普乐可复在肾移植中的临床应用

目的 研究普乐可复（ＦＫ５０６）对肾移植患者免疫抑制的疗效与安全性。方法 肾移植术后应用ＦＫ５０６免疫抑制治疗８２例,分为临床验证组４２例和切换治疗组４０例。结果 临床验证组有４０例（９５．２％）肾功能在１４ｄ内恢复正常,１例（２．４％）发生急性排斥反应,经治疗逆转。切换治疗组有２４例肝功能正常;３例移植肾发生急性肾小管坏死（ＡＴＮ）伴急性排斥反应,６例发生慢性排斥反应,４例发生难治性排斥反应,均     

小肠移植麻醉处理一例

2004年7月,我院为一例短肠综合征患者成功施行部分小肠移植,现将本例的手术麻醉处理报道如下。患者为男性,50岁,体重55 kg。2003年5月因肠系膜血管栓塞并发肠坏死行小肠切除术(残余回肠约20cm)。小肠移植前肌肉注射苯巴比妥钠100 mg、阿托品0.5 mg,术中开放上肢静脉通路,行颈内静脉、桡动脉置管。全身麻醉诱导用药:咪达唑仑5 mg,丙泊酚40 mg,罗库溴铵50 mg,芬太     

小肠移植在短肠综合征治疗中的应用

小肠移植是治疗短肠综合征最理想的方法,但由于供体的短缺和其剧烈的排斥反应及因此而导致的远远低于实质脏器移植的成功率,使小肠移植的临床开展受到极大的限制。1小肠移植的发展和现状小肠移植的实验研究早在1902年即已开始,而首例临床小肠移植于1964年由Detterling等开展,至     

小肠移植治疗短肠综合症

小肠移植为短肠综合征患者的治疗开辟了新的途径。本文介绍了我国首例临床小肠移植术，并就小肠移植有关的技术、免疫、感染及肠功能恢复问题进行了讨论。     

同种异体小肠移植治疗短肠综合征一例

我院于2004年7月14日为1例短肠综合征患者施行了小肠移植，现将我们的体会报告如下。     

1例活体部分小肠移植的术前准备

小肠移植是挽救短肠综合征及其他肠功能不全病人生命的重要手段之一。小肠移植的成功除有赖于成功的手术及对排斥反应、血栓、感染的防治外 ,术前、术后妥善的管理措施也很重要。 1 999年 5月2 0日我院成功地施行了我国首例活体部分小肠移植术 ,病人目前已健康存活 1 9个月 ,现将术前准备总结如下。1　病例简介男 ,1 8岁 ,身高 1 .85m。因肠系膜扭转、肠坏死于 1 998年 9月 1 3日在外院行小肠大部分切除术(残余小肠 40 cm)后并发肠瘘。 1 998年 1 1月 2 6日在我院行肠瘘修补术 ,切口愈合良好 ,但经口进食后频繁腹泻 ,每天多达十余次。严重营…     

普乐可复预防同种肾移植排斥反应的研究

目的 评价并比较新型免疫抑制普乐可复（ＦＫ５０６）对预防同种肾移植受者排斥反应的疗效及安全性。方法 随机将９８例肾移植受者分成２组。（１）ＦＫ５０６组（ｎ＝４０）;主要用药为ＦＫ５０６＋霉酚酸酯（ＭＭＦ）＋泼尼松（Ｐｒｅｄ）;（２）环孢素９Ａ（ＣｓＡ组）（ｎ＝５８）;主要用药为;ＣｓＡ＋ＭＭＦ＋Ｐｒｅｄ。结果 ２组受者平均随访时间为１２．５个月。     

活体部分小肠移植一例报告

目的 对临床活体部分小肠移植进行总结。方法 为1例患超短肠综合的18岁男必患者施行父亲供肠的活体部分小肠移植术,移植肠段为150cm长之回肠,以UW液灌洗。移植肠动、静脉分别与受者的腹主动脉及下腔静脉端侧吻合,移植肠近端与受者的空肠近端行端端吻合,远端与受者的空肠远端行侧端吻合,末端造口。术后给予抗排斥、抗感染、抗凝及营养支持等治疗。结果 术后曾出现贫血、单纯疱疹病毒感染和 急性排斥反应,经积极处理行到控制目前患者已健康存活14月余。结论 活体部分小肠移植是治疗短肠综合征的一理想方法。     

Long‐term small bowel allograft function induced by short‐term FK 506 application is associated with split tolerance

Abstract Functional long‐term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high‐dose FK 506 has been shown to induce stable long‐term graft function. In order to examine whether this long‐term function is associated with donor‐specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One‐step orthotopic SBT was performed in the allogeneic Brown Norway (BN)‐to‐Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0‐5 in the rejection model and from days 0‐9 in the long‐term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long‐term functional model survived long term (> 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor‐specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely (> 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third‐party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor‐specific heart allografts.     

