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[PMID]: 29210421 [Au] Autor: Molinski TF [Ad] Endereço: Department of Chemistry and Biochemistry, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Dr 0358, La Jolla, California 92093, USA. tmolinski@ucsd.edu. [Ti] Título: Cyclic azole-homologated peptides from Marine sponges. [So] Source: Org Biomol Chem;16(1):21-29, 2017 Dec 19. [Is] ISSN: 1477-0539 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: This review discusses the chemistry of cyclic azole-homologated peptides (AHPs) from the marine sponges, Theonella swinhoei, other Theonella species, Calyx spp. and Plakina jamaicensis. The origin, distribution of AHPs and molecular structure elucidations of AHPs are described followed by their biosynthesis, bioactivity, and synthetic efforts towards their total synthesis. Reports of partial and total synthesis of AHPs extend beyond peptide coupling reactions and include creative construction of the non-proteinogenic amino acid components, mainly the homologated heteroaromatic and α-keto-ß-amino acids. A useful conclusion is drawn regarding AHPs: despite their rarity, exotic structures and the potent protease inhibitory properties of some members, their synthesis is under-developed and beckons solutions for outstanding problems towards their efficient assembly. [Mh] Termos MeSH primário: Azóis/química Peptídeos/química Poríferos/química [Mh] Termos MeSH secundário: Animais Azóis/isolamento & purificação Conformação Molecular Peptídeos/isolamento & purificação [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Azoles); 0 (Peptides) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171207 [St] Status: MEDLINE [do] DOI: 10.1039/c7ob02628e

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[PMID]: 29337257 [Au] Autor: Dimopoulou M; Verhoef A; Gomes CA; van Dongen CW; Rietjens IMCM; Piersma AH; van Ravenzwaay B [Ad] Endereço: Division of Toxicology, Wageningen University, The Netherlands; National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Electronic address: myrto.dimopoulou@wur.nl. [Ti] Título: A comparison of the embryonic stem cell test and whole embryo culture assay combined with the BeWo placental passage model for predicting the embryotoxicity of azoles. [So] Source: Toxicol Lett;286:10-21, 2018 Apr. [Is] ISSN: 1879-3169 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: In the present study, we show the value of combining toxico-dynamic and -kinetic in vitro approaches for embryotoxicity testing of azoles. Both the whole embryo culture (WEC) and the embryonic stem cells test (EST) predicted the in vivo potency ranking of twelve tested azoles with moderate accuracy. Combining these results with relative placental transfer rates (Papp values) as determined in the BeWo cell culture model, increased the predictability of both WEC and EST, with R values increasing from 0.51 to 0.87 and from 0.35 to 0.60, respectively. The comparison of these in vitro systems correlated well (R = 0.67), correctly identifying the in vivo strong and weak embryotoxicants. Evaluating also specific gene responses related with the retinoic acid and sterol biosynthesis pathways, which represent the toxicological and fungicidal mode of action of azoles respectively in the WEC and EST, we observed that the differential regulation of Dhrs3 and Msmo1 reached higher magnitudes in both systems compared to Cyp26a1 and Cyp51. Establishing sensitive biomarkers across the in vitro systems for studying the underlying mechanism of action of chemicals, such as azoles, is valuable for comparing alternative in vitro models and for improving insight in the mechanism of developmental toxicity of chemicals. [Mh] Termos MeSH primário: Azóis/toxicidade Bioensaio Embrião de Mamíferos/efeitos dos fármacos Células-Tronco Embrionárias Murinas/efeitos dos fármacos Placenta/efeitos dos fármacos Teratogênios/toxicidade Testes de Toxicidade/métodos [Mh] Termos MeSH secundário: Oxirredutases do Álcool/genética Oxirredutases do Álcool/metabolismo Animais Transporte Biológico Diferenciação Celular/efeitos dos fármacos Linhagem Celular Relação Dose-Resposta a Droga Técnicas de Cultura Embrionária Embrião de Mamíferos/metabolismo Embrião de Mamíferos/patologia Feminino Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos Seres Humanos Cinética Camundongos Oxigenases de Função Mista/genética Oxigenases de Função Mista/metabolismo Células-Tronco Embrionárias Murinas/metabolismo Células-Tronco Embrionárias Murinas/patologia Miócitos Cardíacos/efeitos dos fármacos Miócitos Cardíacos/metabolismo Miócitos Cardíacos/patologia Placenta/metabolismo Placenta/patologia Gravidez Reprodutibilidade dos Testes Ácido Retinoico 4 Hidroxilase/genética Ácido Retinoico 4 Hidroxilase/metabolismo Medição de Risco Esterol 14-Desmetilase/genética Esterol 14-Desmetilase/metabolismo [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Azoles); 0 (Teratogens); EC 1.- (Mixed Function Oxygenases); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.1.71 (DHRS3 protein, mouse); EC 1.14.13.70 (Cyp51 protein, mouse); EC 1.14.13.70 (Sterol 14-Demethylase); EC 1.14.13.72 (methylsterol monooxygenase); EC 1.14.14.1 (Cyp26a1 protein, mouse); EC 1.14.14.1 (Retinoic Acid 4-Hydroxylase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180220 [Lr] Data última revisão: 180220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180117 [St] Status: MEDLINE

