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The main aim of the paper was to simulate the drug release by a multifractal theoretical model, as a valuable method to assess the drug release mechanism. To do this, drug delivery films were prepared by mixing poly(vinyl alcohol boric acid) (PVAB) and diclofenac (DCF) sodium salt drug in different mass ratios from 90/10 to 70/30, in order to obtain drug delivery systems with different releasing rates. The different drug content of the three systems was confirmed by energy-dispersive spectroscopy (EDAX) analysis, and the encapsulation particularities were investigated by scanning electron microscopy (SEM), atomic force microscopy (AFM), and polarized optical microscopy (POM) techniques. The ability of the PVAB matrix to anchor the DCF was assessed by Fourier transform infrared (FTIR) spectroscopy. The in vitro release of the diclofenac sodium salt from the formulations was investigated in biomimetic conditions (pH = 7.4 and 37°C) by UV-Vis spectroscopy, measuring the absorbance of the drug at 275 nm and fitting the results on a previously drawn calibration curve. An estimation of the drug release kinetics was performed by fitting three traditional mathematical models on experimental release data. Further, the drug delivery was simulated by the fractal theory of motion, in which the release dynamics of the polymer-drug complex system is described through various Riccati-type "regimes." To explain such dynamics involved multifractal self-modulation in the form of period doubling, quasiperiodicity, intermittency, etc., as well as multifractal self-modulation of network type. Standard release dynamics were explained by multifractal behaviors of temporary kink type. The good correlation between the traditional mathematical models and the new proposed theoretical model demonstrated the validity of the multifractal model for the investigation of the drug release., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Daniela Ailincai et al.)

Background: Although arthroscopic rotator cuff repair (ARCR) often results in good outcomes, some patients have severe pain postoperatively. This study investigated the efficacy of nerve block for ARCR., Methods: This study was retrospective, and consent was obtained from all patients. We divided 50 patients who had undergone ARCR into 4 groups: continuous interscalene nerve block was performed for 11 patients (continuous-injection group), single interscalene nerve block for 10 (single-injection group), suprascapular nerve block for 8 (suprascapular group), and intravenous analgesic administration for 10 (intravenous group). Eleven patients received no nerve block (control group). We evaluated diclofenac sodium and pentazocine dosing, visual analog scale (VAS) scores, and perioperative complications in each group. VAS scoring was done immediately after surgery and 1 and 6 hours and 1, 2, 3, 7, and 14 days postoperatively., Results: The doses of diclofenac sodium and pentazocine did not differ between groups. VAS scores immediately after surgery and at 1 and 6 hours after surgery were significantly lower in the single-injection and continuous-injection groups than in the suprascapular, intravenous, and control groups. VAS score at 1 day postoperatively was significantly lower in the continuous-injection group than in the other groups. One patient in the continuous group reported temporary paralysis of the fingers and drug solution leakage., Conclusion: Interscalene nerve blocks yielded good pain relief for ARCR. Although continuous interscalene nerve block produced continuous pain relief, complications are a concern.

The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett-Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde's concentration had a statistically significant impact on microsphere's final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug's release for up to 30 days, governed by a Fickian diffusion release mechanism.

Competing Interests: Competing interests: None declared.

Background: The European Society of Gastrointestinal Endoscopy recommends rectal indomethacin or diclofenac before endoscopic retrograde cholangiopancreatography (ERCP) to prevent post-ERCP pancreatitis. However, data on the prophylactic effect in patients with primary sclerosing cholangitis (PSC) are lacking., Methods: This was a retrospective case-control study. In 2009-2018, a total of 2000 ERCPs were performed in 931 patients with PSC. Case procedures ( N  =   1000 after November 2013) were performed after administration of rectal diclofenac. Control procedures ( N  =   1000 before November 2013) were performed with the same indication but without diclofenac. Acute post-ERCP pancreatitis and other ERCP-related adverse events (AEs) were evaluated., Results: Post-ERCP pancreatitis developed in 49 (4.9%) procedures in the diclofenac group and 62 (6.2%) procedures in the control group ( p  =   0.241). No difference existed between the groups in terms of the severity of pancreatitis or any other acute AEs. The risk of pancreatitis was elevated in patients with native papilla: 11.4% in the diclofenac group and 8.7% in the control group ( p  =   0.294). In adjusted logistic regression, diclofenac did not reduce the risk of pancreatitis (odds ratio (OR) = 1.074, 95% confidence interval 0.708-1.629, p  =   0.737). However, in generalised estimation equations with the advanced model, diclofenac seemed to diminish the risk of pancreatitis (OR = 0.503) but not significantly ( p  =   0.110)., Conclusion: In this large patient cohort in a low-risk unit, diclofenac does not seem to reduce the risk of post-ERCP pancreatitis in patients with PSC. The trend in the pancreatitis rate after ERCP is decreasing. The evaluation of the benefits of diclofenac among PSC patients warrants a randomised controlled study targeted to high-risk patients and procedures.

