Recent changes in the landscape of combination RAS blockade

The renin–angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.     

Self-Guided Online Cognitive Behavioral Strategies for Chemotherapy-Induced Peripheral Neuropathy: A Multicenter,Pilot, Randomized,Wait-List Controlled Trial

The purpose of this pilot, parallel, randomized controlled trial was to examine the efficacy of a self-guided online cognitive and behaviorally-based pain management intervention (Proactive Self-Management Program for Effects of Cancer Treatment [PROSPECT]) to reduce “worst” pain for individuals with chronic painful chemotherapy-induced peripheral neuropathy (CIPN). Secondary outcomes included “average” pain, nonpainful CIPN symptom severity, impression of change, and pain interference. Sixty patients with chronic painful CIPN were recruited from 5 outpatient academic and community cancer centers. Patients were randomized in a 1:1 ratio to receive either 8 weeks of PROSPECT or usual care. A 7-day electronic “worst” pain intensity diary and standardized measures of pain interference, nonpainful CIPN symptom severity, impression of change, and “average” pain were administered pre/post intervention. Postintervention mean scores were evaluated between groups using analysis of covariance adjusting for baseline. Individuals who received the PROSPECT intervention (n?=?19) had significantly greater improvements in “worst pain” compared with individuals receiving usual care (n?=?19; P?=?.046, d?=?.58). There were no significant differences in mean scores between groups for the secondary outcomes (n?=?42). A larger, adequately powered study testing the PROSPECT intervention is needed to determine if improvements in pain may be sustained, evaluate the effect of the intervention on the secondary outcomes, and identify mediators of pain intensity-related improvement.

Angiotensin receptor blockers and secondary stroke prevention: the MOSES study

Hypertension control is critical to prevent stroke. With several clinical trials conducted over the last decade, it seems that the use of an angiotensin-modulating antihypertensive agent conveys benefits beyond blood pressure reduction. Currently, there is evidence supporting the use of either an angiotensin receptor blocker or an angiotensin-converting enzyme inhibitor in the primary-prevention context. However, in the secondary prevention of stroke, the choice of agent is less clear. There is evidence that intensive blood pressure reduction with a combination of an angiotensin-converting enzyme inhibitor and a diuretic can reduce stroke recurrence, but do angiotensin receptor blockers have the same ability? The Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) trial endeavors to answer this question and strives to demonstrate the benefit of angiotensin receptor blockers in the secondary prevention of stroke.     

Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in blood pressure regulation and hypertension-related complications. Angiotensin-converting enzyme inhibitors (ACEIs) were the first to be used to block the RAAS and now have many compelling indications in the treatment of hypertension and its cardiovascular and renal complications. Angiotensin II receptor blockers (ARBs), introduced 20 years later, have been shown to be equally as effective as antihypertensive treatment and are also associated with a lower number of side effects. Furthermore, in clinical trials ARBs and ACEIs were associated with comparable benefits for their most typical indications. This was confirmed in the 2007 New European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension by comparable specific recommendations for ARB and ACEI treatment. There is sufficient theoretical background and, in some cases, also clinical evidence that combination therapy with ACEIs and ARBs may be more beneficial than monotherapy with either of the groups alone, both in uncomplicated hypertension and with concomitant heart failure or renal dysfunction. However, the combination of ACEI and ARB was not recommended in the ESH/ESC 2007 Guidelines. This may change after the publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, the preliminary results of which have just been presented. In heart failure, recent studies have shown that the combination of ACEI and ARB decreases cardiovascular mortality and the number of hospitalizations due to aggravation of heart failure. These results have been reflected in the newest ESC guidelines of the heart failure treatment. Nephroprotective properties of the combination of ACEs and ARBs have been proved both in studies on nondiabetic and diabetic nephropathy. The potential benefits, indications in prespecified groups of patients, the most recent data from clinical trials and latest research regarding dual blockade of RAAS will be reviewed in this article.     

