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Although pain is common in osteoarthritis, most people fail to achieve adequate analgesia. Increasing acknowledgement of the contribution of pain sensitisation has resulted in the investigation of medications affecting pain processing with central effects. Antidepressants contribute to pain management in other conditions where pain sensitisation is present.To assess the benefits and harms of antidepressants for the treatment of symptomatic knee and hip osteoarthritis in adults.We used standard, extensive Cochrane search methods. The latest search was January 2021.We included randomised controlled trials of adults with osteoarthritis that compared use of antidepressants to placebo or alternative comparator. We included trials that focused on efficacy (pain and function), treatment-related adverse effects and had documentation regarding discontinuation of participants. We excluded trials of less than six weeks of duration or had participants with concurrent mental health disorders.We used standard Cochrane methods. Major outcomes were pain; responder rate; physical function; quality of life; and proportion of participants who withdrew due to adverse events, experienced any adverse events or had serious adverse events. Minor outcomes were proportion meeting the OARSI (Osteoarthritis Research Society International) Response Criteria, radiographic joint structure changes and proportion of participants who dropped out of the study for any reason. We used GRADE to assess certainty of evidence.Nine trials (2122 participants) met the inclusion criteria. Seven trials examined only knee osteoarthritis. Two also included participants with hip osteoarthritis. All trials compared antidepressants to placebo, with or without non-steroidal anti-inflammatory drugs. Trial sizes were 36 to 388 participants. Most participants were female, with mean ages of 54.5 to 65.9 years. Trial durations were 8 to 16 weeks. Six trials examined duloxetine. We combined data from nine trials in meta-analyses for knee and hip osteoarthritis. One trial was at low risk of bias in all domains. Five trials were at risk of attrition and reporting bias. High-certainty evidence found that antidepressants resulted in a clinically unimportant improvement in pain compared to placebo. Mean reduction in pain (0 to 10 scale, 0 = no pain) was 1.7 points with placebo and 2.3 points with antidepressants (mean difference (MD) -0.59, 95% confidence interval (CI) -0.88 to -0.31; 9 trials, 2122 participants). Clinical response was defined as achieving a 50% or greater reduction in 24-hour mean pain. High-certainty evidence demonstrated that 45% of participants receiving antidepressants had a clinical response compared to 28.6% receiving placebo (RR 1.55, 95% CI 1.32 to 1.82; 6 RCTs, 1904 participants). This corresponded to an absolute improvement in pain of 16% more responders with antidepressants (8.9% more to 26% more) and a number needed to treat for an additional beneficial effect (NNTB) of 6 (95% CI 4 to 11). High-certainty evidence showed that the mean improvement in function (on 0 to 100 Western Ontario and McMaster Universities Arthritis Index, 0 = best function) was 10.51 points with placebo and 16.16 points with antidepressants (MD -5.65 points, 95% CI -7.08 to -4.23; 6 RCTs, 1909 participants). This demonstrates a small, clinically unimportant response. Moderate-certainty evidence (downgraded for imprecision) showed that quality of life measured using the EuroQol 5-Dimension scale (-0.11 to 1.0, 1.0 = perfect health) improved by 0.07 points with placebo and 0.11 points with antidepressants (MD 0.04, 95% CI 0.01 to 0.07; 3 RCTs, 815 participants). This is clinically unimportant. High-certainty evidence showed that total adverse events increased in the antidepressant group (64%) compared to the placebo group (49%) (RR 1.27, 95% CI 1.15 to 1.41; 9 RCTs, 2102 participants). The number needed to treat for an additional harmful outcome (NNTH) was 7 (95% CI 5 to 11). Low-certainty evidence (downgraded twice for imprecision for very low numbers of events) found no evidence of a difference in serious adverse events between groups (RR 0.94, 95% CI 0.46 to 1.94; 9 RCTs, 2101 participants). The NNTH was 1000. Moderate-certainty evidence (downgraded for imprecision) showed that 11% of participants receiving antidepressants withdrew from trials due to an adverse event compared to 5% receiving placebo (RR 2.15, 95% CI 1.56 to 2.97; 6 RCTs, 1977 participants). The NNTH was 17 (95% CI 10 to 35).There is high-certainty evidence that use of antidepressants for knee osteoarthritis leads to a non-clinically important improvement in mean pain and function. However, a small number of people will have a 50% or greater important improvement in pain and function. This finding was consistent across all trials. Pain in osteoarthritis may be due to a variety of causes that differ between individuals. It may be that the cause of pain that responds to this therapy is only present in a small number of people. There is moderate-certainty evidence that antidepressants have a small positive effect on quality of life with heterogeneity between trials. High-certainty evidence indicates antidepressants result in more adverse events and moderate-certainty evidence indicates more withdrawal due to adverse events. There was little to no difference in serious adverse events (low-certainty evidence due to low numbers of events). This suggests that if antidepressants were being considered, there needs to be careful patient selection to optimise clinical benefit given the known propensity for adverse events with antidepressant use. Future trials should include alternative antidepressant agents or phenotyping of pain in people with osteoarthritis, or both.

Background: Prior research suggests that women with endometriosis are at greater risk of coronary heart disease. Therefore, our objective was to prospectively investigate the association between laparoscopically confirmed endometriosis and risk of incident stroke during 28 years of follow-up. Methods: Participants in the NHSII cohort study (Nurses’ Health Study II) were followed from 1989 when they were between the ages of 25 to 42 until 2017 for development of incident stroke (ischemic and hemorrhagic). Cox proportional hazard models were used to calculate hazard ratios and 95% CI, with adjustment for potential confounding variables (alcohol intake, body mass index at age 18, current body mass index, age at menarche, menstrual cycle pattern in adolescence, current menstrual cycle pattern, parity, oral contraceptive use history, smoking history, diet quality, physical activity, NSAID use, aspirin use, race/ethnicity, and income). We estimated the proportion of the total association mediated by history of hypertension, hypercholesterolemia, hysterectomy/oophorectomy, and hormone therapy. We also tested for effect modification by age (≥ 50 years), infertility history, body mass index (≥ 25 kg/m 2 ), and menopausal status. Results: We documented 893 incident cases of stroke during 2 770 152 person-years of follow-up. Women with laparoscopically confirmed endometriosis had a 34% greater risk of stroke in multivariable-adjusted models (hazard ratio, 1.34 [95% CI, 1.10–1.62]), compared to those without a history of endometriosis. Of the total association of endometriosis with risk of stroke, the largest proportion was attributed to hysterectomy/oophorectomy (39% mediated [95% CI, 14%–71%]) and hormone therapy (16% mediated [95% CI, 5%–40%]). We observed no differences in the relationship between endometriosis and stroke by age, infertility history, body mass index, or menopausal status. Conclusions: We observed that women with endometriosis were at elevated risk of stroke. Women and their health care providers should be aware of endometriosis history, maximize primary cardiovascular prevention, and discuss signs and symptoms of cardiovascular disease.

