New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.info:eu-repo/semantics/publishedVersio

Tentativas de suicídio em um hospital geral no Rio de Janeiro, Brasil Suicide attempts recorded at a general hospital in Rio de Janeiro, Brazil

A história pregressa de tentativa de suicídio é um importante preditor do suicídio e de novas tentativas. Este artigo apresenta o perfil dos casos de tentativas de suicídio detectados por meio de um sistema de monitoramento para esses agravos em um hospital geral no Rio de Janeiro, Brasil. Entre abril de 2001 e março de 2002 foram registrados 160 tentativas de suicídio, sendo 68% entre mulheres e 26% entre adolescentes. A ingestão de pesticidas e o abuso de medicamentos foram os principais métodos utilizados. Mulheres utilizaram os dois métodos na mesma proporção, enquanto 2/3 dos homens empregaram pesticidas. Em relação à prevalência dos fatores de risco para tentativas de suicídio, identificou-se que 21% dos pacientes haviam procurado serviços de saúde nos trinta dias anteriores ao evento, 28% referiram tentativas anteriores, 23% fizeram referência a casos de tentativas ou suicídio na família. Ainda que os dados populacionais disponíveis sejam escassos, as tentativas de suicídio parecem ser um evento importante de morbidade, particularmente entre adolescentes e adultos jovens. Sistemas de vigilância para esse agravo podem ser úteis para um melhor conhecimento do problema.<br>Previous suicide attempts are an important predictor of both repeated attempts and suicide. This paper presents the profile of patients who had attempted suicide and were admitted to a general hospital in Rio de Janeiro, Brazil. From April 2001 to March 2002, 160 suicide attempts were recorded (68% women; 26% adolescents). Ingestion of pesticides and prescription drugs were the two most common methods used. The two methods had been used by similar numbers of women, while two-thirds of men had used pesticides. As for prevalence of factors associated with attempted suicide, 21% of patients had been in contact with health services within 30 days prior to the event, 28% mentioned previous suicide attempts, and 23% reported other cases of suicide or attempts in the family. Despite the limited data in Brazil, suicide attempts appear to be an important health problem, particularly among youth. Surveillance systems for suicide attempts could help expand knowledge on this problem