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1.
Rev Med Virol ; 31(6): e2221, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34773448

RESUMO

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proteína C-Reativa/antagonistas & inibidores , COVID-19/tratamento farmacológico , Proteínas do Sistema Complemento/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/patogenicidade , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/genética , Proteína ADAM17/imunologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Biomarcadores/sangue , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Celecoxib/uso terapêutico , Proteínas do Sistema Complemento/genética , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Doxiciclina/uso terapêutico , Regulação da Expressão Gênica , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Análise de Sobrevida
2.
Int J Pharm ; 609: 121157, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34626795

RESUMO

Microwave-induced in situ amorphization is an emerging technology to tackle the persistent stability issue of amorphous solid dispersions (ASDs) during manufacture and storage. The aim of this study was to introduce new effective polymeric carriers with diverse properties to microwave-induced in situ amorphization and to better understand their functions in relation to the final dissolution performance of microwaved tablets. Tablets composed of indomethacin (IND) and different polymers were compacted, stored at 75% relative humidity for at least 1 week and microwaved at 1000 W to induce amorphization. A series of polymers, polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios displaying varyingproperties in functional groupratio, hygroscopicity, molecular weight (Mw), and glass transition temperature (Tg) of the polymer were used as model carriers. The results suggested that more than 90% of IND was amorphized after 20 mins microwaving in all 20% (w/w) drug loaded tablets except for IND:PVAc tablets presenting approx. 36% residual crystallinity. Among them, tablets composed of PVP/VA I-335 and PVP K30 achieved complete in situ amorphization upon microwaving. Further analysis indicated that the influencing factors, polymer Mw and Tg of moisture-plasticized polymer, played a major role in microwave-induced in situ amorphization. In in vitro dissolution study, ASDs containing PVP/VA I-535 with moderate hydrophilicity and 0.96 ± 1.92% IND residual crystallinity showed the most rapid and complete drug release among all formulations, presenting the most promising dissolution performance. Further study on the chemical stability of such formulation showed a statistically insignificant decrease of drug content after pre-conditioning and microwaving (P = 0.288 > 0.05).


Assuntos
Micro-Ondas , Polímeros , Celecoxib , Estabilidade de Medicamentos , Indometacina , Povidona , Solubilidade
3.
Pediatrics ; 148(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34686572

RESUMO

Our understanding of inflammatory bowel disease is changing as we identify genetic variants associated with immune dysregulation. Inflammatory bowel disease undetermined, even when diagnosed in older children and adolescents, in the setting of multiple inflammatory and infectious diseases should raise the suspicion of complex immune dysregulation with a monogenic basis. We report a case of inflammatory bowel disease undetermined triggered by exposure to a nonsteroidal antiinflammatory drug in a 16-year-old girl with a background history of juvenile idiopathic arthritis, cytopenias, recurrent respiratory tract and middle ear infections, and esophageal candidiasis. Immunologic assessment included measurement of immunoglobulin levels, lymphocyte immunophenotyping, B-cell functional tests, and whole-exome sequencing. Laboratory investigation revealed defects of humoral immunity, including mild persistent hypogammaglobulinemia affecting all 3 isotypes and absent isohemagglutinins. Whole exome sequencing revealed a heterozygous TNFRSF13B (Tumor Necrosis Factor Receptor Superfamily Member 13B, or Transmembrane Activator and Calcium-modulating cyclophilin ligand Interactor, TACI) gene variant, which is associated with common variable immunodeficiency and the development of autoimmune diseases. In conclusion, a clinical history of recurrent infections, atypical histologic features of inflammatory bowel disease, additional autoimmune manifestations, and an inadequate response to conventional therapy should prompt the physician to refer to an immunologist with the query of inborn error of immunity. We report how extensive immune evaluation and genetic diagnosis can individualize care and facilitate a multidisciplinary team approach.


Assuntos
Doenças Autoimunes/genética , Doenças Inflamatórias Intestinais/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adolescente , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite Juvenil/diagnóstico , Doenças Autoimunes/imunologia , Celecoxib/efeitos adversos , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Feminino , Heterozigoto , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/imunologia , Sequenciamento Completo do Exoma
4.
PLoS One ; 16(8): e0247735, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34403420

