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.     

重组人白介素-11在人体内的药动学

目的研究皮下注射重组人白介素-11(rhIL-11)在人体内的药动学过程。方法24名健康志愿者,男女各半,随机分成2组。rhIL-11皮下注射剂量分别为5和7.5μg·kg~(-1),定时采血,用ELISA法测定不同时间血浆中rhIL-11的浓度。浓度-时间数据经3P97软件进行房室模型拟合,计算药动学参数。结果rhIL-112种剂量(5、7.5μg·kg~(-1))的主要药动学参数分别为:t_(max)(2.25±0.53)、(3.32±0.85)h;c_(max)(6.42±2.57)、(9.75±3.75)μg·L~(-1);T_(1/2)(4.03±1.24)、(4.42±1.32)h;AUC(52.68±14.06)、(102.73±36.26)μg·h·L~(-1)。体内过程符合一室模型。结论rhIL-11的药动学特征和参数可作为临床合理用药和制定给药方案的依据。     

注射用重组人淋巴毒素α衍生物在中国晚期肿瘤患者体内的药代动力学研究

目的评价注射用重组人淋巴毒素α衍生物(rhL Tα)在中国晚期肿瘤患者中多次给药的药代动力学特征。方法 12例晚期食管鳞癌患者和12例晚期胃癌患者分别接受10μg·m^-2或20μg·m^-2rhL Tα连续5 d静脉滴注给药,每个剂量组各12例受试者。用酶联免疫吸附法分别测定第1,5天血浆中LTα的浓度,用Winonlin 5.2软件计算主要药代动力学参数。结果第1,5天主要药代动力学参数如下,10μg·m^-2:AUC_0-t分别为(9473.40±6976.95)和(9390.14±6494.89)pg·mL^-1·min,AUC_0-inf分别为(10324.26±7611.415)和(10163.09±6795.82)pg·mL^-1·min,C_max分别为(156.92±106.57)和(174.44±100.62)pg·mL^-1,t_max分别为(53.42±14.87)和(54.17±17.43)min,t_1/2分别为(17.78±5.91)和(20.43±5.35)min,CL分别为(128.44±128.63)和(120.68±106.06)L·h^-1·m^-2,V_d分别为(126.63±115.60)和(129.98±127.04)L·m^-2;20μg·m^-2:AUC_0-t分别为(26458.97±16064.90)和(25314.11±9587.38)pg·mL^-1·min,AUC_0-inf分别为(27531.84±16562.03)和(27297.33±10295.65)pg·mL^-1·min,C_max分别为(467.73±288.74)和(473.14±200.79)pg·mL^-1,t_max分别为(60.91±8.31)和(60.50±3.69)min,t_1/2分别为(30.12±6.79)和(28.20±6.53)min,CL分别为(69.69±56.21)和(55.94±27.51)L·h^-1·m^-2,V_d分别为(88.25±86.02)和(73.23±36.97)L·m^-2。结论 rhL Tα多次给药后LTα暴露有增加的趋势,但多次给药后平均药物谷浓度C_min并不随给药次数增加而升高。rhLTα的药代动力学行为显示出肿瘤患者的异质性以及个体的差异性。     

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.     

重组人粒细胞-巨噬细胞集落刺激因子和白细胞介素3融合蛋白在大鼠体内的药代动力学研究

研究重组人粒细胞-巨噬细胞集落刺激因子和白细胞介素3融合蛋白(GM-CSF/IL-3,MX)在大鼠体内的药代动力学。方法:实验采用同位素示踪技术结合HPLC分析,建立了MX在大鼠血浆中的测定方法,并测定了MX皮下注射3个剂量水平和静脉注射中剂量水平在大鼠体内的药动学参数。结果:高中低剂量T1/2分别为(1 5.4±2.0),(1 6.1±1.8)h,(1 3.2±2.2)h;AUC分别为(5 8 8±1 2 0),(2 8 6±4 7),(1 4 2±2 0)μg/(L.h),Cmax分别为(3 1.2±8.3),(1 4.8±1.2),(8.3±1.4)μg/L。结论:MX皮下注射给药后,Cmax和AUC与剂量成比例,MX在大鼠体内的代谢和消除是线性的。7 0μg/kg组生物利用度为3 5.6%。     

