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1.
Nihon Shokakibyo Gakkai Zasshi ; 118(9): 840-850, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34511551

RESUMO

BACKGROUND & AIMS: Capsule endoscopy has revealed that nonsteroidal anti-inflammatory drugs may cause damage not only to the stomach but also to the small intestine, which has become one of the most serious issues in gastroenterology. However, few studies have reported the effect of ibuprofen (IBP), which is widely prescribed worldwide, on the small intestine, and it remains unclear whether IBP can cause small intestinal damage. We have previously shown that acetaminophen (APAP), which is used as an antipyretic/analgesic drug, inhibits IBP-induced gastric damage by suppressing matrix metalloprotease-13 (MMP-13) gene expression. In this study, we investigated the ability of IBP to induce small intestinal damage and the efficacy of APAP against IBP-induced small intestinal damage in rats. MAIN METHODS: Nonfasted male Sprague-Dawley rats were orally administered with IBP (200mg/kg) and then euthanized at various time points (0, 4, 8, 16, and 24h) after the administration. The small intestine, jejunum, and ileum were removed, and intestinal lesions were measured. To elucidate the efficacy of APAP against IBP-induced small intestinal damage, the rats were treated with IBP (200mg/kg) with or without APAP (200mg/kg), and small intestinal damage was evaluated 24h after the administration. Moreover, the expression levels of GAPDH, TNFα, iNOS, and MMP-13 genes were determined at various time points (8, 16, and 24h) by RT-qPCR. KEY FINDINGS: The oral administration of IBP induced obvious small intestinal damage, which was found to be significant at 24h (p<0.05 vs 0h, Dunnett's test). The coadministration of APAP significantly prevented IBP-induced damage (p<0.05, Student's t-test). In addition, the expression levels of TNFα and iNOS genes were significantly increased by IBP (p<0.01 and p<0.05 vs. vehicle, respectively, Tukey-Kramer test), whereas the cotreatment with APAP suppressed the increases at 8h. Moreover, compared with the vehicle, the IBP treatment significantly increased the expression level of the MMP-13 gene (p<0.01) at each time point (8, 16, and 24h, Tukey-Kramer test), whereas the APAP cotreatment significantly suppressed the increase (p<0.01 vs. IBP at 8h, p<0.05 vs. IBP at 16 and 24h, Tukey-Kramer test). CONCLUSIONS: This study suggested that a single administration of IBP was associated with the risk of inducing small intestinal ulcers in rats, and APAP could prevent IBP-induced small intestinal damage by suppressing the MMP-13 gene expression.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Ibuprofeno/farmacologia , Intestino Delgado , Fígado , Masculino , Metaloproteinase 13 da Matriz/genética , Ratos , Ratos Sprague-Dawley
2.
RMD Open ; 7(3)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497153

RESUMO

Non-steroidal anti-inflammatory drugs are a widely used symptomatic treatment in osteoarthritis (OA), but their effects on cartilage remain controversial. We studied the effects of ibuprofen on gene expression in chondrocytes from patients with OA using RNA-Seq. Chondrocytes were isolated from cartilage samples of patients with OA undergoing knee replacement surgery, cultured with ibuprofen, and total mRNA was sequenced. Differentially expressed genes were identified with edgeR using pairwise comparisons. Functional analysis was performed using ingenuity pathway analysis (IPA). Ibuprofen did not induce statistically significant changes in chondrocyte transcriptome when the cells were cultured in the absence of added cytokines. In inflammatory conditions (when the cells were exposed to the OA-related cytokine interleukin (IL)-1ß), 51 genes were upregulated and 42 downregulated by ibuprofen with fold change >1.5 in either direction. The upregulated genes included anti-inflammatory factors and genes associated with cell adhesion, while several mediators of inflammation were among the downregulated genes. IPA analysis revealed ibuprofen having modulating effects on inflammation-related pathways such as integrin, IL-8, ERK/MAPK and cAMP-mediated signalling pathways. In conclusion, the effects of ibuprofen on primary OA chondrocyte transcriptome appear to be neutral in normal conditions, but ibuprofen may shift chondrocyte transcriptome towards anti-inflammatory phenotype in inflammatory environments.


