他克莫司治疗特发性膜性肾病临床疗效分析

目的 探讨他克莫司治疗特发性膜性肾病（IMN）临床效果。方法 根据患者治疗意愿分为观察组28例,对照组16例;观察组采用他克莫司治疗,对照组采用激素联合环磷酰胺治疗。测定两组患者治疗前及治疗后3个月、6个月24 h尿蛋白定量、血肌酐、血尿素、血白蛋白和抗 M 型磷脂酶A2受体1的抗体(PLA2R-Ab)。两组患者均在治疗6个月后评价治疗效果。结果 两组患者在治疗3个月、6个月后24 h尿蛋白定量、血白蛋白、三酰甘油、胆固醇均有明显改善,差异均有统计学意义（P<0.05);并且观察组较对照组改善更明显（P<0.05）;观察组治疗6个月后血肌酐、尿素较治疗前有升高,差异均有统计学意义（P<0.05）;对照组空腹血糖、白细胞治疗3个月、6个月后较治疗前升高,差异有统计学意义（P<0.05）。两组患者治疗3个月、6个月后血PLA2R-Ab均有明显降低,差异均有统计学意义（P<0.05);并且与治疗3个月比较,两组治疗6个月后血PLA2R-Ab降低更明显（P<0.05）;观察组治疗后3个月、6个月后均较对照组同时间降低更明显（P<0.05）。治疗后6个月,观察组缓解率85.7%,对照组缓解率68.8%,缓解率差异有统计学意义（P<0.05）。观察组中3例患者出现血肌酐轻度增高,1例牙龈增生;对照组3例血糖升高,2例恶心呕吐。结论 他克莫司治疗IMN效果明显,不良反应轻微,明显降低血PLA2R-Ab。     

A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis

Background: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients.

Methods: A search for studies with keywords ‘autoimmune hepatitis’ and ‘tacrolimus’ was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected.

Results: Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8?mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7?ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis.

Conclusion: TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function.

Key Points

• There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy.

• Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined.

• We report the use and efficacy of tacrolimus (TAC) in patients with AIH.

• We found that TAC can be safely and effectively used in patients with AIH with minimal side effects.

• TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

     

Clinical determinants of calcineurin inhibitor disposition: a mechanistic review

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.     

Efficacy and safety of topical tacrolimus for the treatment of face and neck vitiligo

Vitiligo is a common acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented maculae. The conventional treatments are limited by their inconsistent and incomplete responses, relapse rate, inconvenience to apply, side-effects and especially long-term effects. The aim of the present study was to determine the efficacy and safety of topical tacrolimus as monotherapy for the treatment of face/neck vitiligo in Taiwan. This was a multicenter, open-label, non-comparative study. Patients were at least 16 years old and had vitiligo lesions with Vitiligo Index of Disease Activity score +1 or more on face or neck. Patients received a monotherapy with 0.1% of tacrolimus ointment twice daily for 12 weeks. The efficacy was measured by the percentage of repigmentation of target lesion, which was graded as minimal (1–25%), mild (26–50%), moderate (51–75%) or excellent (76–100%). Patients who had at least mild repigmentation were defined as responders. A total of 61 patients were enrolled in this investigation. Most of the patients showed repigmentation at week 4. At the end of treatment, all patients showed repigmentation and 45.9% of patients were responders. During the study, 15 adverse events related to the ointment were reported. All the reported adverse events were mild and similar to the well-known adverse effect of tacrolimus in the treatment of atopic dermatitis. Tacrolimus ointment is effective and well tolerated for the treatment of patients with vitiligo in Taiwan. It will be another drug of choice for persons with vitiligo who are unable to receive regular phototherapy and fear the side-effects of topical steroid in long-term use.     

0.03%他克莫司软膏治疗眼睑皮炎临床疗效观察

目的探讨0.03%他克莫司软膏治疗眼睑部皮炎的疗效。方法 26例患者外用0.03%他克莫司软膏,2次/d,共2周。于治疗前及治疗后第3天,第1、2周和停药后1月各随访1次。结果 26例患者治疗后3天、1周、2周及停药1个月后临床痊愈率分别为57.69%,76.94%,92.30%,73.08%。对红斑、瘙痒的控制起效迅速,而脱屑及肥厚改变较缓。4例(15.38%)患者局部有灼热感,均发生在治疗初3天。停药1个月后共有7例(26.92%)患者复发。结论 0.03%他克莫司软膏治疗眼睑部皮炎起效快,疗效明显,长期使用的安全性需大样本观察研究。     

Effects of Tacrolimus and Nifedipine,Alone or in Combination,on Gingival Tissues

Background: The aim of this study is to compare gingival changes induced by short‐ and long‐term tacrolimus and nifedipine administration, alone or in combination, and evaluate the expression levels of tumor suppressor phosphatase and tensin homolog (PTEN) in drug‐induced gingival overgrowth. Methods: Eighty rats were equally divided into eight groups: 1) tacrolimus for 8 weeks; 2) nifedipine for 8 weeks; 3) tacrolimus and nifedipine for 8 weeks; 4) 8‐week control; 5) tacrolimus for 24 weeks; 6) nifedipine for 24 weeks; 7) tacrolimus and nifedipine for 24 weeks; and 8) 24‐week control. Histomorphometric analyses included measurements of epithelial thickness, connective tissue thickness, and height. Stereologic analyses included measurements of volumetric densities of fibroblasts (V_f), collagen fibers (V_cf), and blood vessels (V_bv). In addition, PTEN expression was analyzed using immunohistochemistry. Results: Epithelial thickness and connective tissue thickness were significantly increased in groups 5, 6, and 7 compared to group 8 (P <0.05), whereas connective tissue height was significantly increased in groups 5 and 7 (P <0.001). V_f and V_cf were significantly increased in group 7 compared to group 8 (P <0.001). PTEN immunoreactivity was significantly decreased in all experimental groups compared to the control groups (P <0.05). Conclusions: Results suggest that duration of drug administration is a more important risk factor than drug combination. The results include a potentially new insight about PTEN's role in the etiology of drug‐induced gingival overgrowth.