The Anti-Arthritic Activity of Diclofenac Lipid-Core Nanocapsules: Stereological Analysis Showing More Protection of Deep Joint Components.

Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is associated with serious adverse effects, even in regular-dose regimens. Drug delivery systems can overcome this issue by reducing adverse effects and optimizing their efficacy. This study evaluated the activity of lipid-core nanocapsules loaded with diclofenac (DIC-LNCs) in an experimental model of adjuvant-induced arthritis. The diclofenac nanoformulation was obtained via self-assembly. A stereological analysis approach was applied for the morphological quantification of the volume, density, and cellular profile count of the metatarsophalangeal joints of rats. Proinflammatory cytokines and biochemical profiles were also obtained. Our results showed that the diclofenac nanocapsule DIC-LNCs were able to reduce arthritis compared with the control group and the DIC group. DIC-LNCs efficiently reduced proinflammatory cytokines, C-reactive protein, and xanthine oxidase levels. Additionally, DIC-LNCs reduced the loss of synoviocytes and chondrocytes compared with the DIC (p < 0.05) and control groups (p < 0.05). These data suggest that DIC-LNCs have anti-arthritic activity and preserve joint components, making them promising for clinical use.

In vitro and in vivo anti-inflammatory activity of Cupressus torulosa D.DON needles extract and its chemical characterization.

ETHNOPHARMACOLOGICAL RELEVANCE: Cupressus torulosa (family Cupressaceae), widely distributed in the north western Himalayan region of India, is a coniferous aromatic tree with various traditional uses of its aerial parts. Its needles have been used for anti-inflammatory, anticonvulsant, antimicrobial, and wound-healing properties. AIM OF THE STUDY: The study aimed at investigating the previously unknown anti-inflammatory activity of the hydromethanolic extract of the needles employing in vitro and in vivo assays and scientifically validate traditional claim of their use in treatment of inflammation. Chemical characterization of the extract with the aid of UPLCQTOFMS was also of interest. MATERIALS AND METHODS: C. torulosa needles were first defatted with hexane and sequentially extracted with chloroform and 25% aqueous methanol (AM). Since the presence of phenolics (TPCs, 208.21 ± 0.95 mg GAE/g needles) and flavonoids (TFCs, 84.61 ± 1.21 mg QE/g needles) was observed in the AM extract only, it was chosen for biological and chemical examinations. Acute toxicity of the AM extract on female mice was evaluated following the OECD guideline 423. In vitro anti-inflammatory activity of the AM extract was examined using egg albumin denaturation assay while carrageenan-induced paw edema and formalin-induced paw edema models at doses of 100, 200 and 400 mg/kg po were used to determine the in vivo activity of the AM extract on Wistar rats of either sex. The components of the AM extract were analyzed by UPLC-QTOF-MS method using non-targeted metabolomics approach. RESULTS: AM extract was found to be non-toxic at 2000 mg/kg b.w. with no signs of abnormal locomotion, seizures and writhing. The extract demonstrated promising in vitro anti-inflammatory activity (IC50 160.01 µg/mL) compared to standard diclofenac sodium (IC50 73.94 µg/mL) in egg albumin denaturation assay. In carrageenan-induced paw edema and formalin-induced paw edema tests the extract showed significant anti- inflammatory activity (57.28% and 51.04% inhibition of paw edema, respectively) at the dose of 400 mg/kg p.o. after 4 h in comparison to the standard diclofenac sodium which displayed 61.39% and 52.90% inhibition, respectively, at the dose of 10 mg/kg p.o. after 4 h in these models. A total of 63 chemical constituents, majority of them being phenolics, were found in the AM extract of the needles. Two compounds namely monotropein (iridoid glycoside), (±)12-HETE (eicosanoid) and fraxin (coumarin glycoside) were reported to have anti-inflammatory effect. CONCLUSIONS: For the first time our study demonstrated that hydro-methanolic extract of C. torulosa needles exhibit anti-inflammatory activity thereby supporting their traditional use in the treatment of inflammatory disorders. UPLCQTOFMS assisted chemical profile of the extract was also unveiled.

Nociceptive improvements and kynurenine pathway alterations with diclofenac treatment in a rat model of neuropathic pain created by partial sciatic nerve ligation.

OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and anti-hyperalgesic effects and also alters KYNA levels, indicating a potential for therapy. We aimed to assess the nociceptive effects of different doses of diclofenac treatment in a rat model of neuropathic pain and to determine potential relationships with KYNA and QA levels (Graphical Abstract). MATERIALS AND METHODS: Twenty-eight Sprague-Dawley rats were divided into four groups: 40 mg/kg/day diclofenac (high-dose), 20 mg/kg/day diclofenac (normal-dose), non-treatment, and sham. Except for the sham group, the others underwent partial sciatic nerve ligation (left). Baseline (day 0) and post-treatment (day 3) KYNA and QA levels were measured. Allodynia and pain detection were assessed with the von Frey and hot plate tests. RESULTS: Baseline findings were similar in all groups. Compared to baseline, the non-treatment group had significantly worse allodynia on day 3. Baseline and post-treatment von Frey results (left) remained similar in the normal-dose diclofenac group (p=0.336); however, this benefit was not observed in the high-dose group. Relative to baseline, normal-dose diclofenac recipients had significantly higher KYNA concentration (p=0.046) and KYNA-to-QA ratio (p=0.028) on day 3. CONCLUSIONS: Our results show that 3-day therapy with 20 mg/kg/day diclofenac can improve nociceptive findings in neuropathic pain, and that this effect may be associated with increased KYNA or KYNA-to-QA ratio. The lack of dose-dependent effects may be associated with potential adverse influences of exceedingly high diclofenac dosage.

Diclofenac exhibits cytotoxic activity associated with metabolic alterations and p53 induction in ESCC cell lines and decreases ESCC tumor burden in vivo.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of human malignancy, often displaying limited therapeutic response. Here, we examine the non-steroidal anti-inflammatory drug diclofenac (DCF) as a novel therapeutic agent in ESCC using complementary in vitro and in vivo models. DCF selectively reduced viability of human ESCC cell lines TE11, KYSE150, and KYSE410 as compared with normal primary or immortalized esophageal keratinocytes. Apoptosis and altered cell cycle profiles were documented in DCF-treated TE11 and KYSE 150. In DCF-treated TE11, RNA-Sequencing identified differentially expressed genes and Ingenuity Pathway Analysis predicted alterations in pathways associated with cellular metabolism and p53 signaling. Downregulation of proteins associated with glycolysis was documented in DCF-treated TE11 and KYSE150. In response to DCF, TE11 cells further displayed reduced levels of ATP, pyruvate, and lactate. Evidence of mitochondrial depolarization and superoxide production was induced by DCF in TE11 and KYSE150. In DCF-treated TE11, the superoxide scavenger MitoTempo improved viability, supporting a role for mitochondrial reactive oxygen species in DCF-mediated toxicity. DCF treatment resulted in increased expression of p53 in TE11 and KYSE150. p53 was further identified as a mediator of DCF-mediated toxicity in TE11 as genetic depletion of p53 partially limited apoptosis in response to DCF. Consistent with the anticancer activity of DCF in vitro, the drug significantly decreased tumor burdene in syngeneic ESCC xenograft tumors and 4-nitroquinoline 1-oxide-mediated ESCC lesions in vivo. These preclinical findings identify DCF as an experimental therapeutic that should be explored further in ESCC.

Dry needling on latent and active myofascial trigger points versus oral diclofenac in patients with knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Latent and active myofascial trigger points (MTrPs) in knee-associated muscles may play a key role in pain management among patients with knee osteoarthritis (KOA). The aim of this study was to investigate the effect of dry needling treatment on pain intensity, disability, and range of motion (ROM) in patients with KOA. METHODS: This randomized, single-blinded, clinical trial was carried out for 6 weeks of treatment and 6-month follow-up. A total of 98 patients met the entry criteria and were randomly assigned to the dry needling latent and active myofascial trigger point (MTrPs) with the stretching group or the oral diclofenacwith the stretching group. Numeric Pain Rating Scale (NPRS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and ROM were statistically analyzed before and after treatment and at the 6-month follow-up. RESULTS: A total of 42 patients in the dry needling group (DNG) and 35 patients in the diclofenac group (DG), respectively, completed the study, and there was no significant difference in the general data between the two groups. After treatments, both the groups showed a good effect in knee pain, function, and ROM, However, the DNG showed a significantly better result than the DG. Especially in the results of the 6-month follow-up, the DNG showed much better results than the DG. CONCLUSIONS: Dry needling on latent and active MTrPs combined with stretching and oral diclofenac combined with stretching can effectively relieve pain, improve function, and restore knee ROM affected by KOA. However, the effects of dry needling and stretching are better and longer lasting than those of oral diclofenac and stretching for at least 6 months. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ) in 17/11/2017 with the following code: ChiCTR-INR-17013432.

