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1.
Am J Ther ; 30(5): e447-e453, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37713689

RESUMO

BACKGROUND: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate. AREAS OF UNCERTAINTY: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data. DATA SOURCES: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal." THERAPEUTIC ADVANCES: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72). CONCLUSION: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.


Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Diflunisal , Humanos , Neuropatias Amiloides Familiares/tratamento farmacológico , Pré-Albumina/metabolismo , Pré-Albumina/uso terapêutico , Diflunisal/farmacologia , Diflunisal/uso terapêutico , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Cardiomiopatias/tratamento farmacológico
2.
EMBO Rep ; 20(10): e47788, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31418171

RESUMO

Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of diflunisal and open the way to the rational design of functionally specific anti-inflammatory drugs.


Assuntos
Quimiocina CXCL12/metabolismo , Diflunisal/farmacologia , Proteína HMGB1/metabolismo , Leucócitos/metabolismo , Células 3T3 , Animais , Quimiotaxia/efeitos dos fármacos , Diflunisal/química , Dissulfetos/metabolismo , Ácido Glicirrízico/farmacologia , Humanos , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos
3.
Bioorg Med Chem ; 28(23): 115794, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091848

RESUMO

In the past few years, attempts have been made to use decision criteria beyond Lipinski's guidelines (Rule of five) to guide drug discovery projects more effectively. Several variables and formulations have been proposed and investigated within the framework of multiparameter optimization methods to guide drug discovery. In this context, the combination of Ligand Efficiency Indices (LEI) has been predominantly used to map and monitor the drug discovery process in a retrospective fashion. Here we provide an example of the use of a novel application of the LEI methodology for prospective lead optimization by using the transthyretin (TTR) fibrillogenesis inhibitor iododiflunisal (IDIF) as example. Using this approach, a number of compounds with theoretical efficiencies higher than the reference compound IDIF were identified. From this group, ten compounds were selected, synthesized and biologically tested. Half of the compounds (5, 6, 7, 8 and 10) showed potencies in terms of IC50 inhibition of TTR aggregation equal or higher than the lead compound. These optimized compounds mapped within the region of more efficient candidates in the corresponding experimental nBEI-NSEI plot, matching their position in the theoretical optimization plane that was used for the prediction. Due to their upstream (North-Eastern) position in the progression lines of NPOL = 3 or 4 of the nBEI-NSEI plot, three of them (5, 6 and 8) are more interesting candidates than iododiflunisal because they have been optimized in the three crucial LEI variables of potency, size and polarity at the same time. This is the first example of the effectiveness of using the combined LEIs within the decision process to validate the application of the LEI formulation for the prospective optimization of lead compounds.


Assuntos
Ligantes , Pré-Albumina/metabolismo , Diflunisal/análogos & derivados , Diflunisal/farmacologia , Humanos , Cinética , Mutagênese Sítio-Dirigida , Pré-Albumina/antagonistas & inibidores , Pré-Albumina/genética , Ligação Proteica , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
4.
Biol Pharm Bull ; 41(7): 979-984, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962408

RESUMO

Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. In this review, we summarized the natural products and synthetic compounds that have been shown to inhibit the amyloidogenesis of TTR. The stabilizers and/or the amyloid fibril disrupters isolated from natural sources may become lead compounds for the treatment of TTR-related amyloidosis.


Assuntos
Amiloide/antagonistas & inibidores , Amiloidose/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Pré-Albumina/metabolismo , Amiloide/metabolismo , Amiloidose/genética , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Produtos Biológicos/uso terapêutico , Diflunisal/farmacologia , Diflunisal/uso terapêutico , Humanos , Mutação , Pré-Albumina/genética
5.
Mycopathologia ; 182(11-12): 1025-1036, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28795317

