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Abstract: This trial assessed the efficacy of naproxen in patients with sciatica in outpatient clinics across 4 Norwegian hospitals. A total of 123 adults with radiating pain below the knee (≥4 on a 0-10 numeric rating scale) and signs consistent with nerve root involvement were included. Participants were randomized to receive either naproxen 500 mg or a placebo twice daily for 10 days. The primary outcome, daily leg pain intensity measured on a 0 to 10 numeric rating scale throughout the treatment period, revealed a statistically significant difference in favor of naproxen, with an adjusted mean difference of -0.5 (95% CI -0.8 to -0.1, P = 0.015). In the naproxen group, the treatment effect was significantly related to time, and over the whole 10-day period, the average adjusted difference was -0.6 (95% CI -0.8 to -0.5). Mean numbers needed to treat for 30% and 50% improvement were 9.9 (95% CI 4.7-15.0) and 20.7 (8.7-32.7), respectively. The adjusted mean difference for back pain was -0.4 (95% CI -0.8 to 0.0), and for Roland Morris Disability Questionnaire for Sciatica, it was -1.5 (95% CI -3.0 to 0.0). No differences were found for sciatica bothersomeness or consumption of rescue medication or opioids. Participants in the naproxen group exhibited an adjusted odds ratio of 4.7 (95% CI 1.3-16.2) for improvement by 1 level on the global perceived change scale. In conclusion, naproxen treatment showed small, likely clinically unimportant benefits compared with placebo in patients with moderate-to-severe sciatica., (Copyright © 2024 International Association for the Study of Pain.)

Background: Varied responses to acute migraine medications have been observed, with over one-third (34.5%) of patients reporting insufficient headache relief. Sumatriptan-naproxen sodium, a single, fixed-dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care., Methods: A narrative review of clinical trials investigating sumatriptan-naproxen sodium for both adults and adolescents was performed in March 2024., Results: Across a total of 14 clinical trials in nine publications, sumatriptan-naproxen sodium offered greater efficacy for 2-h pain freedom (14/14) and sustained pain-free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well-tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan-naproxen sodium in participants with allodynia, probable migraine, menstrual-related migraine and those with poor responses to acute, non-specific, migraine medication., Conclusions: Multi-mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan-naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen-sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults., Methods: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554., Results: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I 2 between the studies was low., Conclusions: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).

Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic side effects. We, therefore, examined the risk of cardiovascular events associated with NSAID use in patients with gout. We conducted a nationwide, population-based case-crossover study of all Danes ≥ 18 years of age with first-time gout during 1997-2020, who experienced a cardiovascular event (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation/flutter, or cardiovascular death) (n = 59,150). The exposure was use of NSAIDs, overall and according to type (ibuprofen, naproxen, or diclofenac). We used the dates 300, 240, 180, and 120 before the outcome date as reference dates. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and cardiovascular events. NSAID use was overall associated with 12% decreased odds of a cardiovascular event (OR = 0.88, 95% CI: 0.85-0.91). This decreased odds ratio was observed for the use of ibuprofen (OR = 0.92, 95% CI: 0.88-0.97) and naproxen (OR = 0.85, 95% CI: 0.74-0.97), but not for the use of diclofenac (OR = 0.97, 95% CI: 0.90-1.05). Overall, use of NSAIDs was associated with decreased odds of all the individual components of the composite outcome. NSAIDs were not associated with an increased cardiovascular event rate when used in gout patients. Ibuprofen and naproxen appeared to have better cardiovascular risk profiles than diclofenac., (© 2024. The Author(s).)

Background: The mechanisms responsible for menstrual pain are poorly understood. However, dynamic, noninvasive pelvic imaging of menstrual pain sufferers could aid in identifying therapeutic targets and testing novel treatments., Objective: To study the mechanisms responsible for menstrual pain, we analyzed ultrasonographic and complementary functional magnetic resonance imaging parameters in dysmenorrhea sufferers and pain-free controls under multiple conditions., Study Design: We performed functional magnetic resonance imaging on participants with and those without dysmenorrhea during menses and outside menses. To clarify whether regional changes in oxygen availability and perfusion occur, functional magnetic resonance imaging R2∗ measurements of the endometrium and myometrium were obtained. R2∗ measurements are calculated nuclear magnetic resonance relaxation rates sensitive to the paramagnetic properties of oxygenated and deoxygenated hemoglobin. We also compared parameters before and after an analgesic dose of naproxen sodium. In addition, we performed similar measurements with Doppler ultrasonography to identify if changes in uterine arterial velocity occurred during menstrual cramping in real time. Mixed model statistics were performed to account for within-subject effects across conditions. Corrections for multiple comparisons were made with a false discovery rate adjustment., Results: During menstruation, a notable increase in R2∗ values, indicative of tissue ischemia, was observed in both the myometrium (beta ± standard error of the mean, 15.74±2.29 s -1 ; P=.001; q=.002) and the endometrium (26.37±9.33 s -1 ; P=.005; q=.008) of participants who experienced dysmenorrhea. A similar increase was noted in the myometrium (28.89±2.85 s -1 ; P=.001; q=.002) and endometrium (75.50±2.57 s -1 ; P=.001; q=.003) of pain-free controls. Post hoc analyses revealed that the R2∗ values during menstruation were significantly higher among the pain-free controls (myometrium, P=.008; endometrium, P=.043). Although naproxen sodium increased the endometrial R2∗ values among participants with dysmenorrhea (48.29±15.78 s -1 ; P=.005; q=.008), it decreased myometrial R2∗ values among pain-free controls. The Doppler findings were consistent with the functional magnetic resonance imaging (-8.62±3.25 s -1 ; P=.008; q=.011). The pulsatility index (-0.42±0.14; P=.004; q=.004) and resistance index (-0.042±0.012; P=.001; q=.001) decreased during menses when compared with the measurements outside of menses, and the effects were significantly reversed by naproxen sodium. Naproxen sodium had the opposite effect in pain-free controls. There were no significant real-time changes in the pulsatility index, resistance index, peak systolic velocity, or minimum diastolic velocity during episodes of symptomatic menstrual cramping., Conclusion: Functional magnetic resonance imaging and Doppler metrics suggest that participants with dysmenorrhea have better perfusion and oxygen availability than pain-free controls. Naproxen sodium's therapeutic mechanism is associated with relative reductions in uterine perfusion and oxygen availability. An opposite pharmacologic effect was observed in pain-free controls. During menstrual cramping, there is insufficient evidence of episodic impaired uterine perfusion. Thus, prostaglandins may have protective vasoconstrictive effects in pain-free controls and opposite effects in participants with dysmenorrhea., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pheochromocytoma is a chromaffin cell-derived adrenal medullary tumour and usually presents with paroxysms of hypertension, palpitations, sweating and headache due to excessive catecholamine release. These tumours can also secrete a variety of bioactive neuropeptides and hormones other than catecholamines, resulting in unusual clinical manifestations. We report a female in her mid-30s who presented with fever, anaemia, thrombocytosis and markedly elevated inflammatory markers. The fever profile, including cultures, was negative. Contrast-enhanced CT of abdomen showed a large solid-cystic right adrenal lesion with elevated plasma-free normetanephrine levels suggestive of pheochromocytoma. The fever persisted despite empirical antibiotics and antipyretics. Interleukin-6 (IL-6) levels were elevated (41.2 pg/mL (3-4 pg/mL)). She was initiated on naproxen (NPX) at a dose of 250 mg two times per day. The patient responded to NPX, and after stabilisation, she underwent an adrenalectomy. There was a complete resolution of fever with normalisation of IL-6 levels postoperatively., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-specific low back pain (LBP) represents a challenging and prevalent condition that is one of the most common symptoms leading to primary care physician visits. While established guidelines recommend prioritizing non-pharmacological approaches as the primary course of action, pharmacological treatments are advised when non-pharmacological approaches are ineffective or based on patient preference. These guidelines recommend non-steroidal anti-inflammatory drugs (NSAIDs) or skeletal muscle relaxers (SMRs) as the first-line pharmacological options for acute or subacute LBP, while NSAIDs are the exclusive first-line pharmacological option for chronic LBP. Although SMRs are generally effective for acute LBP, the available evidence does not support the view that they improve functional recovery, and their comparative efficacy to NSAIDs and other analgesics remains unknown, while studies have shown them to introduce adverse events without significantly reducing LBP. Moreover, opioids continue to be widely prescribed for LBP, despite limited evidence for effectiveness and known risks of addiction and overdose. Broader use of non-opioid pharmacotherapy, including the appropriate use of OTC options, is critical to addressing the opioid crisis. The balance of evidence indicates that NSAIDs have a favorable benefit-risk profile when compared to other available pharmacological treatment options for non-specific LBP, a condition that is primarily acute in nature and well-suited for self-treatment with OTC analgesics. While clinical guidelines do not differentiate between NSAIDs, evidence indicates that OTC naproxen sodium effectively relieves pain across multiple types of pain models, and furthermore, the 14-h half-life of naproxen sodium allows sustained, all day pain relief with reduced patient pill burden as compared to shorter acting options. Choosing the most appropriate approach for managing LBP, including non-pharmacological options, should be based on the patient's condition, severity of pain, potential risks, and individual patient preference and needs., Competing Interests: SW and GiC are employed by Lumanity Clinical and Regulatory. GrC is employed by the Princeton Spine and Joint Center., (Copyright © 2024 Weisman, Ciavarra and Cooper.)

