Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 µM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 µM concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1.

From combinations to multitarget-directed ligands: A continuum in Alzheimer's disease polypharmacology.

The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm "one-drug, one-target, one-disease." In parallel, the ever-increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease-modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug-discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD polypharmacology to full potential.

From Combinations to Single-Molecule Polypharmacology-Cromolyn-Ibuprofen Conjugates for Alzheimer's Disease.

Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (4-6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aß42-amyloid self-aggregation, and their cellular neuroprotective effect against Aß42-induced neurotoxicity. The fact that 6 effectively reduced Aß-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aß42-expressing Drosophila and to improve fly locomotor performance.

Inequalities in the access to diagnosis and treatment of obstructive sleep apnea in Brazil: a cross-sectional study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is highly prevalent, and positive airway pressure (PAP) therapy is the primary treatment. This study aimed to assess the diagnostic and PAP treatment resources for OSA within Brazil's Unified Health System and to identify potential inequalities and gaps. METHODS: A structured survey was sent to members of the Brazilian Sleep Association and the Brazilian Association of Sleep Medicine to identify sleep laboratories providing OSA diagnosis and/or treatment within Brazil's Unified Health System. The numbers of centers, care team structure, sleep studies availability, PAP accessibility, and follow-up services were characterized in all 5 Brazilian regions. RESULTS: Forty-seven centers were identified: Midwest (n = 4), Northeast (n = 10), North (n = 3), Southeast (n = 22), and South (n = 8). Most centers (70%) provided both OSA diagnosis and treatment, mainly in capitals and/or metropolises (87%). Ten out of 27 Brazilian Federal Units lacked sleep services for OSA management, with the North having the highest proportion of states without a sleep service (71%). The annual number of diagnostic exams for OSA was 14,932, with significant heterogeneity across regions (Midwest: 240; North: 400; Northeast: 3,564; South: 4,380; Southeast: 6,348). Mean waiting times for diagnosis and treatment were 11 and 8 months, respectively. Only 46% of PAP treatments were publicly funded, making legal injunctions and out-of-pocket expenditure common practices. CONCLUSIONS: This study revealed significant disparities in OSA diagnosis and treatment resources across Brazil, with the North region being particularly underserved. The findings underscore an urgent need for strategies to improve sleep care nationwide. CITATION: Drager LF, Santos RB, Pachito D, Albertini CS, Sert Kuniyoshi FH, Eckeli AL. Inequalities in the access to diagnosis and treatment of obstructive sleep apnea in Brazil: a cross-sectional study. J Clin Sleep Med. 2024;20(5):735-742.

Legal action for access to resources inefficiently made available in health care systems in Brazil: a case study on obstructive sleep apnea.

OBJECTIVE: Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, associated with morbidity and mortality. Although effective treatment for OSA is commercially available, their provision is not guaranteed by lines of care throughout Brazil, making legal action necessary. This study aimed at presenting data related to the volume of legal proceedings regarding the access to diagnosis and treatment of OSA in Brazil. METHODS: This was a descriptive study of national scope, evaluating the period between January of 2016 and December of 2020. The number of lawsuits was analyzed according to the object of the demand (diagnosis or treatment). Projections of total expenses were carried out according to the number of lawsuits. RESULTS: We identified 1,462 legal proceedings (17.6% and 82.4% related to diagnosis and treatment, respectively). The projection of expenditure for OSA diagnosis in the public and private spheres were R$575,227 and R$188,002, respectively. The projection of expenditure for OSA treatment in the public and private spheres were R$2,656,696 and R$253,050, respectively. There was a reduction in the number of lawsuits between 2017 and 2019. CONCLUSIONS: Legal action as a strategy for accessing diagnostic and therapeutic resources related to OSA is a recurrent practice, resulting in inefficiency and inequity. The reduction in the number of lawsuits between 2017 and 2019 might be explained by the expansion of local health care policies or by barriers in the journey of patients with OSA, such as difficulties in being referred to specialized health care and low availability of diagnostic resources.

Discovery of Dual Aß/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-ß (Aß) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aß clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aß and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aß42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 µM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aß42 expressing flies and generating a better outcome than doxycycline (50 µM). Moreover, 22 proved to be able to decrease Aß42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aß/Tau aggregation inhibition in AD.

Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis.

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 µM) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 µM) might add a piece to the puzzle of its anti-ALS molecular profile.

Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aß and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases.

Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in a new, single chemical entity. Recently, it has been recognized as an effective approach to design ligands able to modulate multiple targets of interest. Hybrid compounds can be obtained by linking (presence of a linker) or framework integration (merging or fusing) strategies. Although very promising to combat the multifactorial nature of complex diseases, the development of molecular hybrids faces the critical issues of selecting the right target combination and the achievement of a balanced activity towards them, while maintaining drug-like-properties. In this review, we present recent case histories from our own research group that demonstrate why and how molecular hybridization can be carried out to address the challenges of multitarget drug discovery in two therapeutic areas that are Alzheimer's and parasitic diseases. Selected examples spanning from linker- to fragment- based hybrids will allow to discuss issues and consequences relevant to drug design.

