Unraveling Prostaglandin and NLRP3 Inflammasomemediated Pathways of Primary Dysmenorrhea and the Role of Mefenamic Acid and Its Combinations

Painful menstrual cramps during or around the time of the monthly cycle are known as dysmenorrhea. The estimated global prevalence in women of reproductive age ranges from 45% to 95%. It has a significant negative impact on regular activities and productivity at work. However, despite the severe consequences on quality of life, primary dysmenorrhea (PD) is underdiagnosed. Dysmenorrhea has complex pathogenesis. It involves the release of prostaglandins and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and also includes the involvement of other mediators such as bradykinin, histamine and acetylcholine. Even though nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most common type of pain medication, the question of which one should be the most preferred is still open to debate. The current review examines the existing evidence for the pathogenesis of PD and makes evidence based and clinical experience based recommendations for the use of mefenamic acid and its combination in the treatment of dysmenorrhea. Mefenamic acid alleviates PD by inhibiting endometrial prostaglandin formation, restoring normal uterine activity, and reducing the inflammatory response by inhibiting the NLRP3 inflammasome and reducing the release of cytokines such as interleukin (IL)-1?. It is also known to have bradykinin antagonist activity. Dicyclomine has a dual action of blocking the muscarinic action of acetylcholine in postganglionic parasympathetic effect or regions and acting directly on uterine smooth muscle by blocking bradykinin and histamine receptors to relieve spasms. According to the experts, mefenamic acid and dicyclomine act synergistically by acting on the different pathways of dysmenorrhea by blocking multifactorial agents attributed to the cause of dysmenorrhea. Hence, the combination of mefenamic acid and dicyclomine should be the preferred treatment option for dysmenorrhea.

NLRP3 Inflammasome in the Pathogenesis of Dysmenorrhea and Role of Mefenamic Acid as its Inhibitor

While the role of prostaglandin as a trigger in dysmenorrhea is well known, not many are aware that inflammation and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome are also implicated in primary dysmenorrhea (PD). Inhibition of NLRP3 inflammasome and inflammation pathways is an important approach to treating dysmenorrhea and also the symptoms of premenstrual syndrome. Mefenamic acid is an effective and selective inhibitor of the NLRP3 inflammasome, which can be considered the most important option for PD treatment owing to its action via various pathways. In this article, the authors have reviewed the role of inflammation and NLRP3 inflammasome in causing PD, how inhibitors of NLRP3 inflammasome can treat dysmenorrhea and the mechanism of action of mefenamic acid as NLRP3 inflammasome inhibitor and its role in PD.

Role of Prostaglandins in Pathogenesis of Dysmenorrhea and Place of Mefenamic Acid and Dicyclomine in its Management

Despite being one of the most common gynecological issues faced by women of reproductive age, dysmenorrhea largely remains an ignored, underdiagnosed and untreated condition. It continues to be a public health issue and has a significant impact on the quality of life of the affected women in terms of inability to lead routine activities, absenteeism from academic activities or work and reduced social activities. Currently, existing evidence correlates and implicates the excessive synthesis of prostaglandins with the menstrual pain. Hence, treatment approaches that can inhibit prostaglandins' production or already formed prostaglandins can provide relief in dysmenorrhea. In this review, the impact of dysmenorrhea on the quality of life of women, the role of prostaglandins in the pathogenesis of dysmenorrhea, and how nonsteroidal anti-inflammatory drugs (NSAIDs) like mefenamic acid can be safe and effective in managing dysmenorrhea are discussed.

Formulation and evaluation of a mucoadhesive buccal tablet of mefenamic acid

Buccal route of administration has many advantages such as improving patient compliance, bypassing the GIT and hepatic first pass effect. The objectives are to formulate mucoadhesive buccal tablet using Mefenamic acid and compatible excipients, and to evaluate the product using quality control tests and in vitro tests. The ingredients were subjected to Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy studies for compatibility test and the results showed no interaction. Two batches of mefenamic buccal tablet were prepared. The tablet thickness and diameter are 3.75 mm and 12 mm respectively. All tablets are within the specification of +/- 5%. The in-house tablet hardness is 6.8-15kg and percent friabilation is not more than 0.8%. The disintegration test showed that all tablets disintegrated within 4 hours. The content uniformity showed that tablets are within the range of 85%-115%. The tablet weight is within the 5% range. The percent swelling is 53.83% to 58.86% and moisture absorption is 14.79% to 15.56%. The surface pH of the tablet is close to the salivary pH, which means that it would not irritate the buccal mucosa. The buccal tablet has a mucoadhesiveness of 0.196 to 0.200. There was no change in pH and size after subjecting it to stability studies in human saliva. Drug release studies showed 80.7% to 83.4% after 3 hours. Even after 3 months of subjecting the tablets to 40 ºC and 75% RH, results are within acceptable range. The results show the potential of the formulation as a mucoadhesive buccal tablet.

