Design,delivery and efficacy testing of therapeutic nucleic acids used to inhibit hepatitis C virus gene expression in vitro and in vivo

Despite major achievements in the treatment ofchronic hepatitis C with the combination ofinterferons and the nucleoside analog ribavirin themajority of patients with chronic hepatitis C virus(HCV) infection cannot be treated effectively.Toimprove this response rate we used antisensetechnologies to inhibit HCV translation as possibleadditional option for experimental treatment.Antisense oligodeoxynucleotides(ODN) are

Therapeutic and Medicinal Uses of <i>Aloe vera</i>: A Review

The plant Aloe vera is used in Ayurvedic, Homoeopathic and Allopathic streams of medicine, and not only tribal community but also most of the people for food and medicine. The plant leaves contains numerous vitamins, minerals, enzymes, amino acids, natural sugars and other bioactive compounds with emollient, purgative, anti-microbial, anti inflammatory, antioxidant, aphrodisiac, anti-helmenthic, antifungal, antiseptic and cosmetic values for health care. This plant has potential to cure sunburns, burns and minor cuts, and even skin cancer. The external use in cosmetic primarily acts as skin healer and prevents injury of epithelial tissues, cures acne and gives a youthful glow to skin, also acts as extremely powerful laxative.

Continuous Wear of Hydrogel Contact Lenses for Therapeutic Use

Purpose: To investigate the efficacy and complications of continuous wear of etafilcon A for therapeutic use. Materials and Methods: The subjects were 228 eyes of 219 outpatients prescribed contact lens (CL) for one week of continuous therapeutic wear during 10 years. The reason for prescription of CLs, the primary disease, the duration of CL wear and the complications were assessed retrospectively. Results: The predominant reason for prescription of CLs was relief of pain or a foreign-body sensation (62.3%) and protection of the corneal epithelium (20.6%). The primary disease was post-penetrating keratoplasty (36.8%), followed by corneal epithelial erosion (14.5%), post-lamellar keratoplasty (14.0%) and bullous keratopathy (12.2%). The average duration of wearing single lens was 6.5 ± 3.2 days. The average duration of wearing CLs in total was 9.2 ± 10.7 months. The most frequent problem associated with continuous wear of CLs was their dropping out of CLs (12.3%). The complications associated with CLs included conjunctivitis with papillary hyperplasia, corneal erosion and superficial punctate keratitis, but corneal ulcer and corneal infiltrates were not found. Conclusion: Serious complications were not shown changing the lenses every week to keep to the prescribed time limit for continuous therapeutic wear, even if corneal epithelial barrier function is impaired.

Comparison of long-lasting therapeutic effects between succimer and penicillamine on hepatolenticular degeneration

AIM To compare the long term effect of succimer (Suc) with that of penicillamine (Pen) in treating hepatolenticular degeneration (HLD). METHODS One hundred and twenty patients with HLD were divided into 2 groups. Group A ( n =60) received Suc 750mg , po. bid. Group B ( n =60) received Pen 250mg , po. qid. The period of maintenance treatment varied from 6 months to 3 years, averaging 1 5 years. Symptoms and therapeutic effects were evaluated by modified Goldstein scale. RESULTS The total effectiveness of group A in two different periods of treatment were 80% and 85% respectively, higher than those of group B (58% and 59% respectively) ( P <0 05). Suc also had obvious curative effects for the patients who failed in the use of Pen. There were fewer side effect in group A than in group B ( P <0 05). Suc and Pen could increase urinary copper excretion effectively and continually. CONCLUSION Suc is more effective and safer than Pen. Clinically, it can replace Pen as first choice drug for long term maintenance therapy of HLD.

Functional dyspepsia of ulcer-dysmotility type:clinical incidence and therapeutic strategy

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Therapeutic role of template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract

Lymphadenectomy for urothelial carcinoma of the upper urinary tract has attracted the attention of physicians. The mapping study of lymphatic spread has shown that a relatively wide area should comprise the regional nodes for tumors of the right renal pelvis or the right upper two-thirds of the ureter. A prospective study showed that an anatomical templatebased lymphadenectomy significantly improved patient survival in tumors of the renal pelvis. This benefit was more evident for patients with p T2 stage tumors or higher. The risk of regional node recurrence is significant reduced by template-based lymphadenectomy,which is likely to be associated with improved patient survival. The removal of lymph node micrometastases is assumed to be the reason for therapeutic benefit following lymphadenectomy. The number of resected lymph nodes can be used to assess the quality of lymphadenectomy,but not to determine the extent of lymphadenectomy. The guidelines currently recommend lymphadenectomy for patients with muscle-invasive disease,even though the current recommendation grades are still low. The present limitation of lymphadenectomy is the lack of standardization of the extent of lymphadenectomy and the randomized trials. Further studies are warranted to collect the evidence to support lymphadenectomy.