Acanthamoeba keratitis is caused by a protozoal infection of the cornea, with 80% of cases involving the improper use of contact lenses. The infection causes intense pain and is potentially blinding. However, early diagnosis improves treatment efficacy and the chances of healing. Despite the apparent accessibility of the cornea, patients do not always respond well to current eye drop treatments largely due to rapid dose loss due to blinking and nasolacrimal drainage. Here, the topical drug delivery of voriconazole alone and in combination with diclofenac via drug-loaded contact lenses, were investigated in vitro. The contact lenses were applied onto excised porcine eyeballs and maintained at 32 °C under constant irrigation, with simulated tear fluid applied to mimic in vivo conditions. The drug delivered to the corneas was quantified by HPLC analysis. The system was further tested in terms of cytotoxicity and a scratch wound repopulation model, using resident cell types. Sustained drug delivery to the cornea was achieved and for voriconazole, the MIC against Acanthamoeba castellanii was attained alone and in combination with diclofenac. MTT and scratch wound data showed reasonable cell proliferation and wound repopulation at the drug doses used, supporting further development of the system to treat Acanthamoeba keratitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Various analgesic applications can be used during extracorporeal shock wave lithotripsy (SWL) for pain relief and maximal success rate. Intracutaneous sterile water injection (ISWI) has been shown to be effective in several types of pain, but a gap exists about its use during SWL. In this paper, we aimed to evaluate the effect of ISWI during SWL and compare that with diclofenac sodium injection used commonly to provide ideal patient contentment. Patients with kidney stone were randomized to have either ISWI therapy or intramuscular non-steroid anti-inflammatory drug (diclofenac sodium) injection. Using a syringe, 2-3 ml of sterile water was administered to the triangle area bounded by the 12th costal margin, the iliac crest and the vertebral spine in prone position. Visual analog scale (VAS) was employed to record pain scores of patients. Other parameters including stone size, SWL duration, total shock waves given, used energy and the necessity of rescue analgesia were also noted. A total of 524 patients were recruited, of those 216 patients were treated with ISWI and 308 patients had diclofenac sodium injections. The characteristics of the patients and shockwave therapy did not differ significantly between the two groups. Although the mean VAS scores prior to SWL and at every voltage increment during the procedure did not differ, more patients in the diclofenac sodium injection group required rescue analgesia with significantly greater side effects. ISWI is found to be as effective as the diclofenac sodium injection for pain management during SWL with lower adverse event rates.

Aim: The objective was to systematically review the efficacy and safety of topical diclofenac in both acute and chronic musculoskeletal pain in adults. Methods: We used standard Cochrane methods. Searches were conducted in MEDLINE, EMBASE and The Cochrane Register of Studies; date of the final search was November 2018. Included studies were randomized, double blinded, with ten or more participants per treatment arm. The primary outcome of "clinical success" was defined as participant-reported reduction in pain of at least 50%. Details of adverse events (AEs) were recorded. Results: For acute pain, 23 studies (5170 participants) were included. Compared to placebo, number needed to treat (NNT) for different formulations were as follows: diclofenac plaster, 4.7 (95% CI 3.7-6.5); diclofenac plaster with heparin, 7.4 (95% CI 4.6-19); and diclofenac Emulgel, 1.8 (95% CI 1.5-2.1). 4.1% (78/1919) reported a local AE. For chronic pain, 21 studies (26 publications) with 5995 participants were included. Formulations included gel, solution with or without DMSO, emulsion and plaster. A clinical success rate of ∼60% (NNT 9.5 [95% CI 7-14.7]) was achieved with a variety of formulations. Local AEs (∼14%) were similar for both diclofenac and placebo. Conclusion: This systematic review of 11,000+ participants demonstrates that topical diclofenac is effective for acute pain, such as sprains, with minimal AEs. The effectiveness of topical diclofenac was also demonstrated in chronic musculoskeletal pain but with a higher NNT (worse) compared with acute pain. Formulation does play a part in effectiveness but needs further studies.

Objective: to compare the effect of administering diclofenac sodium and/or oral hyoscine in pain perception during and after outpatient diagnostic hysteroscopy without anesthesia., Study Design: a randomized, double-blind placebo-controlled clinical trial was performed in an University Hospital. We included 217 patients submitted to office hysteroscopy for the following indications: diagnosis of abnormal uterine bleeding, endometrial polyps, submucous myomas, infertility and recurrent miscarriage. Patients were allocated into 3 groups: (Group 1) placebo, (Group 2) diclofenac sodium 50 mg and (Group 3) diclofenac sodium 50 mg plus Hyoscine-N-Butylbromide 10 mg. The primary outcome was the visual analogue score immediately after the procedure. The secondary outcomes included Likert acceptance scale, the need for extra analgesia after the procedure, need to stay in the observation room and the occurrence of vagal symptoms., Results: Groups were similar according to age, color, age of menarche, gravity, c-section, abortion, presence of pelvic pain, presence of uterine scar, height and body mass index. Patients in all three groups demonstrated similar visual pain scores when submitted to office hysteroscopy (Group 1: 4.18 ± 3.1, Group 2: 4.68 ± 2.9, group 3: 4.45 ± 2.9, P = 0.59). Moreover, patients presented high acceptance scores of the procedure, similar between groups. We performed a subgroup analysis in patients in treatment for chronic pelvic pain and, in this subgroup, prior medication with diclofenac sodium isolated or associated with hyoscine were both effective in decreasing pain levels when compared to placebo (Group 1: 6.0 ± 1.9, Group 2: 3.6 ± 2.1, group 3: 4.2 ± 1.5, P = 0.04)., Conclusion(s): Office hysteroscopy is a well tolerated procedure and prior use of analgesic medication was not effective in decreasing pain. In selected patients with chronic pelvic pain the use prior analgesic medication may be beneficial., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined following a single intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 ± 0.3 years and 53.5 ± 5 kg of body weight) were used. A longitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the second and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxifloxacin was assayed by high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a two-compartment open pharmacokinetic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t 1/2β ), total body clearance (Cl T ), volume of distribution at steady state (V dss ) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h -1  kg -1 , 1.66 L/kg and 8.91 hr*µg/ml, respectively. While diclofenac and flunixin meglumine significantly increased the t 1/2β and AUC of moxifloxacin, they significantly reduced the Cl T and V dss . These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics., (© 2020 John Wiley & Sons Ltd.)