Computer-Based Patient Interviewing

Before the computer can become truly useful in clinical research, diagnosis and therapy, new ways to collect data must be developed. The computer itself can be adapted to take medical histories directly from patients. These data, in computer- processable form, are then available for physician use in patient care and clinical research. Results obtained with computer-based histories are reviewed and the technic is compared with traditional methods. Also discussed is the potential role of computer-based interviewing in modern medical practice.     

糖尿病状态对甲钴胺预防大鼠外周神经病变作用的影响

目的 探讨血糖水平和病程对甲钴胺预防糖尿病外周神经病变（PN）作用的影响。方法 80只SD大鼠随机选取16只为正常对照组，余64只制作四氧嘧啶诱导糖尿病模型，后者又根据外源胰岛素控制血糖水平分为血糖控制较好组和较差组各32只，每组再选取16只给予甲钴胺（500μg／kg）肌注。分别在造模前和造模后2周、8周、12周测定大鼠的坐骨神经运动、感觉和相应诱发电位的波幅，进行果糖胺等糖代谢监测。结果 注射甲钴胺的血糖控制较好组大鼠（果糖胺1.0mmol／L）运动、感觉神经传导速度和波幅的下降比血糖控制较差组（果糖胺1．2mmol／L）明显延缓（P〈0．05～0．01）。至第8周，注射甲钴胺的血糖控制较好组大鼠的电生理指标与正常对照组无显著性差异；12周时，血糖控制较差组大鼠中，注射甲钴胺大鼠的电生理指标与未注射甲钴胺的无显著性差异（P〉0．05）。未见甲钴胺对血糖的影响。结论 甲钴胺延缓糖尿病PN的效应受血糖和病程的影响，病程早期、血糖控制较者效果较好。     

甲基维生素B12治疗糖尿病周围神经病变的系统评价

目的了解甲基维生素B12治疗糖尿病周围神经病变的疗效和安全性.方法按照国际Cochrane协作网的系统评价方法,检索全世界关于甲基维生素B12治疗糖尿病周围神经病变的随机或半随机对照试验,包括Cochrane 图书馆2003年第4期、临床对照试验资料库、MEDLINE、EMBASE、中国生物医学文献光盘数据库、中文科技期刊全文数据库以及所有纳入研究的参考文献.由两位评价者独立地对符合纳入标准的试验进行质量评价和资料提取.采用下列指标对甲基维生素B12治疗糖尿病周围神经病变的疗效和安全性进行评价:临床症状体征的总有效率、感觉及运动神经传导速度以及严重不良反应的发生率.结果 30个试验共纳入1 949例糖尿病周围神经病变患者.大部分试验的方法学质量较低.甲基维生素B12与其他B族维生素比较的13个试验的"漏斗图"图分析显示基本对称,提示发表偏倚的可能性较小,结果比较可靠,但是不一定能代表整体发表偏倚情况.Meta分析结果显示:甲基维生素B12可明显改善糖尿病周围神经病变的临床症状和体征,且疗效优于其他B族维生素;甲基维生素B12改善某些周围神经传导速度的疗效优于其他B族维生素;在治疗期间,试验未发现严重不良反应. 结论甲基维生素B12可能是一种相对安全和有效的治疗糖尿病周围神经病变的药物.但由于纳入试验的方法学质量低下和可能存在发表偏倚,证据强度不足,尚有待大样本、高质量的多中心随机双盲对照试验加以证实.     

Treatment of Rheumatoid Arthritis

This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed Ave double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, POSTGRADUATE MEDICINE, 4530 W 77th St, Minneapolis, MN 55435.     

