青蒿素及其衍生物的研究进展

青蒿素类化合物是含过氧桥的化合物,在治疗多药抗药性恶性疟疾方面卓有成效。除此之外,该类化合物还具有抗肿瘤、抗真菌、抗心律失常、抗寄生虫等活性。本文就近年来国内外学者对青蒿素及其衍生物的结构改造及生物活性等方面的研究进行概述。     

青蒿素类药物的药理作用新进展

青蒿素是从植物黄花蒿中提取的抗疟疾的活性成份，目前在临床上广泛用于治疗疟疾。近些年研究发现青蒿素不仅可以抗寄生虫，包括疟原虫、血吸虫，而且具有显著的抗炎、调节免疫和抗肿瘤等多方面的药理作用。本文在介绍青蒿素抗疟疾作用、应用和作用机制的基础上，对近年来青蒿素类药物的其它主要生物学作用研究的现状进行综述。     

Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents

Artemisinin, the first and last naturally occurring 1, 2, 4-trioxane originated from Artemisia annua, L. and its derivatives are a potent class of antimalarial drugs. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant. Furthermore, artemisinin and many of its analog possess not only antiparasitic effect against Plasmodium falciparum, Schistosoma japonicum and Clonorchis sinensi but also immuno-modulation effects, and antitumor activities. This review covers the chemistry of artemisinin including synthesis of acetal-, non acetal-type C-12 analogs, C-11- and C-13 derivatives from artemisitene, ring-contracted derivatives, dimers, and trimers. Modes of biological action of artemisinin - derived analogs are also reviewed. The main objective of this article is to review the literatures of recent progress taken place in chemistry, mode of biological actions of artemisinin, and its derivatives as antimalarial and antitumor agents during the last three years (1999-2001).     

青蒿素类抗疟药的作用机制及耐药机制研究进展

青蒿素及其衍生物是一类全新结构的抗疟药，具有抗疟作用迅速、高效、低毒且与大多数抗疟药无交叉抗性等特点。一般认为，青蒿素类药物的作用机制与其结构中的内过氧桥有关，最近又提出一些与以往不同的观点。治疗疟疾的其他药物如氯喹、甲氟喹、乙胺嘧啶等在治疗疟疾的过程中均已产生耐药性，而青蒿素类药物由于其独特的化学结构，是至今唯一没有出现耐药性的抗疟药，因此确定其作用机制，对避免其耐药性的产生，延长其使用寿命具有重要意义。     

New trends in extraction, identification and quantification of artemisinin and its derivatives.

Artemisinin, a sesquiterpene lactone endoperoxide, and a number of its precursors, metabolites and semisynthetic derivatives have shown to possess antimalarial properties. Several methods have been reported for the measurement of artemisinin and its main derivatives in plant material and biological fluids. However, most of them are either not sufficiently sensitive and do not offer reliable results, or are difficult to apply in routine analyses. Therefore, new methods for the determination of these compounds, such as supercritical fluid extraction and chromatography, pressurized solvent extraction, microwave-assisted extraction, high-performance liquid chromatography coupled to mass spectrometry or evaporative light scattering detection, will be presented. Applications to plant material, pharmaceutical formulations and biological fluids will also be reviewed.     

Review of the use of artemisinin and its derivatives in the treatment of malaria

This article reviews the development of the artemisinins used in the treatment of drug-resistant Plasmodium falciparum malaria. The story starts in China with Artemisia annua L., a plant that was traditionally used as an antipyretic. The activity of Annual wormwood can be explained by the presence of the active substance artemisinin. Soon, artemether, artemotil, artenimol, artesunate and sodium artesunate, derivatives of artemisinin, have been developed. Each has its own physical and pharmaceutical properties, dosage and dosage forms. Other aspects, such as the general guidelines for use, safety during pregnancy and the perspectives of artemisinin compounds, are being discussed.     

