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

Drager, Luciano F / Santos, Ronaldo B / Pachito, Daniela / Albertini, Claudia S / Sert Kuniyoshi, Fatima H / Eckeli, Alan L

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine

2024

Abstract: Study objectives: Obstructive sleep apnea (OSA) is highly prevalent, and positive airway pressure (PAP) therapy is the primary treatment. The study aimed to assess the diagnostic and PAP treatment resources for OSA within Brazil's Unified Health System ( ...

Abstract	Study objectives: Obstructive sleep apnea (OSA) is highly prevalent, and positive airway pressure (PAP) therapy is the primary treatment. The study aimed to assess the diagnostic and PAP treatment resources for OSA within Brazil's Unified Health System (SUS) 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 the SUS. The number of centers, care team structure, sleep studies availability, PAP accessibility, and follow-up services were characterized in all five Brazilian regions using a structured survey. Results: Forty-seven centers were identified: Midwest (n=4), Northeast (n=10), North (n=3), Southeast (n=22), 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%). Annual number of diagnostic exams for OSA was 14,932 with significant heterogeneity across regions (Midwest: 240; North: 400, Northeast: 35,64; South: 4,380; Southeast: 6,348. Mean waiting times for diagnosis and treatment were 11 and 8 months, respectively. Only 56% 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.
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2397213-0
ISSN	1550-9397 ; 1550-9389
ISSN (online)	1550-9397
ISSN	1550-9389
DOI	10.5664/jcsm.10976
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Article ; Online: Legal action for access to resources inefficiently made available in health care systems in Brazil: a case study on obstructive sleep apnea.

Pachito, Daniela V / Finkelstein, Beny / Albertini, Claudia / Gaspar, Antonio / Pereira, Carolina / Vaz, Paulo / Eckeli, Alan Luiz / Drager, Luciano F

Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia

2023 Volume 49, Issue 2, Page(s) e20220092

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, ...

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.
MeSH term(s)	Humans ; Brazil ; Sleep Apnea, Obstructive/diagnosis ; Delivery of Health Care
Language	Portuguese
Publishing date	2023-02-20
Publishing country	Brazil
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2223157-2
ISSN	1806-3756 ; 1806-3713
ISSN (online)	1806-3756
ISSN	1806-3713
DOI	10.36416/1806-3756/e20220092
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Article ; Online: Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Albertini, Claudia / Petralla, Sabrina / Massenzio, Francesca / Monti, Barbara / Rizzardi, Nicola / Bergamini, Christian / Uliassi, Elisa / Borges, Fernanda / Chavarria, Daniel / Fricker, Gert / Goettert, Marcia / Kronenberger, Thales / Gehringer, Matthias / Laufer, Stefan / Bolognesi, Maria L

Archiv der Pharmazie

2024 , Page(s) e2300525

Abstract: 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 ...

Abstract	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 (IC
Language	English
Publishing date	2024-02-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6381-2
ISSN	1521-4184 ; 0365-6233 ; 1437-1014
ISSN (online)	1521-4184
ISSN	0365-6233 ; 1437-1014
DOI	10.1002/ardp.202300525
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Article ; Online: From combinations to multitarget-directed ligands: A continuum in Alzheimer's disease polypharmacology.

Albertini, Claudia / Salerno, Alessandra / de Sena Murteira Pinheiro, Pedro / Bolognesi, Maria L

Medicinal research reviews

2020 Volume 41, Issue 5, Page(s) 2606–2633

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Alzheimer Disease/drug therapy ; Drug Discovery ; Humans ; Ligands ; Pharmaceutical Preparations ; Polypharmacology
Chemical Substances	Ligands ; Pharmaceutical Preparations
Language	English
Publishing date	2020-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.21699
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Article ; Online: From Combinations to Single-Molecule Polypharmacology-Cromolyn-Ibuprofen Conjugates for Alzheimer's Disease.

Albertini, Claudia / Naldi, Marina / Petralla, Sabrina / Strocchi, Silvia / Grifoni, Daniela / Monti, Barbara / Bartolini, Manuela / Bolognesi, Maria Laura

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 4

Abstract: 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 ... ...

Abstract	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 (
MeSH term(s)	Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/toxicity ; Animals ; Behavior, Animal/drug effects ; Cell Survival/drug effects ; Cromolyn Sodium/chemical synthesis ; Cromolyn Sodium/chemistry ; Cromolyn Sodium/pharmacology ; Cromolyn Sodium/therapeutic use ; Drosophila/drug effects ; Drug Design ; Endocytosis/drug effects ; Ibuprofen/chemical synthesis ; Ibuprofen/chemistry ; Ibuprofen/pharmacology ; Ibuprofen/therapeutic use ; Immunomodulation/drug effects ; Mice ; Microglia/drug effects ; Microglia/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Neuroprotective Agents/pharmacology ; Neurotoxins/toxicity ; Polypharmacology ; Protein Aggregates/drug effects ; Rats, Wistar ; Rats
Chemical Substances	Amyloid beta-Peptides ; Neuroprotective Agents ; Neurotoxins ; Protein Aggregates ; Cromolyn Sodium (Q2WXR1I0PK) ; Ibuprofen (WK2XYI10QM)
Language	English
Publishing date	2021-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26041112
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Article ; Online: Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases.

