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1.
Acta Cir Bras ; 34(12): e201901206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049186

RESUMO

PURPOSE: To evaluate the effects of prednisolone against sodium diclofenac both with ciprofloxacin compared to artificial tears on the symptoms and signs of acute viral conjunctivitis. METHODS: Study included 37 patients diagnosed with acute conjunctivitis and distributed by three groups: A (1% prednisolone acetate + ciprofloxacin (0.3%); B (Sodium diclofenac (0.1%) + ciprofloxacin (0.3%) and C (artificial tears + ciprofloxacin (0.3%). Patients received medication 6/6 hours daily. Signs and symptoms (e.g. lacrimation, burning, photophobia, etc.) were scored at baseline and on the first, third, fifth and seventh days and in the end of treatment using a standardized questionnaire and slit lamp anterior segment examination. RESULTS: All three groups demonstrated an improvement in the signs and symptoms of conjunctivitis in their follow-up visits. There was no significant difference in symptom and sign scores between Group A and B and B and C in the study visits ( p >0.05). However, the comparison between groups A and C showed a clinical trend (p=0.05) on third evaluation suggesting better clinical action using the corticosteroids. CONCLUSION: The prednisolone acetate was not superior to the use of sodium diclofenac or artificial tears in relieving the signs and symptoms of viral conjunctivitis.


Assuntos
Corticosteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Ciprofloxacino/administração & dosagem , Conjuntivite Viral/tratamento farmacológico , Diclofenaco/administração & dosagem , Prednisolona/análogos & derivados , Doença Aguda , Adolescente , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Interferon gama , Interleucinas/análise , Lubrificantes Oftálmicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase/análise , Soluções Oftálmicas/administração & dosagem , Prednisolona/administração & dosagem , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise , Adulto Jovem
2.
Chem Biol Interact ; 317: 108941, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926916

RESUMO

m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF3-PhSe)2 restorative properties in models of acute and chronic inflammatory pain induced by complete Freund's adjuvant (CFA). Male adult Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h (acute) or 14 days (subchronic) later they were treated with a single or repeated (m-CF3-PhSe)2 schedule via intragastric route, respectively. The mechanical and thermal hypernociceptive behaviors were assessed by von Frey hair and hot plate tests. Samples of injected paw were collected to evaluate the tissue edema and myeloperoxidase (MPO) activity while cerebral contralateral cortex samples were used to determine the inflammatory proteins content (subchronic protocol). The acute (m-CF3-PhSe)2 administration (1 and 10 mg/kg) reduced the hypernociceptive behavior and both paw thickness and MPO activity induced by CFA injection. In the subchronic protocol, the repeated administration with a low effective dosage of (m-CF3-PhSe)2 reduced the mechanical and thermal hypernociception as well as restored the edema and MPO activity in paw samples. In addition, the repeated treatment schedule mitigated the increase in TNF-α, IL-1ß and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF3-PhSe)2 presents anti-inflammatory properties, which could be mediated by an interplay between peripheral and central mechanisms of action, reinforcing the potential biological properties of the compound.


Assuntos
Inflamação/induzido quimicamente , Compostos de Organossilício/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Adjuvante de Freund/toxicidade , Inflamação/tratamento farmacológico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Compostos de Organossilício/administração & dosagem , Medição da Dor , Sintase do Porfobilinogênio/metabolismo , Carbonilação Proteica , Compostos de Sulfidrila/metabolismo
3.
J Pharm Biomed Anal ; 177: 112852, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499432

RESUMO

The effect of insertion of SH and S-protected groups on the binding and mucoadhesion properties of quaternary ammonium-chitosans and their nanoparticulate forms has been investigated by NMR spectroscopy. Diclofenac sodium salt has been assumed as low molecular weight probe to detect the different binding behaviour of polymeric materials; mucin from bovine submaxillary glands was selected as the model protein for differentiating their mucoadhesion. NMR proton selective relaxation rates of the probe molecule were remarkably sensitive to the presence of very low amounts of sulfurated moieties. Impact of supramolecular aggregation in nanostructured species was demonstrated as well as the relevance of S-protection.


