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Background: Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week., Methods: This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50 mg, tizanidine 2 mg, or placebo every 6 hours for 2 weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals., Results: Two hundred and ninety-one patients were analyzed with the mean age of 47.4 years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo., Conclusion: Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain., Methods: The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination., Key Findings: DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively)., Conclusions: All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the efficacy and safety of diclofenac etalhyaluronate (DF-HA) (ONO-5704/SI-613), a novel DF-conjugated hyaluronate, in patients with knee OA in Japan., Methods: In this randomized, double-blind, placebo-controlled phase 2 study, patients were randomly assigned (1:1) to receive either 30 mg of DF-HA or placebo intra-articularly at weeks 0, 4 and 8 and were followed up for 24 weeks. The primary outcomes were changes from baseline in the WOMAC pain subscores, 50-foot walk test pain score and daily pain score. The secondary outcomes were the WOMAC physical function subscores, patient global assessment, responder rate and safety outcome., Results: Overall, 176 patients received the investigational drugs (87 received DF-HA and 89 received placebo). The mean changes in the WOMAC pain subscores and daily pain score from baseline over 12 weeks after the first injection were significantly higher in the DF-HA than placebo group; the mean difference was -7.0 mm [95% CI, -12.7, -1.2; P =0.018] and -0.61 (95% CI, -1.06, -0.16; P =0.008), respectively. The difference in the 50-foot walk test pain score was -5.0 mm (95% CI, -10.3, 0.3; P =0.065). Improvement of pain by DF-HA was observed at week 1 and maintained from week 12 to week 24. Significantly greater improvements in the secondary outcomes were also observed with DF-HA than with placebo. No clinically significant adverse events occurred., Conclusion: DF-HA reduced pain in patients with knee OA without major safety concerns., Trial Registration: UMIN Clinical Trials Registry, https://www.umin.ac.jp/ctr/index.htm, UMIN000015858., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Competing Interests: Competing interests: None declared.

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.)

Background: Ingenol mebutate (IngMeb) and diclofenac sodium (DS) are approved treatments for actinic keratosis (AK)., Objectives: To compare the efficacy and safety of IngMeb 0·015% gel with DS 3% gel (NCT02406014)., Methods: Patients with 4-8 visible, discrete AK lesions on the face/scalp in a 25 cm 2 contiguous area of skin were randomized 1:1 to IngMeb once-daily for three consecutive days or DS twice-daily for 90 days. Patients with AK lesions at Week 8 following IngMeb were offered a second IngMeb course. Primary end point was complete clearance of AK lesions (AKCLEAR 100) at end of first treatment course (Week 8, IngMeb; Week 17, DS). Secondary end points included AKCLEAR 100 at end of last treatment course and Week 17; adverse events (AEs) were assessed at these time points. Patients completed treatment satisfaction questionnaires for medication (TSQM; Week 17)., Results: AKCLEAR 100 at end of first treatment course was higher with IngMeb (34%) vs. DS (23%; P = 0·006). AKCLEAR 100 at end of last IngMeb course (53%) and Week 17 (45%) was higher than DS (both P < 0·001). The most frequent AE was application-site erythema (IngMeb 19%; DS 12%). Treatment-related AE (TRAE) duration was shorter with IngMeb. TRAE withdrawals were lower for IngMeb (2%) vs. DS (6%). TSQM scores for global satisfaction (P < 0·001) and effectiveness (P = 0·002) were higher with IngMeb, as was dosing instruction adherence (≥ 90% vs. 70%)., Conclusions: AKCLEAR 100, patient treatment satisfaction and effectiveness were significantly higher with IngMeb compared with DS, demonstrating superiority of IngMeb for AK treatment on face/scalp., (© 2017 British Association of Dermatologists.)

Background: A gel containing diclofenac and hyaluronic acid (DHA) and photodynamic therapy with methyl aminolaevulinate (MAL-PDT) are widely used treatments for actinic keratoses (AKs)., Objectives: The aim of this single-centre, open-label, prospective, nonsponsored, randomized controlled clinical trial was to compare the treatment results and cost-effectiveness of MAL-PDT and DHA., Methods: Patients with multiple AKs of the face and scalp were randomized to receive MAL-PDT or DHA. After 90 days, the overall complete remission (CR) rate of patients and the CR rate of lesions according to thickness score were assessed, and patients and an investigator scored the cosmetic outcome. In addition, patients scored their overall satisfaction with the treatment. Patients with CR of all lesions were followed up for 12 months., Results: Two hundred patients with a total of 1674 AKs were enrolled. The lesion CR rates at 3 months were 85·9% with MAL-PDT and 51·8% with DHA (P < 0·0001). AKs of all thicknesses were significantly more responsive to MAL-PDT. The patient CR rates at 3 months were 68% with MAL-PDT and 27% with DHA. At the 12-month examination, the number of patients with CR reduced to 37 with MAL-PDT and seven with DHA. Rating of cosmetic outcome was very good or excellent in the vast majority of patients with both treatments. The analysis of cost-effectiveness showed that the costs per patient with CR at 3 months and at 12 months are €566·7 and €1026·2, respectively, with MAL-PDT and €595·2 and €2295·6, respectively, with DHA., Conclusions: Efficacy, cosmetic outcome and patients' overall satisfaction with MAL-PDT are superior in comparison with DHA. MAL-PDT is more expensive but it is more cost-effective., (© 2014 British Association of Dermatologists.)

