Distribution kinetics of FK-506, a novel immunosuppressant, after intravenous administration to rats in comparison with cyclosporin A.

The distribution kinetics of a novel potent immunosuppressant, FK-506 (FK) has been studied in comparison with cyclosporin A (CyA) both in vivo and in vitro using blood specimens. The infusion studies on FK, 5.0 mg kg-1 through the portal and femoral veins showed that the mean hepatic extraction ratio of FK was 27.9 per cent. The effect of clamping both the hepatic artery and the portal vein on the plasma disappearance profiles of FK, 5.0 mg kg-1, and CyA, 3.5 mg kg-1 was studied. The plasma disposition kinetics of CyA was almost the same as in the normal rats. However, the plasma FK levels were about 10 times higher than those obtained in the control group rats. This difference is attributed to the restricted initial distribution of FK to the liver, because the volume of the initial distribution space, V1, of FK was about 10 times smaller than that obtained in normal rats. In in vitro experiments, drug distribution was studied in blood samples (2.0 ml) spiked with FK or CyA, 1.0 micrograms ml-1. The plasma drug levels measured at 2 min after drug administration were 0.842 +/- 0.012 micrograms ml-1 and 0.769 +/- 0.047 micrograms ml-1 for FK and CyA, respectively. The distribution volume in the blood compartment, VB, was determined by dividing the spiked amount of drugs with these plasma concentrations. The VB was 2.38 +/- 0.04 ml for FK and 2.62 +/- 0.16 ml for CyA. There was no significant difference in VB between FK and CyA. The plasma free fraction, fp of the drugs was measured by the equilibrium dialysis method. For FK, the mean fp values (+/- SE) were 1.31 +/- 0.18 per cent (2.0 micrograms ml-1) and 1.93 +/- 0.18 per cent (5.0 micrograms ml-1). For CyA, the fp values were 4.85 +/- 0.36 per cent (1.0 micrograms ml-1) and 5.75 +/- 0.82 per cent (5.0 micrograms ml-1). The hydrophobicity parameter, logP' determined through the HPLC method was 0.386 for FK and 0.545 for CyA. Although FK was less hydrophobic than CyA, its protein binding was higher than CyA.     

麦考酚酸酯及其临床应用进展

目的:麦考酚酸酯(MMF)是一种新型的免疫抑制剂.在临床应用中,MMF的使用也越来越广泛,已不仅仅局限于器官移植,还涉及到系统性红斑狼疮(SLE)、自体免疫风湿性疾病的治疗,以及在糖尿病,肺部血管高压的辅助治疗等诸多方面.肠包衣麦考酚酸钠,是一种新的可抵抗胃溶作用的麦考酚酸肠包衣剂型,药物在肠内释放,可以降低胃肠道(GI)不良反应的发生.     

免疫抑制剂SIIA9268A的研究.Ⅰ.发酵、分离及理化性质

在用含ｒａｐａｍｙｃｉｎ结合蛋白基因（ＲＢＰ）的啤酒酵母ＲＳ１８８Ｎ及其变株ＲＳ１８８Ｎ△ｒｂｐ：：：ＬＥＵ筛选免疫抑制剂的过程中，得到活性菌株Ｎｏ．ＳＩＩＡ９２６８（鉴定为吸水链霉菌东湖变种）。应用硅胶柱层析和制备ＴＬＣ等方法从其发酵液中分离出活性化合物ＳＩＡ９２６８Ａ。经理化性质鉴定与ｒａｐａｍｙｃｉｎ同质。     

Distribution characteristics of immunosuppressants FK506 and cyclosporin A in the blood compartment

Using two representative immunosuppressants, FK506 (FK) and cyclosporin A (CyA), of which the mechanism of pharmacological action is the same although there is a great difference in the pharmacological intensity, the distribution characteristics were studied in both in vivo and in vitro experiments using rat, dog, and human blood. Blood samples were fractionated by means of sedimentation in Ficoll-Paque®, and the drug contents in the diluted plasma fraction, erythrocyte fraction, and lymphocyte fraction were measured by an HPLC method. FK distributes to the lymphocyte fraction to a level about three times greater than that of CyA, while CyA distributes to the erythrocyte fraction to a level ten times that of FK. The distribution pattern of these fractions was independent of the drug concentration and species after correcting the drug concentration in each fraction with the blood drug concentration. The uptakes of FK and CyA in the isolated lymphocytes obtained from the rat spleen and human peripheral blood were also studied. The amount of FK taken up by the spleen lymphocytes is five times greater than that of CyA. In the case of the uptake study using human peripheral blood lymphocytes, the concentration of FK in the lymphocyte is 100-fold higher than that of CyA. This difference in the lymphocyte level between the two immunosuppressants is thought to be one of the reasons why FK is more potent than CyA, a difference of about 100-fold in the in vitro pharmacological study and about tenfold in the in vivo organ transplantation experiments.     

