他克莫司在心脏移植患者体内的临床药动学

目的 :了解他克莫司在心脏移植患者体内的药代动力学特征 ,为患者实施用药的个体化。方法 :采集 4例心脏移植患者稳态时一个用药间隔 （τ）内 9个不同时间点血样 ,以微粒子酶标免疫分析法 （MEIA）测定全血中他克莫司的浓度 ,计算他克莫司在个体患者体内的药动学参数 ,并以此参数为依据实施用药的个体化。以他克莫司谷浓度结合患者临床疗效及不良反应的情况 ,总结他克莫司在心脏移植术后的治疗窗。结果 :患者口服他克莫司 （4～ 5mg/ 8h）后 ,其体内处置为一室开放模型 ,平均药动学参数 Tm ax,Cmax,T1 /2 ke和 AUC依次分别为 1.2± 0 .4h,2 9± 7m g· L- 1 ,7.6± 1.2 h和 2 75± 10 8mg· h- 1 · L- 1 。术后 1年来他克莫司谷浓度控制在 2 5～ 5 m g· L- 1 ,患者未出现严重的排斥或中毒反应。结论 :他克莫司药动学的个体差异较大 ,应加强全血谷浓度监测 ,确保用药的安全有效。他克莫司在心脏移植的治疗窗 （谷浓度 ）为 :0～ 1个月 15～ 2 0 mg· L- 1 ,1～ 3个月 10～ 15 mg· L- 1 ,3～ 6个月8～ 12 m g· L- 1 ,6个月后 5～ 8mg· L- 1 ,此浓度范围即可有满意的免疫抑制效果 ,又可减少他克莫司不良反应。     

他克莫司软膏联合窄谱中波紫外线治疗白癜风疗效和安全性探讨

目的探讨白癜风的有效治疗方法。方法将120例白癜风患者随机分为三组。综合组40例予他克莫司软膏联合窄谱UVB（NB-UVB）照射治疗;照射组40例行NB-UVB单纯照射治疗;软膏组40例外用他克莫司软膏治疗。三组均连续治疗3个月,进行临床疗效和不良反应评价。结果综合组总有效率明显高于照射组及软膏组（P〈0．05）;三组均无严重不良反应发生。结论他克莫司软膏联合NB-UVB治疗白癜风疗效确切,安全性好。     

细胞色素P450基因多态性对他克莫司临床应用的影响

肝移植是终末期肝病患者最有效的治疗手段,而免疫抑制剂的应用是影响患者移植术后长期存活的关键。本文介绍了最常用的免疫抑制剂——他克莫司的作用机制,以及细胞色素P450基因多态性对他克莫司应用影响的最新研究进展。为临床上合理使用他克莫司,减少相关并发症的发生,提高肝移植患者的长期生存率提供参考。     

腹泻对肾移植受者他可莫司血药浓度的影响

目的:观察腹泻对肾移植受者他克莫司谷浓度的影响,并探讨其发生的可能原囚和机制. 方法:观察了肾移植术后出现腹泻的患者27例,在他克莫司和环孢素治疗组中分别有20例和7例.观察了围腹泻期药物剂量及谷浓度变化,并进行了与腹泻相关病原学检查. 结果:在腹泻期间分别有15例(75%)和2例(28.6%)患者他克莫司和环孢素谷浓度明显升高.通过抗感染、减低霉酚酸酯剂量及止泻等综合治疗,腹泻治愈,他克莫司谷浓度在腹泻愈后3～17 d内下降至治疗范围. 结论:腹泻是引起他克莫司谷浓度升高的重要因素.腹泻期间应适当减低他克莫司剂量和密切监测他克莫司谷浓度变化.     

