右美托咪定对腹腔镜结直肠癌根治术患者术后转归的影响

目的 探讨盐酸右美托咪定注射液对腹腔镜结直肠癌根治术患者术后转归的影响。方法 选取2015年6月-2017年6月眉山市人民医院行腹腔镜结直肠癌根治术患者160例作为研究对象，按随机数字表法将患者分为对照组和观察组，每组各80例。两组患者均采用全身麻醉，观察组在此基础上于麻醉诱导前10 min采用微量注射泵静脉输注盐酸右美托咪定注射液0.5 μg/（kg·h），10 min内泵完，再以0.5 μg/（kg·h）维持至手术结束。对照组按照相同的输注方式给予相同剂量的生理盐水。比较两组术后复苏指标、不同时间点血流动力学指标、镇痛及镇静效果分数。结果 术后两组患者睁眼时间、呼吸恢复时间、拔管时间差异无统计学意义；观察组躁动评分显著低于对照组（P<0.05）。治疗后，T₀-T₃时刻两组患者平均动脉压（MAP）、心率（HR）水平先降低再升高最终又降低，且T₁、T₂时刻观察组明显低于对照组（P<0.05）。术后观察组患者Ramsay镇静评分、静息及咳嗽VAS评分均明显降低于对照组（P<0.05）。结论 盐酸右美托咪定注射液可显著减少腹腔镜结直肠癌根治术的应激反应，改善血流动力学，镇静镇痛效果显著，减少复苏期躁动的发生，且未增加不良反应，有利于患者术后转归。     

右美托咪定辅助臂丛麻醉的镇静效果及安全性

目的 观察右美托咪定辅助臂丛麻醉的镇静效果和安全性。方法 选取2014年2月至2015年10月上海交通大学医学院附属第九人民医院行臂丛麻醉手术的120例患者为研究对象,采用随机双盲法分为A、B、C组,每组40例。A组术前予静脉注射咪达唑仑0.04 mg/kg;B组在阻滞前10 min静脉泵入0.5μg/kg右美托咪定,10 min泵完;C组在阻滞前10 min静脉泵入0.5μg/kg右美托咪定,10 min泵完,同时术前静脉注射咪达唑仑0.04 mg/kg。记录3组患者给药前（T₀）、给药10 min后（T₁）、20 min后（T₂）、30 min后（T₃）、60 min后（T₄）以及手术结束时（T₅）的心率（HR）、平均动脉压（MAP）、血氧饱和度（SpO₂）及警觉/镇静（OAA/S）评分。结果 与B、C两组比较,A组患者的感觉完全阻滞时间、运动完全阻滞时间显著缩短,差异有统计学意义（F=5.133、5.849,P=0.007、0.004）。与给药前（T₀）HR、MAP和OAA/S评分相比,A组仅T₁时显著降低,C组T₁～T₄均显著降低（P均<0.05）;B组各个时刻均保持平稳（P均>0.05）;组间上述各指标比较,A组患者T₁时刻低于B组,C组患者T₁～T₄时刻均低于B组,且T₂～T₄时刻低于A组（P均<0.05）;3组的SpO₂比较,差异无统计学意义（P>0.05）;C组患者术中因心率减慢而给予阿托品治疗的例数多于A、B两组,差异有统计学意义（χ²=7.50,P=0.02）。结论 右美托咪定辅助臂丛神经阻滞具有较高的镇静效果和安全性能。     