Background: Diclofenac potassium for oral solution (CAMBIA®) may be an alternative for patients who would otherwise need to be seen in a healthcare setting for parenteral ketorolac. CAMBIA® is FDA-approved for the abortive treatment of migraine and has demonstrated superiority over generic diclofenac tablets with rapid migraine reduction. This study assessed for efficacy of CAMBIA® as an alternative outpatient treatment for refractory migraine to parenteral ketorolac., Methods: We performed an exploratory, single-center, double-blind, double-dummy randomized controlled trial comparing CAMBIA® with IM ketorolac. Participants were randomized to receive either ketorolac 60 mg IM with dummy oral solution or CAMBIA® 50 mg, together with IM injection of normal saline. The primary endpoint was headache severity, self-rated on a scale 0-3. Secondary endpoints included self-rated nausea, disability, and photo- or phonophobia, as well as presence of side effects and need for additional rescue therapy., Results: A total of 23 patients were enrolled. Ten patients received the study drug and 13 patients received IM ketorolac as the control. There were no major differences observed with respect to the primary outcome of mean headache severity at successive time points over a 24-h follow-up period. No major differences were found with respect to average disability, nausea, and photo- or phonophobia ratings. No major adverse events were reported., Conclusion: In treatment of refractory migraine headache, CAMBIA® may provide similar benefits as IM ketorolac without increasing the risk of treatment failure, major bleeding, or cardiovascular events. However, larger studies are needed to confirm this finding., Trial Registration: Clinicaltrials.gov: NCT # 02664116, Titled "IM Ketorolac vs Diclofenac Potassium Powder for Oral Solution (CAMBIA®) for the Acute Treatment of Severe Migraine". Registered 26 January 2016, https://clinicaltrials.gov/ct2/show/NCT02664116?term=02664116&rank=1.

Supraspinal mechanisms of non-steroidal anti-inflammatory drug (NSAID)-induced antinociception are not well understood. In the present study, the possible antinociceptive mechanisms induced by intra-medial prefrontal cortex (intra-mPFC) microinjection of diclofenac were investigated after blockade of GPR55, cannabinoid CB1, and mu-opioid receptors in this area and ventrolateral periaqueductal gray (vlPAG). For drug delivery, unilateral (left side) of mPFC and bilateral (right and left sides) of vlPAG were surgically cannulated. Formalin test was induced by subcutaneous injection of a diluted formalin solution into the right vibrissa pad. A typical biphasic (neurogenic and inflammatory phases) pain behavior was produced following formalin injection. Microinjection of diclofenac (2.5, 5, and 10 μg/0.25 μL) into the mPFC suppressed both phases of pain. Intra-mPFC microinjection of naloxonazine (a mu-opioid receptor antagonist, 1 μg/0.25 μL) and AM251 (a cannabinoid CB1 receptor antagonist, 1 μg/0.25 μL) increased both phases of pain intensity. In addition, intra-mPFC-microinjected diclofenac-induced antinociception was inhibited by prior intra-mPFC and intra-vlPAG administration of naloxonazine and AM251. On the other hand, intra-mPFC and intra-vlPAG microinjection of AM251 (0.25 μg/0.25 μL) decreased pain severity which was inhibited by prior administration of ML193. The above-mentioned drugs did not alter locomotor activity. In conclusion, diclofenac suppressed both the neurogenic and inflammatory phases of formalin-induced orofacial pain at the level of mPFC. GPR55, cannabinoid CB1, and mu-opioid receptors of the mPFC and vlPAG might be involved in the mPFC analgesic effects of diclofenac.

The non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen and diclofenac are highly prescribed worldwide and their presence in aquatic system may pose a potential risk to aquatic organisms. Here, we systematically assessed their cardiovascular disruptive effects in zebrafish (Danio rerio) at environmentally relevant concentrations between 0.04 and 25.0 μg/L. Ibuprofen significantly increased the cardiac outputs of zebrafish embryos at actual concentrations of 0.91, 4.3 and 21.9 μg/L. It up-regulated the blood cell velocity, total blood flow and down-regulated the blood cell density at concentrations of 4.3 μg/L and higher. In comparison, diclofenac led to inhibition of spontaneous muscle contractions and decreased hatching rate of zebrafish embryos at the highest concentration (24.1 μg/L), while it had negligible effects on the cardiac physiology and hemodynamics. Transcriptional analysis of biomarker genes involved in cardiovascular physiology, such as the significantly up-regulated nppa and nkx2.5 expressions response to ibuprofen but not to diclofenac, is consistent with these observations. In addition, both ibuprofen and diclofenac altered the morphology of intersegmental vessels at high concentrations. Our results revealed unexpected cardiovascular functional alterations of NSAIDs to fish at environmental or slightly higher than surface water concentrations and thus provided novel insights into the understanding of their potential environmental risks., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2019. Published by Elsevier Ltd.)

