on the metabolic and cardiovascular effects of oral antidiabetic agents that go beyond glucose-level lowering. Such effects include lipid modifying actions, antithrombotic and profibrinolytic activities, and direct action at the level of the vessel wall to improve endothelial function or prevent smooth muscle hyperplasia. These additional activities, particularly those seen with the newer oral antidiabetic agents, hold the promise of reducing cardiovascular complications beyond that achievable by glucose lowering alone.     

Treatment of type 1 diabetes with anti-T-cell agents: From T-cell depletion to T-cell regulation

Studies in animal models of type 1 diabetes had suggested that the disease was due to an immune-mediated destruction of insulin-producing cells. As this understanding was developed, clinical trials that were directed against T cells were begun, because these lymphocytes were thought to be the primary mediators of disease. Initial studies used broad-spectrum agents and showed general efficacy in either preventing the loss of insulin secretion or reducing the need for exogenous insulin. Although encouraging, the enthusiasm for this approach waned due to the lack of long-term effects and toxicities. These studies were followed by trials with more specific agents, but the issue of toxicity remained. Newer agents, such as anti-CD3 antibody, are also targeted against T cells but the toxicity and efficacy of modified anti-CD3 antibody, for example, appears to be improved over previously tested agents. In addition, our understanding of the immunologic effects of anti-T-cell agents has evolved. Data now suggest that efficacy and duration of the effects of anti-T-cell drugs can be enhanced when the agents provoke immune modulation rather than depletion of effector cells.     

Reassessment of digoxin and other low-dose positive inotropes in the treatment of chronic heart failure

Summary Digoxin and other low doses of drugs that have inotropic properties may have an important role to play in the therapy of patients with chronic heart failure. There is convincing evidence that digoxin is effective in relieving the signs and symptoms of heart failure due to systolic dysfunction. While earlier results with some of the other agents have been disappointing, recent data suggest that a reevaluation of these agents is necessary. There is now compelling evidence that lower doses of these agents may be clinically useful without necessarily having any significant hemodynamic effects. The recent experience with vesnarinone is especially promising in showing that therapy with these agents may improve survival in addition to improving clinical status. It is becoming recognized that hemodynamic activity should not necessarily be a prerequisite for clinical utility for these agents. The neuroendocrine and electrophysiologic effects of many of these agents, including digitalis, remain incompletely characterized and may play an important role in their therapeutic benefit. It appears that certain drugs that have inotropic properties may be effective only when their inotropic effects are not readily demonstrated. Further research into the appropriate mechanisms of action and proper dosing of these drugs may lead to a renewed interest in the use of positive inotropes for chronic heart failure.     

Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents

An understanding of the important role of neurohormonal compensatory mechanisms in heart failure has been translated into therapeutic options that can improve cardiac function, after disease progression, and improve survival. Angiotensin-converting enzyme inhibitors are of proven benefit in this regard, and β-adrenergic receptor antagonists are potentially another such class of agents. By inhibiting the myocardial effects of chronic adrenergic activation, β blocking agents may improve left ventricular function or delay its deterioration in patients with heart failure. Aside from blocking β-adrenergic receptors, other ancillary properties inherent in third-generation β-blocking agents (such as vasodilation) may exert additional favorable effects. Clinical data generated in subjects with heart failure indicate that β-antagonist therapy exerts its physiologic and clinical effects through neurohormonal antagonism, generally analogous to angiotensin-converting enzyme inhibitors, virtually all controlled long-term studies show that β-blocking agents improve cardiac function and hemodynamics in patients with chronic heart failure, but largescale trials are needed to ascertain a favorable effect on the natural history of heart failure.     

Chemotherapy Induced Cardiotoxicity: A State of the Art Review on General Mechanisms,Prevention, Treatment and Recent Advances in Novel Therapeutics