Assuntos
Diclofenaco/administração & dosagem , Portadores de Fármacos/química , Membrana Mucosa/metabolismo , Nanopartículas/química , Adesividade , Animais , Bovinos , Quitosana/química , Quitosana/metabolismo , Portadores de Fármacos/metabolismo , Peso Molecular , Mucinas/metabolismo , Nanopartículas/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/metabolismo , Enxofre/química
4.
Clin Ter ; 170(5): e332-e336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612188

RESUMO

INTRODUCTION: Post-Endoscopic Retrograde Cholangio-Pancreatography pancreatitis (PEP) is a relevant (1-4%) complication of biliopancreatic operative endoscopy. Rectal nonsteroidal anti-inflammatory drugs (specifically, 100 mg of diclofenac) have shown promising prophylactic activity in PEP. The aim of our prospective study is to report whether prophylactic oral versus rectal suppository versus intramuscular diclofenac versus placebo are able to reduce the incidence and the severity of ERCP-induced pancreatitis. MATERIALS AND METHODS: In this randomized, double-blinded, prospective study, 100 patients (49 male, 51 female), similar with regard to indication for ERCP, were enrolled between January 2016 and November 2017 to undergo ERCP in the Section of General and Thoracic Surgery of University Hospital of Palermo. They were randomized into five groups, respectively 20 patients with placebo by mouth; 20 patients with 50 mg diclofenac sodium enteric-coated capsules by mouth; 20 with 100 mg rectal suppository diclofenac, 20 with 75 mg/3 ml intramuscular diclofenac sodium, 20 with 75 mg/3 ml intramuscular diclofenac sodium and 20 with 75 mg/3 ml intravenous diclofenac. All drugs were administered 30 to 90 minutes before ERCP. All clinical data were collected one day before and 2, 12 and 24 hour after ERCP. RESULT: Data were prospectively collected and to demonstrate the preventive effect of rectal diclofenac on PEP, a two-by-two table and chi-square test with Yates correction were used: the incidence of PEP was significantly lower (p < 0.001) in the rectal diclofenac group respect to other groups and, in the same way, the incidence of post-ERCP pain was significantly lower in the rectal diclofenac group than in the other groups (p = 0.001) and patients discharge was consequently earlier (p < 0.01). CONCLUSION: 100 mg dose rectal diclofenac administered 30-60 minutes before ERCP can effectively prevent PEP.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Diclofenaco/administração & dosagem , Pancreatite/prevenção & controle , Doença Aguda , Administração Retal , Adulto , Colangiopancreatografia Retrógrada Endoscópica/métodos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/etiologia , Estudos Prospectivos , Resultado do Tratamento
5.
Artigo em Russo | MEDLINE | ID: mdl-31626158

RESUMO

Osteoarthritis (OA) is a serious sociomedical problem, one of the leading causes of persistent disability and reduced quality of life. Modern publications on the use of transdermal drug formulations for OA evaluate the efficiency and safety of isolated drug administration. Pulse magnetotherapy is a modern method for potentiating the therapeutic effects of both the drug and the magnetic field (MF) in the single magnetophoretic technique. AIM: to determine the effect of pulsed MF on the clinical efficacy and tolerability of magnetophoretic transdermal diclofenac delivery in patients with gonarthrosis. SUBJECTS AND METHODS: A clinical randomized placebo-controlled study was conducted in 65 patients with Kellgren-Lawrence grade 2-3 knee OA, who were divided into 3 groups. Group 1 including 25 patients received magnetophoretic diclofenac gel delivery using a traveling MF (intensity, 20 mT; frequency, 6.25 Hz; exposure. 20 min, 12 sessions); Group 2 consisting of 20 patients used placebo magnetotherapy with diclofenac without MF; Group 3 comprising 20 patients had low-frequency pulse magnetotherapy with traveling MF without topical diclofenac therapy. VAS and WOMAC and the EQ-5D questionnaire were used during the examination. The results of treatment were analyzed according to the OMERACT-OARSI criterion. RESULTS: According to VAS and WOMAC scores, combination therapy showed a marked analgesic effect in the patients who had received magnetotherapy (p<0.01), as well as a significant reduction in stiffness and an improvement in functional characteristics, which were more pronounced in those who had magnetophoresis (p<0.001). According to the EQ-5D questionnaire, magnetotherapy was noted to have a positive impact on quality-of-life indicators. Analysis according the OMERACT-OARSI criterion demonstrated a high rate (67.8%) of response to magnetophoretic sis using diclofenac application formulations. CONCLUSION: Magnetophoretic transdermal diclofenac delivery using low-frequency pulsed MF is effective and safe for patients with knee OA and causes no serious adverse events.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fenômenos Magnéticos , Osteoartrite do Joelho/tratamento farmacológico , Administração Cutânea , Humanos , Qualidade de Vida , Resultado do Tratamento
6.
Pol J Vet Sci ; 22(2): 423-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31269359