This work reports on the preparation and systematic testing of a novel multi-layered coating, comprised of the non-steroid anti-inflammatory drug diclofenac and biopolymer carboxymethyl cellulose. Drug release testing was performed on an Automated Transdermal Diffusion Cells Sampling System in combination with UV-VIS spectroscopy as the released drug concentration determination method. The results showed that most of the drug is released in the first six hours, whereas the overall released amount could be tailored through changes in the multi-layered coating composition. Biocompatibility tests performed on human osteoblast cells, showed cell viability improvement between 7% and 17% compared to the control sample. The expression of proteins playing important roles in extracellular matrix production and functioning was performed in order to obtain additional proof of the prepared materials' osteointegration boosting capacity. Finally, electrochemical measurements confirmed that the coatings do not influence the corrosion susceptibility of AISI 316LVM stainless steel., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

m-Trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF 3 -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-CF 3 -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-CF 3 -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-CF 3 -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-1β and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF 3 -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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The paper deals with the design and investigation of the morphology, in vitro drug release and biocompatibility of some new formulations based on polyvinyl alcohol boric acid (PVAB) and diclofenac sodium salt (DCF), with the aim to explore the ability of PVAB to act as a matrix for controlled drug delivery systems. A series of three formulations was obtained by mixing the drug and the polymeric matrix in different mass ratios, with high drug content from 10% w/w to 30% w/w. Their structural and supramolecular characterization, performed by FTIR spectroscopy and X-ray diffraction, revealed important physical interactions between the drug and the polymeric matrix. The morphological data, obtained by X-ray diffraction, polarized optical microscopy and scanning electron microscopy revealed the presence of the drug into the PVAB polymeric matrix, as micrometric polycrystals with a mean diameter in the range 10-15 μm, depending on the drug/polymer ratio. The investigation of their surface peculiarities indicated highly hydrophilic surfaces with a water to air contact angle between 29.9 and 41.4 deg and a surface free energy of 45.6-54.2 N/m 2 . The in vitro release kinetics was monitored by UV-VIS spectroscopy and the cytotoxic effect was investigated in vitro on fibroblasts and HeLa cells. The PVAB proved excellent cytocompatibility, a relative cell viability of the fibroblasts higher than 90% being recorded for concentrations of PVAB up to 7.5% w/v. The drug has been strongly anchored into the electron deficient PVAB matrix, fact which led to its prolonged release up to 5 days. These findings recommend PVAB as a versatile tool for the development of sustained release drug delivery systems with real chances to cross the gap from theory to applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs., Competing Interests: The authors declare no conflict of interest.

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE 2 ) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE 2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log 10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is characterized by degenerative knees, fingers and hip joints. In OA joints, the concentration and polymerization of hyaluronic acid (HA) are changed; affecting the viscosity of the synovial fluid. Replenishing HA synovial fluid content, along with an anti-inflammatory drug could be a cost-effective strategy. As free drugs are rapidly cleared out of the synovial fluid, we aimed to prepare Hyalomer in situ forming gel for intra-articular (IA) injection. Hyalomer contains poloxamer 407 (PX) as thermogelling agent, HA, and diclofenac potassium (DK) as an anti-inflammatory. Hyalomer formulations were prepared and characterized in terms of sol-gel transition, gelation time, in vitro release and 3-month stability. The selected Hyalomer formula was injected IA in OA rat model, in comparison to its individual components. The optimized Hyalomer formulation showed 25% DK release after 24 h and 40% after 4 days. The gelation time was 40 ± 2.08 s and gelation temperature was 26 ± 1.87 °C. Hyalomer maintained the percentage drug release and DK content after 3-months storage. In OA rats, Hyalomer showed the highest anti-nociceptive and anti-edematous effect. Both radiography and histopathology revealed regenerated cartilage profile in Hyalomer-treated group. combining IA HA and diclofenac in thermoresponsive gel represents a promising therapeutic alternative for OA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Endoscopic retrograde pancreatography (ERCP) is sometimes complicated by post-ERCP pancreatitis (PEP), which is a severe adverse effect., Objective: The present study was performed to (i) evaluate the risk factors for PEP and (ii) compare the risk of PEP after ERCP performed in the off hours versus regular hours., Methods: This retrospective study included 374 patients who underwent ERCP from January 2013 to December 2017. Among these patients, 38 (10.2%) developed PEP. The potential risk factors for PEP were evaluated by multivariate regression analysis, and the risk of PEP was compared between ERCP performed during regular hours and off hours., Results: The independent risk factors for PEP were a relatively younger age (<75 years; p = 0.024), female sex (p = 0.002), a history of pancreatitis (p = 0.044), and performance of pancreatography (p = 0.010). Use of a diclofenac suppository and performance of pancreatic stenting were not preventive for PEP after ERCP. The complication rate of PEP did not differ between ERCP performed during the off hours versus regular hours., Conclusions: A relatively younger age (<75 years), female sex, a history of pancreatitis, and performance of pancreatography were potential risk factors for PEP, whereas the risk of PEP was not different between ERCP performed during the off hours versus regular hours., (© 2019 S. Karger AG, Basel.)

