霉酚酸的药代动力学与药效学研究进展

霉酚酸是一种选择性、非竞争性、可逆的次黄嘌呤单核苷酸脱氢酶(IMPDH)抑制药,其作为免疫抑制剂已被国内外广泛应用于移植器官急性排异反应以及自身免疫性疾病的预防和治疗。本文对霉酚酸的药代动力学、药效学及其相关性研究等作一综述。     

新型口服抗凝药和唑类抗真菌药相互作用及其机制研究进展

新型口服抗凝药(new oral anticoagulants,NOACs)已广泛用于防治静脉血栓栓塞以及预防非瓣膜性房颤患者的系统性栓塞.NOACs是细胞色素P4503A4(CYP3A4)和/或P糖蛋白的底物,NOACs的暴露量易受CYP3A4和/或P糖蛋白抑制剂的影响.唑类抗真菌药是CYP3A4和/或P糖蛋白抑制剂...     

免疫抑制剂的研究进展

免疫抑制剂是一类具有免疫抑制作用的药物 ,可抑制机体异常的免疫反应 ,目前已广泛应用于器官移植抗排斥反应和自身免疫性疾病的治疗。免疫抑制剂一般可分为类固醇类药物、抗代谢药、Ｔ淋巴细胞抑制剂、抗体类免疫抑制剂４大类 ,且许多新型免疫抑制剂也相继问世。本文拟就免疫抑制剂的研究进展作一综述。１类固醇类药物类固醇类药物 (肾上腺皮质激素类药物 )有泼尼松、氢化泼尼松和地塞米松等。此类药物对免疫反应的多个环节均有抑制作用 ,包括防止和抑制细胞中介的免疫反应 (延迟性过敏反应 ) ,减少Ｔ淋巴细胞、单核细胞、嗜酸性细胞的数目…     

抗深部真菌药的进展

近年来，随着广谱抗菌药物和免疫抑制剂的大量应用以及肿瘤化疗、器官移植和艾滋病(AIDS)的出现，免疫抑制人群不断增多，真菌感染的发病率呈上升趋势，特别是深部真菌感染日益引起人们关注，抗深部真菌药的研究是目前抗微生物药的研究热点之一。     

群体药动学在免疫抑制剂合理用药中的应用

群体药动学(PPK)应用统计学原理,综合评价影响药动学个体间及个体内差异的各种因素,进一步利用Bayesian反馈,能够较为准确地预测患者个体药动学参数。PPK在免疫抑制剂环孢素、他克莫司、霉酚酸及西罗莫司的合理用药均有广泛应用。     

肾移植术后患者口服环孢素的药代动力学研究

环孢素A(CsA)是一种高效能的免疫抑制剂，广泛应用于肾脏、肝脏等器官移植及其他疾病的治疗。但由于其不良反应多，治疗窗较窄，个体差异较大，因此根据血药浓度监测情况及时调整用药剂量日益受到临床重视。在器官移植术后CsA的剂量调整中，(CsA谷值(C0值)是一个常用的指标。     

雷公藤内酯醇滴眼液眼内药代动力学的实验研究

角膜移植免疫排斥反应是角膜移植失败的主要原因 ,寻找高效低毒的免疫抑制剂一直是临床面临的主要问题。雷公藤 (ＴｒｉｐｔｅｒｙｇｉｕｍｗｉｌｆｏｒｄｉｉＨｏｏｋ ｆ ,ＴＷＨｆ)有免疫抑制、抗炎、抗生育、抗肿瘤和抗菌作用 ,可用于治疗多种自身免疫性疾病 ,过敏性疾病 ,皮肤性疾病 ,器官移植术后抑制免疫排斥反应[1] ,但由于其全身应用对造血系统、心、肝、肾及生殖系统毒副作用较大 ,阻碍了其广泛的临床应用。雷公藤单体研究发现 ,雷公藤内酯醇 (ｔｒｉｐｔｏｌｉｄｅ,又称Ｔ10 、甲素 )是ＴＷＨｆ的主要活性成分[2 ] ,目前虽有Ｔ10 …     