Mastocytosis is a rare neoplastic disorder of the mast cell lineage resulting in unregulated proliferation and activation of mast cells. Symptoms worsen in about one-third of pregnant patients. Treatment focuses on management of symptoms with antimediator therapy (H1H2 antihistamines, glucocorticoids, and epinephrine, if required). Medication selection requires care during labor and delivery. Although it is generally considered safe to use a medication patient tolerated before, some common medications may need to be avoided or used with caution (eg, codeine, morphine, nonsteroidal antiinflammatory drugs, vancomycin) if the patient does not have any history of exposure to them.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, inhibits cytokine signaling in psoriasis pathogenesis.The objective of this study was to demonstrate deucravacitinib superiority versus placebo and apremilast in moderate to severe plaque psoriasis based on ≥75% reduction from baseline in Psoriasis Area and Severity Index and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline at week 16.POETYK psoriasis second trial (NCT03611751), a 52-week, double-blinded, phase 3 trial, randomized patients 2:1:1 to deucravacitinib 6 mg every day (n = 511), placebo (n = 255), or apremilast 30 mg twice a day (n = 254).At week 16, significantly more deucravacitinib-treated patients versus placebo and apremilast patients achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index (53.0% vs 9.4% and 39.8%; P .0001 vs placebo; P = .0004 vs apremilast) and static Physician's Global Assessment score of 0 or 1 (49.5% vs 8.6% and 33.9%; P .0001 for both). Efficacy was maintained until week 52 with continuous deucravacitinib. The most frequent adverse event with deucravacitinib was nasopharyngitis. Serious adverse events and discontinuations due to adverse events were infrequent. No clinically meaningful changes were observed in laboratory parameters.The study duration was 1 year.Deucravacitinib demonstrated superiority versus placebo and apremilast and was well tolerated in adults with moderate to severe plaque psoriasis.

The present work argues for the involvement of the zinc chelating ability of some non-steroidal anti-inflammatory drugs as an additive mechanism able to increase their efficacy against COVID-19.

Background: Cyclooxygenase (COX) and Lipoxygenase (LOX) enzymes catalyze the production of pain mediators like Prostaglandins (PGs) and Leukotrienes (LTs), respectively from arachidonic acid. Introduction: The COX and LOX enzyme modulators are responsible for the major PGs and LTs mediated complications like asthma, osteoarthritis, rheumatoid arthritis, cancer, Alzheimer’s disease, neuropathy and Cardiovascular Syndromes (CVS). Many synthetic Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) used in the treatment have serious side effects like nausea, vomiting, hyperacidity, gastrointestinal ulcers, CVS, etc. Methods: The natural inhibitors of pain mediators have great acceptance worldwide due to fewer side effects on long-term uses. The present review is an extensive study of the advantages of plantbased vs synthetic inhibitors. Results: These natural COX and LOX inhibitors control inflammatory response without causing side-effect-related complicacy. Conclusion: Therefore, the natural COX and LOX inhibitors may be used as alternative medicines for the management of pain and inflammation due to their less toxicity and resistivity.

After a scorpion sting, patients commonly present to hospitals with pain. Our study sought to compare the analgesic efficacy of IV paracetamol, IV dexketoprofen trometamol, topical lidocaine, and placebo in patients reporting pain after presenting with a history of scorpion sting.This double-blind, randomized, placebo-controlled study was conducted in the emergency department of a tertiary hospital. Adult patients who presented with the complaint of pain after a scorpion sting and did not have systemic findings were randomly assigned to 1 of the following 4 groups: IV paracetamol, IV dexketoprofen trometamol, topical lidocaine, and placebo. The visual analog scale scores were measured at the time of presentation to the emergency department and at 30 and 60 min to determine the pain intensity.The study included 106 patients, of whom 30 were in the paracetamol group, 26 in the dexketoprofen trometamol group, 25 in the topical lidocaine group, and 25 in the placebo group. We did not find a different analgesic effect among the groups in the first 30 min (P=0.185). IV paracetamol, dexketoprofen trometamol, and topical lidocaine did not show different analgesic effects in the first 60 min (P0.05). IV paracetamol and dexketoprofen trometamol were found to provide a more effective analgesia than the placebo at 60 min (P0.05). The analgesic effects of topical lidocaine and placebo did not differ (P=0.330).IV paracetamol and IV dexketoprofen trometamol provided analgesia in the first 60 min, similar to topical lidocaine but superior to placebo.

Acute calcium deposit (ACD) in the hand and wrist is a cause of acute pain due to crystal-induced soft-tissue inflammation. There are no standard management guidelines for this condition, which is frequently treated with non-steroidal anti-inflammatory drugs (NSAIDs), with variable efficacy, some patients presenting symptoms for several months. We retrospectively analyzed the results of all patients treated with anakinra for hand or wrist ACD in our department in 2020. We extracted data on treatment duration, pain, range of motion, skin erythema, hypervascularization, edema, and X-ray findings. Ten patients were treated for hand or wrist ACD with anakinra 100 mg per day for a mean 2.7 days. We observed rapid and significant improvement in pain, range of motion, local erythema and edema from day 2 and a decrease in skin temperature from day 3. Calcifications significantly decreased in size or disappeared in the majority of the patients. There were no adverse events or recurrences at 1 year's follow-up. Anakinra was associated with significant clinical improvement after only two days' treatment and may be considered to treat patients with hand or wrist ACD, especially in case of contraindications to NSAIDs or glucocorticoids. Further controlled studies are needed to confirm the present observations.

Various metals have been complexed with drugs to improve their cellular impact. Inflammatory diseases like rheumatoid arthritis (RA) are characterized by unbalanced production of proinflammatory cytokines (PICs) and prostaglandins with decreased levels of vitamin D and calcium. The inflammation can be suppressed through targeting the formation of PICs or related enzymes by various treatment strategies that involve the use of corticosteroids, disease-modifying antirheumatic drugs and NSAIDs. We present a detailed review on the impact of calcium complexes of oxicams as an advanced treatment strategy for RA. The calcium complexes demonstrate promising capabilities to cure the disease, improve the strength of bones and suppress PICs in RA.

Background/Aims: We aimed to estimate the prevalence of comorbidities and medication use in Korean women with rheumatic diseases (RDs) during their childbearing years.Methods: We included women aged 20 to 44 years with seropositive rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) (n = 41,547) and age-matched women without seropositive RA, SLE, and AS (n = 208,941) from the National Health Insurance Service-National Health Information Database (2009 to 2016). The prevalence of hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and cancer and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CSs), and disease-modifying anti-rheumatic drugs (DMARDs) were estimated.Results: Women of childbearing age with RDs were more likely to have at least one of the measured comorbidities than the controls (odds ratio [OR], 3.0; 95% confidence interval [CI], 2.9 to 3.1). The OR (95% CI) was 2.9 (2.8 to 3.0) for HTN, 2.8 (2.7 to 2.9) for HLD, 1.4 (1.4 to 1.5) for DM, and 1.3 (1.3 to 1.4) for cancer. The SLE group had the highest prevalence and odds of all four measured comorbidities. Almost all (97.9%) women of childbearing age with RDs were taking RD-related medications (NSAIDs, 81.6%; CSs, 77.8%; DMARDs, 87.3%). The RD group was 13.8 times more likely to take NSAIDs and 68.2 times more likely to take CSs than the controls. Use of NSAIDs was more prevalent in RA and AS than SLE, whereas use of CSs and DMARDs was more prevalent in RA and SLE than AS.Conclusions: Korean women with RDs have a greater burden of comorbidities and medication use during their childbearing years than women without RDs of the same age.