RESUMO

Indoor mold due to water damage causes serious human respiratory disorders, and the remediation to homes, schools, and businesses is a major expense. Prevention of mold infestation of building materials would reduce health problems and building remediation costs. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit yeasts and a limited number of filamentous fungi. The purpose of this research was to determine the possible inhibitory activity of nonsteroidal anti-inflammatory drugs (NSAIDs) on germination, fungal growth, and reproduction of Chaetomium globosum and other important filamentous fungi that occur in water-damaged buildings. Several NSAIDs were found to inhibit C. globosum germination, growth, and reproduction. The most effective NSAIDs inhibiting C. globosum were ibuprofen, diflunisal, and diclofenac. Fusarium oxysporum, Fusarium solani, Aspergillus niger, and Stachybotrys atra were also tested on the various media with similar results obtained. However, F. oxysporum and A. niger exhibited a higher level of resistance to aspirin and NaSAL when compared to the C. globosum isolates. The inhibition exhibited by NSAIDs was variable depending on growth media and stage of fungal development. These compounds have a great potential of inhibiting fungal growth on building materials such as gypsum board. Formulations of sprays or building materials with NSAID-like chemical treatments may hold promise in reducing mold in homes and buildings.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antifúngicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Chaetomium/crescimento & desenvolvimento , Germinação/efeitos dos fármacos , Acetaminofen/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Aspirina/farmacologia , Chaetomium/efeitos dos fármacos , Diclofenaco/farmacologia , Diflunisal/farmacologia , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Humanos , Ibuprofeno/farmacologia , Pneumopatias Fúngicas/prevenção & controle , Testes de Sensibilidade Microbiana , Micoses/prevenção & controle , Stachybotrys/efeitos dos fármacos , Stachybotrys/crescimento & desenvolvimento
6.
Antimicrob Agents Chemother ; 60(9): 5322-30, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27324764

RESUMO

Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.


Assuntos
Antibacterianos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Preparações de Ação Retardada/farmacologia , Diflunisal/farmacologia , Reposicionamento de Medicamentos , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteomielite/microbiologia , Osteomielite/patologia , Cultura Primária de Células , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/patogenicidade , Transativadores/antagonistas & inibidores , Transativadores/genética , Transativadores/metabolismo , Resultado do Tratamento
7.
J Microencapsul ; 33(5): 475-86, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27499126

RESUMO

Diflunisal (DIF) is non-steroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis. The current engrossment was aimed at formulation and assessment of DIF-loaded solid lipid nanoparticles (SLNs) for topical/dermal application. SLNs formulated by hot homogenisation method based on microemulsification technique were spherical with a mean size of 124.0 ± 2.07 nm; PDI 0.294 ± 0.15. The cumulative amount permeated/area was 109.99 ± 0.008 µg/cm(2), along with permeation flux (6.30 ± 0.09 µg/cm(2)/h) and skin retention (11.74 ± 0.155 µg/cm(2)) across mice skin. The SLNs of DIF showed significant decrease in fluid volume, granuloma tissue weight, leukocyte count/mm(3) after application of SLN formulation in mice air pouch model. Similarly, in mice ear oedema and rat paw oedema model, there was 2.30 and 1.29 time increase in percentage inhibition of oedema after SLN formulation application, respectively, as compared with conventional cream. Hence, the SLNs of DIF may prove to be a potential nanocarrier to effectively treat the local inflammatory conditions associated with arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Diflunisal , Portadores de Fármacos , Nanopartículas/química , Absorção Cutânea , Animais , Diflunisal/química , Diflunisal/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Camundongos , Ratos
8.
Biochemistry ; 54(2): 268-78, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25478940

RESUMO

The circulating protein transthyretin (TTR) can unfold, oligomerize, and form highly structured amyloid fibrils that are deposited in tissues, causing organ damage and disease. This pathogenic process is caused by a heritable TTR point mutation in cases of familial TTR-related amyloidosis or wild-type TTR in cases of age-associated amyloidosis (previously called senile systemic amyloidosis). The TTR amyloid cascade is hypothesized to begin with the dissociation of the TTR native tetrameric structure into folded but unstable monomeric TTR subunits. Unfolding of monomeric TTR initiates an oligomerization process leading to aggregation and fibril formation. Numerous proteostatic mechanisms for regulating the TTR amyloid cascade exist. Extracellular chaperones provide an innate defense against misfolded proteins. Clusterin (CLU), a plasma protein, has the capacity to recognize exposed hydrophobic regions of misfolded proteins, shielding them from aggregation. We have previously demonstrated that CLU is associated with the amyloid fibrils in cardiac tissues from patients with TTR amyloidosis. In this study, we have used tetrameric and monomeric TTR structural variants to determine the ability of CLU to inhibit TTR amyloid fibril formation. Using circular dichroism spectroscopy, we determined that CLU preferentially stabilizes monomeric TTR and generates increasingly stable conformations under acid stress. Moreover, studies using surface plasmon resonance showed a direct interaction of CLU with high-molecular weight TTR oligomers. The interactions of CLU with monomeric and aggregated TTR proceed in a cooperative manner in the presence of diflunisal, a small molecule drug used to stabilize TTR tetramers.


