第二代三唑类抗真菌药物的研究进展

侵袭性真菌病的发病率和病死率逐年上升,新型抗真菌药物的研究和开发也越来越受到重视,尤其是三唑类抗真菌药物。本文综述国内外近期关于第二代三唑类抗真菌药物的研究进展,以期为未来临床真菌病的治疗及新药研发提供新的思路。     

三唑类抗真菌药物致肝损伤的研究进展

药物性肝损伤是临床常见的药源性疾病之一,也是药物临床试验失败和撤市的主要原因之一。三唑类抗真菌药物是治疗侵袭性真菌感染的主要药物,对多种临床常见真菌具有良好的抗菌活性,临床应用广泛。但随着三唑类抗真菌药物临床应用的日益增多,其肝损伤不良反应的报道也越来越多,给该类药物的临床应用带来一定挑战。三唑类抗真菌药物致肝损伤的影响因素包括药物浓度、年龄、基因多态性、炎症等,发生机制包括氧化应激、胆汁淤积、调节细胞色素P450的表达及脂质代谢异常等多个方面。本文将对三唑类抗真菌药物致肝损伤的临床特点、影响因素及发生机制的研究进展进行综述,以期为该类药物肝损伤的深入研究及临床安全合理应用提供参考。     

抗真菌药与药物相互作用研究进展

自20世纪以来抗真菌药物及药物相互作用研究有很大进展，除一些的三唑类抗真菌药物外，还有一些作用于真菌细胞壁的抗真菌药物，这些药物与其他药物的相互作用，尤其是与共同靶位为细胞色素P450酶的药物的相互作用研究也有了较多进展。     

非白念珠菌对常用抗真菌药物的敏感性分析

目的 了解非白念珠菌对我国常用抗真菌药物的耐药状况.方法 采用Roseo Neo-Sensitab纸片扩散法检测116株非念珠菌对常用抗真菌药物的敏感性.结果 除2株光滑念珠菌对两性霉素B耐药外,其它菌株均对两性霉素B敏感;86.4%的热带念珠菌和80%的近平滑念珠菌对氟康唑敏感;光滑念珠菌对两性霉素B、氟康唑和伊曲康唑的耐药率分别为3.6%、16.1%和10.7%;所有克柔念珠菌对氟康唑和氟胞嘧啶均耐药.结论 绝大多数非白念珠菌对两性霉素B敏感,克柔念珠菌对氟胞嘧啶及三唑类抗真菌药物的耐药率高,光滑念珠菌对常用抗真菌药物包括两性霉素B的敏感性低,对三唑类抗真菌药物的耐药率高,且对三唑类抗真菌药物存在交叉耐药.     

三唑类抗深部真菌药的临床药学进展

1概述为适应临床抗深部真菌感染的需要,抗深部真菌药逐渐向低毒、广谱和高效的方向发展。如通过改进两性霉素B的剂型而研制出3种脂质型制剂,减少了肾毒性和发热等即刻反应。在筛选新的化学结构寻求新靶点方面开发出β-D-葡聚糖合成酶抑制剂棘白菌素类抗真菌药。而三唑类抗真菌药物的开发在优化氟康唑等化学结构,研制出第二代三唑类伏立康唑和开发β-环糊精包合型新制剂等两方面都获得了显著的成就(见表1)。本文仅对抗深部真菌感染的三唑类的临床药学进展进行简介。2三唑类抗深部真菌药概况唑类(吡咯类)按化学结构可分为咪唑类和三唑类,按其…     

唑类抗真菌药物临床应用现状

目的关注近年来唑类抗真菌药物临床应用现状。方法查阅相关文献进行总结、归纳。总结新三唑类抗真菌药物的研发成功为临床治疗提供了更多的选择。     

三唑类抗真菌药的研究新进展

近年来三唑类抗真菌药发展很快，有多个广谱、低毒、高效的新化合物进入临床研究：综述了三唑类抗真菌药的最新研究进展，介绍了伏立康唑、泊沙康唑、ravaconazole 3个新药物，与其他抗真菌药比较，均显示了其优点。     

国产氟康唑胶囊治疗霉菌性阴道炎疗效观察

氟康唑(Fluconazole)是一新型的三唑类口服抗真菌药物，具有抗菌谱广，口服吸收好     

难治性真菌感染抗真菌药物联合治疗的研究进展

棘球白素类、第二代三唑类抗真菌药物和两性霉素B脂质体的出现重新激发了联合抗真菌药物治疗难治性真菌感染的兴趣。除了隐球菌感染外，目前不推荐联合治疗为侵袭性真菌感染的一线治疗方案。然而，对于多重耐药、难治的侵袭性真菌感染，联合性抗真菌治疗可能是一种选择。     

