First clinical trial with etomoxir in patients with chronic congestive heart failure

In the failing human myocardium, both impaired calcium homoeostasis and alterations in the levels of contractile proteins have been observed, which may be responsible for reduced contractility as well as diastolic dysfunction. In addition, levels of a key protein in calcium cycling, i.e. the sarcoplasmic reticulum Ca(2+)-ATPase, and of the alpha-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltransferase inhibitor, in normal and pressure-overloaded rat myocardium. We therefore studied, for the first time, the influence of long-term oral application of etomoxir on cardiac function in patients with chronic heart failure. A dose of 80 mg of etomoxir was given once daily to 10 patients suffering from heart failure (NYHA functional class II-III; mean age 55+/-4 years; one patient with ischaemic heart disease and nine patients with dilated idiopathic cardiomyopathy; all male), in addition to standard therapy. The left ventricular ejection fraction was measured echocardiographically before and after a 3-month period of treatment. Central haemodynamics at rest and exercise (supine position bicycle) were defined by means of a pulmonary artery catheter and thermodilution. All 10 patients improved clinically; no patient had to stop taking the study medication because of side effects; and no patient died during the 3-month period. Maximum cardiac output during exercise increased from 9.72+/-1.25 l/min before to 13.44+/-1.50 l/min after treatment (P<0.01); this increase was mainly due to an increased stroke volume [84+/-7 ml before and 109+/-9 ml after treatment (P<0.01)]. Resting heart rate was slightly reduced (not statistically significant). During exercise, for any given heart rate, stroke volume was significantly enhanced (P<0.05). The left ventricular ejection fraction increased significantly from 21.5+/-2.6% to 27.0+/-2.3% (P<0.01). In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties. Thus, although the results of this small pilot study are not placebo-controlled, all patients seem to have benefitted from etomoxir treatment. Etomoxir, which has no acute inotropic or vasodilatory properties and is thought to increase gene expression of the sarcoplasmic reticulum Ca(2+)-ATPase and the alpha-myosin heavy chain, improved clinical status, central haemodynamics at rest and during exercise, and left ventricular ejection fraction.     

CVVH治疗慢性肾功能不全伴充血性心力衰竭患者的疗效观察

目的探讨连续性静脉静脉血液滤过(CVVH)治疗慢性肾功能不全(CRF)伴充血性心力衰竭(CHF)患者的临床疗效及影响预后的因素。方法对上海交通大学第六医院2002年1月～2005年2月的42例CRF伴CHF的患者接受CVVH治疗,观察治疗前后心率(HR)、呼吸(RR)、血压(BP)、心功能改善情况及APACHEⅡ评分等指标变化,并检测血肌酐(Scr)、尿素氮(BUN)、血碳酸氢根浓度(HCO3-)、动脉血pH值(pH)。结果CVVH治疗能明显减少CRF伴CHF患者的水、钠潴留,改善心功能,降低APACHEⅡ评分。对死亡组和存活组进行统计学分析发现死亡组APACHEⅡ评分更高,而容量负荷(FO%)与死亡率密切相关。结论CRF伴CHF患者在血肌酐不高的情况下,如容量负荷过重即行CVVH治疗,可减少并发症,降低死亡率。     

The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial

Objective  To determine if statin therapy reduces the incidence of severe sepsis and the levels of inflammatory cytokines in patients with acute bacterial infection. Design  Double-blind placebo controlled randomized clinical trial. Setting  Department of medicine and medical intensive care unit in a tertiary university medical center. Patients and participants  A total of 83 patients with suspected or documented bacterial infection were enrolled. We randomly assigned 42 patients to receive 40 mg of simvastatin orally, followed by 20 mg of simvastatin, and 41 to receive matching placebo. Measurements and results  The study was prematurely terminated due to slow recruitment rate. Here we report the analysis of the secondary outcome: change in cytokines levels at 72 h. Both groups were evenly matched in terms of co-morbidity and severity of illness on admission. Four of the 83 patients enrolled developed severe sepsis, two in each group. No difference was observed in other clinical variables and there were no mortalities. Cytokine levels were randomly assessed in 40 patients (20 in each group). Both TNF-α and IL-6 levels were significantly reduced in the simvastatin group (p = 0.02 and p = 0.02, respectively), while no such difference was observed in the placebo group (p = 0.35 and 0.39, respectively). Conclusions  Statin therapy may be associated with a reduction in the levels of inflammatory cytokines in patients with acute bacterial infections. Large controlled trials will determine if this reduction will translate into a clinical benefit. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A randomized,double-blind,placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain

ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 μg BID, ABT-594 225 μg BID, or ABT-594 300 μg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0–10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, −1.1; 150 μg BID, −1.9; 225 μg BID, −1.9; 300 μg BID, −2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 μg BID, 46% for 225 μg BID, and 66% for 300 μg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.     

A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia

An open clinical trial was carried out to compare the efficacy and the tolerability of 1 g/day alpha-glycerylphosphorylcholine (alpha-GPC) with 1 g/day cytosine diphosphocholine (CDP) both given intramuscularly for 90 days in 120 patients with mild to moderate vascular dementia. The clinical evaluation, carried out at the start as well as halfway through (45 days) and at the end of treatment (90 days), was expressed by psychometric tests (modified Parkside behaviour rating scale, Sandoz clinical assessment geriatric scale, word fluency test, Hamilton's rating scale of depression, narration subtest of Wechsler memory scale). Both treatments produced a definite symptomatic improvement and showed a very good tolerability. The results suggest that in most tests alpha-GPC possessed a statistical higher efficacy and an overall more satisfactory activity assessed by both patients and investigators compared with CDP.     

两种剂量辛伐他汀治疗115例高脂血症的疗效比较

目的：探讨不同辛伐他汀剂量的调脂疗效、安全性和预防心脏性事件的作用。方法：将１１５例高脂血症随机单盲分为２组：１０ｍｇ组５７例,辛伐他汀１０ｍｇ／ｄ;２０ｍｇ组５８例,辛伐他汀２０ｍｇ／ｄ,均观察１年,观察调脂效果、不良反应及心脏性事件发生情况。结果：２０ｍｇ组治疗后总胆固醇（ＴＣ）、甘油三酯（ＴＧ）Ｇ、ＬＤＬ－Ｃ、载脂Ｂ均明显下降,ＨＤＬ－Ｃ、ＡｐｏＡ１均显著升高,疗效明显优于１０ｍｇ组。调脂总     

托拉塞米联合环磷腺苷葡胺治疗老年慢性心功能不全的疗效分析

目的:观察托拉塞米联合环磷腺苷葡胺对老年慢性心功能不全患者的心功能和血浆脑钠素(BNP)的影响.方法:58例老年慢性心功能不全患者分为治疗组和对照组,对照组给予常规抗心力衰竭治疗,治疗组在常规治疗的基础上应用托拉塞米和环磷腺苷葡胺,治疗14 d后评价两组患者治疗前后的临床心功能分级情况、左室收缩末期内径(LVESD)、左室舒张末期内径(LVEDD)和左室射血分数(LVEF)的改善情况及血浆BNP水平的变化.结果:治疗组患者心功能改善显著,LVEDD、LVEF和血浆BNP改善明显优于对照组(P均＜ 0.01).结论:托拉塞米联合环磷腺苷葡胺可显著改善老年慢性心功能不全患者的心功能,降低血浆BNP水平.     

Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: A double-blind,randomized, placebo-controlled clinical trial

In this double-blind, randomized, placebo-controlled, prospective study, the clinical efficacy and tolerability of oral Hypericum extract STW 3-VI (Laif) 900 mg once daily was compared with that of placebo. A total of 140 outpatients (94 women; 46 men) with moderate depressive disorders and a 17-item Hamilton Depression Scale (HAMD-17) score of 20 to 24 were enrolled in this study. Following a single-blind placebo run-in period of 7 days, the patients were randomized to Hypericum extract 900 mg or placebo for the 6-week treatment period. Nineteen patients have been excluded from the per protocol collective because of violations of protocol regarding the scheduling of study visits and intake of study medication. The primary endpoint for treatment efficacy was the change in total HAMD-17 score at the end of the 6-week treatment period. The HAMD-17 total score decreased significantly from baseline by approximately 11.1 +/- 4.5 points (from 22.8 +/- 1.1 to 11.8 +/- 4.4) in the Hypericum group and by approximately 3.4 +/- 3.9 points (from 22.6 +/- 1.2 to 19.2 +/- 3.8) in the placebo group (P < .001). Comparable group differences in favor of Hypericum were revealed by an additional responder analysis, the von Zerssen's Adjective Mood Scale, the Clinical Global Impressions scale, and a global efficacy assessment. Tolerability was very good in both groups; neither serious adverse events nor clinically relevant changes in safety parameters were observed, and only 2 cases demonstrated a possible connection between an adverse event and the study medication. The final safety assessment showed no differences between the Hypericum extract and placebo groups. The study provided evidence that Hypericum extract STW 3-VI in a once-daily dosing regimen may be an effective and well-tolerated option for patients with moderate depressive disorders.     

帕罗西汀与多虑平治疗癫痫伴抑郁的效果评估:随机对照

目的:观察帕罗西汀治疗癫痫伴发抑郁患者的安全性和疗效。方法:将延安大学医学院附属医院就诊的伴发抑郁的癫痫患者67例随机分为治疗组(n=33)和对照组(n=31),两组均常规应用抗癫痫药物。治疗组用帕罗西汀,对照组用多虑平改善抑郁症状。治疗8周后行汉密顿抑郁量表和汉密顿焦虑量表评分,比较两组的治疗效果和不良反应。结果:治疗组和对照组治疗后汉密顿抑郁量表和汉密顿焦虑量表评分均较治疗前有明显降低,差异有显著性(P<0.05)。两组治疗后的汉密顿抑郁量表和汉密顿焦虑量表评分和显效率差异无显著性(P>0.05);治疗组患者出现的不良反应少于对照组。结论:帕罗西汀治疗癫痫伴发抑郁是安全和有效的,可作为首选药物;多虑平也有很好的疗效,但副作用较大,可作为次选药物。     

Review of randomized trials of angiotensin receptor blockers in the treatment of patients with congestive heart failure]

Angiotensin-converting enzyme (ACE) inhibitors are the first-line drugs for the treatment of congestive heart failure, but many patients could not receive those benefits because of intolerance. Recent randomized trials of angiotensin receptor blockers (ARB) in the treatment of patients with congestive heart failure elucidated clinical benefits of ARB as well as ACE inhibitors. ELITE II showed equivalent effect on mortality and morbidity between losartan and captopril and less adverse events in losartan. Val-HeFT showed additive benefits of valsartan on standard treatment with ACE inhibitors, diuretics and digitalis in patients with heart failure. CHARM would be elucidate the clinical usefulness of candesartan cilexetil in a broad spectrum of patients with symptomatic heart failure including patients whose LVEF greater than 40%.     

Results of a multicenter, 8-week, parallel-group, randomized,double-blind, double-dummy, Phase III clinical trial to evaluate the efficacy and tolerability of amlodipine maleate versus amlodipine besylate in Korean patients with mild to moderate hypertension

