Integra Project: strengthening social participation in the agenda of health policies, services, and technologies. / Projeto Integra: fortalecimento da participação social na agenda das políticas, serviços e tecnologias em saúde.

The 16th National Health Conference illustrated the interest of health councils to intervene in public policies in order to guarantee the right to health technologies. The INTEGRA project (Integration of policies for Health Surveillance, Pharmaceutical Care, Science, Technology, and Innovation in Health) is a partnership among the National Health Council, the National School of Pharmacists, and the Oswaldo Cruz Foundation (Fiocruz), with support from the Pan American Health Organization (PAHO), with the goal of strengthening participation and social engagement in the theme, as well as the integration of health policies and practices within different sectors of society (social movements, health councils, and health professionals), with the various stages related to the access to medicines (research, incorporation, national production, and services) being the main theme in the context of the COVID-19 pandemic. It seeks to offer training for leadership groups in the health regions and activities with a broad national and political scope, and it hopes to establish an intersectorial and integrated network of leaders capable of acting collaboratively to defend the development of science, public policies, national sovereignty, and social control of health.

A 16ª Conferência Nacional de Saúde demonstrou o interesse do controle social em intervir sobre as políticas públicas a fim de garantir o direito às tecnologias de saúde. O projeto Integra - Integração das Políticas de Vigilância em Saúde, Assistência Farmacêutica, Ciência, Tecnologia e Inovação em Saúde -, nasce da parceria entre o Conselho Nacional de Saúde, a Escola Nacional dos Farmacêuticos e a Fundação Oswaldo Cruz (Fiocruz), com apoio da Organização Pan-Americana de Saúde (OPAS) com objetivo de fortalecimento da participação e engajamento social na temática e a integração das políticas e práticas de saúde em diferentes setores da sociedade (movimentos sociais, controle social e profissionais de saúde), tendo as diversas etapas relacionadas ao acesso aos medicamentos (pesquisa, incorporação, produção nacional e serviços) como mote principal, no cenário da pandemia de COVID-19. Oferta-se, neste projeto, capacitação para grupos de lideranças nas regiões de saúde e atividades de grande abrangência nacional e política. Espera-se alcançar o estabelecimento de uma rede intersetorial, integrada de lideranças capazes de atuar colaborativamente para a defesa do desenvolvimento da ciência, das políticas públicas, da soberania nacional e do controle social da saúde.

Projeto Integra: fortalecimento da participação social na agenda das políticas, serviços e tecnologias em saúde / Integra Project: strengthening social participation in the agenda of health policies, services, and technologies

Resumo A 16ª Conferência Nacional de Saúde demonstrou o interesse do controle social em intervir sobre as políticas públicas a fim de garantir o direito às tecnologias de saúde. O projeto Integra - Integração das Políticas de Vigilância em Saúde, Assistência Farmacêutica, Ciência, Tecnologia e Inovação em Saúde -, nasce da parceria entre o Conselho Nacional de Saúde, a Escola Nacional dos Farmacêuticos e a Fundação Oswaldo Cruz (Fiocruz), com apoio da Organização Pan-Americana de Saúde (OPAS) com objetivo de fortalecimento da participação e engajamento social na temática e a integração das políticas e práticas de saúde em diferentes setores da sociedade (movimentos sociais, controle social e profissionais de saúde), tendo as diversas etapas relacionadas ao acesso aos medicamentos (pesquisa, incorporação, produção nacional e serviços) como mote principal, no cenário da pandemia de COVID-19. Oferta-se, neste projeto, capacitação para grupos de lideranças nas regiões de saúde e atividades de grande abrangência nacional e política. Espera-se alcançar o estabelecimento de uma rede intersetorial, integrada de lideranças capazes de atuar colaborativamente para a defesa do desenvolvimento da ciência, das políticas públicas, da soberania nacional e do controle social da saúde.

Abstract The 16th National Health Conference illustrated the interest of health councils to intervene in public policies in order to guarantee the right to health technologies. The INTEGRA project (Integration of policies for Health Surveillance, Pharmaceutical Care, Science, Technology, and Innovation in Health) is a partnership among the National Health Council, the National School of Pharmacists, and the Oswaldo Cruz Foundation (Fiocruz), with support from the Pan American Health Organization (PAHO), with the goal of strengthening participation and social engagement in the theme, as well as the integration of health policies and practices within different sectors of society (social movements, health councils, and health professionals), with the various stages related to the access to medicines (research, incorporation, national production, and services) being the main theme in the context of the COVID-19 pandemic. It seeks to offer training for leadership groups in the health regions and activities with a broad national and political scope, and it hopes to establish an intersectorial and integrated network of leaders capable of acting collaboratively to defend the development of science, public policies, national sovereignty, and social control of health.

Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity.

Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2-aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na+ channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na+, and Ca++ionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na+ currents, but 12-fold higher in inhibiting L-type Ca++ currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca++, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, ß2-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na+ channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca++ inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by life-threatening bronchoconstriction.

Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels.

Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (Cmax), maximum time (Tmax), area under the blood concentration-time curve (AUC0-t) and area under the blood concentration-time curve from 0-Inf (AUC0-inf) of 163.3 ± 38.3 ng/mL, 1.2 ± 0.3 h, 729.4 ± 118.3 ng*h/ml and 868.9 ± 117.1 ng*h/ml (means ± S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.

Laudato Si': a bridge towards access to medicines / Laudato Si': uma ponte para acesso a medicamentos

Pope Francis' Encyclical Laudato Si', albeit not explicitly, has drawn attention worldwide to the access to medicines as a fundamental human right, as it raises awareness about the current situation of the world and the poor. The reflections set forward by the Encyclical Laudato Si' bring us to the intersections between trade and health care, and how to correctly frame the need for innovation, affordable and accessible health technologies to those in need and how to reach the poorest of the poor. The issues of how to provide access, promote innovation, stimulate reasonable competitive market forces and ensure viable supply are central to the question of how to address Universal Human Rights. Also in this context, intellectual property has gained particular significance with increased attention to new essential medicines for the treatment of diseases of global incidence, including communicable and non-communicable diseases. This article intends to bring elements for a reflection on the debate on universal access to medicines.

A Encíclica Laudato Si' do Papa Francisco, ainda que não explicitamente, chamou a atenção mundial para o acesso aos medicamentos como um direito humano fundamental, quando conscientiza sobre a situação atual do mundo e dos pobres. As reflexões propostas pela Encíclica Laudato Si' nos trazem as interseções entre o comércio e a saúde, como enquadrar corretamente a necessidade de ter tecnologias de saúde inovadoras, acessíveis aos necessitados e como alcançar os mais pobres dos pobres. As questões sobre maneiras de fornecer acesso, promover inovação, estimular forças de mercado competitivas razoáveis e assegurar fornecimento viável são centrais para a questão de como abordar os Direitos Humanos Universais. Também neste contexto, a propriedade intelectual ganhou particular importância com maior atenção a novos medicamentos essenciais para o tratamento de doenças de incidência global, tanto as transmissíveis como as não transmissíveis. Este artigo pretende trazer elementos de reflexão para o debate sobre o acesso universal a medicamentos.

JMF2-1, a lidocaine derivative acting on airways spasm and lung allergic inflammation in rats.

BACKGROUND: Prior reports show that nebulized lidocaine might be an effective treatment for asthma. OBJECTIVE: We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity. METHODS: Blockade of Na(+) currents was assayed in cultured GH(3) cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro. RESULTS: The 50% inhibitory concentration values for blockade of Na(+) currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue. CONCLUSION: Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung. CLINICAL IMPLICATIONS: Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.

Síntese e avaliação da atividade antiinflamatória e espasmolídica de análogos de lidocaína / Synthesis and evaluation of the anti-inflammatory and spasmodic activity of analogous of lidocaine

A prevalência da asma vem aumentando alarmantemente em todo o mundo. A busca por terapias alternativas capazes de tratar com eficiência esta doença tem sido a meta de vários centros de pesquisas. Demonstrou-se recentemente que a nebulização do anestésico local lidocaína promoveu melhora significativa no quadro sintomático de pacientes portadores de asma moderada e severa, embora o mecanismo de ação permaneça pouco esclarecido. Contudo, efeitos colaterais tais como marcada irritação brônquica e desconforto respiratório, aparentemente relacionados à anestesia das vias aéreas, têm sido reportados. O objetivo desta tese foi avaliar a atividade antiinflamatória e espasmolítca de análogos da lidocaina sintetizados e selecionados para apresentar reduzida ação anestésica local. Dado que o sistema aromático tem papel crucial na atividade anestésica da lidocaína, foram feitas alterações no padrão de substituição do anel benzênico e na cadeia lateral alifática. A síntese das moléculas em escala multigrama foi realizada em reator tubular de vidro em 3 etapas; uma reação de cloroacetilação de anilinas, seguida da incorporação do grupamento dietilamino e, finalmente, da formação dos respectivos cloridratos. O valor do ângulo de torsão de todas as moléculas foi determinado por técnica de modelagem molecular. As 15 moléculas sintetizadas foram testadas quanto a sua potência anestésica, com base na resposta neuro-comportamental ao estímulo mecânico cutâneo dorsal em ratos, tendo lidocaína como anestésico de referência. As moléculas menos anestésicas e desprovidas de alterações comportamentais, do tipo piloereção, incoordenação motora e/ou tremor, foram testadas no ensaio de inibição de contração isotônica anafilática do íleo isolado de cobaia para avaliação da potencial atividade espasmolítica. Os achados indicaram que enquanto o cloridrato de lidocaína (4 µMol/site) anestesiou a pele dorsal de ratos por 163,5 ± 2,5 min, os análogos (21), (22), (23), (38) e (39) apresentaram...