Recent Developments in Drug Delivery to Prolong Allograft Survival in Lung Transplant Patients

Since the discovery of cyclosporine in 1971, calcineurin inhibitors have played a critical role in the therapeutic suppression of the immune response. Patients receiving solid organ transplants rely heavily on these medications to prevent the acute and chronic rejection of allografted tissue. These therapies can prove difficult because of potential toxicity, heightened risk of invasive infection, and erratic oral bioavailability, requiring frequent blood samples for monitoring of systemic levels. Added challenges are presented in immunosuppression of lung transplant patients owing to the increased susceptibility to invasive infection and extensive immune mechanisms inherent in lung tissue. With the introduction of tacrolimus, a more potent calcineurin inhibitor, clinical outcomes of transplants have continued to improve; however, little improvement has been noted in lung transplantation. While very effective upon arrival at the site of action, tacrolimus and cyclosporine present a variety of formulation challenges such as poor solubility, potential systemic toxicity, and extensive first pass metabolism. Initial attempts to improve solubility in both oral and intravenous formulations have resulted in variable drug absorption and increased systemic toxicity, respectfully, creating a need for formulation improvement. Through alternative routes of delivery and novel formulation techniques, researchers have addressed these issues and, in some cases, demonstrated improved clinical outcomes. Through enhanced solubilization, reduction in absorption variability, and more effective drug targeting with reduced systemic levels, improvements in outcomes and overall patient survival in lung and other solid organ transplantation can be expected.     

Inductive modulation on P-glycoprotein and cytochrome 3A by resveratrol,a constituent of grapes

Resveratrol has been reported to show various beneficial pharmacological effects. Nowadays, resveratrol dietary supplement (RDS) is available in the market. Cyclosporin (CsA), a probe drug of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4), is an important immunosuppressant. This study investigated the effect of coadministration of RDS on CsA pharmacokinetics.     

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design,Synthesis, and in Vitro Validation

Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A₂ (PLA₂), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA₂-catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine-tuning. This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.     

化学修饰的环孢菌素类非免疫抑制性亲环素抑制剂进展

亲环素(Cyps) 是一类在自然界分布广泛、具有高度保守性的多功能蛋白家族,也是重要的免疫抑制药物环孢菌素 A(CsA) 的蛋白受体,具有肽基脯氨酰顺反异构酶(PPIase) 活性。非免疫抑制性亲环素抑制剂是基于CsA 骨架而改造得到的衍生物,这些衍生物能够在抑制亲环素活性的同时降低免疫抑制活性。一些非免疫抑制性亲环素抑制剂(Alisporivir、SCY-635 和 NIM811) 已经证明对丙型肝炎传染病治疗有临床疗效。最近的研究发现亲环素蛋白抑制剂还具有治疗多种病毒性感染,炎性症状,以及癌症的潜力。文章综述了非免疫抑制性环孢菌素衍生物在临床和临床前开发的构效关系,并讨论了这些候选药物的药代动力学和化学生物学特性。     

十全大补丸对环孢菌素A肝毒性的作用

目的 观察十全大补丸对环孢菌素A(CsA)所致大鼠肝毒性的作用。方法 大鼠分为4 组:ⅠCsA 组(50 mg/kg), Ⅱ CsA +十全大补丸高剂量组(50 mg/kg +0.6 g/kg), Ⅲ CsA +大补丸低剂量组(50 mg/kg +0.3 g/kg), Ⅳ空白对照组(等量2 %羧甲基纤维素CMC)。灌胃给药, 每日1 次, 连续7 天后取血, 测定血清谷丙转氨酶(GPT)、硷性磷酸酶(AKP)及血清超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽s-转移酶(GST)。取肝组织作病理检查。结果 用药7天后, CsA +十全大补丸高、低剂量组, 均有明显降低血清GPT、AKP 的作用, 与单用CsA 相比, 有显著性差异。各用药组SOD 活力与对照组比都有所下降, 差异显著:但合并用药组与单用CsA 组比, 无显著性差异。各用药组GST 活力与对照组比也有所下降, 但无显著性差异;合并用药组MDA 均高于对照组, 单用CsA 组低于对照组。结论 十全大补丸对CsA 所致大鼠肝毒性有保肝降酶作用, 其抗氧化清除自由基作用不明显。     