Cancer is a significant global public health concern, ranking as the leading cause of mortality worldwide. This study thoroughly explores boron-doped carbon dots (B-CDs) through a simple/rapid microwave-assisted approach and their versatile applications in cancer therapy. The result was highly uniform particles with an average diameter of approximately 4 nm. B-CDs exhibited notable properties, including strong fluorescence with a quantum yield of 33%. Colloid stability tests revealed their robustness within a pH range of 6-12, NaCl concentrations up to 0.5 M, and temperatures ranging from 30 to 60 °C. The study also delved into the kinetics of naproxen release from B-CDs as a drug delivery system. The loading efficacy of naproxen exceeded 55.56%. Under varying pH conditions, the release of naproxen from B-CDs conformed to the Peppas-Sahlin model, demonstrating the potential of Naproxen-loaded CDs for cancer drug delivery. In vitro cytotoxicity assessments, conducted using the CCK-8 Assay and flow cytometry, consistently indicated low toxicity with average cell viability exceeding 80%. An in vivo toxicity test on female mice administered 20 mg/kg of B-CDs for 31 days revealed reversible histological changes in the liver and kidneys, while the pancreas remained unaffected. Importantly, B-CDs did not impact the mice's physical behavior, body weight, or survival. In vivo experiments targeting benzo( a )pyrene-induced fibrosarcoma demonstrated the efficacy of B-CDs as naproxen carriers in the treatment of cancer. This in vivo study provides a thorough comprehension of B-CDs synthesis and toxicity and their potential applications in cancer therapy and drug delivery systems.

Background: Pain is an unpleasant experience and annoying sensation. To control this pain during orthodontic separation, different pharmacological and non-pharmacological methods have been used., Objective: This systematic review and meta-analysis aimed to critically assess the evidence of the effectiveness of pharmacological and non-pharmacological methods in reducing pain induced by orthodontic separation., Search Strategy: An electronic search was conducted using the following databases: PubMed® (Medline), Scopus®, EMBASE®, Web of ScienceTM, Google ScholarTM, ProQuest, and Cochrane Central Register of controlled trials (CENTRAL) searching for the studies published between January 2012 and April 2023., Selection Criteria: Only randomized controlled trials (RCTs) were included, each experimental group included patients who received elastomeric separators and one kind of pharmacological or non-pharmacological interventions for pain reduction during the separation stage., Data Collection and Analysis: Cochrane's risk of bias tool (RoB2 tool) was applied. The Grading of Recommendations Assessment, Development, and Evaluation [GRADE] approach was used to evaluate the strength of the evidence., Results: Thirty-one studies (RCTs) were included in this systematic review. Nineteen of them were appropriate for quantitative synthesis and used VAS for pain assessment. Meta-analysis showed that low-level laser therapy (LLLT) was an effective approach for pain relief after separators placement with standard mean difference of 13.79 mm (95% confidence interval (CI): -15.64, -11.94) at 6 h and 23.34 mm at 24 h (95% CI: -25.91, -20.77). LLLT was also effective when applied in split-mouth and the standard mean difference was 8.9 mm at 6 h (95% CI: -12.86, -3.33) and 17.15 mm at 24 h (95% CI: -30.12, -4.17). Ibuprofen had a pain control effect at 6 h and at 24 h compared with the placebo group. The standard mean difference was 14.37 mm (95% CI: -20.54, -8.19) and 20.46 mm (95% CI: -27.79, -13.13), respectively. There was no difference in pain control between ibuprofen and acetaminophen. Naproxen had lower visual analog scale scores in pain perception at 6 h and the standard mean difference was 7.03 mm (95% CI: -12.67, -1.40)., Conclusions: The application of LLLT decreased the pain induced by the separation during the first day of teeth separation; the pain reduction showed an increase from 6 h to the end of the 24 h. However, the evidence is weak to moderate. The analgesics reduced the pain compared to placebo; this pain reduction had shown an increase from 6 h to the end of the 24 h. The strength of the evidence is moderate. Naproxen gel effectively reduced the pain compared to placebo; the evidence in this regard is moderate. Naproxen gel effectively reduced the pain compared to placebo, but it was less effective than the oral intake of non-steroidal anti-inflammatory drugs. However, the evidence in this regard is moderate., Registration: This systematic review was registered with PROSPERO (CRD42022335553) during the first stages of its conduction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Heterotopic ossification (HO) is a known complication diagnosed following hip arthroscopy., Purpose/hypothesis: This study sought to review the current literature on chemoprophylaxis for HO following hip arthroscopy and to describe what agents and doses are being utilized., Study Design: Systematic Review., Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines on the use of chemoprophylactic medications for HO prevention following hip arthroscopy. Mechanical and radiation prophylaxis were not included in the current analysis., Results: A total of 203 studies were identified, of which 15 were included with 6463 patients. There was one randomized control trial (RCT) and 4 additional comparative studies. The most commonly utilized chemoprophylactic agents were the following: naproxen (n ​= ​8), celecoxib (n ​= ​3), indomethacin (n ​= ​3), aspirin (n ​= ​1), etoricoxib (n ​= ​1), and etodolac (n ​= ​1), and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) (n ​= ​1). Naproxen was either given at a dose of 500 ​mg once or twice daily for 2-4 weeks. RCTs and additional comparative studies showed significant HO prevention using chemoprophylactic agents following hip arthroscopy., Conclusions: HO is a known and common complication following hip arthroscopy. The current systematic review found significant heterogeneity across the literature with respect to specific chemoprophylactic agents and their dosing regimens aimed to reduce the incidence and severity of HO following hip arthroscopy. Additionally, this review demonstrates that most studies that utilize chemoprophylaxis use NSAIDs with successful reduction in the incidence of HO., Level of Evidence: Level IV Evidence., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Overdoses on over-the-counter (OTC) drugs are increasing in the United States, which includes widely available non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen. Symptoms of NSAID toxicity are well known and nonspecific, including nausea, vomiting, abdominal pain, and headaches. Extreme cases can present with confusion, seizures, and renal failure. CASE REPORT We present the case of 63-year-old man with a history of hyperthyroidism and polysubstance use who had an elevated total bilirubin level after attempting suicide via ingestion of 16 tablets of naproxen. The patient presented with vague abdominal pain and nausea in the setting of 2 weeks of worsening psychiatric symptoms, including suicidal ideation. Vital signs, physical examination, and review of systems revealed no significant findings. Medical workup was notable only for an elevated total bilirubin level; workup for hemolysis, biliary stasis, hepatic dysfunction was all within normal limits. Direct bilirubin was not elevated. The patient received intravenous fluids and antiemetic medications, and indirect hyperbilirubinemia resolved by the following day. After ruling out other causes of hyperbilirubinemia, it was determined that his elevated bilirubin was due a naproxen metabolite, O-desmethylnaproxen (ODMN), that has been shown to interfere with certain bilirubin assays when naproxen is ingested over the therapeutic dose. CONCLUSIONS Supratherapeutic naproxen ingestion can lead to laboratory findings of elevated total bilirubin in some assays due to ODMN interference. With the rise in suicide attempts in the United States with OTCs, clinicians should consider laboratory error in such clinical circumstances where the clinical data does not fit the history and physical examination.