Legal action for access to resources inefficiently made available in health care systems in Brazil: a case study on obstructive sleep apnea / Judicialização para acesso a recursos disponibilizados de forma ineficiente nos sistemas de saúde do Brasil: estudo de caso sobre apneia obstrutiva do sono

ABSTRACT Objective: Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, associated with morbidity and mortality. Although effective treatment for OSA is commercially available, their provision is not guaranteed by lines of care throughout Brazil, making legal action necessary. This study aimed at presenting data related to the volume of legal proceedings regarding the access to diagnosis and treatment of OSA in Brazil. Methods: This was a descriptive study of national scope, evaluating the period between January of 2016 and December of 2020. The number of lawsuits was analyzed according to the object of the demand (diagnosis or treatment). Projections of total expenses were carried out according to the number of lawsuits. Results: We identified 1,462 legal proceedings (17.6% and 82.4% related to diagnosis and treatment, respectively). The projection of expenditure for OSA diagnosis in the public and private spheres were R$575,227 and R$188,002, respectively. The projection of expenditure for OSA treatment in the public and private spheres were R$2,656,696 and R$253,050, respectively. There was a reduction in the number of lawsuits between 2017 and 2019. Conclusions: Legal action as a strategy for accessing diagnostic and therapeutic resources related to OSA is a recurrent practice, resulting in inefficiency and inequity. The reduction in the number of lawsuits between 2017 and 2019 might be explained by the expansion of local health care policies or by barriers in the journey of patients with OSA, such as difficulties in being referred to specialized health care and low availability of diagnostic resources.

RESUMO Objetivo: A apneia obstrutiva do sono (AOS) é uma doença crônica altamente prevalente, associada a morbidade e mortalidade. Embora tratamentos efetivos para a AOS estejam disponíveis comercialmente, seu fornecimento não é garantido pelos fluxos de atendimento em todo o Brasil, tornando necessária a judicialização. Este estudo teve como objetivo apresentar dados referentes ao volume de processos judiciais relacionados ao acesso ao diagnóstico e tratamento da AOS no Brasil. Métodos: Estudo descritivo de abrangência nacional, avaliando o período entre janeiro de 2016 e dezembro de 2020. O número de demandas judiciais foi analisado de acordo com o objeto da demanda (diagnóstico ou tratamento). As projeções das despesas totais foram realizadas de acordo com o número de demandas judiciais. Resultados: Foram identificados 1.462 processos judiciais (17,6% e 82,4% referentes a diagnóstico e tratamento, respectivamente). A projeção dos gastos com o diagnóstico da AOS nas esferas pública e privada foi de R$ 575.227 e R$ 188.002, respectivamente. A projeção dos gastos com o tratamento da AOS nas esferas pública e privada foi de R$ 2.656.696 e R$ 253.050, respectivamente. Houve redução do número de demandas judiciais entre 2017 e 2019. Conclusões: A judicialização como estratégia de acesso a recursos diagnósticos e terapêuticos relacionados à AOS é uma prática recorrente, resultando em ineficiência e iniquidade. A redução do número de demandas judiciais entre 2017 e 2019 pode ser explicada pela expansão das políticas locais de saúde ou por barreiras na jornada dos pacientes com AOS, como dificuldades de encaminhamento para atendimento especializado e a baixa disponibilidade de recursos diagnósticos.

Impacto econômico da implementação de políticas públicas para distúrbios de sono no Brasil: uma revisão integrativa / Economic impact of the implementation of public policies for sleep disorders in Brazil: an integrative review

Objetivo: Identificar estudos sobre políticas públicas, ações de saúde e análises econômicas relacionados aos distúrbios de sono no Brasil e discutir os seus resultados para o sistema de saúde, gestores de políticas públicas e a sociedade. Métodos: Revisão integrativa da literatura nas bases de dados Lilacs (via BVS), SciELO e PubMed (via Medline), incluindo estudos publicados nos idiomas português, inglês e espanhol, entre os anos de 1960-2023; foram excluídos estudos que não apresentaram a perspectiva brasileira ou aqueles cuja versão integral não estava disponível (seja gratuitamente ou na versão paga). Resultados: A busca retornou 536 resultados, dos quais apenas dois atendiam aos critérios de inclusão e mais cinco trabalhos foram incluídos manualmente, após consulta com especialistas de sono (todos abordaram apneia obstrutiva do sono, sendo: um relato sobre alteração na legislação de trânsito focada em prevenção de acidentes por sonolência excessiva; uma revisão de escopo sobre análises de custo-efetividade do tratamento da doença com uso de CPAP; dois relatos sobre linha de cuidado em um município e outros três em Secretarias Estaduais de Saúde). Conclusões: A revisão integrativa encontrou poucas evidências acerca do tema e aponta para a necessidade de futuros estudos que visem a suprir essa lacuna científica e de que seja necessário o desenvolvimento de futura linha de cuidado que amplie o acesso ao tratamento de doenças do sono no Sistema Único de Saúde.

Objective: To identify studies on public policies, health actions, and economic analyses related to sleep disorders in Brazil and discuss their results for public policy managers and society. Methods: Integrative literature review using Lilacs (via BVS), SciELO, and PubMed (via Medline) databases, including studies published in Portuguese, English, and Spanish languages, between years of 1960-2023; studies that did not present the Brazilian perspective or whose full version was not available were excluded (free or paid version). Results: The search returned 536 results, of which only two met the inclusion criteria, and five more studies were included manually after consulting sleep experts (all addressing obstructive sleep apnea, namely: a report on changes in traffic legislation focused on preventing accidents caused by excessive sleepiness; a scoping review on cost-effectiveness analysis of CPAP for sleep apnea treatment; two reports on care lines in one municipality and another three in State Secretariats). Conclusions: The integrative review found few evidences on the topic and points to the need for future studies aimed at filling this scientific gap and the development of a care line that expands access to sleep disorder treatment in Brazilian Public Health System.