严重脓毒症治疗药物重组人活化蛋白C

重组人活化蛋白C(recombinanthumanactivatedproteinC ,又名drotrecoginalfa,商品名Xigris)是美国FDA在 2 0 0 1年 11月批准的第一个用于治疗成人严重脓毒症的新一类药物 ,具有抗血栓、抗炎和促纤维蛋白溶解作用。该药由礼莱公司研制开发 ,上市剂型为注射用冻干粉针 ,规格为 5和 2 0mg/ml。在抗击“非典”的特殊时期 ,我国紧急进口本品用于危重病人的救治。蛋白C通路受损在脓毒症的发病机理中起着重要作用 ,给予重组人活化蛋白C可以恢复异常的抗凝血机制 ,抑制凝血酶生成和微血管血栓形成 ,同时调节全身的致炎应答 ,保护器官功能。药理…     

国产重组人血小板生成素单次皮下注射的药代动力学研究

目的研究国产重组人血小板生成素单次皮下注射在人体内的药代动力学特征.方法24名健康志愿者随机分为0.5 mg.kg-1,1.0 mg.kg-1和2.0 mg.kg-13个剂量组,单次皮下注射相应剂量的重组人血小板生成素.于给药前和给药后不同时间取血,分离血清,采用ELISA测定血药浓度.结果正常人皮下注射重组人血小板生成素0.5,1.0和2.0 μg.kg-1后,tpeak分别为9.0±1.9 h,10.8±2.4 h和11.8±5.1 h,Cmax分别为0.298±0.081 mg.L-1,0.438±0.076 mg.L-1和0.831±0.079 μg.L-1,AUC与给药剂量基本成正比.人体内重组人血小板生成素的消除较缓慢,3个组的t1/2ke分别为46.3±6.9 h,40.2±9.4h和38.7±11.9 h.结论当以0.5～2.0μg.     

放射免疫法研究乳糖基重组人生长激素和重组人生长激素的药代动力学

目的 :比较研究乳糖基重组人生长激素 (L -rhGH )和重组人生长激素 (rhGH )在小鼠血和肝中的药代动力学。方法 :用注射免疫法测定L -rhGH和rhGH在小鼠血、肝脏中的药物浓度。结果 :静脉注射后 ,两者的药代动力学过程存在显著性差异 ,L -rhGH在肝中的分布量较rhGH增加 ,且T1/2 仅为rhGH的17 9 % ;L -rhGH在血中亦表现为短维持时间、低分布量。结论 :L -rhGH呈现出更符合人体生理的药代动力学特征     

重组人白介素-11衍生物人体药代动力学研究

目的研究皮下注射重组人白介素-11( rhIL-11) 衍生物在人体内的药代动力学过程.方法16例健康志愿者,男女各半,随机分成2组.rhIL-11皮下注射剂量分别为40和25蘥*kg-1.定时采血,利用酶标仪测定不同时间血浆中rhIL-11衍生物浓度.采用WinNonlin软件进行房室模型拟合, 求算药代动力学参数.结果rhIL-11衍生物两种剂量的主要药代动力学参数分别为T max为(1.76±0.80)和(2.49±1.20)h;Cmax为(25.50±4.98)和(18.28± 5.82)ng*mL-1;t1/2为(6.33±0.76)和(5.14±0.92)h;AUC为(277.10 ±40.79)和(189.38±54.27)ng*h*mL-1.rhIL-11衍生物的体内过程符合一室模型.结论rhIL-11衍生物的药代特征可为指导临床制订给药方案及合理用药提供重要信息.     