右美托咪定复合舒芬太尼对心脏手术快通道麻醉术后镇痛效果及血清C反应蛋白的影响

目的 评价右美托咪定复合舒芬太尼对婴幼儿心脏手术快通道麻醉术后镇痛效果及血清C反应蛋白（CRP）的影响。方法 选择2017年1月至2018年1月在河南科技大学第一附属医院行先天性心脏病房缺和室缺修补术的患儿60例,采用随机数字表法分为右美托咪定复合舒芬太尼镇痛组（Ⅰ组）和舒芬太尼镇痛组（Ⅱ组）,每组30例。Ⅰ组患儿于缝皮前20 min开始静脉泵注右美托咪定1 μg/（kg·h）,至手术结束,Ⅱ组患儿给予等容量生理盐水。术后镇痛泵药液配方：Ⅰ组为右美托咪定37.5 μg/kg+舒芬太尼2.5 μg/kg+托烷司琼0.1 mg/kg,Ⅱ组为舒芬太尼2.5 μg/kg+托烷司琼0.1 mg/kg,均加生理盐水至100 mL,泵速2 mL/h。记录术毕（T₁）、苏醒（T₂）、拔管（T₃）、术后第6小时（T₅）、术后第24小时（T₆）、术后第48小时（T₇）的心率（HR）、平均动脉压（MAP）;记录术后4 h （T₄）、T₅、T₆、T₇疼痛行为量表（FLACC）评分和Ramsay镇静评分;记录术前（T₀）、T₅、T₆、T₇的血清CRP水平;记录术后48 h内不良反应的发生情况。结果 Ⅱ组患儿在T₂、T₃、T₅、T₆时点的MAP和HR均高于Ⅰ组（MAP：F_组间=10.105,P=0.034;HR：F_组间=10.830,P=0.030）;Ⅰ组患儿在T₄、T₅、T₆时点FLACC评分低于Ⅱ组（F_组间=23.091,P=0.001）,Ramsay镇静评分高于Ⅱ组（F_组间=21.534,P=0.002）;Ⅱ组患儿T₆、T₇时点血清CRP水平高于I组（F_组间=14.981,P=0.018）。与Ⅱ组比较,Ⅰ组患儿术后48 h内恶心、呕吐发生率降低,差异有统计学意义（P<0.05）。结论 右美托咪定复合舒芬太尼用于婴幼儿心脏手术快通道麻醉,术后镇痛安全有效,不良反应少,术后应激反应减轻。     

右美托咪定对快速心房起搏后兔心房电生理学特性及Cx43 Cx40表达的影响

目的 探讨右美托咪定对快速心房起搏后兔心房电生理学特性及Cx43、Cx40表达的影响。方法 选择成年雄兔24只,随机分为对照组（C组）、快速心房起搏组（RAP组）与快速心房起搏+右美托咪定灌流组（RAP+DEX组）,每组8只。制备Langendorff离体心脏灌注模型,通过快速心房起搏构建房颤模型。分别检测3组心房90%单相动作电位复极时程（MAPD₉₀）、心房有效不应期（ERP）、ERP与MAPD₉₀比值（ERP/MAPD₉₀）、房颤诱发率及持续时间,取心房组织,采用Western-bolt法和免疫荧光法检测Cx43、Cx40的蛋白含量和分布。结果 T₁~T₃时,3组MAPD₉₀比较,差异有统计学意义（P<0.05）。RAP组MAPD₉₀随时间的推移有逐渐下降趋势（P<0.05）,不同的处理方式和时间对MAPD₉₀有交互作用（P<0.05）。T₃时,RAP组ERP、ERP/MAPD₉₀、Cx43和Cx40蛋白含量均低于C组和RAP+DEX组,房颤诱发率高于C组和RAP+DEX组,差异有统计学意义（P<0.05）。3组房颤持续时间比较,差异无统计学意义（P>0.05）。电镜下,RAP组Cx43和Cx40分布不规律且侧面分布增多,而C组和RAP+DEX组Cx43和Cx40分布较规律且主要集中在两端。结论 右美托咪定可抑制房颤时的心房电重构,降低房颤的易感性,其机制可能与其抑制Cx43、Cx40的表达下调和再分布有关。     