青蒿素类药物抗肿瘤作用的基础与临床研究

青蒿素类(Art)抗疟药具有多种药理活性,近年来对其抗肿瘤作用的基础研究较多,相关的临床研究也逐渐开展。大量体外和动物体内实验结果显示:Art可抑制或杀伤肿瘤细胞;诱导肿瘤细胞凋亡:阻滞细胞周期;抑制血管生成;延缓或逆转肿瘤细胞的多药耐药性;与铁制剂合用或与转铁蛋白结合可提高对肿增细胞的选择性杀伤作用。临床探索提示Art对肿瘤具有治疗或辅助治疗作用。Art对人体毒性低,与传统化学治疗药物有协同增效作用且无交叉耐药性。应加强Art抗肿瘤的临床研究以明确其抗肿瘤性质、范围、剂量、疗程及不良反应。     

青蒿素及其衍生物药理作用研究有关进展

青蒿素属倍半萜内酯化合物,其衍生物主要有双氢青蒿素、青蒿琥酯、蒿甲醚和蒿乙醚,现在临床上主要用于治疗疟疾。随着对青蒿素及其衍生物药理作用的研究不断深入,除抗疟作用外,近年来又相继报道了抗炎、抗细菌脓毒症、抗肿瘤、放射增敏、抗菌增敏、抗组织纤维化等作用。笔者在此对国内外近年发现的青蒿素及其衍生物药理作用研究的最新现状作一综述。     

大黄素及其衍生物：合成与药理作用研究进展

大黄酸是大黄的主要成分之一,其应用广泛,可用于抗肿瘤、抗病毒、糖尿病肾病、抑菌、抗炎等,具有不错的临床应用价值。本文主要综述近年大黄酸及其衍生物的合成与药理活性方面的研究进展,以期为大黄酸及其衍生物的开发应用提供参考依据。     

Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics

Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases.KEY WORDS: Fibrosis, Artemisia, Artemisinin, Artesunate, Fibroblast, Myofibroblast, Scar, TGF-β-glucosaminidase, NICD, Notch intracellular domain, PCNA, proliferating cell nuclear antigen, PHN, passive heymann nephritis, ROS, reactive oxygen species, sCr, serum creatinine, STZ, streptozotocin, TGF, β-transforming growth factor-β, TIMP, tissue inhibitor of metalloproteinase, UUO, unilateral ureteral obstruction     

青蒿素类衍生物抗炎免疫抑制活性研究进展

青蒿素类衍生物具有抗炎和免疫抑制活性。临床研究结果表明,青蒿素类衍生物对各类红斑狼疮、皮炎及关节炎有效;研究表明,青蒿素类衍生物在多种疾病动物模型上具有抗炎和免疫抑制活性。为了研究和获得免疫抑制活性更高的化合物,一系列经过结构改造后合成的新型青蒿素类化合物相继被报道。但到目前为止,有关青蒿素类衍生物免疫抑制活性的作用机制尚不清楚。本文主要综述了近年来青蒿素类衍生物抗炎和免疫抑制药理作用及其作用机制的研究进展。     

Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy

Esophageal cancer is one of the most lethal malignancies. Surgical resection of the tumor from the primary site has been the standard treatment, especially for localized squamous cell carcinoma, but considerable clinical efforts during the last decade have resulted in novel courses of treatment. These options include chemoradiotherapy, consisting of a continuous infusion of 5-fluorouracil (5-FU), cisplatin (CDDP), and concurrent radiation. Given the substantial inter- and/or intra-individual variation in clinical outcome, future improvements will likely require the incorporation of a novel anticancer drug, pharmacokinetically guided administration of CDDP or 5-FU, and identification of potential responders by patient genetic profiling prior to treatment. In this review, the latest information on incidence, risk factors, biomarkers, therapeutic strategies, and the pharmacokinetically guided or genotype-guided administration of CDDP and 5-FU is summarized for future individualization of esophageal cancer treatment.     

Pharmacokinetics and pharmacogenomics in gastric cancer chemotherapy

Despite extensive efforts, treatment of gastric cancer by chemotherapy, the globally accepted standard, is yet undetermined, and uncertainty remains regarding the optimal regimen. Recent introduction of active “new generation agents” offers hope for improving patient outcomes. Current chemotherapeutic trials provided several regimens that may become a possible standard treatment, including docetaxel/cisplatin/5-FU (TCF) and cisplatin/S-1 for advanced and metastatic cancer and S-1 monotherapy in the adjuvant setting. Along with the development of novel active regimens, individual optimization of cancer chemotherapy has been attempted in order to reduce toxicity and enhance tumor response. Unlike the rare and limited contribution of pharmacokinetic studies, pharmacogenomic studies are increasing the potential to realize the therapeutics against gastric cancer. Despite the limited data, pharmacogenomics in gastric cancer have provided a number of putative biomarkers for the prediction of tumor response to chemotherapies and of toxicity.     

