Primary headache conditions are frequently associated with multiple sclerosis (MS), but the mechanism that triggers or worsens headaches in patients with MS is poorly understood. We previously showed that the proalgesic transient receptor potential ankyrin 1 (TRPA1) mediates hind paw mechanical and cold allodynia in a relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE) model in mice. Here, we investigated the development of periorbital mechanical allodynia (PMA) in RR-EAE, a hallmark of headache, and if TRPA1 contributed to this response. RR-EAE induction by injection of the myelin oligodendrocyte peptide fragment_35-55 (MOG_35-55) and Quillaja A adjuvant (Quil A) in C57BL/6J female mice elicited a delayed and sustained PMA. The PMA at day 35 after induction was reduced by the calcitonin gene–related peptide receptor antagonist (olcegepant) and the serotonin 5-HT1_B/D receptor agonist (sumatriptan), 2 known antimigraine agents. Genetic deletion or pharmacological blockade of TRPA1 attenuated PMA associated with RR-EAE. The levels of oxidative stress biomarkers (4-hydroxynonenal and hydrogen peroxide, known TRPA1 endogenous agonists) and superoxide dismutase and NADPH oxidase activities were increased in the trigeminal ganglion of RR-EAE mice. Besides, the treatment with antioxidants (apocynin or α-lipoic acid) attenuated PMA. Thus, the results of this study indicate that TRPA1, presumably activated by endogenous agonists, evokes PMA in a mouse model of relapsing–remitting MS.

Introduction: Monoclonal antibodies (mAb) are an important therapeutic alternative in cancer treatment. However, access to this therapy is unequal in countries with heterogeneous incomes. Objective: Compare the mAb approved for cancer in the USA with those already approved in Brazil, as well as to discuss, through the mechanism of action, the available therapeutic alternatives. Method: The list of mAb approved by the US FDA were collected from previously publication and the agency’s site. Mechanism of action, date of approval and clinical indications were obtained from the drug labels on the FDA website and the date of ANVISA approval was obtained from this agency's website. The drugs were organized according to their structural characteristics (murine, chimeric, humanized and human) and separated into four major groups, according to their mechanism of action. Results: Until 2022, 48 mAb have been approved for cancer by the FDA. Of these, 37 have already been approved by ANVISA for use in Brazil, with an average time between approval abroad and in Brazil close to two years. The majority of these mAb are human or humanized (77%) and vary greatly in terms of their mechanism of action, with the B lymphocyte antigen CD20 and the immune checkpoint PD-1/PD-L1 as the main targets of the mAb evaluated. Conclusion: Although some drugs approved abroad are not yet approved in Brazil, the delay in the registration does not seem to be related to ANVISA's delay. Furthermore, for most of the cases of drugs not yet approved in Brazil, therapeutic alternatives are available. Introducción: Los anticuerpos monoclonales (mAb) son una importante alternativa terapéutica en el tratamiento del cáncer. Sin embargo, el acceso a esta terapia es desigual en países con diferentes ingresos. Objetivo: Este trabajo buscó comparar los mAb aprobados para su uso contra el cáncer en los EUA con los ya aprobados en Brasil, así como discutir, por el mecanismo de acción, las alternativas terapéuticas disponibles. Método: La lista de mAb aprobados por la FDA fue recopilada de publicación anterior y complementada con datos presentes en el sitio web de esta agencia. El mecanismo de acción, la fecha de aprobación y las indicaciones clínicas se obtuvieron de los prospectos del medicamento en el sitio web de la FDA y los datos sobre la fecha de aprobación por parte de la Anvisa se obtuvieron de consultas en el sitio web de esta agencia. Los fármacos fueron tabulados y organizados según sus características estructurales (murinos, quiméricos, humanizados y humanos) y separados en cuatro grandes grupos, según su mecanismo de acción. Resultados: Hasta 2022, la FDA ha aprobado 48 mAb para su uso contra el cáncer. De ellos, 37 ya fueron aprobados por Anvisa para su uso en Brasil, con el tiempo promedio entre la aprobación en el extranjero y en Brasil es de alrededor de dos años. La mayoría de estos mAb son humanos o humanizados (77%) y varían mucho en cuanto a su mecanismo de acción, siendo el antígeno de linfocitos B CD20 y el checkpoint inmunológico PD-1/PD-L1 las principales dianas farmacológicas de los mAb evaluados. Conclusión: Aunque algunos medicamentos aprobados en el exterior aún no están aprobados en Brasil, la tardanza en ese registro no parece estar relacionada con demora por parte de Anvisa. Además, para la mayoría de los casos de estos medicamentos aún no aprobados en Brasil, existen alternativas terapéuticas disponibles. Introdução: Os anticorpos monoclonais (mAb) são alternativa terapêutica importante no tratamento do câncer. Porém, o acesso a essa terapia é desigual entre países com diferentes rendas. Objetivo: Comparar os fármacos mAb aprovados para uso contra câncer nos EUA com os aprovados no Brasil e discutir, por meio do mecanismo de ação, alternativas terapêuticas disponíveis. Método: A lista de fármacos mAb aprovados pelo FDA foi coletada de publicação prévia e complementada com dados presentes no site dessa agência, assim como mecanismo de ação, data de aprovação e indicações clínicas foram obtidos das bulas dos medicamentos nesse mesmo site. Da mesma forma, os dados de data de aprovação pela Anvisa foram obtidos em consultas ao site dessa agência. Os fármacos foram tabelados e organizados conforme características estruturais e separados em quatro grandes grupos, conforme seu mecanismo de ação. Resultados: Até 2022, 48 mAb foram aprovados para uso contra o câncer pelo FDA. Destes, 37 foram aprovados pela Anvisa para uso no Brasil, com tempo médio entre aprovação no exterior e no Brasil próximo a dois anos. A maioria dos mAb são humanos ou humanizados (77%) e variam bastante com relação ao mecanismo de ação, sendo o antígeno de linfócitos B CD20 e o checkpoint imunológico PD-1/PD-L1 os principais alvos dos mAb avaliados. Conclusão: Apesar de alguns fármacos aprovados no exterior ainda não estarem aprovados no Brasil, o atraso para registro não parece estar relacionado à demora da Anvisa. Além disso, para a maioria dos casos de fármacos ainda não aprovados no Brasil, existem alternativas terapêuticas disponíveis.

Fused-bicyclic heteroaromatic cores are a common framework in drugs and other biologically active compounds. Those containing azine rings are widely used in drug discovery campaigns. Although these cores are very common, C–H functionalization of their azine moieties remains challenging, especially in annulation reactions. Therefore, this review highlights the progress made over the years in C–H annulation reactions that have produced these essential 6,5-fused bicyclic heteroaromatic cores for drug discovery. For that, the review was divided according to the five-membered rings moiety (pyrrole, pyrazole, imidazole, furan, thiophen, and thiazole) fused to different azines (pyridine, pyrazine, pyridazine, pyrimidine, and triazine). Although some important advances have been made over the years, there remains a need for research in synthetic methodology to expand the use of these heteroaromatic cores in biologically active compounds.