Objectives: The aim of this study was to prepare diclofenac/hydroxypropylmethylcellulose (HPMC) and diclofenac-loaded nanoparticles/HPMC films as potential systems for ocular delivery., Methods: Two different concentration of the polymer were used: 1.5 and 2.0% w/v. Chitosan-hyaluronic acid nanoparticles were prepared by the ionotropic gelation technique. Nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, drug encapsulation efficiency and rheological studies. In-vitro drug studies and corneal penetration release studies were carried out. Drug release mechanism was finally evaluated by fitting the Ritger and Peppas equation to data. In addition corneal hydration level was calculated to determine whether films could damage the corneas., Key Findings: Diclofenac HPMC films presented a faster drug release and a higher drug penetration than nanoparticles; on the contrary nanoparticles containing films were able to give a more sustained release of the drug and thus a slower diclofenac permeation through the cornea than HPMC films., Conclusions: Nanoparticles loaded with diclofenac sodium in HPMC films may be a valuable alternative for the treatment of ocular inflammatory diseases, since these formulations offer the benefit of sustained releasing directly to the site of action., (© 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society.)

In this study, we demonstrated that in vitro Candida albicans biofilms grown in the presence of diclofenac showed increased susceptibility to caspofungin. These findings were further confirmed using a catheter-associated biofilm model in rats. C. albicans-inoculated catheters retrieved from rats that were treated with both diclofenac and caspofungin contained significantly fewer biofilm cells and showed no visible biofilms inside the catheter lumens, as documented by scanning electron microscopy, as compared to catheters retrieved from rats receiving only caspofungin or diclofenac. This report indicates that diclofenac could be useful in combination therapy with caspofungin to treat C. albicans biofilm-associated infections.

Objective: Non-steroidal anti-inflammatory drugs decrease the glomerular filtration rate. However, few studies have been conducted on renal function in patients treated with non-steroidal anti-inflammatory drugs during the first week after laparoscopic radical nephrectomy. The purpose of this study is to determine whether short-term administration of non-steroidal anti-inflammatory drugs during the first week after laparoscopic radical nephrectomy is a risk factor for impaired renal function., Methods: Renal carcinoma patients undergoing laparoscopic radical nephrectomy in Nagoya University Hospital from April 2004 to July 2010 were identified in a retrospective cohort study. The 164 patients were divided into non-non-steroidal anti-inflammatory drug-treated (n=50) and non-steroidal anti-inflammatory drug-treated (n=114) groups., Results: Elderly patients (>60 years old) in the non-steroidal anti-inflammatory drug-treated group showed a significant correlation between the residual renal function ratio and the total dose of diclofenac sodium (r=-0.277, P<0.05). There was no significant correlation between the residual renal function ratio and the total dose of loxoprofen sodium. The time to doubling of the serum creatinine level was significantly shorter in elderly patients treated with diclofenac sodium compared with that in patients treated with non-non-steroidal anti-inflammatory drugs (P=0.034). These results suggest that renal ischemia induced by short-term administration of diclofenac sodium impairs renal function in elderly patients after laparoscopic radical nephrectomy., Conclusions: In the present study, we found the first evidence that short-term administration of diclofenac sodium is one risk factor for renal impairment after laparoscopic radical nephrectomy in elderly patients. To prevent renal impairment after laparoscopic radical nephrectomy in elderly patients, the use of loxoprofen sodium, which has a negligible effect on renal function compared with diclofenac sodium, is recommended.

Objectives: Spray-dried emulsion (SDE) was prepared and characterized to improve the intestinal absorption and oral bioavailability of ZLR-8, a nitric oxide-releasing derivative of diclofenac, currently under preclinical development., Methods: The intestinal absorption of ZLR-8 was characterized by single pass intestinal perfusion technique to obtain its absorption and permeability parameters. SDE of ZLR-8 was prepared and characterized by particle size measurements and in-vitro release study. Accurate and precise RP-HPLC methods for the detection of ZLR-8 and its metabolite diclofenac were constructed to perform the bioavailability study., Key Findings: It was demonstrated that ZLR-8 was absorbed in the whole intestine, of which the duodenum segment exhibited the largest absorption ability. ZLR-8 can be classified into BCS Class 2. SDE significantly enhanced the intestinal absorption rate of ZLR-8 in duodenum and jejunum but had indistinctive effect on permeability. All concentrations of ZLR-8 in rat plasma was lower than the limit of detection. A bicompartment model gave the best fit to the plasma diclofenac concentration-time curves. Calculated on AUC(0-12h) , the mean relative bioavailability of SDE was 105.4-fold that of ZLR-8 suspension., Conclusions: SDE significantly improved the intestinal absorption of ZLR-8 and resulted in a dramatic improvement in its bioavailability., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