Migraine as a common primary headache disorder has a significant negative effect on quality of life of the patients. Its pharmacotreatment includes acute and preventative therapies. Based on the shared therapeutic guideline of the European Headache Federation and the European Academy of Neurology for acute migraine treatment a combination of triptans and non-steroidal anti-inflammatory drugs is recommended for acute migraine treatment in triptan-nonresponders. In this short review we summarized the results of the randomized controlled clinical trials evaluating the effectiveness and safety of sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination. It was revealed that the fix-dose combination was better than placebo for the primary outcomes of exemption of pain and headache relief at 2 hours. Furthermore the combination showed beneficial effect on accompanying symptoms of migraine attack (i.e. nausea, photo- and phonophobia). Adverse events were mild or moderate in severity and rarely led to withdrawal of the drug.
It can be concluded that sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination is effective, safe and well-tolerated in the acute treatment of migraine. 

Background: Serotonin receptors 5-HT1B and 5-HT1D in the cerebral arteries are activated by the 5-hydroxytryptophan agonists (triptans) to relieve the discomfort associated with migraines. Even though triptans are often used to treat acute migraines, there is some debate over their effectiveness., Objective: Our systematic review aimed to evaluate the effectiveness of triptans for acute treatment of migraine in young individuals., Methods: Utilizing the databases of Google Scholar, Cochrane Library, and PubMed, a literature search was conducted, and all papers published till July 2022 were included. This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. In addition to the Boolean operators AND, OR, and NOT, the following descriptive terms were also used: "Triptans," "Pediatric Migraine," "Migraine disorders," "Headache," "Children," and "Adolescent.", Results: A total of 1047 studies were identified, and 25 articles were finally included in the study. 17 of them were RCTs while the remaining were non-randomized trials. Most studies recruited participants aged between 12-17 years. Among 25 studies, 7 reported sumatriptan use, 3 assessed a combination of sumatriptan and naproxen, 4 were on almotriptan, 1 on eletriptan, 6 on rizatriptan, and 4 on zolmitriptan use., Conclusion: We found that rizatriptan (good tolerability profile with a dose of 5 mg) and sumatriptan (nasal spray, 10 mg and 20 mg) had higher efficiency as compared to other triptans. Regardless of type or dose, all triptans are generally well tolerated by patients, but a few adverse effects such as light-headedness (sumatriptan), nasopharyngitis, and, muscular spasms (sumatriptan/ naproxen), somnolence, and dry mouth (rizatriptan), and dizziness (zolmitriptan group) were reported with the triptans.

This large randomized controlled trial examined the effect of naproxen, simvastatin or both on patients with schizophrenia. This was a large multi-center, twelve-week, randomized, double-blind, placebo-controlled, four-arm clinical trial administering naproxen, simvastatin or both to 232 subjects with schizophrenia or schizoaffective disorder. The primary outcome was change in PANSS total score. ANCOVA and mixed model analyses of the PANSS total score change showed no significant difference between naproxen and placebo (adjusted p = 0.78), simvastatin and placebo (adjusted p = 0.38) or the combination of naproxen and simvastatin compared to placebo (adjusted p = 0.72). No statistically significant drug-placebo differences were found in the PANSS subscales, CGI or BACS between all groups. There was a near significant improvement in negative symptoms (p = 0.06), and an analysis of the 5 factor PANSS factors analysis found a significant improvement in simvastatin above placebo in withdrawal (p = 0.03). These finding were not significant after correcting for multiple comparisons. A meta-analysis on changes in total PANSS scores in studies on statins in schizophrenia, including the present study together with six other studies showed a significant improvement for statins compared to placebo (Hedges' G of -0.245 (CI= -0.403, -0.086, p = 0.002). When one outlying study which showed particularly strong effects of statins was removed, part of the effect went away. In conclusion, in this study, naproxen and simvastatin alone or in combination were not efficacious in the treatment of symptoms in schizophrenia. However, the meta-analysis of all studies of simvastatin for schizophrenia indicates further research on this topic., Competing Interests: Declaration of Competing Interest Mark Weiser is an employee of the Stanley Medical Research Institute; Linda Levi has no potential conflicts of interest to disclose; Jinyoung Park has no potential conflicts of interest to disclose; Igor Nastas has no potential conflicts of interest to disclose; Valentin Matei has no potential conflicts of interest to disclose; Michael Davidson is an employee of Minerva Neurosciences Inc., a biotech developing CNS drugs; Ido Arad has no potential conflicts of interest to disclose; Israel Dudkiewicz has no potential conflicts of interest to disclose; John M. Davis has no potential conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Study Objective: To compare nifedipine, naproxen, or placebo for pain relief during diagnostic hysteroscopy., Design: Double-blind, randomized controlled pilot study., Setting: University hospital., Patients: Women scheduled for office diagnostic hysteroscopy (n = 60)., Interventions: Women received nifedipine (2 tablets of 10 mg), naproxen (2 tablets of 250 mg), or placebo (2 tablets of 500 mg lactose) 30 to 60 minutes prior to hysteroscopy., Measurements and Main Results: Sixty patients were enrolled in the study (21 in the nifedipine group, 19 in the naproxen group, and 20 in the placebo group). The median pain scores during hysteroscope insertion, measured on a Visual Analog Scale (VAS), were 1 (interquartile range (IQR) 0-0), 2 (0-4) and 1 (0-1) in the nifedipine, naproxen and placebo group, respectively (P,14). The median VAS scores during hysteroscopy were 5 (IQR 2-7), 5 (4-8) and 5 (3-7) in the nifedipine, naproxen and placebo group, respectively (P,73). The median VAS scores immediately after hysteroscopy were 2 (IQR 0-4), 3 (0-6) and 3 (1-5) in the nifedipine, naproxen and placebo group, respectively (P,40). The median VAS scores 30 minutes after hysteroscopy were 1 (IQR 0-2), 1 (0-1) and 1 (0-2) in the nifedipine, naproxen and placebo group, respectively (P,63). Hysteroscope insertion failed in 1 case (naproxen group) because of cervica`l stenosis (P,32). Flushes, fatigue and vertigo, 30 minutes after the procedure, were significantly more prevalent in the nifedipine group compared to the naproxen (p < .001, p,03, p,03, respectively) and the placebo group (p < .001, p,01, p,01, respectively). Palpitations occurred only in the nifedipine group (p < .001). The day after the procedure, the headache was most prevalent in the nifedipine group compared to the naproxen group (p,001) and the placebo group (p,001)., Conclusion: In our pilot study, pain relief and success rates for office diagnostic hysteroscopy were not significantly different between nifedipine, naproxen, and placebo. Nifedipine was associated with more, albeit tolerable, side-effects., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the effects of naproxen sodium-codeine phosphate, naproxen sodium-dexamethasone, and naproxen sodium on myofascial pain., Methods: This randomized, double-blind prospective clinical study was conducted with patients who applied with the complaint of pain in the temporomandibular region. A total of 169 patients were randomly divided into four groups and received the following treatments: Group A: naproxen sodium 550 mg; Group B: naproxen sodium 550 mg + codeine phosphate 30 mg; Group C: naproxen sodium 550 mg + single-dose dexamethasone 8 mg, and Group D: paracetamol 500 mg., Results: Of the patients, 132 were female, and 37 were male, with a mean age of 27.04 ± 10.56 (18-69 years). Analgesic efficiency of the naproxen sodium-codeine phosphate group was the most effective at the 2nd week and 4th week ( p < 0.05)., Conclusion: Naproxen sodium-codeine phosphate might be preferred as an analgesic in similar cases with severe myofascial pain.