As medicine advances to employ sophisticated anticancer agents to treat a vast array of oncological conditions, it is worth considering side effects associated with several chemotherapeutics. One adverse effect observed with several classes of chemotherapy agents is cardiotoxicity which leads to reduced ejection fraction (EF), cardiac arrhythmias, hypertension and Ischemia/myocardial infarction that can significantly impact the quality of life and patient outcomes. Research into possible mechanisms has elucidated several mechanisms, such as ROS generation, calcium overload and apoptosis. However, there is a relative scarcity of literature detailing the relationship between the exact mechanism of cardiotoxicity for each anticancer agent and observed clinical effects. This review comprehensively describes cardiotoxicity associated with various classes of anticancer agents and possible mechanisms. Further research exploring possible mechanisms for cardiotoxicity observed with anticancer agents could provide valuable insight into susceptibility for developing symptoms and management guidelines. Chemotherapeutics are associated with several side effects. Several classes of chemotherapy agents cause cardiotoxicity leading to a reduced ejection fraction (EF), cardiac arrhythmias, hypertension, and Ischemia/myocardial infarction. Research into possible mechanisms has elucidated several mechanisms, such as ROS generation, calcium overload, and apoptosis. However, there is a relative scarcity of literature detailing the relationship between the exact mechanism of cardiotoxicity for each anticancer agent and observed clinical effects. This review describes cardiotoxicity associated with various classes of anticancer agents and possible mechanisms. Further research exploring mechanisms for cardiotoxicity observed with anticancer agents could provide insight that will guide management.     

Newer and alternative non-steroidal treatments for asthmatic inflammation.

Although most patients with asthma can be effectively managed with minimal toxicity using available treatments, some patients are relatively resistant to treatment or are at risk for adverse effects from treatment, such as high-dose systemic corticosteroids. In considering new or alternative therapeutic candidates for asthma treatment, those possessing anti-inflammatory properties are of greatest interest because inflammation is recognized as having central importance in the pathogenesis of persistent asthma. Of non-steroidal agents that have well-established positions in asthma treatment, nedocromil and cromolyn possess significant anti-inflammatory effects, and theophylline and beta agonists possess some anti-inflammatory effects of potential relevance to asthma. In addition, there are a number of newer or alternative therapies that have theorized or demonstrated anti-inflammatory effects in asthma, including leukotriene modifier agents, anti-IgE, gold, nebulized lidocaine, cyclosporine, intravenous immunoglobulin, methotrexate, hydroxychloroquine, dapsone, and troleandomycin. This review summarizes available data about these agents for asthma, focusing on their putative or proven mechanisms of action, evidence for clinical benefit, and their potential role as corticosteroid sparing agents, and principal toxicities. The review also discusses factors that confound assessment of the clinical benefit of agents in asthma, including variability in the natural history of asthma, heterogeneity of airway inflammation, and varying responses to treatment in different subsets of asthmatics.     

Hormonal effects of beta-receptor blockade during exercise

The effects of two different beta-receptor blocking agents, beta 1-selective metoprolol (150 mg/day) and non-selective propranolol (120 mg/day), on hormonal responses to physical exercise (30 min bicycle ergometer test) were compared with placebo within a double-blind, cross-over design in 7 healthy male volunteers. Plasma prolactin levels decreased from the initial values during and after exercise during treatments with placebo and beta-receptor blocking agents, but they were constantly higher with the two beta-blocking agents than with placebo. Exercise did not affect plasma testosterone levels, but during propranolol they remained higher than during placebo and metoprolol. The plasma LH and FSH levels were not affected by exercise, nor were they significantly modified by beta-blockade. The results of this study as well as those of previous studies indicate that beta-receptor blocking agents interfere with physiological endocrine functions and that the non-selective agents may have more distinct effects in this respect.     

Current treatment of psoriatic arthritis

The definition of PsA is still being refined, as is the understanding of the genetic and immunologic contributors to the pathophysiology of this disease. As knowledge of the underlying immunologic causes of PsA evolves, so too do treatment choices. Conventional therapies with broadly immunosuppressive effects have been the standard of therapy, but the clinical benefits of these agents are often unpredictable and might be limited by their side effects. Newer agents with mechanisms of action targeted toward specific components of the immune cascade are expected to provide more reliable responses with fewer efficacy-limiting side effects than the more conventional agents borrowed from the RA armamentarium. Anti-TNF medicines such as etanercept, the first agent approved specifically for treatment of PsA, are an advance in the treatment of PsA, and other biological agents are on the horizon that might continue to help define the immunopathogenesis of PsA and treat the disease effectively.     