RESUMO

The pharmacokinetics of a diclofenac sodium was investigated in swine. A single intravenous (i.v.) or intramuscular (i.m.) injection of 5% diclofenac sodium (concentration = 2.5 mg · kg-1) was administered to 8 healthy pigs according to a two-period crossover design. The pharmacokinetic parameters were calculated by non-compartmental analysis with DAS2.1.1 software. After a single i.v. administration, the main pharmacokinetic parameters of diclofenac sodium injection in swine were as follows: the elimination half-time (T1/2ß) was 1.32±0.34 h; the area under the curve (AUC) was (55.50±5.50 µg · mL-1 h; the mean residence time (MRT) was 1.60±0.28 h; the apparent volume of distribution (Vd) was 0.50±0.05 L · kg-1; and the body clearance (CLB) was 0.26±0.04 L · (h · kg)-1. After the single i.m. administration, the pharmacokinetic parameters were as follows: peak time (Tmax) was 1.19±0.26 h; and peak concentration (Cmax) was 11.61±5.99 µg mL-1. The diclofenac sodium has the following pharmacokinetic characteristics in swine: rapid absorption and elimination; high peak concentration; and bioavailability.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/farmacocinética , Suínos/sangue , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Diclofenaco/administração & dosagem , Diclofenaco/sangue , Feminino , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas , Masculino , Distribuição Aleatória
7.
Inflammopharmacology ; 27(5): 903-910, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359235

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammatory conditions such as arthritis. However, both arthritis and many NSAIDs increase cardiovascular (CV) risks. The dose-dependency of the elevated CV risks of NSAIDs has not been well-studied. We tested the hypothesis that low but still effective doses of these drugs are void of CV side effects. As the model drug, we chose diclofenac because of its known high CV toxicity, as markers of CV risks, we assessed concentrations of cytochrome P450-mediated metabolites of arachidonic acid (ArA), and we used adjuvant arthritis as an experimental model of arthritis. Following 7 daily doses (2.5-15 mg/kg), the effective dosage range of diclofenac was identified (> 5 mg/kg/day). While 7 consecutive days of low therapeutic doses did not alter the CYP-mediated ArA metabolism, the highest dose of 15 mg/kg/day caused imbalances in ArA metabolic profiles toward cardiotoxicity by increasing the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids. This is suggestive of dose-dependency of NSAID cardiotoxicity, and that low therapeutic doses may be void of CV side effects. Human studies are needed to examine the safety of low but effective doses of NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite Experimental/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Animais , Ácido Araquidônico/metabolismo , Artrite Experimental/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Risco
8.
Int J Pharm ; 569: 118531, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31323372