Objective: We introduced a fast-track program for our cardiac operations requiring adjustment in anaesthesia techniques to facilitate rapid extubation and discharge from the intensive care unit (ICU). Our objective was to investigate the quality of analgesia in fast-track paediatric cardiac patients., Methods: We performed a retrospective review of the records of all patients who were fast-tracked in our institution between January 2006 and January 2007. Data collected included surgical procedure, anaesthesia technique, intra-operative opioids, ventilation time, intensive care stay, postoperative morphine consumption, pain scores, patient-controlled analgesia/nurse-controlled analgesia (PCA/NCA) duration, supplemental analgesia and incidence of vomiting., Results: Fifty-four patients were studied, with a median age of 5.6 years (8 months-18 years), median weight 15.6 kg (range: 6.4-101 kg), median intensive care unit (ICU) ventilation time 1.1h (range: 0-8h) and median ICU stay of 4.1h (1-52 h). All patients received intra-operative fentanyl, median dose of 16.8 mcg kg⁻¹ (range: 15-20 mcg kg⁻¹). Twenty-three children received a bolus of morphine intra-operatively median dose of 102 mcg kg⁻¹ (range: 50-170 mcg kg⁻¹). Those patients who did not receive a morphine bolus intra-operatively, received a 100 mcg kg⁻¹ loading dose of morphine in the ICU. Twenty-four patients received intravenous paracetamol intra-operatively and five patients were given both paracetamol and diclofenac. Twenty-five children were not given either paracetamol or diclofenac intra-operatively. During the postoperative period, all patients received morphine by infusion administered via either PCA (18%) or NCA)(73%). The median PCA/NCA infusion time was 28.9h. Forty-eight patients received paracetamol and non-steroidal analgesics postoperatively, either diclofenac or ibuprofen. Five patients received only paracetamol and only one patient required no supplemental analgesia. The bedside nurse reported the pain scores on an hourly basis on a 10-point visual analogue score where 0=no pain and 10=strongest pain. Pain scores showed that most patients after day 0 (which was the day of surgery) had only mild pain., Conclusions: Our data showed that our program achieves high-quality analgesia in fast-track paediatric cardiac patients., (Copyright © 2011. Published by Elsevier B.V.)

Although calcium pyrophosphate dehydrate (CPPD) deposition disease, including pseudogout, is a relatively common disease affecting the major joints, especially the knee, pseudogout in the acromioclavicular (AC) joint is very uncommon. We describe two cases of acute pseudogout attacks of the AC joint in elderly patients. Radiological findings showed chondrocalcinosis in the AC joints. Microscopically, aspirated articular synovial fluid demonstrated CPPD crystals. Conservative therapy with non-steroidal anti-inflammatory drugs completely resolved all symptoms within 1 week.

Background: There is a wide spectrum of treatments available for actinic keratosis (AK). Topical diclofenac sodium and imiquimod are two topical treatments, which are noninvasive, easily applied, well-tolerated and effective., Aim: To compare the effects of topical 3% diclofenac sodium plus hyaluranon (DFS) gel, 5% imiquimod (IMQ) cream, and base cream (BC) in patients with AK., Methods: In total, 61 patients, diagnosed clinically and histopathologically as having AK, were randomized into three treatment groups to receive topical treatment with either DFS (twice daily for 12 weeks), IMQ (twice per week for 16 weeks) or BC (twice daily for 12 weeks). Patients were evaluated clinically at 0, 4, 8, 12, 16, 20 and 24 weeks. Treatment efficacy was assessed by Total Thickness Score (TTS) and Patient Global Improvement Index (PGII)., Results: Complete clearance rates for DFS, IMQ and BC at the end of the treatment and at the end of the total follow-up period were 19.1%, 20% and 0%, and 14.3%, 45% and 0%, respectively. Although the average TTS value of the DFS group at week 24 was significantly higher than that of the IMQ group, the PGII values were not significantly different., Conclusions: Although DFS and IMQ each had considerable efficacy in the treatment of AK, the efficacy of DFS seemed to decrease after cessation of treatment., (© The Author(s). CED © 2011 British Association of Dermatologists.)

Objectives: Nanoparticles were designed for the oral administration and transmucosal colon delivery of drugs., Methods: Preparation parameters were studied in order to develop solid pH-dependent drug-release nanoparticles, constituted by hydroxypropyl-β-cyclodextrin and/or Eudragit(®) L100 loaded with diclofenac sodium. Nanoemulsions were prepared by the emulsion-evaporation method using various homogenizers. Different preparative conditions were tested. The emulsions obtained were analysed in terms of size and then dried to obtain solid nanoparticles which were characterized in vitro (particle size, morphology, dissolution, solid state characterization). The effect of nanoparticles on drug permeation through synthetic membranes, colonic pig mucosa and Caco2 cell line were performed. Toxicity studies were carried out to assess the safety of the raw materials used and the nanosystems produced., Key Findings: Appropriate parameters to obtain nanoemulsions stable enough to be desiccated were determined: Panda NS100L was the most suitable homogenizer for the preparation; particle size ranged between 100 and 600 nm depending on the production method. Solid nanoparticles were obtained by an exsiccation process, which does not modify the mean size. pH-dependent drug-release nanoparticles were obtained. The nanoencapsulation process decreased the crystallinity of the drug. Materials and nanoparticles were highly biocompatible. Transmucosal delivery of drug is dependent on the polymer and the test employed: cyclodextrin improved drug permeation across colonic pig mucosa., Conclusions: Formulations containing hydroxypropyl-β-cyclodextrin represent new colon-targeted nanoparticles for transmucosal delivery of drugs., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

A method is described for the simultaneous determination of paracetamol, tizanidine, and diclofenac in mixtures. The method was based on HPLC separation of the three drugs followed by UV detection at 254 nm. The separation was carried out on a Hypersil ODS, C18 (250 x 4.6 mm id, 10 microm particle size) column using the mobile phase aqueous 0.2% ammonium carbonate-methanol (60 + 40, v/v) at a flow rate of 1 mL/min. The linear regression analysis data were used for the regression curve in the range of 170-10 000 ng/mL for paracetamol, 120-10 000 ng/mL for tizanidine, and 20-10 000 ng/mL for diclofenac. No chromatographic interference from tablet excipients was found. In order to check the selectivity of the proposed method, degradation studies were carried out using hydrolysis (acid, basic, and neutral), thermolysis, and oxidation. The developed method, after being validated in terms of precision, robustness, recovery, LOD, and LOQ, was successively applied to the analysis of pharmaceutical formulations and human serum.