Cardiovascular effects of iodinated contrast agents

The ideal intravascular contrast agent would be biologically inert and have no pharmacologic actions. Pharmacologic actions of currently used radiographic contrast agents are determined principally by 3 physicochemical properties of the iodine-bearing molecule and its formulation: osmolality, sodium concentration and calcium-binding properties. Within this framework, the calcium-binding 1.5 ratio agents have the most marked effects, and the 3.0 ratio nonionic agents the least, with the noncalcium-binding formulations of 1.5 ratio agents and ioxaglate (the only 3.0 ratio ionic agent) in between. Differences in hemodynamic effects are predominantly related to osmolality with the 3.0 agents causing less hemodynamic disturbance. The magnitude of difference is small enough that the 3.0 ratio agents have no important clinical advantage when used in patients with good or moderately impaired left ventricular function. However, the difference may be important in patients with severely impaired circulatory performance. The principal electrophysiologic differences are between the calcium-binding 1.5 ratio agents (which are associated with a clear-cut greater frequency of ventricular fibrillation during coronary injection than the noncalcium-binding 1.5 ratio agents) and the 3.0 ratio agents. There is no justification for the use of calcium-binding 1.5 ratio agents, since noncalcium-binding formulations of the same molecule are available at the same price. The circulatory reserve of most patients makes the differences between 3.0 ratio agents and noncalcium-binding 1.5 ratio agents clinically unimportant. In view of the substantial price disparity between 1.5 ratio and 3.0 ratio agents, noncalcium-binding 1.5 ratio agents are appropriate for patients with good circulatory performance and 3.0 ratio agents are best reserved for patients with impaired circulatory performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

抗结核药物引起的副作用综合报告

目的了解各种抗结核药物引起的副作用并掌握一般处理原则。方法直接或间接证明６２例中由抗结核药物引起的副作用，观察并分析各种副作用分布情况、出现时间及表现形式。结果过敏反应频度占副作用的首位，共３７例，占６０％；严重副反应绝大多数由利福霉素类引起；副作用出现时间多为服药后２个月以内；药物服用过量易导致副反应发生；多种药物可同时或相继产生严重副作用。结论一旦发生严重药物副作用，必须立即停药，及时治疗，否则后果严重；利福霉素类药停药后再服，有可能加重过敏反应程度，故要详细询问既往用药情况，对有肝炎史、酗酒史、药物过敏史和年老体弱者用药过程中要严密观察；对多种药物过敏者，无论反应轻重，以快停药、早脱敏为原则；必须确定过敏原时，要使用常量的１／１０以下，并制定应急处理措施，严重过敏者不应进行重复验证     

Mechanism of renin inhibition by beta adrenergic blocking agents. Effects of dl-, d-, l-propranolol and pindolol on renin release

In order to reveal the mechanism of renin inhibition by beta adrenergic blocking agents, the effects of dl-, d-, l-propranolol and pindolol on renin release were studied. This was done by injecting them intraperitoneally or by using an in vitro system of rat kidney slices. In the in vivo study, dl-, d-, and l-propranolol inhibited plasma renin activity and renal renin content significantly in normal rats. Furthermore, in the in vitro study, the basal levels of renin in the media and that in the kidney were significantly inhibited by these agents. Pindolol also inhibited renin release, but its effects were significantly less than those of other agents. The finding that d-propranolol which has little beta adrenergic blocking action inhibited renin release, and that the effects of pindolol which displays strong beta adrenergic blocking action but little membrane stabilizing action, were less than those of other agents, may suggest that the inhibitory effects of beta adrenergic blocking agents on renin release are dependent mainly on the membrane stabilizing action rather than the beta adrenergic blocking action.     

Potassium channel openers: Clinical applications in ischemic heart disease—Overview of clinical efficacy of nicorandil

Nicorandil is a balanced arterial and venodilator that may also possess cardioprotective properties via its activation of ATP-sensitive potassium channels. It has a number of beneficial hemodynamic effects and has been shown to be effective in treating angina with similar efficacy as the currently available antianginal agents. In addition, it may have useful effects in unstable and variant angina. In this review we examine the hemodynamic effects of nicorandil and discuss the currently available data on its clinical efficacy, both in isolation and in comparison with other agents.     

Effects of chemotherapeutic agents on the function of primary human osteoblast-like cells derived from children

Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D(3) concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D(3) was also evaluated. Type I collagen synthesis was reduced by all agents (P < 0.01) other than methotrexate, whereas the relative AP activity was increased (P < 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P < 0.05), and AP mRNA expression was increased (P < 0.01) with vincristine. 1,25-Dihydroxyvitamin D(3) ameliorated (P < 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D(3)-mediated AP activity (P < 0.01). We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.     