Effects of Cholestasis on Whole Blood Concentration of Tacrolimus, an Immunosuppressant, in Living-Related Liver Transplant Recipients

Background: To explore the effects of cholestasis on whole blood concentration of tacrolimus (TAC), an immunosup-pressant, we investigated the relationship among blood TAC concentration, bile flow, and TAC metabolites in bile, as well as the relationship between total bilirubin (T-Bil), an index of cholestasis, and blood TAC concentration, in liver transplant recipients. Methods: Data were collected retrospectively from 16 male and 19 female patients (mean age: 38 years;range: 12 -59 years) who had undergone a living-related liver transplantation at Kyoto Prefectural University of Medicine from 2004 through 2008. Analysis of TAC, demethyl-TAC, and hydroxy-TAC in bile was performed by LC-MS/MS. Results: There was no correlation between the ratio of TAC metabolite to TAC in bile (M/P) of demethyl-TAC and post operation days (POD), whereas a weak linear correlation was demonstrated between M/P of hydroxy-TAC and POD (r = -0.345). Moreover, linear correlations were not observed between M/P and the TAC trough level normalized dose (TLTAC/dose), and between TLTAC/dose and POD. A negative linear correlation was demonstrated between bile flow and T-Bil in blood (r = -0.495). Furthermore, a positive linear correlation was observed between TLTAC/dose and T-Bil (r = 0.598), whereas there was no correlation between bile flow and TLTAC/dose. Conclusions: Improvement of hepatic function and the increase of TAC clearance after postoperative day 7 did not significantly contribute to hepatic TAC metabolism, bile excretion, and TLTAC/dose. Postoperative biliary stricture from liver transplantation with/without biliary drainage caused inter-and intra-patient variability in TLTAC/dose after liver transplantation, which could be assessed by T-Bil. T-Bil in blood might be a predictive biomarker for determining the degree of bile duct stricture and TAC dose in liver transplantation patients. Along with an appropriate dosing regimen, therapeutic drug monitoring including T-Bil would be beneficial and enable individual adjustment of TAC dose in liver transplantation patients.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype

BACKGROUND Tacrolimus extended-release tablets have been Food and Drug Administrationapproved for use in the de novo kidney transplant population.Dosing requirements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression.Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus,but this has not been established for tacrolimus extended-release tablets in the de novo setting.AIM To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype.METHODS Single-arm,prospective,single-center,open-label,observational study(ClinicalTrials.gov:NCT037-13645).Life cycle pharma tacrolimus(LCPT)orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight.If weight is more than 120%of ideal body weight,an adjusted body weight was used.LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL.Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion.RESULTS Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(6 d vs 13.5 d vs 4.5 d;P=0.025).Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(16 mg vs 16 mg vs 12 mg;P=0.010)(0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg;P=0.018).CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers(7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL;P=00.008).No differences were identified with regards to kidney graft function at 30-d post-transplant.Serious adverse events were reported for 13(36%)patients.CONCLUSION Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacrolimus to achieve target trough concentrations.We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Blastocystis hominis as a cause of chronic diarrhea in low-resource settings:A systematic review

BACKGROUND Blastocystis hominis(B.hominis),an anaerobic unicellular protist parasite,is known for its diverse clinical manifestations upon infecting the human gastrointestinal tract.Although globally distributed,it is particularly prevalent in developing nations.Examining the symptoms and treatment outcomes of B.hominis infection in low-resource settings holds immense significance,providing healthcare practi-tioners with valuable insights to enhance patient care.AIM To synthesize existing evidence on the symptomatology and treatment outcomes of B.hominis infection in low-resource settings.METHODS Following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines,a systematic review was conducted.The search spanned electronic databases including PubMed,Scopus,and Google Scholar.After a comprehensive screening process,a thorough examination of the papers,adhering to inclusion and exclusion criteria,and data extraction from eligible studies was conducted.The findings underwent summarization through simple descriptive analysis.RESULTS The search yielded 1200 papers,with 17 meeting inclusion criteria.Chronic diarrhea due to B.hominis infection was reported in only two studies,while abdominal pain,diarrhea,flatulence,constipation,and nausea/vomiting emerged as the most commonly documented symptoms.Recovery rates after one week of treatment ranged from 71.8%to 100%,and after two weeks,from 60%to 100%.CONCLUSION In low-resource settings,chronic diarrhea resulting from B.hominis infection is infrequent.Common symptoms include abdominal pain,diarrhea,flatulence,constipation,and nausea/vomiting.Post-treatment,clinical outcomes are notably favorable,supporting the recommendation for treatment.Metronidazole is advocated as the first-line agent,with consideration for switching to a second-line option in cases of treatment failure or poor response.