Assuntos
Condrócitos , Osteoartrite , Células Cultivadas , Expressão Gênica , Humanos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , RNA-Seq
3.
J Enzyme Inhib Med Chem ; 36(1): 1810-1828, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338135

RESUMO

Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hidrazinas/química , Ibuprofeno/química , Indóis/química , Quinazolinonas/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Indóis/síntese química , Indóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodos
4.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200719

RESUMO

The potential of bacterial cellulose as a carrier for the transport of ibuprofen (a typical example of non-steroidal anti-inflammatory drugs) through the skin was investigated. Ibuprofen and its amino acid ester salts-loaded BC membranes were prepared through a simple methodology and characterized in terms of structure and morphology. Two salts of amino acid isopropyl esters were used in the research, namely L-valine isopropyl ester ibuprofenate ([ValOiPr][IBU]) and L-leucine isopropyl ester ibuprofenate ([LeuOiPr][IBU]). [LeuOiPr][IBU] is a new compound; therefore, it has been fully characterized and its identity confirmed. For all membranes obtained the surface morphology, tensile mechanical properties, active compound dissolution assays, and permeation and skin accumulation studies of API (active pharmaceutical ingredient) were determined. The obtained membranes were very homogeneous. In vitro diffusion studies with Franz cells were conducted using pig epidermal membranes, and showed that the incorporation of ibuprofen in BC membranes provided lower permeation rates to those obtained with amino acids ester salts of ibuprofen. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes indicates the enormous potentialities of using BC membranes for transdermal application of ibuprofen in the form of amino acid ester salts.


Assuntos
Aminoácidos/química , Anti-Inflamatórios não Esteroides/farmacologia , Celulose/química , Ésteres/química , Ibuprofeno/farmacologia , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Bactérias/metabolismo , Sistemas de Liberação de Medicamentos , Ibuprofeno/administração & dosagem , Ibuprofeno/química , Suínos
5.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204472

RESUMO

The ostrich oil of Struthio camelus (Ratite) found uses in folk medicine as an anti-inflammatory in eczema and contact dermatitis. The anti-inflammatory effect of a γ-lactone (5-hexyl-3H-furan-2-one) isolated from ostrich oil and its formulated nano-emulsion in formalin-induced paw edema was investigated in this study. Ostrich oil was saponified using a standard procedure; the aqueous residue was fractionated, purified, and characterized as γ-lactone (5-hexyl-3H-furan-2-one) through the interpretation of IR, NMR, and MS analyses. The γ-lactone was formulated as nano-emulsion using methylcellulose (MC) for oral solubilized form. The γ-lactone methylcellulose nanoparticles (γ-lactone-MC-NPs) were characterized for their size, shape, and encapsulation efficiency with a uniform size of 300 nm and 59.9% drug content. The γ-lactone was applied topically, while the formulated nanoparticles (NPs) were administered orally to rats. A non-steroidal anti-inflammatory drug (diclofenac gel) was used as a reference drug for topical use and ibuprofen suspension for oral administration. Edema was measured using the plethysmograph method. Both γ-lactone and γ-lactone-MC-NPs showed reduction of formalin-induced paw edema in rats and proved to be better than the reference drugs; diclofenac gel and ibuprofen emulsion. Histological examination of the skin tissue revealed increased skin thickness with subepidermal edema and mixed inflammatory cellular infiltration, which were significantly reduced by the γ-lactone compared to the positive control (p-value = 0.00013). Diuretic and toxicity studies of oral γ-lactone-MC-NPs were performed. No diuretic activity was observed. However, lethargy, drowsiness, and refusal to feeding observed may limit its oral administration.


Assuntos
Lactonas/isolamento & purificação , Lactonas/farmacologia , Struthioniformes/metabolismo , Administração Oral , Administração Tópica , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Edema/tratamento farmacológico , Emulsões/farmacologia , Formaldeído/efeitos adversos , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacologia , Masculino , Paleógnatas/metabolismo , Ratos , Ratos Wistar , Pele/efeitos dos fármacos
6.
Medicine (Baltimore) ; 100(26): e26516, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190183

