Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres.

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.

A Double-Blind, Randomized Controlled Trial of Pre-incision Wound Infiltration Using Diclofenac Versus Bupivacaine for Post-operative Pain Relief in Open Thyroid and Parathyroid Surgery.

BACKGROUND: Pre-incision wound infiltration using NSAID is an alternative method to manage post-operative pain in surgery. It is postulated that NSAID delivered peripherally exerts efficient analgesic and anti-inflammatory effect with minimal systemic complication. This study explored the efficacy of using diclofenac for wound infiltration in open thyroidectomy and parathyroidectomy as compared to conventional agent, bupivacaine. METHODOLOGY: The study was designed as a double-blind, randomized controlled trial involving 94 patients who underwent open thyroidectomy or parathyroidectomy in Hospital Pulau Pinang, Malaysia, from November 2015 to November 2016. The study compared the efficacy of pre-incision wound infiltration of diclofenac (n = 47) versus bupivacaine (n = 47) in post-operative pain relief. Wound infiltration is given prior to skin incision. Mean pain score at designated time interval within the 24-h post-operative period, time to first analgesia, total analgesic usage and total analgesic cost were assessed. RESULTS: Ninety-four patients were recruited with no dropouts. Mean age was 49.3 (SD = 14.2) with majority being female (74.5%). Ethnic distribution recorded 42.6% Chinese, 38.3% Malay, followed by 19.1% Indian. Mean duration of surgery was 123.8 min (SD = 56.5), and mean length of hospital stay was 4.7 days (SD = 1.8). The characteristics of patient in both groups were generally comparable except that there were more cases of total thyroidectomy in the diclofenac group (n = 31) as compared to the bupivacaine group (n = 16). Mean pain score peaked at immediate post-operative period (post-operative 0.5 h) with a score of 3.5 out of 10 and the level decreased steadily over the next 20 h starting from 4 h post-operatively. Pre-incision wound infiltration using diclofenac had better pain control as compared to bupivacaine at all time interval assessed. In the resting state, the mean post-operative pain score difference was statistically significant at 2 h [2.1 (SD = 1.5) vs. 2.8 (SD = 1.8), p = 0.04]. During neck movement, the dynamic pain score difference was statistically significant at post-operative 1 h [2.7 (SD = 1.9) vs. 3.7 (SD = 2.1), p = 0.02]; 2 h [2.7 (SD = 1.6) vs. 3.7 (SD = 2.0), p = 0.01]; 4 h [2.2 (SD = 1.5) vs. 2.9 (SD = 1.7), p = 0.04], 6 h [1.9 (SD = 1.4) vs. 2.5 (SD = 1.6), p = 0.04] and 12 h [1.5 (SD = 1.5) vs. 2.2 (SD = 1.4), p = 0.03]. Mean dose of tramadol used as rescue analgesia in 24 h duration was lower in the diclofenac group as compared to bupivacaine group [13.8 mg (SD = 24.9) vs. 36.2 mg (SD = 45.1), p = 0.01]. The total cost of analgesia used was significantly cheaper in diclofenac group as compared to bupivacaine group [RM 3.47 (SD = 1.51) vs. RM 13.43 (SD = 1.68), p < 0.01] or [USD 0.83 (SD = 0.36) vs. USD 3.21 (SD = 0.40), p < 0.01]. CONCLUSION: Pre-incision wound infiltration using diclofenac provides better post-operative pain relief compared to bupivacaine for patient who had underwent open thyroidectomy or parathyroidectomy. Diclofenac is cheap and easily available in the limited resource setting. This approach offers a superior alternative for post-operative pain relief as compared to bupivacaine.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

PainVision® Apparatus for Assessment of Efficacy of Pulsed Radiofrequency Combined with Pharmacological Therapy in the Treatment of Postherpetic Neuralgia and Correlations with Measurements.

