Mutagenicity of New Lead Compounds to Treat Sickle Cell Disease Symptoms in a Salmonella/Microsome Assay

A series of phthalimide derivatives planned as drugs candidates to treat the symptoms of sickle cell anemia were evaluated in a mutagenicity test using strains of Salmonella typhimurium TA100 and TA102, without and with addition of S9 mixture, with the aim to identify the best structural requirements for a drug candidate without genotoxic activity. The compounds (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (1); (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (2); 3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)benzyl nitrate (3); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (4); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (5) and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (6) presented mutagenic potency ranging between 0–4,803 revertants/μmol. These results allowed us to propose that a methyl spacer linked to a nitrate ester subunit associated to meta aromatic substitution decreases mutagenicity

Abordagem da Latenciação de Fármacos como Ferramenta para Descoberta de novos Antichagásicos

Chagas disease, discovered more than one century ago by Carlos Chagas, is still a serious Public Health problem. It is considered an extremely neglected disease, for it affects specially the population of developing countries. The patients with this disease have, in the great majority, low income and, for not representing market, they are excluded from the aims and efforts of research and development of pharmaceutical industries. About 8 to 11 million people may be infected with Trypanosoma cruzi, the etiological agent of the disease and about 100 million people are in risk in Latin America. The treatment of the disease is still a challenge, for only two nytroheterociclic drugs are commercialized in the world: nifurtimox and benznidazole, being this last one, the only available drug in the Brazilian market. However, these drugs are active only in the acute phase of the disease, and the treatment is not efficient in patients in the chronic phase. Consequently it is relevant to develop efficient anti-chagas compounds, particularly for the chronic phase of the disease. This paper discusses the importance of latency for the development of new pro-drugs. The literature describes several methodological techniques that have enabled significant advances in the planning and development of new anti-chagas agents, with emphasis on the search for pro-drugs that allow the enhancement of drug matrices.A doença de Chagas, descoberta por Carlos Chagas há mais de um século, ainda constitui um grave problema de Saúde Pública. É considerada doença extremamente negligenciada, uma vez que afeta particularmente as populações dos países em desenvolvimento. Os pacientes dessa doença são, em sua maioria, de baixa renda e, não representando mercado, ficam excluídos do escopo e dos esforços de Pesquisa e Desenvolvimento das Indústrias Farmacêuticas. Estima-se que entre 8 e 11 milhões de indivíduos estejam infectados pelo Trypanosoma cruzi, agente etiológico da doença, e em, aproximadamente, 100 milhões, a população em risco na América Latina. Considerando que o tratamento da doença de Chagas continua sendo um desafio, pois apenas dois fármacos nitro-heterocíclicos são comercializados no mundo: nifurtimox e benznidazol, sendo este último o único fármaco disponível no mercado brasileiro; no entanto, esses fármacos são ativos na fase aguda da doença e o tratamento é ineficaz em pacientes na fase crônica, portanto, é relevante o desenvolvimento de agentes antichagásicos eficazes, principalmente para a fase crônica da doença. Este trabalho aborda a importância da latenciação para o desenvolvimento de novos pró-fármacos. Diversas técnicas metodológicas vêm sendo descritas na literatura, permitindo avanços significativos no planejamento e desenvolvimento de novos agentes antichagásicos, com ênfase na busca de pró-fármacos que permitem o aprimoramento do fármaco matriz

Securing mhealth applications with grid-based honey encryption

Mobile healthcare (mHealth) application and technologies have promised their cost-effectiveness to enhance healthcare quality, particularly in rural areas. However, the increased security incidents and leakage of patient data raise the concerns to address security risks and privacy issues of mhealth applications urgently. While recent mobile health applications that rely on password-based authentication cannot withstand password guessing and cracking attacks, several countermeasures such as One-Time Password (OTP), gridbased password, and biometric authentication have recently been implemented to protect mobile health applications. These countermeasures, however, can be thwarted by brute force attacks, man-in-the-middle attacks and persistent malware attacks. This paper proposed grid-based honey encryption by hybridising honey encryption with grid-based authentication. Compared to recent honey encryption limited in the hardening password attacks process, the proposed grid-based honey encryption can be further employed against shoulder surfing, smudge and replay attacks. Instead of rejecting access as a recent security defence mechanism in mobile healthcare applications, the proposed Grid-based Honey Encryption creates an indistinct counterfeit patient's record closely resembling the real patients' records in light of each off-base speculation legitimate password