RESUMO

Novel emulsions with a nanostructured continuous phase have been proposed as controlled drug delivery systems to enhance topical delivery of active ingredients avoiding systemic effects. In this study, oil-in-water (O/W) emulsions with two surfactant/water (S/W) weight ratios of 40:60 and 35:65, and oil concentrations of 10 wt% (diluted emulsion), 40 wt% (concentrated emulsion) and 85 wt% (highly concentrated emulsion) have been investigated to identify the presence of liquid crystalline structures and their influence on drug release and skin permeation. The emulsions have been characterized in terms of visual appearance, rheology and drug release. The presence of cubic liquid crystalline structures in emulsions with S/W 40:60 was confirmed by small angle X-ray scattering (SAXS). Rheology results showed a markedly different behaviour in emulsions with S/W 40:60 compared with nonstructured emulsions. A model drug, diclofenac sodium (DS) was successfully incorporated in the emulsions. DS release was studied with hydrophilic and lipophilic membranes, and the amount of DS in the receptor solution was significantly lower in the formulations containing cubic liquid structures. An in vitro skin permeation study with dermatomed human skin showed that emulsions with a nanostructured continuous phase are suitable formulations for topical delivery with DS retention in skin layers. The results indicate that the amount of drug retained in skin structures may be tuned by modification of liquid crystal concentration and emulsion structure.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Cristais Líquidos , Absorção Cutânea , Administração Cutânea , Anti-Inflamatórios não Esteroides/química , Diclofenaco/química , Liberação Controlada de Fármacos , Emulsões , Humanos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Pele/metabolismo , Triglicerídeos/administração & dosagem , Triglicerídeos/química
9.
Emerg Med J ; 36(7): 401-406, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31217178

RESUMO

OBJECTIVE: The current study aimed to ascertain differences in early postmedication pain reduction in participants presenting with acute musculoskeletal injuries (MSI) to the ED receiving intramuscular (IM) versus per oral (PO) diclofenac. METHODS: This was a prospective, double-blinded, randomised controlled trial conducted between January and June 2018 at the ED of Hamad General Hospital in Doha, Qatar. Adults (18-65 years of age) presenting to the ED within 24 hours of an acute MSI, who had a triage pain score measured using numerical rating scale of at least five or above were enrolled in this trial. Participants randomised to either IM (75 mg) with oral placebo, or oral (100 mg) diclofenac group with IM placebo using a computer-generated randomised concealed list in blocks of six and eight. The primary objective was to compare the proportion of IM versus PO participants attaining a 50% reduction in pain score at 30 min from t0. RESULTS: 300 participants were enrolled (150 in the IM diclofenac group and 150 in the PO diclofenac group) in the trial. The primary outcome was achieved in 99.3 (95% CI 96.3 to 100) in the IM group and 86.7 (95% CI 80.2 to 91.7) in PO group. There was an absolute risk difference of 12.7%. This corresponds to a number needed to treat of 8 cases (95% CI 6 to 14) receiving IM rather than the PO diclofenac in order to achieve one additional case of 50% pain reduction within 30 min of drug administration. There were no adverse events experienced in any treatment groups. CONCLUSION: IM diclofenac injection provides rapid analgesia over PO administration of diclofenac. However, given the preparation needed for an IM injection, oral administration may be preferable when and if clinical circumstances allow a choice in non-steroidal anti-inflammatory drug administration route.


Assuntos
Administração Oral , Diclofenaco/administração & dosagem , Injeções Intramusculares/métodos , Doenças Musculoesqueléticas/tratamento farmacológico , Dor Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Método Duplo-Cego , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/epidemiologia , Estudos Prospectivos , Catar/epidemiologia
10.
Biopharm Drug Dispos ; 40(7): 217-224, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31242332