Background: Thoracotomy is a surgical procedure associated with severe pain. Operative morbidity rates reduce by effective postoperative pain control. The aim of this study is to compare the effectiveness of the thoracic epidural blockade (TEB) and the paravertebral blockade (PVB) methods in relieving the pain caused by a thoracotomy incision., Materials and Methods: We studied 44 consecutive patients who underwent elective posterolateral thoracotomy. The patients were classed into two groups: TEB (n=19) and PVB (n=25). Patients in both the groups could self-control the infusion of bupivacaine infusion and diclofenac sodium. The groups were compared according to the parameters such as analgesic efficacy (VAS), respiratory function tests (forced expiratory volume in 1s (FEV(1)), peak expiratory flow rate (PEFR) and arterial blood gases), stress response (serum cortisol and glucose levels), adverse effects, necessity for additional analgesia, duration of catheter application procedure, mean hospital stay and postoperative follow-up. Results are analysed statistically by Mann-Whitney U, Wilcoxon, chi-square and Fisher's exact tests, and a p-value of <0.05 was accepted to be statistically significant., Results: There was no significant difference between the two groups with regard to age, gender, VAS, FEV(1), PEFR, serum cortisol and glucose levels, necessity for additional analgesia and hospital staying days. In contrast, adverse effects and duration of catheterisation were statistically significantly lower in group PVB (p=0.001 and p<0.001, respectively)., Conclusion: PVB catheterisation can be easily performed and placed in a short span perioperatively. Therefore, it might be the preferred method over TEB which has a high incidence of adverse effects and complication rates., (Copyright 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

This paper reviews retrospectively the results obtained in a case series of multiple refractory actinic keratoses (AKs), treated sequentially with topical diclofenac 3% gel followed by cryotherapy. In total, 29 patients were reviewed; all had >or= 5 lesions (mean 8.2; range 5-12) and a long-term history of recurrence after repeated cryotherapy. After a first-line, 12 week treatment phase with diclofenac 3% gel alone, the number of AKs per subject was reduced to an average of 1.5 AKs (range 0-5), with complete clearance of lesions in 21 cases (71%). Patients showing incomplete response to the above treatment (n = 8) then received liquid-nitrogen ablation for all residual lesions. This procedure resulted in complete clearance of all cases. Significantly, during the post-treatment follow-up period, patients had no AK recurrences for an average of 10 months (range 6-20). Sequential treatment with diclofenac 3% gel followed by cryotherapy may therefore represent an effective approach for the management of multiple refractory AKs.

Aims: The interactions between nonsteroidal anti-inflammatory drugs (NSAID) and Listeria monocytogenes have not been sufficiently documented to date. The aim of this study was to investigate the possible effects of Diclofenac (Dc) in a murine listerial infection model., Methods and Results: Dc was administered orally at 2.5 mug g(-1) to female albino strain of laboratory mouse (BALB/c) thrice postinfection (1 x 10(8) CFU ml(-1) oral challenge with L. monocytogenes ATCC 51774), which resulted in significantly (P < 0.01) reduced bacterial counts in liver and spleen, decreased (10-fold, P < 0.05) hepatic colonization and necrosis, and caused up-regulation of the expression of inflammatory cytokines (interferon-gamma, interleukin-1beta, tumour necrosis factor-alpha), compared with drug-free control., Conclusions: Dc may be useful as a promising adjuvant to the existing therapies in controlling systemic listerial infection. Further, quantitative structure-activity relationship studies might contribute in manipulating it as a lead compound for the synthesis of new, more effective nonantibiotics, perhaps, devoid of side-effects that could be recommended as a compassionate therapy for listeriosis., Significance and Impact of the Study: This is the first in vivo study designed to evaluate the antilisterial effect of the NSAID Dc with special emphasis on the immunological mechanism of action of the drug.

Objectives: To demonstrate non-inferiority of lumiracoxib 400 mg once daily (o.d.) compared with indomethacin 50 mg three times daily (t.i.d.) in the treatment of acute gout, and to compare the safety and tolerability of these treatments., Methods: In this 1-week, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study, patients with a clinical diagnosis of gout, an acute attack of gout in four or more joints within the 48 h prior to evaluation, and at least moderate pain intensity in the target joint were randomized to treatment with lumiracoxib 400 mg o.d. (n = 118) or indomethacin 50 mg t.i.d. (n = 117). The primary efficacy endpoint was the mean change in pain intensity from baseline over days 2-5, assessed on a 5-point Likert scale, where non-inferiority could be claimed if the lower limit of the confidence interval (CI) was greater than -0.5. The patient's and physician's global assessment of response to treatment, and physician's assessment of tenderness, swelling and erythema of the study joint were also assessed., Results: The estimated difference between treatments for the change from baseline in pain intensity over days 2-5 was -0.004 (95% CI -0.207 to 0.199, P > 0.05), indicating that lumiracoxib 400 mg o.d. had comparable efficacy to indomethacin 50 mg t.i.d. for the primary efficacy variable. There was no significant difference between treatments in any of the secondary efficacy variables. Adverse events were reported by 10.2% of patients treated with lumiracoxib and 22.2% of those receiving indomethacin., Conclusions: Lumiracoxib is as effective as indomethacin for treatment of acute gout and may have a better safety and tolerability profile.