小剂量右美托咪定对剖宫产术中寒战的预防效果及安全性

目的 探讨小剂量右美托咪定预防剖宫产术中寒战的有效性和安全性。方法 选择2015年12月至2016年8月合肥市第三人民医院60例ASA I-II级剖宫产患者,依据随机数字表随机分成Dex0.1组、Dex0.3组、对照组,各20例,3组患者均行连续硬膜外麻醉,硬膜外麻醉阻滞完善后,Dex0.1组和Dex0.3组分别从静脉缓慢输注负荷剂量的右美托咪定0.1 μg/kg和0.3 μg/kg,输注时间10 min,对照组输注生理盐水。观察各组产妇麻醉前（T₀）、给药后5分钟（T₁）、给药后10分钟（T₂）、给药后30分钟（T₃）的平均动脉压、心率、自主呼吸、氧饱和度、及寒战发生情况和新生儿1、5、10 min的Apgar评分。结果 3组患者自主呼吸和氧饱和度比较,差异无统计学意义（P>0.05）;3组患者平均动脉压和心率在T₀、T₃时组间比较,差异无统计学意义（P>0.05）,平均动脉压（MAP）和心率（HR）在T₁、T₂时组间比较如下：Dex0.1组与生理盐水组比较,差异无统计学意义（P>0.05）,Dex0.3组与Dex0.1组、生理盐水组比较,平均动脉压和心率下降,其中T₁时Dex0.3组MAP（82±9）mmHg,HR（83±10）次/分,Dex0.1组MAP（86±8）mmHg,HR（86±9）次/分,生理盐水组MAP（87±6）mmHg,HR（89±8）次/分;T₂时Dex0.3组MAP（81±7）mmHg,HR（82±10）次/分,Dex0.1组MAP（86±8）mmHg,HR（88±10）次/分,生理盐水组MAP（85±7）mmHg,HR（90±10）次/分,差异有统计学意义（P<0.05）;Dex0.3组与生理盐水组和Dex0.1组比较,寒战发生率及寒战时长显著降低：Dex0.3组、Dex0.1组、生理盐水组寒战发生率分别为15%、45%和50%,寒战时长Dex0.3组、Dex0.1组、生理盐水组分别为（7.8±3.0）min、（10.0±2.9）min和（10.2±3.1）min,差异具有统计学意义（P<0.05）;3组Apgar评分比较差异无统计学意义（P>0.05）。结论 小剂量右美托咪定可以安全且有效预防剖宫产术中寒战的发生,0.3 μg/kg为一适宜剂量。     

盐酸右美托咪定对ICU患者气管插管应激反应的影响

目的 探讨盐酸右美托咪定对ICU患者气管插管应激性反应的影响。方法 选取解放军昆明总医院2015年1月-2016年1月ICU病房收治的危重症患者76例作为研究对象，按随机数字表法分为对照组和观察组，每组38例，两组均于气管插管前进行桡动脉穿刺，并建立静脉通道，观察组静脉泵注盐酸右美托咪定0.5 μg/kg，持续10 min，对照组静脉泵注等量生理盐水，随后两组均静脉滴注适量顺-阿曲库铵和丙泊酚。观察两组麻醉用药剂量；检测两组插管前（T₁）、插管后（T₂）、插管后3 min（T₃）及插管后5 min（T₄）时刻患者动脉压（MAP）、心率（HR）、血浆皮质酮水平的变化。结果 两组丙泊酚、顺-阿曲库铵麻醉用药剂量比较差异不显著；观察组T₃、T₄时刻MAP、HR、血浆皮质酮水平均显著低于对照组（P<0.05）。结论 在ICU患者气管插管中应用盐酸右美托咪定可维持血浆皮质醇水平、血流动力学稳定。     

右美托咪定与丙泊酚用于子痫前期产妇剖宫产手术术中镇静的比较

目的 比较右美托咪定与丙泊酚用于子痫前期患者剖宫产手术术中镇静的有效性和安全性。方法 腰硬联合麻醉下行择期剖宫产手术的子痫前期患者90例,随机均分为右美托咪定组、丙泊酚组及对照组,各组按预定方法分别给予药物。记录患者入室时(T₀)、CSEA给药前(T₁)、切皮时(T₂)、清理腹腔时(T₃)及手术结束时(T₄)的平均动脉压(mean arterial pressure,MAP)、心率(heart rate,HR)、脉搏血氧饱和度(oxygen saturation,SpO₂)、警觉-镇静(observer’s assessment of alertness/sedation,OAA/S)评分,记录新生儿Apgar评分及各组不良反应发生情况。结果 MAP、HR及OAA/S T_1-4右美托咪定组及丙泊酚组均低于对照组,MAP T_1-4,HR T₁、T₃及T₄及OAA/S T₄右美托咪定组低于丙泊酚组(P<0.05)。新生儿Apgar 评分,3组组间比较差异无统计学意义。恶心呕吐、牵拉痛及寒战发生率右美托咪定组及丙泊酚组均低于对照组(P<0.05);低血压及心动过缓发生率右美托咪定组及丙泊酚组略高于对照组,呼吸抑制及躁动发生率右美托咪定组低于丙泊酚组,但差异均无统计学意义。结论 右美托咪定和丙泊酚均可安全有效地应用于子痫前期患者剖宫产术中镇静,比较而言,右美托咪定镇静后可唤醒,血流动力学更平稳,呼吸抑制等不良反应更少。     