Are all glitazones the same?

This supplement focuses on the benefits of targeting insulin resistance through therapy with a new class of oral antidiabetic agents, the thiazolidinediones (TZDs) or 'glitazones'. There are important differences between the three TZD class members that warrant discussion to enable physicians to make rational and informed therapeutic choices between the agents. Overall the TZDs appear to be similar in their effects on blood glucose, as all class members have demonstrated effective glycaemic control, both as monotherapy and in combination with sulphonylureas, metformin or exogenous insulin. The safety profiles of the three agents are more diverse, with what appear to be 'TZD class effects', (probably mediated via activation of peroxisome proliferator-activated receptor gamma [PPAR gamma]) and 'TZD-specific effects', which are unique to each agent and may be a consequence of differing chemical structures. While rosiglitazone and pioglitazone share some class effects with troglitazone, they have several characteristics that define them as unique agents. By tackling the control of type 2 diabetes through direct effects on insulin resistance, the TZDs represent an important new therapeutic tool for healthcare professionals.     

The differential efficacy of antihypertensive agents in the elderly

A number of controlled trials have shown that antihypertensive therapy is beneficial to the elderly (greater than or equal to 60 years of age). Even so, there may be deleterious age-related effects associated with such therapy. Because of physiological and pathophysiological problems peculiar to the elderly (many of which remain to be defined precisely), both benefits and untoward effects of antihypertensive drugs differ, sometimes within classes of agents themselves. None of the traditional agents is ideal for the management of hypertension in the elderly. Differential efficacy and tolerability of various antihypertensive agents has often been claimed but none of these claims appears established beyond dispute. Increasing evidence, however, suggests that the serotonin antagonist ketanserin may be more effective and better tolerated in elderly hypertensives. If the elderly are to derive maximum benefit from antihypertensive therapy, the question of age-related differential effects of agents used needs to be addressed in carefully designed studies to determine the nature and magnitude of such effects, where they exist and what clinical implications they may have.     

Old and new intravenous inotropic agents in the treatment of advanced heart failure

Inotropic agents are administered to improve cardiac output and peripheral perfusion in patients with systolic dysfunction and low cardiac output. However, there is evidence of increased mortality and adverse effects associated with current inotropic agents. These adverse outcomes may be ascribed to patient selection, increased myocardial energy expenditure and oxygen consumption, or to specific mechanisms of action. Both sympathomimetic amines and type III phosphodiesterase inhibitors act through an increase in intracellular cyclic adenosine monophoshate and free calcium concentrations, mechanisms that increase oxygen consumption and favor arrhythmias. Concomitant peripheral vasodilation with some agents (phosphodiesterase inhibitors and levosimendan) may also lower coronary perfusion pressure and favor myocardial damage. New agents with different mechanisms of action might have a better benefit to risk ratio and allow an improvement in tissue and end-organ perfusion with less untoward effects. We have summarized the characteristics of the main inotropic agents for heart failure treatment, the data from randomized controlled trials, and future perspectives for this class of drugs.     

Differentiation of low-molecular-weight heparins: impact on the future of the management of thrombosis

Low-molecular-weight heparins (LMWHs) are now universally accepted as drugs of choice for postsurgical prophylaxis and treatment of deep vein thrombosis (DVT). Currently, these agents are also being developed for the treatment of various cardiovascular conditions. Because of manufacturing differences, each of the LMWHs exhibits distinct pharmacologic and biochemical profiles. The specific activity of these agents in anticoagulant assays ranges from 35 to 45 anti-IIa U/mg, whereas the activity in terms of anti-Xa units is designated as 80 to 145 U/mg. These LMWHs are also capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although the ex vivo effects are initially present at dosages that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and various clinical trials, these agents also have been found to release tissue factor pathway inhibitor and von Willebrand factor. In addition, LMWHs have been reported to produce fibrinolytic effects. The effect of repeated administration also exhibits product-based augmentation of the antithrombotic and hemorrhagic effects. Several new agents are being investigated as possible substitutes for heparins. These include anti-thrombin, anti-Xa, anti-TF (tissue factor), heparinoids, oral formulations of heparin, activated protein C, and biotechnologically derived serpins. These agents may not have the broad clinical spectrum as that observed with the heparins. More recently, several pharmaceutical companies have produced generic LMWHs.