Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world’s population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the "Medicines for Malaria Venture" organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds’ ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 μM. The Half Effective Concentrations (EC50) of these compounds ranged from 0.04 to 0.92 μM, while the Half Cytotoxic Concentrations (CC50) ranged from 2.48 to over 50 μM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion®) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0.001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.
RESUMOO lúpus eritematoso sistêmico (LES) é uma doença autoimune crônica, cujo desenvolvimento pode estar associado à infecção por vírus, como o vírus Epstein-Barr (EBV), parvovírus B19 e vírus linfotrópico de células T humanas (HTLV). Durante o período de junho a setembro de 2014, foi realizado um estudo transversal, incluindo 85 pacientes oriundos do Hospital Jean Bitar, na Cidade de Belém, Estado do Pará, Brasil. Foi realizada a pesquisa de anticorpos específicos contra os agentes virais estudados, assim como pesquisa da presença do genoma para EBV e HTLV. Foram avaliadas também variáveis clínicas e epidemiológicas. A maioria dos pacientes eram mulheres, tinham média de idade de 30 anos e se declararam brancos. Para EBV, detectou-se positividade de 37,6% para IgM, 98,8% para IgG e 2,4% por qPCR, com quantificações de 85.028 e 298 cópias do genoma/mL de plasma. Para B19, a positividade para IgM foi 0% e para IgG 67,1%. Não houve detecção sorológica ou por qPCR de HTLV. Foi verificada relação estatisticamente significante entre a positividade para IgM anti-EBV e pacientes mais jovens. Esse achado pode estar relacionado com a maior eficiência na produção dessa imunoglobulina nas infecções primárias agudas, que ocorrem geralmente em indivíduos infantes ou adultos jovens. Adicionalmente, o resultado de IgG anti-B19 foi associado à idade avançada dos pacientes, provavelmente por um maior tempo de exposição ao vírus aliado à persistência desse marcador após o contato. A presença dos marcadores não esteve associada às variáveis clínicas e epidemiológicas. Entretanto, o percentual de positividade para o marcador de infecção aguda por EBV pode sugerir um envolvimento do vírus com o LES. Palavras-chave: Lúpus Eritematoso Sistêmico; Vírus Epstein-Barr; Parvovírus B19; HTLV. ARTIGO ORIGINAL | ORIGINAL ARTICLE ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whose development may be associated with viral infections, such as Epstein-Barr virus (EBV), parvovirus B19, and human T-cell lymphotropic virus (HTLV).A cross-sectional study was performed between June and September 2014 involving 85 patients from the Hospital Jean Bitar, located in Belém, Pará State, Brazil. A survey of specific antibodies against the studied viral agents was conducted, in addition to a survey of the EBV and HTLV genomes. Clinical and epidemiologic variables were also evaluated. Most patients were female, approximately 30 years old, and declared themselves as Caucasians. The following positive results were detected for EBV: IgM = 37.6%, IgG = 98.8%, and qPCR = 2.4%, with 85,028 and 298 copies of the genome per milliliter of plasma. Positive results for B19 were: IgM = 0%, IgG = 67.1%. Serological or qPCR detection did not reveal HTLV. A significant statistical correlation was observed between anti-EBV IgM antibodies and younger patients. These findings may be related to the highly efficient production of this immunoglobulin during acute primary infections, which frequently occurs in children and young adults. Furthermore, t...
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