白细胞介素-6在小鼠体内药代动力学研究

本文应用生物活性测定法在小鼠体内对白细胞介素-6静脉给药、腹腔给药进行药代动力学研究.结果表明:静脉给药后,白细胞介素-6在小鼠体内分布较快,T1/2α=1.5min,消除也较快,T1/2β=0.38h,体内停留时间较短,不适于临床治疗;腹腔给药后缓慢吸收,Tp=0.73h,Cp=5.9×10~4u/ml,分布及消除较静脉给药慢,T1/2α=0.67h;T1/2β=2.9h,给药后6h内体内仍保留一定量的药物,适于临床治疗.     

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。     

重组人肿瘤坏死单抗白细胞介素2融合蛋白在大鼠体内的药代动力学实验研究

目的研究125I标记的重组人肿瘤坏死单抗白细胞介素2融合蛋白(rhTNTIL2)单次静脉注射后在大鼠体内的药代动力学过程。方法用125I标记rhTNTIL2,γ放射免疫计数器检测三氯醋酸(TCA)沉淀前后血浆、组织、尿和粪的放射性计数,用DSA1.0软件拟合药物动力学模型,并计算相应参数。结果125IrhTNTIL2单次静脉注射后在大鼠体内的动力学过程符合三室模型,T12α为1.77～3.03h,T12β为24.58～28.88h,T1/2γ为82.17～114.09h。125IrhTNTIL2在大鼠肝、脾、肺、肾、卵巢等组织器官中有较高的积聚,而脑中放射性活度较小。125IrhTNTIL2主要经肾由尿排泄,给药后24h,67.1%的药物由尿排出。125IrhTNTIL2从粪中排泄的量甚微。结论125IrhTNTIL2在大鼠体内药代动力学过程的研究为其进一步的开发具有指导价值。     

Pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male subjects

Aims To study the pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male volunteers following subcutaneous (s.c.) and intravenous (i.v.) administration.
Methods RhIL-11 was infused intravenously at 10–50  μg  kg⁻¹ for 1 or 3  h, or administered subcutaneously at 3–50  μg  kg⁻¹ to volunteers. RhIL-11 was also administered at 3  μg  kg⁻¹ s.c. once daily for 7 days. Plasma and urinary concentrations were measured by enzyme-linked immunosorbent assay (ELISA).
Results RhIL-11 showed linear pharmacokinetics after both intravenous infusion and s.c. administration. Comparison of t _1/2 and MRT values after i.v. administration with those after s.c. administration indicated that rhIL-11 pharmacokinetics after s.c. administration were absorption rate-limited. Bioavailability after s.c. administration was about 65%. Since RhIL-11 was not detected in urine after a single 50  μg  kg⁻¹ s.c. dose, rhIL-11 was considered to be eliminated by metabolism. There was no significant change in the pharmacokinetic profile of rhIL-11 following repeated s.c. administration.
Conclusions RhIL-11 demonstrated linear pharmacokinetics at these dose ranges after single and repeated s.c. administration or constant-rate i.v. infusion in healthy volunteers.     

聚乙二醇化重组人白细胞介素-6在Beagle犬体内的药物动力学

目的 研究聚乙二醇化重组人白细胞介素-6(PEG-rhlL-6)皮下注射后在Beagle犬体内的药物动力学过程,为临床应用提供药物动力学数据.方法 采用同位素示踪法,碘标记PEG-rML-6,用液体闪烁计数仪检测放射性浓度,3p97软件判断房室模型并计算参数,检测Beagle犬皮下注射125I-PEG-rhlL-6后不同时间的血药浓度.结果 Beagle犬皮下注射125I-PEG-rhlL-6后,t1/2ka为0.07～2.34 h,t1/Zke为66～258 h,Tmax为0.8～10.7 h,体内滞留时间70～94 h,AUC与剂量呈正相关.结论 PEG-rhlL-6在Beagle犬体内的药物动力学过程基本符合线性药动学特征,药一时曲线符合一房室模型.经聚乙二醇(PEG)修饰的rML-6能明显延长rhlL-6在Beagle犬体内的生物半衰期,延长药物的有效作用时间.     

