芩术安胎散的毒性和临床安全性试验研究

试验通过对芩术安胎散的急性毒性、亚慢性毒性和临床安全性进行研究,为芩术安胎散对家猫先兆性流产的预防与治疗提供参考。急性毒性试验:制备芩术安胎散药液,取6周龄健康昆明小白鼠60只,随机分为5组,每组12只,第1~4组的给药剂量分别为6000、4800、3840和3072 mg/kg,对照组给予等量纯净水,10 d内观察有无中毒和死亡,计算半数致死量(LD50);另取6周龄健康昆明小白鼠20只,随机分为2组:试验组给予2.0 g/mL芩术安胎散药液,18 h内灌服3次,每次0.8 mL,对照组给予等量纯净水,给药后饲养7 d,计算最大耐受量(MTD)。亚慢性毒性试验:24只7周龄SD雌性大鼠随机均分为高、中、低剂量组和对照组,在30 d内,每日分别给予4800、2400和1200 mg/kg芩术安胎散,对照组以等量纯净水进行灌胃,每日观察和记录各组大鼠的精神状态、有无中毒症状和死亡;第31天对各组大鼠称重、采血,进行血液学检测,剖检各组大鼠,观察主要脏器有无病变并制作病理切片。临床安全性试验:选取2~5岁健康雌性家猫20只,适应性饲养10 d,随机分组,每组5只,分别为低剂量组(1倍临床推荐剂量:1.15 g/kg)、中剂量组(3倍临床推荐剂量:3.45 g/kg)、高剂量组(5倍临床推荐剂量:5.75 g/kg)及空白对照组,将药物置于胶囊内,口服给药,空白对照组给予空胶囊,每日1次,连续给药7 d,每日观察各组家猫食欲、精神状态及排便情况,于第8天对各组家猫进行静脉采血,检测血常规和血液生化指标。结果显示,急性毒性试验无小鼠死亡,LD50>6000 mg/kg;小鼠对芩术安胎散的最大耐受量为240 g/kg,表明该受试药物无明显毒性。在亚慢性毒性试验中,各组大鼠的生长发育情况、血常规指标、脏器系数与对照组相比均无显著差异(P>0.05);高、中剂量组与低剂量组、对照组相比血清总胆固醇含量显著下调(P<0.05),除此之外的生化指标均无显著差异(P>0.05)。病理剖检和组织切片观察结果显示,高剂量组大鼠主要组织器官与对照组相比无明显异常。在临床安全性试验中,不同剂量组家猫精神状态、被毛光泽度、粪便情况均正常,血液学指标与对照组相比差异均不显著(P>0.05)。本试验结果表明,中药芩术安胎散无明显毒性,家猫按临床推荐剂量使用是安全的。

武田制药的阿格列汀临床安全性试验达到主终点

武田制药有限公司宣布其治疗2型糖尿病治疗药阿格列汀（alogliptin）临床EXAMINE心血管安全性试验达到主终点。该试验为全球、大型、随机、双盲和安慰剂对照研究，总入选5380名患有2型糖尿病、

中药新药非临床安全性试验中受试物的相关问题

药物的安全性评价贯穿于药物研发的整个过程，包括前期筛选、非临床试验研究、临床试验，甚至上市后。其中基于实验动物的非临床安全性评价在整个药物安全性评价中占有很大的比重。

重视新药非临床安全性试验中供试品的检测

本文探讨了新药非临床安全性试验中供试品检测的相关内容,以便得到可靠的新药非临床安全性试验数据。

甲型H1N1流感病毒裂解疫苗的免疫原性和安全性

目的：评价甲型H1N1流感病毒裂解疫苗（简称甲型H1N1流感疫苗）的免疫原性和安全性。方法按照随机、双盲、安慰剂对照的原则，采用0、21天免疫程序，选择3岁及3岁以上健康者1202人。分组为3～11岁、12～17岁、≥60岁组，按照人数基本为1∶1的比例随机分别接种7．5μg和15．0μg 甲型H1N1流感疫苗；18～59岁组按照人数基本为1∶1∶1的比例随机分别接种7．5μg、15．0μg甲型 H1 N1流感疫苗和安慰剂对照。观察各组接种后的不良反应率以及免疫前后血凝抑制（ HI）抗体阳转率、保护率、GMT水平和平均增长倍数。结果受试对象的安全性结果显示7．5μg和15．0μg组不良反应发生率分别为8．74％（48／549）和13．88％（74／533），其中Ⅱ级反应率分别为03．6％（2／549）和1．13％（6／533），未观察到Ⅲ级及以上不良反应和其他异常反应及严重不良事件。2剂接种未见不良反应叠加现象。7．5μg或15．0μg试验疫苗首剂免疫后，血清抗体阳性率分别为85．13％（395／464）和90．77％（413／455），保护率分别为85．56％（397／464）和91．43％（416／455），抗体GMT较免疫前分别增长36．1倍和526．倍。2剂免疫后，血清抗体阳性率分别是97．84％（454／464）和99．12％（451／455），保护率分别是98．06％（455／464）和99．56％（453／455），抗体GMT较免疫前分别增长63．3倍和96．0倍。4个年龄组（3～11岁、12～17岁、18～59岁及≥60岁年龄组）7．5μg和15．0μg组HI抗体阳性率和保护率均大于70％，GMT较免疫前均增长2．5倍以上，结果显示7．5μg和15．0μg甲型H1N1流感疫苗接种1剂后抗体水平已达到研究方案中设定的预期标准，免疫2剂后抗体阳性率和抗体水平明显提高。结论临床试验表明甲型H1 N1流感疫苗具有良好的安全性和免疫原性，且接种1剂15．0μg甲型H 1N1流感疫苗，即可在3岁和3岁以上人群中产生良好的免疫效果。