改变病情抗风湿药临床研究进展

改变病情抗风湿药(Disease modifying antirheumatic dru_gs,DMARDs)是一类减轻类风湿性关节炎(Rheumatoid arthr_itis,RA)症状体征、控制病情发展和阻止关节结构继续破坏的药物[1]。主要通过抑制或调节机体免疫反应中的某一环节而起作用,起效慢,一般在6wk以上才显示作用,故又称慢作用抗风湿药(SAARDs)。根据其作用特点和来源,可分为经典的慢作用抗风湿药、抗疟药、免疫抑制剂、生物制剂、植物提取物等。1经典的慢作用抗风湿药包括多种传统上未用于RA治疗的药物如青霉胺、金诺芬、柳氮磺胺吡啶。其抗风湿机制可能与对某些免疫细胞和…     

抗真菌药研究进展与不良反应

<正> 近年随着广谱抗生素、免疫抑制剂和糖皮质激素的广泛使用,器官移植术后、肿瘤化疗,特别是艾滋病的广泛传播,机体免疫力降低,真菌感染的发病率大大提高,深部真菌感染已成为免疫功能低下患者发病和死亡最常见的原因。由于真菌感染的发病率逐年增加,抗真菌药物的临床应用也愈来愈     

甲氨蝶呤的药动学特性与给药方案

甲氨蝶呤(Methotrexate,简称MTX)为抗癌药,亦为免疫抑制剂,MTX在人体内的过程是极复杂的,影响血药浓度的因素很多,它的血浆水平存在着很大的个体差异。因此,临床多提倡使用血药浓度监测。     

Design and synthesis of nonpeptide mimetics of jaspamide

Jaspamide is a novel metabolite of mixed peptide/polyketide biosynthesis that was isolated from sponges of the genus Jaspis, and that has been reported to exhibit both insecticidal and antifungal activity. We have evaluated three nonpeptide mimetic designs, and have synthesized a nonpeptide mimic of the proposed bioactive region to investigate the structure activity relationship. Structural investigations of potential mimetics, utilizing molecular modeling in conjunction with spectroscopic and crystallographic data, indicate that positioning of the critical functional groups in two mimetics corresponds closely to that observed in jaspamide, and that the flexibility of mimetic 4 approximates that of jaspamide. Initial biological evaluation suggests that lactam mimetic 4 exhibits a biological profile similar to jaspamide.     

Mobilization and fusion of a non-recycling pool of synaptic vesicles under conditions of endocytic blockade

At vertebrate central synapses, it has been demonstrated that a resting pool of synaptic vesicles (SVs) exists that normally does not participate in SV release and recycling. It remains unclear whether SVs within the resting pool are capable of mobilization and fusion. Here, we combine live imaging of SV exo- and endocytosis using pH-sensitive GFP (synapto-pHluorins) with pharmacological and genetic manipulations of the SV cycle at the Drosophila NMJ. We demonstrate that a resting pool of SVs exists at this synapse that encompasses 30-41% of the total SV pool. Under conditions of endocytic blockade, using a temperature-sensitive dynamin mutation, the resting pool of SVs can be mobilized and released. We present a model for the presence of a resting pool of SVs that does not require molecular specification of a subpopulation of SVs.     

Application of multi-factorial design of experiments to successfully optimize immunoassays for robust measurements of therapeutic proteins

Developing a process that generates robust immunoassays that can be used to support studies with tight timelines is a common challenge for bioanalytical laboratories. Design of experiments (DOEs) is a tool that has been used by many industries for the purpose of optimizing processes. The approach is capable of identifying critical factors and their interactions with a minimal number of experiments. The challenge for implementing this tool in the bioanalytical laboratory is to develop a user-friendly approach that scientists can understand and apply. We have successfully addressed these challenges by eliminating the screening design, introducing automation, and applying a simple mathematical approach for the output parameter.     

Influence of solvents on the variety of crystalline forms of erythromycin

The influence of the organic solvents widely used in the pharmaceutical industry (acetone, methylethylketone, ethanol, and isopropanol) both in the presence and in the absence of water on the crystallization behavior of erythromycin (Em), a clinically relevant antibiotic of the macrolide group, was investigated. It was observed that despite a high preference for water as a guest molecule, Em rather easily forms solvates with the organic solvents studied. Consequently, 4 distinct solvates of Em have been isolated by recrystallization: acetonate, methylethylketonate, ethanolate, and isopropanolate. It was established that in a pure organic solvent, or 1∶9 or 1∶1 water-organic solvent mixtures, the corresponding solvate is always crystallized. However, the recrystallization of erythromycin from 2∶1 water-organic solvent (excluding methylethylketone) mixture results in the formation of a crystal hydrate form. X-ray powder diffraction revealed the isostructurality of the solvates with acetone and methylethylketone. Thermogravimetric analysis showed that the loss of volatiles by all of the solvated crystals is nonstoichiometric. The desolvation behavior of the solvates with the organic solvents studied by means of variable-temperature x-ray powder diffraction indicates that in contrast to erythromycin dihydrate, they belong to a different class of solvates—those that produce an amorphous material upon desolvation.     