TLSFJM抑制大鼠心脏移植排斥反应的作用

目的　在同种异体大鼠异位心脏移植模型中 ,探讨TLSFJM对急性移植排斥反应的抑制作用及机制。方法　以F344大鼠作为心脏移植受体 ,以LOU/CN大鼠作为心脏移植供体 ,建立大鼠异位心脏移植模型。受体大鼠分为 3组 ,于移植前后分别施以RPMI16 4 0、CsA或TLSFJM。每天观察移植心脏跳动情况 ,并于停跳当天或之前解剖观察。分别取供体大鼠脾细胞作为刺激细胞 ,取受体大鼠脾细胞作为反应细胞 ,进行单向混合淋巴细胞反应。结果　TLSFJM可明显延长大鼠异位移植心脏的存活时间 :RPMI16 4 0对照组移植心脏的存活期全部为 6d ,TLSFJM治疗组最长均可存活 2 7d ,高剂量 (15mg/kg·d)CsA治疗组存活期超过 2 7d。TLSFJM治疗组大鼠脾细胞增殖的cpm值均低于对照组。结论　TLSFJM具有良好的抗急性移植排斥反应作用。TLSFJM对同种异体抗原诱导T细胞增殖的明显抑制 ,可能是其发挥免疫抑制作用的机制之一     

Canine laryngeal transplantation: preliminary studies and a new heterotopic allotransplantation model

While transplantation of the larynx may eventually be useful in post-laryngectomy reconstruction, three criteria must first be met before human transplants can be attempted: transplant viability must be high, immunosuppression must be safe and effective and functional recovery of the larynx must occur. To study these first two criteria, a total of 11 canine larynx transplants were performed: 3 autografts, 6 orthotopic allografts and 2 heterotopic allografts. The rationale and technical performance of these different transplant procedures are reviewed in detail. Orthotopic transplant recipients received cyclosporin A (CsA) while the heterotopic allograft recipients received RS-61443 and methylprednisolone in addition to CsA. Overall, 9 of 11 of the transplants remained viable. In contrast, all 3 autografted animals developed esophageal-cutaneous fistulas; 2 developed sepsis and were sacrificed on post-operative days (POD) 5 and 28, respectively. The third survived for 91 days and demonstrated a high degree of regeneration in the recurrent and superior laryngeal nerves of the transplant. Orthotopically transplanted dogs also had a high morbidity and perioperative mortality (5 of 6 animals). The single long-term survivor was treated with CsA alone, but developed complete transplant rejection on POD 33. The two heterotopic transplant recipients had no perioperative morbidity and the combination of CsA, RS-61443 and methylprednisolone given these latter animals was effective in the longterm prevention of rejection. One of these heterotopic recipients died of sepsis on POD 68 while the other remained alive and well on POD 168. Our present findings show that currently available microsurgical techniques allow experimental canine laryngeal transplantation to be done with significantly high transplant viability rates. In the dog, CsA alone is inadequate for the long-term prevention of transplant rejection while combined therapy with CsA, RS-61443 and methylprednisolone can provide long-term rejection-free larynx transplant survival. The newly developed heterotopic larynx transplant model allows studies of transplant viability, rejection mechanisms and neural regeneration and functional recovery to be performed with minimal animal morbidity and lowered research costs.Presented at the combined meeting of the Society of Head and Neck Surgeons and the European Organization for Research and Treatment of Cancer (EORTC), Paris, France, 25–28 May, 1994     

新型免疫抑制剂FTY720研究的文献分析

通过对国内外五大权威数据库MEDINE、CBMDISC、清华同方全文数据库、万方期刊全文数据库、维普中文期刊全文数据库收入FTY720文献的计量学分析。了解国内外FTY720研究的概况及意义；分析发表FTY720研究成果的核心期刊、语种、国家；比较国内外在FTY720研究领域的差距，并对此提出思考。     

免疫抑制剂对实验性矽肺的影响研究

目的：探讨免疫抑制剂对矽肺发病的影响。方法：动物采用随机法，分对照组，免疫抑制组。石英粉尘非暴露式吸人4周后，测定肺巨噬细胞功能，气管、支气管、肺显微镜观察。结果：免疫抑制组肺巨噬细胞吞噬功能受到明显抑制，肺内细胞结节增多，肺细支气管等管壁增厚并胶原纤维增生。结论：免疫抑制剂可加重矽肺的病程。     

4826例免疫抑制剂及相关器官移植用药致药品不良反应自发报告分析

目的:了解免疫抑制剂及相关器官移植用药致药品不良反应(adverse drug reaction,ADR)的发生特点与规律,为临床合理用药提供参考。方法:采用回顾性研究方法,对2009年1月1日至2019年1月1日中国人民解放军ADR监测中心收集的免疫抑制剂相关ADR报告进行统计分析。结果:共收集到来自151家医院的4826例免疫抑制剂致ADR报告,男女患者之比为1∶1;发生严重的ADR患者中,≥60岁患者所占比例较高;ADR发生时间以用药后2~<7 d为主;引发ADR的药物主要涉及糖皮质激素、抗体和烷化剂;ADR累及器官和(或)系统主要为胃肠系统及全身性损害,严重的ADR主要累及血液系统;经过治疗,4314例患者(占89.39%)痊愈或好转;有4例死亡报告(1例与移植相关)。其中,442例ADR与器官移植术后用药相关,男女患者之比为2∶1;ADR发生时间以用药后≥15 d为主;引发ADR的药物主要涉及钙调磷酸酶抑制剂、抗体和抗代谢/增殖药;经过治疗,379例患者(占85.75%)痊愈或好转。结论:免疫抑制剂治疗窗较窄,但疗效无法替代,应加强患者治疗期间尤其是器官移植术后的临床用药安全性监测,并及时有效地干预,尽可能防止严重的ADR发生。