Uso de compostos derivados ftalimídicos e/ou sulfonamídicos no tratamento de doenças em que há a necessidade de diminuição dos níveis do fator TNF-α e a necessidade de uma fonte exógena de óxido nítrico, compostos derivados ftalimídicos, compostos derivados sulfonamídicos, método de obtenção de um composto derivado sulfonamídico

Em 15/12/2016: Anuidade de pedido de patente de invenção no prazo ordinário.DepositadaA presente invenção se refere ao uso de compostos derivados ftalimídicos e/ou sulfonamídicos com propriedades doadoras de óxido nítrico, os quais apresentam importantes atividades no aumento da expressão gênica de gama globina e atividades anti-inflamatórias e analgésicas, potenciais ao tratamento de doenças hematológicas em que há a necessidade de diminuição dos níveis do fator TNF-α e a necessidade de uma fonte exógena de óxido nítrico. Mais particularmente, a presente invenção descreve o uso de tais derivados ftalimídicos e/ou sulfonamídicos para o tratamento de anemia falciforme. A invenção também apresenta como característica inovadora, a descrição de novos derivados ftalimídicos funcionalizados, desenhados a partir dos protótipos talidomida e hidroxiuréia e planejados racionalmente através da estratégia de hibridação molecular para o tratamento das doenças citadas. A invenção apresenta ainda um novo método de obtenção de um derivado sulfonamídico específico que pode ser utilizado na preparação de um medicamento para tratamento de doenças em que há a necessidade de diminuição dos níveis do fator TNF-α e a necessidade de uma fonte exógena de óxido nítrico

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Sickle cell disease (SCD) is one of the most common genetic disorders worldwide. It is caused by a point mutation that changes glutamic acid (Glu6) to valine (Val6) in the β chain of hemoglobin. Vaso-occlusion is the most well-known problem associated with SCD. Despite recent advances in understanding the disease at the molecular level, few therapeutic strategies are available. Hydroxyurea is the only drug currently approved by the U.S. Food and Drug Administration for the disease, and it has serious adverse effects and lack of efficacy in some patients. However, new therapeutic approaches are under investigation in the hope of discovering new drugs to treat SCD. These include agents that: a) increase nitric oxide bioavailability; b) modify the rheological properties of the blood; c) bind covalently to hemoglobin; d) prevent hemoglobin dehydration; e) reduce iron overload; and f) induce the expression of gamma globin and fetal hemoglobin. In this chapter, we discuss the current treatment of SCD and the advances made in medicinal chemistry to find new drugs to treat this neglected hematological disease

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi.

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents

A városi tipizálás, a gazdasági növekedés és a járműipar főbb összefüggései Kelet-Közép-Európában = Main Correlation of the City Structures, Economic Growth and Automotive Industry in Central and Eastern Europe

Napjainkban a városkutatások reneszánszát tapasztalhatjuk, a városok a regionális és országos gazdasági növekedés, a fejlődés és a versenyképesség gócpontjai, amelyben igen koncentráltan zajlanak a térbeli folyamatok. Ezen kijelentést alapul véve, a dolgozat célja összetettnek tekinthető. Egyrészt röviden be kívánja mutatni a napjainkban is átalakulóként jellemezhető kelet-közép-európai térség speciális területi egyenlőtlenségeit, a városokat és városias térségeket. További célként a különböző városias térségtípusok, a járműipari központok és a gazdasági növekedés összefüggéseinek kimutatását határoztuk meg. Konvergencia vizsgálatunk világosan bebizonyította, hogy az autóipari központok városai hozzájárulnak Kelet-Közép-Európa térségi gazdasági- és térségi dinamikáihoz