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[PMID]: 29362778 [Au] Autor: Kreijkamp-Kaspers S; Hawke KL; van Driel ML [Ad] Endereço: Primary Care Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, Australia. [Ti] Título: Oral Medications to Treat Toenail Fungal Infection. [So] Source: JAMA;319(4):397-398, 2018 Jan 23. [Is] ISSN: 1538-3598 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Clinical Question: Which oral antifungal medication is associated with the highest clinical (ie, normal appearance of the toenail) and mycological (negative culture, microscopy, or both) cure rates vs placebo or other antifungals when used to treat fungal infections? Bottom Line: Both terbinafine and azole-based medications were associated with higher clinical and mycological cure rates compared with placebo (high-quality evidence). Azoles were associated with lower cure rates than terbinafine when compared directly. [Mh] Termos MeSH primário: Antifúngicos/administração & dosagem Azóis/administração & dosagem Dermatoses do Pé/tratamento farmacológico Naftalenos/administração & dosagem Onicomicose/tratamento farmacológico [Mh] Termos MeSH secundário: Administração Oral Azóis/efeitos adversos Seres Humanos Naftalenos/efeitos adversos Literatura de Revisão como Assunto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Azoles); 0 (Naphthalenes); G7RIW8S0XP (terbinafine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180131 [Lr] Data última revisão: 180131 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 180125 [St] Status: MEDLINE [do] DOI: 10.1001/jama.2017.20160