妊娠相关可逆性后部白质脑病综合征的临床与MRI表现3例报告

可逆性后部白质脑病综合征（reversible posterior leukoencephalopathy syndrome,RPLS）的概念最早于1996年由Judy Hinchey提出,是由恶性高血压、子痫、严重肾脏疾病、某些已被证实与RPLS相关的免疫抑制剂和化疗药物等引起的临床综合征。现将我科收治的3例妊娠相关RPLS的临床表现和影像学特征报道如下,以提高对该病的认识。     

肾移植术后应用他克莫司诱发急性胰腺炎1例

药物性胰腺炎是AP的一种罕见病因, 占所有AP病例的2%～5%。他克莫司是器官移植术后患者应用的一种免疫抑制剂, 目前, 肾移植术后应用他克莫司导致AP的报道很少。本文报道1例肾移植术后他克莫司导致AP的病例, 以供临床参考。     

他克莫司治疗重症肌无力疗效及安全性评价

目的 评价他克莫司治疗全身型重症肌无力(MG)的疗效及不良反应.方法 回顾性分析69例全身型MG患者接受他克莫司(2～6 mg/d)治疗前及治疗后1、3、6及12个月时MG严重程度评分及不良反应,并监测服药1个月后他克莫司血药浓度(FK506),分析其与临床疗效的相关性.结果 他克莫司治疗1、3、6及12个月的总有效率分别为81.2％、87.6％、92.2％及93.8％.治疗1个月后,临床显效及好转组FK506[(7.1±3.9) μg/L,(6.3±3.8) μg/L]明显高于无效组[(3.4±1.3) μg/L] (P ＜0.01,P＜0.05).主要的不良反应:血糖升高5例,出现白细胞减少及头晕、耳鸣各3例.结论 他克莫司治疗MG,起效快,临床疗效确切.在治疗剂量范围内其副作用小,主要为血糖升高及骨髓抑制.     

他克莫司和霉酚酸酯分别联合激素治疗特发性膜性肾病Ⅲ期疗效比较

目的 观察不同疗程中他克莫司、霉酚酸酯分别联合激素治疗有肾病综合征表现的特发性膜性肾病Ⅲ期患者的疗效和安全性.方法 选择2010年9月～2012年7月我院肾内科收治的表现为肾病综合征的特发性膜性肾病Ⅲ期患者60例,并将60例患者分为他克莫司、霉酚酸酯分别联合激素治疗两组,每组30例,观察两组的临床疗效、他克莫司的浓度变化及两组的复发等情况.结果 他克莫司联合激素治疗组治疗6个月后完全缓解15例,部分缓解12例,无效3例;出现呼吸道感染2例,出现血糖和血压升高各3例.治疗期间他克莫司的平均血药浓度维持在4.5～7.8 μg/L;治疗结束后,复发6例.霉酚酸酯联合激素治疗组完全缓解11例,部分缓解14例,无效5例;患者出现胃肠道反应3例,血白细胞减少3例,无肝功能异常及血压升高;治疗结束后,复发10例.结论 他克莫司、霉酚酸酯分别联合激素治疗均可缓解病情,他克莫司组与霉酚酸酯组比较复发率低,病情缓解率高.     

他克莫司对类风湿关节炎关节滑膜液淋巴细胞协同刺激分子的作用

目的研究他克莫司对类风湿关节炎（RA）患者关节滑膜液淋巴细胞协同刺激分子的作用．并初步探讨其免疫抑制的机制。方法分离培养RA关节滑膜液淋巴细胞，经100nmol/L的他克莫司处理后．用流式细胞仪检测T淋巴细胞协同刺激分子CD28、CD154（CD40L）和B淋巴细胞协同刺激分子CD80、CD86、CD40的表达。同时检测T、B淋巴细胞活化标志CD69、CD25、HLA—DR和CD71的表达．用酶联免疫吸附法（ELISA）检测淋巴细胞培养上清Th1细胞分泌的细胞因子白细胞介素（IL）-2、干扰素（IFN）-γ和Th2细胞分泌的细胞因子IL-6、IL-10的水平，并设不加他克莫司处理的为对照组。结果经他克莫司处理后。T淋巴细胞的CD154（CD40L）和B淋巴细胞的CD86表达阳性率低于对照组（P〈0．05），而T淋巴细胞的CD28和B淋巴细胞的CD80、CD40表达阳性率与对照组相比差异无统计学意义；T、B淋巴细胞的HLA—DR表达阳性率明显低于对照组（P〈0．01），而CD69、CD25、CD71表达阳性率与对照组相比差异无统计学意义；淋巴细胞培养上清Th1细胞分泌的细胞因子IL-2、IFN-γ和Th2细胞分泌的细胞因子IL-6、IL-10的水平与对照组相比均显著下降（P〈0．01）。结论他克莫司能明显抑制RA关节滑膜液淋巴细胞的活化，降低Th1细胞因子和Th2细胞因子的分泌水平，这种作用可能是通过下调淋巴细胞的协同刺激分子的表达而实现。     

