Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity.

Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models was established to optimize the 2-thiazolylhydrazone skeleton and obtain novel compounds with higher potency, better solubility in water, and enhanced absorption. Twenty-nine novel compounds were obtained and most showed low micromolar MIC values against different species of Candida and Cryptococcus spp., including Candida auris, an emerging multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 µM) was selected for further studies: cytotoxicity evaluation, permeability study in Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection model. All results obtained indicate the great potential of 28 as a novel antifungal agent.

Intenções de fecundidade: uma revisão da literatura acerca da variável em países de renda alta e no Brasil / Fertility intentions: a literature review on high-income countries and Brazil / Intenciones de fecundidad: una revisión de la literatura sobre la variable en países de ingresos altos y en Brasil

Resumo A literatura sobre intenções de fecundidade tem ganhado crescente relevância em estudos demográficos porque, sendo um determinante próximo da fecundidade, auxilia o entendimento do comportamento reprodutivo de diferentes populações. Contudo, esta literatura não foi ainda organizada segundo os principais e mais recorrentes aspectos dispersos na literatura. Estudos geralmente utilizam uma única característica acerca das intenções de fecundidade, seja por meio dos seus conceitos, das principais teorias ou de principais indicadores. Este trabalho possui, portanto, o objetivo de organizar e articular os principais e mais recorrentes aspectos presentes nos estudos sobre intenções de fecundidade. Ao longo da discussão, aprofunda-se na relação existente entre intenções de fecundidade e fecundidade observada. A princípio, foca-se nos países de renda alta, sobre e para os quais a literatura referente ao tema foi desenvolvida. Contudo, também são abordados países de renda média e fecundidade baixa, com ênfase no Brasil, para os quais a produção, especialmente a partir de uma abordagem teórica, ainda é incipiente.

Abstract The literature on fertility intentions has gained increasing relevance in demographic studies because, as a close determinant of fertility, it helps understand the reproductive behavior of different populations. However, this literature has not yet been organized according to the main and most recurrent aspects covered. Studies generally use one single aspect of fertility intentions, whether through its concepts, main theories or main indicators. Therefore, the goal of this work is to organize and articulate the main and most recurrent aspects present in studies on fertility intentions. It begins by presenting the main concepts. Then, it discusses important theoretical approaches on the formation of fertility intentions, as well as its main determinants. Finally, it contextualizes fertility intentions (and their levels) in different scenarios. Throughout the discussion, for each topic presented, the paper delves deeper into the relationship between fertility intentions and observed fertility. Its first focus is on high-income countries covered in the literature on the subject. However, it also discusses middle-income countries with low fertility, focusing on Brazil, for which academic production, especially from a theoretical approach, is still incipient.

Resumen La literatura sobre las intenciones de fecundidad ha ganado relevancia en los estudios demográficos porque, al ser estas determinantes próximos de la fecundidad, ayudan a entender el comportamiento reproductivo de diferentes poblaciones. Sin embargo, esta literatura no se ha organizado según sus aspectos principales y más recurrentes. Así, los estudios trabaja en general sobre un solo aspecto de las intenciones de fecundidad, sea a través de sus conceptos, de sus principales teorías o de sus principales indicadores. El objetivo de este artículo es, por lo tanto, organizar y articular los principales y más recurrentes aspectos presentes en los estudios sobre intenciones reproductivas. Así, comienza presentando sus conceptos principales. Luego, discute importantes corrientes teóricas sobre la formación de intenciones de fecundidad y también analiza sus principales determinantes. Finalmente, contextualiza las intenciones de fecundidad (y sus niveles) en diferentes escenarios. A través de cada tema presentado, se profundiza en la relación entre las intenciones de fecundidad y la fecundidad observada en las poblaciones. Es para ello que se centra, en un primer momento, en los países de ingresos altos, sobre y para los cuales se elaboró la literatura sobre el tema. Sin embargo, también se analizan los países de ingresos medios y de baja fecundidad, con énfasis en Brasil, cuya producción, especialmente desde un enfoque teórico, es aún incipiente.

Exposure to itraconazole influences the susceptibility to antifungals, physiology, and virulence of Trichophyton interdigitale.

Dermatophytosis is the most common human skin infection worldwide caused by dermatophytes, such as Trichophyton interdigitale and Trichophyton rubrum. Itraconazole (ITZ) is one of the main antifungals used to treat these infections. However, especially for onychomycosis, the treatment requires long-term regimens, increasing the possibility of drug resistance. We evaluated the effects of ITZ in the physiology, virulence, and interaction of T. interdigitale with phagocytes and mice cutaneous infection. In a screening test, fungal growth in the presence of ITZ led to the spontaneous selection of less susceptible T. interdigitale and T. rubrum strains. Interestingly, this phenotype was permanent for some T. interdigitale strains. Then, we studied three T. interdigitale strains: one susceptible and two ITZ-adapted. The ITZ-adapted strains were also less susceptible to the cell wall and membrane stressors, suggesting a multidrug resistance (MDR) phenotype associated with the increased ERG11 and MDR3 expression. These strains also presented substantial alterations in ergosterol content, lipid peroxidation, biofilm, and extracellular matrix production. During interaction with macrophages, ITZ-adapted strains were less engulfed but increased the intracellular oxidative and nitrosative bursts. In addition, ITZ-adapted strains presented a reduced ability to grow in a murine model of dermatophytosis, although causing the same tissue damage as the parental strain. In conclusion, the T. interdigitale ITZ adaptation increases tolerance to antifungals and alters the interaction with macrophages and a mammalian host. We hypothesized that successive exposure to ITZ may influence the emergence of adapted strains and lead to the recalcitrance of dermatophytosis.

Randomized, phase 1/2, double-blind pioglitazone repositioning trial combined with antifungals for the treatment of cryptococcal meningitis - PIO study.

BACKGROUND: Cryptococcosis affects more than 220,000 patients/year, with high mortality even when the standard treatment [amphotericin B (AMB), 5-flucytosin (5-FC) and fluconazole] is used. AMB presents high toxicity and 5-FC is not currently available in Brazil. In a pre-clinical study, pioglitazone (PIO - an antidiabetic drug) decreased AMB toxicity and lead to an increased mice survival, reduced morbidity and fungal burden in brain and lungs. The aim of this trial is to evaluate the efficacy and safety of PIO combined with standard antifungal treatment for human cryptococcosis. METHODS: A phase 1/2, randomized, double blind, placebo-controlled trial will be performed with patients from Belo Horizonte, Brazil. They will be divided into three groups (placebo, PIO 15 mg/day or PIO 45 mg/day) and will receive an additional pill during the induction phase of cryptococcosis' treatment. Our hypothesis is that treated patients will have increased survival, so the primary outcome will be the mortality rate. Patients will be monitored for survival, side effects, fungal burden and inflammatory mediators in blood and cerebrospinal fluid. The follow up will occur for up 60 days. CONCLUSIONS: We expect that PIO will be an adequate adjuvant to the standard cryptococcosis' treatment. TRIAL REGISTRATION: ICTRP/WHO (and International Clinical Trial Registry Plataform (ICTRP/WHO) (http://apps.who.int/trialsearch/Trial2.aspx?TrialID=RBR-9fv3f4), RBR-9fv3f4 (http://www.ensaiosclinicos.gov.br/rg/RBR-9fv3f4). UTN Number: U1111-1226-1535. Ethical approvement number: CAAE 17377019.0.0000.5149.