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[PMID]: 28454766 [Au] Autor: Rieke S; Heise T; Schmidt F; Haider W; Bednarz H; Niehaus K; Mentz A; Kalinowski J; Hirsch-Ernst KI; Steinberg P; Niemann L; Marx-Stoelting P [Ad] Endereço: Bundesinstitut für Risikobewertung (BfR), Department for Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. [Ti] Título: Mixture effects of azole fungicides on the adrenal gland in a broad dose range. [So] Source: Toxicology;385:28-37, 2017 06 15. [Is] ISSN: 1879-3185 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: Consumers are exposed to low concentrations of a variety of pesticide residues in or on food. Some of them might interfere with the endocrine system. While each individual active substance has been extensively tested for toxicity and safety, potential combination effects possibly resulting from combined exposure to different pesticides have seldomly been tested so far, especially in vivo. Since the adrenal gland is a key endocrine organ, we investigated if and how substances of a group of fungicides presumed to interfere with the biosynthesis of steroid hormones affect this organ when applied individually and in combination in a broad dose range. A 28-day feeding study was conducted in Wistar rats by using three (tri)azole fungicides considered to potentially affect the endocrine system (cyproconazole, epoxiconazole and prochloraz) individually at five dose levels, ranging from 0.9ppm to 2400ppm, and in combination at three dose levels. The parameters analysed included classical toxicology (pathology, histopathology, clinical chemistry) and molecular toxicology endpoints (gene expression arrays and quantitative real time PCR e.g. of Star, HSD3ß, Cyp11a1, Cyp11b1, Cyp11b2, Cyp 21, ApoE), as well as hormone analysis. A dose-dependent decrease in the adrenal gland weight of rats treated with epoxiconazole alone, which was accompanied by an atrophy of the adrenal gland as well as by an increase in the serum cholesterol level and which only became statistically significant at the top dose levels, was observed. These effects were attenuated in the combination experiments, although the same epoxiconazole concentration was used. [Mh] Termos MeSH primário: Glândulas Suprarrenais/efeitos dos fármacos Azóis/toxicidade Fungicidas Industriais/toxicidade [Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/genética Glândulas Suprarrenais/metabolismo Glândulas Suprarrenais/patologia Aldosterona/sangue Animais Apolipoproteínas E/genética Colesterol/sangue Corticosterona/sangue Sistema Enzimático do Citocromo P-450/genética Interações Medicamentosas Expressão Gênica/efeitos dos fármacos Masculino Nível de Efeito Adverso não Observado Tamanho do Órgão/efeitos dos fármacos Fosfoproteínas/genética Progesterona/sangue Ratos Wistar [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Apolipoproteins E); 0 (Azoles); 0 (Fungicides, Industrial); 0 (Phosphoproteins); 0 (steroidogenic acute regulatory protein); 4964P6T9RB (Aldosterone); 4G7DS2Q64Y (Progesterone); 9035-51-2 (Cytochrome P-450 Enzyme System); 97C5T2UQ7J (Cholesterol); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); W980KJ009P (Corticosterone) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 180122 [Lr] Data última revisão: 180122 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 28463038 [Au] Autor: Thabet NM; Moustafa EM [Ad] Endereço: a Radiation Biology Department , National Centre for Radiation Research and Technology (NCRRT), Atomic Energy Authority , Cairo , Egypt. [Ti] Título: Synergistic effect of Ebselen and gamma radiation on breast cancer cells. [So] Source: Int J Radiat Biol;93(8):784-792, 2017 08. [Is] ISSN: 1362-3095 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: PURPOSE: To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro. MATERIALS AND METHODS: Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 µg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6 Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-ß), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated. RESULTS: The results showed that the effective dosage of this combination was observed at 25 µg/ml of Ebs with γ-radiation at 6 Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-ß with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed. CONCLUSIONS: We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines. [Mh] Termos MeSH primário: Azóis/farmacologia Neoplasias da Mama/patologia Raios gama Compostos Organosselênicos/farmacologia [Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos Apoptose/efeitos da radiação Caspase 3/metabolismo Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Proliferação Celular/efeitos da radiação Citocinas/metabolismo Granzimas/metabolismo Seres Humanos Células MCF-7 NF-kappa B/metabolismo Transdução de Sinais/efeitos dos fármacos Transdução de Sinais/efeitos da radiação Ligante Indutor de Apoptose Relacionado a TNF/metabolismo Fator A de Crescimento do Endotélio Vascular/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Azoles); 0 (Cytokines); 0 (NF-kappa B); 0 (Organoselenium Compounds); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (Vascular Endothelial Growth Factor A); 40X2P7DPGH (ebselen); EC 3.4.21.- (Granzymes); EC 3.4.22.- (Caspase 3) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 180111 [Lr] Data última revisão: 180111 [Sb] Subgrupo de revista: IM; S [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1080/09553002.2017.1325024

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[PMID]: 29182862 [Au] Autor: Cebrián-Prats A; Rovira T; Saura P; González-Lafont À; Lluch JM [Ad] Endereço: Departament de Química and ‡Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona , 08193 Bellaterra, Barcelona, Spain. [Ti] Título: Inhibition of Mammalian 15-Lipoxygenase by Three Ebselen-like Drugs. A QM/MM and MM/PBSA Comparative Study. [So] Source: J Phys Chem A;121(51):9752-9763, 2017 Dec 28. [Is] ISSN: 1520-5215 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ebselen is a potent competitive inhibitor of the active form of rabbit 15-lipoxygenase, an enzyme involved in many inflammatory diseases. Light-induced Z-to-E isomerization of the ebselen-like 2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester (BODTCM) molecule was used to convert the weak (Z)-BOTDCM inhibitor into the (E)-isomer with much higher inhibitory capacity. In this study, the binding modes of ebselen, (E)-BOTDCM and (Z)-BOTDCM, have been analyzed to provide molecular insights on the inhibitory potency of ebselen and on the geometric-isomer specificity of (E)- and (Z)-BOTDCM inhibitors. The inhibitor-enzyme structures obtained from docking and molecular dynamics simulations as well as from QM/MM calculations show that the inhibitor molecules are not coordinated to the nonheme iron in the active site. Thermal motion allows ebselen and (E)-BOTDCM to visit a wide range of the configurational space competing with the polyunsaturated fatty acid for binding at the active site. Both molecules present similar MM/PBSA binding free energies. The energy penalty for the bigger geometric deformation undergone by (E)-BODTCM would explain its lower inhibitor potency. The (Z)-isomer is the weakest inhibitor because thermal motion moves it to a region very far from the first coordination sphere of Fe, where it could not compete with the fatty acid substrate. [Mh] Termos MeSH primário: Araquidonato 15-Lipoxigenase/metabolismo Azóis/farmacologia Compostos Férricos/farmacologia Inibidores de Lipoxigenase/farmacologia Compostos Organosselênicos/farmacologia Teoria Quântica Termodinâmica [Mh] Termos MeSH secundário: Animais Azóis/síntese química Azóis/química Compostos Férricos/síntese química Compostos Férricos/química Ligantes Inibidores de Lipoxigenase/síntese química Inibidores de Lipoxigenase/química Modelos Moleculares Estrutura Molecular Compostos Organosselênicos/síntese química Compostos Organosselênicos/química Coelhos [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Azoles); 0 (Ferric Compounds); 0 (Ligands); 0 (Lipoxygenase Inhibitors); 0 (Organoselenium Compounds); 40X2P7DPGH (ebselen); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180108 [Lr] Data última revisão: 180108 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jpca.7b10416