In vitro characterization and in vivo performance of mefenamic acid-sodium diethyldithiocarbamate based liposomes

Mefenamic acid (MFA) is a hydrophobic drug with low dissolution rate. This study aimed to develop stable and reproducible aqueous formulations of MFA using liposomes as drug carriers. The drug entrapment, particles size and drug release profiles, and stability and reproducibility of the liposomes were determined. In addition, the maximum tolerated dose (MTD) was determined in rats via the oral and intraperitoneal routes of administration. Also, the anti-inflammatory efficacy of these liposomes was evaluated using carrageenan-induced paw edema model in rats. MFA-DDC based liposomes demonstrated a drug entrapment efficacy of 93.6%, particles size of 170.9 nm, and polydispersity index of 0.24 which were not statistically affected when stored in room and refrigerated temperatures for at least 4 weeks. The MTD of the intraperitoneally administrated MFA-loaded liposomes was 20 mg MFA/kg, whereas for those of oral administrations, it was up to 80 mg MFA/kg. Intraperitoneal dose (80 mg MFA/kg) of MFA-DDC liposomes induced extrapyramidal symptoms associated with significant elevation in serum potassium and muscle enzymes. Moreover, significant inhibition of paw edema was demonstrated by the oral and intraperitoneal routes. These findings suggest that MFA-DDC based liposomes are an effective formulation of MFA and recommend the use of bioequivalence assessments with commercial formulations.

Mefenamic acid and diclofenac in the treatment of menorrhagia and dysmenorrhea in dysfunctional uterine bleeding: a randomized comparative study

Background: There is a perception that Mefenamic Acid should be the preferred NSAID for menorrhagia. However, there are insufficient evidences to prove this. Further RCTs are required to compare individual NSAIDs.Purposes of the study were to assess and compare the efficacy of mefenamic acid and diclofenac in control of menorrhagia in patients with DUB, to assess and compare their analgesic effects in dysmenorrhea associated with DUB and to study their adverse effects.Methods: Sixty-eight patients were randomized into either Mefenamic Acid (n=34) or Diclofenac (n=34) group. Efficacy variables (Pictorial Blood loss Assessment Chart quantification, Number of pads used, Number of days of menstrual bleeding, Visual Analog Scale score) and adverse effects were recorded over three menstrual cycles.Results: The median reduction of menorrhagia with Mefenamic Acid was 43.39% (Range: 2.86% to 94.4%) and for Diclofenac was 57.5% (Range: 9.9% to 93.58%). The Diclofenac group showed a statistically significant decrease in median bleeding volume, median number of pads used and median number of days of bleeding compared to the Mefenamic Acid group (p<0.05, CI = 95%) but did not show a statistically significant decrease in median VAS score compared to the Mefenamic Acid group. Adverse effects with both groups were mild.Conclusions: Mefenamic Acid and Diclofenac individually managed to significantly reduce excessive bleeding compared to baseline. Diclofenac fared better than Mefenamic Acid in terms of control of excessive menstrual bleeding. Both these agents were able to reduce the menstrual pain and on comparison, were found to be equi-efficacious.

Formation and Characterization of Mefenamic acid-Nicotinamide Cocrystal during Co-milling based on X-ray Powder Diffraction Analysis.

Mefenamic acid (MFA) and Nicotinamide (NIC) cocrystal formation in co-milling treatment was investigated by x-ray powder diffractometry (XRPD). Two polymorphic form of Mefenamic acid (MFA form I and MFA form II) were used to form a cocrystal with nicotinamide. Co-milling treatment was carried out at room temperature in a 1:2 molar ratio of MFA and NIC for various times up to 60 min. Samples were analyzed by XRPD. The XRPD showed that MFA form I and MFA form II formed cocrystal with NIC in the same diffractograms pattern. There was no intermediate amorphous form during milling process. The cocrystal formation mechanism was predicted via intermediate eutectic mixtures. The cocrystal formation from MFA form II (15 min) was faster than from MFA form I (45 min) which may explained by variations unit cell dimensions of MFA form I and MFA form II and also the polymorphic transformation of MFA form I.