Clinacanthus nutans:a review of the medicinal uses,pharmacology and phytochemistry

Clinacanthus nutans Lindau is known as snake grass belonging to the Acanlhaceae family.This plant has diverse and potential medicinal uses in traditional herbal medicine for treating skin rashes,insects and snake bites,lesions caused by herpes simplex virus,diabetes,and gout in Malaysia.Indonesia.Thailand and China.Phylochemieal investigations documented the varied contents of bioaclive compounds from litis plant namely flavonoids,glycosides,glycoglyeerolipids.cerebrosides and monoacylmonogalatosylglycerol.The pharmacological experiment proved that various types of extracts and pure compounds from this species exhibited a broad range of biological properties such as anti-inflammatory,antiviral,antioxidant,and anti-diabetic activities.The lindings of toxicity study showed that extracts from this plant did not show any toxicity thus it can be used as strong therapeutic agents for specific diseased conditions.However,further experiments on chemical components and their mode of action showing biological activities are required to elucidate the complete phytochemical profile and assess to confirm their suitability tor future drugs.This review summarizes the medicinal uses,phytochemistry and pharmacology of this plant in order to explore its therapeutic potential and gaps necessitating for prospected research work.

High-intensity focused ultrasound extracorporeal ablation of liver tissuesin rabbits

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环孢素A和他克莫司的高效液相色谱-串联质谱检测及其室内质控评价

目的建立环孢素A和他克莫司治疗药物监测的高效液相色谱-串联质谱(HPLC-MS/MS)质控方法,应用Westgard多规则理论对质控样品进行评估。方法利用HPLC-MS/MS建立人全血中环孢素A和他克莫司的血药浓度检测方法。对治疗药物监测过程中低、中、高3个浓度水平的质控样品进行统计分析,绘制Levery-Jennings和Z分数质控图,应用Westgard多规则理论进行室内质控评估。结果环孢素A和他克莫司的线性范围分别为10.40~1040.00和0.50~49.50 ng·mL^(-1),定量下限分别为10.40和0.50 ng·mL^(-1),提取回收率分别为108.61%~113.24%和101.99%~109.37%,内标归一化的基质因子分别为106.68%~111.27%和95.70%~97.81%,日内和日间的准确度及精密度均小于15.0%,其他参数也均符合生物样本定量分析要求。Levery-Jennings和Z分数质控图显示,2022年第三季度26组质控样品的检测结果提出警告4次(违反12s规则),未出现失控现象。结论建立的环孢素A和他克莫司治疗药物监测室内质控体系能够有效保障血药浓度检测的准确性。

他克莫司治疗药物监测异常结果干预及评价研究

目的:探究欧洲医药保健网(Pharmaceutical Care Network Europe,PCNE)分类系统用于评价肾移植受者他克莫司浓度波动药物相关问题(drug related problems,DRPs)的作用。方法:以门诊随访中出现他克莫司血药浓度波动、临床药师介入干预的肾移植受者为研究对象,利用PCNE(9.0)分类系统评价他克莫司的DRPs,并对存在DRPs的问题、原因、介入方案、介入方案的接受和状态进行分析。结果:本研究纳入2019年7月至2021年12月肾移植受者700例,发现1014个他克莫司DRPs。DRPs的问题包括发生药物不良事件(P2.1,60.16%)和治疗效果不佳(P1.2,39.84%);原因主要包括剂量选择(C3,43%)、其他(C9,38.4%)和药物选择(C1,9.41%);临床药师从受者层面(I2,98.92%)和药物层面(I3,1.08%)积极介入;介入方案(A1.1+A1.3)的接受率达98.62%,完全执行(A1.1)率达72.09%;79.29%的DPRs被全部解决或部分解决(O1.1和O2.1)。结论:临床药师可将PCNE用于评价他克莫司治疗药物监测(therapeutic drug monitoring,TDM)相关DRPs,助力TDM药学服务模式标准化,规范TDM异常结果解读和干预工作,促进安全合理用药。