重组人活化蛋白C治疗儿童脓毒症休克的临床观察

目的观察重组人活化蛋白C（rhAPC）对儿童脓毒症休克的疗效及安全性。方法选择我院儿科及重症监护病房2011年1月-2014年3月间收治的60例脓毒症休克患儿,随机分为对照组（n=30）和rhAPC组（n=30）。对照组患儿给予对症治疗,rhAPC组患儿在此基础上静脉注射rhAPC 24μg/（kg·h）,连续给药4 d。2组患儿于治疗前及治疗后检测血浆纤维蛋白原和D-二聚体水平及炎症因子IL-6、IL-8、TNF-α、动脉血氧饱和度（SaO2）和中心静脉压（CVP）。结果 rhAPC组患儿治疗后血浆纤维蛋白原和D-二聚体水平及炎症因子IL-6、IL-8和TNF-α均显著低于对照组,而SaO2和CVP高于对照组,其差异均有统计学意义（P〈0.05）。rhAPC组1例患儿发生出血性膀胱炎。结论 rhAPC能有效抑制脓毒症休克患儿的炎症反应,降低血液高凝状态。     

ELISA法研究聚乙二醇重组人生长激素注射液单次给药人体药代动力学

目的 建立ELISA方法研究聚乙二醇重组人生长激素(PEG-rhGH)注射液单次给药人体药代动力学.方法 将30名健康受试者随机分成4组(其中两组为自身对照),分别单次皮下注射PEG-rhGH注射液(0.1 mg·kg-1、0.2 mg·kg-1、0.4 mg·kg-1)、注射用重组人生长激素(rhGH)(0.067mg· kg-1).ELISA法测定不同时间点PEG-rhGH、rhGH的血药浓度,并计算药代动力学参数.结果 PEG-rhGH、rhGH血药浓度分别在0.312 5～40.0000 ng·ml-1、0.312 5～10.0000 ng· ml-1范围内线性关系良好,最低检测性均为0.312 5ng· ml-1,批间、批内RSD均＜15％. PEG-rhGH(0.1、0.2、0.4 mg·kg-1)、rhGH(0.067mg· kg-1)的t1/2分别为:(31.70±4.70)h、(32.19±4.58)h、(30.39±5.93)h、(1.95±0.44)h,Tmax为:(22.20±9.82)h、(29.40±10.75)h、(40.80±8.39)h、(3.20±1.10)h,Cmax:(105.24±45.37)ng·ml-1、(379.09±109.61)ng·m1-1、(920.69±293.21)ng·ml-1、(30.17±3.20)ng·m1-1,CL/F:(26.97±13.86) ml· kg-1· h-1、(9.21±4.05) ml· kg-1· h-1、(6.29±2.87) ml· kg-1· h-1、(284.26±43.47)ml· kg-1· h-1,AUC0→∞:(4657.70±2337.30) ng· m1-1·h、(25279.58±9407.63) ng· ml-1·h、(74438.89±29 007.81) ng·ml-1·h、(240.97±39.40) ng·ml-1·h.结论 PEG-rhGH体内过程符合线性动力学特征,与rhGH相比,明显推迟达峰时间、延长半衰期、减慢清除率,具有长效特征.     

重组人活性蛋白C在治疗严重脓毒血症中的疗效评价

全身炎性反应综合征（ＳＩＲＳ）可由多种原因所致，如胰腺炎、烧伤、创伤、感染等［１，２］。脓毒血症通常指由感染引起的ＳＩＲＳ，一般见于细菌感染，但也可见于其它病原微生物，如真菌、病毒及寄生虫感染［２］。脓毒血症病人有半数会发生多器官衰竭即严重脓毒血症，或者发生感染性休克。尽管有机械通气、腹膜透析、营养支持、抗生素等治疗，但仍有许多病人死于这个病理生理过程，而且脓毒血症后遗症的发生率也居高不下。 在过去的几年里，多数学者治疗的目标着眼于减轻或抑制过度的人体反应［２］。由于治疗效果不佳，死亡率没有明显…     