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[PMID]: 29183661 [Au] Autor: El-Wahab HAAA; Accietto M; Marino LB; McLean KJ; Levy CW; Abdel-Rahman HM; El-Gendy MA; Munro AW; Aboraia AS; Simons C [Ad] Endereço: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, Wales, UK; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. [Ti] Título: Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics. [So] Source: Bioorg Med Chem;26(1):161-176, 2018 01 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH -imidazole or CH -triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 µg/mL, 17a 50 µg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Šcrystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. [Mh] Termos MeSH primário: Antituberculosos/farmacologia Azóis/farmacologia Dipeptídeos/farmacologia Desenho de Drogas Mycobacterium tuberculosis/efeitos dos fármacos Peptídeos Cíclicos/farmacologia Piperazinas/farmacologia [Mh] Termos MeSH secundário: Antituberculosos/síntese química Antituberculosos/química Azóis/química Sítios de Ligação/efeitos dos fármacos Sistema Enzimático do Citocromo P-450/química Sistema Enzimático do Citocromo P-450/metabolismo Dipeptídeos/química Relação Dose-Resposta a Droga Ligantes Testes de Sensibilidade Microbiana Modelos Moleculares Estrutura Molecular Mycobacterium tuberculosis/metabolismo Peptídeos Cíclicos/química Piperazinas/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antitubercular Agents); 0 (Azoles); 0 (Dipeptides); 0 (Ligands); 0 (Peptides, Cyclic); 0 (Piperazines); 0 (cytochrome P-450 CYP12A1 (house fly)); 1RTM4PAL0V (piperazine); 5625-40-1 (cyclo(tyrosyl-tyrosyl)); 9035-51-2 (Cytochrome P-450 Enzyme System) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180106 [Lr] Data última revisão: 180106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171130 [St] Status: MEDLINE

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[PMID]: 28464338 [Au] Autor: Sari S; Dalkara S; Kaynak FB; Reynisson J; Saraç S; Karakurt A [Ad] Endereço: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, Turkey. [Ti] Título: New Anti-Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies. [So] Source: Arch Pharm (Weinheim);350(6), 2017 Jun. [Is] ISSN: 1521-4184 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: (Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABA Rs), was reported to be sensitive to Asn265 of the ß2/ß3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure. We performed molecular docking studies for our active compounds using GABA R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA R is elucidated. [Mh] Termos MeSH primário: Anticonvulsivantes/uso terapêutico Azóis/uso terapêutico Simulação de Acoplamento Molecular Convulsões/tratamento farmacológico [Mh] Termos MeSH secundário: Animais Anticonvulsivantes/administração & dosagem Anticonvulsivantes/síntese química Azóis/administração & dosagem Azóis/síntese química Relação Dose-Resposta a Droga Injeções Intraperitoneais Masculino Camundongos Camundongos Endogâmicos Estrutura Molecular Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anticonvulsants); 0 (Azoles) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171201 [Lr] Data última revisão: 171201 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1002/ardp.201700043