Assuntos
Amiloide/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Clusterina/metabolismo , Diflunisal/farmacologia , Pré-Albumina/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Amiloide/metabolismo , Humanos , Masculino , Mutação , Pré-Albumina/química , Pré-Albumina/genética , Estrutura Secundária de Proteína/efeitos dos fármacos , Desdobramento de Proteína/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
9.
Dalton Trans ; 53(36): 15215-15235, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39221624

RESUMO

Fourteen cobalt(II) complexes with the non-steroidal anti-inflammatory drugs sodium meclofenamate, tolfenamic acid, mefenamic acid, naproxen, sodium diclofenac, and diflunisal were prepared in the presence or absence of a series of nitrogen-donors (namely imidazole, pyridine, 3-aminopyridine, neocuproine, 2,2'-bipyridine, 1,10-phenanthroline and 2,2'-bipyridylamine) as co-ligands and were characterised by spectroscopic and physicochemical techniques. Single-crystal X-ray crystallography was employed to determine the crystal structure of eight complexes. The biological profile of the complexes was investigated regarding their interaction with serum albumins and DNA, and their antioxidant potency. The interaction of the compounds with calf-thymus DNA takes place via intercalation. The ability of the complexes to cleave pBR322 plasmid DNA at the concentration of 500 µM is rather low. The complexes demonstrated tight and reversible binding to human and bovine serum albumins and the binding site of bovine serum albumin was also examined. In order to assess the antioxidant activity of the compounds, the in vitro scavenging activity towards free radicals, namely 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and their ability to reduce H2O2 were studied.


Assuntos
Anti-Inflamatórios não Esteroides , Cobalto , Complexos de Coordenação , DNA , Ácido Mefenâmico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Cobalto/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Humanos , DNA/química , DNA/metabolismo , Bovinos , Animais , Ácido Mefenâmico/química , Ácido Mefenâmico/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Diflunisal/química , Diflunisal/farmacologia , Ácido Meclofenâmico/química , Ácido Meclofenâmico/farmacologia , Cristalografia por Raios X , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Diclofenaco/química , Diclofenaco/farmacologia , Naproxeno/química , Naproxeno/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia
10.
Antimicrob Agents Chemother ; 57(8): 3645-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23689713

RESUMO

Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha-hemolysin and phenol-soluble modulin α in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti-inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections.


Assuntos
Toxinas Bacterianas/antagonistas & inibidores , Diflunisal/farmacologia , Proteínas Hemolisinas/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Fatores de Virulência/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Hemólise , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacologia , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Estrutura Terciária de Proteína , Coelhos , Transcrição Gênica
11.
ChemMedChem ; 18(4): e202200599, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36533570

RESUMO

Here we report the encapsulation of an osteosarcoma stem cell (OSC) potent gallium(III)-diflunisal complex 1 into polymeric nanoparticles, and its delivery into osteosarcoma cells. At the optimum feed (20 %, 1 NP20 ), nanoparticle encapsulation of 1 enhances potency towards bulk osteosarcoma cells and OSCs (cultured in monolayer and three-dimensional systems). Strikingly, the nanoparticle formulation exhibits up to 5645-fold greater potency towards OSCs than frontline anti-osteosarcoma drugs, doxorubicin and cisplatin. The nanoparticle formulation evokes a similar mechanism of action as the payload, which bodes well for future translation. Specifically, the nanoparticle formulation induces nuclear DNA damage, cyclooxygenase-2 downregulation, and caspase-dependent apoptosis. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver an OSC-active metal complex into osteosarcoma cells.


Assuntos
Neoplasias Ósseas , Diflunisal , Gálio , Nanopartículas , Osteossarcoma , Humanos , Diflunisal/farmacologia , Micelas , Gálio/farmacologia , Linhagem Celular Tumoral , Osteossarcoma/tratamento farmacológico , Polímeros/farmacologia , Células-Tronco Neoplásicas
12.
J Med Chem ; 64(1): 797-811, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33369426

RESUMO

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-ß-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD+ levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC50) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 µM (22) and 3.10 ± 0.11 µM (20), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD+ levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.