RESUMO

OBJECTIVE: To evaluate the analgesic efficacy and safety of ibuprofen in children with musculoskeletal injuries. METHODS: PubMed, EMBASE, Web of science, and the Cochrane Central register of Controlled Trials (CENTRAL) were systematically searched to identify eligible randomized controlled trials (RCTs) that compared ibuprofen with other analgesics for pain relief in children with musculoskeletal injuries. Primary outcomes included change of visual analog scale (VAS) scores from baseline to post-medication, the proportion of patients achieving adequate analgesia, and the proportion of patients requiring additional analgesia. Secondary outcome was the incidence of adverse effects. Data analysis was performed using RevMan 5.3 software. RESULTS: Five RCTs involving 1034 patients were included in this meta-analysis. Compared to the control group, change of VAS scores was greater in ibuprofen group at 60 min (standardized mean difference [SMD] = 0.28; 95% confidence intervals [CI], 0 to 0.57; P = .05), 90 min (SMD = 0.38; 95% CI, 0.17 to 0.59; P = .0005), and 120 min (SMD = 0.4; 95% CI, 0.23 to 0.57; P < .00001) after treatment. No difference was found in the change of VAS scores at 30 min (SMD = 0.07; 95% CI, -0.08 to 0.22; P = .36) after treatment. The proportion of patients who received adequate analgesia was higher in the ibuprofen group (risk ratios [RR] = 1.36; 95% CI, 1.20 to 1.56; P < .00001). The proportion of patients that required additional analgesia was lower in the ibuprofen group (RR = 0.7; 95% CI, 0.53 to 0.92; P = .01). The incidence of total adverse effects was lower in the ibuprofen group (RR = 0.59; 95% CI, 0.45 to 0.79; P = .0002). CONCLUSIONS: Ibuprofen provides a better pain relief with a lower incidence of adverse effects in children with musculoskeletal injuries as compared to other analgesics. PROSPERO REGISTRATION NUMBER: CRD42021231975.


Assuntos
Ibuprofeno/farmacologia , Dor Musculoesquelética , Ferimentos e Lesões , Analgésicos não Narcóticos/farmacologia , Criança , Humanos , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ferimentos e Lesões/complicações , Ferimentos e Lesões/fisiopatologia
7.
Brain Behav Immun ; 96: 135-142, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34052365

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have shown initial promise in producing antidepressant effects. This is perhaps due to these drugs being peroxisome proliferator-activated receptor gamma (PPARγ) agonists, in addition to their inhibition of cyclooxygenase enzymes. Some, albeit mixed, evidence suggests that PPARγ agonists have antidepressant effects in humans and animals. This double-blind, placebo-controlled, pharmacologic functional magnetic resonance imaging (ph-fMRI) study aimed to elucidate the impact of ibuprofen on emotion-related neural activity and determine whether observed effects were due to changes in PPARγ gene expression. Twenty healthy volunteers completed an emotional face matching task during three fMRI sessions, conducted one week apart. Placebo, 200 mg, or 600 mg ibuprofen was administered 1 h prior to each scan in a pseudo-randomized order. Peripheral blood mononuclear cells were collected at each session to isolate RNA for PPARγ gene expression. At the doses used, ibuprofen did not significantly change PPARγ gene expression. Ibuprofen dose was associated with decreased blood oxygen level-dependent (BOLD) activation in the dorsolateral prefrontal cortex and fusiform gyrus during emotional face processing (faces-shapes). Additionally, PPARγ gene expression was associated with increased BOLD activation in the insula and transverse and superior temporal gyri (faces-shapes). No interaction effects between ibuprofen dose and PPARγ gene expression on BOLD activation were observed. Thus, results suggest that ibuprofen and PPARγ may have independent effects on emotional neurocircuitry. Future studies are needed to further delineate the roles of ibuprofen and PPARγ in exerting antidepressant effects in healthy as well as clinical populations.


Assuntos
Ibuprofeno , PPAR gama , Animais , Ciclo-Oxigenase 2 , Emoções , Humanos , Ibuprofeno/farmacologia , Leucócitos Mononucleares
8.
Front Immunol ; 12: 659943, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995381

RESUMO

Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.


Assuntos
Modelos Animais de Doenças , Ácidos Graxos Ômega-3/farmacologia , Ibuprofeno/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C3H , Mycobacterium tuberculosis/fisiologia , Fatores de Tempo , Tuberculose/microbiologia
10.
Eur J Pharmacol ; 902: 174098, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33848541

RESUMO

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Colistina/farmacologia , Fibrose Cística/tratamento farmacológico , Tobramicina/farmacologia , Antibacterianos/química , Antibacterianos/toxicidade , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colistina/análogos & derivados , Colistina/química , Colistina/toxicidade , Combinação de Medicamentos , Humanos , Ibuprofeno/química , Ibuprofeno/farmacologia , Ibuprofeno/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/química , Tobramicina/toxicidade
11.
PLoS One ; 16(4): e0250276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886622