Evaluating the effect of ursodeoxycholic acid (UDCA) in comparison with dexamethasone and diclofenac in a rat model of rheumatoid arthritis.

Ursodeoxycholic acid (UDCA) is known for its major effects on the liver, but its impact on autoimmune diseases is not well understood. This study aimed to assess the effectiveness of UDCA in controlling rheumatoid arthritis (RA) in an in vivo setting. Experimental RA was induced in rats using Freund's complete adjuvant, and the effects of UDCA (50,100 mg/kg) were compared to those of dexamethasone and diclofenac by measuring changes in paw size, IL-17, pro-inflammatory cytokines, oxidative stress (GSH, MDA), and radiological changes. The administration of UDCA resulted in decreased cartilage damage, reduced paw edema, and a decrease in the release of pro-inflammatory cytokines and oxidative stress. Additionally, X-ray joint alterations were observed in the UDCA-treated group compared to the dexamethasone and diclofenac groups. These results suggest that UDCA has anti-rheumatoid arthritis properties due to its ability to minimize oxidative stress and inflammation in arthritis-affected rats.

Effect of external use of Qingluo San on clinical efficacy in patients with acute gouty arthritis.

OBJECTIVE: The present study aimed to observe the clinical efficacy of the external use of Qingluo San combined with diclofenac sodium double-release enteric capsules in the treatment of acute gouty arthritis (dampness-heat accumulation syndrome). METHODS: A total of 58 acute gouty arthritis patients were divided into two groups using the random number table method. Diclofenac sodium double-release enteric capsules were orally administered in the control group. Based on the treatment in the control group, the external use of Qingluo San was given in the treatment group, with 7-day course of treatment. The changes in visual analog scale (VAS) scores, the tenderness, swelling, and mobility function of the joint, and the traditional Chinese medicine (TCM) syndrome scores before and after the treatment, at day 0, 1, 3, 5 and 7, were observed in both groups, together with the comparison of laboratory indicators (erythrocyte sedimentation rate, ESR; C-reactive protein, CRP; uric acid, UA). RESULTS: The total effective rate was 96.55% in the treatment group and 82.76% in the control group. After treatment, the VAS score, the tenderness, swelling and function scores of the joint, and the TCM syndrome scores decreased in both groups. The treatment group was superior in improving the VAS scores, the tenderness, swelling and mobility function of the joint, and TCM syndrome scores, when compared to the control group (p < 0.05). The laboratory indicators, which included the ESR, CRP and UA, obviously decreased in both groups after treatment (p < 0.05). The ESR significantly decreased in the treatment group, when compared to the control group (p < 0.05). CONCLUSION: The combination of the external use of Qingluo San and oral administration of diclofenac sodium double-release enteric capsules can more rapidly relieve joint pain, and improve the clinical efficacy. This combination therapy also has certain advantages in relieving joint swelling and improving the mobility function of the joint. Hence, this is worthy of clinical promotion and application.

2022 Taiwan Guidelines for Acute Treatment of Migraine.

The Taiwan Headache Society published its guidelines for acute migraine treatment in 2017. Since then, emerging drugs and treatment options have developed rapidly. The migraine-specific drugs gepants and ditans and several noninvasive neuromodulation devices have been approved for use in Europe and the United States. Although not all emerging drugs and treatment options have been approved for use in Taiwan, keeping pace with international trends and updating treatment guidelines are imperative. Therefore, the Treatment Guideline Subcommittee of the Taiwan Headache Society reviewed the quality of recent trials, evaluated the corresponding grade of evidence, and appraised the reported clinical efficacy to reach a new consensus. To ensure that the updated Taiwan guidelines are appropriate and feasible, the subcommittee also referred to the guidelines from the United States, Europe, Canada, and other countries concerning the main roles, recommendation levels, clinical efficacy, and adverse reactions of drugs for the acute migraine treatment. Several types of drugs are currently available for acute migraine treatment in Taiwan. These drugs can be categorized into migraine-specific and migraine-non-specific. Among them, migraine-specific triptans (oral or nasal spray formulations) and migraine-nonspecific acetaminophen and NSAIDs (diclofenac, ibuprofen, naproxen) are highly recommended because they are supported by strong evidence and demonstrate high efficacy. Prochlorperazine injection has been upgraded to a highly recommended level because of the rich clinical experience for this treatment. Ergotamine/caffeine remains a second-line drug because of its lower specificity and efficacy compared with triptans. High-dose aspirin was downgraded to rescue treatment because of potential gastrointestinal side effects. Although evidence supports the combination of oral tramadol and acetaminophen, this combination should be used as a rescue treatment due to concerns about dependence. Evidence supporting the use of intravenous tramadol or morphine is insufficient; therefore, their use is not recommended. As for non-pharmacological approaches, there are only limited controlled data. The choice of treatment for acute migraine attacks should follow the concept of "stratified care." For mild to moderate migraine attacks, oral NSAIDs are the first choice, with combination analgesics, intravenous/intramuscular NSAIDs as alternatives. For moderate to severe attacks, oral or nasal spray triptans and ergotamine/caffeine compounds are recommended and should be administered in the early stage of migraine attacks. Antiemetics can be used as supplements to alleviate nausea and vomiting. Other emerging migraine-specific drugs, such as gepants or ditans, may also have a role in the future. Notably, a combination of a triptan and a NSAID yielded a better efficacy compared with either therapy alone. Parenteral steroids and fluid supply are the first-line treatment for status migrainosus. Acetaminophen is suitable for mild to moderate migraine attacks and remains the first choice for children and pregnant women. To prevent medication overuse headache, the use of acute treatment should be limited to a maximum of 2 days per week. Key words: acute migraine treatment, evidence-based medicine, treatment guidelines, triptans, ergotamine, neuromodulation.

