Successful treatment of relapsing disseminated coccidioidomycosis with cutaneous involvement with posaconazole

A 52‐year‐old woman with pulmonary sarcoidosis on immunosuppressive therapy developed pulmonary infiltrates and cutaneous granulomatous abscesses after a trip to the USA in April 2005. A hyphomycete was identified, further characterized by a gene probe as Coccidioides spp. and then definitively identified as Coccidioides posadasii by polymerase chain reaction and sequencing. Antibodies towards Coccidioides spp. were detected. The infection was successfully treated with posaconazole (Noxafil^®), 2 x 400 mg/d.     

Clinically relevant drug interactions of current antifungal agents

Antifungal agents are often prescribed in critically ill patients who are receiving many other medications. When using systemic antifungals, clinicians may possess susceptibility data and they are typically aware of the potential toxicity of these agents. However, the myriad of potential drugs that antifungal agents can interact with is daunting and can be confusing. This article reviews the pharmacokinetic properties of antifungal agents and their clinically relevant drug interactions. The antifungal agents differ markedly in their pharmacokinetic properties and in how they interact with other medicines. The amphotericin B formulations interact with other medicines primarily by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting biotransformation or by affecting drug distribution and elimination. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal–drug interactions varies substantially. While certain interactions are benign and result in little or no untoward clinical outcomes, others can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed and the particular combination of antifungal and interacting medicine should be avoided.     

Investigation of the reaction of 6-amino-3-methyl-4-oxo-3,4-dihydro-2-pyrimidinylhydrazine

The hydrazine derivative2 has been utilized for the synthesis of three different fused 1,2,4-triazolo [4,3-a] pyrimidine derivatives4, 5 &6 and a tetrazolo[1,5-a] pyrimidine derivative7. Reaction of2 with the chalcone analogue 2-thenylidene-2′-acetothienone, gave the pyrazoline derivative8.     

Green synthesis of novel antifungal 1,2,4-triazoles effective against γ-irradiated Candida parapsilosis

This study reports the green synthesis of 11 novel 3-substituted-4-amino-5-mercapto-1,2,4-triazole derivatives using water as a readily available nontoxic solvent. Evaluation of their antimicrobial potential against several clinical pathogenic microorganisms was carried out. The newly synthesized cysteine derivative 6 showed promising antifungal activity against both γ-irradiated and nonirradiated Candida parapsilosis 216, with the lowest MIC (minimum inhibitory concentration) value of 3.125 µg/ml, probably through inhibition of 14α-demethylase. In addition, compound 6 showed complete inhibition of gelatinase, a virulence enzyme of C. parapsilosis. Also, scanning electron microscopy was carried out. Interestingly, compound 6 acted as a dual agent as it also showed good antibacterial activity against strains of Gram-positive bacteria used in the study. The synthesized compounds showed no cytotoxicity.     

Efficient regioselective three-component domino synthesis of 3-(1,2,4-Triazol-5-yl)-1,3-thiazolidin-4-ones as potent antifungal and antituberculosis agents

In research for promising antibacterial and antifungal compounds, a series of 2‐aryl 3‐[1,2,4]triazol‐5‐yl 4‐thiazolidinones 1 were synthesized by a domino reaction of 5‐amino‐1H‐[1,2,4]triazoles 3 , aromatic aldehydes, and α‐mercaptoacids in boiling toluene in the presence of molecular sieves 4 Å. Of the twenty novel 3‐[1,2,4]triazol‐5‐yl 4‐thiazolidinone derivatives, four compounds 2‐benzo[d][1,3]dioxol‐6‐yl‐3‐[(3‐morpholin‐4‐yl)‐1H‐1,2,4‐triazol‐5‐yl)]‐1,3‐thiazolidin‐4‐one ( 1i ), 2‐(4‐chlorophenyl)‐5‐methyl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1p ), 2‐benzo[d][1,3]dioxol‐6‐yl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1s ), 2‐benzo[d][1,3]dioxol‐6‐yl‐5‐methyl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1t ) exhibited MICs of 4 µg/mL or less versus Mycobacterium tuberculosis. Moreover, these compounds were screened against Candida albicans. Compounds 1p , 1s gave MICs of 1 µg/mL or less, and were fungicidal. Finally, compound 1s was evaluated against an expanded fungal panel and showed good activity against Cryptococcus neoformans. In addition, compound 1s also appeared to be fungicidal against Aspergillus arrhizus, with MIC <1 µg/mL.     

