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Studies in menorrhagia: (a) mefenamic acid, (b) endometrial prostaglandin concentrations.

Twenty-two women with unexplained heavy menstrual blood loss (average loss for two cycles of >80 ml) were treated with the prostaglandin synthetase inhibitor menfenamic acid during two consecutive menstruations. There was a significant reduction in menstrual blood loss on mefenamic acid therapy, the median loss being 137 ml before treatment and 76 ml while on treatment. Reduction in menstrual loss was achieved in 20 of the 22 patients but varied from a 2% to 78% reduction. The greater the menstrual loss before treatment, the more it was reduced on mefenamic acid therapy. Endometrial concentrations of prostaglandins E2 and F2 alpha in the follicular phase of the cycle were similar whether or not patients had menorrhagia. In the luteal phase, however, 6 of 14 patients with menorrhagia had higher endometrial prostaglandin E2 and F2 alpha concentrations than all 13 controls.

Adolescent↗

Solid-state characterization of mefenamic acid.

The purpose of this study was to characterize mefenamic acid (MA) from commercial samples and samples crystallized from different solvents. Various techniques used for characterization included microscopy (hot stage microscopy, scanning electron microscopy), intrinsic dissolution rate, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and powder X-ray diffractometry (pXRD). The commercial samples varied in their crystal habit, thermal behavior, and intrinsic dissolution rate. It was found that the commercial samples were polymorphic Form I, which converted to Form II on heating in a DSC pan. Similarly, compression in an intrinsic dissolution rate (IDR) press resulted in the conversion of Form I to Form II. On the other hand, the samples recrystallized from different solvents under varying conditions yielded different crystal habits. Stirring and degree of supersaturation significantly influenced the crystal habit in all the solvents used in the study. Samples crystallized from ethanol and tetrahydrofuran yielded Form I, which behaved similarly to the commercial samples (M1 and M3). Recrystallization from ethyl acetate at a fast cooling rate yielded Form I, which on melting crystallized to Form II. The form I crystallized from ethyl acetate by fast cooling converted partially to form II on storing at ambient conditions. Forms I and II of MA were enantiotropically related. The results demonstrate the variable material characteristics of the commercial samples of MA and the influence of the crystallizing conditions on the formation of the polymorphs.

Anti-Inflammatory Agents, Non-Steroidal↗

A double-blind, crossover trial of mefenamic acid, sulindac and flurbiprofen in rheumatoid arthritis.

A double-blind crossover trial was carried out in 24 patients to compare the effects of mefenamic acid, flurbiprofen, sulindac and placebo. Each drug was given for 2 weeks, the treatment sequence being randomized. Daily doses were 1500 mg mefenamic acid, 150 mg flurbiprofen or 150 mg sulindac. All of the active drugs were significantly superior to placebo in terms of pain score, patients' assessment, articular index of joint tenderness, and duration and severity of morning stiffness. There was improvement in grip strength compared with placebo, but the differences were not statistically significant with sulindac. There was slight reduction in joint circumference but this was only statistically significant in the right hand with flurbiprofen and sulindac. No significant differences were found in technetium uptake in knee joints. The three drugs appeared to be equally effective and tolerated, and no significant differences were noted.

Adult↗

Comparative study of mefenamic acid and dextropropoxyphene plus paracetamol in an accident and emergency department.

A randomized double-blind trial was carried out in an accident and emergency department to reassess mefenamic acid as a suitable alternative analgesic to the combination of dextropropoxyphene plus paracetamol. Analysis of data from 87 patients showed that mefenamic acid was equally effective in relieving pain and was less likely to produce adverse side-effects.

Accidents↗

Mefenamic acid: an under-rated antirheumatic?

A double-blind crossover study was carried out in 18 patients with classical rheumatoid arthritis to assess the effectiveness of mefenamic acid (500 mg t.d.s.) compared with placebo or indomethacin (25 mg q.d.s.). Each treatment was given for 1 week and subjective and objective assessments were carried out at the end of each period. Results showed that both mefenamic acid and indomethacin were significantly better than placebo in most parameters. Although duration of morning stiffness and patient preference favoured indomethacin it was considered that there was no demonstrable difference of any clinical significance between the two active medications.

Adult↗

Mefenamic acid and dextropropoxyphene with paracetamol as analgesics in the accident department.

A double-blind study was carried out in 48 patients with soft-tissue injuries to compare the effectiveness of mefenamic acid and dextropropoxyphene plus paracetamol in relieving acute post-injury pain. Patients received capsules containing either 250 mg mefenamic acid or 32.5 mg dextropropoxyphene hydochloride plus 325 mg paracetamol and were instructed to take up to 6 capsules daily as necessary. By the third post-injury day both preparations had controlled pain adequately and lessened local tenderness in most cases. There was no significant difference in response between the two patient groups. Two patients in each group stopped treatment because of gastro-intestinal intolerance, and a further 4 patients in each group reported troublesome side-effects.