BACKGROUND: Recently, amlodipine maleate was developed and tested in preclinical and Phase I clinical trials in Korea. The studies found pharmacokinetics and pharmacodynamics similar to those of amlodipine besylate. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of amlodipine maleate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. METHODS: This was a multicenter, 8-week, parallel-group, randomized, double-blind, double-dummy, Phase III clinical trial. Eligible patients were Korean, aged 18 to 75 years, had hypertension, and were either taking antihypertensive medications or had a documented sitting diastolic blood pressure of 90 to 109 mm Hg. After a washout period of 2 weeks, patients were randomized to amlodipine maleate or amlodipine besylate for 8 weeks. In both groups, the medications were initiated at 5 mg QD. At day 29, the medication dose was increased to 10 mg QD if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. RESULTS: One hundred eighteen patients were enrolled. Fifty-seven patients received amlodipine maleate (29 men, 28 women; mean [SD] age, 49.0 [11.4] years) and 61 received amlodipine besylate (35 men, 26 women; mean [SD] age, 51.6 [9.4] years). Baseline mean (SD) values for sitting systolic blood pressure and SiDBP were 152.0 (12.2) mm Hg and 98.1 (5.6) mm Hg, respectively, for the amlodipine maleate group and 153.4 (14.0) mm Hg and 98.1 (5.5) mm Hg, respectively, for the amlodipine besylate group. In this population, amlodipine maleate was not inferior to amlodipine besylate: the lower limit of the 2-sided 95% CI for the treatment difference in SiDBP was greater than -4 mm Hg. The between-group difference in SiDBP response rate (the proportion of patients who experienced adequate SiDBP reductions) did not reach statistical significance: 85.7% (42/49) for the amlodipine maleate group and 91.8% (45/49) for the amlodipine besylate group. Compliance rates were similar between groups, with mean (SD) compliance rates of 97.4% (2.8%) and 97.1% (3.6%) in the amlodipine maleate and amlodipine besylate groups, respectively. Also, there were no significant differences in the incidences of drug-related clinical and laboratory adverse events; the most common were headache, flushing, facial edema, and paresthesia. CONCLUSION: In this population, the efficacy and tolerability observed with amlodipine maleate were similar to those seen with amlodipine besylate.     

Efficacy and safety of metamizol vs. acetylsalicylic acid in patients with moderate episodic tension-type headache: a randomized, double-blind, placebo- and active-controlled, multicentre study

We assessed the efficacy and safety of oral single doses of 0.5 and 1 g metamizol vs. 1 g acetylsalicylic acid (ASA) in 417 patients with moderate episodic tension-type headache included in a randomized, double-blind, placebo- and active-controlled, parallel, multicentre trial. Eligibility criteria included 18-65 years of age, history of at least two episodes of tension-type headache per month in the 3 months prior to enrollment, and successful previous pain relief with a non-opioid analgesic. Treatment arms were metamizol 0.5 g (n = 102), metamizol 1 g (n = 108), ASA 1 g (n = 102) and placebo (n = 105). The analgesic efficacy of 0.5 and 1 g metamizol vs. placebo was highly statistically significant (alpha: 0.025; one-sided) for sum of pain intensity differences, maximum pain intensity difference, number of patients with at least 50% pain reduction, time to 50% pain reduction, maximum pain relief and total pain relief. A trend towards an earlier onset of a more profound pain relief of 0.5 and 1 g metamizol over 1 g ASA was noticed. All medications including placebo were almost equally safe and well tolerated.     

美托洛尔联合苯那普利治疗充血性心力衰竭伴室性心律失常的临床疗效观察

目的探讨美托洛尔联合苯那普利治疗充血性心力衰竭(CHF)伴室性心律失常的临床效果。方法选择98例CHF伴室性心律失常为研究对象,采用随机数字表法分为分为对照组(47例)和观察组(51例)。对照组予以常规内科治疗加苯那普利,观察组在上述基础上联合美托洛尔治疗。比较两组临床治疗效果,心功能指标[心率(HR)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESDD)、左室射血分数(LVEF)、QT间期(QTc)、QT离散度(QTd)、24 h室性早搏数(24 h VPB)、24 h室性心动过速(24 h PVT)]改善情况。结果观察组总有效率、心律失常下降率明显高于对照组(98.1%vs.78.7%,49.0%vs.27.7%);HR、LVESD、LVESDD等心功能指标均明显低于对照组,LVEF明显高于对照组;QTc明显高于对照组,QTd、24 h VPB、24 h PVT明显低于对照组。结论美托洛尔联合苯那普利有利于患者心室重塑,改善心功能,降低QT离散度,减少24 h室性早搏数与24 h室性心动过速数,提高治疗效果。     

