Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

BACKGROUND: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity. METHODS: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted. RESULTS: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities. CONCLUSIONS: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.

Drug-drug interaction of ciprofol injectable emulsion with mefenamic acid capsules in healthy subjects.

AIMS: To investigate the drug-drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. METHODS: Twenty healthy subjects were enrolled in this single-centre, open-label, two-period DDI study. Ciprofol (0.4 mg kg-1 ) was administered as a single dose on days 1 and 5. A 500-mg oral loading dose of mefenamic acid was given on day 4 followed by a 250-mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). RESULTS: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ), area under the plasma concentration-time curve calculated from 0 to the last measurement point (AUC0-last ) and AUC to infinity (AUC0-inf ) were 91.6% (86.5-96.9%), 103.3% (100.3-106.4%) and 107.0% (101.2-113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. CONCLUSIONS: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid.

Use of non-steroidal anti-inflammatory drugs in renal transplant patients: A retrospective study.

BACKGROUND: Renal transplants are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for analgesic purposes. OBJECTIVE: Considering the dearth of data, we carried out the present study to evaluate the use of various NSAIDs and the incidence of acute kidney injury (AKI) in transplant patients. METHODS: A retrospective study amongst renal transplant patients prescribed at least one dose of NSAID was carried between January and December 2020 at the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. The patients' demographic details, serum creatinine values, and drug-related details were obtained. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used for defining AKI. RESULTS: Eighty-seven patients were included. Forty-three patients were prescribed diclofenac, 60 received ibuprofen, six received indomethacin, 10 were administered mefenamic acid, and 11 received naproxen. Due to multiple courses of NSAID prescription, a total of 70 prescriptions were identified for diclofenac, 80 for ibuprofen, six for indomethacin, 11 for mefenamic acid, and 16 for naproxen. No significant differences were observed in the absolute (p = 0.08) and percent changes in serum creatinine (p = 0.1) between the NSAIDs. Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. Age (OR: 1.1, 95% CI: 1.007, 1.2; p = 0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p = 0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p = 0.005) administration were observed with significant risk of NSAID-induced AKI. CONCLUSION: We observed possible NSAID-induced AKI to an extent of around 15.2% in our renal transplant patients. No significant differences were observed in the incidence of AKI between various NSAIDs and none of them had either graft failure or death.

Cross-reactivity between nonsteroidal anti-inflammatory drugs in fixed drug eruption: Two unusual cases and a literature review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.

Molecular docking-guided synthesis of NSAID-glucosamine bioconjugates and their evaluation as COX-1/COX-2 inhibitors with potentially reduced gastric toxicity.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1 and COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has been associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. We report herein the conjugation of commonly prescribed NSAIDs to glucosamine hydrochloride and the use of molecular docking to show that addition of the carbohydrate moiety to the parent NSAID can enhance binding in the active site of COX-2. In a preliminary, in vitro screening assay, the diclofenac-glucosamine bioconjugate exhibited 10-fold greater activity toward COX-2, making it an ideal candidate for future in vivo studies. Furthermore, in an intriguing result, we observed that the mefenamic acid-glucosamine bioconjugate displayed enhanced activity toward COX-1 rather than COX-2.

Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.

Celecoxib versus mefenamic acid in the treatment of primary dysmenorrhea.

Background The objective was to compare the effectiveness and tolerability of mefenamic acid and celecoxib in women with primary dysmenorrhea (PD) and to compare the quality of life of study participants pre- and post-treatment. Materials and methods This was a randomized crossover clinical trial conducted among sexually inactive female adults aged 18-25 years with PD. Participants were asked to rate their pain score and answer a validated quality of life questionnaire (EQ-5D-3L) before and after consumption of each medication in two menstrual cycles. The effectiveness of celecoxib and mefenamic acid in treating PD was compared with regard to reduction in pain score and the need for medical leave and rescue therapy. Drug tolerability was determined by comparing the occurrence of side effects of both drugs. Quality of life scores pre- and post-intervention were measured and compared. Results Mefenamic acid had a comparable effect to celecoxib in relieving symptoms of PD. Both drugs were equally tolerable and showed similar impacts on quality of life. Conclusions This study demonstrated that mefenamic acid and celecoxib had similar effectiveness in improving pain score and quality of life in women with PD.

Comparative safety of NSAIDs for gastrointestinal events in Asia-Pacific populations: A multi-database, international cohort study.