Purpose Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) are severe and potentially lethal adverse drug reactions characterized by acute inflammation of the skin, mucous membranes, and ocular surface that typically occurs within weeks of a culprit drug ingestion. The purpose of this study is to report a retrospective trend analysis of SJS spectrum diagnoses and associated culprit drugs in patients admitted to the Loyola University Medical Center (LUMC) Burn Unit, the major referral center in the Chicagoland region for patients with SJS disease spectrum. Methods The electronic medical records (EMR) of 163 patients with a diagnosis of SJS/TENS admitted to the LUMC Burn Unit from 2000 to 2019 were reviewed. Clinical data in addition to the well-established algorithm of drug causality for epidermal necrolysis (ALDEN) allowed us to identify the single most probable culprit drug in 131 cases. Results From 2000 to 2019, the most common spectrum classification was TENS (48.1%), followed by SJS (33.6%) and SJS-TEN Overlap Syndrome (18.3%). Anticonvulsants were found to be the most probable culprit class in 30% of cases followed by Trimethoprim-Sulfamethoxazole in 19% of cases. Beta-lactams were the most probable culprit class in 11% of cases while NSAIDs and allopurinol were each the most probable culprit class/drug in 8.4% of cases. Conclusions This is one of the largest single center series of SJS/TENS cases in the United States. Further study into culprit drug distribution by region as well as continuous monitoring of trends is crucial in order to advise prescribing practices.

Chronic joint pain is common in patients with osteoarthritis (OA). Non-steroidal anti-inflammatory drugs and opioids are used to relieve OA pain, but they are often inadequately effective. Dorsal root ganglion field stimulation (GFS) is a clinically used neuromodulation approach, although it is not commonly employed for patients with OA pain. GFS showed analgesic effectiveness in our previous study using the monosodium iodoacetate (MIA) - induced OA rat pain model. This study was to evaluate the mechanism of GFS analgesia in this model.After osteoarthritis was induced by intra-articular injection of MIA, pain behavioral tests were performed. Effects of GFS on the spontaneous activity (SA) were tested with in vivo single-unit recordings from teased fiber saphenous nerve, sural nerve, and dorsal root.Two weeks after intra-articular MIA injection, rats developed pain-like behaviors. In vivo single unit recordings from bundles teased from the saphenous nerve and third lumbar (L3) dorsal root of MIA-OA rats showed a higher incidence of SA than those from saline-injected control rats. GFS at the L3 level blocked L3 dorsal root SA. MIA-OA reduced the punctate mechanical force threshold for inducing AP firing in bundles teased from the L4 dorsal root, which reversed to normal with GFS. After MIA-OA, there was increased retrograde SA (dorsal root reflex), which can be blocked by GFS.These results indicate that GFS produces analgesia in MIA-OA rats at least in part by producing blockade of afferent inputs, possibly also by blocking efferent activity from the dorsal horn.

Background: The European Network for Drug Allergy (ENDA) proposed a consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in 2011. A subgroup of patients with NSAIDs-exacerbated respiratory disease (NERD) develop urticaria/ angioedema type reactions in response to NSAIDs. The Kalyoncu classification might be a novel option to classify patients with NSAID hypersensitivity (NH). In this study, we compare the ENDA and the Kalyoncu classifications. Methods: This study enrolled a total of 196 patients. NH reaction types were categorized as asthma, rhinitis, urticaria/angioedema and anaphylaxis. Based on the reaction history and oral provocation test findings, patients were grouped according to ENDA and Kalyoncu classifications. Results: The mean age of the 196 patients was 40.32±13.28 years, and 130 (66.3%) of them were female. Under the ENDA and Kalyoncu classifications, the most common NH subgroups were NERD (32%), and isolated NH (34.2%), the least prevalent NH subgroups were single NSAID-induced delayed reactions (SNIDR) (1.5%), and pseudo Samter’s syndrome (11.7%). Conclusions: Our research revealed that the Kalyoncu classification is more descriptive of patients with NERD exhibiting urticaria/angioedema-type reactions. It also provides future risk assessment for development of NERD. For controversial cases, the Kalyoncu classification can be utilized as a new complimentary option alone or in conjunction with ENDA classification.

Background: It has been over a year since the first documented case of the COVID-19 virus was recorded. Since then, our understanding of this virus has continually evolved, however, its wide-ranging effects are still unfolding. Similar to previously studied viral infections, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) has been shown to lead to a degree of autoimmunity in patients who are recovering from its effects. Due to its effects on the innate im-mune system, such as the toll-like receptors and complement system, a varying degree of pro-inflammatory markers can become widespread in those who continue to recover from the virus. This case series offers a unique perspective on how COVID-19 has had dramatic effects on those already suffering from inflammatory rheumatic conditions, such as rheumatoid arthritis, systemic lupus erythematosus, or fibromyalgia. As the ever-lasting effects of COVID-19 are still unfolding, this case series is one of few to discuss the development and changes of patients with rheumatic conditions. This study hopes to encourage larger studies to be conducted on the effects of COVID-19 on autoimmune conditions. Case presentation: Seven patients were identified with new manifestations of rheumatic conditions, which included 3 cases of rheumatoid arthritis, 2 cases of polymyalgia rheumatica, 1 case of reac-tive arthritis, and 1 case of cutaneous lupus. Post-COVID syndrome was also diagnosed in 7 other patients. Patients with rheumatoid arthritis presented with symptoms 4-5 weeks after being diagnosed with COVID-19. Symptoms of polyarticular joint pain, swelling, and morning stiffness were reported in this group. These patients were treated with disease-modifying anti-rheumatic drugs and experi-enced an improvement in symptoms on follow-up. Two cases of polymyalgia rheumatica were identified in patients that were previously diagnosed with COVID-19 six weeks prior. One patient had no significant past medical history and the other patient had a history of rheumatoid arthritis, which was well controlled. These patients experienced weakness and tenderness in the proximal joints with elevated levels of ESR and CRP. They were treated with prednisone and showed improvement. Reactive arthritis was diagnosed in 1 patient who presented with swelling in both hands and wrists 2 days after being diagnosed with COVID-19. This patient began to experience symptoms of reac-tive arthritis 2 days after resolution of initial COVID-19 symptoms and this persisted for 3 months. The patient was managed with methylprednisolone injections and NSAIDs, which improved her symptoms. Post-COVID syndrome was identified in 7 patients. All patients were female and had a history of well-controlled fibromyalgia. Patients generally experienced fatigue, headaches, and memory fog, which had variable onset from a few days and up to 4 weeks after being diagnosed with COVID-19. One patient had a complete recovery of her symptoms at follow-up 3 months after the initial presen-tation. The other 6 patients continued to report symptoms of post-COVID syndrome at follow-up. Patients were managed with lifestyle modifications and their previous fibromyalgia treatment. Conclusion: While cases of COVID-19 continue to rise, complications of this disease are still being discovered. Those who initially recover from COVID-19 may experience new-onset rheumatic con-ditions, worsening of previously diagnosed rheumatic conditions, or post-COVID syndrome. As we continue to learn more about the effects of COVID-19, the awareness of these manifestations will play a key role in the appropriate management of these patients.