试论安全药理学研究的基本要求及规范化

安全药理学（safety pharmacology）研究是新药非临床安全性评价的一项重要内容，主要研究药物在治疗范围内或治疗范围以上剂量时，出现潜在的不期望的不良影响，并研究观察到的／或推测的药物不良反应机制。从而最大限度地保障新药进入临床研究之前或上市之后，及早发现可能出现的治疗作用之外的不良反应。安全药理学研究概念最早出现于1997年人用药品注册技术国际协调会（ICH）的实施新药临床研究所需非临床安全性试验的时间安排（M3指导原则）和生物技术药物的临床前安全性评价（S6指导原则）中，要求在非临床安全性评价中必须进行安全药理学研究，用于支持药物的人体临床研究。ICH于2000年发布的《人用药品安全药理学研究指南》促进了该学科的快速发展，使安全药理学的设计原则、研究内容、动物模型选择、观察指标确定等有了规范的要求。

2017年12月美国FDA公布的药品安全信息

长效β受体激动剂（LABAs）和吸入激素（ICS）：药物安全通讯——撤除与哮喘相关死亡的黑框警告事件：与哮喘相关的死亡从含ICS和LABAs制剂标签的黑框警告中撤除黑框警告是FDA最醒目的警告。FDA审查了四项大型临床安全性试验,显示相比单独使用吸入糖皮质激素（ICS）,长效β受体激动剂（LABAs）联合吸入糖皮质激素（ICS）治疗哮喘不会导致更严重的哮喘相关副作用。

Safety and Tolerance of Adefovir Dipivoxil in Chinese Healthy Volunteers: A PhaseⅠRandomized and Open-Label Trial

Aim To assess the safety and tolerance of adefovir dipivoxil （ADV） in Chinese healthy volunteers. Methods A total of 52 healthy volunteers, 26 males and 26 females, aged from 19 to 26 were enrolled in the study. Forty-two subjects were randomized into 5, 10, 20, 40, and 60 mg dose groups （6 - 10 subjects in each） matched by sex and weight for single-dose trial. Ten subjects were orally given 10 mg of ADV tablets once daily for 7 d for multiple-dose trial. Physical examination, vital signs examination, electrocardiography, type-B ultrasonography, chest fluoroscopy, routine blood test, routine urine test, coagulation tests, and blood biochemical test were conducted on schedule and statistically evaluated. Results Asthenia frequently occurred in multiple-dose trial, nausea, abdominal pain, and diarrhea occurred in both single- and multiple-dose trials. ALT, bilirubin, CK, and LDH were slightly elevated. All adverse reactions and laboratory abnormalities were mild, and the frequency and severity were not related to doses. Conclusion ADV is safe and well tolerated in Chinese healthy volunteers at dose of 5 - 60 mg oncedaily or 10 nag once daily for 7 d. The recommended oral dosage regimen is 10 mg once daily. Attention should be paid to renal and liver functions, CK, AMY and LDH, if we take ADV for a long period of time.

A Chinese Compound Prescription Ding Xin Recipe Combined with Amiodarone for Treating Premature Ventricular Complexes: A Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial

Objective To evaluate the efficacy and safety of Ding Xin Recipe(DXR)combined with amiodarone in patients with PVCs.Methods A total of360patients with PVCs across7centers in China were randomly assigned in a1:1:1ratio to receive up to8weeks of amiodarone combined with DXR placebo(amiodarone group),DXR combined with amiodarone placebo(DXR group),or DXR combined with amiodarone(DCA group)from July2012to December2013.Randomization was conducted according to a centralized randomization schedule prepared by an independent steering committee.Staff and patients at all sites were masked to treatment allocation.All patients received best-evidence advice.The primary outcome was the efficacy for treating PVCs,with efficacy assessed by the reduction of premature ventricular contractions.Other outcome measures included PVCs-related symptom scores.All data were analyzed by intention to treat.Results The efficacy for treating PVCs in the DCA group(90.7%)significantly increased compared with that in the amiodarone group(72.3%)and the DXR group(73.9%).The frequency,the degree,and the duration per week of heart palpitations,chest tightness,shortness of breath and fatigue improved significantly in the DCA group in comparison with the amiodarone group and the DXR group(P<0.05),while no significant difference was observed in the improvement of insomnia among the three groups(P>0.05).With regard to laboratory parameters for safety,there were no clinically relevant changes in the three groups.Conclusion The present study demonstrates that DXR combined with amiodarone is significantly more effective than DXR or amiodarone alone for treating PVCs.