PURPOSE: The safety of nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in Asia-Pacific countries has had limited study. We assessed the risk of hospitalization for gastrointestinal events with loxoprofen and mefenamic acid compared with other NSAIDs in Asia-Pacific populations. METHODS: We conducted a cohort study using a distributed network with a common data model in Australia, Hong Kong, Japan, Korea, and Taiwan. We included patients who initiated diclofenac, loxoprofen, mefenamic acid, or celecoxib and followed them until their first gastrointestinal hospitalization, switch or discontinuation of medication, disenrollment, or end of database coverage. We used Cox proportional hazards models to assess hospitalization risk. RESULTS: We identified 9879 patients in Japan, 70 492 in Taiwan, 263 741 in Korea, and 246 in Hong Kong who initiated an NSAID, and 44 013 patients in Australia, a predominantly Caucasian population. The incidence of gastrointestinal hospitalization was 25.6 per 1000 person-years in Japan, 32.8 in Taiwan, 11.5 in Korea, 484.5 in Hong Kong, and 35.6 in Australia. Compared with diclofenac, the risk of gastrointestinal events with loxoprofen was significantly lower in Korea (hazards ratio, 0.37; 95% CI, 0.25-0.54) but not in Japan (1.65; 95% CI, 0.47-5.78). The risk of gastrointestinal events with mefenamic acid was significantly lower in Taiwan (0.45; 95% CI, 0.26-0.78) and Korea (0.11; 95% CI, 0.05-0.27) but not Hong Kong (2.16; 95% CI, 0.28-16.87), compared with diclofenac. CONCLUSIONS: Compared with diclofenac, loxoprofen was associated with a lower risk of gastrointestinal hospitalizations in Korea and mefenamic acid with a lower risk in Taiwan and Korea.

Comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs in patients with hypertension: a population-based cohort study.

AIMS: Previous studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. However, few have been active comparison studies that directly assessed the potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase 2 (COX-2)-selective and nonselective NSAIDs in patients with hypertension. METHODS: We conducted a cohort study of patients with hypertension who initiated COX-2-selective or nonselective NSAIDs in a population-based Taiwanese database. The outcomes included hospitalization for the following major cardiovascular events: ischaemic stroke, acute myocardial infarction, congestive heart failure, transient ischaemic attack, unstable angina or coronary revascularization. We followed patients for up to 4 weeks, based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates, and estimated the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs). RESULTS: We identified 2749 eligible COX-2-selective NSAID users and 52 880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2-selective with nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI 0.65, 1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR 1.17; 95% CI 0.61, 2.25), ibuprofen (HR 1.36; 95% CI 0.58, 3.18) or naproxen (HR 0.75; 95% CI 0.23, 2.44). There was an increased risk with COX-2-selective NSAIDs, however, when comparing COX-2-selective NSAIDs with mefenamic acid (HR 2.11; 95% CI 1.09, 4.09). CONCLUSIONS: Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension.

Severe enteropathy with villous atrophy in prolonged mefenamic acid users - a currently under-recognized in previously well-recognized complication: Case report and review of literature.

RATIONALE: Mefenamic acid-induced enteropathy may be an under-recognized condition because few reported cases and no review of literature to comprehensively describe all reported cases exist. From inception until February 2017, a systematic literature search identified twenty original reports of cases of mefenamic acid-induced enteropathy. Additional five cases were identified at our hospital. All cases were included in the analyses. PATIENT CONCERNS: Most patients had been regularly taking therapeutic dosages of mefenamic acid for at least three months before symptoms developed. All patients presented with chronic diarrhea with significant weight loss. Approximately one-third of the cases had some degree of anemia and hypoalbuminemia. DIAGNOSES: Endoscopic findings could range from very mild abnormalities, such as mild atrophic mucosa, to marked abnormalities, such as blunted villi with scalloping appearance in the small intestine and inflamed mucosa with a few superficial ulcers in the ileum and colon. Pathological findings included flattened small intestinal villi and mixed inflammatory infiltrates including eosinophils in lamina propria. INTERVENTION: After identifying history of prolong mefenamic acid exposure, all patients were prescribed to stop this medication. Nutritional support and substitutional treatment for mefenamic acid were provided as well. OUTCOMES: All symptoms responded dramatically to drug withdrawal. Some patients could change to use other nonsteroidal anti-inflammatory drugs (NSAIDs) without symptoms reoccurring. LESSONS: Unlike other traditional NSAIDs, mefenamic acid could induce intestinal villous atrophy. An adequate drug history is crucial to identifying the condition. Protracted diarrhea occurring during treatment should be the indication to cease the medicine promptly.

Traitement analgésique après des interventions en médecine dentaire.

This script gives a pragmatic advice for dentists on pain control and anti-inflammation treatment considering current literature and state of the art of analgesic treatment. Naproxen seems to be the feasible anti-inflammatory painkiller as it has a lower cardio-vascular risk profile compared to other NSAID. The higher gastrointestinal bleeding risk can be mitigated using proton-pump inhibitors. Additionally, the duration of the drug effect of about 12–15 hours allows excellent patient compliance and comfort in comparison to other NSAID.