Aim: Cancer patients undergoing chemotherapy report cognitive changes collectively termed "chemo brain." Neuroinflammation is among the factors believed to contribute to "chemo brain" suggesting a potential beneficial role for anti-inflammatory drugs in cancer patients undergoing chemotherapy. We investigated whether the non-steroidal anti-inflammatory drug naproxen influenced hippocampal inflammation in non-tumor bearing female mice receiving the chemotherapy drug cyclophosphamide (CP). Materials and methods: Intact and ovariectomized C57BL/6 mice were used to examine potential role of ovarian hormones on neuroinflammation. The mice were placed on naproxen (375 ppm) or control diet, and a week later CP (100 mg/kg; i.p.) was administered every 3 days for 2 weeks. We analyzed hippocampal inflammatory biomarkers, anxiety-like behavior, spatial working memory, exploratory behavior, spontaneous locomotor activity and depression-like behavior. Results: CP produced significant effects on anti-inflammatory but not pro-inflammatory biomarkers. However, CP and naproxen in combination produced significant effects on both pro- and anti- inflammatory biomarkers. Naproxen and ovariectomy individually produced significant effects on pro- and anti-inflammatory biomarkers as well. Working memory and depression-like behavior were not significantly influenced by CP, naproxen or ovariectomy individually although CP and ovariectomy produced significant interaction effects on depression-like behavior. Exploratory behavior and locomotor activity showed significant effects of CP, and interaction between CP and naproxen was significant for locomotor activity. Conclusions: Ovariectomy, naproxen and a combination of CP and naproxen upregulate hippocampal pro- and anti- inflammatory biomarkers. None of the factors individually produce significant behavioral changes that could be consistent with chemo brain, although CP and ovariectomy in combination produced significant effects on depression-like behavior, a co-morbidity of chemo brain.

Current treatment for Rheumatoid arthritis (RA) utilizes Disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs or its combination, to decrease joint inflammation. In the present study, naproxen (NAP) and sulfapyridine (SULF) ethosomes were prepared by a thin-film hydration technique using PL90G and cholesterol, later crosslinked with carbopol®934. The ethosomes and ethosomal hydrogel were evaluated for rheological properties, physico-chemical analysis, in vitro and in vivo study. The results show, NAP and SULF ethosomes exhibited an average vesicle size between 251.1 ± 1.80-343.5 ± 3.23 nm and 269.0 ± 1.17-358.8 ± 1.22 nm, respectively, with good stability (zeta potential > 30 mV) and polydispersity index. Differential scanning calorimeter and Fourier transform infrared studies reveal no significant changes in the drug properties of ethosomes. Transmission electron microscopy analysis discloses spherical shape vesicles below 200 nm. The entrapment efficiency of NAP and SULF ethosomes was above 66%, and NAP-SULF ethosomes-hydrogel (EH) exhibited a sustained release effect (>8 h). In vivo studies on NAP-SULF EH shows significant inhibition of inflammation (84.63%), with less paw volume (0.1935 ± 0.08 ml) on induced arthritis Albino Wistar rats, ( p  < .01). NAP-SULF EH was stable at 25 °C ± 0.5 for 3-months. To conclude, a hybrid composite of NAP-SULF in hydrogel carrier prevents inflammation effectively, and could be novel for trans delivery of drugs in RA.

Background: Magnesium sulfate has been reported to be effective in perioperative pain treatment and in blunting somatic, autonomic, and endocrine reflexes provoked by noxious stimuli. The pre-emptive analgesic effects of magnesium in reducing postoperative pain could be beneficial in abdominal and gynecologic surgeries., Objective: The aim of study was to compare the pre-emptive analgesic effects of oral magnesium oxide and naproxen for hysterectomy surgery., Methods: This study evaluated all patients who were candidates for hysterectomy in 2 months. The 64 patients were randomly divided into two groups using a random allocation sequence. The patients in the intervention and control groups received either magnesium oxide tablet (500 mg) or naproxen tablet (500 mg) orally half an hour before surgery, respectively. The severity of postoperative pain is assumed as a primary outcome which is evaluated using the visual analogue scale (VAS)., Results: In this study, 64 patients were assessed. The results showed age, weight, systolic and diastolic blood pressure, and pulse rate of the patients in the two groups were not significantly different (p > 0.05). The mean score of pain intensity for these patients was significantly lower than the patients receiving naproxen (p-value: 0.03). Besides, more than one-quarter of patients in the magnesium oxide group (n = 9, 28.12%) received this analgesia with lower dose than the patients in the naproxen group (p-value: 0.03)., Conclusion: The results of this study showed that preoperative oral magnesium oxide had a significant effect on the severity of postoperative pain and consumption of postoperative analgesia., (© 2022. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Burrowing behaviour is used to assess pain-associated behaviour in laboratory rodents. To gain insight into how models of disease-associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma-induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (nonsteroidal anti-inflammatory drug and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation ( R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin, and naproxen showed reduced burrowing behaviour at high doses, whereas ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease-associated pain., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in infants, children, and adolescents worldwide; however, despite sufficient evidence of the beneficial effects of NSAIDs in children and adolescents, there is a lack of comprehensive data in infants. The present review summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available, and includes ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, ketorolac, indomethacin, niflumic acid, meloxicam, celecoxib, parecoxib, rofecoxib, acetylsalicylic acid, and nimesulide. The efficacy of NSAIDs has been documented for a variety of conditions, such as fever and pain. NSAIDs are also the main pillars of anti-inflammatory treatment, such as in pediatric inflammatory rheumatic diseases. Limited data are available on the safety of most NSAIDs in infants. Adverse drug reactions may be renal, gastrointestinal, hematological, or immunologic. Since NSAIDs are among the most frequently used drugs in the pediatric population, safety and efficacy studies can be performed as part of normal clinical routine, even in young infants. Available data sources, such as (electronic) medical records, should be used for safety and efficacy analyses. On a larger scale, existing data sources, e.g. adverse drug reaction programs/networks, spontaneous national reporting systems, and electronic medical records should be assessed with child-specific methods in order to detect safety signals pertinent to certain pediatric age groups or disease entities. To improve the safety of NSAIDs in infants, treatment needs to be initiated with the lowest age-appropriate or weight-based dose. Duration of treatment and amount of drug used should be regularly evaluated and maximum dose limits and other recommendations by the manufacturer or expert committees should be followed. Treatment for non-chronic conditions such as fever and acute (postoperative) pain should be kept as short as possible. Patients with chronic conditions should be regularly monitored for possible adverse effects of NSAIDs., (© 2022. The Author(s).)

