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According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

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A hemofilia adquirida idiopática é uma condição médica extremamente rara, causada pelo desenvolvimento espontâneo de autoanticorpos contra o fator VIII (FVIII), com incidência estimada em 1,5/milhão de habitantes/ano. Embora esteja descrita a associação com outras doenças, seu fator precipitante é desconhecido. O quadro clínico se caracteriza por hemorragias graves, sem história pessoal ou familiar prévia de coagulopatias. Os autores relatam um caso clínico de hemofilia adquirida idiopática com evolução desfavorável.

Idiopathic acquired hemophilia is an extremely rare medical condition caused by the spontaneous development of autoantibodies against factor VIII (FVIII), with an estimated incidence of 1.5 / million inhabitants / year. Although the association with other diseases is described, its precipitating factor is unknown. The clinical picture is characterized by severe hemorrhages, with no previous personal or family history of coagulopathies. The authors report a clinical case of idiopathic acquired hemophilia with unfavorable outcome.

RESUMO

OBJETIVO: Comparar resultados de densitometrias ósseas e do risco de fratura pela plataforma Fracture Risk Assessment Tool® (FRAX®). Métodos: Estudo observacional, transversal, de natureza quantitativa, realizado por meio da análise de prontuários de indivíduos que realizaram densitometria óssea e seus respectivos laudos, com cálculo posterior do risco de fratura maior e de quadril nos próximos 10 anos pela FRAX®. RESULTADOS: A média de idade foi de 60,19±9,44 anos, e houve predomínio de mulheres (96,5%). Dos indivíduos, 1,1% foi classificado como com risco de fratura maior e 9,1% com risco de fratura de quadril. A osteoporose foi encontrada em 12,4% da amostra, com predomínio nos pacientes mais idosos, e a coluna foi o sítio mais comum (53,7%). Admitindo-se a densitometria óssea como padrão-ouro para diagnóstico de osteoporose, a sensibilidade da plataforma para detectar risco de fratura maior foi 4,5%. Observou-se correlação positiva entre idade e risco de fratura, e negativa entre idade e T-score. CONCLUSÃO: Foi baixa a sensibilidade da plataforma, e não foi importante a relação entre os resultados da densitometria óssea e da FRAX®, sugerindo que esta ferramenta não se mostrou adequada para ser inserida como método de rastreio para osteoporose na população estudada.(AU)

OBJECTIVES: To compare the results of bone densitometry and fracture risk through the platform Fracture Risk Assessment Tool (FRAX®). METHODS: This is a cross-sectional, observational study of quantitative approach performed through the analyses of medical records of individuals who underwent bone densitometry and their respective reports, with a posterior calculation of the risk of major and hip fracture in the next 10 years through FRAX®. RESULTS: The mean age was 60.19±9.44 years, with a predominance of women (96.5%). Of the individuals, 1.1% were classified as having a major fracture risk, and 9.1% as having a hip fracture risk. Osteoporosis was found in 12.4% of the sample, with predominance in the older patients, and the spine was the most common site (53.7%). Assuming bone densitometry as the gold standard for diagnosis of osteoporosis, the sensitivity of the platform to detect major fracture risk was 4.5%. There was a positive correlation between age and fracture risk, and a negative correlation between age and t-score. CONCLUSION: The platform showed low sensitivity, and the relationship between the results of the bone densitometry and FRAX® was not significant, suggesting that this tool is not adequate to be inserted as a screening method for osteoporosis in the studied population.(AU)

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Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC50 values of 1.8 and 1.9gmL(-1) against T.cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.

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Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=231 mu M, LiEC50 = 6.14 mu M, TcEC50 = 1.31 mu M) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6 fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

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RATIONALE: There are very few data as to the social and occupational adaptation of patients with bipolar disorder in Spain and even less is known about the resource use they generate. OBJECTIVE: To determine the functional status and healthcare resource use of the Spanish sample of the pan European EMBLEM (European Mania in Bipolar Longotudinal Evaluation of Medication) study of bipolar patients in manic or mixed phase. METHOD: The EMBLEM study recruited 3536 patients, 312 of whom (8.82%) were enrolled in Spain. Patients had to be adults with a diagnosis of bipolar disorder who were initiating at the discretion of their treating psychiatrist oral treatment for an acute manic phase. They were evaluated using the Spanish versions of rating scales for the severity of mania (Young Mania Rating Scale), bipolar disorder (CGI BD) for mania, depression and hallucinations delusions, and depression (HAMD 5 item version of the Hamilton Scale); the Life Chart Method (LCM) and 2 items of the SLICE of LIFE were used to evaluate functioning. Information was collected on healthcare resource utilization during the preceding year. RESULTS: Sixty three percent of the patients presented with moderate to very severe work related difficulties in the year preceding his her manic episode. Forty percent of the patients failed to comply either totally or partly with their prescribed treatment. Subjects required an average of 1.5 hospitalizations during the year prior to enrollment, with a mean stay of approximately 10 days, and between 7 and 8 outpatient visits per year.

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