HPLC-MS/MS法同时测定患者全血中他克莫司和五酯胶囊4种主要成分的浓度

建立HPLC-MS/MS法同时测定人全血中他克莫司和五酯胶囊4种主要成分五味子甲素、五味子乙素、五味子醇甲、五味子酯甲的浓度,并用于免疫抑制剂他克莫司联用保肝中药五酯胶囊临床药物浓度监测的研究中。采用了WatersAcquity UPLC■BEH C18色谱柱(50×2.1mm,1.7μm),以5mmol/L乙酸铵-0.1%甲酸水溶液为水相,乙腈为有机相,流速为0.3mL/min,柱温60℃。各成分均采用他克莫司同位素化合物(13C,2H4)作为内标(IS),全血样本首先经硫酸锌处理,再加入含内标的乙腈沉淀蛋白,最后离心后取上清液进样,质谱采用电喷雾离子源,以多反应离子监测(MRM)、正离子扫描模式检测。建立的HPLC-MS/MS法在1~100ng/m L范围内,他克莫司和五酯胶囊的4种主要成分色谱响应与浓度相关性良好,定量下限均为1ng/m L;他克莫司、五味子甲素、五味子乙素、五味子醇甲、五味子酯甲以及内标的保留时间分别为2.54、2.33、2.65、1.14、1.56、2.54min;准确度、回收率和经内标校准后的基质效应及稳定性数据均符合相关要求。方法灵敏、专属性强、准确性好,适用于人全血中他克莫司、五味子甲素、五味子乙素、五味子醇甲、五味子酯甲的浓度测定。

肝肾移植受者外周血单个核细胞内他克莫司浓度监测研究进展

免疫抑制剂他克莫司(TAC)是肝肾移植术后的基础药物,其治疗窗窄、个体差异大,目前临床对其全血药物谷浓度进行治疗药物监测,以保证药物疗效和避免药物过度暴露。但TAC血药浓度不完全与其对靶细胞的药理作用相关,不能可靠地反映药物疗效和避免不良反应。本文阐述外周血单个核细胞内TAC浓度与药效、不良反应之间的相关性以及影响胞内药物浓度的因素,探讨靶细胞内TAC浓度监测的价值。

个体化给药辅助决策系统JPKD对肾移植受者他克莫司血药浓度预测能力评估

目的分析个体化给药辅助决策系统Java PK®for Desktop(JPKD)对肾移植受者他克莫司血药浓度的预测能力及影响因素。方法收集149例肾移植术后早期受者他克莫司血药浓度监测数据,使用JPKD预测他克莫司剂量调整后的血药谷浓度,计算实测浓度与预测浓度之间的绝对值权重偏差和相对预测误差。使用单因素和多因素logistic回归分析影响绝对权重偏差的相关因素,并绘制受试者工作特征(ROC)曲线评价影响因素对软件预测准确性的判断价值。结果收集149例患者266例次血药浓度数据,他克莫司血药浓度实测值为(6.5±3.0)ng/mL(1.1~16.6 ng/mL),JPKD进行计算的预测值为(5.6±2.5)ng/mL(1.4~14.4 ng/mL),计算结果的绝对权重偏差为28.38%,相对预测误差为−13.55%。单因素分析显示性别、白蛋白、红细胞比容变化、细胞色素P450(CYP)3A5*3基因型、C3435T基因型与预测结果不准确有关。多因素logistic回归分析显示CYP3A5*3基因型为AA、红细胞比容变化是影响JPKD预测他克莫司血药浓度准确性的独立危险因素。ROC曲线分析显示,红细胞比容变化>2.25%时,软件预测不准确的风险增加。结论JPKD用于预测肾移植受者他克莫司血药浓度具有一定的准确性,可以提高血药浓度的达标率,但CYP3A5*3基因型、红细胞比容变化会影响预测的准确性。

Controversies regarding transplantation of mesenchymal stem cells

Mesenchymal stem cells(MSCs)have tantalized regenerative medicine with their therapeutic potential,yet a cloud of controversies looms over their clinical tran-splantation.This comprehensive review navigates the intricate landscape of MSC controversies,drawing upon 15 years of clinical experience and research.We delve into the fundamental properties of MSCs,exploring their unique immuno-modulatory capabilities and surface markers.The heart of our inquiry lies in the controversial applications of MSC transplantation,including the perennial debate between autologous and allogeneic sources,concerns about efficacy,and lingering safety apprehensions.Moreover,we unravel the enigmatic mechanisms surro-unding MSC transplantation,such as homing,integration,and the delicate balance between differentiation and paracrine effects.We also assess the current status of clinical trials and the ever-evolving regulatory landscape.As we peer into the future,we examine emerging trends,envisioning personalized medicine and innovative delivery methods.Our review provides a balanced and informed perspective on the controversies,offering readers a clear understanding of the complexities,challenges,and potential solutions in MSC transplantation.