Background: Actinic cheilitis is a frequent manifestation of actinic dysplasia and requires early therapy to prevent its progression into invasive squamous cell carcinoma (SCC). Several therapies are used, ranging from unspecific lesion-adapted destructive techniques (i.e. laser) to ambitious surgical field-management (vermillionectomy). There is increasing awareness of the effectiveness of field adapted, non destructive therapies, such as photodynamic therapy or 5% imiquimod. Diclofenac 3% gel is used in the treatment of actinic keratosis (AK), but it has not been evaluated for the treatment of actinic cheilitis., Objectives: This non-blinded, uncontrolled case series study evaluated the effects of diclofenac 3% gel in the treatment of actinic cheilitis., Patients/methods: Six patients with histologically verified actinic cheilitis were treated with diclofenac 3% gel, twice daily for 6 weeks. Clinical assessment was performed 2-4 weeks after the end of treatment., Results: Four out of six patients showed clinical clearing of actinic cheilitis 2-4 weeks after the end of treatment. Biopsies were taken from the treated areas at the final visit to verify clinical clearance. Side effects in most of the patients included mild erythema and mild to moderate swelling of the lips., Conclusions: Topical therapy with diclofenac 3% gel may be an efficient, cosmetically more appealing alternative treatment for actinic cheilitis than currently used destructive therapies. However, future studies and long-term follow-up of patients will be needed to compare its efficacy with established forms of therapy.

Background: Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity in organ transplant patients; the relative risk of squamous cell carcinoma and actinic keratosis (AK) is 100 and 250 times higher, respectively, compared with immunocompetent patients., Objectives: The aim of this study was to investigate the effects of 3% diclofenac gel on the clearance rates of multiple AKs in organ transplant recipients (OTRs)., Patients/methods: An open-label study was conducted in six patients (three kidney, one liver and two heart transplant patients) with histories of multiple NMSCs and extensive actinic keratoses (AKs). Patients were treated with diclofenac 3% gel, twice daily for 16 weeks. Complete and partial clearance rates of AKs were assessed after 16 weeks and biopsies were performed 4 weeks post-therapy on clinically typical AKs identified prior to the start of treatment., Results: Three out of six patients showed complete clinical and histological clearance after 16 weeks of treatment with diclofenac 3% gel. Two further patients showed a marked (> or = 75% lesion reduction) improvement in their overall AK lesion count in the treatment area. One patient showed a 30% lesion reduction in the area treated. Local adverse events at the site of application were very mild and included mild erythema and marginal erosion. No systemic side effects were reported., Conclusions: Results suggest that diclofenac 3% gel may be useful in the treatment and control of multiple AK lesions in OTRs. Further studies are needed to investigate the efficacy and safety of this therapy for the local treatment of AK in greater numbers of immunosuppressed patients.

Progression from actinic keratosis (AK) and Bowen's disease (BD) to invasive disease involves a complex cascade of events. The preparation of diclofenac 3% gel (Solaraze; Shire Pharmaceuticals) has been shown to be efficacious and well tolerated in AK. The inhibition of the COX enzymes results in a decrease in downstream by-products of arachidonic acid metabolism. These metabolites have been shown to play a pivotal role in promoting epithelial tumour growth. Given its mechanism of action, we hypothosize that diclofenac 3% gel may have potential to halt the progression of actinic keratoses (AKs) in the setting of field cancerisation and BD. We report a series of five patients with BD, all treated with diclofenac 3% gel with clinical and histological clearance.

Diclofenac 3% gel is an effective treatment for actinic keratoses (AKs) and is reported to be generally well tolerated with only mild local reactions. However, there is a subset of patients that seem to be susceptible to developing severe local reactions following application of diclofenac 3% gel. Although some of these reactions can be explained as being allergic contact dermatitis and/or photoallergic contact dermatitis, others cannot. We report a series of 10 patients who all developed severe local reactions following application of diclofenac 3% gel, despite negative diclofenac patch testing. This raises the question as to whether there is a subset of patients with skin cancer or AK lesions that are highly/more susceptible to local reactions caused by cyclo-oxygenase-2 (COX-2) inhibitors and peroxisome proliferator-activated receptor (PPAR) agonists? We speculate that underlying molecular differences exist in these patients that make the skin more susceptible to COX-2 inhibitors.