Mefenamic acid: A possible cause of drug-induced acute pancreatitis.

INTRODUCTION: Drug-induced acute pancreatitis (AP) is rare, but as there are no systematic data on it, the true incidence is not known. CASE REPORT: This case report is a first description of two episodes of AP occurring after administration and subsequent re-administration of mefenamic acid to a young woman without comorbidities. Other common causes of AP could be ruled out. With both episodes, the latency of AP was less than 24 h after drug intake. CONCLUSION: Mefenamic acid should be considered as a possible cause of drug-induced AP.

Ciprofloxacin-induced crystal nephropathy.

Ciprofloxacin is a commonly used antibiotic. Renal side effects are rare and are usually immune mediated. Clinical and experimental studies have suggested that crystalluria and crystal nephropathy occur in alkaline urine. Preexisting kidney function impairment, high dose of the medication, and advanced age predispose to this complication. We report a case of crystal nephropathy in a young woman treated with ciprofloxacin and a nonsteroidal anti-inflammatory drug.

Seizures after single-agent overdose with pharmaceutical drugs: analysis of cases reported to a poison center.

CONTEXT: Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. OBJECTIVES: To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. METHODS: A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. RESULTS: We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. CONCLUSIONS: Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.

Compounded ointment results in severe toxicity in a pediatric patient.

BACKGROUND: Dermal drug delivery is becoming more common, as evidenced by the increased numbers of compounding pharmacies preparing topical products for chronic pain management. Consumers may not appreciate the potency or dangers associated with some of the drugs in these preparations. Pediatric patients are especially at risk for significant toxicity with accidental exposures. We report a case of severe toxicity in an 18-month-old boy from exposure to his father's compounded pain ointment. CASE: An 18-month-old previously healthy child had an ointment applied topically to a diaper rash by his mother, consisting of a single pump of a prescription ointment that her husband received from a compounding pharmacy for neck pain. Approximately 20 minutes later, when the child had been put down for a nap, he had gasping respiration but was otherwise unresponsive. Emergency medical services was called, and the child was unresponsive. In the ED, vital signs were pulse of 57 beats/min, blood pressure 74/35 mm Hg, respiratory rate 21 breaths/min, and O2 saturation 98% on a nonrebreather. Fingerstick glucose was 105 mg/dL. In the ED, physical examination was significant for unresponsiveness, pinpoint pupils, and hyporeflexia. The patient's mental status continued to deteriorate with depressed respirations, and he was intubated. Laboratory results were noncontributory. Electrocardiogram revealed only sinus bradycardia. The patient was transported to a pediatric intensive care unit. He did well over the next several hours with supportive care and had return to normal vital signs over the following 12 hours. He was extubated the following morning without problems. Blood taken at the time of ED presentation had a serum clonidine level of 9.2 ng/mL (reference range, 0.5-4.5 ng/mL) and a norketamine level of 41 ng/mL (reporting limit, >20 ng/mL). CONCLUSIONS: Dermal absorption of drugs leading to significant toxicity in children is well known. Our patient had toxicity from a topical pain medication compounded with several potent drugs known to cause central nervous system depression. There has been an increase in the use of this drug delivery system for management of chronic painful conditions. The popularity and attractiveness of such preparations may be the perception that they are somehow safer and more natural than taking pills. This perception and the fact that these are not dispensed in child-proof containers and are often mailed to the patients without pharmacist counseling can lead to increased inadvertent exposures in the pediatric population.

[Infection after dental intervention. Iatrogenic or general medical cause? Case report]. / Infektion nach zahnärztlichem Eingriff. Zahnärztliche oder allgemeinmedizinische Ursache? Ein Fallbericht.

Whenever a dentist is dealing with abscess formation in the oral and maxillofacial region, it is mostly from dental origins. However, sometimes uncommon (co-)factors are present and responsible for major complications. Many general conditions or medications can significantly influence the course of an inflammation. It might spread faster and wider and also be resistant to "correct" therapy. This case report should raise awareness about general conditions supporting inflammation and demonstrate the importance of interdisciplinary treatment in these situations. A 76-year-old patient was referred to the maxillofacial surgery clinic after extraction of two teeth resulted in therapy-resistant painful swelling. Her dentist already had initiated "standard" therapy including Ponstan® (mefenamic acid) and Clamoxyl® (amoxicillin) without success. Initial blood testing came back with severe agranulocytosis. Immediately all potentially myelosuppressing drugs were stopped while myelosupporting drugs were prescribed. Under close interdisciplinary treatment conditions, healing was then uneventful without the necessity of surgical intervention. The challenge in inflammation treatment is to identify patients with uncommonly severe, fast-progressing, or therapy-resistant disease as early as possible. Further examination including blood workup for several medical parameters is indispensable in those patients.