Drugs acting on the heart: heart failure and coronary insufficiency

Heart failure (HF) and coronary insufficiency are common amongst surgical and critical care patients. Both are chronic conditions interrupted by acute episodes. HF activates neurohormonal mechanisms that worsen renal and cardiac function. Acute heart failure (AHF) commonly presents with dyspnoea as a consequence of systolic and/or diastolic dysfunction. Goals of treatment are symptom relief to maintain tissue perfusion and optimize cardiac function. Diuretics and vasodilators are used early; positive inotropic drugs are reserved for when other treatment has failed. Chronic heart failure (CHF) is treated using changes in lifestyle and drugs to manage symptoms. ACE inhibitors and beta-blockers are effective in systolic heart failure and are associated with improved mortality. HF with preserved ejection fraction (HFPEF) is less responsive to drug therapy, though outcomes are better than for systolic HF. Coronary insufficiency occurs because of an imbalance of myocardial oxygen balance, leading to symptoms of ischaemic heart disease (IHD). Treatment goals are maintaining coronary blood flow and reducing myocardial oxygen demand. Beta-blockers and anti-platelet drugs improve outcomes; modern anti-platelets are more effective but are associated with risks of haemorrhage. Statins are effective for primary and secondary prevention of myocardial infarction; they have additional anti-inflammatory properties.     

HIV treatment outcomes among people who acquired HIV via injecting drug use in the Asia‐Pacific region: a longitudinal cohort study

INTRODUCTIONData on HIV treatment outcomes in people who inject drugs (PWID) in the Asia‐Pacific are sparse despite the high burden of drug use. We assessed immunological and virological responses, AIDS‐defining events and mortality among PWID receiving antiretroviral therapy (ART).METHODSWe investigated HIV treatment outcomes among people who acquired HIV via injecting drug use in the TREAT Asia HIV Observational Database (TAHOD) between January 2003 and March 2019. Trends in CD4 count and viral suppression (VS, HIV viral load <1000 copies/mL) were assessed. Factors associated with mean CD4 changes were analysed using repeated measures linear regression, and combined AIDS event and mortality were analysed using survival analysis.RESULTSOf 622 PWID from 12 countries in the Asia‐Pacific, 93% were male and the median age at ART initiation was 31 years (IQR, 28 to 34). The median pre‐ART CD4 count was 71 cells/µL. CD4 counts increased over time, with a mean difference of 401 (95% CI, 372 to 457) cells/µL at year‐10 (n = 78). Higher follow‐up HIV viral load and pre‐ART CD4 counts were associated with smaller increases in CD4 counts. Among 361 PWID with ≥1 viral load after six months on ART, proportions with VS were 82%, 88% and 93% at 2‐, 5‐ and 10‐years following ART initiation. There were 52 new AIDS‐defining events and 50 deaths during 3347 person‐years of follow‐up (PYS) (incidence 3.05/100 PYS, 95% CI, 2.51 to 3.70). Previous AIDS or TB diagnosis, lower current CD4 count and adherence <95% were associated with combined new AIDS‐defining event and death.CONCLUSIONSDespite improved outcomes over time, our findings highlight the need for rapid ART initiation and adherence support among PWID within Asian settings.     

2017—2019年包头医学院第一附属医院细菌耐药性监测

目的 了解包头医学院第一附属医院2017—2019年临床分离菌的分布及对临床常见抗菌药物的耐药性。方法 收集2017年1月1日至2019年12月31日临床分离的非重复菌株,采用自动化仪器法、纸片扩散法和E-试验法进行药敏试验。 结果 3年我院临床分离非重复菌共4679株,其中革兰阳性菌1358株（32.9%）,革兰阴性菌3141株（67.1%）。金黄色葡萄球菌和凝固酶阴性葡萄球菌中甲氧西林耐药株（Methicillin-resistant Staphylococcus aureus,MRSA和Methicillin-coagulase negative staphylococcus,MRCNS）检出率分别为16.2%(96/592),56.5%(245/434）,未发现万古霉素、替考拉宁和利奈唑胺耐药葡萄球菌株。屎肠球菌对多数抗菌药物的耐药率高于粪肠球菌。 产ESBL的大肠埃希菌和克雷伯菌属细菌的检出率分别为48.2%（567/1177）和16.6%（140/841）,碳青霉烯耐药肠杆菌科细菌（Carbapenem resistant enterobacteriaceae bacteria,CRE）的检出率为0.8%（19/2411）。肠杆菌科细菌对碳青霉希类抗菌药物的耐药率仍然处于较低水平,总体低于0.8%（19/2411）。铜绿假单胞菌和嗜麦芽窄食单胞菌对常见抗菌药物的耐药率均较低,鲍曼不动杆菌对常用抗菌药物的耐药率较高,对环丙沙星和头孢他啶的耐药率均高于60.0%。结论 该院临床常见菌的耐药性仍然比较严峻,进行细菌耐药监测有助于及时了解本院耐药变迁情况,为临床合理使用抗菌药物提供依据。     

磁处理水对抗癌药物的解毒作用

我们的实验发现，磁处理水对环磷酰胺等五种抗癌药物的毒性具有不同程度的缓解作用，能增加小鼠的存活率，能降低药物引起的白细胞减少。对目前癌化疗中使用率最高的环磷酰胺，其作用最明显。     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.     