他克莫司治疗大鼠脊髓损伤效果观察

目的观察他克莫司治疗大鼠脊髓损伤的效果。方法 80只脊髓损伤模型Wsitar大鼠,随机分为A、B组,各40只,A组大鼠采用他克莫司治疗。同时选取40只健康大鼠作为空白对照（C组）。观察并比较三组大鼠治疗后脊髓功能评分（BBB评分和斜板试验评分）、细胞凋亡率及热休克蛋白70表达情。结果 BBB评分和斜板试验评分B组〈A组〈C组,P均〈0.05。A组大鼠脊髓热休克蛋白70表达水平高于B组,细胞凋亡率低于B组,P均〈0.05。结论 他克莫司治疗脊髓损伤可有效促进脊髓功能修复、减轻细胞凋亡,效果好。     

Clinical features of reversible posterior leukoencephalopathy syndrome in patients with systemic lupus erythematosus

To characterize reversible posterior leukoencephalopathy syndrome (RPLS) in systemic lupus erythematosus (SLE) in terms of treatments for resolution and its clinical course, we reviewed 28 cases of RPLS in SLE including our cases in view of the treatment. Of these, 15 cases improved with blood pressure control and 13 required immunosuppressive therapy for activity of SLE presenting neurological manifestations. Patients without immunosuppressants at onset of RPLS more frequently required immunosuppressive therapy to recover it than those precedingly using these agents [31% (4/13) versus 87% (13/15), p = 0.008, chi-square test]. Brain magnetic resonance imaging (MRI) is important for diagnosis of RPLS-SLE in the patient with SLE who develops neurological disturbance and rapidly increasing blood pressure. When 7-day therapy for hypertension and convulsion does not reverse the manifestations, immunosuppressive treatments would be recommended to reverse RPLS.     

Clinical features of reversible posterior leukoencephalopathy syndrome in patients with systemic lupus erythematosus

Abstract

To characterize reversible posterior leukoencephalopathy syndrome (RPLS) in systemic lupus erythematosus (SLE) in terms of treatments for resolution and its clinical course, we reviewed 28 cases of RPLS in SLE including our cases in view of the treatment. Of these, 15 cases improved with blood pressure control and 13 required immunosuppressive therapy for activity of SLE presenting neurological manifestations. Patients without immunosuppressants at onset of RPLS more frequently required immunosuppressive therapy to recover it than those precedingly using these agents [31% (4/13) versus 87% (13/15), p = 0.008, chi-square test]. Brain magnetic resonance imaging (MRI) is important for diagnosis of RPLS-SLE in the patient with SLE who develops neurological disturbance and rapidly increasing blood pressure. When 7-day therapy for hypertension and convulsion does not reverse the manifestations, immunosuppressive treatments would be recommended to reverse RPLS.     