Ivasiv, Viktoriya / Albertini, Claudia / Gonçalves, Ana E / Rossi, Michele / Bolognesi, Maria L

Current topics in medicinal chemistry

2019 Volume 19, Issue 19, Page(s) 1694–1711

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Alzheimer Disease/drug therapy ; Animals ; Antiprotozoal Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; Chemistry, Pharmaceutical ; Drug Design ; Humans ; Ligands ; Molecular Structure ; Parasitic Diseases/drug therapy
Chemical Substances	Antiprotozoal Agents ; Antipsychotic Agents ; Ligands
Language	English
Publishing date	2019-06-24
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026619666190619115735
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Article ; Online: Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a

Gandini, Annachiara / Gonçalves, Ana Elisa / Strocchi, Silvia / Albertini, Claudia / Janočková, Jana / Tramarin, Anna / Grifoni, Daniela / Poeta, Eleonora / Soukup, Ondrej / Muñoz-Torrero, Diego / Monti, Barbara / Sabaté, Raimon / Bartolini, Manuela / Legname, Giuseppe / Bolognesi, Maria Laura

ACS chemical neuroscience

2022 Volume 13, Issue 23, Page(s) 3314–3329

Abstract: Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating ... ...

Abstract	Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) 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-Aβ 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 Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact
MeSH term(s)	Animals ; Alzheimer Disease/drug therapy ; Drosophila ; tau Proteins ; Drosophila melanogaster
Chemical Substances	tau Proteins
Language	English
Publishing date	2022-11-29
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00357
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Article ; Online: Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.

Perone, Rosaria / Albertini, Claudia / Uliassi, Elisa / Di Pietri, Flaminia / de Sena Murteira Pinheiro, Pedro / Petralla, Sabrina / Rizzardi, Nicola / Fato, Romana / Pulkrabkova, Lenka / Soukup, Ondrej / Tramarin, Anna / Bartolini, Manuela / Bolognesi, Maria Laura

ChemMedChem

2020 Volume 16, Issue 1, Page(s) 187–198

Abstract: 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 ... ...

Abstract	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 Aβ 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.
MeSH term(s)	Acetylcholinesterase/chemistry ; Acetylcholinesterase/metabolism ; Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/metabolism ; Antioxidants/chemistry ; Antioxidants/metabolism ; Antioxidants/pharmacology ; Blood-Brain Barrier/diagnostic imaging ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cholinesterase Inhibitors/chemistry ; Cholinesterase Inhibitors/metabolism ; Cholinesterase Inhibitors/pharmacology ; Cholinesterase Inhibitors/therapeutic use ; Donepezil/chemistry ; Donepezil/metabolism ; Donepezil/pharmacology ; Donepezil/therapeutic use ; Drug Design ; Humans ; Indans/chemistry ; Ligands ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/metabolism ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Oxidative Stress/drug effects ; Protein Aggregates/drug effects ; Structure-Activity Relationship
Chemical Substances	Amyloid beta-Peptides ; Antioxidants ; Cholinesterase Inhibitors ; Indans ; Ligands ; Neuroprotective Agents ; Protein Aggregates ; Donepezil (8SSC91326P) ; indacrinone (B926Y9U4QN) ; Acetylcholinesterase (EC 3.1.1.7)
Language	English
Publishing date	2020-08-31
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202000484
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Article ; Online: Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis.

Albertini, Claudia / Salerno, Alessandra / Atzeni, Silvia / Uliassi, Elisa / Massenzio, Francesca / Maruca, Annalisa / Rocca, Roberta / Mecava, Marko / Silva, Filomena S G / Mena, Débora / Valente, Pedro / Duarte, Ana I / Chavarria, Daniel / Bissaro, Maicol / Moro, Stefano / Federico, Stephanie / Spalluto, Giampiero / Soukup, Ondřej / Borges, Fernanda /

Alcaro, Stefano / Monti, Barbara / Oliveira, Paulo J / Menéndez, Josè C / Bolognesi, Maria Laura

ACS chemical neuroscience

2022 Volume 13, Issue 15, Page(s) 2252–2260

Abstract: 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 ... ...

Abstract	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 (
MeSH term(s)	Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Indans ; Ligands ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Riluzole/pharmacology ; Riluzole/therapeutic use
Chemical Substances	Indans ; Ligands ; Neuroprotective Agents ; rasagiline (003N66TS6T) ; Riluzole (7LJ087RS6F)
Language	English
Publishing date	2022-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00261
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