2009-2011年杭州地区抗深部真菌感染药利用分析

摘要：目的 评估2009~2011年杭州地区抗深部真菌感染药的临床应用状况,为临床合理应用抗真菌药提供依据。方法 根据杭州地区16家三级医院和9家二级医院2009年~2011年的抗真菌药消耗数据,采用金额分析法、用药频度(DDDs)分析法、日均费用（DDC）分析法进行统计分析。结果 杭州地区25家医院抗真菌药购药总金额三年呈逐年上升趋势,分别为35.56%和26.13%。其中米卡芬净增长108.3%和78.77%;伏立康唑78.31%和84%;卡泊芬净58.5%和70.22%;氟康唑为18.82%和-14.65%;伊曲康唑7.77%和-33.22%;两性霉素B -3%和-50.01%;用药频度（DDDs）最大的是伊曲康唑;DDC最高为米卡芬净。结论 杭州地区抗真菌药市场呈明显增长趋势,药品消费结构稳定,早年上市的产品出现负增长,新近上市的药品快速增长,涨跌互现。临床医生应严格依据感染菌及药敏结果,合理选择抗真菌药,避免耐药菌的发生和扩散,延长抗真菌药的使用周期。     

A novel series of substituted 1,2,3‐triazoles as cancer stem cell inhibitors: Synthesis and biological evaluation

An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series ( A : 4′‐allyl‐2′‐methoxyphenoxymethyl‐1,2,3‐triazoles; B : 4′‐acetamidophenoxymethyl‐1,2,3‐triazoles; C : naphthalene‐1′‐yloxymethyl‐1,2,3‐triazoles, and D : naphthalene‐2′‐yloxymethyl‐1,2,3‐triazoles) were synthesized via Copper (I)‐catalyzed alkyne‐azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs ( 39–68 ) were screened at 10 μM concentration in cell viability assay against cancer cell lines such as breast (MDA‐MB‐231), prostate (PC‐3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C ( 56–60 ) and D ( 61–68 ) were more potent than those in Series A ( 39‐45 ) and Series B ( 46–55 ) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 μM were evaluated for dose response. A total of five NCEs, 48 , 56 , 61 , 65 and 66 , were further assessed in soft‐agar assay and found to be relatively potent (IC₅₀ < 10 μM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA‐MB‐231) and prostatospheres (PC‐3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells.     

4-S-(5"-烃基-4"-氨基-1",2",4"-三唑-3"-基)-4-去氧-4'-去甲基表鬼臼毒素衍生物的合成及抗肿瘤活性

许多有显著抗肿瘤活性的鬼臼毒素类化合物,其母核Ｃ４侧链上往往连接有刚性较强的脂环或芳香环结构,而且侧链多含有一定数量的杂原子［１～３］。另外,三氮唑类化合物大都有广泛的生物活性,如抗菌［４～５］、抗病毒［６］、抗肿瘤［７］等,据此,我们设计并合成了...     

Euxyl K 400: a new sensitizer in cosmetics

A case of allergic contact dermatitis from miconazole is reported. Patch testing with a series of azole antimycotics was positive only to miconazole, isoconazole, tioconazole and oxiconazole. Those reacting are all beta-substituted 1-phenethyl imidazoles with an ortho-chlorine substitution on the aromatic ring. For this hitherto unreported pattern of cross-sensitivity, the designation of "ortho-chloro cross-sensitivity" is proposed.