Reversible posterior leukoencephalopathy in connective tissue diseases

OBJECTIVES: To describe a case of reversible posterior leukoencephalopathy (RPLS) involving a patient with systemic lupus erythematosus (SLE) and to review the medical literature to define the epidemiological, clinical, radiological, and therapeutic aspects of this syndrome in various connective tissue diseases. METHODS: Report of 1 case and review of the English literature using Medline search from 1967 to 2005. RESULTS: Including our reported case, RPLS has been identified in 13 patients with connective tissue disease. In separate case reports, 9 SLE patients, 2 Wegener's granulomatosis (WG) patients, and 1 patient with SLE and systemic sclerosis presented with RPLS. Associated risk factors included malignant hypertension, acute renal failure, and recent treatment with cyclophosphamide, cyclosporine, or methylprednisolone. Patients were treated with blood pressure control, hemodialysis, or withdrawal of the offending drug. In our patient, plasmapheresis and high-dose methylprednisolone resulted in a full recovery. In most cases, complete resolution of neurological symptoms occur within 2 weeks of presentation, along with improvement or resolution of imaging abnormalities. CONCLUSION: RPLS is a clinicoradiological entity, associated with reversible white matter edema involving most commonly the posterior central nervous system circulation. Seizures and altered mental status in patients with SLE or WG can pose difficult diagnostic and therapeutic challenges. The differential diagnosis is broad and includes infection, uremia, hypertension, infarction, thrombosis, demyelinating disorders, and vasculitis. Accurate diagnosis of RPLS and its differentiation from other, more common causes of the central nervous system is essential to ensure the best possible outcome in this rare but life-threatening neurological disorder.     

Unusual neurologic manifestations (II): posterior reversible encephalopathy syndrome (PRES) in the context of juvenile systemic lupus erythematosus

Posterior reversible encepalopathy syndrome (PRES), or reversible posterior leukoencephalopathy, is a neurologic condition characterized by recognizable pattern of altered mental status, headache, visual changes and seizures in association with findings indicating a predominantly posterior leucoencephalopathy on imaging studies. It has rarely been described in children. We report two cases of pediatric systemic lupus erythematosus (SLE) complicated by PRES and review the literature.     

Neuropsychiatric lupus and reversible posterior leucoencephalopathy syndrome: a challenging clinical dilemma

Reversible posterior leucoencephalopathy syndrome (RPLS) has been increasingly recognized and reported in the literature. While the condition has been well described in patients with acute hypertension, pre-eclampsia, eclampsia, post-transplantation and chemotherapy, RPLS has been increasingly identified in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Though experience in the diagnosis and management of RPLS in patients with SLE is likely accumulating, few have systematically worked out the strategy to distinguish RPLS from neuropsychiatric SLE (NPSLE) and lupus-related complications of the central nervous system (CNS). Prompt recognition of, and differentiation between, these conditions is essential since their clinical presentations substantially overlap and yet their management strategy and subsequent outcomes can be entirely different. Indeed, inappropriate treatment such as augmentation of immunosuppression may be detrimental to patients with RPLS. A high index of suspicion of RPLS, prompt magnetic resonance imaging of the brain, including diffusion imaging, exclusion of CNS infection and metabolic derangement, a comprehensive medication review accompanied by timely and aggressive control of blood pressure and seizure are keys to successful management of RPLS. Such treatment strategy ensures a very high chance of total neurological recovery in lupus patients with RPLS.     

Reversible posterior leucoencephalopathy syndrome in systemic lupus and vasculitis

OBJECTIVES: Reversible posterior leucoencephalopathy syndrome (RPLS) may develop in patients with renal insufficiency, hypertension, and immunosuppression, and is managed by prompt antihypertensive and anticonvulsant treatment. Four patients with renal insufficiency and fluid overload associated with Wegener's granulomatosis (one patient) and systemic lupus erythematosus (SLE) (three patients) are described, whose clinical picture and neuroimaging indicated RPLS. CASE REPORTS: All patients had headache, seizures, visual abnormalities, and transient motor deficit, and were hypertensive at the onset of the symptoms. Head computed tomography (CT) scan and magnetic resonance imaging showed predominantly posterior signal abnormalities, which were more conspicuous on T(2) weighted spin echo images than on CT scan. All patients had some form of cytotoxic treatment shortly before the syndrome developed, and dramatically responded to blood pressure control and anticonvulsant treatment. In two patients with SLE, dialysis was required for renal insufficiency. DISCUSSION: Follow up neuroimaging studies showed almost complete resolution of signal abnormalities, and suggested that RPLS was associated with cerebral oedema without concomitant infarction. The treatment of hypertension and neurotoxic condition such as uraemia appears of primary importance, while immunosuppressive treatment may cause further damage of the blood-brain barrier.     