RESUMO

Cyclooxygenase (COX) is a two-step enzyme that converts arachidonic acid into prostaglandin H2, a labile intermediate used in the production of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α). In vertebrates and corals, COX must be N-glycosylated on at least two asparagine residues in the N-(X)-S/T motif to be catalytically active. Although COX glycosylation requirement is well-characterized in many species, whether crustacean COXs require N-glycosylation for their enzymatic function have not been investigated. In this study, a 1,842-base pair cox gene was obtained from ovarian cDNA of the black tiger shrimp Penaeus monodon. Sequence analysis revealed that essential catalytic residues and putative catalytic domains of P. monodon COX (PmCOX) were well-conserved in relation to other vertebrate and crustacean COXs. Expression of PmCOX in 293T cells increased levels of secreted PGE2 and PGF2α up to 60- and 77-fold, respectively, compared to control cells. Incubation of purified PmCOX with endoglycosidase H, which cleaves oligosaccharides from N-linked glycoproteins, reduced the molecular mass of PmCOX. Similarly, addition of tunicamycin, which inhibits N-linked glycosylation, in PmCOX-expressing cells resulted in PmCOX protein with lower molecular mass than those obtained from untreated cells, suggesting that PmCOX was N-glycosylated. Three potential glycosylation sites of PmCOX were identified at N79, N170 and N424. Mutational analysis revealed that although all three residues were glycosylated, only mutations at N170 and N424 completely abolished catalytic function. Inhibition of COX activity by ibuprofen treatment also decreased the levels of PGE2 in shrimp haemolymph. This study not only establishes the presence of the COX enzyme in penaeid shrimp, but also reveals that N-glycosylation sites are highly conserved and required for COX function in crustaceans.


Assuntos
Penaeidae/enzimologia , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Sequência de Bases , Inibidores de Ciclo-Oxigenase/farmacologia , Análise Mutacional de DNA/métodos , DNA Complementar/genética , Dinoprosta/metabolismo , Dinoprostona/metabolismo , Feminino , Glicosilação/efeitos dos fármacos , Células HEK293 , Hemolinfa/metabolismo , Humanos , Ibuprofeno/farmacologia , Peso Molecular , Ovário/metabolismo , Prostaglandina-Endoperóxido Sintases/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transfecção , Tunicamicina/farmacologia
13.
AAPS PharmSciTech ; 22(4): 141, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33884533

RESUMO

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.


Assuntos
Formas de Dosagem , Composição de Medicamentos , Paladar , Administração Oral , Criança , Humanos , Ibuprofeno/análogos & derivados , Ibuprofeno/farmacologia , Lisina/análogos & derivados , Lisina/farmacologia , Preparações Farmacêuticas , Polímeros , Solubilidade
14.
Mater Sci Eng C Mater Biol Appl ; 123: 111941, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33812576

RESUMO

Electrospun membranes and hydrogels are widely used to prevent tendon adhesion. Hydrophobic anti-inflammatory drugs could be fully loaded on the electrospinning membrane through the electrospinning process, which can better prevent tendon adhesion. Basic fibroblast growth factor (bFGF) could promote tendon healing. However, the bioactivity of free bFGF is easily inactivated, therefore, a suitable carrier is needed. As a carrier, hydrogel has little effect on the bioactivity of the protein drugs. In this work, a poly(lactic-co-glycolic) acid (PLGA) electrospun membrane loaded with ibuprofen (IBU) was prepared and named EMI. Additionally, Methoxy poly(ethylene glycol)-block-poly(L-valine) (PEG-PLV) was synthesized. bFGF was added to the PEG-PLV solution, a hydrogel containing bFGF (PLVB) was obtained after gelling. PLVB was applied to the surface of EMI, a double-layer composite membrane named EMI-PLVB was obtained. This membrane was used to prevent Achilles tendon adhesion and promote healing. IBU and bFGF in EMI-PLVB were continuously released in vitro. The inflammatory factors at the tendon healing site were significantly reduced, and the production of type I collagen (Col- I) and type III Collagen (Col-III) at the tendon healing site was also increased in vivo. In conclusion, this double-layer composite membrane drug release system can effectively prevent tendon adhesion and promote tendon healing.


