Desenvolvimento de um medicamento brasileiro nanoencapsulado para o tratamento da esquistossomose

Schistosomiasis is a parasitic disease that, according to the World Health Organization, constitutes a major public health problem associated with severe morbidity, mostly children in preschool age. The administration of drugs in children always constitutes a difficult task, especially when formulations are not developed specifically for pediatric use, when high doses of drug are required and the drug has a bitter taste, as in the case of praziquantel. Polymer nanoparticles are promising systems for development of encapsulated drugs with low water solubility and bitter taste, due to the good physical and chemical stability, adequate biocompatibility and simple manufacturing processes. Moreover, they can enhance the bioavailability and reduce variability of treatment among patients. Poly(methyl methacrylate) doped with praziquantel was produced through a miniemulsion polymerization process to compose a pediatric pharmaceutical suspension. Nanoparticles were characterized in terms of physico-chemical properties, toxicological properties and biological activity in mice, being concluded that obtained results were satisfactory. The results were encapsulation rate around 90%, absence of chemical interaction drug - polymer and the presence of biological activity. A collaborative approach was used for this development, involving national partnerships and independent funding mechanisms, a powerful pathway for development of drugs for neglected diseases.A esquistossomose é uma doença parasitária que, segundo a Organização Mundial da Saúde, é um dos principais problemas de saúde pública associados à morbidade severa, sendo boa parte crianças. A administração de medicamentos em crianças constitui uma tarefa difícil, principalmente quando não há formulações pediátricas, quando altas doses de fármaco são requeridas e o fármaco apresenta um sabor amargo, como é o caso do praziquantel. Nanopartículas poliméricas são sistemas promissores para o desenvolvimento de fármacos com baixa hidrossolubilidade e gosto ruim, apresentam estabilidade físico-química, biocompatibilidade e fáceis processos de produção. Podem ainda proporcionar o aumento da biodisponibilidade e redução da variabilidade do tratamento entre pacientes. O polímero poli(metacrilato de metila) com o praziquantel encapsulado foi sintetizado pelo processo de polimerização em miniemulsão para compor uma suspensão farmacêutica pediátrica. As nanopartículas foram caracterizadas em termos das propriedades físico-químicas, toxicológicas e da atividade biológica em camundongos. Os resultados encontrados foram satisfatórios, taxa de encapsulamento de 90%, ausência de interação química fármaco - polímero e presença de atividade biológica. Uma abordagem colaborativa foi utilizada para este desenvolvimento, envolvendo parcerias nacionais e mecanismos de financiamento independentes, uma maneira nova e poderosa de desenvolver medicamentos para doenças negligenciadas

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Requisitos de bioisenção com base no Sistema de Classificação Biofarmacêutica no Brasil e no mundo