右美托咪定对超声引导下臂丛神经阻滞的辅助镇静效果

目的 观察前臂手术中右美托咪定对超声引导下臂丛神经阻滞辅助镇静的影响。方法 选择2015年3～6月昆山市第二人民医院择期行前臂手术患者60例,随机分成试验组（D组）及对照组（N组）,每组30例。D组患者麻醉前15 min予以右美托咪定0.7 μg／kg微量泵静注,0.4 μg/（kg·h）维持,N组患者入手术室后静卧15 min,两组患者均在超声引导下予0.375%左旋布比卡因+1%利多卡因混合液20 mL行锁骨上臂丛神经阻滞。观察并记录两组患者入手术室时（T₀）、穿刺前（T₁）、穿刺时（T₂）、穿刺后（T₃）、切皮时（T₄）及手术开始后20分钟时（T₅）的平均动脉压（MAP）、心率（HR）、脉搏血氧饱和度（SpO₂）及镇静评分（Ramsay评分）,记录麻醉操作时视觉模拟评分法（VAS）评分,手术开始切皮时VAS评分,观察并记录不良反应,术后记录麻醉满意度评分。结果 在T₁、T₂、T₃、T₄、T₅时间点,D组患者的MAP低于N组（P<0.05）,HR慢于N组（P<0.05）,Ramsay评分高于N组（P<0.05）;D组患者麻醉操作及手术开始切皮时VAS评分低于N组（P<0.05）,麻醉满意度高于N组（P<0.05）。结论 在前臂骨科麻醉及手术中,应用右美托咪定可明显降低患者在麻醉穿刺操作时的不适感,切皮时麻醉效果更加完善,减轻患者的焦虑情绪,利于维持麻醉及手术中血流动力学的稳定,同时患者对麻醉的满意度更高。     

右美托咪定对妇科腹腔镜手术患者围术期炎症因子及应激反应的影响

目的 探讨右美托咪定对妇科腹腔镜手术患者围术期炎症因子及应激反应的影响。方法 选择180例妇科腹腔镜手术患者,随机分为两组,每组90例。对照组患者静脉输注0.5 μg/kg舒芬太尼、1.8 mg/kg丙泊酚、0.6 mg/kg罗库溴铵进行麻醉诱导,术中吸入七氟醚行麻醉维持,并间断静脉推注顺苯磺阿曲库铵维持肌松。观察组麻醉诱导前静脉泵注0.5 μg/kg右美托咪定负荷剂量,之后以0.5 μg/（kg·h）输注至术毕前10 min,其余麻醉方法与对照组相同。观察麻醉诱导前10 min（T₀）、气管插管后即刻（T₁）、建立气腹时（T₂）、气腹建立30 min后（T₃）、手术结束时（T₄）5个时间点的血流动动力学变化情况,使用酶联免疫吸附法检测炎症指标,以及血管紧张素Ⅱ、皮质醇及醛固酮等应激反应指标。结果 与T₀时间点比较,观察组T₁～T₃ 心率（HR）均明显下降（P<0.05）,对照组T₁～T₃ HR均明显上升（P<0.05）,对照组发生心动过速1例,观察组未发生;与T₀时间点比较,观察组T₁～T₄有创平均动脉压（MAP）未发生明显变化,对照组T₁～T₄ MAP明显上升,组间比较差异明显（P<0.05）;与T₀时间点比较,两组的IL-6、IL-10及TFN-α均明显上升,而对照组上升程度明显高于观察组（P<0.05）;与T₀时间点比较,两组的血管紧张素Ⅱ、皮质醇及醛固酮均明显上升,且对照组上升程度明显高于观察组（P<0.05）。结论 麻醉诱导前静脉泵注0.5 μg/kg右美托咪定负荷剂量,之后以0.5 μg/（kg·h）输注至术毕前10 min,可以维持妇科腹腔镜手术围术期的血流动力学稳定,抑制围术期炎症反应及应激反应。     