老年维持性血液透析并充血性心力衰竭患者生存状况的影响因素

目的探讨影响老年维持性血液透析（MHD）合并充血性心力衰竭（CHF）患者生存时间的危险因素。方法选择2008年1月1日至2015年12月31日期间曾因MHD合并CHF住过院、又因CHF再入院或死亡患者46例,另选32例老年MHD未合并CHF或仅合并1次CHF患者为对照,通过门诊收集临床资料,以CHF再入院或全因死亡为终点事件（生存时间终止）,随访截止时间为2015年12月31日。通过Kaplan Meier生存曲线和COX比例风险回归模型分析患者生存时间的影响因素。结果Kaplan Meier生存曲线显示年龄、左心室扩大或肥厚、感染、左心室射血分数（LVEF）、透析间期体质量增加对老年MHD合并CHF患者的生存时间有显著影响（P＜0.05）。COX比例风险回归模型分析显示年龄、左心室扩大或肥厚、LVEF、透析间期体质量增加为影响老年MHD患者CHF生存时间的独立危险因素（P＜0.05）。结论年龄分层、左心室扩大或肥厚、透析间期体质量增加、LVEF降低是影响老年维持性血液透析并CHF患者生存时间的独立危险因素。     

0.1%西吡氯铵含漱液治疗牙龈炎和抑制菌斑疗效及安全性的多中心随机双盲临床试验

目的 对0．1％西吡氯铵含漱液治疗牙龈炎和抑制菌斑的疗效及安全性进行评价。方法多中心随机、双盲、阳性药物对照、左右半口对照设计。首诊(D0)时对左侧上下牙齿洁治，结束时右侧洁治。两组均每日漱口5次，方法相同。从治疗前后临床及微生物学改变评价疗效，第4(D4)、8(D8)日复查。D0-D4停止刷牙，D4-D8恢复刷牙。结果 符合纳入标准144例，4例失访，试验组69例、对照组71例可进行分析。基线分析表明两组性别年龄分布、临床及微生物学指标均具有可比性。D4复查治牙侧两组菌斑累积量在同一水平并均显低于未治牙侧。两侧牙龈指数(GI)、出血指数(SBI)及口臭VAS记分均显低于基线值。D8复查两组菌斑指数(PI)、GI、SBI、口臭VAS比D4复查值进一步显减少，菌斑及唾液中可疑致病菌半数以上被清除，菌量显减少，但组间比较均无显差异，均未见菌群失调。试验组17例(24．6％)发生不良反应，均轻微一过性。体外抑菌实验证实试验药可杀灭或抑制多种与口咽、颌面部感染、牙龈炎、牙周炎、龋齿等有关的可疑致病菌。结论 西吡氯铵含漱液确能减少或抑制牙菌斑的形成、治疗牙龈炎、减少口臭，与国家已批准上市的西吡氯铵含漱液疗效相同。     

AVANTI 1: randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus loviride in HIV-infected antiretroviral-naive patients. AVANTI Study Group

The objective of this randomized double-blind, placebo-controlled trial was to investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess the safety and tolerability of such regimens. The trial was carried out in seven European countries, Australia and Canada and involved antiretroviral-naive patients (n = 106) with CD4 counts between 150-300 cells/mm3 (CDC group A) and 150-500 cells/mm3 (CDC group B/C). Patients were randomly assigned to zidovudine (200 mg three times daily) plus lamivudine (300 mg twice daily) or to zidovudine plus lamivudine plus loviride (100 mg three times daily) for 52 weeks. The main outcome measures were degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR and the development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation. A mild, though statistically significant difference in favour of zidovudine plus lamivudine plus loviride for log10 plasma HIV-1 RNA (P = 0.022), as compared to zidovudine plus lamivudine, was observed using area-under-the-curve minus baseline (AUCMB). An increase in CD4 cell count in the zidovudine plus lamivudine plus loviride group was observed with a median improvement of 124 cells/mm3 at week 52 compared with 70 cells/mm3 in the zidovudine plus lamivudine group (P = 0.06). Both treatment regimens were well tolerated.