Owing to intrinsic and acquired chemoresistance, the response of gastric adenocarcinoma (GAC) to chemotherapy is very poor. Here we have investigated the role of transportome in reducing the intracellular content of anticancer drugs and conferring multidrug resistance (MDR) phenotype. Tumors specimens and paired adjacent tissue were analyzed to determine the MDR signature by TaqMan Low-Density Arrays and single-gene qPCR. Strategies of sensitization were evaluated in vitro using the GAC-derived cell line AGS and in vivo using a subcutaneous xenograft model in immunodeficient nude mice. Several transporters involved in drug uptake and export, which are present in healthy stomach, were highly expressed in GAC. In contrast, the cancer-type OATP1B3 was almost exclusively expressed in tumor tissue. The transportome profile varied depending on tumor anatomical location, differentiation, and stage. Immunofluorescence analysis revealed high MRP1 and MRP4 expression at the plasma membrane of tumor cells as well as AGS cells in culture, in which MRP inhibition resulted in selective sensitization to cytotoxic MRP substrates, such as sorafenib, docetaxel, etoposide, and doxorubicin. In mice with subcutaneous tumors formed by AGS cells, sorafenib alone failed to prevent tumor growth. In contrast, this drug induced a marked inhibitory effect when it was co-administered with diclofenac. In conclusion, MRP1 and MRP4 play an important role in the lack of response of GAC to drugs that are transported by these export pumps. Moreover, agents, such as sorafenib, considered at present useless to treat GAC, may become active antitumor drugs when co-administered with non-toxic MRP inhibitors, such as diclofenac., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine the effects of preoperative anxiety on the postoperative pain and analgesic consumption in patients undergoing cesarean deliveries (CDs). Materials and methods: This observational cohort study included 160 women, with ages ranging from 18 to 40 years old and a 37-week minimum gestation, received general (Group 1, n  = 80) or spinal (Group 2, n  = 80) anesthesia during an elective CD. The State Anxiety Inventory (SAI), Trait Anxiety Inventory (TAI), and Somatosensory Amplification Scale (SSAS) were used to measure the prenatal anxiety. The postoperative pain intensity was evaluated using the Visual Analogue Scale (VAS), and the pain and analgesic requirements were recorded at the 1st, 6th, 12th, 18th, and 24th postoperative hours. Results: No statistically significant differences were found between the groups in the demographics, clinical characteristics, or laboratory parameters. In addition, there were no differences with regard to the mean SAI, TAI, and SSAS scores and the diclofenac and pethidine consumptions ( p  > .05). The 1st hour [4.15 ± 1.84 versus 3.28 ± 2.41, odds ratio (OR) = 0.832, 95% confidence interval (CI) = 0.725-0.956, p  = .009], 6th hour (3.85 ± 2.02 versus 3.13 ± 1.51, OR = 0.793, 95% CI = 0.668-0.942, p  = .008), and 12th hour (3.64 ± 2.11 versus 2.94 ± 2.03, OR = 0.851, 95% CI = 0.737-0.983, p  = .028) VAS scores were lower in Group 2 than in Group 1. No correlations were noted between the SAI, TAI, and SSAS scores and the VAS. Conclusions: While the patients with preoperative SAI scores >45 and who underwent cesarean deliveries (CDs) with general anesthesia had higher pain intensity scores in the first 12 hours than those underwent CDs with the spinal anesthesia, no difference was observed between the groups in terms of the postoperative analgesic requirements. Evaluating the patient's anxiety state and psychiatric evaluation may be useful for decreasing the postoperative pain intensity. Further studies are needed to corroborate our findings.

Osteoarthritis is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have reported that the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), exerted a potent and long-lasting analgesic effect in experimental arthritis models. In this study, we evaluated the properties of residual SI-613 in the knee joint after an intra-articular (IA) administration. After IA administration of fluorescent labeled SI-613 (FA-SI-613) or fluorescent labeled hyaluronic acid (FA-HA) to rabbits, fluorescence intensities in the synovial membrane and cartilage were higher in the FA-SI-613 group until 7 d after administration than in the FA-HA group. After IA administration of radiolabeled SI-613 ( 14 C-SI-613) to rabbits, the radioactivity remained in the joint cavity and the joint tissues such as synovial membrane and cartilage until 84 d after administration. This residual radioactivity was identified mainly as HA linked with DF, since 14 C-SI-613 was labeled at the benzene ring of DF and since more DF-linked HA oligomer was detected on metabolite analysis than free DF in the synovial membrane and synovial lavage fluid up to 28 d after administration. These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological effects of both HA and DF by remaining in the joint as HA linked with DF.

Background: Diclofenac and curcumin is anticipated to have synergistic action. Hence, topical route of administration can be used in minimizing the issues with oral administration of both drugs., Objective: This research aims at formulation of controlled release dosage form containing curcumin microspheres and diclofenac diethylamine and then incorporating it into gel formulation for treatment of inflammation associated with rheumatoid arthritis., Methods: Curcumin microspheres were prepared, optimized and assayed. Gel containing microspheres was formulated and evaluated for physicochemical parameters like spreadability and viscosity. In vitro and ex vivo diffusion studies were carried out followed by evaluation of efficacy. Efficacy of the developed formulation was evaluated for anti-inflammatory activity., Results: Particle size, Zeta potential, pH, spreadability and viscosity of optimized Batch F1 was found to be in range 0.5 µm - 5 µm,-27.9 mV, 6.2, 105 g cm/s and 7500 cps respectively. In vitro diffusion of developed gel of diclofenac diethylamine and curcumin was found to be 92.16 ± 0.0040 % in 3 h and 92.54 ± 0.0036 % in 12 h as compared to 79.57 ± 0.004 % diffusion in 2 h for marketed gel, thus showing controlled delivery of curcumin., Conclusion: Decreased inflammation in formulation treated group by 72.53% and 50.75% in marketed treated group was seen. Thus the formulation developed showed prolonged activity as well as better anti-inflammatory activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To evaluate effects of topical ophthalmic administration of diclofenac on intraocular pressure (IOP) when applied at 4 frequencies to eyes of Beagles., Animals: 8 ophthalmologically normal Beagles., Procedures: The study involved four 5-day experimental periods each separated by a 16-day washout period. During each period, 1 drop of 0.1% diclofenac sodium ophthalmic solution was administered to the right eye at 4 treatment frequencies (1, 2, 3, or 4 times/d); 1 drop of eyewash was administered to the left eye as a control treatment. A complete ophthalmic examination was performed on days 0 (day before first treatment) and 5 of each experimental period. Gonioscopy was performed on day 0 of the first period. The IOPs were measured at 7 am and 7 pm on days 1 through 5., Results: No abnormalities were detected during neuro-ophthalmic and ophthalmic examinations on day 0 of each experimental period. No adverse reactions to administration of diclofenac or eyewash were observed at any time point. No abnormalities were detected during ophthalmic examinations performed on day 5, and IOPs remained < 25 mm Hg in all 4 periods. No significant differences were identified between the treated and control eyes or among the 4 treatment frequencies., Conclusions and Clinical Relevance: Topical ophthalmic administration of diclofenac up to 4 times/d in dogs with no ophthalmic abnormalities did not significantly increase the IOP. Additional research is needed to evaluate the effect of topical ophthalmic administration of diclofenac on IOP in dogs with anterior uveitis.

Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference formulations of diclofenac diethylamine emulgels were evaluated. While the test formulation met the requirements for equivalence in both the in vivo bioequivalence and in vitro release study, the rheological properties were considered equivalent depending on the criteria used. The 90% confidence interval of the ratios between geometric mean values of both formulations were within the limits of 75-133%, but outside the 90-111% limit under discussion in the scientific community. Altogether these data indicate that differences beyond ±10% between rheological parameters of test and reference formulation might not translate into meaningful release nor bioavailability divergence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The co-administration of sciatic and femoral nerve blocks can provide anaesthesia and analgesia in patients undergoing lower extremity surgeries. Several approaches to achieve sciatic nerve block have been described, including anterior and posterior approaches., Methods: In total, 58 study patients were randomly assigned to receive either anterior (group A, n = 29) or posterior (group P, n = 29) sciatic nerve block. Thereafter, the following parameters were determined: sensory and motor block start and end times, time to first fentanyl requirement after blockade but before the start of the operation, time to first fentanyl requirement after the start of the operation, mean fentanyl dose administered after blockade but before the start of the operation, mean fentanyl dose after the start of the operation, time to first diclofenac sodium dose, and total dose of diclofenac sodium required. The trial was retrospectively registered on 11 July 2018., Results: The time to initiation of sensory block was significantly shorter in group P than in group A (7.70 ± 2.05 min and 12.88 ± 4.87 min, respectively; p = 0.01). Group P also had a significantly shorter time to first fentanyl requirement after block but before the start of the operation (00.00 ± 00.00 min for group P and 4.05 ± 7.47 min for group A; p < 0.01), significantly higher mean fentanyl dose per patient after block but before the start of the operation (44.03 ± 23.78 μg for group P and 31.20 ± 27.79 μg for group A), significantly longer time to first fentanyl requirement after the start of the operation (16.24 ± 7.13 min for group P and 00.00 ± 00.00 min for group A; p = 0.01), and significantly lower mean fentanyl dose per patient after the start of the operation (11.51 ± 2.87 μg for group P and 147.75 ± 22.30 μg for group A). Patient satisfaction (p < 0.01), anaesthesia quality (p = 0.006), and surgical quality (p = 0.047) were significantly higher in group P., Conclusions: Anterior and posterior approaches can be used to achieve sciatic nerve block in patients undergoing surgery for malleolar fractures. However, better anaesthesia and pain control results can be obtained if analgesia is administered preoperatively in patients with a posterior approach block and after the start of the operation in patients with an anterior approach block.

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.

Objective: To evaluate and compare regulation of diabetes mellitus (DM) in dogs with cataracts and well-controlled DM that received an ophthalmic preparation of prednisolone acetate versus diclofenac sodium., Animals: 22 client-owned dogs with cataracts and well-controlled DM., Procedures: A prospective, randomized, double-masked, experimental study was conducted. On days 0 and 32, serum fructosamine concentrations (SFCs), clinical scores, and body weights were determined. Dogs were assigned to receive a topically administered ophthalmic preparation of either prednisolone acetate 1% or diclofenac sodium 0.1% in each eye 4 times daily for 28 days. Data analysis was conducted with generalized linear mixed models., Results: Findings indicated no meaningful differences in SFCs, clinical scores, or body weights between the treatment groups on days 0 or 32. Clinical score on day 0 was positively associated with SFC, as indicated by the corresponding rate of change such that each 1 -unit increase in clinical score was associated with an approximately 45.6 ± 9.4 μmol/L increase in SFC. In addition, the least squares mean ± SEM SFC was higher in spayed females (539.20 ± 19.23 μmol/L; n = 12) than in castrated males (458.83 ± 23.70 μmol/L; 8) but did not substantially differ between sexually intact males (446.27 ± 49.72 μmol/L; 2) and spayed females or castrated males regardless of the treatment group assigned., Conclusions and Clinical Relevance: Findings indicated no evidence for any differential effect on DM regulation (assessed on the basis of SFCs, clinical scores, and body weights) in dogs treated topically with an ophthalmic preparation of prednisolone versus an ophthalmic preparation of diclofenac. Additional research investigating plasma concentrations of topically applied ophthalmic glucocorticoid medications is warranted. (Am J Vet Res 2019;80:1129-1135).

The aim of the current investigation is to delineate the buccal applicability of an in situ composite gel containing aceclofenac (AC) amino methacrylate copolymer microparticles (MPs), surmounting limitations of oral existing conventional therapy. AC Eudragit RL100 MPs were fabricated and statistically optimized using 2 2 4 1 factorial design. Better buccal applicability and enhanced localization were achieved by combining the optimum MPs with in situ ion-activated gellan gum gel. The crosslinking and gelation of in situ gel were investigated by morphological and solid state characterizations. Suitability for buccal delivery and in vivo therapeutic efficacy in inflammation model of rats were also assessed. Results showed that the best performing formula displayed particle size (PS) of 51.00 µm and high entrapment efficiency (EE%) of 94.73%. MPs were successfully entrapped inside the gel network of the composite system. Gelation tendency, pH, shear-thinning properties and mucoadhesivity of the prepared in situ composite gel guaranteed its buccal suitability. Sustained AC release features and promising in vitro anti-arthritic response were also demonstrated. Moreover, consistent and prolonged in vivo anti-inflammatory effect was achieved, relative to standard AC. Taken together; this study proves the potential of in situ composite gel as an appropriate therapeutic proposal for AC buccal delivery.