Background and Purpose: The direct effects of ultrasound (US) and phonophoresis of a nonsteroidal anti-inflammatory drug (NSAID) on injured peripheral tissue have been widely investigated, but evidence concerning the effects of central spinal nociceptive modulation seems to be lacking. The purpose of this study was to investigate the peripheral influences of US and phonophoresis on the modulation of spinal inducible nitric oxide synthase (iNOS) expression elicited by hind paw stimulation with an ankle injection of complete Freund adjuvant (CFA)., Subjects and Methods: Inflammatory arthritis was induced in 18 male Wistar rats with intra-articular tibiotarsal injections of CFA. Serial changes in inflammatory pain reactions, including hind-limb edema, and the locomotor activity of the arthritic animals were measured. Arthritic rats underwent US (n=6), diclofenac phonophoresis (n=6), or sham treatment (n=6) on the CFA-injected leg at 18 hours after injection. At 20 hours after injection, spinal inducible nitric oxide synthase-like immunoreactive (iNOS-LI) cells were examined., Results: Following the CFA injection, all animals' paw diameters and ankle circumferences ipsilateral to the injected leg were significantly increased compared with the values prior to injection. The rearing behavior of arthritic animals had improved significantly after US and diclofenac phonophoresis treatments. The mean total number (+/-SD) of iNOS-LI cells per section of segments L1 and L2 of the bilateral spinal cord of the sham treatment, US, and phonophoresis groups were 531.20+/-6.11, 124.20+/-4.09, and 114.80+/-3.23, respectively. The total numbers of iNOS-LI cells in rats treated with US and diclofenac phonophoresis were significantly smaller than in those receiving sham treatment. There were no significant differences in the total number of iNOS-LI cells ipsilateral to the injected leg between the US and diclofenac phonophoresis groups., Discussion and Conclusion: Ultrasound and phonophoresis treatments probably modulate and prevent the CFA-insult-induced increase in total and regional iNOS-LI neurons. Peripheral use of diclofenac phonophoresis offers little advantage over US alone in affecting the central mechanisms of nociception. The peripheral influences of US and phonophoresis on the central modulation of the spinal nociceptive processing system are important and may reflect the work being done through the neuroplasticity of spinal cord in response to peripheral input of US and phonophoresis.

The effect of magnesium aluminium silicate (MAS) on rheological, release and permeation characteristics of diclofenac sodium (DS) aqueous gels was investigated. DS aqueous gels were prepared using various gelling agents, such as 15% w/w poloxamer 407 (PM407), 1% w/w hydroxypropylmethylcellulose (HPMC), and 1% w/w high and low viscosity grades of sodium alginate (HV-SA and LV-SA, respectively). Different amounts of MAS (0.5, 1.0 and 1.5% w/w) were incorporated into the DS gels. Incorporation of MAS into the DS gels prepared using SA or PM407 caused a statistical increase in viscosity (P<0.05) and a shift from Newtonian flow to pseudoplastic flow with thixotropic property. The DS release rates of these composite gels were significantly decreased (P<0.05) when compared with the control gels. This was due to an interaction between MAS and PM407 or SA, and adsorption of DS onto MAS particles. Moreover, a longer lag time and no change in DS permeation flux were found when MAS was added to the gels. The findings suggest that the rheological characteristics of gels prepared using PM407 or SA could be improved by incorporating MAS. However, the use of MAS could retard the DS release and extend the lag time of DS permeation.

In contrast to economic models that provide probabilistic estimates of economic impact, data extracted from clinical trials may be used to evaluate and compare actual resource utilization and costs. Health-care resource utilization and the costs of these resources were compared from the perspective of the UK National Health Service using data obtained in a 6-month clinical trial of oral valdecoxib 20 mg once daily and diclofenac 75 mg twice daily for the symptomatic treatment of rheumatoid arthritis. However, calculated health-care costs were exclusive of drug acquisition costs because the price of valdecoxib was not available at the time of analysis. While the efficacy of the two treatments was similar, use of valdecoxib was associated with a reduction in total health-care costs amounting to approximately 200 British pounds per patient. This lower cost was associated with reduced use of health-care resources for gastrointestinal serious adverse events (gastrointestinal SAEs). In particular, the incidence of hospitalization and number of hospital days for gastrointestinal SAEs was lower in the valdecoxib group. Analysis of cost per gastrointestinal SAE favoured valdecoxib (cost savings of 742 British pounds), suggesting that even when these events did occur they were less severe. When costs of gastrointestinal SAEs were averaged over the entire population, valdecoxib was suggested to have lower total costs per patient compared with diclofenac (cost savings of 115 British pounds per patient), mainly resulting from significant savings in hospitalization costs (76.49 British pounds per patient). These data are consistent with economic models and suggest that the favourable gastrointestinal profile of valdecoxib observed in clinical trials will be of economic benefit.

Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders.

The aim of the study was to calculate absorption parameters, including permeability coefficients (P(app)), from the non-steady-state portion of the outflow to inflow concentration ratio vs time profiles and compare them with those obtained via the more traditionally used steady-state phase. The rat in-situ intestinal perfusion method was used. The compounds studied, diclofenac and macrogol 4000 (polyethylene glycol (PEG) 4000), were perfused at four different flow rates (0.1-2.0 mL min(-1)). The estimates of P(app) from the non-steady-state data were systematically lower for both compounds. The non-steady-state analysis gave estimates of the intestinal radius, r. The internal diameter of the intestine segment increased as the flow rate increased. When this effect was taken into account similar P(app) estimates were obtained by the two approaches. Thus the convention of using a constant value of intestinal radius in the steady-state equation leads to an over estimate of the P(app) when high flow rates are employed. The different trends observed, between P(app) and perfusate flow rate, for the two compounds, macrogol 4000 and diclofenac, may be linked to increased surface area and exposure to membrane pores of larger size. The longitudinal spreading coefficient, De, increased with flow rate and was approximately 1000 times greater than that estimated for molecular diffusion. The high values obtained were consistent with the non-smooth biological surface and peristaltic movement present in-vivo.