The purpose of this study is to compare the efficacy and safety of pharmacotherapies for chronic pain due to osteoarthritis (OA) between a group with duloxetine (DLX) and S-flurbiprofen plaster (SFPP) (the SFPP group) and a group with DLX and conventional non-steroidal anti-inflammatory drugs (NSAIDs) (the control group). The subjects were 49 patients (17 men and 32 women). The evaluation of factors associated with treatment termination due to symptoms improvement showed that significantly more women terminated treatment than did men, and significantly more members of the SFPP group terminated treatment than did members of the control group. The visual analogue scale (VAS) score in the SFPP group was significantly improved from 6.6 ± 1.7 before treatment to 3.6 ± 2.1 one month later and showed significant difference until nine months later. The VAS score in the control group was significantly improved from 6.7 ± 1.9 to 4.1 ± 2.8 one month later. The VAS score improvement rate was significantly higher in the SFPP group than in the control group, suggesting that the DLX-SFPP combination had higher efficacy than the DLX-conventional NSAIDs combination. The incidence of adverse drug reactions was 55% in the SFPP group, which is not significantly different from 50% incidence in the control group. The treatment discontinuation rate due to adverse drug reactions, however, was 60% in the control group and 19% in the SFPP group. It was suggested that the efficacy and safety of the DLX-SFPP combination for chronic pain due to OA are equal to or higher than that of the DLX-conventional NSAIDs combination.

Introduction: Ibuprofen is the most common culprit drug causing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children. We aimed to evaluate the frequency, clinical characteristics, and risk factors of confirmed ibuprofen allergy in children presenting with a history of suspected immediate type ibuprofen-induced hypersensitivity reactions. Methods: We evaluated 50 (35 M, 15 F) children with a median age of 7 years, who were referred to our clinic with suspected immediate ibuprofen hypersensitivity. Patients were subjected to a diagnostic work up including drug provocation tests (DPTs) with the culprit drug. Reactions were classified according to the European Academy of Allergy and Clinical Immunology Task Force recommendations for pediatric patients. Proven ibuprofen allergic patients underwent DPT to find a safe alternative drug. Results: Ibuprofen allergy was confirmed in 34% (n: 17) of children; 9 patients were diagnosed by DPTs and 8 patients diagnosed based on their histories. Angioedema was the most common clinical manifestation (n: 30, 60%). Among patients with proven ibuprofen allergy, 7 of them were classified as cross-intolerant. Cross-intolerance reactions were further classified as NSAID-exacerbated cutaneous disease (n = 1) and NSAID-induced urticaria/angioedema/anaphylaxis (n = 6). As an alternative drug, paracetamol was safely tolerated, whereas 1 patient developed angioedema and urticaria with nimesulide. Older age and male gender were identified as independent risk factors for immediate-type ibuprofen allergy. Conclusion: DPTs should be performed to confirm or exclude ibuprofen allergy in children and to find safe alternative drugs. Male gender and older age are risk factors for ibuprofen allergy. NSAID-induced hypersensitivity reactions in the pediatric population cannot be well defined using the adult classification system.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

The article discusses the treatment of osteoarthritis (OA), the prevalence of which is high, and according to some forecasts it will increase by 50% in the next 20 years. The authors emphasize the high comorbidity among patients suffering from OA and high cardiovascular and gastrointestinal risks with frequent use of NSAIDs, the volume of consumption of which is constantly increasing. Discussing recommendations for the treatment of patients with OA, the article focuses on the use of hyaluronic acid (HA) preparations in the treatment of OA. The mechanisms of anti-inflammatory and chondroprotective actions of HA in the joint, its effect on cartilage and synovial membrane are discussed. Attention is drawn to the fact that, despite more than 30 years of experience in the effective use of HA preparations in the treatment of OA, this procedure is still a subject of controversy among international professional communities. The article presents data from meta-analyses and systematic reviews confirming the effectiveness of the use of intra-articular management of HA preparations in OA of various localization (knee joints, hip joints, hand joints). In conclusion, the recommendations of the technical expert group established at the International Symposium on Intra-Articular Treatment are given to determine the criteria for the successful administration of HA in OA of various localizations, as well as predictors of success and non-success of therapy with HA drugs. The experts identified indications, contraindications for intra-articular administration of HA preparations, as well as conditions associated with an increased risk of therapy failure. In conclusion, the authors draw conclusions about the importance of using HA preparations for intra-articular administration for the treatment of OA, starting from the early stages, following the recommendations of experts.В статье обсуждаются вопросы лечения остеоартрита (ОА), распространенность которого в настоящее время достаточно высока и, по данным некоторых прогнозов, увеличится еще на 50% в ближайшие 20 лет. Авторы делают акцент на высокой коморбидности среди пациентов, страдающих ОА, и высоких сердечно-сосудистых и желудочно-кишечных рисках при частом использовании нестероидных противовоспалительных препаратов, объем потребления которых постоянно растет. При обсуждении рекомендаций по лечению пациентов с ОА уделяется внимание использованию препаратов гиалуроновой кислоты (ГК) в схеме терапии, а также дискуссии о механизмах противовоспалительного и хондропротективного действия ГК в суставе, ее влиянии на хрящ и синовиальную оболочку. Обращается внимание на то, что, несмотря на более чем 30-летний опыт эффективного использования препаратов ГК в лечении ОА, эта процедура по-прежнему является предметом споров в международных профессиональных сообществах. В статье представлены результаты метаанализов и систематических обзоров, подтверждающие эффективность использования внутрисуставного введения препаратов ГК при ОА различной локализации (коленные и тазобедренные суставы, суставы кистей). В завершении приводятся рекомендации технической экспертной группы, созданной на Международном симпозиуме по внутрисуставному лечению для определения критериев успешного введения ГК при ОА различных локализаций, а также предикторов успешности и неуспешности терапии препаратами ГК. Экспертами определены показания и противопоказания для внутрисуставного введения препаратов ГК, а также состояния, связанные с повышенным риском неудачи терапии. В заключении авторы делают выводы о важности препаратов ГК для внутрисуставного введения с целью лечения ОА, начиная с ранних его стадий, согласно рекомендациям экспертов.

Postoperative pain management is essential for patient satisfaction; however, no reports have described the effect of perioperative duloxetine administration on the postoperative pain management following knee surgery. This study aimed to determine whether perioperative duloxetine administration reduces pain following high tibial osteotomy.In this prospective clinical trial, 35 and 33 patients receiving (40 mg/day) and not receiving duloxetine (control), respectively were enrolled. The knee pain and quality of recovery were evaluated using the numeric rating scale (NRS) scores, the frequency of analgesic drugs used, and patient-reported outcome measures, including the NRS score at rest and the Knee Injury and Osteoarthritis Outcome Score (KOOS), were compared between the groups.The NRS scores of the duloxetine group (D) were significantly reduced compared with those of the control group (C) on postoperative day 1 (D:3.8 vs C:5.1, p = 0.022), day 7 (D:2.1 vs C:2.9, p = 0.021), and day 14 (D:1.6 vs C:2.9, p = 0.001). Non-steroidal anti-inflammatory drug administration was significantly lower in the duloxetine group than in the control group (p 0.001). Although the KOOS score was not significantly different in several subcategories at the pre- and postoperative time-points, the Function in Sport subcategory of the KOOS was significantly improved in the duloxetine group compared with that in the control group at 3 months postoperatively (p 0.05).Perioperative use of duloxetine from 2 weeks before surgery to 2 weeks after surgery is advantageous in perioperative pain management and KOOS improvement following high tibial osteotomy.