重组人白细胞介素-11对肿瘤患者化疗后血小板的影响

目的 观察重组人白细胞介素-11(rhIL-11)治疗化疗所致血小板(PLT)减少的疗效和不良反应.方法 采用患者自身对照研究,对第1个周期化疗(对照组)后PLT≤70×109/L的42例实体瘤患者,第2个周期(治疗组)采用相同方案化疗,化疗结束后24 h开始,皮下注射rhIL-Ⅱ25 g/kg,1次/d,连用7～14 d,或至PLT≥100×109/L时停药.结果 治疗组化疗后各时点PLT计数均高于对照组.化疗后,治疗组和对照组PLT最低值分别为(105.2±51.5)×109/L、(54.6±45.5)×109/L,两组差异有统计学意义(P＜0.01).PLT恢复正常时间,治疗组为2～20 d,对照组为5～28 d,中位数分别为6、13 d,两组差异有统计学意义(P＜0.01).rhIL-Ⅱ的不良反应主要包括乏力、关节肌肉酸痛、头痛、心悸、水肿和发热等,大多较轻,可以耐受.结论 rhIL-11能刺激血小板增生,治疗化疗引起得血小板降低,是一种有效、安全的药物,值得进一步研究.     

重组人白细胞介素－3在小鼠体内的药代动力学及组织分布

用Ｉｏｄｏｇｅｎ法制备１２５Ｉ－γｈＩＬ－３。产品用ＳｅｐｈａｄｅｘＧ－５０凝胶过滤纯化。流出的组分用ＳＤＳ－ＰＡＧＥ测定纯度。选取放化纯度高于９５％的进行药代动力学研究。在ｉＶ剂量为５００、１０００及２５００ｎｇ·ｍｏｕｓｅ－１的１２５Ｉ－γｈＩＬ－３后，浓度－时间曲线按三房室模型拟合，其快分布相约为２ｍｉｎ。慢分布相约为５０ｍｉｎ。终末消除相为８ｈ左右。ＡＵＣ与剂量呈较好的线性关系（ｒ＝０．９９７０）。ｉｍ１２５Ｉ－γｈＩＬ－３１０００ｎｇ·ｍｏｕｓｅ－１后浓度一时间曲线符合一室一级吸收，绝对生物利用度为０．８８，达峰浓度，时间分别为４２．７６μｇ·Ｌ－１和０．５０ｈ。ｉｖ１５ｍｉｎ后，在肾脏中的浓度最高，２４ｈ内排出约８６％的标记药物。     

基因重组人白细胞介素-2在小鼠的药物动力学和分布(英文)

lodogen法制备~(125)I-rlL-2,放射纯度95％,ⅳ后快速、慢速分布和消除T_(1/2)分别为<2,30—120和6—15h,AUC与剂量呈正比,血尿原药占81±13％,im生物利用度0.57,ⅳ后15min浓度顺序为肝>胆汁>肾>血>肾上腺>>血浆>肺>甲状腺>脾>小肠>肠系膜淋巴结>肠内容>卵巢>心>膀胱>胸腺>粪>肌肉>>睾丸>脑>脂肪,24 h排出80％第2天5％。     

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application

Aims The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×10⁶  IU  m⁻² once daily and group B 10×10⁶ IU  m⁻² twice daily (every 12  h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated.
Results The mean area under the serum concentration-time curve to 24  h (AUC(0,24  h)) was 627  IU  ml⁻¹  h in treatment group A and 1130  IU  ml⁻¹  h ( P =0.029) in treatment group B. In both study groups C _max and AUC(0,12  h) were not significantly different. Seventy-two  hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly ( P =0.016), and sIL-2R levels over 1200  pmol  l⁻¹ seemed to reduce the AUC.
Conclusions In patients with metastatic renal cell cancer administration of 20×10⁶  IU  m⁻² of rhIL-2  s.c. in two daily doses (10×10⁶  IU  m⁻² every 12  h) provides better bioavailability and is preferable to the single dose administration.     