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[PMID]: 29016694 [Au] Autor: Galvão EL; Rabello A; Cota GF [Ad] Endereço: Pesquisa Clínica e Políticas Públicas em Doenças Infecto-Parasitárias-Centro de Pesquisas René Rachou-Fundação Oswaldo Cruz, Fiocruz, Belo Horizonte, Minas Gerais, Brazil. [Ti] Título: Efficacy of azole therapy for tegumentary leishmaniasis: A systematic review and meta-analysis. [So] Source: PLoS One;12(10):e0186117, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Several controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We conducted a systematic literature review of studies evaluating the efficacy and toxicity associated with azole therapy for tegumentary leishmaniasis. METHODOLOGY: PRISMA guidelines for systematic reviews and the Cochrane manual were followed, and the review methodology was registered (PROSPERO; CRD42016048668). Sources included the EMBASE, Web of Science, MEDLINE, LILACS, and IBECS databases along with a manual search of references from evaluated studies. Additional resources such as Google Scholar and clinicaltrials.gov were also searched. We included all studies reporting cure rate after cutaneous or mucosal leishmaniasis treatment with systemic azole drugs, regardless of their design. R software was used to estimate global rates of success and adverse events with each drug. The main outcome of interest was clinical cure, defined as complete re-epithelialization of all lesions. RESULTS: A total of 37 studies involving 1259 patients that reported outcomes after fluconazole (9), ketoconazole (14) and itraconazole (15) treatments were included. Only 14 (38%) were randomized controlled trials (RCT). The pooled azole final efficacy rate was 64% (CI95%: 57-70%) for all studies and 60% (CI95%: 50-70%) (p = 0.41) if only RCTs studies were considered. Twenty-four studies were conducted in the Old World and 13 studies in the Americas. The final efficacy rate according to New and Old World were 62% (CI95%: 43-77%) and 66% (CI95%: 58-73%), respectively. The final efficacy rate of azoles according to species were 89% (CI95%: 50-98%) for L. mexicana; 88% for L. infantum (CI95%: 27-99%); 80% for L. donovani; 53% (CI95%: 29-76%) for L. major; 49% for L. braziliensis (CI95%: 21-78%); and 15% (CI95%: 1-84%) for L. tropica. The cure rates were similar among the fluconazole, ketoconazole and itraconazole group arms (p = 0.89), specifically 61% (CI95%: 48-72%), 64% (CI95%: 44-80%) 65% (CI95%: 56-72%), respectively. Adverse events during fluconazole, itraconazole and ketoconazole therapy were reported in 7% (CI95%: 3-14%), 12% (CI95% 8-19%) and 13% (CI95%: 6-29%) of treated patients, respectively, without difference among them (p = 0.35). This systematic review included studies with small samples and both non-comparative and non-randomized studies and the main limitation was the low quality of the available studies. CONCLUSIONS: Available evidence suggests that fluconazole, ketoconazole and itraconazole have similar and modest efficacy rates for tegumentary leishmaniasis treatment. There is insufficient evidence to support the exclusive use of azole therapy as a single agent for leishmaniasis treatment. [Mh] Termos MeSH primário: Antifúngicos/uso terapêutico Azóis/uso terapêutico Leishmaniose Cutânea/tratamento farmacológico Leishmaniose Mucocutânea/tratamento farmacológico [Mh] Termos MeSH secundário: Administração Cutânea Administração através da Mucosa Antifúngicos/efeitos adversos Azóis/efeitos adversos Bases de Dados Factuais Seres Humanos Itraconazol/efeitos adversos Itraconazol/uso terapêutico Cetoconazol/efeitos adversos Cetoconazol/uso terapêutico Leishmaniose Cutânea/epidemiologia Leishmaniose Cutânea/parasitologia Leishmaniose Mucocutânea/epidemiologia Leishmaniose Mucocutânea/parasitologia [Pt] Tipo de publicação: JOURNAL ARTICLE; META-ANALYSIS; REVIEW [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Azoles); 304NUG5GF4 (Itraconazole); R9400W927I (Ketoconazole) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171011 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186117

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[PMID]: 28911043 [Au] Autor: Arendrup MC; Patterson TF [Ad] Endereço: Unit of Mycology, Statens Serum Institut. [Ti] Título: Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment. [So] Source: J Infect Dis;216(suppl_3):S445-S451, 2017 Aug 15. [Is] ISSN: 1537-6613 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. [Mh] Termos MeSH primário: Candida glabrata/efeitos dos fármacos Candida/efeitos dos fármacos Candidíase Invasiva/tratamento farmacológico Farmacorresistência Fúngica Múltipla [Mh] Termos MeSH secundário: Animais Antifúngicos/farmacologia Azóis/farmacologia Candida/classificação Candidíase Invasiva/epidemiologia Estado Terminal/epidemiologia Estado Terminal/terapia Modelos Animais de Doenças Equinocandinas/farmacologia Seres Humanos Testes de Sensibilidade Microbiana [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Azoles); 0 (Echinocandins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170921 [Lr] Data última revisão: 170921 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170916 [St] Status: MEDLINE [do] DOI: 10.1093/infdis/jix131

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