Currently a variety of tools and techniques are used to deliver complex medicines. Whereas, certain advanced methods assure the safety and usefulness by regulating the pharmacokinetic and pharmacodynamic. Thus, we aimed this study to develop a novel gastro retentive floating tablets. The formulation was designed to provide the desired controlled and complete release of drug for prolonged period of time. The formulations were evaluated for physical characterization. The obtained results of hardness (4.6-5.1), friability (0.20-0.43%), weight variation (350 ±2 - 350±5) and in vitro buoyancy were found within official limits of United Stated Pharmacopoeia (USP). Whereas, the F-7 showed most optimized intra gastric floating characteristics and exhibited 93.87% release of diclofenac sodium in 9 hours. The Floating Lag Time of 8 minutes and Total Floating Time >12 hours were recorded. In-vitro drug release kinetics evaluated using the linear regression method was found to follow the Zero Order and Peppas model for the release of both the drugs. DSC thermograph and FTIR spectra depicted that there was no chemical incompatibility between drugs and polymers. In conclusion the desgined tablet can be use in clinical practice as model drug. Because, the pre-compression and post-compression parameters were satisfactory and within desired limits.

Diclofenac is one of the world's largest selling nonsteroidal anti-inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti-inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti-inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in-situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4-hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE 2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting., (© 2019 Wiley Periodicals, Inc.)

Adlay ( Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Postoperative pain control is a significant aspect of patient treatment after an oral and maxillofacial surgical procedure. The use of a transdermal patch is one such method to provide postoperative analgesia. The present study was undertaken to investigate the efficacy of a single-dose transdermal patch of ketoprofen compared with that of diclofenac postoperatively after therapeutic extraction of first premolar teeth for patients undergoing orthodontic treatment., Patients and Methods: A split mouth randomized clinical trial was conducted of 40 patients aged 15 to 25 years who had required therapeutic extraction of both maxillary and mandibular first premolar teeth bilaterally. A single ketoprofen patch was applied for the first and fourth quadrant extraction, and diclofenac patch was applied for the second and third quadrant extraction after atraumatic therapeutic exodontia at 2 consecutive appointments with the patient under local anesthesia. The data were obtained and analyzed using the Student t test and Shapiro-Wilk test using SPSS software (IBM Corp, Armonk, NY)., Results: All 40 patients who had received a single-dose ketoprofen patch had experienced less postoperative pain and did not require a rescue analgesic with a mean visual analog scale (VAS) score of 1.13 ± 0.335 (P < .00001). The patients who had received a diclofenac patch reported comparatively elevated pain scores in the initial 24 hours, with a mean VAS score of 2.0 ± 0.5064 postoperatively, and 20% of the diclofenac treatment arm had required a rescue analgesic. No complications were observed among the patients postoperatively in either treatment arm., Conclusions: Both the ketoprofen and diclofenac transdermal patches were effective in achieving postoperative analgesia in patients after therapeutic extraction, with ketoprofen superior to diclofenac as a transdermal medicament., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-β-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 (AUC 0-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 (AUC 0-∞ ). The maximum observed plasma concentration (C max ) 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.

Therapeutic contact lenses were developed from bacterial cellulose (BC) by the Institute of Chemistry at Brazil's São Paulo State University (UNESP). In a previous study, cyclodextrins (CD) and medications such as ciprofloxacin (CP) and diclofenac sodium (DS) were incorporated into the lenses to provide therapeutic properties and control drug release. However, significant opacity was seen in the material inherent to cellulose. In order to achieve full material transparency, the lenses were coated with an organic-inorganic hybrid compound containing aluminum alkoxide and glycidoxypropyltrimethoxysilane (GPTS)(H), or chitosan (Q) nanoparticles. This study evaluated the toxicity of these contact lenses to ensure the safety of these materials for future availability to the medical device industry. Lenses composed of BC and coated with either GPTS (H) or chitosan (Q), incorporating ciclodextrin (CD) to release diclofenac sodium (DS) or ciprofloxacin (CP), were submitted to cytotoxicity assays (XTT and Clonogenic Survival), genotoxicity (Comet Assay) and mutagenicity (Cytokinesis-blocked micronucleus assay) directly in cell culture. Statistical analyses were performed using the Tukey and Dunnett or Kruskal-Wallis and Dunn tests. All of the nanoparticles used in the lense coatings did not show cytotoxic effects by the XTT test (p > 0.05; Dunnett). Only materials associated with diclofenac sodium (BC-H-CD-DS and BC-Q-CD-DS) presented significantly different survival fractions compared to negative control (p < 0.001; Dunnett). Genotoxicity evaluation revealed a genotoxic effect in BC-H-CD-DS (p < 0.05; Dunn). All tested lenses did not present any mutagenic effect. These results indicate that improvements in DS incorporation are needed to eliminate toxicity. We demonstrated promising results in the safety of employing BC lenses functionalized with a drug delivery system permitting the bioavailability of ophthalmic drugs. Further studies utilizing other specific tests, such as corneal lineage are required before safe and efficient ophthalmologic use., (Copyright © 2019 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

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.