重组人白细胞介素—11的临床应用及其研究进展

综述了近年来重组人白细胞介素－11（rhIL-11)的研究进展。rhIL-11能刺激造血干细胞和巨核细胞的增殖,诱导巨核细胞的成熟分化,从而增加体内血小板的产量。临床前及临床研究表明其有明显的升血小板作用,能降低因化疗所致的输注血小板的需要。rhIL-11治疗化疗所致的血小板减少,疗效好,不良反应较轻,展现了良好的应用前景。     

Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease

BACKGROUND: Interleukin-11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin-11 (rhIL-11) in patients with Crohn's disease. AIM: To determine the safety and preliminary estimate of efficacy of rhIL-11 in treating active Crohn's disease. METHODS: Patients with mild to moderately active Crohn's disease, defined as a Crohn's disease activity index (CDAI) > or = 220 and < or = 450, were enrolled in a multicentre trial. Stable doses of 5-aminosalicylates, antibiotics, 6-mercaptopurine or azathioprine were permitted with appropriate wash-in periods. Oral, intravenous or rectally administered corticosteroids were not allowed. Patients were randomized to 6 weeks of subcutaneous injection with rhIL-11 15 microg/kg or placebo weekly, or rhIL-11 7.5 microg/kg or placebo twice weekly. The primary end-point was per cent change in CDAI at week 6; the major secondary end-point was the proportion of patients in remission, defined as a 100 point decrease in CDAI and absolute CDAI < or = 150. RESULTS: Baseline characteristics were similar among the 148 evaluated patients (49 placebo, 49 rhIL-11 15 microg/kg once weekly, 50 rhIL-11 7.5 microg/kg twice weekly). Treatment was well-tolerated, with mild injection site reactions occurring more frequently among patients treated with rhIL-11. Headache, oedema, and increased platelet count occurred significantly more often in the rhIL-11 7.5 microg/kg twice weekly group, but not the 15 microg/kg once weekly group. There was a trend toward decreased mean per cent change in CDAI in the rhIL-11 15 micro/kg once weekly group vs. placebo (-31.5% vs. -18.5%, 95% confidence interval for the difference -27.9-1.6%). A significantly greater proportion of patients receiving rhIL-11 15 microg/kg once weekly achieved remission compared to placebo (36.7% vs. 16.3%, 95% confidence interval for the difference 3.4-37.4%; 16.4% for rhIL-11 7.5 microg/kg, N.S.). CONCLUSIONS: Weekly subcutaneous injection with rhIL-11 15 microg/kg is safe and effective in inducing remission in a subset of patients with active Crohn's disease.     

重组人白细胞介素-11对化疗动物血小板减少症的影响

目的观察重组人白细胞介素 11(rhIL 11)对化疗药所致血小板减少症的影响。方法采用口服环磷酰胺引起犬和静脉注射卡铂造成食蟹猴急性血小板减少症模型 ,观察rhIL 11增加血小板生成作用和对其它血细胞及骨髓的影响。结果rhIL 11对环磷酰胺所致犬血小板减少症和卡铂诱发的食蟹猴血小板减少症可明显增加血小板生成 ,但不影响血小板聚集功能 ;也能增加外周血网织红细比例 ,而且能刺激骨髓 ,促进巨核细胞和多种细胞集落的形成。结论rhIL 11可刺激受抑制的骨髓 ,促进血小板和巨核细胞及多种细胞集落形成单位的产生