促进肝星状细胞凋亡的抗肝纤维化药物的研究进展

肝星状细胞（HSC）在肝纤维化的发生、发展和消退过程中均发挥着重要作用,通过特异性诱导活化的肝星状细胞（aHSC）凋亡,既可减少细胞外基质产生,又可促进其降解,有助于逆转肝纤维化。研究发现,多种药物可通过线粒体途径、死亡受体途径和内质网应激途径等诱导aHSC凋亡。该文就诱导aHSC凋亡的药物及其作用机制作一综述,以期为抗肝纤维化药物的研发提供参考。     

药物的肝脏毒性

近年来,有两种药物因其肝脏毒性被美国食品与药物管理局从市场撤出,药物的肝毒性再次受到公众关注.据美国统计,被批准进入市场的药物从市场撤出的最常见原因是肝毒性作用;同时,一半以上的急性肝衰竭由于不当用药引起.因此,本文对药物的肝脏毒性作一综述.     

抗纤软肝颗粒对肝星状细胞增殖的影响

目的 :研究抗纤软肝颗粒对肝星状细胞增殖的影响。方法 :传代培养的大鼠肝星状细胞系 (HSC- T6 )与中药复方抗纤软肝颗粒 (终浓度为 5 m g/ ml、2 .5 mg/ m l、1.2 5 mg/ ml)及药物血清 (5 %、10 %、2 0 %)共同培养 48h后 ,应用 MTT法及流式细胞仪测定细胞增殖。结果 :抗纤软肝颗粒无论是药物还是含药血清 ,均能显著抑制 HSC-T6增殖 ,并使细胞周期阻滞于 G1 期 ,在安全浓度范围内 ,5 m g/ ml组和 10 %药物血清组作用最强 (P <0 .0 1,<0 .0 5 )。结论 :抗纤软肝颗粒抗肝纤维化的作用机制可能在于阻滞细胞周期的进行 ,从而抑制 HSC增殖。     

抗结核药物致肝损害的相关因素分析

目的总结抗结核药物致肝损害的相关因素。方法65例活动性结核病患者应用抗结核药物治疗后出现肝损害,分析引起肝损害的相关因素及特点。结果抗结核药物致肝损害的发生率为16.6%（65/391）。其中营养不良结核病患者肝损害的发生率高于营养好者（29.6%和13.2%,P〈0.01）,HbsAg阳性结核病患者肝损害的发生率高于HbsAg阴性者（51.2%和12.4%,P〈0.01）,有饮酒史的结核病患者肝损害的发生率高于无饮酒史者（37.0%和15.1%,P〈0.01）。结论肝损害是抗结核药物的常见不良反应,营养不良、HbsAg阳性、饮酒史与抗结核药物诱发肝损害密切相关。     

抗结核药物致严重肝损害9例诊治体会

目的提高抗结核药物致严重肝损害的诊治水平。方法回顾性分析9例抗结核药物致严重肝损害病人的临床资料。结果停用抗结核药物,加强抗炎保肝等综合基础治疗,配合人工肝,多数患者病情好转。结论抗结核药物致严重肝损害早预防、早诊断、早处理,预后好。     

抗纤软肝颗粒对大鼠肝星状细胞增殖的影响

目的:探讨抗纤软肝颗粒(KXRG)对大鼠肝星状细胞(HSC)增殖的影响。方法:传代培养的HSC-T6(肝星状细胞系)与KXRG(1.25mg/ml、2.5mg/ml、5mg/ml)及其药物血清(5%、10%、20%)共同培养72小时后,应用MTT法测定细胞增殖、流式细胞仪测定HSC细胞周期各时相的DNA含量。结果:KXRG及药物血清均能显著抑制HSC的增殖,使细胞周期阻滞于S期,且2.5mg/ml药物和10%药物血清作用最强(P0.01)。结论:KXRG通过抑制HSC的活化,阻滞其细胞周期的正常进行,进而抑制HSC增殖,从而起到抗肝纤维化的作用。     

