Effect of S-Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor.

In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3-8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1-8). However, the N-methylated compounds (2, 6-8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3-5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.

Anti-inflammatory, antioxidant, and antimicrobial activities of Cocos nucifera var. typica.

BACKGROUND: Teas from the husk fiber of Cocos nucifera are used in the folk medicine to treat arthritis and other inflammatory processes. Some works show that some varieties have biological activities. However, one of the main variety of the species, C. nucifera var. typica, known in Brazil as "gigante", was not studied yet. Thus, this study evaluates if this variety has the anti-inflammatory and antimicrobial activities already reported in other varieties. METHODS: C. nucifera aqueous crude extract (10, 50, and 100 mg/kg) and the reference drugs morphine (1 mg/kg) and acetylsalicylic acid (100 mg/kg) were evaluated in models of inflammation (formalin-induced licking and subcutaneous air pouch). The antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) photometric assay and compared with those of the standards (quercetin, rutin, and ascorbic acid). The extract was also screened against Candida albicans, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA), in the agar diffusion method. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by the broth micro-dilution assay. Activities of combinations of the extract and antibiotics (methicillin or vancomycin) against MRSA were evaluated using checkerboard assays. RESULTS: The extract significantly inhibited the time that the animals spent licking the formalin-injected paws (second phase). The extract also inhibited the inflammatory process induced by subcutaneous carrageenan injection by reducing cell migration, protein extravasation, and TNF-α production. Additionally, the extract showed an antioxidant potential in vitro as good as standards in their antioxidant activity. The extract was active only against S. aureus and MRSA. MIC and the bactericidal concentrations were identical (1,024 µg/ml). The extract and methicillin acted synergistically against the clinical MRSA isolate, whereas an indifferent effect was detected when the extract was combined with vancomycin. CONCLUSIONS: The extract exhibits anti-inflammatory activity through the inhibition of the cell migration. The mixture of extract constituents and methicillin could lead to the development of a new combination antibiotic against MRSA infections.

L-proline transporter inhibitor (LQFM215) promotes neuroprotection in ischemic stroke.

BACKGROUND: L-proline transporter (PROT/SLC6A7) is closely associated with glutamatergic neurotransmission, where L-proline modulates the NMDA receptor (NMDAR) function. NMDAR-mediated excitotoxicity is a primary cause of neuronal death following stroke, which is triggered by the uncontrolled release of glutamate during the ischemic process. After ischemic stroke, L-proline levels show a reduction in the plasma, but high circulating levels of this molecule indicate good functional recovery. This work aimed to produce new PROT inhibitors and explore their effects on ischemic stroke. METHODS: Initially, we built a three-dimensional model of the PROT protein and run a molecular docking with the newly designed compounds (LQFM215, LQFM216, and LQFM217). Then, we synthesized new PROT inhibitors by molecular hybridization, and proline uptake was measured in ex vivo and in vivo models. The behavioral characterization of the treated mice was performed by the open-field test, elevated plus-maze, Y-maze, and forced swimming test. We used the permanent middle cerebral artery occlusion (MCAO) model to study the ischemic stroke damage and analyzed the motor impairment with limb clasping or cylinder tests. RESULTS: LQFM215 inhibited proline uptake in hippocampal synaptosomes, and the LQFM215 treatment reduced proline levels in the mouse hippocampus. LQFM215 reduced the locomotor and exploratory activity in mice and did not show any anxiety-related or working memory impairments. In the MCAO model, LQFM215 pre-treatment and treatment reduced the infarcted area and reduced motor impairments in the cylinder test and limb clasping. CONCLUSIONS: This dataset suggests that the new compounds inhibit cerebral L-proline uptake and that LQFM215 promotes neuroprotection and neuro-repair in the acute ischemic stroke model.

Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases.