Assuntos
Tendão do Calcâneo , Cicatrização , Humanos , Hidrogéis , Ibuprofeno/farmacologia , Aderências Teciduais/prevenção & controle
15.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808785

RESUMO

In implantable materials, surface topography and chemistry are the most important in the effective osseointegration and interaction with drug molecules. Therefore, structural and surface modifications of nanostructured titanium dioxide (TiO2) layers are reported in the present work. In particular, the modification of annealed TiO2 samples with -OH groups and silane derivatives, confirmed by X-ray photoelectron spectroscopy, is shown. Moreover, the ibuprofen release process was studied regarding the desorption-desorption-diffusion (DDD) kinetic model. The results proved that the most significant impact on the release profile is annealing, and further surface modifications did not change its kinetics. Additionally, the cell adhesion and proliferation were examined based on the MTS test and immunofluorescent staining. The obtained data showed that the proposed changes in the surface chemistry enhance the samples' hydrophilicity. Moreover, improvements in the adhesion and proliferation of the MG-63 cells were observed.


Assuntos
Portadores de Fármacos , Ibuprofeno , Nanoestruturas , Osseointegração/efeitos dos fármacos , Osteoblastos/metabolismo , Linhagem Celular , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacologia , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Titânio/química , Titânio/farmacocinética , Titânio/farmacologia
16.
Int J Biol Macromol ; 181: 426-434, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33775768

RESUMO

Advanced glycation end products (AGEs) formation produces free radicals that play a role in diabetes mellitus; hence inhibition of glycation plays a part in minimizing diabetes-related complications. This study was intended to examine the AGEs formation of HSA upon prolonged incubation of 28 days at 37 °C and further investigate the antiglycation potential of folic acid (FA). FA shows a significant binding affinity to the HSA with a binding constant (K) of 104 M-1. The evaluation of enthalpy change (∆H0) and entropy change (∆So) implied that the HSA-FA complex is stabilized primarily by hydrophobic interaction and hydrogen bonding. Molecular docking analysis depicted that FA binds with HSA in subdomain IIA (Sudlow's site I) with a binding energy of -7.0 kcal mol-1. AGEs were characterized by free lysine and thiol groups, carbonyl content, and AGEs specific fluorescence. The presence of FA significantly decreased glycation from free lysine and carbonyl content estimation and AGEs specific fluorescence. Multispectroscopic observations and molecular docking and examination of various biomarkers demonstrate the antiglycation activity of FA and its capacity to prevent disease progression in diabetes.


Assuntos
Ácido Fólico/farmacologia , Simulação de Acoplamento Molecular , Albumina Sérica Humana/metabolismo , Análise Espectral , Sítios de Ligação , Dicroísmo Circular , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação/efeitos dos fármacos , Humanos , Ibuprofeno/farmacologia , Lisina/metabolismo , Concentração Osmolar , Carbonilação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Compostos de Sulfidrila/metabolismo , Termodinâmica , Varfarina/farmacologia
17.
J Mater Chem B ; 9(11): 2727-2735, 2021 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-33683250

RESUMO

The preparation of dual-release pharmaceutical microfibers provides an ideal material for new biomedical applications. We describe a microfluidic spinning method for engineering heterotypic bead-on-string fibers with the ability to carry dual cargos and to deliver on demand. The core of our technology is to combine microfluidic spinning with biomaterial preparation, in which hydrophobic and hydrophilic cargos can be integrated into a bead-on-string microfiber structure. We demonstrate the loading of bovine serum albumin (BSA) in the sodium alginate phase and ibuprofen in the polylactic acid (PLA) phase, respectively. The heterotypic bead-on-string fibers are biocompatible and show hemostatic ability in vivo. These heterotypic bead-on-string fibers are then woven as a skin scaffold and shown to promote wound healing by loading antibacterial and anti-inflammatory cargos.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Ibuprofeno/farmacologia , Dispositivos Lab-On-A-Chip , Soroalbumina Bovina/metabolismo , Cicatrização/efeitos dos fármacos , Alginatos/química , Animais , Antibacterianos/química , Anti-Inflamatórios não Esteroides/química , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/química , Masculino , Camundongos , Células NIH 3T3 , Imagem Óptica , Poliésteres/química , Soroalbumina Bovina/química
18.
Molecules ; 26(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669839