以肝星状细胞为靶向的药物载体系统

肝星状细胞是抗肝纤维化治疗的重要靶点,如何安全有效地将治疗药物靶向递送至肝星状细胞,提高药物疗效,减小药物脱靶的毒副作用,是目前抗肝纤维化药物开发的重要策略。许多蛋白标志物在活化的肝星状细胞中表达升高,因此它们的配体被用来特异性地传递各种抗纤维化药物。从受体靶向及药物载体的种类方面总结了目前靶向肝星状细胞治疗肝纤维化的研究进展。     

抗结核药物致肝损害54例临床分析

目的探讨抗结核药物致肝损害出现的时间、程度及治疗后肝功恢复正常的时间。方法对54例临床应用抗结核药物致肝损害病人的资料进行分析。结果抗结核药物的肝损害多出现在用药后4周内，以2—4周为最多，表现在胃肠道不适及ALT增高，经保肝药物治疗或调整抗结核药2周内肝功多能恢复正常。结论抗结核药物肝损害只要早期发现、及时治疗，肝功均可恢复正常，不会影响结核病的治疗效果。     

药物性肝损害41例临床分析

目的分析药物性肝损害(DILI)的病因及临床特点,提高对药物性肝损害的认识。方法对本院41例药物性肝损害患者的临床资料进行回顾性分析,根据服药时间及服用药物种类、临床表现、肝损害的分型进行综合评价,总结药物性肝损害的临床特点。结果引起肝损害的药物前3名依次为:中草药及中成药14例(32.6%),抗生素10例(23.3%),降压药5例(11.6%)。临床分型:肝细胞损伤型13例,占31.7%;胆汁淤积型15例,占36.6%;混合型12例,占39.3%。结论临床上多种药物可导致肝损害,因此在使用有肝损害副作用药物时,应及时检测肝功能,以求早发现、早治疗。     

肝纤维化体外细胞模型研究的概况与展望

肝纤维化的发病率和不良结果发生率高, 在治疗方面尚未有公认特异有效的化学药物和生物制剂, 缺乏稳健且具有代表性的肝纤维化体外模型是阻碍抗肝纤维化药物研发的主要原因之一。现总结肝纤维化体外细胞模型研发的最新进展, 重点分析基于肝星状细胞的诱导激活、细胞共培养及3D模型共建的肝纤维化体外模型, 同时还基于肝窦内皮细胞展望了建立肝纤维化体外模型的潜在方法。     

Cardiovascular effects of iodinated contrast agents

The ideal intravascular contrast agent would be biologically inert and have no pharmacologic actions. Pharmacologic actions of currently used radiographic contrast agents are determined principally by 3 physicochemical properties of the iodine-bearing molecule and its formulation: osmolality, sodium concentration and calcium-binding properties. Within this framework, the calcium-binding 1.5 ratio agents have the most marked effects, and the 3.0 ratio nonionic agents the least, with the noncalcium-binding formulations of 1.5 ratio agents and ioxaglate (the only 3.0 ratio ionic agent) in between. Differences in hemodynamic effects are predominantly related to osmolality with the 3.0 agents causing less hemodynamic disturbance. The magnitude of difference is small enough that the 3.0 ratio agents have no important clinical advantage when used in patients with good or moderately impaired left ventricular function. However, the difference may be important in patients with severely impaired circulatory performance. The principal electrophysiologic differences are between the calcium-binding 1.5 ratio agents (which are associated with a clear-cut greater frequency of ventricular fibrillation during coronary injection than the noncalcium-binding 1.5 ratio agents) and the 3.0 ratio agents. There is no justification for the use of calcium-binding 1.5 ratio agents, since noncalcium-binding formulations of the same molecule are available at the same price. The circulatory reserve of most patients makes the differences between 3.0 ratio agents and noncalcium-binding 1.5 ratio agents clinically unimportant. In view of the substantial price disparity between 1.5 ratio and 3.0 ratio agents, noncalcium-binding 1.5 ratio agents are appropriate for patients with good circulatory performance and 3.0 ratio agents are best reserved for patients with impaired circulatory performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacotherapies for Alcoholism: Promising Agents and Clinical Issues

The past 10 years have witnessed important advances in research on pharmacotherapy for alcoholism. Promising drugs are discussed under six headings: agents to treat alcohol withdrawal; anticraving agents; agents that make drinking an aversive experience; agents to alleviate concomitant psychiatric problems; agents to treat concurrent drug abuse; and amethystic ("sobering-up") agents. Research on the drug classes is summarized and clinical issues surrounding specific agents and alcoholism pharmacotherapy in general are discussed. Finally, long-range therapeutic implications of recent findings on the actions of alcohol on basic mechanisms of the brain are offered.     