盐酸右美托咪定联合酒石酸布托啡诺对机械通气患者的镇痛镇静效果

目的 评价盐酸右美托咪定联合酒石酸布托啡诺对重症监护室行机械通气患者的镇痛镇静效果。方法 收集2013年1月至2016年12月无锡市第二人民医院急诊重症监护室行机械通气治疗的患者150例,采用随机数字表法将患者分为咪达唑仑组、右美托咪定组和复合组,各50例。其中,咪达唑仑组患者静脉泵入咪达唑仑,右美托咪定组患者静脉泵入右美托咪定,复合组患者采用右美托咪定联合酒石酸布托啡诺的镇痛方案;采用Richmond镇静躁动评分（RASS）评估镇静效果,重症监护室疼痛观察工具法（CPOT）评估镇痛效果,同时比较3组患者治疗过程中的不良反应。结果 咪达唑仑组、右美托咪定组和复合组患者的镇痛起效时间分别为（32.9±8.6）、（31.2±7.3）、（23.6±5.5） s,复合组患者镇痛起效时间低于其余两组（P<0.05）;咪达唑仑组、右美托咪定组和复合组患者的唤醒时间分别为（6.8±2.2）、（3.7±1.4）及（3.5±0.9） min,咪达唑仑组患者唤醒时间长于其余两组（P<0.05）。复合组平均RASS评分小于右美托咪定组,大于咪达唑仑组;复合组CPOT评分小于其他两组,差异均有统计学意义（P<0.05）。咪达唑仑组、右美托咪定组和复合组患者治疗过程中的不良反应率为24%、8%和6%,复合组和右美托咪定组患者不良反应发生率低于咪达唑仑组（P<0.05）。结论 盐酸右美托咪定联合酒石酸布托啡诺对机械通气患者有较好的镇痛镇静效果,可降低患者不良反应发生率。     

肝包虫囊肿的手术治疗

目的 总结肝包虫囊肿手术治疗体会。方法 回顾性总结9例肝包虫囊肿患的13个囊肿手术方法的选择,行包虫囊肿穿刺、内囊除术4例7个,子囊取出、内囊剥除术4例5个,肝左叶部分切除术1例。结果 术后橡皮管外引流少量胆汁漏5例,较大量胆汁漏（>200ml.d^-1)1例,全部痊愈出院。结论 包虫囊肿穿刺、内囊除术为二种安全可靠的手术方法。     

Precision of Estimates of an ADI (or TDI or PTWI)

Factors influencing the precision of an acceptable daily intake (ADI) are discussed in this paper. As the same principles apply to tolerable daily intake (TDI) or provisional tolerable weekly intake (PTWI), although not specifically mentioned, this paper also refers to TDI and PTWI. The allocation of an ADI is in principle based on the most critical (many times the lowest) no-observed (adverse)-effect level [NO(A)EL] established in toxicological studies in experimental animals or in humans by applying a uncertainty factor for extrapolation from animals or humans to the general human population (and for the extrapolation from high to low intake levels). As the ADI predicts a virtual safe intake level for a life span exposure, to establish a NO(A)EL in general the toxicological database should include long-term studies, otherwise only a provisional ADI will be allocated for which a higher uncertainty factor is applied. The validity of an ADI greatly depends on the precision of the toxicological studies considered for the safety of a food additive or contaminant. The precision of the ADI is also inversely related to the uncertainty factors applied, although these uncertainty factors are not totally independent of the completeness and precision of the toxicological data from which a NO(A)EL is derived. This paper focuses on the precision of the toxicological data and the established NO(A)EL. Human data on the toxicity of a chemical which are preferred for the safety evaluation or hazard assessment are frequently not available or incomplete with respect to a quantitative dose–response assessment. Epidemiological studies will have inherent difficulties for hazard assessment such as possible confounders, restricted number of toxicological end points which can be studied, and limited quantitative data on oral exposure levels. Case report studies include the same limitations but in addition the exposure data are usually very imprecise due to reconstruction of the possible dose level(s). Case reports of intoxication are mainly restricted to acute and at best subacute effects. Controlled human exposure studies (human volunteer studies) are restricted in their experimental design such as the level of the dose and the toxicological end points due to medical ethical reasons. Therefore, quite rarely a safety evaluation of a food chemical will be solely based on human data. In the practice of hazard assessment of chemicals in foods the experimental animal studies will be totally or partly the basis for establishing an ADI. In these toxicological studies in animals there are many experimental variables which can affect the precision of an ADI, such as (1) duration of the experiment, dose ranges, identity, and purity of the substance; (2) the parameters and toxicological end points studied; (3) the species and strain used; (4) the gut microflora of the test animals; (5) dietary composition; (6) statistics performed; and (7) knowledge about the kinetic behavior and metabolism (e.g., elimination half-life and bioavailability of the chemical and its main metabolites) of the chemical considered. How these factors can influence the precision of a NO(A)EL, respectively the ADI, is illustrated by several examples. In relation to the question of incidental excursions of an ADI, it can be concluded that due to the variation in precision of experiments slight incidental excursions would not lead to an increased risk. However, to answer in general the question of how often and/or how much the total intake of a chemical in food may exceed the ADI is not possible. This should be considered case by case. To answer such a question, the precision for those studies representative for incidental excursions should be considered. Other factors which should be considered are (1) type of effect on which the ADI was based, (2) mechanism of toxicity, (3) toxicokinetics and metabolism, and (4) difference in NO(A)ELs from short-term toxicity studies with the NO(A)EL on which the ADI was based. Nevertheless, slight excursions of the intake above the ADI for a substance should always trigger additional consideration and if possible additional studies with high precision.     