唑类抗真菌药进展

近些年来,真菌感染的发病率呈上升趋势,日益引起人们的重视,抗真菌药的研究也成为热点之不,目前临床应用和研究得较多的是唑类抗真菌药,相继有几代产品问世,唑类抗真菌药的结构大致可分为４类,多苯甲基唑类,α－卤代苯乙基－β,Ｎ－咪唑乙基苄醚类,α－卤代苯乙基－α－环氧戊环唑类和α－卤代苯乙基三唑类,其代表药物分别为克霉唑、咪康唑、酮康唑和氟康唑。其基本药效基团为无取代唑环（咪唑或三唑）,间位Ｎ与真菌１４     

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents

A series of 2-{[2'-(3'-chloro-2'-oxo-4'-substitutedaryl-1'-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2'-substitutedaryl-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2'-p-hydroxy-m-methoxyphenyl)-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.     

Hemorrhagic activity of the Duvernoy''s gland secretion of the xenodontine colubrid Philodryas patagoniensis from the north-east region of Argentina

Colubrid snakes belonging to Philodryas genus, widespread all over South America, bring about lesions (swelling, ecchymosis, transient bleeding from the bite site punctures), that are similar to those produced by Bothrops species (yarará). In the present work we began the characterization of Philodryas patagoniensis venom. We examined if this venom produces hemorrhagic lesions as those observed in victims bitten by Philodryas olfersii. Hemorrhagic, proteolytic and fibrinogenolytic activities were evaluated, and histological observations in samples of gastrocnemius muscle were carried out. Inhibition studies were carried out in metal chelator (ethylenediaminetetraacetic acid) presence. Our results show a small Minimum Hemorrhagic Dose (MHD=0.035 μg) and a high proteolytic activity (143 U/mg), and prove the capacity of this venom to degrade fibrinogen in vitro rendering it unclottable by thrombin, supporting the presence of proteases, principally metalloproteases, in P. patagoniensis venom that are able to alterate the vascular wall and degrade fibrinogen, being both activities responsible of a high hemorrhagic activity.     

Anti-inflammatory,Antinociceptive, and Neuropharmacological Activities of Clerodendron viscosum.

Abstract

The crude methanol extract of Clerodendron viscosum. Vent. (Verbenaceae) leaves was evaluated for its anti-inflammatory, antinociceptive, and neuropharmacological activities. When given orally to rats at doses of 200 and 400 mg/kg of body weight, the extract showed a significant (p < 0.001) anti-inflammatory activity against carrageenan-induced rat paw edema comparable with the standard drug phenylbutazone at the dose of 100 mg/kg of body weight. It also produced a significant writhing inhibition in acetic acid–induced writhing in mice at the oral dose of 250 and 500 mg/kg of body weight (p < 0.001), which was comparable with the standard drug diclofenac sodium at the dose of 25 mg/kg of body weight. Moreover, when given intraperitoneally to albino mice, it potentiated the pentobarbital-induced sleeping time (p < 0.001), decreased the open field score in open field test (p < 0.001), decreased the number of holes crossed from one chamber to the other in the hole-cross test (p < 0.001), and decreased the head dip responses in the hole-board test (p < 0.001) at the dose of 250 and 500 mg/kg of body weight. The overall results tend to suggest the anti-inflammatory, antinociceptive, and central nervous system depressant activities of the crude methanol extract of Clerodendron viscosum..     

Resveratrol isoforms and conjugates: A review from biosynthesis in plants to elimination from the human body

The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.     

Structure-antibacterial,antitumor and hemolytic activity relationships of cecropin A-magainin 2 and cecropin A-melittin hybrid peptides

In order to elucidate the structure-antibiotic activity relationship of cecropin A-magainin 2 and cecropin A-melittin hybrid peptides, several truncated peptides and the analogues with amino acid substitutions were synthesized and their antibacterial, antitumor and hemolytic activities of were examined. Cecropin A-magainin 2 hybrid analog, L¹⁶-CA(1–8)-MA(1–12) (termed as L-CA-MA in this study: KWKLFKKIGIGKFLHLAKKF-NH₂), is known to have potent antibacterial and antitumor activity with less hemolytic activity. We found that the C-terminal region of L-CA-MA is more involved in the α-helical structure on cell membrane-like environment than N-terminal one by circular dichroism analysis. Deletion of the Gly-lle-Gly sequence, the central hinge region of L-CA-MA, produced a considerable reduction in antitumor and hemolytic activity rather than an antibacterial one. The insertion of Pro, Gly-lle or Gly-Pro in this hinge region of L-CA-MA caused retention of both antibacterial and antitumor activity while causing a significant decrease in hemolytic activity. However, the substitution with Gly-Pro-Gly instead of the Gly-lle-Gly in CA(1–8)-MA(1–12), CA(1–8)-ME(1–12), CA(1–13)-MA(1–13) and CA(1–13)-ME(1–13) hybrids resulted in a drastic decrease in antibacterial, antitumor and hemolytic activity. The increase of hydrophobicity at position 16 in CA(1–8)-MA(1–12) by substituting Trp or Phe induced a significant increase in hemolytic activity without a considerable change in either antibacterial or antitumor activity. Therefore, these results suggested that the appropriate flexibility in the hinge region of CA-MA and CA-ME hybrid peptides and the appropriate hydrophobicity at position 16 in the hydrophobic region of CA (1–8)-MA(1–12) are important in potent antibacterial and antitumor activity with no hemolytic effect.     