Radioprotective effect of mefenamic acid against radiation-induced genotoxicity in human lymphocytes

PURPOSE: Mefenamic acid (MEF) as a non-steroidal anti-inflammatory drug is used as a medication for relieving of pain and inflammation. Radiation-induced inflammation process is involved in DNA damage and cell death. In this study, the radioprotective effect of MEF was investigated against genotoxicity induced by ionizing radiation in human blood lymphocytes. MATERIALS AND METHODS: Peripheral blood samples were collected from human volunteers and incubated with MEF at different concentrations (5, 10, 50, or 100 microM) for two hours. The whole blood was exposed to ionizing radiation at a dose 1.5 Gy. Lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis blocked binucleated lymphocyte. RESULTS: A significant decreasing in the frequency of micronuclei was observed in human lymphocytes irradiated with MEF as compared to irradiated lymphocytes without MEF. The maximum decreasing in frequency of micronuclei was observed at 100 microM of MEF (38% decrease), providing maximal protection against ionizing radiation. CONCLUSION: The radioprotective effect of MEF is probably related to anti-inflammatory property of MEF on human lymphocytes.

Stability Indicating Method for the Determination of Mefenamic Acid in Pharmaceutical Formulations by HPLC.

A simple, RP-HPLC stability indicating method was developed for determination of mefenamic acid in pharmaceutical formulations and its degradation products using C8 column with the mobile phase containing mixture of Buffer : Acetonitrile + THF in the ratio of 55:45 v/v at a flow rate of 1.0 ml/min was found to yield satisfactory retention time of about 18.253 min with sharp symmetrical peak at a detection wavelength of 285 nm. The method was validated using ICH guidelines and was found to be linear in the range 0.5-2 μg/ mL. The proposed method shows good separation of mefenamic acid and its degradation products. The developed method can be applied successfully for the determination of mefenamic acid and its degraded products.

Trace analysis of mefenamic acid in human serum and pharmaceutical wastewater samples after pre-concentration with Ni-Al layered double hydroxide nano-particles / 药物分析学报

In this work, the nickel-aluminum layered double hydroxide (Ni-Al LDH) with nitrate interlayer anion was synthesized and used as a solid phase extraction sorbent for the selective separation and pre-concentration of mefenamic acid prior to quantification by UV detection at λmax ? 286 nm. Extraction procedure is based on the adsorption of mefenamate anions on the Ni-Al(NO3? ) LDH and/or their exchange with LDH interlayer NO3? anions. The effects of several parameters such as cations and interlayer anions type in LDH structure, pH, sample flow rate, elution conditions, amount of nano-sorbent and co-existing ions on the extraction were investigated and optimized. Under the optimum conditions, the calibration graph was linear within the range of 2-1000 mg/L with a correlation coefficient of 0.9995. The limit of detection and relative standard deviation were 0.6 mg/L and 0.84% (30 mg/L, n ? 6), respectively. The presented method was successfully applied to determine of mefenamic acid in human serum and pharmaceutical wastewater samples.

Epidural hematoma after thoracic epidural analgesia in a patient treated with ketorolac, mefenamic acid, and naftazone: a case report / 대한마취과학회지

A 26-year-old male undergoing thoracotomy and bleeding control received a preoperative thoracic epidural for postoperative analgesia. On the fifth postoperative day, paralysis of both lower limbs occurred and urgent magnetic resonance imaging showed massive anterior epidural hematoma. During laminectomy and decompression, platelet dysfunction was diagnosed and preoperative non-steroidal anti-inflammatory drugs medications were supposed to the cause of platelet dysfunction. After infusion of ten units of platelet concentrate, coagulopathy was improved. We should be more careful to drugs with antiplatelet effect when using regional analgesia.

Mefenamic acid-induced bilateral transient myopia, secondary angle closure glaucoma and choroidal detachment.

Drug-induced secondary angle closure is quite common and in the majority of cases simply stopping the medication leads to rapid reversal of the condition and resolution of glaucoma. We describe here a patient who presented with secondary angle closure glaucoma and myopia following mefenamic acid ingestion which was managed successfully by stopping the medication, symptomatic treatment and reassurance.