Effect of Adjunctive Acupuncture on Pain Relief Among Emergency Department Patients With Acute Renal Colic Due to Urolithiasis: A Randomized Clinical Trial.

Importance: Renal colic is described as one of the worst types of pain, and effective analgesia in the shortest possible time is of paramount importance. Objectives: To examine whether acupuncture, as an adjunctive therapy to analgesics, could accelerate pain relief in patients with acute renal colic. Design, Setting, and Participants: This single-center, sham-controlled, randomized clinical trial was conducted in an emergency department in China between March 2020 and September 2020. Participants with acute renal colic (visual analog scale [VAS] score ≥4) due to urolithiasis were recruited. Data were analyzed from October 2020 to January 2022. Interventions: After diagnosis and randomization, all patients received 50 mg/2 mL of diclofenac sodium intramuscular injection immediately followed by 30-minute acupuncture or sham acupuncture. Main Outcomes and Measures: The primary outcome was the response rate at 10 minutes after needle manipulation, which was defined as the proportion of participants whose VAS score decreased by at least 50% from baseline. Secondary outcomes included response rates at 0, 5, 15, 20, 30, 45, and 60 minutes, rescue analgesia, and adverse events. Results: A total of 115 participants were screened and 80 participants (66 men [82.5%]; mean [SD] age, 45.8 [13.8] years) were enrolled, consisting of 40 per group. The response rates at 10 minutes were 77.5% (31 of 40) and 10.0% (4 of 40) in the acupuncture and sham acupuncture groups, respectively. The between-group differences were 67.5% (95% CI, 51.5% to 83.4%; P < .001). The response rates of acupuncture were also significantly higher than sham acupuncture at 0, 5, 15, 20 and 30 minutes, whereas no significant difference was detected at 45 and 60 minutes. However, there was no difference between the 2 groups in rescue analgesia rate (difference 2.5%; 95% CI -8.8% to 13.2%; P > .99). No adverse events occurred during the trial. Conclusions and Relevance: These findings suggest that acupuncture plus intramuscular injection of diclofenac is safe and provides fast and substantial pain relief for patients with renal colic compared with sham acupuncture in the emergency setting. However, no difference in rescue analgesia was found, possibly because of the ceiling effect caused by subsequent but robust analgesia of diclofenac. Acupuncture can be considered an optional adjunctive therapy in relieving acute renal colic. Trial Registration: Chinese Clinical Trial Registry: ChiCTR1900025202.

Efficacy of Combined Management with Nonsteroidal Anti-inflammatory Drugs for Prevention of Pancreatitis After Endoscopic Retrograde Cholangiography: a Bayesian Network Meta-analysis.