Most neurodegenerative diseases are multifactorial, and the discovery of several molecular mechanisms related to their pathogenesis is constantly advancing. Dopamine and dopaminergic receptor subtypes are involved in the pathophysiology of several neurological disorders, such as schizophrenia, depression and drug addiction. For this reason, the dopaminergic system and dopamine receptor ligands play a key role in the treatment of such disorders. In this context, a novel series of conformationally restricted N-arylpiperazine derivatives (5a-f) with a good affinity for D2/D3 dopamine receptors is reported herein. Compounds were designed as interphenylene analogs of the drugs aripiprazole (2) and cariprazine (3), presenting a 1,3-benzodioxolyl subunit as a ligand of the secondary binding site of these receptors. The six new N-arylpiperazine compounds were synthesized in good yields by using classical methodologies, and binding and guanosine triphosphate (GTP)-shift studies were performed. Affinity values below 1 µM for both target receptors and distinct profiles of intrinsic efficacy were found. Docking studies revealed that Compounds 5a-f present a different binding mode with dopamine D2 and D3 receptors, mainly as a consequence of the conformational restriction imposed on the flexible spacer groups of 2 and 3.

Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice.

The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)- 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (Ki around 5-9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors.

Perfil das mulheres atendidas pela ambulância do programa cegonha carioca / Profile of women attended by the "cegonha carioca" program ambulance

A taxa de mortalidade materna mundial permanece inaceitavelmente alta e no Brasil e no Rio de Janeiro não é diferente. Na tentativa de reduzi-la, instituiu-se em âmbito nacional a Rede Cegonha e no município do Rio de Janeiro o Programa Cegonha Carioca. Ambos os programas dispõem de ambulâncias para atender mulheres no ciclo gravídico. O objetivo deste trabalho foi descrever o perfil das mulheres atendidas pela ambulância do Programa Cegonha Carioca. Trata-se de uma pesquisa transversal com abordagem quantitativa que permitiu analisar as fichas de classificações de risco, oriundas dos atendimentos realizados por enfermeiros de uma ambulância nos períodos compreendidos entre setembro e dezembro de 2012 e de 2013. O teste estatístico utilizado para variáveis categóricas foi o Qui-quadrado e para variáveis contínuas o Teste T. Observou-se predominância nos atendimentos urgentes para gestantes jovens adultas, primigestas no terceiro trimestre de gestação. As principais queixas identificadas foram "dores abdominais e nas costas" e "perdas transvaginais". Percebeu-se que foram atendidas mais adolescentes e menos mulheres com mais de 35 anos que a média nacional. Concluiu-se que novos estudos sobre os atendimentos realizados nessas ambulâncias precisam ser conduzidos para possibilitarem a análise de sua eficácia, a fim de estudar a expansão desse serviço para outros municípios visando a promover acessibilidade ao sistema de saúde.

The world's maternal mortality rate remains unacceptably high, and it is no different in Rio de Janeiro in Brazil. In an attempt to reduce it, a program was created at a national level, known as Rede Cegonha, and the program "Cegonha Carioca" was created in Rio de Janeiro. Both programs provide ambulances to attend women during their pregnancy cycles. The aim of this study was to describe the profile of women attended by the ambulance from the Cegonha Carioca Program. It is a cross-sectional study with quantitative approach that analyzed the risk classification records from the cares provided by nurses in an ambulance from September to December 2012 and 2013. A Chi-square test was used for categorical variables analysis and a T-test was used for continuous variables analysis. A predominance in urgent care for young adult, first pregnancy girls at the third trimester of pregnancy was observed. The main complaints presented were "abdominal pain and backache" and "transvaginal losses". It could be observed that most patients were teenagers and fewer patients aged >35 years old than the national average were attended. It can be concluded that further studies regarding the care provided in those ambulances need to be performed in order to analyze the effectiveness and assess the expansion possibility to other locations, and to expand women's access to the public health system.

Uso da realidade virtual na reabilitação motora de uma criança com paralisia cerebral atáxica: estudo de caso / El uso de la realidad virtual en la rehabilitación motora de un niño con parálisis cerebral ataxia: un estudio experimental / Using virtual reality for motor rehabilitation in a child with ataxic cerebral palsy: case report