Study on the inclusion compounds and solid dispersions of mefenamic acid / 西安交通大学学报(医学版)

Objective To prepare ?-CD(?-cyclodextrin) inclusion compounds and PEG- 4000[poly-(ethylene glycol) 4000] solid dispersions of mefenamic acid (MFA)in order to improve its dissolution. Methods The inclusion compounds of MFA were prepared using saturated ?-CD solution method by orthogonal test. The solid dispersions were prepared using melt-cool process with PEG- 4000 as a carrier. The inclusion compounds and solid dispersions were identified by differential scanning calorimetry (DSC) gram and their dissolution rates were tested in pH8.0 buffer solution. Results The suitable condition for preparing ?-CD inclusion compounds of MFA industrially was the weight ratio of 1∶4 between MFA and ?-CD, agitating for 4 h at 70 ℃. The suitable proportion for preparing solid dispersions of MFA was the weight ratio of 1∶4 between MFA and PEG- 4000. Conclusion Dissolution rates of MFA are apparently improved in inclusion compounds and PEG- 4000 solid dispersions, and the solubility of MFA is apparently increased by 2～3 times in inclusion compounds and PEG- 4000 solid dispersions.

A Comparative Study of the Effects of Intravenous Indomethacin and Oral Mefenamic Acid in the Treatment of Premature Infants with Patent Ductus Arteriosus

PURPOSE: For the management of patent ductus arteriosus(PDA) in premature infants, fluid restriction, correction of anemia, mechanical ventilation, diuretics, and surgery have been used, and the closure rate of PDA has improved significantly since the introduction of indomethacin and mefenamic acid as pharmacologic treatments of PDA. We studied to evaluate and compare the therapeutic effects of indomethacin and mefenamic acid in the management of premature infants with PDA. METHODS: 32 inborn premature infants who were hospitalized in NICU and diagnosed as PDA by cardiac sector were retrospectively studied and divided into two groups : An indomethacin treated group and a mefenamic acid treated group. Their gestational age, birth weight, blood urea nitrogen(BUN), creatinine(Cr), platelet count, urine output, fluid therapy, postnatal age, closure rate of PDA, and etc. were examined and conpared through the medical record review. RESULTS: The mean postnatal age on drug use was 4.6 days in intravenous indomethacin treated group(n=18), 9.0 days in oral mefenamic acid treated group(n=14), and the mean gestational age was 32.0 weeks and 32.3 weeks, respectively. After the use of each drugs, platelet count and urine output decreased, whereas blood urea nitrogen and creatinine increased. The closure rate of PDA was 94.4%(17/18) in the indomethacin treated group and 85.7%(12/14) in the mefenamic acid treated group(P=0.568). On the multivariate analysis except for the drugs, the most significant factor on PDA closure in preterm neonates was total amount of intake(P=0.000). CONCLUSION: We conclude that intravenous indomethacin is as effective as oral mefenamic acid in the therapy of preterm infants with PDA.

Effect of Prostaglandin Synthetase Inhibitor Pretreatment on Pentylenetetrazol-induced Seizures / 대한소아신경학회지