An evaluation of the role of smoking context on a biobehavioral index of distress tolerance

The present study evaluated the effect of smoking deprivation on a biobehavioral index of distress tolerance, breath-holding duration, among 43 adult smokers in a repeated measures test (Session 1=smoking-as-usual, Session 2=12-h smoking deprivation). We theorized that distress tolerance is a context-dependent individual difference variable whose expression varies prospectively, within-individuals, as a function of smoking context. As predicted, participants' breath-holding duration was significantly shorter during an experimental session that immediately followed a 12-h smoking deprivation period than during a smoking-as-usual session. Furthermore, we theorized that among individuals with a pre-existing diathesis (i.e., psychiatric symptoms), smoking deprivation may activate a vulnerability process that decreases capacity to tolerate distress; in the absence of this stressor, these psychiatrically vulnerable smokers may express variable levels of distress tolerance. As predicted, we observed that level of psychiatric symptoms was significantly negatively correlated with breath-holding duration during the smoking deprivation, but not the smoking-as-usual session. These data advance our understanding of smoking and distress tolerance and the context-dependent phenomenology of distress tolerance.     

The evaluation of psoriasis therapy with biologics leads to a revision of the current view of the pathogenesis of this disorder

Psoriasis is a common chronic, recurring skin disease that is characterised by typical macroscopic and microscopic skin alterations. It is widely accepted that the immune system plays an important role in the pathogenesis of this disorder. Since the early 1990s, the dominant role of a subpopulation of T cells, so-called T1 cells, and their prominent cytokine IFN-γ has been assumed in the pathogenesis of psoriasis. Surprisingly, the comparison of the therapeutic success of treatments with recombinant proteins directed against defined immunological structures shows that those that directly affect T cells (alefacept, efalizumab, Hu-max-CD4, OKTcdr4a) were clearly less effective than those targeting TNF-α (etanercept, adalimumab, infliximab). For this reason, the authors critically re-evaluated the view of psoriasis pathogenesis and postulate that in the majority of patients the T1 cells do not play a dominant role in the clinical, visible stage of this disease.     

Comparison of the cytotoxic effects of cadmium (Cd) in high and low resistance strains of MDCK cells that express different levels of E-Cadherin

Previous studies from our laboratory have shown that cadmium (Cd²⁺) can disrupt the adhering and occluding junctions between MDCK cells. Recently, we have obtained evidence to suggest that Cd²⁺ produces this effect by interacting with E-cadherin, a Ca²⁺-dependent cell adhesion molecule that is localized at the adhering junctions of epithelial cells. The objective of the present study was to examine the junctional and cytotoxic effects of Cd²⁺ in subcloned strains of MDCK cells that express different levels of E-cadherin. One strain (MDCK I) expresses high levels of E-cadherin and develops a transepithelial electrical resistance of more than 800 Ω·cm², whereas the other strain (MDCK II) expresses much lower levels of E-cadherin and develops a transepithelial resistance of less than 100 Ω·cm². The results showed that exposure to 20 μ Cd²⁺ for 2–4 hours caused a pronounced loss of E-cadherin from the cell borders in both strains of cells. In the MDCK I cells, the loss of E-cadherin coincided with a decrease in the transepithelial electrical resistance and the loss of the tight junction-associated proteins, ZO-1 and occludin, from the cell borders. By contrast, the MDCK II cells first exhibited a significant increase in the transepithelial electrical resistance that did not begin to decline until the cells had been exposed for 4–6 hours, a time that coincided with the loss of ZO-1 and occludin from the cell borders. Additional results showed that the MDCK I cells were slightly more sensitive to the lethal effects of Cd²⁺ than were the MDCK II cells. These findings indicate that E-cadherin may be an early target for Cd²⁺ toxicity in both high and low resistance strains of MDCK cells. However, they also suggest that the disruption of E-cadherin-dependent cell–cell junctions may trigger somewhat different responses in the two cell lines.     