Acetaminophen↗

Case report: acute renal failure, thrombocytopenia and nonhemolytic icterus probably caused by mefenamic acid (Parkemed)-dependent antibodies.

A 65-year-old, previously healthy man developed acute renal failure, severe thrombocytopenia and hepatic icterus after a small dose of mefenamic acid (Parkemed). Drug-dependent antibodies reacting against platelets could be identified as the most probable cause for this acute and rapidly reversible disorder. A concomitant hemolytic reaction was not observed and accordingly no drug-dependent red cell antibodies could be demonstrated. The drug-specific antibodies were found only during the acute phase using the platelet immunofluorescence test and a solid-phase immunoassay but not with the monoclonal antibody specific immobilization of platelet antigens assay. After discontinuation of the drug the patient steadily improved and fully recovered until day 22 after admission and drug removal. The clinical course strongly suggests that drug-dependent antibodies against mefenamic acid and/or its metabolites reacting by immune complex mechanism were responsible not only for the thrombocytopenia but also for the renal and hepatic failure.

Acute Kidney Injury↗

Factors influencing capping and cracking of mefenamic acid tablets.

The tendency of capping and longitudinal cracks of mefenamic acid tablets was evaluated in relation to the amount of the binder, the influence of the granulation technique, and the relative humidity of the granules. Tablets made from fluidized bed granules using methylcellulose in the granulating liquid showed significantly lower capping and longitudinal cracks than tablets from conventional granules prepared by wet granulation using methylcellulose as a dry binder.

Anti-Inflammatory Agents, Non-Steroidal↗

Comparison of two formulations of lignocaine spray with mefenamic acid in the relief of post-episiotomy pain: a placebo-controlled study.

The analgesic effectiveness of aqueous and alcoholic formulations of lignocaine (5%) spray was compared with that of mefenamic acid (500 mg) or placebo in a double-blind study in 103 primiparous patients complaining of moderate or severe perineal pain associated with episiotomy. The results, assessed after a single dose, showed that the aqueous lignocaine formulation provided a level of pain relief superior to that obtained with the alcoholic formulation or placebo, and similar to that obtained with mefenamic acid.

Adult↗

A case of Stevens-Johnson syndrome, cholestatic hepatitis and haemolytic anaemia associated with use of mefenamic acid.

A woman with a history of drug allergy, renal impairment and carcinoma of the breast with pulmonary micrometastases developed haemolytic anaemia and Stevens-Johnson syndrome following the use of mefenamic acid, paracetamol (acetaminophen) and furosemide (frusemide). In addition there was severe cholestatic hepatitis in the absence of clinical evidence of sepsis, biliary obstruction or recurrent metastases. The rash resolved on steroid therapy but the patient eventually died from both renal and liver failure. Acute tubular necrosis with a background of chronic tubulointerstitial nephritis was also found at autopsy. Although in the presence of multiple drug therapy the causative agent cannot be identified with absolute certainty, the association of these severe idiosyncratic hepatic and dermatological reactions with haemolytic anaemia strongly suggests mefenamic acid as the most likely culprit.

Acetaminophen↗

Studies on Ponstan (mefenamic acid): I. Gastro-intestinal blood loss; II. Absorbtion and excretion of a new formulation.

Using improved techniques in a study of faecal blood loss no significant change over control level occurred during administration of mefenamic acid 500 mg t.i.d. for six days. This lack of gastro-intestinal bleeding is at variance with earlier findings for this compound. Studies of two mefenamic acid formulations (250 mg capsule and 500 mg filmseal tablet) showed no significant difference in area under blood level curves or in urinary output data, indicating equivalent total absorption. The 500 mg film-coated tablet gave significantly higher serum levels at 0.5 hours, whereas the 250 mg capsule gave significantly higher serum levels at 6 and 8 hours.

Adult↗

Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus.

The pharmacokinetics of mefenamic acid (MA), 2 mg/kg, were studied in 17 preterm infants with symptomatic patent ductus arteriosus. They were given this dosage orally at 24 h intervals. There were marked inter-individual differences in some of the pharmacokinetic parameters after the first dose; peak plasma concentration (Cmax) varied from 1.2 to 6.1 micrograms/mL with a mean of 3.8 micrograms/mL, time to reach Cmax (tmax) varied from 2 to 18 h with a mean of 7.7 h and plasma half-life (t1/2) varied from 3.8 to 43.6 h with a mean of 18.7 h. The group of infants (10/17) who had ductus closure after the first dose had significantly lower clearance (P < 0.01), longer t1/2 (P < 0.01) and higher 24 h plasma concentration (P < 0.001) compared to the group of infants (7/17) who had no ductus closure after the first dose. It appeared that the plasma concentration of MA had to be above 2.0 micrograms/mL and maintained at this concentration for at least 12 h for MA associated with ductus closure in preterm infants to take effect. In view of the inter-individual variation of plasma MA concentration and the effective plasma concentration, we suggest that measurement of the plasma concentration should be done 24 h after the first dose. This might be useful for safe and effective therapy for infants with ductus closure failure after the first dose.