The 4-allyl guaiacol is a natural phenolic molecule that has been widely studied for its antioxidant capacity against reactive-oxygen-species-mediated cellular damage. Therefore, we hypothesized that concomitant use of an antioxidant and NSAID may decrease the risk of gastrointestinal toxicity and make the therapy safer. To address the gastrointestinal toxicity of conventional NSAIDs, a new S-naproxen-4-allyl guaiacol chimera (MAS-1696) was computationally developed, chemically synthesized, and tested for anti-inflammatory effectiveness and gastrointestinal safety. The inhibitory potency of MAS-1696 tested against cyclooxygenase-2 (COX2), 15-lipoxygenase-2 (15-LOX2), and lipoxygenase-5 (5-LOX) in vitro revealed a stronger inhibition of COX2. Furthermore, the MAS-1696 chimera increased the COX selectivity index by 23% as compared to the parent compound naproxen, implying higher efficacy and gastric safety. In vivo data showed that MAS-1696 was less likely to cause gastrointestinal harm than naproxen while also exerting anti-inflammatory and analgesic effects equivalent to or superior to naproxen. In conclusion, MAS-1696 is orally active, bio-labile, and crystalline, making it a medication that may be administered orally.

Importance: In arthroscopic knee and shoulder surgery, there is growing evidence that opioid-sparing protocols may reduce postoperative opioid consumption while adequately addressing patients' pain. However, there are a lack of prospective, comparative trials evaluating their effectiveness., Objective: To evaluate the effect of a multimodal, opioid-sparing approach to postoperative pain management compared with the current standard of care in patients undergoing arthroscopic shoulder or knee surgery., Design, Setting, and Participants: This randomized clinical trial was performed at 3 clinical sites in Ontario, Canada, and enrolled 200 patients from March 2021 to March 2022 with final follow-up completed in April 2022. Adult patients undergoing outpatient arthroscopic shoulder or knee surgery were followed up for 6 weeks postoperatively., Interventions: The opioid-sparing group (100 participants randomized) received a prescription of naproxen, acetaminophen (paracetamol), and pantoprazole; a limited rescue prescription of hydromorphone; and a patient educational infographic. The control group (100 participants randomized) received the current standard of care determined by the treating surgeon, which consisted of an opioid analgesic., Main Outcomes and Measures: The primary outcome was postoperative oral morphine equivalent (OME) consumption at 6 weeks after surgery. There were 5 secondary outcomes, including pain, patient satisfaction, opioid refills, quantity of OMEs prescribed at the time of hospital discharge, and adverse events at 6 weeks all reported at 6 weeks after surgery., Results: Among the 200 patients who were randomized (mean age, 43 years; 73 women [38%]), 193 patients (97%) completed the trial; 98 of whom were randomized to receive standard care and 95 the opioid-sparing protocol. Patients in the opioid-sparing protocol consumed significantly fewer opioids (median, 0 mg; IQR, 0-8.0 mg) than patients in the control group (median, 40.0 mg; IQR, 7.5-105.0; z = -6.55; P < .001). Of the 5 prespecified secondary end points, 4 showed no significant difference. The mean amount of OMEs prescribed was 341.2 mg (95% CI, 310.2-372.2) in the standard care group and 40.4 mg (95% CI, 39.6-41.2) in the opioid-sparing group (mean difference, 300.8 mg; 95% CI, 269.4-332.3; P < .001). There was no significant difference in adverse events at 6 weeks (2 events [2.1%] in the standard care group vs 3 events [3.2%] in the opioid-sparing group), but more patients reported medication-related adverse effects in the standard care group (32% vs 19%, P = .048)., Conclusions and Relevance: Among patients who underwent arthroscopic knee or shoulder surgery, a multimodal opioid-sparing postoperative pain management protocol, compared with standard opioid prescribing, significantly reduced postoperative opioid consumption over 6 weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT04566250.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is one of the leading causes of gastric ulcers. Excellent therapeutic properties have made the use of NSAIDs widespread. Nano-drug delivery to reduce systemic toxicity through modulating drug pharmacokinetics may be a better choice. Presently, we investigated if naproxen nanoformulation (PVA capped NPRS-MgO NPs) is less toxic to be used as an alternative drug. Groups of mice were assigned to control, NPRS-treated, CNF-treated, UNF-treated, and MgO NPs-treated groups. Analyses included gross examination of gastric mucosa, calculation of ulcer and inhibition indices, determination of tissue levels of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and reduced glutathione (GSH), histological and immunohistochemical assessment of i-NOS, COX-2, and caspase-3 of stomach mucosa, q-PCR for the detection of mRNA expression of IL-1β, IL-6, and TNF-α. Results were compared statistically at P < 0.05. Compared to NPRS-treated mice which developed multiple ulcers, had elevated MDA and ROS levels, and deceased CAT, POD, SOD, and GSH levels, significantly increased expression of IL-1β, IL-6, and TNF-α mRNA, damaged surface epithelium with disrupted glandular architecture and leucocyte infiltration of lamina propria with a marked increase in mucosal COX-2, i-NOS, and caspase-3 expression, oral administration of coated and uncoated naproxen nanoformulations prevented the gross mucosal damage by a restoration of all biochemical, histological, and immunohistochemical alterations to near control levels. The present study demonstrates that naproxen sodium nanoformulation has a gastroprotective action and in the clinical setting can be a better alternative to conventional naproxen., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article are reported., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib., Case Presentation: A 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months., Conclusions: Our data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient., (© 2022. The Author(s).)