RESUMO

PURPOSE: Topical nonsteroidal anti-inflammatory drug formulations are used commonly to treat musculoskeletal pain and inflammation. Drug properties and formulation composition are the primary determinants of the transdermal drug delivery rate. The ex vivo transdermal flux through human skin of three topical diclofenac formulations was compared. METHODS: The formulations tested were hydrogel 1% diclofenac sodium and two emulsion gels (1.16%/2.32% diclofenac diethylamine, equivalent to 1%/2% diclofenac sodium). Human abdominal skin obtained during unrelated surgical procedures was stored at -20 °C until use. Skin specimens were thawed, prepared and placed in Franz diffusion cells (stratum corneum facing donor cell). The test formulation (~200 mg) was applied to the donor cell skin surface, and the receptor compartment was periodically sampled over 48 hours. The drug concentration in the receptor medium was determined by a validated HPLC method. Raman spectral imaging was performed to visualize the location and distribution of diclofenac. RESULTS: After 5 hours, the cumulative amount of hydrogel diclofenac transiting the skin was about 10 times that of the emulsion gel 1.16% (P=0.0004) and about twice that of the emulsion gel 2.32% (P=0.022). Similar results were seen after 9 hours. Raman spectroscopy showed that the hydrogel formulation was a homogeneous mixture of its various components, including diclofenac. The emulsion gels were non-homogeneous, with diclofenac in close proximity to the lipophilic (paraffin) phase. CONCLUSIONS: The transdermal transit of diclofenac from the hydrogel demonstrated a faster onset and a greater absorption rate than either emulsion gel formulation, suggesting that the hydrogel formulation may have a faster onset of action in underlying tissues vs. the emulsion gel products.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Hidrogéis/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , Permeabilidade/efeitos dos fármacos , Pele/metabolismo
11.
Int J Pharm ; 566: 445-453, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31170479

RESUMO

There is a need for bio-predictive and well-characterized in vitro release models in the development of intra-articular depot formulations. Here, the commercially-available Scissor system, a membrane-based two-compartment release testing instrument, was applied to characterize the transport and release of the drug diclofenac employing conditions intended to mimic transport in the synovial joint. The fate of hyaluronic acid and human serum albumin, the main bio-relevant components incorporated in the system, was investigated. A promising strategy for providing sustained drug release upon intra-articular administration are lipid-based preformulations forming non-lamellar liquid crystalline phases in situ. The usefulness of the Scissor system for investigating the initial drug release from these delivery systems was evaluated. The diclofenac release rate upon injection of an aqueous solution was influenced by the composition of the injection site matrix, i.e. the hyaluronic acid content. Hyaluronic acid and human serum albumin were found to escape from the donor compartment into the acceptor medium through the employed polycarbonate membrane. Sustained diclofenac release was obtained by formation of highly viscous liquid crystalline phases upon injection of the lipid-based preformulations. The study shows the feasibility and potential of the Scissor system for testing initial release of intra-articular depot formulations of low-molecular-weight drug compounds.


Assuntos
Injeções Intra-Articulares , Modelos Biológicos , Transporte Biológico , Diclofenaco/administração & dosagem , Diclofenaco/química , Liberação Controlada de Fármacos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Albumina Sérica Humana/administração & dosagem , Albumina Sérica Humana/química
12.
Eur J Pharm Biopharm ; 141: 51-57, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108210

RESUMO

Topical administration of both antibiotic and non-steroidal anti-inflammatory drugs after cataract removal surgery is usually recommended to avoid infection and inflammatory process development. In this work, a HEMA/MMA based hydrogel was developed as a platform for simultaneous release of an antibiotic (moxifloxacin) and a non-steroidal anti-inflammatory drug (diclofenac). Initially, hydrogels with different HEMA/MMA compositions and cross-linking contents were produced and loaded separately with moxifloxacin and diclofenac. The in vitro release profiles of the drugs from the hydrogels were obtained and a mathematical model was employed to estimate the concentration in vivo induced by such systems. The most promising hydrogel was then sequentially loaded with diclofenac and moxifloxacin, and the same mathematical model was applied to the in vitro release results. The results suggest that the dual-drug loaded hydrogel could potentially release effective amounts of antibiotic and anti-inflammatory for three weeks. Nonetheless, adjustment of the concentration profiles can be achieved for example by tailoring of the loading conditions.