Non-reversal of scopolamine- or age-related EEG changes by ondansetron,methysergide or alaproclate

The present studies investigates the effects of a 5HT3-antagonist (ondansetron: 0.01, 0.1, 1, 10 µg), a 5HT2-antagonist (methysergide: 2, 10, 20 mg/kg) and a serotonin uptake inhibitor (alaproclate: 2, 10, 20 mg/kg) on the neocortical electrical activity of young scopolamine-treated and aged rats. The scopolamine (0.2 and 0.8 mg/kg)-induced increase in EEG spectral components was not reversed by ondansetron, methysergide or alaproclate. The scopolamine (0.8 mg/kg)-induced EEG amplitude increase reversing potency of a subthreshold dose of the muscarinic agonist pilocarpine (2 mg/kg) was not potentiated by ondansetron, methysergide or alaproclate. A higher dose of pilocarpine (10 mg/kg) reversed scopolamine-induced EEG slowing. Age-related increase in high voltage spindles (HVS) was not alleviated by either ondansetron, methysergide or alaproclate. The HVS activity stabilizing effect of pilocarpine (2 mg/kg) was not enhanced by ondansetron, methysergide or alaproclate. These results suggest that the serotonergic agents investigated could not alleviate cortical cholinergic activation deficit and once again implicate the role of cholinergic system in both the neocortical electrical activation and age-related cortical electrical arousal deficit.     

Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation

It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, H_ex, between an API–coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest H_exs with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates.     

Rationally engineered proteins or antibodies with absent or reduced immunogenicity

One challenge associated with the clinical use of protein therapeutics destined for chronic administration is the potential for the development of unwanted anti-drug immune reactions. The molecular basis for this reactivity is the binding of peptide fragments (epitopes) derived from the breakdown of the protein drug to the HLA receptors expressed by the patient's immune cells. If these epitopes are recognized as "foreign" by the immune system, specific helper T lymphocytes (HTL), are activated, which initiate and direct the formation of antibodies against the protein drug. These antibodies can bind and neutralize the protein drug, resulting in either decreased efficacy or total ineffectiveness of the drug. Moreover, various safety concerns, such as allergic reactions and other adverse events, are also frequently associated with the formation of anti-drug antibodies. Herein, we describe the development of "ImmunoStealth", an integrated bioinformatics, biochemical and cellular immunology approach that specifically addresses the issue of unwanted immune responses against protein therapeutics. Unwanted HTL epitopes are identified using in silico sequence analysis methods and high throughput in vitro biochemical evaluations and thereafter confirmed using cellular immunogenicity assays. The "offending" epitopes within the drug are then rationally modified to alter their HLA binding capacity, and thus render them non-recognizable by the immune system. This technology will ultimately facilitate the design of safer, more potent and more economical drugs.     

Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine

BackgroundCombinations of hydroxychloroquine (HCQ) and azithromycin have been promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of these events.MethodsData from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) (>13 million total reports) were used. Queries extracted reports based on exposures of HCQ/chloroquine (CQ) alone, azithromycin alone, HCQ/CQ + azithromycin, amoxicillin alone, HCQ/CQ + amoxicillin alone. Amoxicillin served as a control. Events of interest included death and TdP/QT prolongation as well as accidents/injuries and depression as control events. Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal.ResultsLower95CIs for HCQ/CQ alone showed no potential safety signals for TdP/QT prolongation, death, or any of the control events included. The PRRs and 95% CIs for TdP/QT prolongation was 1.43 (1.29–2.59) with HCQ/CQ use alone and 4.10 (3.80–4.42) for azithromycin alone. For the combined HCQ/CQ + azithromycin group, the PRR and 95% CI was 3.77 (1.80–7.87). For the control of amoxicillin, there were no safety signals when used alone or in combination with HCQ/CQ.ConclusionsHCQ/CQ use was not associated with a safety signal in this analysis of FAERS data. However, azithromycin used alone was associated with TdP/QT prolongation events and should be used with caution.