Do antiarrhythmic drugs work? some reflections on the implications of the cardiac arrhythmia suppression trial

Despite major advances in our understanding of the mechanisms of cardiac arrhythmias and how antiarrhythmic drugs appear to work, there remains much doubt whether these agents reduce arrhythmic mortality except in certain subsets of patients. The results of the Cardiac Arrhythmia Suppression Trial (CAST) have indicated that certain antiarrhythmic drugs not only "fail to work" but may substantially increase mortality. The effects of Class Ic agents in CAST and the meta-analysis of randomized antiarrhythmic trials in the survivors of acute infarction suggest that drugs that act primarily by delaying conduction are particularly deleterious in the survivors of acute infarction. Whether these data have a wide applicability in terms of all ventricular arrhythmias is unclear, but beta-blockers remain the only class of agents that in control trials have been shown to reduce sudden death. The effect appears to be related to beta-blockade and not to suppression of premature ventricular contractions (PVCs). Beta blockers appear to act by preventing ventricular fibrillation. It is reasonable to assume that PVC suppression per se is unlikely to produce a reduction in sudden death. Uncontrolled data with amiodarone suggests that it has the potential to prolong survival by controlling arrhythmias. The effects of amiodarone and beta blockers, both significantly attenuating adrenergic stimulation, provide pharmacologic probes to define the crucial determinants of efficacy of a compound for mortality reduction in high risk survivors of myocardial infarction. The focus must now shift from antiectopic and antiarrhythmic agents that delay conduction to those that exert antifibrillatory actions by sympathetic antagonism and those that exhibit the added property of lengthening myocardial refractoriness.     

Effect of administration of diethylcarbamazine with and without fluconazole on experimental fungal infections in mice

Other researchers have found that diethylcarbamazine (DEC) is effective treatment for filariasis despite a lack of demonstrated in vitro antifilarial activity. The results of our previous investigations using feline and murine leukemia virus models encouraged us to investigate the use of DEC with other infections. In our current experiments, DEC treatment was associated with lower brain fungal burden in fluconazole-treated mice following intravenous injection of Aspergillus fumigatus or increasing numbers of Cryptococcus neoformans organisms, and lower brain and kidney levels of Candida albicans following intravenous injection of increasing numbers of C. albicans. Further investigation of combined DEC and fluconazole treatment of fungal infections is warranted.     

Inhibition of uptake1 by (+)-oxaprotiline reveals a differential central regulation of noradrenaline and adrenaline release

Summary Inhibition of uptake, in the central nervous system leads to a decrease of sympathetic outflow to many tissues; central a2-adrenoceptors are involved in this decrease. The aim of the present study was to compare the effects of the selective uptake, inhibitor (+)-oxaprotiline on the plasma kinetics of noradrenaline and adrenaline in anaesthetized and in conscious rabbits. [³H]Noradrenaline and [^3H]adrenaline were infused iv. The arterial plasma concentrations of endogenous and radiolabelled noradrenaline and adrenaline were measured, and the clearance from and spillover into the plasma of noradrenaline and adrenaline were calculated.Results obtained in conscious and anaesthetized rabbits were similar. (+)-Oxaprotiline 0.2, 0.6 and 1.8 mg kg^–1 iv. dose-dependently reduced the clearance of [³H]noradrenaline from the plasma. The clearance of [³H]adrenaline was reduced less. The spillover of endogenous noradrenaline was decreased by up to 35%. In contrast, the spillover of adrenaline tended to be enhanced. Prazosin 0.1 and 1 mg kg^–1 was injected iv. in a second part of each experiment. It lowered the blood pressure and caused a marked increase in noradrenaline spillover but no increase or even a decrease in adrenaline spillover.The results are compatible with the following hypothesis. The sympathetic outflow from the central nervous system is subject to a twofold a-adrenoceptor-mediated modulation: -adrenoceptor-mediated inhibition and ₁-adrenoceptor-mediated excitation. In the control of the sympathetic outflow to many extra-adrenal tissues, the ₂-adrenergic inhibition prevails. Uptake₁ inhibitors depress sympathetic outflow to such tissues by enhancing the ₂-adrenergic inhibition. In the regulation of the sympathetic outflow to the adrenal medulla, in contrast, ₂-adrenergic inhibition and ₁-adrenergic excitation have a similar impact. Uptake, inhibitors, hence, cause little change in adrenaline release: the two opposing influences cancel out. Prazosin produces an increase in noradrenaline but not adrenaline release because the loss of the central ₁ sympathoexcitation attenuates at best slightly the baroreflex to most extra-adrenal tissues but dampens markedly the baroreflex to the adrenal medulla. Correspondence to B. Szabo at the above address