Preparation,Characterization, and Mucoadhesive Properties of Chitosan-Coated Microspheres Encapsulated with Cyclosporine A

The aim of this study was to prepare and characterize chitosan-coated microspheres containing cyclosporine A (CyA). Microspheres encapsulated with CyA were prepared by solvent evaporation-emulsification methods. Microspheres were immersed in chitosan solution (0.5% w/w) to be coated. Morphology, mean size, and encapsulation efficiency of chitosan-coated microspheres were evaluated. To assess the mucoadhesive properties of this drug delivery system, the percent of mucin adsorption to the surface of coated microspheres was determined. Microspheres were spherical in shape. Encapsulation efficiency of different microsphere formulations varied from 78% to 92%. According to the mucin adsorption results, this particulate system showed suitable mucoadhesive properties. It can be concluded that surface modification of microspheres by chitosan coating would increase the prospects of their usefulness as oral drug delivery systems for CyA.     

Amelioration of Cyclosporine A-Induced Acute Nephrotoxicity by Cordyceps cicadae Mycelia via Mg+2 Reabsorption and the Inhibition of GRP78-IRE1-CHOP Pathway: In Vivo and In Vitro

Fruiting bodies of Cordyceps cicadae (CC) have been reported to have a therapeutic effect in chronic kidney disease. Due to the rare and expensive resources from natural habitats, artificially cultivated mycelia using submerged liquid cultivation of CC (CCM) have been recently developed as an alternative to scarce sources of CC. However, little is known regarding potential protective effects of CCM against cyclosporine A (CsA)-induced acute nephrotoxicity in vivo and in vitro. In this study, male Sprague-Dawley rats were divided into six groups: control, CCM (40 mg and 400 mg/kg, orally), CsA (10 mg/kg, oral gavage), and CsA + CCM (40 mg and 400 mg/kg, orally). At the end of the study on day 8, all rats were sacrificed, and the blood and kidneys retrieved. CsA-induced acute nephrotoxicity was evident by increased levels of blood urea nitrogen (BUN). Levels of the endoplasmic reticulum (ER) resident chaperone glucose regulated protein 78 (GRP 78) were increased significantly in rats with acute nephrotoxicity. BUN and GRP 78 were significantly ameliorated in synchronous oral groups of CCM (40 or 400 mg/kg) plus CsA. Examination of hematoxylin and eosin stained kidney tissues revealed that the combined treatment of CCM slightly improved vacuolization in renal tubules upon CsA-induced damage. CsA-induced down-regulation of protein expression of magnesium ion channel proteins and transient receptor potential melastatin 6 and 7 were abolished by the combined treatment of CCM. CCM has the potential to protect the kidney against CsA-induced nephrotoxicity by reducing magnesium ion wasting, tubular cell damage, and ER stress demonstrated further by human renal proximal tubular epithelial cell line HK-2. Our results contribute to the in-depth understanding of the role of polysaccharides and nucleobases as the main secondary metabolites of CCM in the defense system of renal functions in CsA-induced acute nephrotoxicity.     

环孢菌素A柱层析硅胶再生工艺

环孢菌素A工业化生产涉及真菌发酵、萃取、浓缩、结晶、硅胶柱层析、脱色、二次结晶等步骤,目前硅胶柱层析步骤的硅胶只能一次使用,现实生产过程产生了大量的废硅胶,环保处理压力大、企业成本高。据此本文开展了环孢菌素A柱层析硅胶再生工艺研究,针对硅胶上吸附的杂质性质,研究了硅胶再生洗脱溶剂系统,通过响应面法优化再生条件,结果表明：选用含有0.26%聚山梨醇的乙醇反向冲洗4个柱体积,再使用双氧水浓度为0.15%的去离子水正向冲洗2.1个柱体积,冲洗流速为5mL/min;使用压缩空气将再生后的硅胶压出,烘干至水分含量为6%。按照本方法得到的再生硅胶按原工艺使用时,环孢菌素A回收率完全达标,并且可以三次重复使用达标。本研究建立了一套切实可行的环孢素纯化硅胶再生工艺,可有效节约工厂生产成本和减轻环境压力。