医院临床药师的在职培养

目的结合医院临床药学工作开展的情况,探讨在临床药师人才缺乏的现状下,加速临床药师培养的途径和方法。方法根据医院临床药师工作的现状,论述加快临床药师培养的必要性,探讨培养目标、学习计划及培养途径。结果针对临床药师人才缺乏的现状,提出临床药师必需进行临床药学、临床医学和相关知识的拓展,通过自学;参加临床药学培训班、研讨班和学术交流活动;进修学习;研究生学位升造;及临床实践等途径,来完成临床药师的在职培养与继续教育。结论在新的药学服务领域,只有加速临床药师的在职培养与继续教育,才能更好推进医院临床药学工作的健康发展,促使临床药师的工作成为医院整体医疗技术工作中不可获缺的一环,临床药师才能有更广阔的发展空间。     

Photoirradiation of dehydropyrrolizidine alkaloids--formation of reactive oxygen species and induction of lipid peroxidation

Pyrrolizidine alkaloid (PA)-containing plants are widespread in the world and are probably the most common poisonous plants affecting livestock, wildlife, and human. PAs require metabolic activation to generate pyrrolic metabolites (dehydro-PAs) that bind cellular protein and DNA, leading to hepatotoxicity and genotoxicity, including tumorigenicity. In this study we report that UVA photoirradiation of a series of dehydro-PAs, e.g., dehydromonocrotaline, dehydroriddelliine, dehydroretrorsine, dehydrosenecionine, dehydroseneciphylline, dehydrolasiocarpine, dehydroheliotrine, and dehydroretronecine (DHR) at 0-70 J/cm² in the presence of a lipid, methyl linoleate, resulted in lipid peroxidation in a light dose-responsive manner. When irradiated in the presence of sodium azide, the level of lipid peroxidation decreased; lipid peroxidation was enhanced when methanol was replaced by deuterated methanol. These results suggest that singlet oxygen is a photo-induced product. When irradiated in the presence of superoxide dismutase, the level of lipid peroxidation decreased, indicating that lipid peroxidation is also mediated by superoxide. Electron spin resonance (ESR) spin trapping studies confirmed that both singlet oxygen and superoxide anion radical were formed during photoirradiation. These results indicate that UVA photoirradiation of dehydro-PAs generates reactive oxygen species (ROS) that mediated the initiation of lipid peroxidation. UVA irradiation of the parent PAs and other PA metabolites, including PA N-oxides, under similar experimental conditions did not produce lipid peroxidation. It is known that PAs induce skin cancer and are secondary (hepatogenous) photosensitization agents. Our results suggest that dehydro-PAs are the active metabolites responsible for skin cancer formation and PA-induced secondary photosensitization.     

Use of the occlusive patch to evaluate the photosensitive properties of chemicals in guinea-pigs

Guinea-pig tests were conducted on a known photocontact allergen, tetrachlorosalicylanilide (TCSA), a known phototoxin, 8-methoxypsoralen, two reportedly weak photoallergens, musk ambrette and 6-methylcoumarin, and a negative control, octylphenoxy polyethoxyethanol (Triton X-15). The data show that under the test conditions used, photosensitivity responses can be produced, and combinations of these as well as the other biological responses can be readily defined. The results indicate that musk ambrette is photoallergenic, that 8-methoxypsoralen is phototoxic and that Triton X-15 is only a slight irritant. On the other hand, results with TCSA suggest that it is a strong contact allergen and photoallergen, while 6-methylcoumarin would be considered to be a weak contact allergen with weak phototoxic properties. Previous reports that barrier destruction or adjuvanticity is necessary to produce photoallergy to musk ambrette were not confirmed; by ensuring occlusion using standard methods, the photoallergic nature of the response to this material was clearly demonstrated. A device described elsewhere (Newmann & Parker, Fd Chem. Toxic. 1985, 23, 683) has made it possible to develop methods that can be used to differentiate clearly among the possible biological responses that can occur in guinea-pigs when photoreactive materials are applied to their skin and irradiated. The probable biological responses that need to be defined, under the above conditions, are primary irritation, delayed contact hypersensitivity, phototoxicity and/or photoallergenicity.