USE OF CELL-BASED BIOASSAY FOR THE QUALITY CONTROL OF BOTANICAL THERAPEUTICS

The single most important factor in modernization efforts of traditional oriental medicines is the limited understanding of active compounds responsible for claimed therapeutic effects.Indeed,the unknown identity of biologically active molecules generates major difficulties associated with botanical therapeutics in general.This includes management of raw materials,poor understanding of

他克莫司个体化用药指南解读

他克莫司体内过程个体差异大,治疗窗窄,给药剂量难以掌握。为保证其临床实践中安全、有效及合理应用,已有许多国家和地区发布了他克莫司用药的相关指南;但这些指南仅针对特定疾病和人群,具有一定的局限性。文中对相关指南进行解读和分析,并结合他克莫司药物基因组学与治疗药物监测的最新研究进展,归纳整理适合中国人群的他克莫司个体化用药方法,进一步完善他克莫司在临床上的合理使用。

0.05％他克莫司滴眼液治疗难治性免疫相关角膜溃疡的疗效及安全性研究

背景 难治性免疫相关角膜溃疡的局部药物治疗难以奏效,全身使用糖皮质激素和免疫抑制剂有产生严重不良反应的可能.研究表明他克莫司局部用药可以抑制局部的免疫性炎症,但目前没有关于质量分数0.05％他克莫司滴眼剂治疗难治性免疫相关角膜溃疡疗效和安全性的研究. 目的 研究0.05％他克莫司滴眼液点眼治疗难治性免疫相关角膜溃疡的疗效及安全性. 方法 采用观察性研究方法,对2010年7月至2014年9月于河南省立眼科医院用0.05％他克莫司滴眼液治疗的难治性免疫相关角膜溃疡患者17例21眼的疗效进行评估,其中男11例14眼,女6例7眼;平均年龄52岁.患者中11例未发现全身疾病,免疫学检测未见异常;6例有全身免疫性疾病,包括Wegener肉芽肿1例,风湿性关节炎4例,溃疡性肠炎1例,全身免疫性疾病经内科治疗病情已控制.单眼发病者13例,双眼发病者4例.病灶大于3个象限者2例2眼,2个象限以下者15例19眼.患者均经局部质量分数1％环孢素A和糖皮质激素治疗后角膜溃疡不愈或持续进展.采用0.05％他克莫司滴眼液点眼,根据病情调整用药剂量,分别于治疗前、治疗后1周及1、3、6、12和24个月裂隙灯显微镜下动态观察角膜溃疡的病灶变化,采用激光扫描共焦显微镜HRT-Ⅲ检查角膜病灶区炎性细胞密度的变化,评价0.05％他克莫司滴眼液的疗效.治疗期间观察和记录用药后眼部的不良反应,定期应用化学发光微粒子免疫法检测患者的血药质量浓度,实验室检查包括患者血常规、血糖水平和肝肾功能,评价药物的安全性.结果 本组患者治疗疗程为8 ～ 24个月,平均18.1个月.9眼治疗12个月,12眼治疗24个月.裂隙灯显微镜检查可见治疗后1个月15例19眼角膜溃疡面积缩小,2例2眼因溃疡进展而行板层角膜移植术,术后继续给予0.05％他克莫司滴眼液治疗;治疗后3个月角膜溃疡愈合;治疗后6个月病灶部位角膜基质浸润及水肿均消失.激光扫描共焦显微镜检查结果显示,治疗前及治疗后1周、1个月、3个月、6个月、12个月、24个月,患眼角膜病灶部位炎性细胞密度分别为（958±329）、（858±339）、（459±261）、（192±124）、（98±52）、（44±24）和（3±2）/mm2,随着治疗时间的延长,炎性细胞密度逐渐下降,总体比较差异有统计学意义（F=125.439,P=0.000）,其中治疗后1、3、6、12和24个月角膜炎性细胞密度较术前明显减少,差异均有统计学意义（均P=0.000）.患眼治疗期间4例出现一过性局部刺激感或烧灼感;患者血药质量浓度均在1.0 ng/ml以下,实验室检查未见异常. 结论 0.05％他克莫司滴眼液治疗后难治性免疫相关角膜溃疡愈合,炎症反应消失,不良反应轻微。