Assuntos
Hidrogéis/administração & dosagem , Hidrogéis/química , Administração Tópica , Antibacterianos/administração & dosagem , Antibacterianos/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Diclofenaco/administração & dosagem , Diclofenaco/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Lentes Intraoculares , Metacrilatos/química , Metilmetacrilato/química , Moxifloxacina/administração & dosagem , Moxifloxacina/química
13.
Drugs Aging ; 36(Suppl 1): 15-24, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31073921

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely recommended and prescribed to treat pain in osteoarthritis. While measured to have a moderate effect on pain in osteoarthritis, NSAIDs have been associated with wide-ranging adverse events affecting the gastrointestinal, cardiovascular, and renal systems. Gastrointestinal toxicity is found with all NSAIDs, which may be of particular concern when treating older patients with osteoarthritis, and gastric adverse events may be reduced by taking a concomitant gastroprotective agent, although intestinal adverse events are not ameliorated. Cardiovascular toxicity is associated with all NSAIDs to some extent and the degree of risk appears to be pharmacotherapy specific. An increased risk of acute myocardial infarction and heart failure is observed with all NSAIDs, while an elevated risk of hemorrhagic stroke appears to be restricted to the use of diclofenac and meloxicam. All NSAIDs have the potential to induce acute kidney injury, and patients with osteoarthritis with co-morbid conditions including hypertension, heart failure, and diabetes mellitus are at increased risk. Osteoarthritis is associated with excess mortality, which may be explained by reduced levels of physical activity owing to lower limb pain, presence of comorbid conditions, and the adverse effects of anti-osteoarthritis medications especially NSAIDs. This narrative review of recent literature identifies data on the safety of non-selective NSAIDs to better understand the risk:benefit of using NSAIDs to manage pain in osteoarthritis.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Artralgia/tratamento farmacológico , Diclofenaco/efeitos adversos , Meloxicam/efeitos adversos , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/administração & dosagem , Diclofenaco/uso terapêutico , Gastroenteropatias/induzido quimicamente , Humanos , Meloxicam/administração & dosagem , Meloxicam/uso terapêutico , Infarto do Miocárdio/induzido quimicamente , Risco
14.
Drugs Aging ; 36(Suppl 1): 45-64, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31073923

RESUMO

OBJECTIVE: We aimed to assess the safety of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with topical NSAIDs in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, vascular, cardiac, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue. RESULTS: The search strategy identified 1209 records, from which 25 papers were included in the qualitative synthesis and 19 were included in the meta-analysis, after exclusions. Overall, more total AEs (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.04-1.29; I2 = 0.0%) and more withdrawals due to AEs (OR 1.49, 95% CI 1.15-1.92; I2 = 0.0%) were observed with topical NSAIDs compared with placebo. The same results were achieved with topical diclofenac, largely driven by an increase in skin and subcutaneous tissue disorders (OR 1.73, 95% CI 0.96-3.10), although the difference was not statistically significant compared with placebo. No significant difference in the odds for gastrointestinal disorders was observed between topical NSAIDs and placebo (OR 0.96, 95% CI 0.73-1.27). CONCLUSIONS: Topical NSAIDs may be considered safe in the management of OA, especially with regard to low gastrointestinal toxicity. The use of topical NSAIDs in OA should be considered, taking into account their risk: benefit profile in comparison with other anti-OA treatments.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Osteoartrite/tratamento farmacológico , Administração Cutânea , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
Eur J Drug Metab Pharmacokinet ; 44(5): 681-689, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31077065

RESUMO

BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/efeitos adversos , Diclofenaco/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/efeitos adversos , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Diclofenaco/administração & dosagem , Feminino , Humanos , Injeções Intramusculares , Injeções Intravenosas/métodos , Pessoa de Meia-Idade , Adulto Jovem
16.
J Pharm Pharmacol ; 71(8): 1262-1270, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31131893