PURPOSE: Nonsteroidal anti-inflammatory drugs inhibit the synthesis of prostaglandin(PG) through inhibition of the enzyme, cyclooxygenase. Some of the arachidonic acid metabolites may influence the spread of electrocortical activity, and delay the pentylenetetrazol(PTZ)-induced seizures. The purpose of the present study was to evaluate systematically the effect of pretreatment with PG synthetase inhibitors on PTZ-induced seizures. METHODS: To evaluate the effects of pretreatment with PG synthetase inhibitors on seizures produced by 30mg/kg, 60mg/kg PTZ, free-moving Sprague-Dawley rats weighing 250-300gm with chronically-implanted supracortical electrodes were used. Electrocorticogram was recorded for 1hr prior to pretreatment administration of either saline (control) or PG synthetase inhibitor and 1hr after administration of PTZ. RESULTS: 1) A 30mg/kg dose of PTZ produced bursts of high voltage activity after a latency of 616+/-72sec. Although the animals showed spontaneous movements throughout the test period, they were motionless or myoclonus. The number of high voltage bursts during the first hr of the test period was 368+/-31.2) A 30mg/kg of PTZ produced high voltage bursts after a latency of 1118+/-35sec which was significantly greater for the ibuprofen-pretreated groups receiving 90mg/kg when compared to the saline-pretreated group. In addition, the number of high voltage bursts(173+/-17) which occurred during the first hr of the test period was significantly smaller than that recorded from the saline-pretreated group. 3) After pretreatment with a 450mg/kg dose of paracetamol, a 30mg/kg of PTZ produced bursts of electrocortical activity with onset latencies of 665+/-112sec which were not significantly different than those recorded from the saline-pretreated group. The number of high voltage bursts during the first hr of the test period was 141+/-30 which was significantly smaller than that recorded from the saline-pretreated group. 4) A 50mg/kg dose of mefenamic acid pretreatment caused 30mg/kg PTZ-induced high voltage bursts after latency of 227+/-47sec which was significantly shorter than that recorded from the saline-pretreated group. The number of high voltage bursts during the first hr of the test period was 522+/-42 which was significantly greater than that recorded from the saline-pretreated group.5) A 60mg/kg dose of PTZ produced bursts of high voltage activity after a latency of 79+/-14sec. An electrocortical seizure with concurrent convulsions appeared subsequently by 129+/-30sec. 6) A 60mg/kg of PTZ produced high voltage bursts after a latency of 217+/-38sec which was significantly greater for the ibuprofen-pretreated groups receiving 90mg/kg when compared to the saline-pretreated group. An electrocortical seizure with concurrent convulsions appeared subsequently by 287+/-30sec.7) After pretreatment with paracetamol(450mg/kg), a 60mg/kg of PTZ produced bursts of electrocortical activity with onset latencies of 143+/-36sec which were significantly different than those recorded from the saline-pretreated group. There was no convulsive or no electrocortical seizure.8) A 50mg/kg mefenamic acid pretreatment caused 60mg/kg PTZ-induced high voltage bursts after latency of 35+/-5sec which was significantly shorter than that recorded from the saline-pretreated group. An electrocortical seizure appeared subsequently by 58+/-10sec which was significantly different than that recorded from the saline-pretreated group. CONCLUSION: It is possible that the delay and/or block of convulsions induced by the higher doses of PTZ was the result of PG synthesis inhibition. However, the PG synthetase inhibitors had a more differential effect on general PTZ-induced excitation of the CNS evidenced by changes in electrocortical activity. The mechanism underlying this action could be either through inhibition of the activity of cyclooxygenase in tissues which play a role in the manifestation of seizure activity or through an action not related to their common action on cyclooxygenase.

A Case of Generalized Fixed Drug Eruption due to Mefenamic Acid

A 45-year-old woman presented with a generalized fixed drug eruption due to mefenamic acid, characterized by recurring erythematous patches with central bullae on the same sites of the whole body and leaving hyperpigmentation after each attack. Patch testing of a quiescent lesion with 50% mefenamic acid in vaselin revealed an eczematous reaction after 48 hours. The disease course was mild compared to the severe clinical manifestation. We here-in report a case of generalized fixed drug eruption due to mefenamic acid which is considered a rare occurrence.

Contact Urticaria - Relationship between Blocking Effect to Wheal Formation and Antiinflammatory Potencies of Some NSAID / 대한피부과학회지

This study was undertaken to investigate the response of non-immunologic contact urticaria(NICU) test before and after ingestion of cyclo-oxygenase inhibitors such as naproxene, ibuprofen and mefenamic acid. Forty patients who showed positive reaction to 5% benzoic acid (BA) in petrolatum by 20 minutes closed patch test were chosen and divided into 3 groups. Group I was consisted of 13 patients who were taken naproxene 250mg bid, group II, 14 patients, taken ibuprofen 600mg bid, and group III, 13 patients, taken mefenamic acid 500mg bid. All the patients were tested with 5%, 2.5%, 1%, 0.5% and 0.1% BA in petrolatum using Finn chamber on Scanpor tape on the right arm before medication and next day on the left arm after medication of each day. Mefenamic acid did not show any significant differences before and after ingestion of drug. Naproxene reduced reaction about half of patients. Ibuprofen reduced reaction in almost all patients and blocked reaction completely in 9 of 13 patients. This results suggested that there was no correlation between blocking effect to BA induced contact urticaria and so called anti-inflammatory potencies of naproxene and ibuprofen, and that NICU by BA is partly mediated by prostaglandins(PG) or mediated by other mediators, which were potentiated by PG, except histamin.