Pharmacokinetics and pharmacogenomics in breast cancer chemotherapy

Locally advanced or metastatic breast cancer is typically treated with chemotherapy. Multiple combinations of chemotherapy regimens are available, including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs and vinca alkaloids. This review discusses the pharmacokinetic and pharmacogenomic information available for commonly used breast cancer chemotherapy drugs. Pharmacogenomic associations for many drugs have yet to be identified or validated in breast cancer. Further work is needed to identify markers to screen breast cancer patients prior to therapy selection.     

Preparation of chemically robust new artemisinin derivatives

The resurgence of malaria, largely through emergence of drug-resistant strains of the malaria parasite, Plasmodium falciparum, has in recent times substantially increased public and private focus on the development of new treatments for the disease. However, in the absence of any vaccine, major reliance continues to be placed on chemotherapy involving both traditional, largely quinoline-based, antimalarial drugs and the newer class of antimalarial drug based on artemisinin, the remarkable peroxidic sesquiterpene isolated by the Chinese in 1972. Derivatives of this compound, artesunate and artemether, are now used in routine therapy in conjunction with a longer half-life quinoline or related antimalarial. However, problems of instability and neurotoxicity associated with the current artemisinin derivatives has resulted in a vigorous search for new, more stable derivatives with better pharmacological profiles. The Centre Nationale de la Recherche Scientifique patent describes a class of relatively readily accessible new artemisinin derivatives, which in incorporating the trifluoromethyl group, appear to be more stable than the current derivatives.     

青蒿素类衍生物抗肿瘤研究进展

青蒿素类药物是很好的抗疟药物,近年来大量体内、外研究显示青蒿素具有良好的抗肿瘤活性。大多数肿瘤细胞表面有高浓度的转铁蛋白受体,因此与正常细胞相比,细胞内含有更多的亚铁离子,青蒿素与亚铁离子反应生成自由基,可以选择性的杀伤肿瘤细胞。G1期细胞的转铁蛋白受体表达和铁离子摄入都显著增多,青蒿素类药物在此期诱导细胞凋亡,其具体作用靶点和机制还有待进一步研究,青蒿素衍生物还具有抗肿瘤血管生成活性。将青蒿素类药物与转铁蛋白上的糖基共价结合的复合体,可以将铁离子和青蒿素同时摄入肿瘤细胞,增强了青蒿素的高效性和靶向性。     

DrugBank and its relevance to pharmacogenomics

DrugBank is a freely available web-enabled database that combines detailed drug data with comprehensive drug-target and drug-action information. It was specifically designed to facilitate in silico drug-target discovery, drug design, drug-metabolism prediction, drug-interaction prediction, and general pharmaceutical education. One of the most unique and useful components of the DrugBank database is the information it contains on drug metabolism, drug-metabolizing enzymes and drug-target polymorphisms. As pharmacogenomics is fundamentally concerned with the role of genes and genetic variation of how an individual responds to a drug, DrugBank is able to offer a convenient venue to explore pharmacogenomic questions in silico. This paper provides a brief overview on DrugBank and how it can facilitate pharmacogenomic research.     

Molecular complexing ability of quinoline and its simple derivatives

Electron donor-acceptor complexes for a group of quinolines and naphthalenes with 9-(dicyanomethylene)-2,4,7-trinitrofluorene in 1,2-dichloroethane were studied by optical absorption methods. Association constants, molar absorptivities, and charge-transfer transition energies were evaluated for each system, together with theoretically calcualted orbital energies and complex geometries. In contrast to the association constants and structures reported for N-heterocycle-halogen complexes, these studies indicate that, with a moderately large pi-electron acceptor, quinolines function as pi-rather then n-(lone-pair) donors. These results support intercalation models for drug-receptor interactions involving the quinoline moiety.