Assuntos
Carboxiliases/metabolismo , Diflunisal/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Vias Biossintéticas/efeitos dos fármacos , Carboxiliases/antagonistas & inibidores , Domínio Catalítico , Cristalografia por Raios X , Diflunisal/análogos & derivados , Diflunisal/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Cinurenina/metabolismo , Simulação de Acoplamento Molecular , NAD/metabolismo , Pseudomonas fluorescens/enzimologia , Relação Estrutura-Atividade , Triptofano/metabolismo
13.
Int J Nanomedicine ; 16: 1457-1472, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33654396

RESUMO

PURPOSE: Rheumatoid arthritis is an autoimmune disorder that directly affects joints. However, other body organs including heart, eyes, skin, blood vessels and lungs may also be affected. The purpose of this study was to design and evaluate a nanoemulgel formulation of diflunisal (DIF) and solubility enhanced diflunisal (DIF-IC) for enhanced topical anti-inflammatory activity. METHODOLOGY: Nanoemulsion formulations of both DIF and DIF-IC were prepared and incorporated in three different gelling agents, namely carboxymethylcellulose sodium (CMC-Na), sodium alginate (Na-ALG) and xanthan gum (XG). All the formulations were evaluated in term of particle size, pH, conductivity, viscosity, zeta potential and in vitro drug release. The formulation 2 (NE2) of both DIF and DIF-IC which expressed optimum release and satisfactory physicochemical properties was incorporated with gelling agents to produce final nanoemulgel formulations. The optimized nanoemulgel formulation was subjected to three different in vivo anti-inflammatory models including carrageenan-induced paw edema model, histamine-induced paw edema model and formalin-induced paw edema model. RESULTS: DIF-IC-loaded nanoemulgel formulations yielded significantly enhanced in vitro skin permeation than DIF-loaded nanoemulgel. The nanoemulgel formulation of DIF-IC formulated with XG produced improved in vivo anti-inflammatory activity. CONCLUSION: It was recommended that DIF-IC-based nanoemulgel formulation prepared with XG could be a better option for effective topical treatment of inflammatory conditions.


Assuntos
Diflunisal/administração & dosagem , Sistemas de Liberação de Medicamentos , Emulsões/química , Nanogéis/química , Polietilenoglicóis/química , Polietilenoimina/química , Administração Tópica , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Diflunisal/química , Diflunisal/farmacologia , Diflunisal/uso terapêutico , Modelos Animais de Doenças , Composição de Medicamentos , Liberação Controlada de Fármacos , Edema/tratamento farmacológico , Edema/patologia , Condutividade Elétrica , Concentração de Íons de Hidrogênio , Masculino , Tamanho da Partícula , Permeabilidade , Transição de Fase , Ratos , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Solubilidade , Tensoativos/química , Viscosidade
14.
Amyloid ; 28(1): 24-29, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32811187

RESUMO

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM concentrations in 4 distinct pooled wild type TTR (TTRwt) human plasma samples. These experiments reveal that the concentration dependence of the efficacy of each compound at inhibiting TTR dissociation was primarily determined by the ratio between the stabiliser's dissociation constants from TTR and albumin, which competes with TTR to bind kinetic stabilisers. The best stabilisers, tafamidis (80 mg QD), AG10 (800 mg BID), and tolcapone (3 x 100 mg over 12 h), exhibit very similar kinetic stabilisation at the plasma concentrations resulting from these doses. At a 10 µM plasma concentration, AG10 is slightly more potent as a kinetic stabiliser vs. tolcapone and tafamidis (which are similar), which are substantially more potent than diflunisal. Dissociation of TTR can be limited to 10% of its normal rate at concentrations of 5.7 µM AG10, 10.3 µM tolcapone, 12.0 µM tafamidis, and 188 µM diflunisal. The potency similarities revealed by our study suggest that differences in safety, adsorption and metabolism, pharmacokinetics, and tissue distribution become important for kinetic stabiliser clinical use decisions.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Amiloide/genética , Cardiomiopatias/tratamento farmacológico , Pré-Albumina/genética , Amiloide/antagonistas & inibidores , Amiloide/sangue , Amiloide/química , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Benzoatos/farmacologia , Benzoxazóis/farmacologia , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/patologia , Diflunisal/farmacologia , Humanos , Cinética , Pré-Albumina/química , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/sangue , Subunidades Proteicas/química , Subunidades Proteicas/genética , Pirazóis/farmacologia , Tolcapona/farmacologia
15.
J Vis Exp ; (155)2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-32009635