Estrogens influence cardiovascular function through direct and indirect effects and via genomic and nongenomic mechanisms. The pathways underlying the nongenomic mechanisms are not completely understood. Estrogen-induced responses in vascular cells have been shown to influence prostaglandins and cyclooxygenase (COX), a key enzyme in the production of prostaglandins, with two isoforms, COX-1 and COX-2. We investigated the effects of prostaglandins on the acute potentiation by 17beta-estradiol (E) of acetylcholine (ACh)-mediated vasodilation in the cutaneous vasculature. Using a double-blind placebo-controlled design, we assessed skin blood flow in 32 healthy, postmenopausal women by laser Doppler velocimetry with direct current iontophoresis of ACh and sodium nitroprusside before and after 6-wk treatment periods with aspirin (a nonspecific COX-1 and COX-2 inhibitor), diclofenac (predominantly a COX-2 inhibitor, which also inhibits COX-1), celecoxib (a specific COX-2 inhibitor), given at anti-inflammatory doses, or placebo. Blood flux values before iontophoresis of ACh did not differ between the treatment groups or after E administration, excluding a direct cutaneous vasodilator effect of the treatments or of E. Acute E administration enhanced the response to ACh after aspirin, diclofenac, and placebo; however, this effect was completely abolished with celecoxib treatment (P < 0.05). E had no effect on sodium nitroprusside-mediated vasodilation after any of the treatments. We conclude that the COX-2 pathway plays a specific role in the rapid E-induced potentiation of cholinergic vasodilation in postmenopausal women.

Background: Diclofenac is a non-steroidal anti-inflammatory drug, commonly used by reproductive age women for the treatment of a variety of conditions. However, there is limited information regarding the teratogenic effects of this drug., Methods: The effect of diclofenac on the developing embryo during the critical period of organogenesis was investigated by using a whole rat embryo culture model. Embryos were exposed to various concentrations of diclofenac and scored for growth and differentiation at the end of the culture period., Results: Total developmental score and score for caudal neural tube, flexion and hindlimb were significantly lower in embryos exposed to high concentrations of diclofenac (7.5 and 15.0 microg/ml), but no difference in these parameters was observed when embryos were exposed to low concentration of diclofenac (1.5, 2.5 and 5.0 microg/ml). No significant differences in yolk sac diameter, crown-rump length and number of somites was found between embryos in the experimental and the control group., Conclusions: Our study has demonstrated that diclofenac exerts direct teratogenic effects on rat embryos. Until more is known about the effects of diclofenac (especially in moderate to high doses) in women of reproductive age, we suggest its use should be treated with caution.

Early luteal phase administration of a potent anti-progestin like mifepristone (RU486) inhibits blastocyst implantation and the establishment of pregnancy without marked changes in menstrual cyclicity and ovarian steroid hormone profiles; however, the underlying mechanism is not very clear. In the present study, a hypothesis that prostaglandins (PG) are involved in the anti-gestatory action of luteal phase mifepristone was tested. Endometrial changes in rhesus monkeys were examined following luteal phase administration of mifepristone, a prostaglandin synthesis inhibitor (diclofenac) and a prostaglandin analogue (misoprostol) either alone or in combination. Twenty-five monkeys were randomly assigned to six groups: group 1 (n = 4), normal control group; group 2 (n = 4), mifepristone (2 mg, daily, s.c.) treated group; group 3 (n = 4), diclofenac (25 mg, daily, i.m.) treated group; group 4 (n = 4), misoprostol (100 microg, daily, oral) treated group; group 5 (n = 5), mifepristone and diclofenac (same dosages as for groups 2 and 3) treated group; group 6 (n = 4), mifepristone and misoprostol (same dosages as for groups 2 and 4) treated group. All treatments were given to monkeys on days 16-18 of mated cycles and endometrial tissue samples were collected on day 20. With diclofenac alone (group 3), marginal changes were observed in glandular, stromal and vascular compartments, and there were few apoptotic bodies in gland cells; partial inhibition and delay in implantation was earlier reported. Significantly higher oestrogen receptor expression in glandular epithelial cells as compared with all other treatment groups was found after treatment with misoprostol alone (group 4) and was associated with normal fecundity. The anti-nidatory action of luteal phase antiprogestin treatment alone or in combination with diclofenac or misoprostol was associated with altered endometrial histometric features characterized by glandular apoptosis, regression in secretory functions, decreased oedema, extravasation and a higher degree of stromal leukocytic infiltration. In these three groups (groups 2, 5 and 6) receptors for oestrogen and progesterone receptors were significantly higher in stromal cells, and lower in vascular cells, while glandular cells showed significantly higher progesterone receptors compared with the control group. The anti-nidatory activity of mifepristone and associated endometrial changes could not be accentuated or attenuated with co-administration of PGE or diclofenac, nor could these be mimicked by these agents alone.

Poly (lactide-co-glycolide) (PLG), is one of the most widely employed biodegradable synthetic polymers for sustained-release preparations. In the present work, PLG (50:50) copolymer has been used to deliver diclofenac sodium in the form of microspheres and in situ gel-forming systems, both of which can be injected subcutaneously. The pharmacodynamic and pharmacokinetic studies in the adjuvant-induced arthritic rats showed that the microspheres offered steady therapeutic levels of the drug in the plasma for about 16 days following a single subcutaneous injection. However, the in situ gel-forming system provided a significantly higher maximum plasma concentration and increased inhibition of inflammation, maintained for about 10 days. Injectable microspheres and in situ gel-forming implant systems of PLG (50:50) copolymer may therefore be considered as prospective implantable controlled-release dosage forms to deliver drugs in long-term therapy of chronic ailments.

A multicentre, double-blind, randomized study was conducted in patients with osteoarthritis (OA) of the hip or knee in order to compare the efficacy and safety of the new cyclooxygenase-2 (COX-2) inhibitor, meloxicam, with diclofenac sodium, a conventional treatment for this condition. Three hundred and thirty-six patients were treated with oral meloxicam 7.5 mg once daily or diclofenac 100 mg slow release once daily for 6 months. There were no significant differences between the treatment groups with respect to overall pain, pain on movement, global efficacy or quality of life scores at the end of treatment, all of which showed good levels of improvement. Sixty-six patients were withdrawn after the start of the double-blind phase due to adverse events (n = 21, meloxicam; n = 31, diclofenac) or to lack of efficacy (seven in each group). The median of dose paracetamol taken concomitantly was statistically significantly lower in the meloxicam group than in the diclofenac group (185 vs 245 mg/day; P = 0.0123) with a comparable proportion of patients taking concomitant paracetamol therapy in both groups. Both drugs were well tolerated, although severe adverse events, treatment withdrawal and clinically significant laboratory abnormalities were more common with diclofenac than with meloxicam. Thus, meloxicam 7.5 mg is a safe and effective treatment for OA of the hip and knee which demonstrates a trend towards an improved safety profile compared with diclofenac.

Controlled release matrix tablets for diclofenac sodium were developed in this study. Five matrix-tablet formulations were prepared by granulating two viscosity grades of HPMC (hydroxylpropylmethylcellulose) in varying ratios with water in the planetary mixer. The in-vitro dissolution tests indicate that all five matrix formulations prolong the release of diclofenac sodium. The main factors controlling drug release were the HPMC viscosity grade and the amount of HPMC used. The larger the amount of high viscosity grade HPMC used, the slower the resultant release rate of diclofenac sodium. There was no significant degradation of diclofenac sodium or change in drug release rate in any of the five formulations during a three-month period of stability testing. The sustained release ability of four formulations was further demonstrated in an in-vivo study in six healthy subjects. There were in-vitro/in-vivo correlations between Cmax, AUC0-14, and the time for 50 or 80% drug to be released.

Angiostasis and vascular regression in chronic granulomatous inflammation was assessed in mice induced with diclofenac in combination with hyaluronan. The local injection of 0.1 mL HYAL EX-0001 (0.18% diclofenac in 2.5% hyaluronan) reduced granulomatous development after six days treatment from 150.4 +/- 13.8 (0.18 saline) to 117.1 +/- 17.8 mg (dry weight, n = 10), but not significantly when compared with 0.1 mL 2.5% hyaluronan alone or diclofenac in 0.1 mL saline. Diclofenac administered in saline had no significant effect when compared with saline control. The vascular density, expressed as carmine content per mg dry weight tissue, in those animals treated with HYAL EX-0001 was also significantly reduced to 5.27 +/- 0.55 micrograms mg-1 (P < 0.1, n = 10) when compared with saline control (7.99 +/- 1.0), hyaluronan alone (7.20 +/- 1.0), and diclofenac in saline. (7.36 +/- 1.28). A similar profile of activity was seen on topical application except that all treatments did not affect granulomatous tissue development. On therapeutic dosing of mice daily with HYAL EX-0001 from day 7 after induction of the granulomatous tissue, the granulomatous tissue development was dramatically reduced from 111.67 +/- 4.40 mg (n = 14 on day 7) to 60.23 +/- 7.22 (P < 0.001, n = 8 on day 14) and 54.98 +/- 7.88 (P < 0.001, n = 8 on day 21). HYAL EX-0001 after 14 days of application significantly reduced granulomatous tissue mass when compared with the hyaluronan-dosed control on day 21 (89.58 +/- 7.49, P = 0.01, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, randomized, parallel group study was conducted to compare the gastroduodenal safety and antiarthritic efficacy of a fixed combination of diclofenac 50 mg and misoprostol 200 micrograms with that of a combination of diclofenac 50 mg and placebo in patients with osteoarthritis. Three hundred and sixty-one patients with no significant gastroduodenal lesions were enrolled and received study medication two or three times daily for 4 weeks. Post-treatment endoscopic examination of the gastroduodenal mucosa revealed ulcers in 4% of patients in the diclofenac/placebo group compared with none in the diclofenac/misoprostol group (P = 0.015). There were no clinically or statistically significant differences between the two treatment groups in formal assessments of osteoarthritis after either 2 or 4 weeks. It was concluded that diclofenac/misoprostol was associated with significantly less gastroduodenal damage than diclofenac, whilst being as effective as diclofenac alone in the treatment of osteoarthritis.

A rapid, and sensitive high-performance liquid chromatographic method has been developed for the determination of diclofenac sodium in serum using flufenamic acid as the internal standard. Serum protein was precipitated with acetonitrile. The drugs were eluted from a 5 microns C-8 reversed-phase column at ambient temperature with a mobile phase consisting of acetonitrile-water (50:50% v/v) adjusted to pH 3.3 with glacial acetic acid, at a flow rate of 2 mL min-1 with UV detection at 280 nm. Each analysis required no longer than 10 min. Quantitation was achieved by the measurement of the peak-height ratio and the relative and absolute recoveries varied from 90 to 98%. Detection limits for diclofenac sodium in serum is 25 ng mL-1. Intraday coefficients of variation (CV) ranged from 2.47 to 4.61% and interday CVs from 3.52 to 7% at three different concentrations. Preliminary stability tests showed that diclofenac sodium is stable for at least 2 weeks in serum after freezing. The method is applied for the determination of the pharmacokinetic parameters of diclofenac after administration of two formulations (enteric-coated tablet and slow-release tablet), to a healthy male volunteer.