Background: The purpose of the study was to identify macular edema after cataract surgery in eyes with and without pseudoexfoliation syndrome. The study was a post-hoc analysis of a randomized, double-blind, prospective single-center study. Patients were enrolled between January 2016 and October 2016 as per the national guidelines for the management of cataract in the Department of Ophthalmology, Kymenlaakso Central Hospital, Kotka, Finland., Methods: One hundred and fifty-six eyes of 149 patients undergoing routine cataract surgery. Postoperatively anti-inflammatory medication was either dexamethasone (N = 78) or diclofenac (N = 78). Spectral domain optical coherence tomography imaging and laser flare meter measurement of the anterior chamber were conducted before surgery and at the control visit 28 days postoperatively., Results: Baseline variables were comparable between eyes with pseudoexfoliation syndrome (N = 32) and those without (N = 124), except for intraocular pressure ( P  = 0.002) and glaucoma medication ( P  < 0.001). In patients having pseudoexfoliation syndrome, central retinal thickness increase (mean ± standard error of the mean) was 63.3 ± 35.5 μm for dexamethasone and 17.6 ± 5.8 μm for diclofenac, compared to 28.9 ± 8.0 μm ( P  = NS) and 6.9 ± 1.3 μm ( P  = 0.014) in eyes without pseudoexfoliation syndrome, respectively. Aqueous flare at 28 days was 25.8 ± 5.4 pu/ms for patients with pseudoexfoliation syndrome and 18.3 ± 1.8 pu/ms for those without ( P  = 0.030). Best corrected visual acuity gain and best corrected visual acuity at 28 days were less in patients having pseudoexfoliation syndrome compared to those without (0.39 ± 0.07 vs 0.59 ± 0.03 decimals, P  = 0.007; and 0.77 ± 0.06 vs 0.92 ± 0.03 decimals, P  = 0.008, respectively)., Conclusion: Eyes with pseudoexfoliation syndrome may be predisposed to an increased aqueous flare and macular edema after cataract surgery. This study outlines the need to determine the optimal anti-inflammatory medication after cataract surgery in patients with pseudoexfoliation syndrome.

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.

One of the most important aspects of postsurgical care is finding an efficient way for the management of pain. Third molar extractions/surgical impaction is one of the most frequent surgical procedures in dental hospitals, and it is most often associated with postoperative complications like severe pain, oedema and reduced mouth opening. This study was aimed to evaluate the efficacy of 2 g intravenous (IV) vitamin C compared to 100 mg aceclofenac on postsurgical pain, swelling and trismus after the surgical removal of third molars. A total of 101 patients were recruited for the study, and theywere divided into two treatment groups; group A (n = 51) received 2 g IV vitamin C and group B (n = 50) received 100 mg aceclofenac. Pain intensity, facial swelling and mouth opening were assessed till day 3 post-surgically. Statistical analysis of pain intensity revealed that IV vitamin C performed slightly better but not significantly different (p>0.05) from aceclofenac group at the end of day 3. No significant difference for facial swelling and mouth opening between the two treatment protocols was seen (p>0.05). Our results concluded that both treatment groups were overall similar in analgesic efficacy, postoperative oedema and reduction in mouth opening. It was also determined that the method devised administering 2 g IV vitamin C intravenously was well suited to the treatment of postoperative pain, swelling and trismus following the surgical extraction of impacted third molars., Competing Interests: Authors declare no conflict of interest., (© 2019 Journal of Population Therapeutics and Clinical Pharmacology. All rights reserved.)

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., (© 2019 Royal Pharmaceutical Society.)

The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 μg/mL) and DFEE-PCL-TM (1.9 ± 0.6 μg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 μg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Intradermal administration of analgesic drugs with mesotherapy is effective for the local treatment of musculoskeletal pain. Few studies analyzed the effects of different drugs administrated with this technique., Aim: The aim of this study was to compare the efficacy of diclofenac versus lysine acetylsalicylate-based mesotherapy in relieving pain (primary outcome), and disability (secondary outcome) in patients with nonspecific chronic low back pain., Design: Retrospective observational study., Setting: Outpatient rehabilitation medicine center., Population: Records of 101 patients with nonspecific chronic low back pain., Methods: Data were extracted from the outpatients records of patients affected by nonspecific chronic low back pain since 12 weeks before, treated with 5 sessions of mesotherapy with diclofenac mixtures (group A) or aspirin-lysine acetylsalicylate mixture (group B). Assessments recorded were taken before the first treatment (T0), at the end of the 5-week treatment (T1), and at 4 (T2) and 12 weeks (T3) of follow-up after the last treatment, using a pain visual analogue scale (VAS) primary outcome, Oswestry Disability Index (ODI) secondary outcome, and the Short-Form McGill Pain Questionnaire (SF-MPQ) Comparisons within and between groups were performed using the t-test, the χ2 test, and analysis of variance (ANOVA) models, as appropriate., Results: Records from 101 patients consecutively were analyzed, 51 in group A (mean age and standard deviation [SD]=62.8±10.7; F/M=33/18) and 50 in group B (mean age±SD=64.1±15.8; F/M=30/20). At baseline VAS, SF-MPQ, ODI scores were respectively 7.6±1.3, 22.49±9.96, 44.80±15.55 (mean and SD) in group A; VAS, SF-MPQ, ODI scores were respectively 6.7±1.6, 18.66±9.65, 39.04±16.06 (mean and SD) in group B. Mean differences between group A and group B in the changes of scores from baseline (T0) to end of study (T3) were -1.3 (VAS), -5.81 (SF-MPQ) and -17.05 (ODI). Mesotherapy induced significant reductions in pain severity and disability in both groups with better results in diclofenac-based treatment., Conclusions: This retrospective pilot study suggests the efficacy and safety of diclofenac mesotherapy for relieving pain and disability in patients affected by chronic nonspecific low back pain in a convenient sample but further studies will confirm these results., Clinical Rehabilitation Impact: Diclofenac mesotherapy appears to be a viable treatment. to reduce pain and improve function in patients affected by chronic moderate-to-severe nonspecific low back pain.