重组人生长激素在健康猕猴体内的比较药代动力学

目的:比较两种国产重组人生长激素在健康猕猴体内的药代动力学,评价两种药物的相似性。方法:采用交叉自身比较设计,8只健康成年猕猴分别单次皮下注射受试品和参比品0.35 IU·kg-1;采用酶联免疫吸附分析法检测血清中药物浓度,统计矩方法计算各主要药代动力学参数;采用3P97软件参考生物等效性标准对参数进行评价。结果:方法的特异性、灵敏度、精密度和准确度均符合药代动力学研究要求。受试品与参比品的血药浓度-时间曲线基本一致,主要药代动力学参数AUC0～12 h分别为(512±102)和(476±71)μg·h·L-1;AUC0～∞分别为(538±115)和(494±77)μg·h·L-1;Cmax分别为(108±18)和(96±23)μg·L-1;t1/2分别为(2.8±0.7)和(2.2±0.7)h;MRT分别为(4.2±0.8)和(4.0±0.8)h;CLs/Fsc分别为(0.047±0.014)和(0.060±0.013)L·h-1·kg-1;Vd/Fsc分别为(0.194±0.04)和(0.24±0.06)L·kg-1。以AUC0～∞计算,受试品与参比品比较,相对生物利用度F为(109±15)%。受试品相对于参比品的生物等效性用AUC0～12 h,AUC0～∞和Cmax的90%可信区间评价分别为89.2%～114.3%8,7.4%～112.7%和98.5%～124.4%,均符合生物等效性判断标准。结论:受试品与参比品药代动力学参数评价结果满足生物等效接受标准;两种重组人生长激素在猕猴体内呈现相同的药代动力学特征。     

重组人酸性成纤维细胞生长因子皮肤用药的药代动力学

目的研究rhaFGF在健康及破损皮肤用药的药代动力学特征。方法在兔健康及破损皮肤上均匀涂抹¹²⁵I-rhaFGF 180 U·cm^-2后,在不同的时间测血浆及组织中的放射性计数,结合纸层析的方法测定组织和血浆中的¹²⁵I-rhaFGF的含量。结果破损皮肤用药后,血中rhaFGF原型物浓度呈快速上升状态,0.5 h达最大值(73.03 pg·mL^-1),其后迅速下降,3 h后接近0。¹²⁵I-rhaFGF给药后96 h,放射性主要浓集于皮肤,其次是肾,大脑最少。结论rhaFGF不能通过健康皮肤进入体内,可通过破损皮肤进入血循环,但吸收量少,原形物半衰期短,无蓄积作用;吸收后的rhaFGF对皮肤有较大亲和力,可分布于远处皮肤,且含量较高。     

重组人肿瘤坏死因子-NC在肿瘤患者体内的药代动力学研究

目的研究重组人肿瘤坏死因子(rhTNF-NC)在肿瘤患者体内的药代动力学.方法入选9例患者,单剂量静脉注射rhTNF-NC 1.0×106IU@m.应用酶联免疫反应(ELISA)检测 rhTNF-NC的血药浓度.结果rhTNF-NC的量-时曲线符合二室模型.主要的药代动力学参数如下Cmax为(2.273±3 549)ng@L1,AUC(0-t)为(71.43±82 41)ng@min@L1,t1/2 α为(1.62±1.65)min,t1/2 β为(60.94±50.60)min.Cl为(11 22±12 20)Lmin1.结论本品药代动力学参数的个体差导较大,不同患者应根据药代动力学特性调整给药剂量和间隔时间.     

Protective mechanisms of activated protein C in severe inflammatory disorders

The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure–function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

新氟喹诺酮类抗菌药普利沙星

普利沙星是新口服的氟喹诺酮类抗菌药.本品为前体药,其活性代谢产物通过阻碍DNA拓扑异构酶使细菌DNA无法形成超螺旋,导致细菌细胞无法分裂繁殖.临床上用于治疗各种敏感致病菌引起的感染.本品不良反应较少,尤其是光敏性在同类药中是最小的.综述普利沙星的药理作用、药动学及临床评价.     