RESUMO

OBJECTIVES: We investigated changes of renal perfusion after topical and oral diclofenac administration in healthy volunteers using functional magnetic resonance imaging (MRI) with arterial spin labelling (ASL). METHODS: Twenty-four healthy human participants (21-51 years) underwent 1.5T MRI before and 1 h after a single oral dose of diclofenac (50 mg). Twelve of 24 participants underwent an additional MRI examination following 3-day topical diclofenac administration. For renal perfusion imaging, a flow-sensitive alternating inversion-recovery TrueFISP ASL sequence was applied. Plasma concentrations of diclofenac and serum concentrations of thromboxane were determined. KEY FINDINGS: After oral diclofenac application, large interindividual differences in plasma concentrations were observed (range <3-4604 nm). Topical diclofenac application did not result in relevant systemic diclofenac levels (range 5-75 nm). MRI showed a significant reduction of renal perfusion in individuals with diclofenac levels ≥225 nm (baseline: 347 ± 7 vs diclofenac: 323 ± 8 ml/min/100 g, P < 0.01); no significant differences were observed in participants with diclofenac levels <225 nm. Diclofenac levels correlated negatively with thromboxane B2 levels pointing towards target engagement. CONCLUSIONS: Single-dose diclofenac caused a decrease in renal perfusion in participants with diclofenac levels ≥225 nm. We demonstrated that even a single dose of diclofenac can impair renal perfusion, which could be detrimental in patients with underlying chronic kidney disease or acute kidney injury.


Assuntos
Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Rim/efeitos dos fármacos , Adulto , Artérias/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Nefropatias/induzido quimicamente , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Perfusão/métodos , Marcadores de Spin , Adulto Jovem
17.
Ter Arkh ; 91(1): 108-113, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090381

RESUMO

The review presents current information on the role of NSAIDs in the development of cardiovascular disasters. The development of non-desirable cardiovascular effects and an increase in cardiovascular risk with the administration of NSAIDs, most experts assess in terms of the antagonistic effect on the platelet-vascular homeostasis of metabolites of COX-thromboxane A2 and prostaglandin I2 (prostacyclin). All the presented reviews confirming an increase in the risk of MI complications in the administration of NSAIDs, indicate the class-specificity of this undesirable effect, not homogeneous for different representatives of the group. Important clinical aspects of prescribing NSAIDs for patients with low and moderate cardiovascular risk are the clinical features of the patient and the individual set of risk factors for CVD. Such pharmacokinetic characteristics of NSAIDs as a short half-life, a high degree of binding to blood plasma albumins are indicative of greater safety of NSAIDs, but the final decision must be made based on the accumulated data of clinical trials and meta-analyzes. Keywords: nonsteroidal anti-inflammatory drugs, cardiovascular diseases, cardiovascular risk, lornoxicam, diclofenac sodium, thrombo-elastogram, myocardial infarction, stroke.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Fatores de Risco
18.
Drug Deliv ; 26(1): 481-489, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30957571

RESUMO

OBJECTIVES: Ginsenosides Rb1 (Rb1) could form micelles in aqueous solutions. Self-assembled Rb1 micelles could potentially be utilized as ocular drug delivery system, and it was postulated that the encapsulation of a medicine within Rb1 micelles might strengthen the drug's therapeutic action and reduce side effects. METHODS: Diclofenac-loaded Rb1 micelles (Rb1-Dic micelles) were formulated, optimized, and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vivo corneal permeation, and in vivo anti-inflammatory efficacy. RESULTS: Rb1 self-assembled into micelles with ultra-small particle size (<8 nm) in a homogeneous distribution state (polydispersity index [PDI] < 0.3). Diclofenac was highly encapsulated into the micelles according to the weight ratios of Rb1 to diclofenac. The ophthalmic solution of Rb1-Dic micelle was simple to prepare. Rb1 had good cellular tolerance, and it also improved the cellular tolerance of the encapsulated diclofenac. Rb1-Dic micelles also showed non-irritants to the rabbit eyes. The use of Rb1 micelles significantly improved the in vivo corneal permeation as well as the anti-inflammatory efficacy of diclofenac when compared to commercial diclofenac eye drops. CONCLUSION: Rb1 micelle formulations have great potential as a novel ocular drug delivery system to improve the bioavailability of drugs such as diclofenac.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Córnea/metabolismo , Diclofenaco/administração & dosagem , Portadores de Fármacos/química , Ginsenosídeos/química , Nanopartículas/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Micelas , Soluções Oftálmicas , Tamanho da Partícula , Coelhos , Solubilidade
19.
Am J Gastroenterol ; 114(5): 813-821, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31008736