Objective. PainVision device was a developed application for the evaluation of pain intensity. The objective was to assess the efficacy and safety of pulsed radiofrequency (PRF) combined with pharmacological therapy in the treatment of postherpetic neuralgia (PHN). We also discussed the correlation of the measurements. Method. Forty patients with PHN were randomized for treatment with PRF combined with pharmacological therapy (PRF group, n = 20) or pharmacological therapy (control group, n = 20) at postoperative 48 hours. The efficacy measure was pain degree (PD) that was assessed by PainVision and visual analog scale (VAS), short form Mcgill pain questionnaire (SF-Mcgill), and numeric rate scale sleep interference score (NRSSIS). Correlations between PD, VAS, SF-Mcgill, and NRSSIS were determined. Results. The PD for persistent pain (PP) and breakthrough pain (BTP) at postoperative 48 hours assessed by PainVision were significantly lower in PRF group than in control group (PD-PP, P < 0.01; PD-BTP, P < 0.01). PD and VAS were highly correlated for both persistent pain (r = 0.453, ρ = 0.008) and breakthrough pain (r = 0.64, ρ = 0.001). Conclusion. PRF was well tolerated and superior to isolated pharmacological therapy in the treatment of PHN. PainVision device showed great value in the evaluation of pain intensity and PD had an excellent correlation with VAS and SF-Mcgill.

Application of Quality by Design: Development to Manufacturing of Diclofenac Sodium Topical Gel.

The objective of the present study was to develop and optimize generic topical gel formulation of diclofenac sodium through quality by design approaches. The quality target product profile was set for the critical quality attributes of the gel. The key material variables like hydrophilic gelling agent carbopol and penetration enhancer kolliphor were optimized using design of experiments. A central composite design was used considering viscosity and cumulative percent diffusion of the drug after 0.5, 1, 2, 4 and 6 h as responses. The p values for all models generated for different responses were statistically significant (<0.5). Design space was established and verified at the laboratory scale. The predicted and observed values were in close agreement. The robustness of the formula was tested at a higher scale (10X and 200X). The capability index was calculated followed by Monte Carlo simulation and the Cpk values for all the responses were more than 1.33.

Cost-effectiveness of Low-dose Submicron Diclofenac Compared With Generic Diclofenac.

PURPOSE: NSAIDs are commonly prescribed for the treatment of pain and inflammation. Despite the effectiveness of NSAIDs, concerns exist regarding their tolerability. Worldwide health authorities, including the European Medicines Agency, Health Canada, and the US Food and Drug Administration, have advised that NSAIDs be prescribed at the lowest effective dosage and for the shortest duration. Effective lowering of NSAID dosage without compromising pain relief has been demonstrated in randomized, controlled trials of the recently approved NSAID lower-dose submicron diclofenac. Building on previously published work from an independently published systematic review and meta-analysis, a linear dose-toxicity relationship between diclofenac dose and serious gastrointestinal (GI) events was recently demonstrated, indicating that reductions in adverse events (AEs) may be seen even with modest dose reductions in many patients. The objective of the present study was to estimate the potential reduction in risk for NSAID dose-related AEs, corresponding savings in health care costs, and the incremental cost-effectiveness of submicron diclofenac compared with generic diclofenac in the United States. METHODS: Our decision-analytic cost-effectiveness model considered a subset of potential AEs that may be avoided by lowering NSAID dosage. To estimate the expected reductions in upper GI bleeding/perforation and major cardiovascular events with submicron diclofenac, our model used prediction equations estimated by meta-regressions using data from systematic literature reviews. Utilities, lifetime costs, and health outcomes associated with AEs were estimated using data from the literature. The face validity of the model structure and inputs was confirmed by clinical experts in the United States. Results were evaluated in 1-way and probabilistic sensitivity analyses. FINDINGS: The model predicted that submicron diclofenac versus generic diclofenac could reduce the occurrence of modeled GI events (by 18.0%), cardiovascular events (by 6.9%), and acute renal failure (by 18.8%), leading to a 9.8% reduction in costs of treating AEs. Submicron diclofenac was predicted to be cost-saving, with results relatively insensitive to parameter uncertainty. IMPLICATIONS: Submicron diclofenac has the potential to provide clinical and economic value to patients using NSAIDs in the United States. Further investigation regarding the potential effects of submicron diclofenac on the risks for additional NSAID dose-related toxicities should be explored.

Cost-Effectiveness and Cost-Utility Analysis of Ingenol Mebutate Versus Diclofenac 3% and Imiquimod 5% in the Treatment of Actinic Keratosis in Spain. / Análisis de coste-efectividad y coste-utilidad de ingenol mebutato versus diclofenaco 3% e imiquimod 5% en el tratamiento de la queratosis actínica en España.