新型抗真菌药物卡泊芬净

卡泊芬净为美国及欧洲批准的棘球白素类中第一个用于临床的药物,是真菌细胞壁1,3-β-D葡聚糖合成酶抑制剂,用于两性霉素B治疗无效或不能耐受两性霉素B的侵袭性曲霉病成年患者.综述了卡泊芬净(caspofungin)的抗真菌作用机制、药动学及临床评价.     

Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis.

Sepsis remains a major cause of death in hospitalized patients. Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures. Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis. Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use. Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit. It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present. Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.     

新型抗溃疡及促进伤口愈合药--重组人角质细胞生长因子-2

重组人角质细胞生长因子-2(rhKGF-2)能与人体上皮细胞内的成纤维细胞生长因子受体(FGFR)结合而发挥生理作用。研究显示，rhKGF-2可特异性地刺激上皮细胞增殖，促进表皮细胞生长和肉芽组织形成，可用于治疗因上皮细胞损伤引起的溃疡，加速伤口的愈合，耐受性好，值得临床推广。     

Safety of drotrecogin alfa (activated) in the treatment of patients with severe sepsis

While severe sepsis continues to plague hospitals worldwide, new treatment modalities, including activated recombinant protein C (drotrecogin alfa, Xigris?, Lilly), have become a standard treatment alternative in many institutional algorithms. Drotrecogin alfa was shown to have a beneficial effect on mortality versus placebo in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial (p = 0.005), but its use is not completely without risk. An increased risk of bleeding, including severe bleeding episodes, exists ranging 3.5 – 5.2% in the drotrecogin alfa treatment group versus 2.0 – 5.0% in the placebo group. Patients at risk include those on concomitant heparin therapy (> 15,000 units/day), those with platelet counts ≤ 30,000/mm³, and those undergoing an invasive procedure during the scheduled infusion period. After almost three years on the US market, the reported incidence of severe bleeding episodes has risen only slightly from the pre-marketing era, at that time notable for restrictive treatment protocols, devoid of at-risk patients. Drotrecogin alfa, while a promising agent for severe sepsis, requires prudent patient evaluation for bleeding risks.     

抗感染新药重组人溶菌酶的临床前评价

重组人溶菌酶是经生物技术改构后产生的一类对G+和G-菌都有抗菌效应的一类新药。临床前数据表明它对1 040株致病菌具有抗菌活性,最低抑菌浓度(MIC)范围为0．125～>4000μg·mL-1;此外,它还有抑制冠状病毒、抗炎和镇痛作用。现综述其药效学、毒理学和药动学的研究情况。新型重组人溶菌酶在体内外均安全和有效,有望开发成为新型抗感染药物。     

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

Aims

To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients.

Methods

Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme.

Results

A one-compartment model with Michaelis–Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839–0.968] and 0.176 U ml⁻¹ (95% CI: 0.154–0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68–3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml⁻¹ h⁻¹ (95% CI: 1.41–1.88) and 1.60 U ml⁻¹ (95% CI: 1.14–2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml⁻¹) for at least 94% of all patients.

Conclusions

The population PK model for C1INH supports a dosing scheme on a 50 U kg⁻¹ basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration.     

塞来昔布的药理作用、药代动力学及临床评价

目的:评价特异性环氧酶抑制剂——塞来昔布的药理作用、药代动力学及临床疗效。方法:评述国内、外近期有关塞来昔布的文献。结果:推荐剂量的塞来昔布治疗骨关节炎和风湿性关节炎疗效与传统的非甾体抗炎药物(NSAIDs)相似,疗效确切,但较少引起胃肠道溃疡,且不延长出血时间,耐受性良好。结论:塞来昔布与目前国内、外广泛应用的NSAIDs相比,疗效确切,降低了胃肠道损伤的发生率,与治疗高血压、糖尿病等药物联用,没有明显的药物相互作用。