RESUMO

Chitosan-poly(vinyl alcohol) hydrogels can be produced by the freeze-thawing method without using toxic crosslinking agents. The applications of these systems are limited by their characteristics (e.g., porosity, flexibility, swelling capacity, drug loading and drug release capacity), which depend on the freezing conditions and the kind and ratio of polymers. This protocol describes how to prepare hydrogels from chitosan and poly(vinyl alcohol) at 50/50 w/w % of polymer composition and varying the freezing temperature (-4 °C, -20 °C, -80 °C) and freeze-thawing cycles (4, 5, 6 freezing cycles). FT-IR spectra, SEM micrograph and porosimetry data of hydrogels were obtained. Also, the swelling capacity and drug loading and release of diflunisal were assessed. Results from SEM micrographs and porosimetry show that the pore size decreases, while the porosity increases at lower temperatures. The swelling percentage was higher at the minor freezing temperature. The release of diflunisal from the hydrogels has been studied. All the networks maintain the drug release for 30 h and it has been observed that a simple diffusion mechanism regulates the diflunisal release according to Korsmeyer-Peppas and Higuchi models.


Assuntos
Quitosana/química , Hidrogéis/química , Álcool de Polivinil/química , Diflunisal/farmacologia , Congelamento
16.
Bioorg Med Chem Lett ; 19(2): 516-9, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19038546

RESUMO

To improve the medicinal activity, the structure of diflunisal has been modified. Twenty-one amide derivatives of diflunisal were synthesized starting from diflunisal in three steps with total yields from 72% to 89%. All compounds were identified by (1)H NMR, MS, and elemental analysis. The anti-inflammatory and analgesic activities for 19 compounds were evaluated. It was found that 5m possesses an excellent anti-inflammatory activity and a good analgesic activity, maybe a potential anti-inflammatory agent.


Assuntos
Amidas/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Diflunisal/síntese química , Diflunisal/farmacologia , Anti-Inflamatórios/química , Diflunisal/química , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
17.
Bioorg Med Chem Lett ; 19(15): 4399-402, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19515562

RESUMO

To discover the new medicinal activity, the structure of diflunisal has been modified. Forty amide derivatives of diflunisal were synthesized starting from diflunisal in three steps. Their inhibition growth rate of human lung cancer cell (A549) and human endometrial adenocarcinoma cell (Ishikawa) in vitro was evaluated. The preliminary assay results showed that compounds 6j, 7o and 8c exhibited good anti-tumor activities and excellent selectivity for the Ishikawa cell, may be potential anti-tumor agents.


Assuntos
Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Diflunisal/análogos & derivados , Diflunisal/síntese química , Neoplasias/tratamento farmacológico , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X/métodos , Diflunisal/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular
18.
Rinsho Shinkeigaku ; 49(11): 953-5, 2009 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-20030258

RESUMO

Familial amyloid polyneuropathy (FAP) was long considered to be an incurable disease, but a new therapeutic approach was developed 15 years ago. As the liver produces most of the transthyretin (TTR) in serum, it was assumed that the replacement of a liver expressing an abnormal TTR gene should stop the production of the variant TTR, the serum amyloid precursor in FAP. Until now about 1,500 FAP patients underwent liver transplantation, and the 10-year-survival rate is about 77%. After operation the progression of FAP symptoms certainly stopped, and patients who were in an early stage of the disease and underwent successful operations showed considerable improvement in their quality of life. Electrophysiological study of peripheral nerve function has demonstrated that liver transplantation can halt the progression of peripheral neuropathy in FAP patients, and histopathological regression of amyloid deposits was seen on the patients with long post-transplatation courses. Pharmacological therapies have been considered for FAP patients and among them, diflunisal, one of non-steroidal antiinflammatory drugs, is very promising. TTR tetramer dissociation is an initial step for the process of TTR-derived amyloid fibril formation associated with FAP and diflinisal can inhibit this process by stabilization of the TTR tetramer. Clinical trial of this drug for FAP patients is now going worldwide.


