Elevated IL-6 levels in a patient with pheochromocytoma.

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.

Ultrasound and magnetic resonance imaging-based investigation of the role of perfusion and oxygen availability in menstrual pain.

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.

Strategic Assessment of Boron-Enriched Carbon Dots/Naproxen: Diagnostic, Toxicity, and In Vivo Therapeutic Evaluation.

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.

Chemoprophylaxis for heterotopic ossification following hip arthroscopy: A systematic review.

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 â€‹= â€‹8), celecoxib (n â€‹= â€‹3), indomethacin (n â€‹= â€‹3), aspirin (n â€‹= â€‹1), etoricoxib (n â€‹= â€‹1), and etodolac (n â€‹= â€‹1), and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) (n â€‹= â€‹1). Naproxen was either given at a dose of 500 â€‹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.

Efficacy of Oral Nifedipine, Naproxen, or Placebo for Pain Relief During Diagnostic Hysteroscopy in an Office Setting: A Randomized Pilot Study.

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.

Hippocampal neuroinflammation following combined exposure to cyclophosphamide and naproxen in ovariectomized mice.

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.

Effect of a Postoperative Multimodal Opioid-Sparing Protocol vs Standard Opioid Prescribing on Postoperative Opioid Consumption After Knee or Shoulder Arthroscopy: A Randomized Clinical Trial.

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.

Acute kidney injury and long-term renal effects of alectinib in anaplastic lymphoma kinase-positive non-small cell lung carcinoma: a case report.

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.

Naproxen sodium nanoparticles are less toxic and gastroprotective agents than the conventional NSAID drug naproxen sodium in Balb/c mice.

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-1ß, 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-1ß, 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.

Fever as a first presentation of castration-resistant prostate cancer: A case report.

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.

An active tumor-targeting organic photochemotherapy agent with naproxen for enhanced cancer therapy.

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.

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

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

The effect of preoperative oral magnesium oxide on the severity of postoperative pain among women undergoing hysterectomy.

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.

Analgesic efficacy of naproxen sodium versus hydrocodone/acetaminophen in acute postsurgical dental pain: a randomized, double-blind, placebo-controlled trial.

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 (SPID0-12). 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 SPID0-12 (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).

RP-HPLC-DAD Method Development and Validation for Simultaneous Determination of Lansoprazole, Tinidazole, Amoxicillin, and Naproxen in Their Raw Materials and Combined Dosage Form: DOE Approach for Optimization of the Proposed Method.

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.

Use of naproxen versus intracervical block for pain control during the 52-mg levonorgestrel-releasing intrauterine system insertion in young women: a multivariate analysis of a randomized controlled trial.

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/ .

Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation.

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 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 H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

Evaluation of the Antinociceptive, Antiallodynic, Antihyperalgesic and Anti-Inflammatory Effect of Polyalthic Acid.

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.

Design and synthesis of novel (S)-Naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models.

Naproxen is a common non-steroidal anti-inflammatory drug, which is the most usually used propionic acid derivative for the treatment of many types of diseases. In this study, a series of novel (S)-Naproxen derivatives bearing hydrazide-hydrazone moiety were designed, synthesized, and evaluated for anticancer activity. The structures of these compounds were characterized by spectral (1H-13C NMR, FT-IR, and HR-MS analyses) methods. All synthesized compounds were screened for anticancer activity against two different human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, (S)-2-(6-methoxynaphthalen-2-yl)-N'-{(E)-[2-(trifluoromethoxy)phenyl]methylidene} propanehydrazide (3a) showed the most potent anticancer activity against both cancer cell lines with a good selectivity (IC50 = 22.42 and 59.81 µM, respectively). Furthermore, the molecular modeling of these compounds was studied on Vascular Endothelial Growth Factor Receptor 2. Inhibition of VEGFR-2 and apoptotic protein Bcl-2 was investigated in MDA-MB-231 cells treated with compound 3a by using Western Blotting. Apoptosis was also detected by staining with DAPI in fluorescence microscopy. Flow Cytometry analyses related to cell cycle phases showed that a dramatic increase in S and M phases was established compared to untreated control cells indicating the cancer cell cycle arrest. The anticancer activity of compound 3a was investigated in the Ehrlich acid tumor model, a well-validated in vivo ectopic breast cancer model, in mice. Our results showed that compound 3a had anticancer activity and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice.

Naproxen treatment inhibits articular cartilage loss in a rat model of osteoarthritis.

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.