Avaliou-se a influência da Realidade Virtual (RV) com Nintendo Wii (NW) no equilíbrio e na marcha de uma criança com Paralisia Cerebral Atáxica (PC-A). O trabalho é um estudo de caso com uma criança do gênero masculino, 12 anos, diagnosticada com PC-A, sem antecedentes de doenças respiratórias, cardíacas ou ortopédicas prévias, marcha independente e cognitivo preservado, atendida nas dependências da entidade Amarati, localizada em Jundiaí (SP). Inicialmente a criança foi avaliada pela escala de Berg, Protocolo de Kay Cerny, e GMFM-66. Depois se iniciou a reabilitação utilizando a RV 3 vezes por semana em sessões de até 30 minutos, através dos jogos do NW(r), com o jogo Wii Fit plus, plataforma Balance Board e controle Wii Remote durante 04 meses, totalizando 40 sessões. A criança continuou o tratamento cinesioterapêutico na própria instituição durante o período de coleta. Com o término do período proposto, os mesmos parâmetros foram reavaliados. Observou-se aumento na pontuação da GMFM-66 com aumento do escore médio de 71,69 (SD 1,64) para 77,46 (SD 2,06), evoluindo nas dimensões "em pé" e "andar, correr e pular"; aumento na escala de Berg (de 48 para 53 pontos), indicando melhora no equilíbrio estático; não foram observadas mudanças no protocolo de Kay Cerny nos parâmetros avaliados (velocidade, frequência de passos/min, comprimento do passo e passada e largura do passo). Os resultados apresentados sugerem que o uso do NW influencia na melhora principalmente do equilíbrio da criança quando usada em complemento com o tratamento cinesioterapêutico, porém é necessária a realização de estudos com populações maiores para comprovação de sua eficácia.

Se ha evaluado la influencia de la Realidad Virtual (RV) con Nintendo WII (NW) para el equilibrio y la marcha de un niño con Parálisis Cerebral Ataxia (PC-A). Este trabajo es un estudio de caso con niño de 12 años de edad, diagnosticado con PC-A, sin antecedentes de enfermedades respiratorias, cardíacas u ortopédicas previas, marcha independiente y cognitivo preservado, que era asistido en las dependencias de una entidad Amarati, ubicada en Jundiaí (SP), Brasil. Al inicio, se evaluó el niño por la Escala de Berg, por el Protocolo de Kay Cerny, y por GMFM-66. Enseguida, tuvo inicio la rehabilitación con el uso de la RV 3 veces por semana en sesiones hasta 30 minutos de duración, a través de los juegos del NW(r), con el juego Wii Fit plus, plataforma Balance Board y control Wii Remote durante 04 meses, con un total de 40 sesiones. El niño siguió el tratamiento con kinesioterapia en la propia institución durante el periodo de la recolección. Con el término del periodo propuesto, los mismos parámetros se han reevaluados. Se observó el aumento en la puntuación de la GMFM-66 con una subida de la puntuación media de 71,69 (SD 1,64) para 77,46 (SD 2,06), la evolución en las dimensiones "de pie" y "andar, correr y saltar"; el aumento en la Escala de Berg (de 48 para 53 puntos), lo que indica una mejora en el equilibrio estático; no se han observado cambios en el protocolo de Kay Cerny en los parámetros evaluados (velocidad, frecuencia de pasos/min, extensión del paso y de la pasada y anchura del paso). Los resultados presentados muestran que el uso del NW hace una influencia en la mejora, en especial, del equilibrio del niño cuando se usa en complementación al tratamiento con kinesioterapia, pero es necesaria la realización de estudios con poblaciones mayores para comprobar su eficacia.

Was evaluated the influence of Virtual Reality (VR) with Nintendo Wii (NW) on balance and gait of a children with ataxic cerebral palsy (CP-A). A case study, child male, 12 years, diagnosis of CP-A without history of respiratory, cardiac or orthopedic previous diseases, independent and preserved cognitive march, attended the premises of Amarati entity located in Jundiaí (SP). Initially the child was assessed by the Scale Berg, Kay Cerny Protocol and GMFM-66. After it started the rehabilitation using VR, 3 times a week in 30 minute sessions, through games of NW(r), with the game Wii Fit Plus, Balance Board Wii Remote platform and control during 04 months, totaling 40 sessions. The child continued kinesiotherapeutic treatment within the institution during the collection period. With the end of the proposed period, the same parameters were reassessed. There was an increase in the GMFM-66 score with increasing average scores of 71.69 (SD 1.64) to 77.46 (SD 2.06) in the evolving dimensions "standing" and "walking, running and skip "; increase in scale Berg (from 48 to 53 points), indicating an improvement in static equilibrium; the protocol Kay Cerny shows no changes in the evaluated parameters (speed, frequency of steps/min, and last stride length and step width) were observed. These results suggest that the use of the NW influences the improvement mainly to balance the child when used in addition to the kinesiotherapeutic treatment, however is necessary to perform studies with larger populations for evidence of its effectiveness.