Non-steroidal anti-inflammatory drugs are often used as part of multimodal analgesia to control postoperative pain. This randomized, controlled, double-blinded, non-inferiority study aimed to compare the postoperative analgesic effects of intravenous ibuprofen versus ketorolac in children undergoing open unilateral lower abdominal surgery. The authors hypothesized that postoperative analgesia produced by intravenous ibuprofen would be non-inferior to that of intravenous ketorolac.Sixty-six children aged 2 to 8 years who were scheduled to undergo unilateral lower abdominal surgery, were recruited. Patients in the ibuprofen group received 10mg/kg/6h intravenous ibuprofen. Patients in the ketorolac group were given 0.5mg/kg/6h intravenous ketorolac. The primary outcome measure was 24-h postoperative morphine consumption. The secondary outcome measures were postoperative pain score, the incidence of early postoperative fever and the incidence of ibuprofen and ketorolac adverse effects including pain during drug infusion, vomiting, epigastric pain and allergic reaction.Fifty-nine patients completed the study (30 ibuprofen, 29 ketorolac). There was no significant difference (P=0.305) in the mean (SD) 24-h postoperative morphine consumption (μ/kg) between intravenous ibuprofen, 16.00 (5.31), and ketorolac, 14.65 (4.61). The reported pain scores were similar in both groups. The incidence of postoperative fever was significantly lower (p=0.039) in the ibuprofen group (3%) than the ketorolac group (20%). The incidence of adverse effects was similar in both ibuprofen and ketorolac groups.Intravenous ibuprofen can be used as an alternative to ketorolac for postoperative analgesia in children undergoing unilateral lower abdominal surgery because both drugs similarly provide safe and effective postoperative analgesia.

The incidence of pseudophakic cystoid macular edema (PCME) ranges from 0.1% to 20% and is the most common cause of postprocedure vision loss. Currently, there is no widely accepted treatment for PCME. Topical nonsteroidal anti-inflammatory drugs as drops given alone or in combination with topical corticosteroids are often used; however, there is a growing body of literature surrounding the off-label use of various ocular injectable medications. The purpose of this systematic literature review was to characterize the current evidence surrounding these treatments and conduct qualitative analysis to assess the risk for bias of each study. 18 total studies were found and evaluated to have moderate (n = 3, 17%) to high risk (n = 15, 83%) of bias. Although the growing body of real-world data favors improvements in visual acuity and anatomical outcomes with these injectable treatments, larger studies with a better study design are needed to demonstrate their role in the management of PCME.

Identification of disordered platelet function is important to guide peri-operative bleeding management as well as long term treatment and prognostic strategies in individuals with platelet bleeding disorders. Light transmission aggregometry (LTA), the current gold standard diagnostic test of platelet function is a time consuming technique almost exclusively performed in specialised laboratories and almost universally unavailable in regional centres in Australia, where there is an unmet need for access to specialised platelet function diagnostic services. 96-well plate-based aggregometry (Optimul, UK), has been utilised in research laboratories as a novel platform to investigate platelet function. We evaluated the Optimul assay at two centres in Australia, one regional and one tertiary metropolitan, to assess its feasibility as a screening test applicable to remote regional centres. Concentration-response curves were established from 45 healthy volunteers at the participating regional hospital and from 31 healthy volunteers at the tertiary institution. Optimul successfully detected anti-platelet effects in individuals taking aspirin (n=4), NSAID (n=2), clopidogrel (n=2) and dual therapy with aspirin and clopidogrel (n=1). When tested in parallel to LTA in individuals referred for the evaluation of abnormal bleeding symptoms there was overall a very good level of agreement between Optimul and LTA [Cohen's kappa (k

E type prostanoid 4 (EP4) receptors and their signaling pathways have been implicated in the development and malignant transformation of colorectal cancer. We herein demonstrated that the mono(ADP-ribosyl)ation of histone deacetylase (HDAC)1 and HDAC2 by poly(ADP-ribose) polymerase 14 (PARP14) may be required to induce the expression of EP4 receptors. The suppression of PARP14 activity by siRNA and/or its inhibitors reduced the mRNA expression of EP4 receptors. Thus, the expression of their proteins to approximately 50-80% in human colon cancer HCA-7 cells, however, which retained the activities of EP4 receptors to some extent. Since the expression levels of EP4 receptors are important factors for the maintenance of homeostasis, the adequate inhibition of PARP14 activity will be a good target for the prevention of colon cancer and/or as an alternative therapy for this disease. Since non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of heart attacks and stroke, novel PARP14 inhibitors will supersede NSAIDs without causing heart attacks and stroke, while maintaining appropriate EP4 receptor-mediated intestinal homeostasis.

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a condition characterized by the triad of chronic rhinosinusitis with nasal polyps, bronchial asthma, and hypersensitivity to nonsteroidal anti-inflammatory drugs. This article explores the current knowledge on the various pathological mechanism(s) of N-ERD-such as arachidonic acid metabolism, cysteinyl leukotrienes, prostaglandins, platelets, IgE, mast cells, eosinophils, basophils, and innate immune system-and the role of omalizumab in its management. The authors dive deep into the role of IgE in N-ERD and its potential as a therapeutic target. IgE plays a significant role in mediating allergic reactions, is intricately linked with mast cells, interacts with multiple immunopathological pathways involved in N-ERD, and tends to be elevated in patients with N-ERD. Multiple real-world studies, observational studies, and case series, as well as 2 phase III trials, have demonstrated the effectiveness of omalizumab in the management of N-ERD. For a disease with such a well-documented history, the pathophysiology of N-ERD and the most effective ways to manage it remain a mystery. With this background, the authors ask-is IgE a missing piece of the N-ERD puzzle, thus explaining the efficacy of omalizumab in the treatment of the disease?

In an aging population with cardiovascular comorbidities, anticoagulant (AC), antiplatelet (AP), and nonsteroidal anti-inflammatory drug (NSAID) use are increasing. It remains unclear whether these agents pose increased bleeding risk in cirrhosis. This study aimed to assess the association between these medications and bleeding and portal hypertension complications in cirrhosis.The IMS PharMetrics database was used to identify privately insured adults diagnosed with cirrhosis from 2007 to 2015, stratified as compensated or decompensated based on the presence of portal hypertensive complications 1 year before cirrhosis diagnosis. Bleeding or decompensation outcomes were assessed 6 to 18 months after cirrhosis diagnosis using a landmark analysis design. Multivariable Cox proportional hazards regression modeling assessed associations between AC, AP, and NSAID drug exposures and outcomes adjusting for covariates.A total of 18,070 cirrhosis patients were analyzed; 57% male; 74% ages 50 to 64 years; 34% with a prior decompensation. Overall, 377 (2%) had claims for ACs; 385 (2%) APs; and 1231 (7%) NSAIDs. APs were associated with increased bleeding [adjusted hazard ratio (aHR)=1.31; 95% confidence interval (CI): 1.00, 1.72] and decompensation events (aHR=1.44; 95% CI: 1.06, 1.95) in a 9-month landmark analysis. NSAIDs were significantly associated with bleeding events (aHR=1.29; 95% CI: 1.06, 1.57) on 3-month landmark analysis. No statistically significant associations were seen between ACs and bleeding or decompensation outcomes in adjusted analyses.AP use was associated with increased bleeding and decompensation events among privately insured patients with cirrhosis. NSAID use was associated with significant early bleeding, but not decompensations. Lastly ACs were not associated with bleeding or decompensation outcomes.