OBJECTIVES: To systematically evaluate the clinical efficacy of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) alone or in combination with other agents for preventing pancreatitis after endoscopic retrograde cholangiopanography. METHODS: We carried out a literature search of random controlled trials (RCTs) on preventing post-operative pancreatitis by administration of the anti-inflammatory drugs, indomethacin and diclofenac, following endoscopic retrograde cholangiopancreatography (ERCP). The databases searched for relevant publications up to July 7, 2021, included PubMed, Cochrane Library, and Embase. We screened the literature according to inclusion criteria and analyzed the extracted data. The overall population and high-risk patient groups were analyzed, with the main outcome being the incidence of PEP. RESULTS: The search identified 32 RCTs that included 15019 patients with post-ERCP pancreatitis and 9 different interventions. The results of the overall population network meta-analysis showed that NSAIDs alone, high-dose NSAIDs, and a combination of NSAIDs significantly reduced the incidence of PEP compared with placebo. However, compared with placebo, there was no statistically significant difference between the two interventions (NSAIDs + standard hydration and high-dose NSAIDs). In addition, NSAIDs + sublingual nitrates were associated with a lower incidence of PEP compared to that observed with NSAIDs alone. Probability ranking results showed that NSAIDs + sublingual nitrate had the best effect, followed by NSAIDs + standard hydration, NSAIDs + melatonin, NSAIDs + aggressive hydration, NSAIDs + somatostatin, NSAIDs alone, NSAIDs + epinephrine, high-dose NSAIDs, and placebo. In the high-risk subgroup, the results of the network meta-analysis showed that NSAIDs alone, high-dose NSAIDs, and a combination of NSAIDs showed no statistically significant difference in their ability to reduce the incidence of PEP compared with placebo. Probability ranking results showed that NSAIDs + hydration had the best effect, followed by NSAIDs + sublingual nitroglycerin and NSAIDs + aggressive hydration. CONCLUSION: Of the nine interventions, NSAIDs + sublingual nitrates had considerably better efficacy than the other drugs for reducing the incidence of PEP in the overall population. In high-risk patients, NSAIDs + standard hydration may be the best preventive treatment; however, more randomized, controlled trials are needed to validate our results. TRIAL REGISTRATION: Name of the registry: PROSPERO-International prospective register of systematic reviews. Unique identifying number or registration ID: CRD42021282205.

Flaxseed Ethanol Extract Effect in Acute Experimental Inflammation.

Background and Objectives: Previous studies demonstrated antioxidant activities for flaxseed and flaxseed oil. The aim of the present study was to evaluate the prophylactic and therapeutic anti-inflammatory and antioxidant effects of flaxseed ethanol extract in acute experimental inflammation. Materials and Methods: The in vivo anti-inflammatory and antioxidant activity was evaluated on a turpentine-induced acute inflammation (6 mL/kg BW, i.m.) by measuring serum total oxidative status, total antioxidant reactivity, oxidative stress index, malondialdehyde, total thiols, total nitrites, 3-nitrotyrosine, and NFkB. The experiment was performed on nine groups (n = 5) of male rats: negative control; inflammation; three groups with seven days of flaxseed extract (100%, 50%, 25%) pretreatment followed by inflammation on day eight; three groups of inflammation followed by seven days of treatment with flaxseed extract (100%, 50%, 25%); inflammation followed by seven days of treatment with diclofenac (20 mg/kg BW). Results: Flaxseed extract anti-inflammatory activity was better in the therapeutic plan than in the prophylactic one, and consisted of NO, 3NT, and NF-κB reduction in a dose dependent way. ROS was reduced better in the therapeutic flaxseed extracts administration, and antioxidants were increased by the prophylactic flaxseed extracts administration. Both, ROS and antioxidants were influenced more by the total flaxseed extract, which was also more efficient than diclofenac. Conclusions: flaxseed extract prophylaxis has a useful antioxidant activity by increasing the antioxidants, and flaxseed extract therapy has anti-inflammatory and antioxidant activities by reducing NF-κB, RNS, and ROS.

Electroacupuncture vs topical diclofenac sodium gel for patients with hand osteoarthritis: study protocol for a randomized controlled trial.

BACKGROUND: Hand osteoarthritis (OA) is a prevalent joint disorder and a great burden to both patients and society. While electroacupuncture (EA) and topical diclofenac sodium gel (DSG) are both currently used to treat OA, no head-to-head study of EA and topical DSG for hand OA exists. Thus, it remains unknown whether one intervention offers improved outcomes over the other. This study aims to compare the effects of EA and topical DSG in patients with hand OA. METHODS: A total of 108 participants with hand OA according to the American College of Rheumatology criteria will be recruited and randomly assigned to the EA group or topical DSG group with a 1:1 allocation ratio. Participants in the EA group will receive EA treatment thrice weekly for 4 weeks, followed by a 12-week follow-up. In the topical DSG group, topical DSG at a dose of 2 g over the affected joints per hand will be applied four times per day for 4 weeks. The outcomes will be measured at weeks 4, 8, and 16. The primary outcome will be the change in average overall finger joint pain intensity in the dominant hand from baseline to week 4. All outcome variables will be analyzed on an intention-to-treat principle. All statistical tests will be two-sided. DISCUSSION: This study will help determine which of the two treatment protocols, EA or topical DSG, is more effective for the clinical treatment of hand OA. Trial registration ClinicalTrials.gov identifier: NCT04402047. Registered 16 May 2020, https://clinicaltrials.gov/ct2/show/NCT04402047.