Background: Therapeutic plasma exchange (TPE) is gaining popularity for the management of nonsteroidal anti-inflammatory drug (NSAID) overdose in dogs., Hypothesis/objectives: Describe a population of dogs treated with TPE for NSAID overdose., Animals: Sixty-two dogs with NSAID overdose treated with TPE., Methods: Multicenter retrospective study of dogs treated with TPE for ibuprofen, carprofen, or naproxen overdose., Results: The median dose of ibuprofen, carprofen or naproxen ingested was 533 mg/kg (range, 36-4857 mg/kg), 217 mg/kg (range, 88-625 mg/kg) and 138 mg/kg (range, 26-3000 mg/kg), respectively. Based on previously established toxic ranges for each NSAID, 2 (3.2%), 14 (22.6%), and 46 (74.2%) dogs ingested a gastrointestinal, renal, and neurological toxic dose, respectively. The median time between ingestion and presentation was 4 hours (range, 1-20 hours). The median number of plasma volumes processed was 1.6 (range, 0.4-2.2). The median TPE session duration was 2 hours (range, 1-4.5 hours). Circuit clotting developed during 8 (12.9%) sessions. Patient adverse events reported during 21 (33.8%) sessions consisted of urticaria (12.9%), asymptomatic hypocalcemia (9.6%), and hypotension (9.6%). The median duration of hospitalization was 2.25 days (range, 1-11 days). Sixty-one (98.4%) dogs survived to discharge, and none were rehospitalized. Thirty-one (91.1%) of the 34 dogs with at least 1 follow-up visit were not azotemic at the time of reevaluation., Conclusions and Clinical Importance: This population of dogs managed with TPE had excellent outcomes, even in cases of high NSAID dose ingestion. When TPE is available and the time frame is appropriate, this extracorporeal modality should be considered for the management of NSAID overdose., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Heavy menstrual bleeding and pain are common reasons women discontinue intrauterine device (IUD) use. Copper IUD (Cu IUD) users tend to experience increased menstrual bleeding, whereas levonorgestrel IUD (LNG IUD) users tend to have irregular menstruation. Medical therapies used to reduce heavy menstrual bleeding or pain associated with Cu and LNG IUD use include non-steroidal anti-inflammatory drugs (NSAIDs), anti-fibrinolytics and paracetamol. We analysed treatment and prevention interventions separately because the expected outcomes for treatment and prevention interventions differ. We did not combine different drug classes in the analysis as they have different mechanisms of action. This is an update of a review originally on NSAIDs. The review scope has been widened to include all interventions for treatment or prevention of heavy menstrual bleeding or pain associated with IUD use., Objectives: To evaluate all randomized controlled trials (RCTs) that have assessed strategies for treatment and prevention of heavy menstrual bleeding or pain associated with IUD use, for example, pharmacotherapy and alternative therapies., Search Methods: We searched CENTRAL, MEDLINE, Embase and CINAHL to January 2021., Selection Criteria: We included RCTs in any language that tested strategies for treatment or prevention of heavy menstrual bleeding or pain associated with IUD (Cu IUD, LNG IUD or other IUD) use. The comparison could be no intervention, placebo or another active intervention., Data Collection and Analysis: Two review authors independently assessed trials for inclusion and risk of bias, and extracted data. Primary outcomes were volume of menstrual blood loss, duration of menstruation and painful menstruation. We used a random-effects model in all meta-analyses. Review authors assessed the certainty of evidence using GRADE., Main Results: This review includes 21 trials involving 3689 participants from middle- and high-income countries. Women were 18 to 45 years old and either already using an IUD or had just had one placed for contraception. The included trials examined NSAIDs and other interventions. Eleven were treatment trials, of these seven were on users of the Cu IUD, one on LNG IUD and three on an unknown type. Ten were prevention trials, six focused on Cu IUD users, and four on LNG IUD users. Sixteen trials had high risk of detection bias due to subjective assessment of pain and bleeding. Treatment of heavy menstrual bleeding Cu IUD Vitamin B1 resulted in fewer pads used per day (mean difference (MD) -7.00, 95% confidence interval (CI) -8.50 to -5.50) and fewer bleeding days (MD -2.00, 95% CI -2.38 to -1.62; 1 trial; 110 women; low-certainty evidence) compared to placebo. The evidence is very uncertain about the effect of naproxen on the volume of menstruation compared to placebo (odds ratio (OR) 0.09, 95% CI 0.00 to 1.78; 1 trial, 40 women; very low-certainty evidence). Treatment with mefenamic acid resulted in less volume of blood loss compared to tranexamic acid (MD -64.26, 95% CI -105.65 to -22.87; 1 trial, 94 women; low-certainty evidence). However, there was no difference in duration of bleeding with treatment of mefenamic acid or tranexamic acid (MD 0.08 days, 95% CI -0.27 to 0.42, 2 trials, 152 women; low-certainty evidence). LNG IUD The use of ulipristal acetate in LNG IUD may not reduce the number of bleeding days in 90 days in comparison to placebo (MD -9.30 days, 95% CI -26.76 to 8.16; 1 trial, 24 women; low-certainty evidence). Unknown IUD type Mefenamic acid may not reduce volume of bleeding compared to Vitex agnus measured by pictorial blood assessment chart (MD -2.40, 95% CI -13.77 to 8.97; 1 trial; 84 women; low-certainty evidence). Treatment of pain Cu IUD Treatment with tranexamic acid and sodium diclofenac may result in little or no difference in the occurrence of pain (OR 1.00, 95% CI 0.06 to 17.25; 1 trial, 38 women; very low-certainty evidence). Unknown IUD type Naproxen may reduce pain (MD 4.10, 95% CI 0.91 to 7.29; 1 trial, 33 women; low-certainty evidence). Prevention of heavy menstrual bleeding Cu IUD We found very low-certainty evidence that tolfenamic acid may prevent heavy bleeding compared to placebo (OR 0.54, 95% CI 0.34 to 0.85; 1 trial, 310 women). There was no difference between ibuprofen and placebo in blood volume reduction (MD -14.11, 95% CI -36.04 to 7.82) and duration of bleeding (MD -0.2 days, 95% CI -1.40 to 1.0; 1 trial, 28 women, low-certainty evidence). Aspirin may not prevent heavy bleeding in comparison to paracetamol (MD -0.30, 95% CI -26.16 to 25.56; 1 trial, 20 women; very low-certainty evidence). LNG IUD Ulipristal acetate may increase the percentage of bleeding days compared to placebo (MD 9.50, 95% CI 1.48 to 17.52; 1 trial, 118 women; low-certainty evidence). There were insufficient data for analysis in a single trial comparing mifepristone and vitamin B. There were insufficient data for analysis in the single trial comparing tranexamic acid and mefenamic acid and in another trial comparing naproxen with estradiol. Prevention of pain Cu IUD There was low-certainty evidence that tolfenamic acid may not be effective to prevent painful menstruation compared to placebo (OR 0.71, 95% CI 0.44 to 1.14; 1 trial, 310 women). Ibuprofen may not reduce menstrual cramps compared to placebo (OR 1.00, 95% CI 0.11 to 8.95; 1 trial, 20 women, low-certainty evidence)., Authors' Conclusions: Findings from this review should be interpreted with caution due to low- and very low-certainty evidence. Included trials were limited; the majority of the evidence was derived from single trials with few participants. Further research requires larger trials and improved trial reporting. The use of vitamin B1 and mefenamic acid to treat heavy menstruation and tolfenamic acid to prevent heavy menstruation associated with Cu IUD should be investigated. More trials are needed to generate evidence for the treatment and prevention of heavy and painful menstruation associated with LNG IUD., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

An active tumor-targeting organic photochemotherapy agent via the combination of a an organic photothermal material and a naproxen prodrug was developed to precisely kill cancer cells and suppress the inflammatory response induced by cell necrosis; in vitro , and in vivo experiments illustrated its low cytotoxicity and excellent tumor inhibitory effect.