Despite the high prevalence and burden of osteoarthritis (OA) worldwide, management of OA continues to primarily focus on symptom management due to the lack of approved pharmacologic agents that halt disease progression. Recent recommendations from 6 professional societies support the importance of education, self-management approaches, weight loss, and physical modalities in managing OA. These recent guidelines also highlight the paucity of effective and safe treatment options, with recommendations against ineffective therapies outnumbering those for effective ones. NSAIDs, oral and topical, remain the primary recommended pharmacologic management option for OA.

The appendix of the Sauromatum senosum inflorescence is a striking example of thermogenesis in plants. On the day of opening, the Sauromatum appendix becomes hot, reaching up to 32 °C. Aspirin, salicylic acid and 2,6-dihydroxybenzoic acid, a subclass of NSAIDs, induce a temperature rise from three mitochondrial sources: alternative oxidase, F

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na

Phototherapy and apremilast (oral phosphodiesterase-4 inhibitor) are well-known in the treatment of moderate to severe psoriasis vulgaris. However, current evidence on the efficacy and safety of their combination is not sufficient. This multicenter, randomized controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8-week phototherapy regimen comprising irradiation with narrowband UV-B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5-dimensions 5-level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8-week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

The convergence of national priorities to reduce health-care costs and deliver high-value care warrants the need to examine health-care utilization. The objective of this study was to describe the costs associated with nonoperative procedures in the 1-year period leading up to primary total knee arthroplasty (TKA).An observational cohort study was conducted using the IBM Watson Health MarketScan databases. Patients with late-stage knee osteoarthritis (OA) who underwent unilateral, isolated primary TKA from January 1, 2018, to December 31, 2019, were included. The main outcome was the cost of knee OA-related payments for identified nonoperative procedures in the 1-year period before surgery. Nonoperative procedures examined were (1) physical therapy (PT); (2) bracing; (3) intra-articular injections: professional fee, hyaluronic acid (IA-HA), and corticosteroids (IA-CS); (4) medication: nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen; and (5) knee-specific imaging.The study population included 24,492 TKA patients with a mean age of 60.4 ± 8.0 years. The average total cost of nonoperative procedures per patient was $1,355 ± $2,087. The most common nonoperative treatment prescribed was IA-CS (54.3%). The nonoperative procedure with the highest cost per patient was IA-HA ($1,019 ± $913 per patient). The total cost of nonoperative procedures was higher among female compared with male patients ($1,440 ± $2,159 versus $1,254 ± $1,992 per patient; p0.01). The highest costs were found for patients in the Northeast ($1,740 ± $2,437 per patient). A total of 14,346 (58.6%) and 7,831 (32.0%) of the patients had1 and ≥3 nonoperative treatments, respectively.There is substantial variation in the type and the cost of nonoperative treatment for patients with late-stage OA. Future studies should investigate the effectiveness of nonoperative treatments at different stages of the disease.Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Chronic rhinosinusitis with nasal polyps (CRSwNP) associated with type 2 inflammation and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) can be difficult to control with standard medical therapy and sinus surgery. In this group, biologicals are potentially promising treatment options. The phase III clinical trials for omalizumab, dupilumab, mepolizumab and benralizumab in CRSwNP have demonstrated favourable outcomes. Moving forward, direct comparisons among biologicals, refining patient selection criteria for specific biologicals, determining optimal treatment duration and monitoring long-term outcomes are areas of emerging interest. This review summarizes the clinical evidence from the recent 2 years on the role of biologicals in severe CRSwNP and N-ERD, and proposes an approach towards decision-making in their use.

Distal ulcerative colitis (UC) is responsible for distressing symptoms and reduces quality of life (QoL). Oral and topical formulations of 5-amino-salicylic acid are the first line therapy for mild to moderate distal UC.Our aim was to evaluate the impact of mesalazine treatment for mild to moderate ulcerative proctitis and proctosigmoiditis on patient QoL.Ninety-three patients with mild to moderate ulcerative proctitis and proctosigmoiditis, initiating a treatment with Pentasa, were prospectively included. The primary endpoint was the change from baseline to W8 in patient health-related QoL (HRQoL) as measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) total score.More than 80% of patients were prescribed with a rectal formulation, either alone (47.9%) or with an oral formulation (35.1%), and 17.0% of patients were prescribed oral formulation alone. Mean SIBDQ score was improved at W8 in patients affected with mild and moderate disease ( P lt; 0.001 versus baseline in both groups, as well as in patients who achieved clinical remission ( P lt; 0.001). Patients who achieved clinical remission at W8 reached a mean change of +6.7 (±7.1), whereas those who did not achieve clinical remission had a mean change of +1.1 (±8.9). Seventy-five per cent of patients had an improvement of their disability index at W8. Fecal incontinence was also improved at W8.HRQoL measuring with the SIBDQ is proportionally related to disease activity in patients with distal UC treated with mesalazine.

Nonsteroidal anti-inflammatory drugs represent one of the most popularly used classes of drugs. However, their long-term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti-inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a-d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a-d were subjected to further anti-inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%-74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES-1 and cPGES3 by 74%-83% (77% for indomethacin, and 82% for celecoxib) and 48%-70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half-life time 1.5-fold longer than indomethacin. The metabolites of 2b were predicted via UPLC-MS/MS. In silico ADMET profiling study was also included.

Since trimethoprim (TMP) dose-dependently inhibits the excretion of potassium, a population kinetic-pharmacodynamic analysis was performed to establish an adequate dosing schedule and characterize factors of hyperkalaemia. Dataset was constructed using a retrospective observational cohort of hospitalized patients (18 years) with oral sulfamethoxazole/trimethoprim formulation. The model integrated a kinetic model for TMP, a urinary TMP concentration-response curve and a kinetic model for serum potassium using an indirect response model. The model was a function of body weight, renal function, serum potassium levels and TMP dosing schedule. We evaluated covariates by the stepwise forward and backward selection methods. The Monte Carlo simulation determined the probability of hyperkalaemia (5.5 or6.0 meq/L) according to the dosing schedule, renal function and covariates. This study included 317 patients [age 62 (42-72) years] with 4359 serum potassium levels. The significant covariate was non-steroidal anti-inflammatory drugs (NSAIDs), with a 72.3% reduction in 50% inhibitory concentration. Monte Carlo simulation revealed that high-dose TMP (400 mg thrice daily) co-administered with NSAIDs led to mild hyperkalaemia (10%) and severe hyperkalaemia (approximately 5%), regardless of renal function. In conclusion, clinicians should pay attention to hyperkalaemia with TMP high-dose and co-administered NSAIDs.

Post-operative pain is frequent following gastrointestinal surgery and may result in prolonged hospitalisation, delayed recovery, and lower quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and recommended by Enhanced Recovery After Surgery guidelines as part of opioid-sparing multimodal treatment. However, perioperative NSAID treatment may be associated with increased risk of harm. We will investigate the risks of serious adverse events associated with perioperative NSAID treatment in patients undergoing gastrointestinal surgery.This protocol uses the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We wish to assess the effects of NSAIDs versus placebo, usual care, or no intervention on the incidence of serious adverse in patients undergoing gastrointestinal surgery. We will include all randomised trials. To identify trials, we will search the medical literature analysis and retrieval system online, excerpta medica database, cochrane central register of controlled trials, web of science core collection, and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess the risks of systematic errors. We will perform meta-analyses using R. We will use Trial Sequential Analysis to account for the risks of random errors. We will create a "Summary of Findings"-table in which we will present our primary and secondary outcome results. We will assess the certainty of the evidence using grading of recommendations assessment, development and evaluation.This systematic review can potentially elucidate the risks of perioperative NSAID treatment in gastrointestinal surgery and inform the already established non-opioid multimodal pain treatment regimen recommended by enhanced recovery after surgery guidelines.