Analysis of Comparative Studies Using Different Contrast Agents for Endoscopic Retrograde Cholangiopancreatography

Abstract: Pancreatitis induced by ERCP ha been associated with numerous pathogenic factors such as a previous history of pancreatitis, acinarization, mechanical and thermal injury, medications, and lastly the type of contrast agent used. Conventional contrast agents are characterized by both ionicity and high osmolality. These traditional agents have demonstrated deleterious effects upon multiple organ systems. Newer contrast agents have been developed with properties of low osmolality and non-ionicity in efforts to their decrease potential toxic effects, This review analyzes the current literature regarding the role of different contrast agents in the incidence of ERCP related pancreatitis. Nine randomized, double-blind, prospective studies have been published comparing low and high osmolality contrast agents for ERCP. Although five studies have shown lower degrees of amylase/lipase elevation after ERCP for the low osmolality agents, only three studies demonstrated a statistically significant advantage for the reduction of clinical pancreatitis among the low osmolality agent groups. In addition, these studies also varied in terms of specific contrast agents used, inclusion and exclusion criteria, rates of acinarization, and definition of clinical pancreatitis. However, after combining all of the data from these studies, there was a statistically significant advantage in reducing ERCP induced pancreatitis for non-ionic, low osmolality agents (1.44%) compared with the ionic, high osmolality agents (7.39%) [p = 0.007] and the ionic, low osmolality agents (9.67%) [p = 0.0001]. There was no statistical difference between the ionic, high osmolality agents and the ionic, low osmolaltiy agents [p = 0.5481. This data seem to suggest that ionicity rather than osmolality may play a more significant role in the incidence of ERCP induced pancreatitis. The major disadvantage of the use of low osmolality, non-ionic agents is their relatively high cost. Overall, controversy remains about whether these newer agents should be utilized in all patients or be selectively used in only high risk patients. Presently, we utilize these agents routinely.     

急性白血病并发感染时经验性应用抗菌药物的临床分析

目的：分析探讨急性白血病患者并发感染时经验性应用抗菌药物现状。方法：采用整体分析方法,调查我院血液科102例急性白血病并发感染的患者抗菌药物的使用情况,并对抗菌药物的种类、用药频度以及病原学检测对抗菌药物的指导意义进行分析。结果：102例患者中,除了3例死于重症感染外,总体有效率91．2％。病原学检测88例,培养出致病菌株25株（28．4%）,所用抗菌药物已覆盖敏感菌谱的有14例,覆盖率56％。结论：急性白血病患者并发感染时,应及时给予经验性抗菌药物的应用及讲行细菌学检查。     

What’s new in antifungals?

The incidence of fungal infections is steadily rising. Until recently, clinicians have been limited in the number of effective antifungal agents at their disposal. Our traditional antifungal agents have either been hampered by troublesome side effects or a limited spectrum of activity. Due to the rising demand for better antifungal agents there are more agents in development than ever. Voriconazole and caspofungin are the most recent agents approved for use, offer a broad spectrum of activity, and are generally well tolerated. Several other novel agents are moving into clinical trials. A better understanding of these novel agents is critical for clinicians to effectively treat emerging fungal pathogens.     

Iodinated contrast media and contrast-induced nephropathy: is there a preferred cost-effective agent?

Over 20 years have passed since the introduction of the tri-iodinated low-osmolar nonionic contrast agents such as iopamidol, iohexol, ioversol and iopromide. During this time, most cardiology practices have switched to these nonionic agents to avoid the nuisance side effects and cardiac adverse events associated with the older ionic contrast agents. Although the improved tolerability of the nonionic agents is generally attributed to their decreased osmolality (approximately half that of the older ionic contrast agents), in fact, these contrast agents also differ from the older agents in their ionicity, viscosity and direct chemotoxicity. The impact of these properties on safety, together with cost differences, should be considered when selecting a contrast agent.     