Allergy Therapeutics的豚草花粉过敏疫苗试验成功

英国Allergy Themlmutics Plc公司3月24宣布，其豚草（ragweed）花粉过敏疫苗已通过关键性临床安全性试验，促使其股价上扬。

Safety and tolerability of isradipine in Phase I trial in Chinese population

Hypertension is one of the well-established risk factor for cardiovascular diseases. Calcium channel blockers（CCBs）, chemicals that could block voltage-gated calcium channels（VGCCs） in cardiac muscle and blood vessels, has been widely used for the treatment of hypertension. Isradipine, a second-generation CCB with high affinity for voltage-operated calcium channels, has not been marked in China. The purpose of this study was to investigate the efficacy, safety and tolerability of isradipine in a phase I clinical trial including 31 healthy Chinese subjects. All subjects received different doses of isradipine at 2.5, 5.0 and 10.0 mg in single-dose study. When the test is completed, subjects treated with 5.0 mg isradipine stayed at the research center for multiple-dose study（5.0 mg isradipine twice daily for 9 d）. Systolic blood pressure（SBP） and diastolic blood pressure（DBP） were measured pre-dose and post-dose（1, 2, 4, 6, 8, 12, 24, 36 and 48 h after isradipine treatment）. Electrocardiography（ECG） and peripheral edema were monitored pre-dose and 4, 8, 24 and 48 h after isradipine treatment. SBP and DBP in single-dose study decreased after isradipine treatment. SBP reached the lowest values 8 h after dosing with a decrease of（7.0±9.7） mmHg（5.4%, P = 0.111） in 2.5 mg group,（7.0±6.9） mmHg（6.0%, P = 0.008） in 5.0 mg group, and（14.0±10.5） mmHg（12.7%, P = 0.005） for 10.0 mg group respectively. Similarly, DBP also reached the lowest values 8 h after dosing with a decrease of（10.0±7.9） mmHg（12.8%, P = 0.004） in 2.5 mg group,（6.0±7.0） mmHg（8.6%, P = 0.003） in 5.0 mg group, and（11.0±4.1） mmHg（15.1%, P = 0.000） in 10.0 mg group respectively. No significant changes of SBP and DBP were observed in multiple-dose study. We detected mild adverse events（AEs）, such as increased transaminase and headache that resolved rapidly and spontaneously without intervention. No serious or potentially life-threatening AE was detected. Our results indicate that isradipin has a good safety and tolerability in Chinese healthy subjects. Long-term study with larger sample size is needed to confirm our conclusion.

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy(STRATEGY):a multicenter,randomized,controlled,non-inferiority clinical trial

Despite the current guideline's recommendation of a timely stepwise intensification therapy,the "clinical inertia",termed as the delayed treatment intensification,commonly exists in the real world,which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy.In this clinical trial performed in 237 centers in China,5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks.The patients who did not reach the glycated hemoglobin A1c(HbA1c) goal were then further randomized into glimepiride,gliclazide,repaglinide,or acarbose group for an additional 24-week triple therapy.A mean HbAlc reduction of 0.85%was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks.Further HbAlc reductions in the 24-week triple therapy stage were 0.65%in glimepiride group,0.70%in gliclazide group,0.61%in repaglinide group,and 0.45%in acarbose group.The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide,but not for acarbose,compared with glimepiride,when added to metformin/sitagliptin dual therapy.The incidences of adverse events(AEs) were 29.2%in the dual therapy stage and30.3%in the triple therapy stage.Metformin/sitagliptin as baseline therapy,with the addition of a third oral antihyperglycemic agent,including glimepiride,gliclazide,repaglinide,or acarbose,was effective,safe and well-tolerated for achieving an HbAlc<7.0%goal in type 2 diabetic patients inadequately controlled with previous therapies.The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Efficacy and safety of chiglitazar,a novel peroxisome proliferatoractivated receptor pan-agonist,in patients with type 2 diabetes:a randomized,double-blind,placebo-controlled,phase 3 trial(CMAP)

Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies.This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone.Eligible patients were randomly assigned to receive chiglitazar 32 mg(n=167),chiglitazar 48 mg(n=166),or placebo(n=202)once daily.The primary endpoint was the change in glycosylated hemoglobin A_(1c)(HbA_(1c))at week 24 with superiority of chiglitazar over placebo.The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA_(1c),and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were-0.87%(95%confidential interval(CI):-1.10 to-0.65;P<0.0001)and-1.05%(95%CI:-1.29 to-0.81;P<0.0001),respectively.Secondary efficacy parameters including glycemic control,insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups.The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups.Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups.The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.