穴位按摩改善晚期肺癌患者化疗致末梢神经炎的临床效果

目的 探讨穴位按摩改善晚期肺癌患者化疗致末梢神经炎的临床效果.方法 2015年11月至2016年2月,便利抽样法选择在上海市肺科医院应用紫杉醇和/或铂类化疗药物治疗后发生末梢神经炎的晚期肺癌患者50例为研究对象,对其进行外关穴和五虎穴的按摩,2次/d,20 min/穴·次,并跟踪随访4周.结果 经穴位按摩后,患者末梢神经炎的麻木和刺痛症状最早缓解日在第2天.麻木症状完全缓解的有34例,症状减轻的有11例,无效的有3例,有效率为87.5％;刺痛症状完全缓解的有35例、症状减轻的有5例、未缓解的有2例,有效率为92.86％.结论 早期应用外关穴和五虎穴的按摩能有效缓解晚期肺癌患者化疗致末梢神经炎的症状.     

甲钴胺联合前列地尔治疗糖尿病周围神经病变的疗效观察

目的：观察比较甲钴胺联合前列地尔,单用甲钴胺及单用维生素B12治疗糖尿病周围神经病变的疗效。方法：将60例糖尿病周围神经病变患者随机分为3组,治疗组1（20例）给予甲钴胺0.5mg肌内注射,每天1次,同时给予前列地尔10μg＋0.9%氯化钠液10mL静脉推注,每天1次,连续2周;治疗组2（20例）给予甲钴胺0.5mg肌内注射,每天1次,连续2周;对照组（20例）用维生素B120.5mg肌内注射,每天1次,连续2周。每组均辅以丹参针剂静脉滴注治疗。结果：治疗组1、治疗组2患者症状和体征、各项神经传导速度与对照组相比均显著改善,而治疗组1与治疗组2之间临床疗效差异有统计学意义,且各组均无明显不良反应。结论：甲钴胺联合前列地尔治疗糖尿病周围神经病变疗效更好。     

Reducing cardiovascular risk by blockade of the renin-angiotensin-aldosterone system

Many factors contribute to the overall risk of cardiovascular disease (CVD) in a given patient. Activation of the renin-angiotensin-aldosterone system (RAAS) is pivotal in the pathophysiology of CVD and renal disease and appears to place individuals at high risk for cardiovascular (CV) and renal events. Results from many large-scale, long-term clinical trials have demonstrated that RAAS blockade with an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) can significantly decrease CV and renal morbidity and mortality in a wide range of patients. Some of the clinical benefits derived from use of these agents appears to be independent of their ability to lower blood pressure. The combined use of an ACEI and an ARB for antihypertensive therapy has begun to receive considerable attention. Such an approach may seem counterintuitive, but ACEIs and ARBs have distinct and potentially complementary pharmacologic effects. Results from clinical trials thus far suggest that combination therapy with an ACEI plus an ARB may be a rational choice in patients with chronic activation of the RAAS, including those with heart failure or impaired left ventricular systolic function, diabetes, proteinuria, impaired renal function, recent myocardial infarction, or multiple CV risk factors. Results from ongoing, large-scale, clinical endpoint trials will provide important additional information about the benefits of dual RAAS inhibition in patients at high risk for CV morbidity and mortality.     

A Trial of Scrambler Therapy in the Treatment of Cancer Pain Syndromes and Chronic Chemotherapy-Induced Peripheral Neuropathy

ABSTRACT

Neuropathic pain is common among cancer patients and often difficult to treat. This study used Scrambler therapy, a patient-specific electrocutaneous nerve stimulation device, to treat cancer patients with pain. Patients received Scrambler therapy for 10 sessions (one daily) over a two-week period. The primary outcome was changed in pain numerical rating scale (NRS) at one month; secondary outcomes were changes in the Brief Pain Inventory and European Organization for Treatment and Cancer QLC-CIPN-20(EORTC CIPN-20), over time. Thirty-nine patients, mean age 56.5 yr, 16 men and 23 women, were treated over an 18-month period for an average of 9.3 days each. The “now” pain scores reduced from 6.6 before treatment to 4.5 at 14 days, 4.6, 4.8, and 4.6 at 1, 2, and 3 months, respectively (?p < 0.001). Clinically important and statistically significant improvements were seen in average, least, and worst pain; BPI interference with life scores, and motor and sensory scales on the EORTC CIPN-20. No adverse effects were observed. In this single arm trial, Scrambler therapy appeared to relieve cancer-associated chronic neuropathic pain both acutely and chronically, and provided sustained improvements in many indicators of quality of life.     