Recurrent diffuse alveolar haemorrhage in a patient with systemic lupus erythematosus: long-term benefit of rituximab

Diffuse alveolar haemorrhage (DAH) is an uncommon complication of systemic lupus erythematosus (SLE), and recurrences of DAH with remission periods are unusual. We describe a young woman with cachexia as the initial manifestation of SLE who presented posterior reversible encephalopathy syndrome (PRES), intestinal vasculitis and four episodes of DAH even though she was receiving combined immune suppressive therapy. After treatment with rituximab (RTX) the patient has not presented further episodes of DAH.     

Reversible posterior leukoencephalopathy in patients with systemic lupus erythematosus

BACKGROUND: The development of central nervous system (CNS) symptoms in patients with preexisting systemic lupus erythematosus (SLE) evokes a wide differential diagnosis. Reversible posterior leukoencephalopathy (RPLE) is a rapidly evolving neurologic syndrome with characteristic clinical and radiographic features. Conditions commonly associated with RPLE include hypertensive encephalopathy, eclampsia, immunosuppressive drugs, and inflammatory disorders. OBJECTIVES: To describe our experience with RPLE in patients with concomitant SLE and review the literature. METHODS: The details of 5 novel cases and a MEDLINE review of the literature concerning the development of RPLE in association with SLE are presented. RESULTS: All cases included patients with SLE who developed the acute onset of headache, altered mental status, visual changes, and seizures. Neuroimaging demonstrated posterior white matter edema involving the parietal, temporal, and occipital lobes. Complete clinical and radiographic recovery occurred with prompt antihypertensive treatment and supportive care. Literature review identified 16 additional cases of RPLE occurring in patients with active SLE; the majority of these reports was similar in presentation and outcome to our experience. CONCLUSIONS: It is likely that the clinical manifestations and neuroimages in these lupus patients were the result of the RPLE syndrome. Fortunately, this cause of "secondary" CNS symptoms in patients with SLE is readily reversible when diagnosed early and treated with blood pressure control and supportive care.     

Hodgkin's disease-related central nervous system angiopathy presenting as reversible posterior leukoencephalopathy

Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical syndrome characterized by headache, conscious disturbance, seizure, and cortical visual loss with neuroimaging finding of edema in the posterior regions of the brain, with a reversible course (1). The precise pathomechanism of RPLS is not understood. However, association with uncontrolled hypertension, renal failure, eclampsia, or immunosuppressive agents has been implicated (1). We describe herein a case of Hodgkin's disease (HD)-related central nervous system (CNS) angiitis with neuroimaging finding suggestive of RPLS. The pathophysiology of RPLS in cases with CNS angiitis is discussed.     

Stevens–Johnson syndrome induced by mizoribine in a patient with systemic lupus erythematosus

A 32-year-old Japanese woman, who had a treatment history of systemic lupus erythematosus (SLE) with lupus nephritis World Health Organization class IV for 11 months, visited our hospital due to fever, facial erythema, and erosion of the oral cavity on November 10, 2003. Her mucosal erosion and facial skin erythema progressed over the following week, and Stevens–Johnson syndrome was diagnosed due to pathological findings of the skin. Among the administrated drugs, only mizoribine, started 6 months earlier, produced a positive reaction in the drug lym-phocyte stimulation test. Increased prednisolone and high dose intravenous γ-globulin were given successfully. Cyclosporine at 50 mg was administered to control the SLE, followed by an increase to 100 mg on January 7, 2004. She suffered from abdominal pain, blindness, and convulsion on January 9. The magnetic resonance image of her brain prompted a diagnosis of reversible posterior leukoencephalopathy syndrome. After withdrawal of cyclosporine and control of hypertension, symptoms disappeared rapidly. Cyclophosphamide pulse therapy was successfully administrated to control lupus nephritis. This is the first report describing the relationship between Stevens–Johnson syndrome and mizoribine. Although the use of mizoribine is thought to be safe, careful observation is necessary.