RESUMO

Hyperlipidaemia is a major risk factor for cardiovascular diseases, the leading cause of death globally. Celecoxib attenuated hypercholesterolaemia associated with CCl4-induced hepatic injury in rats without improving liver function in our previous study. This present study investigated the lipid lowering potential of celecoxib in normal rats fed with coconut oil subjected to five deep-frying episodes. Male Sprague Dawley rats were randomly assigned to groups (n = 6 rats/group) which received physiological saline (10 mL/kg), unheated coconut oil (UO, 10 mL/kg) or heated coconut oil (HO, 10 ml/kg) for 60 days. Groups that received HO were subsequently treated with either physiological saline, atorvastatin (25 mg/kg), celecoxib (5 mg/kg) or celecoxib (10 mg/kg) in the last fifteen days of the experiment. Rats were sacrificed 24 hours after last treatment and blood and tissue samples collected for analysis. HO consumption produced significant hyperlipidaemia and elevation in marker enzymes of hepatic function. Celecoxib ameliorated the hyperlipidaemia as shown by the significantly (P<0.05) lower total cholesterol, triglycerides, low and very low density lipoprotein in the celecoxib-treated rats when compared with HO-fed rats that received saline. Celecoxib also reduced (P<0.05) alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and liver weight of hyperlipidaemic rats. Similarly, hepatocellular damage with the hyperlipidaemia was significantly reversed by celecoxib. However, serum TNF-α and IL-6 did not change significantly between the various groups. Taken together, data from this study suggest that celecoxib may exert therapeutic benefit in hyperlipidaemia and its attendant consequences.


Assuntos
Celecoxib/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Animais , Atorvastatina/uso terapêutico , Colesterol/sangue , Óleo de Coco/administração & dosagem , Óleo de Coco/efeitos adversos , Modelos Animais de Doenças , Lipoproteínas VLDL/sangue , Masculino , Ratos Sprague-Dawley , Triglicerídeos/sangue
5.
PLoS One ; 16(8): e0254606, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34428217

RESUMO

Acetylsalicylic acid is a globally used non-steroidal anti-inflammatory drug (NSAID) with diverse pharmacological properties, although its mechanism of immune regulation during inflammation (especially at in vivo relevant doses) remains largely speculative. Given the increase in clinical perspective of Acetylsalicylic acid in various diseases and cancer prevention, this study aimed to investigate the immunomodulatory role of physiological Acetylsalicylic acid concentrations (0.005, 0.02 and 0.2 mg/ml) in a human whole blood of infection-induced inflammation. We describe a simple, highly reliable whole blood assay using an array of toll-like receptor (TLR) ligands 1-9 in order to systematically explore the immunomodulatory activity of Acetylsalicylic acid plasma concentrations in physiologically relevant conditions. Release of inflammatory cytokines and production of prostaglandin E2 (PGE2) were determined directly in plasma supernatant. Experiments demonstrate for the first time that plasma concentrations of Acetylsalicylic acid significantly increased TLR ligand-triggered IL-1ß, IL-10, and IL-6 production in a dose-dependent manner. In contrast, indomethacin did not exhibit this capacity, whereas cyclooxygenase (COX)-2 selective NSAID, celecoxib, induced a similar pattern like Acetylsalicylic acid, suggesting a possible relevance of COX-2. Accordingly, we found that exogenous addition of COX downstream product, PGE2, attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro-inflammatory cytokines. Low PGE2 levels were at least involved in the enhanced IL-1ß production by Acetylsalicylic acid.


Assuntos
Aspirina/farmacologia , Citocinas/genética , Inflamação/tratamento farmacológico , Receptores Toll-Like/genética , Adjuvantes Imunológicos/farmacologia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/sangue , Ciclo-Oxigenase 2/genética , Citocinas/biossíntese , Dinoprostona/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indometacina/farmacologia , Inflamação/sangue , Inflamação/patologia , Interleucina-10/genética , Interleucina-1beta/genética , Interleucina-6/genética , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Receptores Toll-Like/sangue , Adulto Jovem
6.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445685

RESUMO

This study investigated the possible anti-inflammatory and chondroprotective effects of a combination of celecoxib and prescription-grade glucosamine sulfate (GS) in human osteoarthritic (OA) chondrocytes and their possible mechanism of action. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination with IL-1ß (10 ng/mL) and a specific nuclear factor (NF)-κB inhibitor (BAY-11-7082, 1 µM). Gene expression and release of some pro-inflammatory mediators, metalloproteinases (MMPs), and type II collagen (Col2a1) were evaluated by qRT-PCR and ELISA; apoptosis and mitochondrial superoxide anion production were assessed by cytometry; B-cell lymphoma (BCL)2, antioxidant enzymes, and p50 and p65 NF-κB subunits were analyzed by qRT-PCR. Celecoxib and GS alone or co-incubated with IL-1ß significantly reduced expression and release of cyclooxygenase (COX)-2, prostaglandin (PG)E2, IL-1ß, IL-6, tumor necrosis factor (TNF)-α, and MMPs, while it increased Col2a1, compared to baseline or IL-1ß. Both drugs reduced apoptosis and superoxide production; reduced the expression of superoxide dismutase, catalase, and nuclear factor erythroid; increased BCL2; and limited p50 and p65. Celecoxib and GS combination demonstrated an increased inhibitory effect on IL-1ß than that observed by each single treatment. Drugs effects were potentiated by pre-incubation with BAY-11-7082. Our results demonstrated the synergistic effect of celecoxib and GS on OA chondrocyte metabolism, apoptosis, and oxidative stress through the modulation of the NF-κB pathway, supporting their combined use for the treatment of OA.