The role of renin–angiotensin– aldosterone system inhibition in chronic kidney disease

Chronic kidney disease (CKD) is emerging as a new health pandemic. Underlying the global rise in CKD is an increase in diabetes, hypertension and other cardiovascular risk factors leading to progressive renal dysfunction. Emerging evidence strongly suggests that achieving target blood pressure goals via inhibition of the renin–angiotensin–aldosterone system confers significant renal and cardioprotection for patients with CKD. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) lower blood pressure, reduce proteinuria and reduce both the progression of CKD and adverse cardiovascular events. The role of aldosterone inhibition and combination therapy, such as ACEI/ARB, in CKD are under investigation. As our understanding of the basic mechanisms underlying CKD progression advances, novel therapies targeting post-translational endothelial and mesangial messengers downstream from angiotensin II and aldosterone may become available for clinical use.     

银杏达莫对糖尿病周围神经病变患者神经传导速度的影响

目的 观察银杏达莫对糖尿病周围神经病变（DPN）患者神经症状、体征及神经传导速度的影响。方法 将60例DPN患者随机分为观察组和对照组各30例．对照组采用DPN的常规治疗．观察组在对照组用药基础上加用银杏达莫注射液20ml／d静脉滴注，连用4周。治疗前后观察患者的神经症状和体征，测定四肢感觉神经和运动神经传导速度，并比较其变化。结果 治疗后，观察组患者的神经症状和体征明显改善，神经传导速度明显增快，与治疗前比较有非常显著性差异（P〈0．01）；与对照组比较亦有非常显著性差异（P〈0．01）。结论 银杏达莫可明显改善DPN患者的临床症状和体征，并能提高神经传导速度。     

依达拉奉对糖尿病周围神经病变大鼠坐骨神经的保护作用

目的:研究依达拉奉对糖尿病周围神经病变(DPN)大鼠坐骨神经的保护作用。方法:SD大鼠80只,采用链脲佐菌素(STZ)一次性腹腔注射诱导建立DPN模型,随机分为对照组和治疗组,治疗组每天给予3 mg/kg依达拉奉腹腔注射4周,观察摆尾温度阈值(TTT)、坐骨神经运动神经传导速度(MCV)、感觉神经传导速度(SCV)、神经形态和坐骨神经中一氧化氮(NO)含量、丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性。结果:对照组大鼠TTT升高,MCV和SCV减慢(P<0.01),形态学明显异常,NO、MDA含量明显增多,SOD活性显著降低(P<0.01)。治疗组与对照组比较TTT明显降低,MCV和SCV明显加快,形态学明显改善,NO、MDA含量明显减少,SOD活性显著增高(P<0.01)。结论:依达拉奉可降低DPN大鼠坐骨神经损伤。     

Discontinuation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Chronic Kidney Disease

ObjectiveTo assess the patterns of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACE-I/ARB) discontinuation in the setting of chronic kidney disease (CKD) progression in real-world clinical practice.Patients and MethodsWe identified incident ACE-I/ARB users with a baseline estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m² and without end-stage renal disease in the Geisinger Health System between January 1, 2004, and December 31, 2015. We investigated the associations of CKD stage, hospitalizations with and without acute kidney injury (AKI), serum potassium, bicarbonate level, thiazide, and loop diuretic use with ACE-I/ARB discontinuation.ResultsAmong the 53,912 ACE-I/ARB users, the mean age was 59.9 years, and 50.6% were female. More than half of users discontinued ACE-I/ARB within 5 years of therapy initiation. The risk of ACE-I/ARB discontinuation increased with more advanced CKD stage. For example, patients who initiated ACE-I/ARB with CKD stage G4 (eGFR: 15-29 mL/min/1.73 m²) were 2.09-fold (95% CI, 1.87-2.34) more likely to discontinue therapy than those with eGFR ≥ 90 mL/min/1.73 m². Potassium level greater than 5.3 mEq/L, systolic blood pressure ≤ 90 mm Hg, bicarbonate level < 22 mmol/L, and intervening hospitalization—particularly AKI-related–were also strong risk factors for ACE-I/ARB discontinuation. Thiazide diuretic use was associated with lower risk, whereas loop diuretic use was associated with higher risk of discontinuation.ConclusionIn a real-world cohort, discontinuation of ACE-I/ARB was common, particularly in patients with lower eGFR. Hyperkalemia, hypotension, low bicarbonate level, and hospitalization (AKI-related, in particular) were associated with a higher risk of ACE-I/ARB discontinuation. Additional studies are needed to evaluate the risk–benefit balance of discontinuing ACE-I/ARB in the setting of CKD progression.     