Background: Sleep disturbances have been singled out for their implication in the risk of several cancer sites. However, results for prostate cancer are still inconsistent. Methods: We used data from the EPICAP study, a French population-based case–control study including 819 incident prostate cancer cases and 879 controls frequency matched by age. Detailed information on sleep duration on work/free days, and sleep medication over lifetime was collected. Results: Sleep duration and sleep deprivation were not associated with prostate cancer, whatever the aggressiveness of prostate cancer. However, sleep deprivation was associated with an increased prostate cancer risk among men with an evening chronotype [OR, 1.96; 95% confidence interval (CI), 1.04–3.70]. We also observed an increased risk of prostate cancer with higher duration of sleep medication use (Ptrend = 0.008). This association with long duration of sleep medication use (≥10 years) was more pronounced among men who worked at night 15 years or more (OR, 3.84; 95% CI, 1.30–11.4) and among nonusers of NSAID (OR, 2.08; 95% CI, 1.15–3.75). Conclusions: Our results suggested that chronotype, night work, or NSAID use could modify the association between sleep disorders and prostate cancer occurrence needing further investigations to go further. Impact: EPICAP is the first study, which investigates several sleep indicators taking into account potential effect modifiers. If our findings were confirmed, we could identify subgroups of men at higher risk of prostate cancer that may be accessible to preventive measures.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that accelerates the biosynthesis of PGs during inflammation and has emerged as an important therapeutic target for anti-inflammatory drugs. Natural compounds may serve as a source of inspiration for pharmaceutical chemists and a foundation for developing innovative COX-2 inhibitors with fewer side effects. Therefore, the objective of this study was to identify the potent COX-2 inhibitor and anti-inflammatory activity of the Fimbristylis aestivalis whole plant extract (FAWE). The plant extract was found dominant with rosmarinic acid followed by catechin hydrate, syringic acid, rutin hydrate, (-) epicatechin, quercetin, myricetin, and catechol. FAWE exhibited considerable dose-dependent analgesic efficacy in all analgesic test models. FAWE also showed promising anti-inflammatory potential in carrageenan-induced inflammations in mice. This result was corroborated by molecular docking, revealing that the aforesaid natural polyphenols adopt the same orientation as celecoxib in the COX-2 active site. On the other hand, molecular dynamics (MD) simulations were performed between the most abundant components (rosmarinic acid, catechin hydrate, and syringic acid) and COX-2. Based on hydrogen bonding, RMSD, RMSF, radius of gyration, PCA, and Gibbs free energy landscape analysis, the results demonstrated that these compounds are very stable in the active site of COX-2, indicating substantial COX-2 inhibitory activity.

Pain and related disability remain a major social and therapeutic problem. Comorbidities and therapies increase drug interactions and side effects making pain management more compounded especially in the elderly who are the fastest-growing pain population. Multimodal analgesia consists of using two or more drugs and/or techniques that target different sites of pain, increasing the level of analgesia and decreasing adverse events from treatment. Paracetamol enhances multimodal analgesia in experimental and clinical pain states. Strong preclinical evidence supports that paracetamol has additive and synergistic interactions with anti-inflammatory, opioid and anti-neuropathic drugs in rodent models of nociceptive and neuropathic pain. Clinical studies in young and adult elderly patients confirm the utility of paracetamol in multimodal, non-opioid or opioid-sparing, therapies for the treatment of acute and chronic pain.Opioid and anti-inflammatory drugs are essential medications to relief pain; however, they may pose a serious health risk especially in elderly patients and in patients with medical conditions. Doctors are studying ways to reduce or eliminate their use. We wanted to see how well paracetamol works together with other painkillers to manage pain. Paracetamol (or acetaminophen) is one of the most prescribed medication for fever and pain. We found strong evidence that paracetamol given in association with other analgesic drugs enhances the pain relief in adult patients and in elderly adult patients, even though more studies are warranted in the latter. The use of paracetamol in combination with other analgesics is recommended by physicians and surgeons of different specialties.

Abstract: Rheumatoid arthritis (RA) is an autoimmune disorder that can attack anyone at any age, but it is most common in those between the ages of 30 and 50. It can impact joints or cause joint stiffness, as well as affect the eyes, skin, and lungs. In the absence of a clear mechanism underlying the occurrence of rheumatoid arthritis in humans, scientists have successfully identified and marked some of the most commonly involved biological targets, such as enzymes or receptors, including human carbonic anhydrase, Janus kinase, Bruton kinase, protein kinase, etc. It is plausible to antici-pate that any of the above-mentioned targets will provide a respite in the search for effective rheu-matoid arthritis treatments. This article attempted to compile recent advances in this field over the last six years (2016-2021) and successfully documented the positive outcomes of each significant research project. Without prejudice to any remaining research on this topic, the current compilation should serve as a starting point for future research works in this field. The structure-activity rela-tionships, mechanistic research, and molecular modelling of each class covered, as well as any clin-ical trial developments, have all been given special attention. This review discusses the design and development of numerous inhibitors for diverse targets, such as BTK, JAKs, MAPK-PDE4, SYK, NSAIDs-CAIs, PKC, and others.

The treatment of stones ureteroscopically is associated with postoperative pain, thought to be due largely to the use of ureteral stents. In some, stent removal precipitates renal colic that can last from minutes to hours. We sought to determine if intramuscular ketorolac could reduce post-stent removal renal colic.We performed a prospective, randomized, double-blind, placebo-controlled trial assessing the effects of ketorolac administered at time of stent removal. Patients were randomized to receive an intramuscular ketorolac 30 mg or placebo immediately prior to stent removal. Patients were contacted 1 and 7 days after stent removal to assess pain, need for opioids, emergency department or clinic visits and the need for surgical/medical interventions.A total of 124 patients (62 patients each in the control and treatment groups) were included in the study. The groups were comparable in demographic/operative characteristics. No difference in mean pain scores or proportion of patients who experienced severe pain at 1 and 7 days post stent removal was detected between groups. However, use of ketorolac resulted in significantly fewer renal colic-related unplanned emergency department/clinic visits in the treatment group (2%) compared with the control group (13%, p=0.032).Although administration of ketorolac prior to stent removal does not significantly reduce overall subjective pain experienced post stent removal compared to placebo, it does reduce the likelihood of severe renal colic requiring emergency department or office visits. Eligible patients may benefit from routine use of ketorolac injection at the time of stent removal.

