酸性成纤维细胞生长因子研究进展

酸性成纤维细胞生长因子(aFGF)是一种重要的生长因子,其生物学效应广泛,具有潜在的临床应用价值.文章概述了aFGF及其受体的结构与功能关系的研究进展,提出了aFGF临床使用时可能存在的问题.     

益气养阴、祛痰化瘀中药复方对糖尿病肾病大鼠干预作用及其机制

目的:观察并证实益气养阴、祛痰化瘀中药复方对早期糖尿病肾病大鼠干预作用,分析其可能的作用机制,为临床防治糖尿病肾病提供可靠的实验依据。方法:实验于2005-01/12在解放军沈阳军区总院动物实验中心完成。SPF级雄性Wistar大鼠72只,随机选出正常组12只,其余大鼠高糖高脂饲料喂养1个月后,腹腔注射链脲佐菌素建立早期糖尿病肾病大鼠模型。造模成功大鼠56只以随机排列表分为4组:模型组、中药10,20g/kg组及中药预防组各14只。中药预防组在成模后立即开始给药,中药10,20g/kg组在成模后2周开始给药。预防组与10g/kg组给予10.15g/(kg·d),20g/kg组给予20.30g/(kg·d)灌胃;正常对照组及模型组灌服相应容量(10mL/kg)的生理盐水,1次/d,连续6周。采用生化法、放射免疫法和蛋白质印迹杂交法等分析血糖、尿微量白蛋白、α1微球蛋白、血清肌肝、尿素氮水平,观察肾皮质转化生长因子β1、血小板衍化生长因子B蛋白表达。结果:纳入实验观察的大鼠共72只,造模不成功4只,模型组死亡3只,中药预防组死亡2只,中药10g/kg组死亡3只,中药20g/kg组死亡2只,最终纳入结果分析58只。①治疗后6周,模型组、中药10,20g/kg组、中药预防组血糖均明显高于正常组(P<0.01);各中药组血糖均低于模型组(P<0.05～0.01);中药预防组血糖低于10,20g/kg组(P<0.01,0.05)。②治疗后6周,模型组、中药10,20g/kg组、中药预防组尿微量白蛋白、尿α1微球蛋白均高于正常组(P均<0.01);各中药组两指标均低于模型组(P均<0.01),中药10g/kg组高于预防组(P<0.01,0.05)。③治疗后6周,模型组、中药10,20g/kg组、中药预防组血尿素氮、血清肌肝均高于正常组(P均<0.01);中药10,20g/kg组、预防组两指标均低于模型组(P<0.05～0.01),10g/kg组高于预防组(P<0.01)。④早期糖尿病肾病大鼠肾皮质转化生长因子β1和血小板衍化生长因子B蛋白表达增加,中药预防组、20g/kg组对两者的表达均有明显抑制作用,各治疗组与模型组间均有显著差别。结论:益气养阴、祛痰化瘀中药复方能有效防治糖尿病肾病,其药效学机制可能通过降低血糖,减少尿微量白蛋白、α1-微球蛋白的水平,改善肾功能,下调肾皮质转化生长因子β1、血小板衍化生长因子B蛋白的过度表达实现。     

A controlled comparison of the efficacy of hetastarch and pentastarch in granulocyte collections by centrifugal leukapheresis

Compared with hetastarch (HS), the low molecular weight analog pentastarch (PS) has been reported to be equally effective for granulocyte collection by centrifugal leukapheresis, to result in fewer adverse donor reactions (ADR), and to have a more rapid elimination profile. We prospectively compared the granulocyte collection efficiency (GCE), granulocyte yield, and ADR in 72 randomly paired granulocytapheresis procedures from 36 volunteer donors using the model CS-3000 Plus Blood Cell Separator (CS) and either PS or HS as the sedimenting agent. Paired collections from each donor allowed us to compare the two agents directly while controlling for intrinsic donor differences. In 33 of 36 (92%) donors, HS procedures were significantly more efficient than PS procedures (P < .001). As an average, HS collections yielded 2.3 +/- 0.67 x 10(10) granulocytes at 58% +/- 8.8% GCE, whereas PS procedures resulted in 1.4 +/- 0.76 x 10(10) granulocytes at 33% +/- 15% GCE. No starch-induced ADR were seen with either agent. For granulocyte harvests using the CS, (1) in most donors, using HS as the red blood cell sedimenting agent during centrifugal leukapheresis results in significantly higher (nearly twofold) GCE and larger granulocyte yields in comparison with using PS, (2) ADR were not observed with either agent, and (3) the potential benefit of more rapid PS elimination should be balanced against significantly lower granulocyte yields.     

Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety,Pharmacokinetics, Pharmacodynamics Analysis

Introduction

PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically.

Methods

In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m² weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed.

Results

Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months.

Conclusions

This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.     

A homozygous FKRP start codon mutation is associated with Walker–Warburg syndrome,the severe end of the clinical spectrum

van Reeuwijk J, Olderode‐Berends MJW, van den Elzen C, Brouwer OF, Roscioli T, van Pampus MG, Scheffer H, Brunner HG, van Bokhoven H, Hol FA. A homozygous FKRP start codon mutation is associated with Walker–Warburg syndrome, the severe end of the clinical spectrum. Dystroglycanopathies are a heterogeneous group of disorders caused by defects in the glycosylation pathway of α‐dystroglycan. The clinical spectrum ranges from severe congenital muscular dystrophy with structural brain and eye involvement to a relatively mild adult onset limb‐girdle muscular dystrophy without brain abnormalities and normal intelligence. Mutations have been identified in one of six putative or demonstrated glycosyltransferases. Many different FKRP mutations have been identified, which cover the complete clinical spectrum of dystroglycanopathies. In contrast to the other known genes involved in these disorders, genotype–phenotype correlations are not obvious for FKRP mutations. To date, no homozygous or compound heterozygous null mutations have been identified in FKRP, suggesting that null mutations in FKRP could result in embryonic lethality. We report a family with two siblings carrying a homozygous mutation in the start codon of FKRP that is likely to result in a loss of functional FKRP protein. The clinical phenotype of the patients was consistent with Walker–Warburg syndrome, the most severe disorder in the disease spectrum of dystroglycanopathies.