Assuntos
Neuropatias Amiloides Familiares/terapia , Transplante de Fígado , Substituição de Aminoácidos/genética , Amiloide/genética , Amiloide/metabolismo , Neuropatias Amiloides Familiares/classificação , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Ensaios Clínicos como Assunto , Diflunisal/administração & dosagem , Diflunisal/farmacologia , Feminino , Humanos , Fígado/metabolismo , Masculino , Mutação , Pré-Albumina/genética , Pré-Albumina/metabolismo
19.
Curr Drug Deliv ; 4(3): 233-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17627497

RESUMO

Bioresorbable polymers offer the potential to deliver biologically active agents that selectively modulate wound healing in bone and periodontal regeneration. This preliminary study characterizes early wound healing in calvarial defects grafted with demineralized bone matrix (DBM) overlaid with membranes made from a novel class of non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters). These polymers chemically incorporate either salicylic acid (SA) or 5-(2',4'-difluorophenyl)salicylic acid (diflunisal) into the polymeric backbone and release the NSAIDs upon hydrolysis. Inflammatory cell infiltrate in response to the novel NSAID-derived polymers was compared to defects grafted with DBM alone at 10 days and to defects grafted with DBM and overlaid with poly(lactic acid) (PLA; Atrisorb) at 21 days in 8 Wistar rats (350-450 g). Histological analysis of the calvarial sites at 10 days revealed that the NSAID-derived polymers were associated with moderate levels of inflammation similar to defects grafted without polymer (2.3 +/- 0.96 versus 2.0 +/- 0.82, respectively), consistent with the therapeutic activity of salicylic acid and diflunisal. Defects grafted with DBM and overlaid with NSAID-derived polymers at 21 days exhibited mild inflammation; whereas, defects treated with PLA were consistently associated with moderate to severe inflammatory cell infiltrate (1.8 +/- 0.50 versus 2.7 +/- 0.58, respectively). Histopathological findings, such as foreign body giant cells or fibrous encapsulation, were not observed in any defects with NSAID-derived polymers. Cellular features consistent with bone formation were found in all grafted defects. This novel class of non-steroidal anti-inflammatory drug-derived poly(anhydride-esters) were well tolerated and elicited no demonstrable increase in inflammation, as shown with PLA, during osseous wound healing in a regenerative application.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Regeneração Óssea/efeitos dos fármacos , Diflunisal/farmacologia , Polímeros/farmacologia , Ácido Salicílico/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Materiais Biocompatíveis , Técnica de Desmineralização Óssea , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Diflunisal/administração & dosagem , Diflunisal/efeitos adversos , Ésteres , Humanos , Hidrólise , Inflamação/tratamento farmacológico , Ácido Láctico/efeitos adversos , Ácido Láctico/farmacologia , Periodonto/efeitos dos fármacos , Polianidridos , Poliésteres , Polímeros/efeitos adversos , Polímeros/síntese química , Distribuição Aleatória , Ratos , Ratos Wistar , Regeneração/efeitos dos fármacos , Ácido Salicílico/administração & dosagem , Ácido Salicílico/efeitos adversos , Cicatrização/efeitos dos fármacos
20.
PLoS One ; 12(8): e0183046, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28817613

RESUMO

The motor protein prestin is a member of the SLC26 family of anion antiporters and is essential to the electromotility of cochlear outer hair cells and for hearing. The only direct inhibitor of electromotility and the associated charge transfer is salicylate, possibly through direct interaction with an anion-binding site on prestin. In a screen to identify other inhibitors of prestin activity, we explored the effect of the non-steroid anti-inflammatory drug diflunisal, which is a derivative of salicylate. We recorded prestin activity by whole-cell patch clamping HEK cells transiently expressing prestin and mouse outer hair cells. We monitored the impact of diflunisal on the prestin-dependent non-linear capacitance and electromotility. We found that diflunisal triggers two prestin-associated effects: a chloride independent increase in the surface area and the specific capacitance of the membrane, and a chloride dependent inhibition of the charge transfer and the electromotility in outer hair cells. We conclude that diflunisal affects the cell membrane organization and inhibits prestin-associated charge transfer and electromotility at physiological chloride concentrations. The inhibitory effects on hair cell function are noteworthy given the proposed use of diflunisal to treat neurodegenerative diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cloretos/metabolismo , Diflunisal/farmacologia , Proteínas Motores Moleculares/antagonistas & inibidores , Animais , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Células Cultivadas , Células HEK293 , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/fisiologia , Humanos , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Motores Moleculares/metabolismo
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