Rationale: Cancer is a well-recognized cause of fever, which is related to cytokines produced by malignant cells. Prostate cancer presenting with fever and other inflammatory markers as a paraneoplastic syndrome rarely occurs., Patients Concerns and Diagnoses: We describe the case of high fever and lower-urinary tract symptoms that progressed 1 month prior to presentation. A 78-year-old man had been diagnosed with prostate cancer 8 months ago. He received androgen deprivation therapy with leuprolide acetate 22.5 mg for every 3 months. Castration-resistant prostate cancer was diagnosed due to elevated prostate specific antigen (1639 ng/mL) and cancer fever., Intervention: The patient received docetaxel-based systemic chemotherapy 50 mg/mm2 biweekly. Naproxen 500 mg was administered twice a day., Outcomes: After one cycle of systemic chemotherapy, the patient had no major side effects, no more fever was observed, and the systemic condition improved., Conclusion: Differentiating cancer-related fever from infection-related fever is important for appropriate patient management. In this case, fever appeared as the first symptom of castration-resistant prostate cancer and was managed by naproxen and resolved with systemic chemotherapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Heterotopic ossification (HO) of the hip joint may happen accompanying skeletal muscle trauma or surgical procedures. The pharmacological prophylaxis of heterotopic ossification (HO) following total hip arthroplasty (THA) is debated., Areas Covered: This expert opinion aims to systematically investigate the efficacy of current pharmacological options as prophylaxis for HO following THA., Expert Opinion: The current evidence identified celecoxib, naproxen, and diclofenac as best option for the prevention of HO in patients who undergo primary THA. The most appropriate pharmacotherapy for the prevention of HO is still debated and should be customized according to patients' comorbidities and medical history. For patients with cardiovascular comorbidities, naproxen, or diclofenac should be considered along with proton pump inhibitors to prevent gastrointestinal complications. For patients with history of gastrointestinal disease, celecoxib can be recommended. These conclusions must be considered within the limitations of the present investigation. Between studies, heterogeneities in the administration protocols were evident. In some RCTs, the length of the follow-up was shorter than 12 months. The current clinical practice would benefit of high-quality recommendations and the development of the shared official guidelines.

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.

Objectives: Opioid/acetaminophen combinations may be overly prescribed in many post-surgical situations where a non-steroidal anti-inflammatory drug with equal or greater efficacy, fewer central nervous system side effects, and no risk for opioid abuse could be substituted. We compared a single, non-prescription dose of naproxen sodium 440 mg (NapS) against hydrocodone plus acetaminophen 10/650 mg (HYD+APAP) in post-impaction surgery pain., Methods: Single-center, randomized, double-blind, placebo-controlled study in moderate-severe pain after surgical removal of impacted third molars (ClinicalTrials.gov: NCT04307940). Patients (n = 212) received NapS, HYD+APAP, or placebo and were assessed over 12 hours. Primary endpoint: summed pain intensity difference from 0 to 12 hours (SPID 0-12 ). Secondary endpoints: pain intensity, pain relief, time to rescue medication, duration of pain at least half gone. Others: onset of pain relief, global assessment of treatment, adverse events., Results: All 221 randomized patients formed the safety population and were included in the intention-to-treat sensitivity analysis. Nine patients discontinued treatment or had protocol violations, and 212 patients were included in the per-protocol, primary efficacy population. Both active treatments were significantly more effective than placebo. NapS was significantly more effective than HYD+APAP regarding SPID 0-12 (p = 0.01; primary endpoint), total pain relief (0-6 and 0-12 hours; p < 0.05), time to rescue medication (p < 0.001), and duration of pain at least half gone (p < 0.001). HYD+APAP was not statistically superior to NapS for any endpoint. More adverse events were reported with HYD+APAP (n = 63) than NapS (n = 2) and placebo (n = 20), including nausea, vomiting, and dizziness., Conclusion: In moderate-to-severe postsurgical dental pain, a single dose of NapS was at least as effective as HYD+APAP in the early hours, significantly more effective at reducing pain intensity and providing greater pain relief over 12 hours, and was better tolerated. When not contraindicated, NapS should be considered a preferred alternative to opioid combinations for acute pain. (ClinicalTrials.gov, Identifier: NCT04307940; https://clinicaltrials.gov/ct2/show/NCT04307940).

The use of proper nanocarriers for dermal and transdermal delivery of anti-inflammatory drugs recently gained several attentions in the scientific community because they pass intact and accumulate payloads in the deepest layers of skin tissue. Ascorbyl palmitate-based vesicles (aspasomes) can be considered a promising nanocarrier for dermal and transdermal delivery due to their skin whitening properties and suitable delivery of payloads through the skin. The aim of this study was the synthesis of multidrug Idebenone/naproxen co-loaded aspasomes for the development of an effective anti-inflammatory nanomedicine. Aspasomes had suitable physicochemical properties and were safe in vivo if topically applied on human healthy volunteers. Idebenone/naproxen co-loaded aspasomes demonstrated an increased therapeutic efficacy of payloads compared to the commercially available Naprosyn® gel, with a rapid decrease of chemical-induced erythema on human volunteers. These promising results strongly suggested a potential application of Idebenone/naproxen multidrug aspasomes for the development of an effective skin anti-inflammatory therapy., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Abstract: The objective of this study is to validate a placebo pill response predictive model-a biosignature-that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders (predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts-CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial., (Copyright © 2021 International Association for the Study of Pain.)

Background: Helicobacter pylori infection is a common cause of peptic ulcer disease and dyspepsia. In addition, it may result in gastric cancer and gastric mucosa associated lymphoid tissue lymphoma. First-line therapy usually consists of triple therapy containing clarithromycin or amoxicillin, one of the proton pump inhibitors, and metronidazole or tinidazole. In addition to the triple therapy, an analgesic is required to relieve pain such as naproxen., Objective: A sensitive and selective method needs to be developed and validated for simultaneous determination of four drugs (amoxacillin, tinidazole, naproxen and lansoprazole), used for treating Helicobacter pylori infection, in their combined dosage forms., Methods: With the aid of experimental design, the cited drugs were separated and quantified. HPLC with a diode array detector was used and metronidazole, one of the drugs also used for treatment, was the internal standard (IS). A Thermo Scientific BDS Hypersil C18 column (5 µm, 250 mm x 4.6 mm) with mobile phase composed of acetonitrile-water (40 + 60, by volume), pH 5 adjusted with phosphoric acid, at 30°C was used for the separation of the cited drugs., Results: The method was linear over the concentration ranges 10-500 µg/mL for amoxacillin, 10-350 µg/mL for tinidazole, 10-250 µg/mL for naproxen, and 2-20 μg/mL for lansoprazole. The proposed method was fully validated according to International Conference of Harmonization (ICH) guidelines. Statistical analysis revealed no significant difference between the results obtained and the four reference methods for the investigated drugs., Conclusion: The method can be easily implemented in QC studies of the cited drugs in their dosage forms., Highlights: Experimental design was applied using Plackett-Burman design for preliminary screening of factors followed by Box-Behnken design for chromatographic method optimization., (© The Author(s) 2021. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

Background and Aim: Alzheimer's disease (AD) is one of the leading causes of dependence and disability among the elderly worldwide. The traditional anti-Alzheimer medication, rivastigmine, one of the cholinesterase inhibitors (ChEIs), fails to achieve a definitive cure. We tested the hypothesis that naproxen administration to the rivastigmine-treated aluminum chloride (AlCl3) Alzheimer's rat model could provide an additive neuroprotective effect compared to rivastigmine alone., Materials and Methods: The studied groups were control (Cont), AlCl 3 treated (Al), rivastigmine treated (RIVA), naproxen treated (Napro), and combined rivastigmine and naproxen treated (RIVA + Napro). Rats' memory, spatial learning, and cognitive behavior were assessed followed by evaluation of hippocampal acetylcholinesterase (AChE) activity. Hippocampal and cerebellar histopathology were thoroughly examined. Activated caspase-3 and the neuroepithelial stem cells marker; nestin expressions were immunohistochemically assayed., Results: AD rats displayed significantly impaired memory and cognitive function, augmented hippocampal AChE activity; massive neurodegeneration associated with enhanced astrogliosis, apoptosis, and impaired neurogenesis. Except for the enhancement of neurogenesis and suppression of apoptosis, the combination therapy had no additional neuroprotective benefit over rivastigmine-only therapy., Conclusion: Naproxen's efficacy was established by its ability to function at the cellular level, improved neurogenesis, and decreased, apoptosis without having an additional mitigating impact on cognitive impairment in rivastigmine-treated AD rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H 2 S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H 2 S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H 2 S levels has a potential therapeutic value. Consequently, synthetic H 2 S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H 2 S donors; furthermore, herein we discuss their preparation, the H 2 S-releasing mechanisms, and their -biological applications.