PURPOSE: To assess whether aqueous cytokine profiles and pupil size are altered when high capsulotomy energy is used in eyes undergoing femtosecond laser–assisted cataract surgery (FLACS), and if preoperative use of a topical non-steroidal anti-inflammatory drug (NSAID) has an effect on this. METHODS: This prospective study recruited 83 eyes (63 patients) that were allocated to four treatment groups: conventional phacoemulsification (n = 20 eyes); FLACS with 90% capsulotomy energy without NSAID pretreatment (n = 20 eyes); FLACS with 90% capsulotomy energy with NSAID pre-treatment (n = 21 eyes); and FLACS with 150% capsulotomy energy with NSAID pretreatment (n = 22 eyes). Aqueous humor was collected before and after phacoemulsification to assess cytokine profiles. Pupil size was measured before and after laser capsulotomy. RESULTS: FLACS increased aqueous concentrations of pros-taglandin E 2 (PGE 2 ), interferon γ (IFN-γ), and interleukin 6 (IL-6) compared to conventional phacoemulsification. However, when increasing capsulotomy energy from 90% to 150% (with topical NSAID pretreatment), there was no significant increase in aqueous concentrations of PGE 2 (37.7 ± 21.7 vs 33.6 ± 27.6 pg/mL, P = .99), IFN-γ (3.6 ± 1.1 vs 3.6 ± 0.8 pg/mL, P = .99), or IL-6 (7.1 ± 2.9 vs 6.3 ± 2.4 pg/mL, P = .99). For 90% and 150% capsulotomy energy, there was significant miosis following laser capsulotomy. Increased PGE 2 concentration was significantly correlated with a reduction in pupil area ( r = −0.58, P < .001) and pupil diameter ( r = −0.57, P < .001). However, when a topical NSAID was given preoperatively, there was no difference in the degree of miosis between the 90% and 150% capsulotomy energy groups. CONCLUSIONS: Pretreatment with a topical NSAID prevented a rise in PGE 2 , IFN-γ, and IL-6 levels and excessive miosis when a higher capsulotomy energy was used. When a topical NSAID is used preoperatively, it is safe to use higher capsulotomy energy settings (with a low pulse energy femtosecond laser system) to achieve a satisfactory capsulotomy. [ J Refract Surg . 2022;38(9):587–594.]

Nonsteroidal anti-inflammatory drugs are an effective nonopiate option for pain control. However, the antiplatelet aggregation of cyclooxygenase-1 (COX-1) inhibitors presents a concern in that they may exacerbate bleeding in patients with solid organ injuries.The aim of the study is to evaluate the impact of nonsteroidal anti-inflammatory drugs on blunt solid organ injury. We hypothesized that nonsteroidal anti-inflammatory drugs would not contribute to intra-abdominal bleed progression.This is a retrospective cohort study of blunt solid organ injury evaluated from June 1, 2015, to June 30, 2019, at an urban midwestern Level I trauma center. Patients receiving and those not receiving nonsterioidal anti-inflammatory drugs were compared on intra-abdominal bleeding progression as assessed by surgical intervention, angioembolization, and blood transfusions.We analyzed 706 patients, of whom 206 were given nonsteroidal anti-inflammatory drugs during their hospital course. Compared with those who were not given nonsteroidal anti-inflammatory drugs, patients given nonsteroidal anti-inflammatory drugs were less likely to have an operation (odds ratio, OR 0.46, 95% confidence interval, CI [0.25, 0.85], p = .012) and were less likely to have an embolization (OR 0.27, 95% CI [0.11, 0.70], p = .004). There was no difference in the need for packed red blood cell transfusion between the nonsteroidal anti-inflammatory drug and non- nonsteroidal anti-inflammatory drug groups (95% CI [0.91, 1.99], p = .13).Patients given nonsteroidal anti-inflammatory drugs had a decreased likelihood of receiving an organ-specific procedure or needing a blood transfusion and had no difference in mortality. Our findings indicate that nonsteroidal anti-inflammatory drugs in patients with blunt solid organ injuries were not associated with an increased risk of adverse events related to intra-abdominal bleeding.

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for the management of pancreaticobiliary disorders. The most troublesome ERCP-associated adverse event is post-ERCP pancreatitis (PEP), which occurs in up to 15% of all patients undergoing ERCP. A substantial body of preclinical data support a mechanistic rationale for calcineurin inhibitors in preventing PEP. The findings are coupled with recent clinical data suggesting lower rates of PEP in patients who concurrently use the calcineurin inhibitor tacrolimus (e.g., solid organ transplant recipients). In this review, we will firstly summarize data in support of testing the use of tacrolimus for PEP prophylaxis, either in combination with rectal indomethacin or by itself. Secondly, we propose that administering tacrolimus through the rectal route could be favorable for PEP prophylaxis over other routes of administration.

Osteoarthritis (OA) is a major cause of chronic pain and disability worldwide. Treatment generally focuses on symptom relief through nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, which may incur side effects. Krill oil, rich in anti-inflammatory long-chain (LC) omega-3 ( ω-3) PUFAs and astaxanthin, may be a safe and effective alternative treatment.This study sought to investigate the effects of a commercially available krill oil supplement on knee pain in adults with mild to moderate knee OA. Secondary outcomes were knee stiffness; physical function; NSAID use; Omega-3 Index; and lipid, inflammatory, and safety markers.Healthy adults (n = 235, 40-65 y old, BMI18.5 to35 kg/m2), clinically diagnosed with mild to moderate knee OA, regular knee pain, and consuming0.5 g/d LC ω-3 PUFAs, participated in a 6-mo double-blind, randomized, placebo-controlled, multicenter trial. Participants consumed either 4 g krill oil/d (0.60 g EPA/d, 0.28 g DHA/d, 0.45 g astaxanthin/d) or placebo (mixed vegetable oil). Knee outcomes were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) numeric scale (normalized to scores of 0-100). Outcomes were assessed at baseline, 3 mo, and 6 mo.Omega-3 Index increased with the krill oil supplement compared with placebo (from 6.0% to 8.9% compared with from 5.5% to 5.4%, P 0.001). Knee pain score improved in both groups with greater improvements for krill oil than for placebo (difference in adjusted mean change between groups at 6 mo: -5.18; 95% CI: -10.0, -0.32; P = 0.04). Knee stiffness and physical function also had greater improvements with krill oil than with placebo (difference in adjusted mean change between groups at 6 mo: -6.45; 95% CI: -12.1, -0.9 and -4.67; 95% CI: -9.26, -0.05, respectively; P 0.05). NSAID use, serum lipids, and inflammatory and safety markers did not differ between groups.Krill oil was safe to consume and resulted in modest improvements in knee pain, stiffness, and physical function in adults with mild to moderate knee OA.This trial was registered at clinicaltrials.gov as NCT03483090.

A male term neonate was admitted to the neonatal intensive care unit in the first hours of life with central cyanosis. Echocardiogram showed severe biventricular hypertrophy, markedly right-sided, tricuspid regurgitation, a patent foramen ovale and a closed ductus arteriosus (CDA). The mother recalled being treated with a single dose of intravenous diclofenac for low back pain 2 weeks earlier. The newborn was started on propranolol with symptomatic improvement and was discharged on day 10. At 1-month follow-up, he showed complete resolution of ventricular hypertrophy and suspended propranolol. In the literature, of the 22 cases of CDA after intrauterine exposure to diclofenac, 11 resolved in utero, 3 required ventilatory and inotropic support and 1 evolved to persistent pulmonary hypertension. In this case, a thorough anamnesis was key to identify the probable cause of an otherwise unexplained transient ventricular hypertrophy. This case also alerts to the fetal risks of non-steroidal anti-inflammatory drugs during the third trimester, requiring close monitoring.