New pharmacological agents for the treatment of gastroesophageal reflux disease

Proton pump inhibitors (PPIs) are currently the most effective and most widely used agents for gastroesophageal reflux disease (GERD). Despite the efficacy of these agents in healing and symptom relief, a substantial proportion of patients require twice-daily therapy with PPIs, and break-through symptoms cause others to use over-the-counter antacids and histamine 2-receptor antagonists to supplement their PPI therapy. Major strategies that are being pursued include the development of agents that have a faster onset of action for on-demand therapy; have better control of acid secretion, resulting in improved healing in advanced grades of esophagitis and better symptom control; and agents that decrease transient lower esophageal sphincter relaxations (TLESRs), thereby reducing distal acid exposure and weakly acidic refluxate. A number of new pharmaceutical agents are currently undergoing clinical evaluation for the treatment of GERD. These include agents that reduce TLESRs, serotonergic agents/ prokinetics, long-acting PPIs, mucosal protectants, and antigastrin agents. One or more of these agents may be the future of GERD therapy.     

Selection of a contrast agent in the cardiac catheterization laboratory

The evolution of contrast material for intravascular use has been directed toward the development of better-tolerated agents. Currently, a variety of such "dyes" are available for coronary angiography and left ventriculography. Considerable animal and human investigation suggests that significant differences exist between the families of contrast agents that relate to patient tolerance. The newer low osmolality agents (especially the nonionic agents) produce less perturbation of the homeostatic state, which is clinically manifested by a lessened incidence of side effects, including those of a hemodynamic and electrophysiologic nature. While controversy continues over the cost/benefit ratio of the low osmolality contrast agents compared to traditional high osmolality agents, the former are rapidly becoming the community standard for diagnostic and especially therapeutic cardiologic procedures. Accepting the advantages of the low osmolality contrast agents, differences between the ionic dimers and the nonionic agents have been examined. Both experimental and clinical data suggest superiority of the nonionic agents. Although controversy still surrounds the issue of thromboembolism with the nonionic agents, accumulating evidence fails to support a clinically significant relation. The choice of contrast material is the responsibility of the invasive cardiologist. While the benefits of low osmolality agents are most obvious in high-risk patients, experience with large-scale intravenous studies suggests that the choice of contrast agent is a better discriminator of adverse reaction than is preprocedural risk stratification.     

Current status of development of anticancer agents in Japan

To investigate the current status of the development of anticancer agents in Japan, we examined the number of these agents developed after 1999, their target diseases, and the association between the number of approved agents and the number of patients with the diseases. The data were obtained via the Internet. Of the 487 agents approved from 1999 to April 2007, 84 were anticancer drugs. Of these 84, 46 were approved based on clinical trials and 38 were approved through the new drug application for off-label usages without clinical trials. The target diseases of the 46 agents approved through clinical trials were nonhematologic tumors in 29, hematologic malignancies in 13, and others in 4. Of the 38 approved through the new drug application for off-label usages, 31 were for nonhematologic tumors and 7 for hematologic malignancies. The number of approved anticancer agents for hematologic malignancies per unit patient population was 6.5-times as many as that for nonhematologic tumors. This study demonstrated that the situation regarding the development of anticancer agents differs among tumor types. The majority of anticancer agents developed target hematologic malignancies, while the newly developed anticancer agents have affected treatment strategies for solid tumors.     

How best to use new therapies in multiple myeloma

Advances in the molecular understanding of myeloma have led to the development of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib). When used alone, these agents have significant activity against myeloma and responses increase significantly when they are combined with additional agents including glucocorticosteroids and chemotherapeutic agents such as alkylators. There is a drive to use these novel agents in patients with newly diagnosed myeloma, where they lead to impressive response rates with increasing duration of responses. In addition, novel agents are now the mainstays of therapy for relapsed disease. In the following paper, we summarize the key observations from recent completed and ongoing studies that determined the effect of these novel therapies both in the setting of newly diagnosed myeloma and for relapsed disease. We also discuss our approach to the use of these agents in specific myeloma settings.