Erythrocyte-derived liposomes for the treatment of inflammatory diseases.

Effective and safe therapies to counteract persistent inflammation are necessary. We developed erythrocyte-derived liposomes (EDLs) with intrinsic anti-inflammatory activity. The EDLs were prepared using lipids extracted from erythrocyte membranes, which are rich in omega-3 fatty acids with several health benefits. Diclofenac, a widely used anti-inflammatory drug, was incorporated into EDLs in relevant therapeutic concentrations. The EDLs were also functionalised with folic acid to allow their active targeting of M1 macrophages, which are key players in inflammatory processes. In the presence of lipopolysaccharide (LPS)-stimulated macrophages, empty EDLs and EDLs incorporating diclofenac were able to reduce the levels of important pro-inflammatory cytokines, namely interleukin-6 (IL-6; ≈85% and 77%, respectively) and tumour necrosis factor-alpha (TNF-α; ≈64% and 72%, respectively). Strikingly, cytocompatible concentrations of EDLs presented similar effects to dexamethasone, a potent anti-inflammatory drug, in reducing IL-6 and TNF-α concentrations, demonstrating the EDLs potential to be used as bioactive carriers in the treatment of inflammatory diseases.

The Effects of Ibuprofen, Naproxen and Diclofenac on cell Apoptosis, Cell Proliferation and Histology Changes in Human Cholangiocarcinoma Cell Lines.

OBJECTIVE: To examine the effects of ibuprofen, naproxen and diclofenac, non-steroidal anti-inflammatory drugs (NSAIDs) on cell proliferation activity of the human CCA cell lines. METHODS: KKU-M139 and KKU-213B cell lines were used in this study. The cell viability was assessed by the MTT assay. Lipid synthesis determined by Oil red O staining and colorimetric assay. An inverted phase-contrast light microscope was used to investigate the histological change of the cells. Caspases 3/7 activity and AnnexinV/PI were used to assess apoptosis by multiple microplate reader. RESULTS: The results showed that ibuprofen, naproxen and diclofenac suppressed the viability of the KKU-M139 and KKU-213B cells in a dose-dependent manner, as measured especially diclofenac. However, these three NSAIDs slightly decreased lipid synthesis determined by Oil red O staining and colorimetric assay. The histological change observations showed the shrinking cell and become star-shaped in high dose treated groups. Interestingly, these NSAIDs exhibited in both of KKU-M139 and KKU-213B cell lines, the diclofenac-treated cells had the most injury cells. The cells exhibited cell injury features. In addition, the detection of caspase 3/7 and AnnexinV/PI in this investigation revealed early cell apoptotic characteristics. CONCLUSION: These finding suggest that ibuprofen, naproxen and diclofenac suppress cell viability. The results reveal that ibuprofen, naproxen and diclofenac, which induce the histological change and apoptosis. This study indicates that these NSAIDs may be used as an anti-proliferation agent for the treatment of CCA in the future.

SZAP exerts analgesic effects on rheumatalgia in CIA rats by suppressing pain hyperalgesia and inhibiting TRPV1 and P2X3.