O acesso a medicamentos pode ser facilitado por programas globais de desenvolvimento farmacêutico, mas há necessidade de que as agencias regulatórias e as indústrias farmoquímicas e farmacêuticas interajam e haja um consenso quanto as exigências para o registro de medicamentos. Este artigo examinou a legislação especifica sobre bi isenção com base no Sistema de Classificação Biofarmacêutica, comparando os cenários do Brasil e do mundo. A partir dessa análise, identificou os entraves a aplicação dos critérios internacionais na realidade regulatória nacional, identificando algumas fragilidades da legislação, como no caso de pro-fármacos. Analisaram-se os critérios de cinco organismos regulatórios (Agência Europeia de Medicamentos, Food and Drug Administration, Health Canada, Conselho Internacional para Harmonização de Requisitos Técnicos para Medicamentos de Uso Humano e Organização Mundial da Saúde) frente aos requisitos da Agência Nacional de Vigilância Sanitária, pontuando as diferenças e o que já se encontra pacificado no tocante a classe do Sistema de Classificação Biofarmacêutica aceita, a comparabilidade entre formulação teste e de referência, solubilidade, permeabilidade intestinal e perfil de dissolução in vitro. Concluiu--se que a Agência Nacional de Vigilância Sanitária deve internalizar os preceitos e critérios da bioisenção com base no Sistema de Classificação Biofarmacêutica por meio de um novo marco regulatório. Além disso, para que esse marco regulatório seja bem-sucedido e produza resultados palpáveis, em especial na área de saúde publica e vigilância sanitária, a agência brasileira deve estar aberta ao diálogo com o setor regulado e as inovações e orientações da academia, sem desviar o foco de sua missão institucional.Access to medicines can be facilitated by global pharmaceutical development programs, but there is a need for regulatory agencies and the pharmochemical and pharmaceutical industries to interact and to have a consensus on the requirements for drug registration. This article examined the specific legislation concerning to biowaiver based on the  Biopharmaceutical Classification System, comparing the scenario in Brazil and worldwide. Based on this analysis, it identified the obstacles to the application of international criteria in the national regulatory reality, identifying some weaknesses of the legislation, as in the case of prodrugs.  The criteria of five regulatory bodies (European Medicines Agency, Food and Drug Administration, Health Canada, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and World Health Organization) were analyzed in relation to the requirements of the Brazilian Health Regulatory Agency (Anvisa), pointing out the differences and what has already been settled regarding the accepted class of the Biopharmaceutical Classification System, the comparability between test and reference formulations, solubility, intestinal permeability and in vitro dissolution profile. It was concluded that Anvisa should internalize the percepts and criteria of the biowaiver based on Biopharmaceutical Classification System, through a new regulatory framework. Moreover, for this regulatory framework to be successful and produce tangible results, especially in the area of public health and health surveillance, Anvisa must be open to dialogue with the regulated sector and to innovations and guidance from academia, without losing focus of its institutional mission

Development of a brazilian nanoencapsulated drug for schistosomiasis treatment

Submitted by Nuzia Santos ([email protected]) on 2018-09-24T18:38:29Z No. of bitstreams: 1 Desenvolvimento de um medicamento brasileiro nanoencapsulado.pdf: 717455 bytes, checksum: b1a95816e0eb7137bb22fc3b73c5a50d (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-09-24T18:55:52Z (GMT) No. of bitstreams: 1 Desenvolvimento de um medicamento brasileiro nanoencapsulado.pdf: 717455 bytes, checksum: b1a95816e0eb7137bb22fc3b73c5a50d (MD5)Made available in DSpace on 2018-09-24T18:55:53Z (GMT). No. of bitstreams: 1 Desenvolvimento de um medicamento brasileiro nanoencapsulado.pdf: 717455 bytes, checksum: b1a95816e0eb7137bb22fc3b73c5a50d (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Produção e Inovação em Saúde. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Técnologia em Fármaco. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa Renê Rachou. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio Grande do Sul. Porto Alegre, RS, BrasilUniversidade Federal do Rio de Janeiro. Escola de Química. Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de Janeiro. Engenharia Química. Rio de Janeiro, RJ, BrasilA esquistossomose é uma doença parasitária que, segundo a Organização Mundial da Saúde, é um dos principais problemas de saúde pública associados à morbidade severa, sendo boa parte crianças. A administração de medicamentos em crianças constitui uma tarefa difícil, principalmente quando não há formulações pediátricas, quando altas doses de fármaco são requeridas e o fármaco apresenta um sabor amargo, como é o caso do praziquantel. Nanopartículas poliméricas são sistemas promissores para o desenvolvimento de fármacos com baixa hidrossolubilidade e gosto ruim, apresentam estabilidade físico-química, biocompatibilidade e fáceis processos de produção. Podem ainda proporcionar o aumento da biodisponibilidade e redução da variabilidade do tratamento entre pacientes. O polímero poli (metacrilato de metila) com o praziquantel encapsulado foi sintetizado pelo processo de polimerização em miniemulsão para compor uma suspensão farmacêutica pediátrica. As nanopartículas foram caracterizadas em termos das propriedades físico-químicas, toxicológicas e da atividade biológica em camundongos. Os resultados encontrados foram satisfatórios, taxa de encapsulamento de 90%, ausência de interação química fármaco-polímero e presença de atividade biológica. Uma abordagem colaborativa foi utilizada para esse desenvolvimento, envolvendo parcerias nacionais e mecanismos de financiamento independentes, uma maneira nova e poderosa de desenvolver medicamentos para doenças negligenciadasSchistosomiasis is a parasitic disease that, according to the World Health Organization, constitutes a major public health problem associated with severe morbidity, mostly children in preschool age. The administration of drugs in children always constitutes a difficult task, especially when formulations are not developed specifically for pediatric use, when high doses of drug are required and the drug has a bitter taste, as in the case of praziquantel. Polymer nanoparticles are promising systems for development of encapsulated drugs with low water solubility and bitter taste, due to the good physical and chemical stability, adequate biocompatibility and simple manufacturing processes. Moreover, they can enhance the bioavailability and reduce variability of treatment among patients. Poly (methyl methacrylate) doped with praziquantel was produced through a miniemulsion polymerization process to compose a pediatric pharmaceutical suspension. Nanoparticles were characterized in terms of physico-chemical properties, toxicological properties and biological activity in mice, being concluded that obtained results were satisfactory. The results were encapsulation rate around 90%, absence of chemical interaction drug - polymer and the presence of biological activity. A collaborative approach was used for this development, involving national partnerships and independent funding mechanisms, a powerful pathway for development of drugs for neglected diseases