Assuntos
Celecoxib/farmacologia , Glucosamina/farmacologia , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Celecoxib/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Quimioterapia Combinada/métodos , Glucosamina/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Nitrilas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia
7.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356673

RESUMO

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Assuntos
Antineoplásicos/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Celecoxib/efeitos adversos , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Pirazóis/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
8.
J Med Chem ; 64(15): 11570-11596, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34279934

RESUMO

Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.


Assuntos
Antineoplásicos/farmacologia , Celecoxib/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Etoricoxib/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Celecoxib/química , Celecoxib/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Etoricoxib/química , Etoricoxib/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade
9.
PLoS One ; 16(7): e0253547, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228745

RESUMO

OBJECTIVES: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding. METHODS: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period. RESULTS: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price. CONCLUSION: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis.


Assuntos
Celecoxib/administração & dosagem , Dor Crônica/tratamento farmacológico , Medicamentos Genéricos/administração & dosagem , Gastroenteropatias/epidemiologia , Fenilpropionatos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Celecoxib/efeitos adversos , Celecoxib/economia , Dor Crônica/diagnóstico , Simulação por Computador , Redução de Custos/estatística & dados numéricos , Análise Custo-Benefício , Custos de Medicamentos , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/economia , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/economia , Humanos , Japão , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econômicos , Fenilpropionatos/efeitos adversos , Fenilpropionatos/economia , Anos de Vida Ajustados por Qualidade de Vida , Medição de Risco/estatística & dados numéricos
10.
Biochemistry ; 60(31): 2407-2418, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34293856

RESUMO

Long residence time enzyme inhibitors with a two-step binding mechanism are characterized by a high internal energy barrier for target association. This raises the question of whether optimizing residence time via further increasing this internal energy barrier would inevitably lead to insufficient target occupancy in vivo due to slow, time-dependent binding. We attempted to address this question during optimization of cyclooxygenase-2 (COX-2) inhibitors. Defining long residence time drugs with acceptable association and dissociation rate constants required for sufficient target occupancy and sustained efficacy, which we termed "balanced internal energetics", provides an important criterion for successful progression during lead optimization. Despite the advancement of several COX-2 inhibitors to marketed drugs, their detailed inhibition kinetics have been surprisingly limiting especially during the structure-activity relationship process mainly due to the lack of robust kinetic assays. Herein, we describe a reoptimized COX enzymatic assay and a novel MS-based assay enabling detailed mechanistic studies for identifying long residence time COX-2 inhibitors with balanced internal energetics. These efforts led to the discovery of promising leads possessing dissociation half-lives of ≤40 h, much greater than the values of 6 and 0.71 h for two marketed drugs, etoricoxib and celecoxib, respectively. Importantly, the inhibition rate constants remain comparable to those of the marketed drugs and above the lower limits set by the criteria of balanced internal energetics, predicting sufficient target occupancy required for efficacy. Taken together, this study demonstrates the feasibility of increasing the internal energy barrier as a viable approach for lead optimization toward discovering long residence time drug candidates.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Descoberta de Drogas/métodos , Ensaios Enzimáticos/métodos , Furanos/química , Espectrometria de Massas/métodos , Piridinas/química , Celecoxib/química , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Etoricoxib/química , Etoricoxib/farmacologia , Fluorescência , Furanos/farmacologia , Humanos , Hidrogênio/química , Cinética , Modelos Teóricos , Oxigênio/química , Pirazóis/química , Pirazóis/farmacologia , Piridinas/farmacologia , Termodinâmica , Fatores de Tempo
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 263: 120137, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34273891