ETHNOPHARMACOLOGICAL RELEVANCE: ShexiangZhuifeng Analgesic Plaster (SZAP) is a traditional Chinese medicine and transdermal formulation composed of many Chinese herbs and active compounds. SZAP was recently approved by the China Food and Drug Administration for the treatment of pain associated with osteoarticular diseases and is preferred by most rheumatoid arthritis patients in China. However, its mechanism has not been elucidated in detail. AIM OF THE STUDY: We sought to determine the analgesic effect of SZAP in collagen-induced arthritis (CIA) rats and explore the underlying mechanisms of pain transmission, such as via the TRPV1 and P2X3 receptors. METHODS: After CIA was established, rats were treated with SZAP for 7 days. Paw thickness, arthritis score, and haematoxylin and eosin staining were used to evaluate the effectiveness of SZAP. Paw withdrawal threshold (PWT) and tail-flick latency (TFL) were used to estimate the analgesic effect of SZAP. The levels of PGE2, BK, 5-HT, SP, and CGRP in the serum and synovium were determined using ELISA kits, and ATP in the synovium was measured using HPLC. The expression of TRPV1 and P2X3 in the DRG was detected using western blotting and immunofluorescence. TRPV1 and P2X3 agonists were further used to determine the analgesic effects of SZAP on CIA rats based on PWT and TFL. RESULTS: SZAP not only significantly ameliorated arthritis scores and paw thickness by improving the pathological damage of synovial joints, but also remarkably alleviated pain in CIA rats. Further, treatment with SZAP significantly reduced peripheral 5-HT, PGE2 BK, SP, CGRP, and ATP. Additionally, the expression of TRPV1 and P2X3 in the DRG was markedly downregulated by SZAP. Interestingly, the analgesic effect of SZAP was weakened (reduction of PWT and TFL) when TRPV1 and P2X3 were activated by capsaicin or α,ß-meATP, respectively. CONCLUSION: SZAP ameliorates rheumatalgia by suppressing hyperalgesia and pain transmission through the inhibition of TRPV1 and P2X3 in the DRG of CIA rats.

Treatment adherence with diclofenac 3% gel among patients with multiple actinic keratoses: an integrated low-intensity intervention program versus standard-of-care.

BACKGROUND: Diclofenac 3% gel is a widely used topical treatment with proven efficacy in reducing the burden of actinic keratosis (AK); however, clinical benefit might not fully translate in clinical practice as nonadherence is substantial for prolonged treatment regimens. We evaluated the efficacy of an integrated low-intensity intervention program versus standard-of-care on treatment adherence among patients with multiple AK receiving diclofenac in hyaluronic acid gel 3%. METHODS: We designed an open label, randomized, parallel group, interventional, multicenter, longitudinal cohort study including patients with multiple, grade I/II AKs. Visits were scheduled for end of treatment (T4), follow-up 1 (T5) and follow-up 2 (T6) at 90, 180 and 365 days from baseline, respectively. Patients in the intervention group received additional visits at 30 and 60 days from baseline, a brief health education intervention, an enhanced patient-physician communication, a weekly SMS reminder to medication prescriptions. RESULTS: Patients were equally allocated between intervention (intervention group [IG], N.=86) and control group ([CG] N.=86); at baseline, both groups had similar socio-demographic and clinical characteristics. Change scores from baseline showed a slight increment in quality of life related to AK in both groups (CG: ΔT4-T1=-0.079; IG: ΔT4-T1=-0.006; P=0.39) and in quality of physician-patient interaction reported by IG (ΔT3-T2=0.18; P<0.0001). Adherence rate was not statistically different between IG and CG (28.4% vs. 40.7%; P=0.11). Patients reported similar satisfaction for effectiveness, convenience and side effects of treatment. Clinical conditions improved over time and results did not differ between groups; complete clearance rate at 1 year was 18% and 29% for CG and IG, respectively. CONCLUSIONS: Our findings showed no difference in adherence rate between the two groups, suggesting that enhanced follow-up interventions and health care education may not be sufficient drivers to promote adherence among this clinical population. Further studies are needed to explore barriers to adherence with treatments for AKs.

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

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.

Tibetan herbal pain-relieving plaster for low back pain: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tibetan traditional medicine CheeZheng Pain-Relieving Plaster (CZPRP) is frequently used as an over-the-counter external analgesic for musculoskeletal pain; however, its evidence for low back pain (LBP) has not been evaluated. AIM OF THE STUDY: This study aims to assess the efficacy and safety of CZPRP for both acute, subacute and chronic LBP through a systematic review and meta-analysis of clinical trials. MATERIALS AND METHODS: PubMed, CENTRAL, CNKI, CQVIP, and Wanfang databases were searched through April 20, 2020 for randomized controlled trials of CZPRP for LBP. Eligible comparators were placebo, active treatment, or usual care. Clinical outcomes included pain severity, lower back function score, pain-free rate, and adverse events (AEs). Qualitative evaluations were conducted using the Cochrane risk of bias assessment tools. Quantitative analyses were conducted using a random-effects model. RESULTS: This study includes 1674 LBP patients from nine clinical studies. Pooled analyses among subjects with acute LBP show 1) significant pain reductions (mean difference -0.84, 95% confidence interval[CI] -1.31, -0.37) in CZPRP plus diclofenac versus diclofenac, 2) significant improvements in lower back function (standard mean difference -1.50, 95% CI -2.16, -0.85) in CZPRP versus diclofenac, and 3) a higher pain-free rate in CZPRP alone (risk ratio 1.48, 95% CI 1.16, 1.89; I2 = 61%) or CZPRP plus nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio 1.66, 95% CI 1.14, 2.40; I2 = 0%) versus NSAIDs. However, in a heterogeneous population with mixed LBP subtypes, there was no significant difference in pain outcomes between CZPRP and diclofenac. Additionally, CZPRP use did not increase AEs compared with no CZPRP (p = 0.40). All nine studies are associated with moderate to high risk of bias. CONCLUSIONS: The use of CZPRP is associated with improved acute LBP outcomes compared to diclofenac. However, due to the moderate to high risk of bias of the studies, future rigorous randomized controlled trials are needed to evaluate the effects of CZPRP for acute and chronic LBP.