山莨菪碱与前列腺素E1治疗糖尿病周围神经病变的疗效

目的 比较大剂量山莨菪碱与常规剂量前列腺素E1治疗糖尿病周围神经病变（DPN）的临床疗效.方法 将40例DPN患者按治疗方法的不同分为A、B2组,每组20例.2组均采用常规治疗,包括糖尿病饮食、口服降糖药物或胰岛素控制血糖及调脂降压等,并采用甲钴胺注射液和依帕司他片治疗.在此基础上,A组加用山莨菪碱注射液治疗,B组加用前列腺素E1注射液治疗.观察2组治疗前后正中神经、腓肠神经的运动神经传导速度（MNCV）、感觉神经传导速度（SNCV）及Toronto评分的情况.结果 2组治疗后Toronto得分和正中神经、腓肠神经的MNCV及SNCV与治疗前比较差异均有统计学意义（均P＜0.01）,2组治疗后Toronto得分和正中神经、腓肠神经的MNCV及SNCV比较差异均无统计学意义（均P＞0.05）.A组治疗后12例出现口干、面色潮红、视物模糊、心率增快及排尿困难等,但均可耐受,并完成治疗;B组治疗后3例出现低热、头痛及静脉炎,但均可耐受,并完成治疗.结论 山莨菪碱与前列腺素E1治疗DPN对改善患者的症状和体征、提高MNCV和SNCV均有效,且不良反应少,但2种方法的疗效未见显著差异.     

文拉法辛和卡马西平治疗痛性糖尿病周围神经病变的随机双盲双模拟多中心临床试验

目的评价文拉法辛和卡马西平治疗痛性糖尿病周围神经病变的疗效和安全性。方法本试验是一个随机双盲双模拟多中心临床试验。3个临床中心共纳入132例患者。随机分为试验组,文拉发辛胶囊,25mg,每日2次,66例和阳性对照组,卡马西平片,0.1g,每日2次,66例,疗程为14天。主要的疗效指标为数字强度分级法评价疼痛强度。次要指标为生活质量评价。结果共119例患者完成试验。在试验的第5、7、10和14天时,文拉法辛组较卡马西平组明显改善疼痛强度(各组的P值分别为:P=0.02,P=0.03,P=0.003,P=0.001)。在治疗的第10天和第14天文拉法辛较卡马西平明显改善生活质量评价的总分(P=0.02;P=0.01)。文拉法辛和卡马西平都能明显改善患者的睡眠和情绪,但文拉法辛的效果优于卡马西平。文拉法辛最常见的不良反应是胃肠道不适、头昏和嗜睡。文拉法辛组的不良反应发生率为43.90%(4例患者因为不良反应退出试验);卡马西平组的不良反应发生率为25.76%(2例患者因为不良反应退出试验)。结论文拉发辛和卡马西平均有减轻糖尿病神经病变性疼痛以及改善患者生活质量的作用,但文拉发辛在减轻疼痛、改善生活质量方面的作用优于卡马西平,两组的不良反应和不良事件均相似,主要的不良事件是胃肠道不适,头昏和嗜睡。