RESUMO

Five simple, selective and accurate spectrophotometric methods have been applied and developed for first time for simultaneous determination of amlodipine besylate (AML) and celecoxib (CEL) in presence of one harmful impurity, 4-methylacetophenone (MAP), in their ternary mixture without prior separation. Those spectrophotometric methods were developed and called: dual wave length in ratio spectra (DWRS), successive ratio-derivative spectra (SDR), modified absorption factor method (MAFM), modified amplitude center method (MACM) and first derivative -zero crossing coupled with amplitude factor method (FDAF). These methods include various steps using zero /or ratio /or derivative spectra and some mathematical techniques. Linear calibration curves were constructed over the concentration range of 2-100, 10-200 and 0.5-20 µg/mL for AML, CEL and MAP, respectively. High sensitivity with low LOD values 0.583, 3.118 and 0.147 for AML, CEL and MAP, respectively were obtained. Moreover, validation of the proposed methods was achieved according to ICH guidelines and satisfactory results were obtained indicating that the developed methods can be used for quality control analysis of AML and CEL concerning its impurity. No significant difference was observed when the obtained results of the developed methods were statistically compared with the reported HPLC method.


Assuntos
Anlodipino , Celecoxib , Espectrofotometria
12.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279377

RESUMO

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (Tg) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (Mw) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different Mw of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer Mw on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes-Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest Mw (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.


Assuntos
Anti-Inflamatórios não Esteroides/química , Celecoxib/química , Raios Infravermelhos , Nanopartículas/química , Povidona/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Celecoxib/administração & dosagem , Estabilidade de Medicamentos , Lasers , Viscosidade
13.
Nanomedicine (Lond) ; 16(19): 1691-1712, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34264123

RESUMO

While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Celecoxib , Reposicionamento de Medicamentos , Humanos , Nanomedicina , Neoplasias/tratamento farmacológico
14.
J Arthroplasty ; 36(10): 3471-3477, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34130870

RESUMO

BACKGROUND: Heterotopic ossification (HO) can result in poorer clinical outcomes following total hip arthroplasty (THA). Multiple modes of intervention have been evaluated for HO prevention, including the use of nonsteroidal anti-inflammatories. Additionally, multimodal pain management strategies including celecoxib have become more prominent. Therefore, this study aims to evaluate the influence of celecoxib as part of postoperative analgesia on the risk of developing HO following the direct anterior approach (DA) for THA. METHODS: A retrospective query identified primary DA THAs performed by a single surgeon between 2013 and 2020. Patients were grouped according to those who received 3 weeks celecoxib upon discharge, and those who did not. Radiographs were used to categorize patients according to the Brooker classification system for HO. Preoperative and 2-week, 6-week, 3-month, and 1-year postoperative X-rays were evaluated. RESULTS: A total of 688 DA THAs were included, demonstrating a 9.6% (n = 66) incidence of HO with Brooker classification: 1: 5.7% (n = 39); 2: 2.6% (n = 18); 3: 1.2% (n = 8); and 4: 0.1% (n = 1). Patients who did not receive celecoxib had a 14.3% (52/364) rate of HO following THA (odds ratio 4.53, P < .001) vs only 4.3% (14/324) in the celecoxib group (odds ratio 0.22, P < .001). Overall, 9 patients (1.3%) went on to develop significant HO (Booker 3 or greater): 8 (2.2%) in the control group and 1 (0.3%) in the celecoxib group (P < .001). CONCLUSION: Our findings suggest a significant reduction in the formation of HO following DA THA when using postoperative analgesic celecoxib as part of a multimodal pain protocol. Future prospective randomized studies are needed to identify ideal dosage, duration, and formulation to reduce the risk of HO while optimizing multimodal pain management.


Assuntos
Artroplastia de Quadril , Ossificação Heterotópica , Anti-Inflamatórios não Esteroides , Artroplastia de Quadril/efeitos adversos , Celecoxib/uso terapêutico , Humanos , Ossificação Heterotópica/epidemiologia , Ossificação Heterotópica/etiologia , Ossificação Heterotópica/prevenção & controle , Complicações Pós-Operatórias , Estudos Retrospectivos
15.
Clin Orthop Surg ; 13(2): 160-167, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34094006