RESUMO

OBJECTIVES: The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that nonsteroidal anti-inflammatory drugs might be better analgesics because of their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, a nonsteroidal anti-inflammatory drug, for adequate analgesia in patients with AP. METHODS: In a double-blind randomized controlled trial, patients with AP were randomized to either intravenous diclofenac 75 mg or pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient-controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as the rescue analgesic, pain-free period, and numbers of effective and ineffective demands of fentanyl. Secondary outcome was adverse events. RESULTS: Fifty patients were randomized, 24 to the pentazocine group and 26 to the diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of the rescue analgesic (fentanyl) required (126 µg (interquartile range (IQR) 65-218 µg) vs 225.5 µg (IQR 133-427 µg); P = 0.028) and longer pain-free period (31.1 ± 8.2 vs 27.9 ± 6.6 hours, P = 0.047). The number of effective and ineffective demands was lower in the pentazocine group compared with the diclofenac group (11.5 (IQR 8-15) vs 16 (IQR 13-20), P = 0.098) although not statistically significant. Adverse events were similar between the groups. CONCLUSIONS: Pentazocine, a kappa-opioid receptor agonist, was significantly better than diclofenac for pain relief in AP (Trial registration number: CTRI/2016/09/007326).


Assuntos
Diclofenaco , Fentanila , Pancreatite , Pentazocina , Receptores Opioides kappa/agonistas , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Medição da Dor/métodos , Pancreatite/diagnóstico , Pancreatite/tratamento farmacológico , Pancreatite/fisiopatologia , Pentazocina/administração & dosagem , Pentazocina/efeitos adversos , Resultado do Tratamento
20.
Int J Pharm ; 563: 395-405, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30978486

RESUMO

Fast dissolution of nonsteroidal anti-inflammatory drugs (NSAIDs) is a prerequisite from patient perspective. However, most NSAIDs are slowly dissolving acidic compounds. Caffeine, a commonly used analgesic adjuvant with NSAIDs showed high potential as eutectic co-former for acidic compounds. The study investigated eutectic forming potential of caffeine with meloxicam, aceclofenac and flurbiprofen. Each drug was co-ground with caffeine in various ratios and the products were characterized by thermal analysis to determine the optimum eutectic composition from phase diagram and Tamman's triangle. The optimum systems were subjected to X-ray powder diffraction (XRPD), Fourier-transform infrared (FTIR) and dissolution studies. Co-ground systems at dose ratio were also assessed for drug dissolution and anti-inflammatory effect using carrageenan induced rat paw edema method. Eutexia was confirmed by thermal analysis with the optimum composition being 1:1, 1:1 and 1:2 (NSAID: caffeine) for aceclofenac, flurbiprofen and meloxicam, respectively. Eutexia did not alter FTIR spectra with minor changes being recorded in XRPD patterns. The eutectic systems underwent fast liberation of drugs with fast dissolution being retained even at dose ratios. Dissolution enhancement was associated with enhanced anti-inflammatory response. The study introduced caffeine as eutectic forming analgesic for fixed dose combination with NSAIDs to enhance drug dissolution and anti-inflammatory effect.


Assuntos
Analgésicos , Anti-Inflamatórios não Esteroides , Cafeína , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Cafeína/administração & dosagem , Cafeína/química , Carragenina , Diclofenaco/administração & dosagem , Diclofenaco/análogos & derivados , Diclofenaco/química , Liberação Controlada de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Flurbiprofeno/administração & dosagem , Flurbiprofeno/química , Masculino , Meloxicam/administração & dosagem , Meloxicam/química , Difração de Pó , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura de Transição , Difração de Raios X
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