Comparación del bloqueo periprostático con lidocaina y supositorio de diclofenac y placebo en la biopsia prostática / Comparison of periprostatic block with lidocaine and diclofenac suppository and placebo in prostate biopsy

El bloqueo del nervio peri prostático con lidocaína, proporciona un buen alivio del dolor en la realización de la biopsia prostática guiada por ultrasonido, pero el dolor post-procedimiento, puede llegar a ser significativo, la adición del supositorio de diclofenac, podría proporcionar alivio adicional. Se asignaron al azar pacientes en 2 grupos el grupo 1 bloqueo con lidocaína del plexo peri prostático + supositorio de diclofenac sódico y el grupo 2 bloqueo con lidocaína del plexo peri prostático + supositorio de placebo, realizando biopsia doble sextante, el dolor a varios intervalos después del procedimiento se registró en una escala visual análoga (EVA) de 0 a 10. Los 2 grupos fueron similares en cuanto a edad, volumen de próstata, antígeno prostático específico, diagnóstico histopatológico. Los pacientes que recibieron diclofenac tuvieron puntajes de dolor significativamente más bajos que los que recibieron placebo (2 frente a 3,35) p 0,02. La administración rectal de diclofenac antes de la realización de la biopsia de próstata es un procedimiento simple que alivia significativamente el dolor experimentado sin aumento en la morbilidad(AU)

The peri-prostatic nerve block with lidocaine, provides good pain relief in performing ultrasoundguided prostate biopsy, but the postprocedure pain can be significant, the addition of diclofenac suppository, could provide additional relief. Patients were randomly assigned in 2 groups to group 1 blockade with lidocaine of the prostatic peri plexus + suppository of diclofenac sodium and group 2 blockade with lidocaine of the prostatic peri plexus + placebo suppository, performing double sextant biopsy, pain at several intervals after the procedure was recorded on a visual analog scale (EVA) from 0 to 10. Thee 2 groups were similar in terms of age, prostate volume, prostate-specific antigen, histopathological diagnosis. Patients who received diclofenac had pain scores significantly lower than those who received placebo (2 vs. 3.35) p 0.02. Rectal administration of diclofenac before performing a prostate biopsy is a simple procedure that relieves significantly pain experienced without increased morbidity(AU)

A sport cream (Harpago-Boswellia-ginger-escin) for localized neck/shoulder pain.

BACKGROUND: Neck/shoulder, sudden pain, or muscular pain (not associated to structural or bone/joints components), due to fascial or muscular strain is common in active subjects, in non-professional athletes and sports performers. The aim of this supplement registry was the evaluation of a cream based on natural, active ingredients for topical application in supporting the improvement of pain and improving head/neck mobility, possibly minimizing the use of systemic drugs. METHODS: The cream includes standardized active ingredients of natural origin as an extract of Harpagophytum procumbes, an extract from Boswellia serrata, a CO2 extract of ginger and escin. Subjects were divided into three groups, all using the standard management (SM) in combination with the Sport Cream or in addition to Flector (diclofenac) patch. RESULTS: The groups were comparable and homogeneous at the baseline. No side effects or skin tolerability issues were observed with the Sport Cream nor with the SM or diclofenac patches. Subjects receiving sport cream + SM reported a significant improvement in pain, stiffness, altered mobility and altered working capacity, with a reduced need for rescue medication (diclofenac) compared to subjects in the other two groups. CONCLUSIONS: Finally, subjects receiving sport cream + SM reported a more remarkable decrease in skin temperature in the affected area associated to an improvement in clinical symptoms.