RESUMO

Backgroud: Postoperative pain following total knee arthroplasty (TKA) may hamper patients from a rapid recovery and increase perioperative blood loss and stress on the cardiovascular system. Therefore, our objective was to assess perioperative outcomes after TKA in patients who were not candidates for the additional nonsteroidal anti-inflammatory drugs (NSAIDs) in a multimodal pain control regimen. Methods: Propensity score matching for age, sex, body mass index, American Society of Anesthesiologists class, and preoperative hemoglobin level was conducted on patients undergoing unilateral TKA, and thereby 52 patients remained in each group. The control group comprised patients who received parenteral parecoxib every 12 hours during the first 48 hours after TKA. The No-NSAIDs group did not receive NSAIDs because of known contraindications. Identical postoperative pain control including intravenous patient-controlled analgesia was applied for all patients. Visual analog scale (VAS) score for pain, knee flexion, blood loss, serum cardiac troponin-T (cTnT), and length of stay (LOS) were determined. Results: The No-NSAIDs group had significantly higher VAS scores in 6-96 hours and consumed more morphine at 24 hours and 48 hours after the surgery than the control group. The No-NSAIDs group had significantly less knee flexion at 48 hours (p = 0.045) and tended to have more emesis and longer LOS than the control group. The blood loss of the No-NSAIDs and control group was 552.52 mL and 397.65 mL (p = 0.02), respectively, and blood transfusion rate was 23.1% and 17.3% (p = 0.63), respectively. The cTnT of the No-NSAIDs group rose over the first 48 hours and was significantly higher than that of the control group at 48 hours. Conclusions: Patients who were not candidates for NSAIDs had significantly higher pain scores and consumed more morphine after TKA. They also tended to have greater blood loss and the rising of cardiac biomarkers during the first 48 hours after TKA. Hence, these patients may benefit from supplementary analgesia and appropriate perioperative monitoring.


Assuntos
Artroplastia do Joelho , Celecoxib/administração & dosagem , Isoxazóis/administração & dosagem , Morfina/administração & dosagem , Manejo da Dor/métodos , Idoso , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória , Estudos Retrospectivos
16.
Front Immunol ; 12: 670088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122428

RESUMO

Chimeric antigen receptor T (CAR-T) cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include nonsteroidal anti-inflammatory drugs (NSAIDs) like cyclooxygenase (COX) inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10 red to JC-10 green CAR-T cells from 6.46 ± 7.03 (mean ± SD) to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10 red to JC-10 green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation of expression of CD27 on CD4+ and CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+ and CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.


Assuntos
Antígenos CD19/genética , Aspirina/farmacologia , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Imunoterapia Adotiva , Linfoma de Células B/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/efeitos dos fármacos , Antígenos CD19/imunologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Células K562 , Ativação Linfocitária/efeitos dos fármacos , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante
17.
Clin Ther ; 43(6): 1051-1065, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34167827

RESUMO

PURPOSE: Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. METHODS: This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0-T, and AUC0-∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0-T, and AUC0-∞ was based on ln-transformed data, and Tmax was rank-transformed. FINDINGS: Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0-T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0-T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. IMPLICATIONS: The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.


Assuntos
Tramadol , Adulto , Área Sob a Curva , Disponibilidade Biológica , Celecoxib , Estudos Cross-Over , Feminino , Humanos , Masculino , Equivalência Terapêutica
18.
Bioanalysis ; 13(12): 969-983, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34085866

RESUMO

Aim: Green, accurate and rapid methods, namely LC-MS/MS and thin layer chromatography-densitometric methods, were developed for determination of amlodipine besylate and celecoxib in presence of its process-related impurities, 4-methylacetophenone in pure and formulated tablets. Results: LC-MS/MS was achieved on ZORBAX Eclipse Plus C18 column using methanol:aqueous solution of 5 mM formic acid (95:5 v/v). High sensitivity with low limit of detection values 0.00028, 0.00027 and 0.0003 for amlodipine, celecoxib and 4-methylacetophenone, respectively were obtained. While, thin layer chromatography-densitometric was established using methanol:water:ammonia (70:25:1.5, by volume). Good linearity was obtained in the range of 0.1-10 µg/band, 1-150 µg/band and 0.01-2 µg/band for amlodipine, celecoxib and 4-methylacetophenone, respectively. Conclusion: The proposed method validation was achieved according to ICH guidelines. Those methods possess advantages of being ecofriendly methods which permit their application in quality control laboratories.


Assuntos
Anlodipino , Celecoxib , Cromatografia Líquida , Comprimidos , Espectrometria de Massas em Tandem
19.
AAPS PharmSciTech ; 22(5): 180, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34129135

RESUMO

Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor-α (TNF-α), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-ΚB), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Celecoxib/síntese química , Celecoxib/farmacocinética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , NF-kappa B/metabolismo , Compostos Orgânicos/síntese química , Compostos Orgânicos/farmacocinética , Compostos Orgânicos/uso terapêutico , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
20.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071951

RESUMO

Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Inflamação/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Celecoxib/farmacologia , Química Farmacêutica/métodos , Feminino , Humanos , Cinética , Ligantes , Imageamento por Ressonância Magnética , Masculino , Camundongos , Papio , Permeabilidade , Ratos
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