RESUMO

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


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cromolina Sódica/uso terapêutico , Ibuprofeno/uso terapêutico , Polifarmacologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromolina Sódica/síntese química , Cromolina Sódica/química , Cromolina Sódica/farmacologia , Drosophila/efeitos dos fármacos , Desenho de Fármacos , Endocitose/efeitos dos fármacos , Ibuprofeno/síntese química , Ibuprofeno/química , Ibuprofeno/farmacologia , Imunomodulação/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Agregados Proteicos/efeitos dos fármacos , Ratos Wistar
19.
PLoS One ; 16(2): e0246695, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33600498

RESUMO

Bovine Respiratory Syncytial virus (BRSV) is one of the major infectious agents in the etiology of the bovine respiratory disease complex. BRSV causes a respiratory syndrome in calves, which is associated with severe bronchiolitis. In this study we describe the effect of treatment with antiviral fusion protein inhibitor (FPI) and ibuprofen, on gene expression in lung tissue of calves infected with BRSV. Calves infected with BRSV are an excellent model of human RSV in infants: we hypothesized that FPI in combination with ibuprofen would provide the best therapeutic intervention for both species. The following experimental treatment groups of BRSV infected calves were used: 1) ibuprofen day 3-10, 2) ibuprofen day 5-10, 3) placebo, 4) FPI day 5-10, 5) FPI and ibuprofen day 5-10, 6) FPI and ibuprofen day 3-10. All calves were infected with BRSV on day 0. Daily clinical evaluation with monitoring of virus shedding by qRT-PCR was conducted. On day10 lung tissue with lesions (LL) and non-lesional (LN) was collected at necropsy, total RNA extracted, and RNA sequencing performed. Differential gene expression analysis was conducted with Gene ontology (GO) and KEGG pathway enrichment analysis. The most significant differential gene expression in BRSV infected lung tissues was observed in the comparison of LL with LN; oxidative stress and cell damage was especially noticeable. Innate and adaptive immune functions were reduced in LL. As expected, combined treatment with FPI and Ibuprofen, when started early, made the most difference in gene expression patterns in comparison with placebo, especially in pathways related to the innate and adaptive immune response in both LL and LN. Ibuprofen, when used alone, negatively affected the antiviral response and caused higher virus loads as shown by increased viral shedding. In contrast, when used with FPI Ibuprofen enhanced the specific antiviral effect of FPI, due to its ability to reduce the damaging effect of prostanoids and oxidative stress.


Assuntos
Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Bovino/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/farmacocinética , Bovinos , Doenças dos Bovinos/imunologia , Inibidores de Ciclo-Oxigenase/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Ibuprofeno/farmacologia , Pulmão/citologia , Pulmão/patologia , Pulmão/virologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Bovino/patogenicidade , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Eliminação de Partículas Virais/efeitos dos fármacos
20.
Artigo em Inglês | MEDLINE | ID: mdl-33551100

RESUMO

Inhibiting inflammatory processes or eliminating inflammation represents a logical role in the suppression and treatment strategy of cancer. Several studies have shown that anti-inflammatory drugs (NSAIDs) act as anticancer agents while reducing metastases and mortality rate. NSAIDs are seriously limited by their side effects and toxicity, which can become cumulative with their long-term administration for chemoprevention. In the current ex vivo / in vitro study, the genotoxicity mechanisms of NSAIDS in bulk and nanoparticle forms allowed a strategy to prevent and minimise the damage in human lymphocytes. When compared to their bulk forms, acetylsalicylic acid (Aspirin) nano and ibuprofen nano (IBU N), both NSAIDs in 500 µg/mL concentration significantly decreased DNA damage measured by alkaline comet assay. Micronuclei (MNi) frequency also decreased after ASP N (500 µg/mL), ASP B (500 µg/mL) and IBU N (200 µg/mL) in prostate cancer patients and healthy individuals, however, the ibuprofen bulk (200 µg/mL) showed a significant increase in MNi formation in lymphocytes from healthy and prostate cancer patients when compared to the respective untreated lymphocytes. These findings suggest that a reduction in particle size had an impact on the reactivity of the drug, further emphasising the potential of nanoparticles to improve the current treatment options.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Aberrações Cromossômicas/efeitos dos fármacos , Dano ao DNA , Ibuprofeno/farmacologia , Linfócitos/patologia , Neoplasias da Próstata/patologia , Idoso , Estudos de Casos e Controles , Humanos , Técnicas In Vitro , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Nanopartículas , Neoplasias da Próstata/tratamento farmacológico
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