OBJECTIVE: To perform a cost-effectiveness and cost-utility analysis of ingenol mebutate in the treatment of actinic keratosis in Spain. METHODS: We used an adapted Markov model to simulate outcomes in a cohort of patients (mean age, 73 years) with actinic keratosis over a 5-year period. The comparators were diclofenac 3% and imiquimod 5%. The analysis was performed from the perspective of the Spanish National Health System based on direct costs (2015 retail price plus value added tax less the mandatory discount). A panel of experts estimated resources, taking unit costs from national databases. An annual discount rate of 3% was applied. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The effectiveness of ingenol mebutate-with 0.192 and 0.129 more clearances gained in treatments for face and scalp lesions and trunk and extremity lesions, respectively-was superior to diclofenac's. The total costs of treatment with ingenol mebutate were lower at € 551.50 (face and scalp) and € 622.27 (trunk and extremities) than the respective costs with diclofenac (€ 849.11 and € 844.93). The incremental cost-effectiveness and cost-utility ratios showed that ingenol mebutate was a dominant strategy vs diclofenac. Ingenol mebutate also proved to be more effective than imiquimod, based on 0.535 and 0.503 additional clearances, and total costs of € 551.50 and € 527.89 for the two drugs, respectively. The resulting incremental cost-effectiveness ratio was € 728.64 per clearance gained with ingenol mebutate vs imiquimod. CONCLUSIONS: Ingenol mebutate was a dominant treatment option vs diclofenac and was efficient vs imiquimod (i.e., more effective at a higher cost, achieving an incremental cost-utility ratio of<€30000/quality-adjusted life-years).

Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial.

BACKGROUND: The excruciating pain of patients with renal colic on presentation to the emergency department requires effective analgesia to be administered in the shortest possible time. Trials comparing intramuscular non-steroidal anti-inflammatory drugs with intravenous opioids or paracetamol have been inconclusive because of the challenges associated with concealment of randomisation, small sample size, differences in outcome measures, and inadequate masking of participants and assessors. We did this trial to develop definitive evidence regarding the choice of initial analgesia and route of administration in participants presenting with renal colic to the emergency department. METHODS: In this three-treatment group, double-blind, randomised controlled trial, adult participants (aged 18-65 years) presenting to the emergency department of an academic, tertiary care hospital in Qatar, with moderate to severe renal colic (Numerical pain Rating Scale ≥ 4) were recruited. With the use of computer-generated block randomisation (block sizes of six and nine), participants were assigned (1:1:1) to receive diclofenac (75 mg/3 mL intramuscular), morphine (0.1 mg/kg intravenous), or paracetamol (1 g/100 mL intravenous). Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants achieving at least a 50% reduction in initial pain score at 30 min after analgesia, assessed by intention-to-treat analysis and per-protocol analysis, which included patients where a calculus in the urinary tract was detected with imaging. This trial is registered with ClinicalTrials.gov, number NCT02187614. FINDINGS: Between Aug 5, 2014, and March 15, 2015, we randomly assigned 1645 participants, of whom 1644 were included in the intention-to-treat analysis (547 in the diclofenac group, 548 in the paracetemol group, and 549 in the morphine group). Ureteric calculi were detected in 1316 patients, who were analysed as the per-protocol population (438 in the diclofenac group, 435 in the paracetemol group, and 443 in the morphine group). The primary outcome was achieved in 371 (68%) patients in the diclofenac group, 364 (66%) in the paracetamol group, and 335 (61%) in the morphine group in the intention-to-treat population. Compared to morphine, diclofenac was significantly more effective in achieving the primary outcome (odds ratio [OR] 1·35, 95% CI 1·05-1·73, p=0·0187), whereas no difference was detected in the effectiveness of morphine compared with intravenous paracetamol (1·26, 0·99-1·62, p=0·0629). In the per-protocol population, diclofenac (OR 1·49, 95% CI 1·13-1·97, p=0·0046) and paracetamol (1·40, 1·06-1·85, p=0·0166) were more effective than morphine in achieving the primary outcome. Acute adverse events in the morphine group occurred in 19 (3%) participants. Significantly lower numbers of adverse events were recorded in the diclofenac group (7 [1%] participants, OR 0·31, 95% CI 0·12-0·78, p=0·0088) and paracetamol group (7 [1%] participants, 0·36, 0·15-0·87, p=0·0175) than in the morphine group. During the 2 week follow-up, no additional adverse events were noted in any group. INTERPRETATION: Intramuscular non-steroidal anti-inflammatory drugs offer the most effective sustained analgesia for renal colic in the emergency department and seem to have fewer side-effects. FUNDING: Hamad Medical Corporation Medical Research Center, Doha, Qatar.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

BACKGROUND: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. OBJECTIVES AND METHODS: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-ß-cyclodextrin (HPßCD) and progesterone/HPßCD associations. RESULTS: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPßCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPßCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. CONCLUSIONS: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.

Enhanced transdermal delivery of luteolin via non-ionic surfactant-based vesicle: quality evaluation and anti-arthritic assessment.

Luteolin (LUT) is a promising molecule with potential anti-arthritic activity. This investigation presents formulation and evaluation of niosomal transgel for enhanced transdermal delivery of LUT. Different non-ionic surfactants and vesicle compositions were employed for preparation of niosomes. The vesicle size analysis showed that all vesicles were in the range from 534.58 to 810.22 nm which favoured efficient transdermal delivery. The entrapment of LUT in vesicle was found to be higher in all surfactant. The developed formulation was proved significantly superior in terms of amount of drug permeation with an enhancement ratio of 2.66 when compared to a control formulation. The in vivo bioactivity studies revealed that the prepared niotransgel formulation of LUT was able to provide good anti-arthritic activity and the results were comparable to standard (diclofenac gel for anti-arthritic and analgesic). Finally, the results were confirmed through radiological analysis which proved that the prepared niotransgel was effectively able to treat arthritis and results were comparable with the standard formulation.

Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a cost-effectiveness analysis.

OBJECTIVES: The aim of the present study was to perform a comparative cost-effectiveness analysis of the different strategies used to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis. METHODS: We performed a cost-effectiveness decision analysis of 4 prophylactic strategies (nonsteroidal anti-inflammatory drugs or NSAIDs, pancreatic stent, stent plus rectal indomethacin, and no prophylaxis) in a simulated cohort of 300 patients during 1 year. Treatment effectiveness was defined as the number of patients who did not develop post-ERCP pancreatitis. RESULTS: The baseline costs of each strategy were as follows: rectal NSAID $359,098, pancreatic stent $426,504, stent plus rectal indomethacin $479,153, and no prophylaxis $491,275. The mean number of cases developing post-ERCP pancreatitis was 16, 21, 23, and 37 for the strategies rectal NSAID, pancreatic stent, stent plus rectal indomethacin, and no prophylaxis, respectively. Taking rectal NSAID prophylaxis as the reference strategy, the odds ratio of an episode of post-ERCP acute pancreatitis after pancreatic stent placement was 1.33 (95% confidence interval [CI], 0.68-2.61); after stent plus indomethacin, it was 1.40 (95% CI, 0.72-2.73), and after no prophylaxis, it was 2.49 (95% CI, 1.35-4.59). CONCLUSIONS: Rectal NSAID administration proved to be the most cost-effective prophylactic strategy used to prevent post-ERCP pancreatitis. The strategy of no prophylaxis for this complication should be avoided.

A cost-effectiveness analysis of celecoxib compared with diclofenac in the treatment of pain in osteoarthritis (OA) within the Swedish health system using an adaptation of the NICE OA model.

OBJECTIVES: Celecoxib for the treatment of pain resulting from osteoarthritis (OA) was reviewed by the Tandvårds- och läkemedelsförmånsverket-Dental and Pharmaceutical Benefits Board (TLV) in Sweden in late 2010. This study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus a PPI in a Swedish setting. METHODS: The National Institute for Health and Care Excellence (NICE) in the UK developed a health economic model as part of their 2008 assessment of treatments for OA. In this analysis, the model was reconstructed and adapted to a Swedish perspective. Drug costs were updated using the TLV database. Adverse event costs were calculated using the regional price list of Southern Sweden and the standard treatment guidelines from the county council of Stockholm. Costs for treating cardiovascular (CV) events were taken from the Swedish DRG codes and the literature. RESULTS: Over a patient's lifetime treatment with celecoxib plus a PPI was associated with a quality-adjusted life year (QALY) gain of 0.006 per patient when compared to diclofenac plus a PPI. There was an increase in discounted costs of 529 kr per patient, which resulted in an incremental cost-effectiveness ratio (ICER) of 82,313 kr ($12,141). Sensitivity analysis showed that treatment was more cost effective in patients with an increased risk of bleeding or gastrointestinal (GI) complications. CONCLUSIONS: The results suggest that celecoxib plus a PPI is a cost effective treatment for OA when compared to diclofenac plus a PPI. Treatment is shown to be more cost effective in Sweden for patients with a high risk of bleeding or GI complications. It was in this population that the TLV gave a positive recommendation. There are known limitations on efficacy in the original NICE model.

A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp.

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.

Application of artificial neural networks in prediction of diclofenac sodium release from drug-modified zeolites physical mixtures and antiedematous activity assessment.

In this study, utilization of artificial neural network (ANN) models [static-multilayer perceptron (MLP) and generalized regression neural networks and dynamic-gamma one-layer network and recurrent one-layer network] for prediction of diclofenac sodium (DS) release from drug-cationic surfactant-modified zeolites physical mixtures comprising different surfactant/drug molar ratio (0.2-2.5) was performed. The inputs for ANNs trainings were surfactant/drug molar ratios, that is, drug loadings in the drug-modified zeolite mixtures, whereas the outputs were percents of drug release in predetermined time points during drug release test (8 h). The obtained results revealed that MLP showed the highest correlation between experimental and predicted drug release. The safety of both natural and cationic surfactant-modified zeolite as a potential excipient was confirmed in an acute toxicity testing during 72 h. DS (1.5, 5, 10, mg/kg, p.o.) as well as DS-modified zeolites mixtures produced a significant dose-dependent reduction of the rat paw edema induced by proinflammatory agent carrageenan. DS antiedematous effect was intensified and prolonged significantly by modified zeolite. These results could suggest the potential improvement in the treatment of inflammation by DS-modified zeolite mixtures.

Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug-drug interaction assessment in a mouse model.

Sunitinib is a tyrosine kinase inhibitor for GIST and advanced renal cell carcinoma. Diclofenac is used in cancer pain management. Coadministration may mediate P450 toxicity. We evaluate their interaction, assessing biomarkers ALT, AST, BUN, creatinine, and histopathological changes in the liver, kidney, heart, brain, and spleen. ICR mice (male, n = 6 per group/dose) were administered saline (group A) or 30 mg/kg diclofenac ip (group B), or sunitinib po at 25, 50, 80, 100, 140 mg/kg (group C) or combination of diclofenac (30 mg/kg, ip) and sunitinib (25, 50, 80, 100, 140 mg/kg po). Diclofenac was administered 15 min before sunitinib, mice were euthanized 4 h post-sunitinib dose, and biomarkers and tissue histopathology were assessed. AST was 92.2 ± 8.0 U/L in group A and 159.7 ± 14.6 U/L in group B (p < 0.05); in group C, it the range was 105.1-152.6 U/L, and in group D, it was 156.0-209.5 U/L (p < 0.05). ALT was 48.9 ± 1.6 U/L (group A), 95.1 ± 4.5 U/L (p < 0.05) in group B, and 50.5-77.5 U/L in group C and 82.3-115.6 U/L after coadministration (p < 0.05). Renal function biomarker BUN was 16.3 ± 0.6 mg/dl (group A) and increased to 29.9 ± 2.6 mg/dl in group B (p < 0.05) and it the range was 19.1-33.3 mg/dl (p < 0.05) and 26.9-40.8 mg/dl in groups C and D, respectively. Creatinine was 5.9 pmol/ml in group A; 6.2 pmol/ml in group B (p < 0.01), and the range was 6.0-6.2 and 6.2-6.4 pmol/ml in groups C and D, respectively (p < 0.05 for D). Histopathological assessment (vascular and inflammation damages) showed toxicity in group B (p < 0.05) and mild toxicity in group C. Damage was significantly lesser in group D than group B (p < 0.05). Spleen only showed toxicity after coadministration. These results suggest vascular and inflammation protective effects of sunitinib, not shown after biomarker analysis.

Clinical, dermoscopic and immunohistochemical assessment of actinic keratoses and evaluation of the effectiveness of diclofenac therapy with immunohistochemical analysis.

Actinic keratoses (AKs) is a keratinocytic neoplasm that typically develops on the face of elderly patients. Little is known regarding the clinical, dermatoscopic and immunohistochemical assessments of AK using topical diclofenac therapy. We sought to determine these assessments and evaluate the efficacy of topical diclofenac gel in AK. In this prospective, open-label study, 44 patients with 66 AKs were treated for 12 weeks with topically applied diclofenac (3% gel in 2.5% hyaluronic acid). Immunohistopathologic analyses were performed before and after diclofenac treatment using epidermal stem cell markers such as Cytokeratin 15 (CK15), Cytokeratin 19 (CK19) and p63, in addition to proliferation markers (Bcl-2, Ki-67). Diclofenac gel was found to be effective in AK, including the hyperkeratotic type. Surprisingly, complete remission was observed at a significantly higher rate in Grade 3 lesions (p = 0.017). However, imunohistochemical and histopathologic examinations revealed that 12-week treatment periods may not be sufficient to fully cure AK. The immunohistochemical analyses revealed no change in the expression levels of CK15, CK19 and Bcl-2 following diclofenac therapy. However, the expression of Ki-67 (p = 0.042) and p63 (p = 0.030) exhibited a significant decrease after therapy. Dermatoscopy is an effective method for diagnosis of AK, and topical diclofenac sodium gel was found as an effective additional treatment modality. Since positive histopathological findings were detected in some patients even with significant remission, a 12-week treatment period should be extended even in patients presenting with positive clinical response. Importantly, anti-proliferative effects of diclofenac were demonstrated by decreased Ki-67 and p63 expression levels.

An initial safety assessment of hepatotoxic and nephrotoxic potential of intramuscular ketoprofen at single repetitive dose level in broiler chickens.

A study was undertaken to assess the hepatotoxic and nephrotoxic potential of ketoprofen in comparison with diclofenac upon short-term intramuscular (i.m.) administration in broiler chickens. Eighteen broiler chickens were randomly divided into 3 groups of 6 birds each. Group I served as the control and received normal saline (0.1 mL, i.m.), group II was the positive control and received diclofenac sodium (2.5 mg/kg, i.m.), and group III received ketoprofen (3 mg/kg, i.m.) daily at 24-h intervals for 5 consecutive days. Diclofenac sodium-treated birds showed severe clinical signs of toxicity with high mortality, a significant increase (P < 0.01) in serum concentrations of creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase, and these changes correlated well with gross and microscopic examination findings of kidney and liver. In contrast, ketoprofen-treated birds did not show any adverse clinical signs and no significant increase in concentration of creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase when compared with birds in group I. Gross and microscopic examination of kidney and liver showed normal organ architecture. Thus, based on the present findings, it was concluded that ketoprofen at the dose of 3 mg/kg administered intramuscularly daily for 5 d was nontoxic to broiler chickens.

An assessment of the efficacy and safety of diclofenac potassium liquid-filled capsules in patients with various levels of baseline pain intensity.

CONTEXT: Diclofenac potassium liquid-filled soft gelatin capsule (DPSGC; Zipsor*) is a novel formulation of diclofenac potassium used to treat mild to moderate acute pain. OBJECTIVE: To investigate whether DPSGC 25 mg provided significant reduction in pain intensity compared with placebo, regardless of baseline pain intensity, a post hoc analysis was performed of pooled data from two replicate randomized controlled trials (NCT00366444 and NCT00375934) that evaluated the safety and efficacy of DPSGC in postbunionectomy treatment. METHODS: Patients from the two randomized trials were assigned to one of two subgroups: patients with baseline numerical pain rating scale (NPRS) scores of 4 or greater to less than 7 and those with baseline NPRS scores of 7 or greater. Within each subgroup, efficacy and safety of DPSGC was compared with placebo. RESULTS: Across the two studies, 73 DPSGC- and 59 placebo-treated patients had baseline pain intensity scores ranging from 4 or greater to less than 7, while 128 DPSGC- and 141 placebo-treated patients had baseline pain intensity scores of 7 or greater. Significantly lower mean 48-hour NPRS scores were observed in the DPSGC group, regardless of baseline pain intensity (P < 0.0001). In both subgroups, at least twice as many patients treated with DPSGC rated the study drug as very good or excellent compared with patients taking placebo. Potential limitations for this post hoc analysis include study design and patient population. As with all studies investigating treatment for pain, the use of rescue medication may also be a potential limitation. CONCLUSIONS: DPSGC provided significantly greater improvements in pain compared with placebo following bunionectomy, regardless of patients' baseline pain level.