Antipyretic, analgesic and anti-inflammatory effects of delta 9-tetrahydrocannabinol in the rat

The effects on body temperature produced by graded doses of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and phenylbutazone were compared in both normal and pyretic rats. Dose related hypothermic responses were produced by the oral administration of Δ⁹-THC in normal animals. Moreover, Δ⁹-THC significantly reduced elevated temperatures in yeast-induced pyretic rats to near normal levels at doses which exhibited little hypothermic activity in normal rats. The oral antipyretic potency of Δ⁹-THC was approximately 2 times that of phenylbutazone. The comparative oral antinociceptive activity of Δ⁹-THC and selected narcotic and non-narcotic analgesics was determined by the increase in response latency to pressure applied to normal and yeast-inflamed paws. Δ⁹-THC administered orally was essentially inactive at dose levels below those producing pronounced central nervous system depression. The oral anti-inflammatory efficacy of Δ⁹-THC was compared to phenylbutazone and acetylsalicylic acid. Δ⁹-THC was ineffective in inhibiting carrageenin-induced edema of the rat paw following acute or chronic administration.     

Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.     

Evaluation of the Antimicrobial Activity of Ammoniacum Gum from Dorema ammoniacum

Antimicrobial activity of the dichloromethane-methanol (1 : 1) extract of ammoniacum gum (from Dorema ammoniacum D. Don) was evaluated against 14 microorganisms which included seven Gram-positive bacteria (Bacillus cereus, Bacillus pumilus, Bacillus subtilis, Micrococcus luteus, Staphylococcus epidermidis, Staphylococcus aureus and Streptococcus faecalis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aereuginosa, Klebsiella pneumoniae and Bordetella bronchiseptica), one yeast (Saccharomyces cereviseae) and two fungi (Aspergillus niger and Candida albicans). The extract of ammoniacum gum exhibited a of broad spectrum antimicrobial activity by inhibiting all the seven Gram-positive bacterium, one Gramnegative bacterium, one yeast and one fungus, with a minimum inhibitory concentration (MIC) of 40µg/ml. To overcome the solubility problem often faced when herbal extracts are added to aqueous medium, we employed a modified broth method where the broth cultures were agitated at 150 rpm in an orbital shaking incubator. This method reduced the MIC of the extract considerably, to 5-20µg/ml, against B. bronchiseptica, S. aureus and S. epidermidis.     

Pharmacological study on piperine

Systematic pharmacological studies on piperine have revealed that this compound elicited diverse pharmacological activities; CNS depressant activity characterized by antagonism against electroshock seizure and by muscle relaxant activity in mice; antipyretic activity in typhoid vaccinated rabbits; analgesic activity as evaluated by tail-clip pressure and writhing syndrome in mice; antiinflammatory activity in carrageenin-induced edema in rats.     

Post-antibacterial effect of thymol

The antibacterial activity of thymol has been well established and reported in the scientific literature. Continued suppression of bacterial growth following limited exposure to antimicrobial compounds at different concentrations greater than or equal to the minimum inhibitory concentration level (MIC) and at concentrations less than the MIC can be used as an indicator of biological activity, and are respectively referred to as a post-antibacterial effect (PAE) and a post-antibiotic sub-MIC effect (PA-SME). In this study, the PAE and the PA-SME of thymol against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus cereus were investigated. A spectrophotometric method was used to determine the PAE and the PA-SME of thymol against the selected test strains. Thymol exhibited a considerable PAE and PA-SME at MIC and sub-MIC concentrations against test strains. The greatest duration of both the PAE and the PA-SME was observed for thymol against E. coli and P. aeruginosa. The PAE and PA-SME times for E. coli were 12 and 8?h, respectively, and for P. aeruginosa were 11 and 7.5?h, respectively. The duration of the PAE and PA-SME observed for S. aureus and B. cereus was shorter than for Gram-negative strains.