Administration, Oral↗

[Effects of strophanthin, mefenamic acid and dexamethasone on the inflammatory and reparative processes in the heart in experimental myocarditis].

In isadrin-induced myocarditis, the rat heart shows an increase in the activity of acid phosphatase, glucose-6-phosphate dehydrogenase. The heart weight also rises, whereas ATPase activity and magnesium content fall. Under these conditions strophanthin produces a marked decrease in acid phosphatase activity, stimulates the activity of glucoso-6-phosphate dehydrogenase, and demonstrates a tendency to increasing the activity of ATP-splitting enzymes, to reducing the activity of ATP-synthetase, and to the recovery of the magnesium content. Mefenamic acid and dexamethasone also decrease the activity of acid phosphatase but this decrease is less pronounced as compared with that induced by strophanthin. They exhibit the same tendency to the inhibition of glucoso-6-phosphate dehydrogenase. Mefenamic acid affects the remaining parameters similarly to strophanthin, while dexamethasone inhibits them.

Animals↗

Treatment of hypermenorrhea with mefenamic acid in women using IUDs.

49 women using either Lippes Loop D or copper T220C IUDs who were complaining of increased menstrual bleeding, were treated with mefenamic acid at a dosage of 500 mg 3 times/day for 5 days during their menstrual periods. Menstrual bleeding of each patient was quantified before initiation of the treatment and figures so obtained were used as pretreatment control values; during their 2nd cycle they received 1 placebo tablet 3 times/day for 5 days, the next 2 cycles utilized treatment with mefenamic acid, followed by a 5th cycle on placebo, and a 6th one without treatment. Of the 49 women admitted to the trial, 20 had pretreatment menstrual bleeding of more than 80 ml and 29 had less than 80 ml; groups 1 and 2, respectively. For group 1, a significant decrease in menstrual bleeding of 49.5% and 37.4% was observed during the 2 treatment cycles. Group 2, subjects with menstrual bleeding within the normal range, showed no decrease in menstrual bleeding.

Biology↗

Spectrophotometric investigations on protolytic equilibria of mefenamic acid and determination by means of Fe(III) in methanol-aqueous media.

Studies have been carried out on the effect of pH (from pH 11.33 to H(O) = -4.65) on the UV spectrum of mefenamic acid. The dissociation constant pKa was found to be 4.55 +/- 0.06 and the protonation constant pK(2) was -1.78 +/- 0.18 in methanol-aqueous media. Mefenamic acid was determined spectrophotometrically by formation of a coloured complex (2:5) with Fe(III). At 495 nm Beer's law was followed for the concentration range 96.52 to 579.12 mug ml(-1).

Journal Article↗

Simultaneous spectrophotometric determination of mefenamic acid and paracetamol in pharmaceutical preparations.

A spectrophotometric procedure for the simultaneous determination of mefenamic acid and paracetamol in a mixture is described. Using 0.01 M methanolic hydrochloric acid as solvent, the absorbance of the mixture is measured at 248, 279 and 351 nm. The concentration of each component can be calculated by solving two equations using two wavelengths, either 248 and 279 nm or 248 and 351 nm.

Acetaminophen↗

Kinetic study of the transformation of mefenamic acid polymorphs in various solvents and under high humidity conditions.

The transformation kinetics of mefenamic acid form II to form I in three kinds of solvents and under high humidity conditions were extensively investigated. Form II crystals were suspended in water, 50% ethanol and ethanol at 28, 33 and 37 degrees C, or stored at 50, 60 and 70 degrees C at 97% RH. Form II transformed to form I under all storage conditions and the rate of transformation depended on the kind of solvent. The transformation followed the three-dimensional nuclei growth mechanism, depending on temperature. The nuclei formation and growth processes were significantly accelerated in ethanol compared with water. The addition of seed crystals of the stable form I shortened the both nuclei formation and growth processes and therefore the transformation was accelerated.

Drug Stability↗

Mefenamic acid bioequivalence assessment with a new statistical procedure.

The bioequivalence of three different formulations of mefenamic acid was tested using the index zeta 2 previously defined by Rescigno. This index is a measure of the distance in Hilbert space of two concentration vs time functions; unlike the approach of Westlake which assumes a multiplicative model for the AUC and Cmax characteristics, this approach does not imply any hypotheses on the structure of the data and no particular model of the absorption or of the elimination processes. The index zeta 2 is simply an indication of how similar two formulations are. Results for this new test were compared with those obtained with two other tests, namely 90 and 95% symmetrical confidence intervals of Westlake and two one-sided t-tests of Shuirmann through the 90% confidence intervals in the ranges 80-125% for AUC and 70-143% for Cmax. Results of the new test are fully comparable with those obtained using the other two tests.

Anti-Inflammatory Agents, Non-Steroidal↗