Background and Aims: The current study was done to examine the efficacy of naproxen in the management of patients with COVID-19 infection., Methods: This randomized, double-blind, placebo-controlled, clinical trial was done on hospitalized adult patients with confirmed COVID-19 infection. Patients were randomly assigned to receive either naproxen (two capsules per day each containing 500 mg naproxen sodium) or placebo (containing starch) for five days along with the routine treatment that was nationally recommended for COVID-19 infection. Clinical symptoms of COVID-19 infection, the time to clinical improvement, blood pressure, laboratory parameters, and death due to COVID-19 infection were considered as the outcome variables in the present study., Results: Treatment with naproxen improved cough and shortness of breath in COVID-19 patients; such that, compared with placebo, naproxen intake was associated with 2.90 (95% CI: 1.10-7.66) and 2.82 (95% CI: 1.05-7.55) times more improvement in cough and shortness of breath, respectively. In addition, naproxen administration resulted in a significant increase in mean corpuscular volume (MCV) and had a preventive effect on the reduction of systolic blood pressure in COVID-19 patients., Conclusion: Treatment with naproxen can improve cough and shortness of breath in COVID-19-infected patients. Further studies are required to confirm our findings., Competing Interests: Declaration of competing interest The authors declare that they have not any conflict of interest about this work., (Copyright © 2021. Published by Elsevier Ltd.)

Background: To compare the effectiveness of 550 mg naproxen sodium versus 6 mL 2%-lidocaine intracervical block in pain lowering at the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) placement in young women., Methods: In this randomized controlled trial, 100 women aged 15-24 years were block-randomized to receive either 6 mL 2%-lidocaine intracervical block 5 min before the LNG-IUS insertion or 550 mg naproxen 30 min before the procedure. Forty-nine women received 550 mg naproxen and 51 received intracervical block. The primary outcome was pain at LNG-IUS insertion. Secondary outcomes were ease of insertion, insertion failures, and correct IUS positioning. Neither participants nor doctors were blinded. Pain at insertion was assessed by using a Visual Analog Scale (VAS)., Results: Women randomized to lidocaine intracervical block presented lower mean pain score at insertion, when compared to women who received naproxen (5.4 vs. 7.3, respectively; p < 0.001). Parous women had a 90.1% lower chance of experiencing severe pain (p = 0.004). There was a 49.8% reduction in the chance of severe pain for every 1-cm increase in the hysterometry (p = 0.002). The only complication observed during insertion was vasovagal-like reactions (7%). The insertion was performed without difficulty in 82% of the women. Participants in the intracervical block group presented higher proportion of malpositioned IUS on transvaginal ultrasound examination compared to women in naproxen group. Nevertheless, all the malpositioned IUS were inserted by resident physicians., Conclusion: Lidocaine intracervical block was found to be more effective than naproxen in reducing LNG-IUS insertion pain., Trial Registration Number: RBR-68mmbp, Brazilian Registry of Clinical Trials, Retrospectively registered (August 4, 2020), URL of trial registry record: https://ensaiosclinicos.gov.br/rg/RBR-68mmbp/ ., (© 2021. The Author(s).)

The effects of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), on articular cartilage degeneration in female Sprague-Dawley rats was examined. Osteoarthritis (OA) was induced by destabilization of the medial meniscus (DMM) in each knee. Rats were treated with acetaminophen (60 mg/kg), naproxen (8 mg/kg), or 1% carboxymethylcellulose (placebo) by oral gavage twice daily for 3 weeks, beginning 2 weeks after surgery. OA severity was assessed by histological Osteoarthritis Research Society International (OARSI) scoring and by measuring proximal tibia cartilage depth using contrast enhanced µCT (n = 6 per group) in specimens collected at 2, 5, and 7 weeks after surgery as well as on pristine knees. Medial cartilage OARSI scores from the DMM knees of naproxen-treated rats were statistically lower (i.e., better) than the medial cartilage OARSI scores from the DMM knees of placebo-treated rats at 5-weeks (8.7 ± 3.6 vs. 13.2 ± 2.4, p = 0.025) and 7-weeks (9.5 ± 1.2 vs. 12.5 ± 2.5, p = 0.024) after surgery. At 5 weeks after DMM surgery, medial articular cartilage depth in the proximal tibia specimens was significantly greater in the naproxen (1.78 ± 0.26 mm, p = 0.005) and acetaminophen (1.94 ± 0.12 mm, p < 0.001) treated rats as compared with placebo-treated rats (1.34 ± 0.24 mm). However, at 7 weeks (2 weeks after drug withdrawal), medial articular cartilage depth for acetaminophen-treated rats (1.36 ± 0.29 mm) was significantly reduced compared with specimens from the naproxen-treated rats (1.88 ± 0.14 mm; p = 0.004). The results indicate that naproxen treatment reduced articular cartilage degradation in the rat DMM model during and after naproxen treatment., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H 2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H 2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile., (© 2021 Federation of American Societies for Experimental Biology.)

Purpose: This study aimed to compare the safety and efficacy of clarithromycin-naproxen-oseltamivir combination therapy to that of oseltamivir therapy alone in hospitalized pediatric influenza patients., Methods: This prospective, single-blind study included children aged 1-18 years hospitalized with influenza, in MacKay Children's Hospital, Taiwan, between December 2017 and December 2019. The primary outcomes were the time to defervescence and decrease of the Pediatric Respiratory Severity Score (PRESS) during hospitalization. The secondary outcomes were serial changes in virus titers, measured using real-time polymerase chain reaction., Results: Fifty-four patients were enrolled (28 in the control group and 26 in the combination group) in total. There were no differences in the patients' baseline characteristics between the groups. The time to defervescence was significantly shorter in the combination group than the oseltamivir group (13.2 h vs. 32.1 h, p = 0.002). The decrease in the virus titer from days 1-3 (log Δ13) was more pronounced in the combination group than the oseltamivir group. (39% vs. 19%, p = 0.001). There were no differences in adverse effects such as vomiting, diarrhea, and abdominal pain during the study or within 30 days after antiviral therapy., Conclusion: The clarithromycin-naproxen-oseltamivir combination group experienced a more rapid defervescence and a more rapid decline of influenza virus titer than the group treated with oseltamivir alone. Further consideration should be given to whether the overall benefits of combination therapy in hospitalized pediatric influenza patients outweigh the risks., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To assess the long-term safety and 16-week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA)., Methods: This was a phase III randomized, double-blind, active treatment-controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56-week treatment/24-week posttreatment follow-up) in adults who were receiving stable-dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals [95% CIs]) were calculated., Results: Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time-adjusted rate/1,000 patient-years 38.3 [95% CI 28.0, 52.5] and 71.5 [95% CI 56.7, 90.2], respectively, versus 14.8 [95% CI 8.9, 24.6]; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant., Conclusion: In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks., (© 2021, American College of Rheumatology.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug-drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56-320 mg/kg), antiallodynic (100-562 mg/kg), and antihyperalgesic and anti-inflammatory (10-178 mg/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.