The superior effect of the combination of FK 506 and deoxyspergualin on rat cardiac allograft survival

In this present study, the effects of FK 506 and 15-deoxyspergualin (DSG), with respect to dose, timing, and combination, were investigated in an ACI-to-LEW rat cardiac allograft model. FK 506 was adminstered intramuscularly for 14 days starting on day 0 after grafting, while DSG was given intraperitoneally for 7 days starting on day 0,4, or 7 after transplantation. FK 506 or DSG monotherapy prolonged cardiac allograft survival in dose-dependent manners, and the minimum effective dose for overcoming rejection was 0.1 mg/kg per day in the case of FK 506 and 1.0 mg/kg per day for DSG. The graft survival rate was higher with administration of DSG starting on day 4 on day 0 after transplantation. A low dosage of FK 506 strating on day 0, in combination with DSG starting on day 0 or day 4 (but not on day 7), had a synergistic effect in prolonging allograft survival for 14.0±3.3 days and 25.4±8.2 days, respectively. The most effective combination treatment schedule for prolongation of allograft survival was FK 506 starting on day 0 and DSG starting on day 4 after transplantation.     

Direct vasodilative effect of FK506 on porcine mesenteric artery in small bowel transplantation

Background

Tacrolimus (FK506) is widely used as an immunosuppressive drug in small bowel transplantation. However, its precise effects on the vascular tone of the transplanted organ have not been studied. This study aimed to clarify the effects of FK506 on the porcine mesenteric artery.

Methods

The effects of FK506 on the changes in cytosolic Ca²⁺ concentration ([Ca²⁺]i) and force using fura-2 fluorometry were investigated in mesenteric arterial strips of the porcine small intestine. The effects of FK506 on the activity of voltage-dependent Ca²⁺ channels and receptor-operated Ca²⁺ channels using high K⁺ (118 mmol/L K⁺) depolarization and thromboxane A₂ analog (U46619) stimulation were also examined.

Results

FK506 inhibited the force development induced by 118 mmol/L K⁺ depolarization and 1 μmol/L U46619 stimulation in a concentration-dependent manner. The extent of inhibition of this contraction was greater than that of the K⁺-induced contraction, and its inhibitory potency was about 10-fold. FK506 (10 μmol/L) inhibited the increases in [Ca²⁺]i (24.9% ± 7.4%) and the force development (52.0% ± 5.6%) induced by 1 μmol/L U46619, respectively.

Conclusions

FK506 induces arterial relaxation by decreasing [Ca²⁺]i. Pretreatment of a graft with FK506 may reduce the risk of vasospasm, ischemia-reperfusion injury, and thrombosis in small bowel transplantation.     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.     

Prolongation of Rat Liver Graft Survival by Splenectomy Combined with Low Dose FK506 Therapy

Abstract: The effects of low dose FK506 therapy (0.1 mg/kg/day × 1 day) on graft survivals were analyzed, and the feasibility of splenectomy was assessed. ACI strain liver grafts were orthotopically implanted into LEW male rat recipients. In the control group, the survival period was 10.4 ± 1.4 days. In the group treated with splenectomy, the survival period was 13.4 ± 2.0 days. In the groups with low dose FK506 therapy, the survival periods were 22.7 ± 6.7 and 39.7 ± 6.3 days with or without splenectomy, respectively. Rats in the group with average dose FK.506 (1.0 mg/kg/day × 7 days) survived more than 100 days. In summary, the effect of low dose FK506 therapy was relatively limited. Splenectomy by itself was marginally effective; however, this effect was enhanced when combined with low dose FK.506 therapy.     

Long-term use of FK 506 in living related liver transplantation

Abstract FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 ± 0.277 mg/kg daily at 1 month after transplantation to 0.078 ± 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 ± 7.1 ng/ml and 4.1 ± 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids.     

The use of plasma levels for FK 506 dosing in liver-grafted patients

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i.e, during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.     

Bombesin can rescue the enteric ganglia from FK506 neurotoxicity on small bowel transplantation

Background/Purpose

FK506 has been reported to have neurotoxic effects. The aim of this study was to investigate whether FK506 causes neurotoxic effects on the transplanted graft enteric ganglia (TGEG) and whether bombesin (BBS) can prevent such atrophy.

Methods

Thirty rats heterotopically underwent small bowel transplantation and were divided into 5 groups as follows: group A, syngraft (SYN) alone; group B, SYN with FK506; group C, SYN with FK506 and BBS; group D allograft with FK506; group E, allograft with FK506 and BBS. From postoperative days 14 to 28, either BBS or normal saline was administered continuously. All recipients except for group A received FK506 daily. The ganglionic count was obtained by counting the number of protein gene product 9.5 immunohistochemically stained ganglia in the cross sections of each graft.

Results

The number of TGEG in groups A, B, and C was 69.7 ± 6.0, 51.5 ± 7.7, and 84.8 ± 10.2 ganglia per cross section, respectively. There was a significant difference between each group (P < .001). The number of TGEG in groups D and E was 44.6 ± 7.5 and 65.1 ± 9.5 ganglia per cross section, respectively. There was a significant difference between the 2 groups (P < .001).

Conclusions

FK506 causes severe neurotoxicity in transplanted grafts, and BBS protects graft enteric ganglia against the neurotoxic effects of FK506.