克柔念珠菌感染致脓胸一例并文献复习

目的提高对克柔念珠菌感染所致脓胸相关特征、诊疗方法及预后的认识。 方法回顾性分析南京医科大学第二附属医院2022年7月收治的1例克柔念珠菌感染致脓胸患者的临床资料,并检索国内外相关文献,对该病的发病、临床特征及诊疗进行探讨。 结果本例患者有长期吸毒及支气管哮喘病史,入院初期存在严重低蛋白血症,克柔念珠菌脓胸诊断明确后,胸腔引流同时先后给予米卡芬净及伏立康唑治疗,脓胸完全吸收后出院;共检索到克柔念珠菌感染致脓胸病例个案报道文献6篇共计8例患者,其中食道穿孔患者4例、食管-气管瘘形成患者2例、心脏移植术后患者1例、动脉导管封堵术后患者1例;本例患者病程中伴支气管-胸膜瘘;本例及文献报道8例患者初始临床表现皆为咳嗽、咯痰、呼吸困难,脓胸病原学诊断均为常规培养;文献报道8例患者中死亡4例,1例使用两性霉素B、2例使用伏立康唑、1例使用棘白霉素类联合伏立康唑抗真菌治疗,存活4例患者中1例单独使用棘白霉素类、3例使用棘白霉素类联合伏立康唑抗真菌治疗。 结论本例克柔念珠菌感染所致脓胸系国内首次报道;该病多见于食管-气管瘘形成及手术创伤后,其临床表现无特征性;确诊后使用棘白霉素类或联合三唑类伏立康唑治疗有助于提高其存活。     

Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.     

Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents

InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target for the development of novel drugs against tuberculosis. We exploited copper-catalyzed [3+2] cycloaddition between alkynes and different azides to afford 1,4-disubstituted triazole or α-ketotriazole derivatives. Several compounds bearing a lipophilic chain mimicking the substrate were able to inhibit InhA. Among them, 1-dodecyl-4-phenethyl-1H-1,2,3-triazole displayed a minimum inhibitory concentration inferior to 2 μg/mL against Mycobacterium tuberculosis H37Rv.     

Synthesis and anticandidal activity of new triazolothiadiazine derivatives

New triazolothiadiazine derivatives were synthesized via the ring closure reaction of 4-amino-5-substituted-2,4-dihydro-3H-1,2,4-triazol-3-thiones with phenacyl bromides. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Among these compounds, the compound bearing cyclohexyl moiety and p-chlorophenyl substituent on triazolothiadiazine ring (2i) was found to be the most potent derivative against Candida albicans (ATCC 90028). It is clear that there is a positive correlation between anticandidal activity and two functional moieties, namely cycloaliphatic group and p-chlorophenyl substituent on triazolothiadiazine ring. The compounds were also investigated for their cytotoxic effects using MTT assay. Compound 2a exhibited the highest cytotoxic activity, whereas compound 2f possessed the lowest cytotoxic activity against NIH/3T3 cells.     

Synthesis of new triazolyl-N,N-Dialkyldithiocarbamates as antifungal agents

N,N-Dialkylditihiocarbamate derivatives have been well known as broad-range fungicides. In this study, the triazole derivatives of ten new N,N-disubstituted dithiocarbamates (3a-j) were synthesized and their structures were identified by spectral and elemental analysis. Results of the antifungal activity studies showed that some of the compounds tested were active against M. canis, M. gypseum, and T. rubrum at the concentration of 12.5 microg/mL when clotrimazol was used as a standard.     

Synthesis,analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles

Background

Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents.

Methods

The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates.

Results and discussion

The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score.

Conclusions

The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.     

棉酚与三氮唑类衍生物的合成及抗菌活性研究

目的:探讨棉酚与三氰唑类衍生物合成工艺的条件及合成物的抗菌活性,反应条件涉及温度、物料比、反应时间及反应溶剂.方法:通过正交设计寻找最佳工艺,运用熔点测定仪、红外、紫外、核磁共振等榆测是否有新物质生成及化学结构,通过TLC监测反应进行程度,用抑菌实验对衍生物的抗菌活性进行研究.结果:棉酚与三氮唑类衍生物合成的最佳工艺的反应温度70℃,反应时间3 h,反应溶剂为无水乙醇,物料比为1:3.结论:生成的衍生物有较强的脂溶性,在优化工艺下进行反应产量较高,为棉酚与三氮唑类衍生物合成提供了较好的方法.     

Antifungal activity of the new azole UK-109, 496 (voriconazole)

The in vitro activity of voriconazole fully includes Aspergillus, and also emerging moulds like Fusarium, Pseudallescheria boydii, and Penicillium marneffei. The minimal inhibitory concentrations of voriconazole for Candida krusei and Candida glabrata, which are resistant or less susceptible to fluconazole, promise clinical efficacy, although they are ten times higher (0.30-0.39 microgram/ml) than those for Candida albicans and other Candida spp. (0.001-0.05 microgram/ml). The endemic fungal pathogens Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, as well as Cryptococcus neoformans, and the dermatophytes are also fully susceptible to voriconazole. The zygomycetes and Sporothrix schenckii remain a problem. Voriconazole has been shown to be effective against invasive aspergillosis (IA) and fluconazole-resistant candidosis in animal models, when administered in doses between 2.5 and 45 mg/kg/day. The pharmacokinetics of voriconazole in man produced sustained high blood and tissue levels following oral and intravenous applications of 50 to 200 mg/day. Side effects included fully reversible mild to moderate visual disturbances (8 to 44%) and raised liver function enzymes (6 to 8%). In conclusion, voriconazole is highly active against Aspergillus and most other medically relevant fungi, it is applicable intravenously, and it appears to have an acceptable safety profile.     

3-硝基三氮唑类衍生物TA-201的体外辐射增敏作用

本文研究了一种新的三氮唑类衍生物TA-201对体外培养的中国仓鼠肺成纤维细胞系(CHL)的辐射增敏作用。用常规克隆形成法证明,TA-201在0.49、0.95和1.82mmol/L3个浓度下的增敏比分别为1.40、1.78和2.17,增敏作用虽不及MISO,但优于AK-212 3。TA-201对乏氧细胞有选择性的毒性作用,对富氧细胞则无毒性,且可能有一定的辐射防护作用。