Development and Validation of a Discriminative Dissolution Test for Nimesulide Suspensions

The dissolution test for oral dosage forms has recently widened to a variety of special dosage forms such as suspensions. For class II drugs, such as nimesulide (NMS), this study is very important because formulation problems may compromise drug bioavailability. In the present work, tests with four brands of commercially available NMS (RA, TS, TB, and TC) have been performed in order to study their dissolution at different conditions. The suspensions have been characterized relatively to particle size, pH, and density besides NMS assay and the amount of drug in solution in the suspension vehicles. The dissolution study was conducted using the following media: simulated intestinal fluid, pH 6.8, containing polysorbate 80 (P80) or sodium lauryl sulfate (SLS); phosphate buffer, pH 7.4, with P80 and aqueous solution of SLS. Concerning the quantitative analysis, the UV–VIS spectrophotometry could have been used in substitution to high-performance liquid chromatography since the methodology had been adequately validated. The influence of the drug particle size distribution was significant on the dissolution profiles of NMS formulations, confirming to be a factor that should be strictly controlled in the development of oral suspensions

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine

Submitted by Nuzia Santos ([email protected]) on 2020-02-13T16:57:29Z No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2020-02-13T17:04:18Z (GMT) No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5)Made available in DSpace on 2020-02-13T17:04:18Z (GMT). No. of bitstreams: 1 Pharmacokinetics.pdf: 4762495 bytes, checksum: bf79584ac633b8db094ea9acfd3ce854 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Vice-Presidência de Pesquisa e Coleções Biológicas. Rio de Janeiro, RJ, Brasil / Liver-pool School of Tropical Medicine, Liverpool, UK.Liver-pool School of Tropical Medicine, Liverpool, UK.Tropical Medicine Research Center of Rondonia (CEPEM). Porto Velho, RO, Brazil / Universidade Federal de Rondonia. Porto Velho, RO, Brazil.Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brazil / Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.Fundação Oswaldo Cruz. Instituto Nacional de Doenças Infecciosas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Presidência. Vice-Presidência de Produção e Inovação em Saúde. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brasil.Liver-pool School of Tropical Medicine, Liverpool, UK.Liver-pool School of Tropical Medicine, Liverpool, UK.Background: Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods: Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results: Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion: Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assuranceabout the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro’s Michaelis–Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease