Lubricating Microneedles System with Multistage Sustained Drug Delivery for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is a typical joint degenerative disease that is prevalent worldwide and significantly affects the normal activities of patients. Traditional treatments using diclofenac (DCF) as an anti-inflammatory drug by oral administration and transdermal delivery have many inherent deficiencies. In this study, a lubricating microneedles (MNs) system for the treatment of osteoarthritis with multistage sustained drug delivery and great reduction in skin damage during MNs penetration is developed. The bilayer dissolvable MNs system, namely HA-DCF@PDMPC, is prepared by designating the composite material of hyaluronic acid (HA) and covalently conjugated drug compound (HA-DCF) as the MNs tips and then modifying the surface of MNs tips with a self-adhesive lubricating copolymer (PDMPC). The MNs system is designed to achieve sustained drug release of DCF via ester bond hydrolysis, physical diffusion from MNs tips, and breakthrough of lubrication coating. Additionally, skin damage is reduced due to the presence of the lubrication coating on the superficial surface. Therefore, the lubricating MNs with multistage sustained drug delivery show good compliance as a transdermal patch for OA treatment, which is validated from anti-inflammatory cell tests and therapeutic animal experiments, down-regulating the expression levels of pro-inflammatory factors and alleviating articular cartilage destruction.

Topical Diclofenac Versus Oral Ibuprofen Versus Diclofenac + Ibuprofen for Emergency Department Patients With Acute Low Back Pain: A Randomized Study.

STUDY OBJECTIVE: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for a variety of musculoskeletal injuries. It is not known whether topical NSAIDs should be used for patients presenting with acute nonradicular musculoskeletal low back pain. METHODS: We conducted a randomized, placebo-controlled double-blind study in which patients 18 to 69 years of age visiting the emergency department (ED) with acute, nontraumatic, nonradicular, musculoskeletal low back pain were randomized at the time of discharge to treatment with 400 mg oral ibuprofen + placebo topical gel, 1% diclofenac topical gel + oral placebo, or 400 mg ibuprofen + 1% diclofenac topical gel. We measured outcomes using the Roland Morris Disability Questionnaire (RMDQ), a 24-item yes/no instrument about the effect of back pain on a respondent's daily activities. The primary outcome was change in RMDQ score between ED discharge and 2 days later. Medication-related adverse events were elicited by asking whether the study medications caused any new symptoms. RESULTS: In total, 3,281 patients were screened for participation, and 198 were randomized. Overall, 36% of the population were women, the mean age was 40 years (standard deviation, 13), and the median RMDQ score at baseline was 18 (25th to 75th percentile: 13 to 22), indicating substantial low back-related functional impairment. In total, 183 (92%) participants provided primary outcome data. Two days after the ED visit, the ibuprofen + placebo group had improved by 10.1 (95% confidence interval [CI] 7.5 to 12.7), the diclofenac gel + placebo group by 6.4 (95% CI 4.0 to 8.8), and the ibuprofen + diclofenac gel by 8.7 (95% CI 6.3 to 11.1). The between-group differences were as follows: ibuprofen versus diclofenac, 3.7 (95% CI 0.2 to 7.2); ibuprofen versus both medications 1.4 (95% CI -2.1 to 4.9); and diclofenac versus both medications, 2.3 (95% CI -5.7 to 1.0). Medication-related adverse events were reported by 3/60 (5%) ibuprofen patients, 1/63 (2%) diclofenac patients, and 4/64 (6%) patients who received both. CONCLUSION: Among patients with nontraumatic, nonradicular acute musculoskeletal low back pain discharged from an ED, topical diclofenac was probably less efficacious than oral ibuprofen. It demonstrated no additive benefit when coadministered with oral ibuprofen.

Incidence of Post-ERCP Pancreatitis in Patients Receiving Rectal Indomethacin vs. Compounded Rectal Diclofenac Prophylaxis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) carries a 3-15% risk of post-ERCP pancreatitis (PEP). Rectal indomethacin reduces the risk of PEP, but its cost has increased more than 20-fold over the past decade. Rectal diclofenac is also used to prevent PEP but is not commercially available in the United States. The aim of this study is to compare the incidence of PEP after administration of commercially available rectal indomethacin versus compounded rectal diclofenac and assess financial implications. METHODS: ERCP cases at our institution with administration of 100 mg rectal indomethacin or 100 mg compounded rectal diclofenac between May 2018 and January 2022 were retrospectively reviewed. The incidence and severity of PEP was compared between the indomethacin (n = 728) and diclofenac (n = 304) groups. Risk factors (young age, female sex, history of pancreatitis or PEP, sphincterotomy during procedure, pancreatic indication, trainee involvement) and protective factors (prior sphincterotomy, pancreatic duct stenting) for PEP were compared between groups. RESULTS: 60 patients (8.2%) in the rectal indomethacin group and 25 patients (8.2%) in the compounded rectal diclofenac group developed PEP, resulting in moderate or severe PEP in 9 (15.0%) and 2 (8.0%) patients, respectively. The compounded rectal diclofenac group had more trainee involvement (46.1% vs. 32.8%, p = 0.0001) and more prior sphincterotomy cases (15.8% vs. 10.6%, p = 0.0193) compared to the rectal indomethacin group; no statistically significant differences were observed in all other risk and protective factors. Following switch to compounded rectal diclofenac, institutional annual cost savings amounted to $441,460.62 and patient charge decreased 45-fold. CONCLUSION: This retrospective single-center real-world analysis showed similar efficacy of rectal indomethacin and compounded rectal diclofenac in preventing PEP but demonstrates substantial cost savings after switching to compounded rectal diclofenac.

Comparison of diclofenac with tramadol, tizanidine or placebo in the treatment of acute low back pain and sciatica: multi-center randomized controlled trial.

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.

Is Diclofenac Transbuccal Mucoadhesive Patch Superior to Oral Diclofenac for the Management of Postoperative Sequelae After Third Molar Surgery?

BACKGROUND: Pain, swelling, and trismus are the most common sequalae following the surgical removal of mandibular third molars. They pose significant challenges for clinicians, prompting the exploration of efficacious management approaches. PURPOSE: The purpose of this study was to assess the efficacy of transbuccal mucoadhesive patch of diclofenac sodium versus an oral tablet in controlling the aforesaid sequelae. STUDY DESIGN, SETTING, SAMPLE: A prospective split-mouth, single-blinded study was conducted in the Department of Oral and Maxillofacial Surgery at AMC Dental College and Hospital, Ahmedabad. The study sample included patients of either sex, aged 18 to 45 years, requiring surgical removal of bilaterally symmetrical mandibular third molars under local anesthesia. Patients who had consumed analgesics within 24 hours prior to the procedure were excluded. PREDICTOR VARIABLE: The primary predictor variable was the route of administration of nonsteroidal anti-inflammatory drug. The study group received transbuccal mucoadhesive patches containing 20 mg diclofenac sodium, whereas the control group received oral tablets of 50 mg. MAIN OUTCOME VARIABLE: Postoperative pain, measured with visual analog scale, was the primary outcome variable, whereas swelling, mouth opening, onset of analgesic effect, and adverse events were assessed as secondary outcome variables. COVARIATES: Two categories of covariates were considered. First, demographic: age and gender. Second, perioperative: pattern of impaction. ANALYSES: Intergroup comparison was made using a paired sample t-test and an independent sample t-test, while intragroup differences were assessed with a one-way ANOVA and a paired t-test. P value ≤ .05 was considered statistically significant. RESULTS: Out of 146 patients screened initially, the final study sample included 37 subjects with a mean age of 26.08 ± 5.09 years (21 (56.75%) males and 16 (43.25%) females). The study group exhibited a significantly lower postoperative pain score compared to the control group on days 0, 1, 2, and 3 postoperatively (P ≤ .05). No statistically significant difference was observed in reduction of facial swelling and improvement in mouth opening on 1st, 2nd, and 3rd days postoperatively between both the groups (P ≥ .05). The mean onset of analgesia was statistically significant in the study group (19.96 ± 5.40 minutes) compared to the control group (52.56 ± 6.33 minutes) (P < .001). CONCLUSION AND RELEVANCE: Transbuccal mucoadhesive patch of diclofenac sodium offers effective pain control with quicker analgesia and fewer side effects compared to an oral tablet.

Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats.

These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.

Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium.

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream-gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream-gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream-gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream-gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

Effect of Fluid Paraffin on the Formulation Properties of Pressure Sensitive Adhesive Formulations Containing Diclofenac Sodium.

Understanding the relationship between the release characteristics of the active ingredient in the tape formulation and the pharmaceutical characteristics of the adhesive layer can optimize therapeutic efficacy and improve patient adherence. This study aimed to clarify the effect of liquid paraffine (LP)/styrene-isoprene-styrene (SIS) triblock copolymer ratio on pressure-sensitive adhesive (PSA) formulation properties, such as adhesive properties and drug release, with a certain amount of diclofenac sodium (DFS) and tackifier. The effects of changes in PSA composition in DFS-containing tape formulations on adhesive and drug release properties were evaluated. The viscoelasticity results showed rigid gel-like behavior at low angular frequencies regardless of the LP/SIS ratio, and deformable gel-like behavior at high angular frequencies, with a maximum plasticizing effect of LP up to an LP/SIS ratio of 3.7. The peel adhesion test results showed that peel adhesion was not affected, but indicated a decreasing trend by increasing the LP/SIS ratio in the presence of DFS. Drug release test results showed that DFS release increased up to 24 h for LP/SIS ratios of up to 3.7, but decreased when the LP/SIS ratio was 6. The results of the drug permeation tests were similar to those of the drug release tests. In conclusion, it is possible to change the drug release properties by changing the amount of LP in the tape formulation; however, no definitive correlation was found between the adhesive and drug release properties.

Study of PT1 Peptide Analgesic and Anti-Inflammatory Activity on a Local Inflammation Model in Mice CD-1.

PT1 peptide isolated from the venom of spider Geolycosa sp. is a modulator of P2X3 receptors that play a role in the development of inflammation and the transmission of pain impulses. The anti-inflammatory and analgesic efficacy of the PT1 peptide was studied in a model of complete Freund's adjuvant-induced paw inflammation in CD-1 mice. The analgesic activity of PT1 peptide was maximum after intramuscular injection at a dose of 0.01 mg/kg, which surpassed the analgesic effect of diclofenac at a dose of 1 mg/kg. The anti-inflammatory activity was maximum after intramuscular injection at a dose of 0.0001 mg/kg; a decrease in paw thickness was observed as soon as 2 h after the administration of the PT1 peptide against the background of inflammation development. All tested doses of PT1 peptide showed high anti-inflammatory activity 4 and 24 h after administration. PT1 peptide at a dose of 0.01 mg/kg when injected intramuscularly simultaneously produced high anti-inflammatory and analgesic effects compared to other doses of the peptide. Increasing the dose of PT1 peptide led to a gradual decrease in its analgesic and anti-inflammatory activity; increasing the dose of intramuscular injection to 0.1 and 1 mg/kg is inappropriate.

[Pain relief after abdominal oncologic surgery. Evaluation of the effectiveness and safety of a fixed combination of diclofenac and orphenadrine]. / Obezbolivanie posle abdominal'nykh onkokhirurgicheskikh vmeshatel'stv. Otsenka effektivnosti i perenosimosti fiksirovannoi kombinatsii diklofenaka i orfenadrina.

OBJECTIVE: Evaluation of the analgesic, opioid-sparing, anti-inflammatory and adverse effects of the diclofenac and orphenadrine (Neodolpasse) fixed combination for analgesia in the postoperative period of surgical cancer patients. MATERIAL AND METHODS: A randomized, single-center, prospective, comparative study evaluated two analgesic regimens in 40 cancer patients undergoing various open cavity surgeries, including extensive combined interventions associated with the resection of 3 or more organs. The study was conducted following the transfer from the ICU to the surgical department during the early activation period, within the first two postoperative days. In the first group N (n=20), "Neodolpasse" (a fixed combination of 75 mg Diclofenac and 30 mg Orphenadrine) was administered as an infusion, twice daily. In the second group K (n=20) analgesia was performed with ketoprofen as an intravenous infusion at a daily dose of 200 mg. Patients in both groups received scheduled prolonged epidural analgesia with 0.2% ropivacaine, and when the severity of pain in a visual analogue scale (VAS) increased to more than 40 mm, so an additional dose of 100 mg tramadol was administered intramuscularly. Daily measurments of blood creatinine level and C-reactive protein were taken, postoperative blood loss was accounted for, as well as postoperative complications according to the Clavien-Dindo classification. RESULTS: The comparative analysis of the indicators of pain syndrome severity showed that the patients in group N exhibited a more pronounced analgesic effect, so on the second postoperative day 30% of patients reported moderate pain (from 50 to 60 mm on the pain scale), on the third day - 15%, and by the fourth day - all 100% of patients experienced pain of low intensity. The additional analgesia with tramadol in group N was required twice less than in the comparison group, and such adverse effects as nausea, drowsiness, and weakness were significantly more common in the ketoprofen group. In both groups, the average blood creatinine level did not exceed permissible values, and the C-reactive protein was elevated at all stages of the study but tended to decrease by the fourth day. The analysis of postoperative complications according to the Clavien-Dindo scale at the time of discharge did not reveal a direct correlation between the occurred complications and the use of NSAIDs. Adverse effects such as anastomotic failure, gastrointestinal complications, or other hemorrhagic manifestations were not recorded. CONCLUSION: The inclusion of Neodolpasse into multimodal analgesic regimens resulted in the most pronounced analgesic and opioid-sparing effects in surgical cancer patients using laparotomy access. Additionally, the application of short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a favorable safety profile.

Melittin and diclofenac synergistically promote wound healing in a pathway involving TGF-ß1.

A dysregulation of the wound healing process can lead to the development of various intractable ulcers or excessive scar formation. Therefore it is essential to identify novel pharmacological strategies to promote wound healing and restore the mechanical integrity of injured tissue. The goal of the present study was to formulate a nano-complex containing melittin (MEL) and diclofenac (DCL) with the aim to evaluate their synergism and preclinical efficacy in an in vivo model of acute wound. After its preparation and characterization, the therapeutic potential of the combined nano-complexes was evaluated. MEL-DCL nano-complexes exhibited better regenerated epithelium, keratinization, epidermal proliferation, and granulation tissue formation, which in turn showed better wound healing activity compared to MEL, DCL, or positive control. The nano-complexes also showed significantly enhanced antioxidant activity. Treatment of wounded skin with MEL-DCL nano-complexes showed significant reduction of interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) pro-inflammatory markers that was paralleled by a substantial increase in mRNA expression levels of collagen, type I, alpha 1 (Col1A1) and collagen, type IV, alpha 1 (Col4A1), and hydroxyproline content as compared to individual drugs. Additionally, MEL-DCL nano-complexes were able to significantly increase hypoxia-inducible factor 1-alpha (HIF-1α) and transforming growth factor beta 1 (TGF-ß1) proteins expression compared to single drugs or negative control group. SB431542, a selective inhibitor of type-1 TGF-ß receptor, significantly prevented in our in vitro assay the wound healing process induced by the MEL-DCL nano-complexes, suggesting a key role of TGF-ß1 in the wound closure. In conclusion, the nano-complex of MEL-DCL represents a novel pharmacological tool that can be topically applied to improve wound healing.

Sustained-release diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 2 study.

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.

Montelukast potentiates the antiinflammatory effect of NSAIDs in the rat paw formalin model and simultaneously minimizes the risk of gastric damage.

OBJECTIVE AND DESIGN: Montelukast, a cysteinyl leukotriene receptor antagonist, exhibits antiinflammatory action. We tested whether exposure to montelukast plus nonsteroidal antiinflammatory drugs (NSAIDs) elicits better control of paw inflammation in the rat formalin test and improves associated gastric damage. MATERIALS: A total of 46 adult male rats were used in the study. TREATMENTS: We evaluated separate and combined effects of montelukast (20 mg/kg), celecoxib (COX2 inhibitor, 10 mg/kg), and diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg) on paw and gastric damage in the rat formalin test. RESULTS: Individual pretreatments of rats with montelukast, diclofenac, or celecoxib partly reduced formalin-induced increases in (i) paw edema, fibrosis, and inflammatory cells, (iii) serum interleukin-6 (IL-6) and leukotrienes (LTB4 and LTD4), and (iv) paw expressions of inducible nitric oxide synthase (iNOS) and COX2. These effects were accentuated in rats treated with montelukast plus diclofenac or montelukast plus celecoxib. Alternatively, montelukast or celecoxib, but not diclofenac, alleviated formalin-evoked gastric damage and increments in tumor necrosis factor-α and decrements in prostaglandin-E2. These advantageous gastric influences were potentiated in rats treated with montelukast plus celecoxib. CONCLUSIONS: While montelukast equally enhances antiinflammatory action of diclofenac or celecoxib via downregulating iNOS/COX2/LTs/IL-6 signaling, its gastroprotective action is preferentially potentiated by celecoxib.

A 25 mg rectal dose of diclofenac for prevention of post-ERCP pancreatitis in elderly patients.

OBJECTIVES: A 50-100 mg rectal dose of diclofenac or indomethacin is recommended for prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP); however, limited data are available regarding the appropriate dose to prevent PEP in elderly patients. We aimed to evaluate the efficacy and safety of 25 mg diclofenac in preventing PEP in elderly patients. Material and methods: Overall, 276 patients with naive papilla, aged over 75 years, were included in the present study between April 2013 and March 2020. We retrospectively evaluated the risk of PEP in patients over 75 years, administered with or without 25 mg diclofenac 30 min before ERCP using inverse probability of treatment weighting (IPTW) analysis. Results: Patients were categorized into the diclofenac group (83 patients) or non-diclofenac group (193 patients). The incidence rate of PEP in the diclofenac group was significantly lower than that in the non-diclofenac group (4% vs. 14%, p = .01). Multivariate analysis revealed that 25 mg diclofenac was an independent protective factor against PEP in elderly patients aged over 75 years (odds ratio [OR] = 0.17; 95% confidence interval [CI] = 0.04-0.67; p = 0.01). This protective effect of diclofenac against PEP remained robust after IPTW analysis (OR = 0.11; 95% CI = 0.03-0.40; p = .001). No adverse events related to diclofenac were observed. Conclusion: Diclofenac (25 mg) was considered effective and safe for preventing PEP in elderly patients. Our results may provide a new strategy for preventing PEP in elderly patients.

Quantification of the inflammatory responses to pro-and anti-inflammatory agents in Manila clam, Ruditapes philippinarum.

Inflammation is a form of innate immune response of living organisms to harmful stimuli. In marine bivalves, inflammation is a common defense mechanism. Several studies have investigated the morphological features of inflammation in bivalves, such as hemocyte infiltration. However, the molecular and biochemical responses associated with inflammation in marine bivalves remain unexplored. Here, we investigated changes in nitric oxide (NO) levels, cyclooxygenase 2 (COX-2) activity, and allograft inflammatory factor-1 (AIF-1) gene expression levels in hemolymph samples collected from Manila clam (Ruditapes philippinarum) exposed to pro- and anti-inflammatory substances. These included the pro-inflammatory agent lipopolysaccharide (LPS), and the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and diclofenac, all widely used in vertebrates. Our study showed that NO levels, COX-2 activity, and AIF-1 expression increased in response to the treatments with LPS and decreased in response to the treatments with NSAIDs in a concentration-dependent manner. These results suggest that the mechanism of inflammatory responses in bivalves is very similar to that of vertebrates, and we propose that inflammatory responses can be quantified using these techniques and used to determine the physiological status of marine bivalves exposed to biotic or abiotic stresses.

Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis with a combination of pharmacological agents based on rectal non-steroidal anti-inflammatory drugs: A systematic review and network meta-analysis.

BACKGROUND AND AIMS: Rectally administered non-steroidal anti-inflammatory drugs (NSAIDs) are effective but suboptimal in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis or PEP. New trials with the combination of rectal NSAIDs and other pharmacological agents have been conducted. This network meta-analysis (NMA) aimed to determine the relative efficacy of combination regimens and identify an optimal regimen for preventing PEP. METHODS: We performed a systematic and comprehensive search to identify and analyze all the randomized controlled studies published until October 15, 2019, examining rectal NSAIDs and their combination with other pharmacological agents for the prevention of PEP. The primary outcome was the frequency of PEP. We conducted an NMA to combine the direct and indirect comparisons of rectal NSAIDs and their combination with other pharmacological agents. RESULTS: The NMA included 24 studies evaluating 14 regimens in 11 321 patients. According to predictive interval plot and surface under the cumulative ranking curve values, indomethacin + lactated Ringer's solution, followed by diclofenac + nitrate and indomethacin + normal saline, is the most efficacious combination of pharmacological agents for the overall prevention of PEP. Rectal indomethacin alone is the most efficacious agent for prevention of moderate to severe PEP, and rectal diclofenac is the most useful agent for prevention of PEP among the high-risk group. CONCLUSIONS: Rectal indomethacin with intravenous hydration and rectal diclofenac with sublingual nitrate are the most efficacious combination regimens for the overall prevention of PEP.

Cefepime and diclofenac sodium combined treatment-potentiated multiple organ injury: Role of oxidative damage and disrupted lipid metabolism.

Concurrent exposure to antimicrobial and nonsteroidal anti-inflammatory drugs (NSAIDs) is usually inevitable in most infections and postsurgery. Consequently, the present study was designed to assess the intertwining impact of coadministration of cefepime (CP, a wide spectrum antibiotic) and diclofenac sodium (DF, an NSAID) on rat's liver, kidney, and testes. Rats received saline, CP (180 mg/kg/day, IM), DF (10 mg/kg/day, IM), or a combination of CP and DF. After 14 days, CP or DF induced tissue damage expressed by marked biochemical alterations in hepatic and renal function tests. Besides this, disrupted lipid metabolism and testosterone levels along with significant histological changes in hepatic, renal, and testicular tissues were noticed. A significant increase in malondialdehyde and decreases in superoxide dismutase and catalase activities alongside significant upregulated caspase 3 expression in tissues following CP or DF treatment suggested a bearable influence of oxidative stress, lipid peroxidation, and cell death. Accordingly, the simultaneous therapy of CP and DF evoked more obvious tissue damage than their individual treatment. Overall, data concluded that concurrent use of CP and DF in medical practice is a worrisome matter, so it should be done cautiously to avoid synergistic deleterious outcomes.

Single-dose intravenous ketorolac for acute postoperative pain in adults.

BACKGROUND: Postoperative pain is common and may be severe. Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.  Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period. Our secondary outcomes were time to and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs. For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg. Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision. Ketorolac versus placebo Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7). Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03). Ketorolac versus NSAIDs  Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19). For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups.   Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE. AUTHORS' CONCLUSIONS: The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events.

Non-steroidal anti-inflammatory drugs (NSAIDs) for trigger finger.

BACKGROUND: Trigger finger is a common hand condition that occurs when movement of a finger flexor tendon through the first annular (A1) pulley is impaired by degeneration, inflammation, and swelling. This causes pain and restricted movement of the affected finger. Non-surgical treatment options include activity modification, oral and topical non-steroidal anti-inflammatory drugs (NSAIDs), splinting, and local injections with anti-inflammatory drugs. OBJECTIVES: To review the benefits and harms of non-steroidal anti-inflammatory drugs (NSAIDs) versus placebo, glucocorticoids, or different NSAIDs administered by the same route for trigger finger. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, CNKI (China National Knowledge Infrastructure), ProQuest Dissertations and Theses, www.ClinicalTrials.gov, and the WHO trials portal until 30 September 2020. We applied no language or publication status restrictions. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and quasi-randomised trials of adult participants with trigger finger that compared NSAIDs administered topically, orally, or by injection versus placebo, glucocorticoid, or different NSAIDs administered by the same route. DATA COLLECTION AND ANALYSIS: Two or more review authors independently screened the reports, extracted data, and assessed risk of bias and GRADE certainty of evidence. The seven major outcomes were resolution of trigger finger symptoms, persistent moderate or severe symptoms, recurrence of symptoms, total active range of finger motion, residual pain, patient satisfaction, and adverse events. Treatment effects were reported as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). MAIN RESULTS: Two RCTs conducted in an outpatient hospital setting were included (231 adult participants, mean age 58.6 years, 60% female, 95% to 100% moderate to severe disease). Both studies compared a single injection of a non-selective NSAID (12.5 mg diclofenac or 15.0 mg ketorolac) given at lower than normal doses with a single injection of a glucocorticoid (triamcinolone 20 mg or 5 mg), with maximum follow-up duration of 12 weeks or 24 weeks. In both studies, we detected risk of attrition and performance bias. One study also had risk of selection bias. The effects of treatment were sensitive to assumptions about missing outcomes. All seven outcomes were reported in one study, and five in the other. NSAID injection may offer little to no benefit over glucocorticoid injection, based on low- to very low-certainty evidence from two trials. Evidence was downgraded for bias and imprecision. There may be little to no difference between groups in resolution of symptoms at 12 to 24 weeks (34% with NSAIDs, 41% with glucocorticoids; absolute effect 7% lower, 95% confidence interval (CI) 16% lower to 5% higher; 2 studies, 231 participants; RR 0.83, 95% CI 0.62 to 1.11; low-certainty evidence). The rate of persistent moderate to severe symptoms may be higher at 12 to 24 weeks in the NSAIDs group (28%) compared to the glucocorticoid group (14%) (absolute effect 14% higher, 95% CI 2% to 33% higher; 2 studies, 231 participants; RR 2.03, 95% CI 1.19 to 3.46; low-certainty evidence). We are uncertain whether NSAIDs result in fewer recurrences at 12 to 24 weeks (1%) compared to glucocorticoid (21%) (absolute effect 20% lower, 95% CI 21% to 13% lower; 2 studies, 231 participants; RR 0.07, 95% CI 0.01 to 0.38; very low-certainty evidence). There may be little to no difference between groups in mean total active motion at 24 weeks (235 degrees with NSAIDs, 240 degrees with glucocorticoid) (absolute effect 5% lower, 95% CI 34.54% lower to 24.54% higher; 1 study, 99 participants; MD -5.00, 95% CI -34.54 to 24.54; low-certainty evidence). There may be little to no difference between groups in residual pain at 12 to 24 weeks (20% with NSAIDs, 24% with glucocorticoid) (absolute effect 4% lower, 95% CI 11% lower to 7% higher; 2 studies, 231 participants; RR 0.84, 95% CI 0.54 to 1.31; low-certainty evidence). There may be little to no difference between groups in participant-reported treatment success at 24 weeks (64% with NSAIDs, 68% with glucocorticoid) (absolute effect 4% lower, 95% CI 18% lower to 15% higher; 1 study, 121 participants; RR 0.95, 95% CI 0.74 to 1.23; low-certainty evidence). We are uncertain whether NSAID injection has an effect on adverse events at 12 to 24 weeks (1% with NSAIDs, 1% with glucocorticoid) (absolute effect 0% difference, 95% CI 2% lower to 3% higher; 2 studies, 231 participants; RR 2.00, 95% CI 0.19 to 21.42; very low-certainty evidence). AUTHORS' CONCLUSIONS: For adults with trigger finger, by 24 weeks' follow-up, results from two trials show that compared to glucocorticoid injection, NSAID injection offered little to no benefit in the treatment of trigger finger. Specifically, there was no difference in resolution, symptoms, recurrence, total active motion, residual pain, participant-reported treatment success, or adverse events.

Intradermal sterile water injection versus diclofenac sodium in acute renal colic pain: A randomized controlled trial.

OBJECTIVES: We aimed to evaluate the efficacy of intracutaneous sterile water injection (ISWI) to relieve the pain of acute renal colic compared with diclofenac and placebo. METHODS: The study included 150 patients presented to the Emergency Department with renal colic randomized into 3 groups: control group received intracutaneous injections of 0.5 cm3 isotonic saline in the flank, group A received intracutaneous injections of 0.5 cm3 ISWI in the flank, and group B received an intramuscular injection of 75 mg Diclofenac in the gluteal region. The severity of the pain was assessed by a visual analogue scale system at baseline and 30, 45 min, and 60 min after injections. Subjects with inadequate pain relief at 1 h received rescue analgesia. RESULTS: The mean baseline pain score was 9.6 ± 0.61 in the ISWI group, 9.72 ± 0.64 in the diclofenac group and 9.26 ± 0.89 in the control group. The mean pain score at 30 min of the control group was reduced to 6.9 ± 1.56. This mean at 30 min after ISWI and diclofenac injections were reduced to 1.98 ± 1.41 and 1.88 ± 1.19 respectively. The mean of pain sore of the ISWI and diclofenac group at 45 and 60 min was constant. Rescue analgesics at 1 h were required by 47 patients receiving the saline injection and by 4 patients and by 7 patients receiving ISWI and diclofenac injection respectively. CONCLUSIONS: ISWI and diclofenac were equally effective for the pain relief of acute renal colic.