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PubMed1991

A comparative study of ethamsylate and mefenamic acid in dysfunctional uterine bleeding.

The effects of ethamsylate and mefenamic acid on menstrual blood loss were compared in a double-blind trial in 34 women with menorrhagia. Both drugs produced statistically significant reductions in blood loss during the 3 months of treatment; the overall reduction was 20% in the ethamsylate group and 24% in the mefenamic acid group. Compared with pretreatment values, blood loss was significantly less in each of the 3 treatment months in the mefenamic acid group, but only in the second and third months of treatment in the ethamsylate group. However, more women had a clinically useful reduction in blood loss (greater than 40%) in the ethamsylate group. The onset of effect of mefenamic acid was rapid but ethamsylate showed a comparatively greater effect as the trial progressed. Cessation of treatment was followed by an increase in blood loss, more pronounced in mefenamic acid group who reverted to pre-treatment levels. A greater number of side-effects were reported with mefenamic acid.

Adolescent↗
PubMed1996

Reactivity of mefenamic acid 1-o-acyl glucuronide with proteins in vitro and ex vivo.

Mefenamic acid is a nonsteroidal anti-inflammatory drug commonly used in analgesia. The use of this drug has been implicated in several cases of nephrotoxicity including acute renal failure and tubulointerstitial nephritis. One theory of drug-induced tubulointerstitial nephritis is that the drug or a derivative of the drug becomes irreversibly bound to certain sites in renal tissue and an immune response is directed against the hapten-host conjugate. Previous studies have shown that in humans the nonsteroidal anti-inflammatory drug mefenamic acid is metabolized by both phase I enzymes and the phase II enzyme family UDP-glucuronosyltransferase. Indeed, three glucuronides were identified and isolated from human urine by semipreparative HPLC after oral administration of mefenamic acid. This study focuses on mefenamic acid glucuronide and further characterizes this acyl glucuronide in terms of stability and its ability to bind irreversibly to proteins. Stability studies of mefenamic acid glucuronide in aqueous buffer highlighted the relative stability of this acyl glucuronide at physiological pH. The half-life at 37 degrees C, pH 7.4, was 16.5 +/- 3.1 hr, which is considerably longer than those reported for many acyl glucuronides. The degradation of mefenamic acid glucuronide was accelerated under alkaline conditions, decreasing the half-life to 5 +/- 1.6 hr at pH 8.0. Mefenamic acid glucuronide, although extremely stable in buffer at physiological pH, was found to bind irreversibly to human serum albumin in vitro. Irreversible binding to cellular proteins in culture was also evident with the addition of mefenamic acid to the heterologous Chinese hamster lung fibroblast cell line V79 expressing the human UDP-glucuronosyltransferase isoenzyme UGT1*02. This binding was directly related to glucuronide formation, because irreversible binding was not evident in the untransfected cell line V79.

Animals↗
PubMed1990

Effect of mefenamic acid on bowel transit time in healthy adult volunteers.

The effect of mefenamic acid on bowel transit time was investigated. Seven healthy adult male subjects of age 39 +/- 2.4 years (mean +/- S.E.M.) received placebo or mefenamic acid (500 mg t.d.s) orally in randomized order for five days, with a 7-day washout between studies. On the third morning after starting the drug they had a meal containing Redi-Brek and baked beans with radio-opaque markers. Small bowel transit time was measured using breath hydrogen, and whole gut transit time was measured using radio-opaque markers. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid (P less than 0.05). The percentages of appearance of marker in stool within 24 h were 24.9 +/- 11.8 (mean +/- S.E.M.) with placebo and 48.9 +/- 11.7 with mefenamic acid (P less than 0.05). The times of appearance of twenty-fifth marker in stool were 41.0 +/- 4.4 h with placebo and 26.9 +/- 3.2 h with mefenamic acid (P less than 0.05). The total weights of faeces in 72 h were 500.9 +/- 96.2 g with placebo and 657.1 +/- 118.8 g with mefenamic acid (P less than 0.05). Mefenamic acid in therapeutic doses (500 mg t.d.s.) accelerated bowel transit time in healthy subjects.

Adult↗
PubMed2003

Multiple effects of mefenamic acid on K(+) currents in smooth muscle cells from pig proximal urethra.

The effects of mefenamic acid on both membrane potential and K+ currents in pig urethral myocytes were investigated using patch-clamp techniques (conventional whole-cell, cell-attached, outside-out and inside-out configuration). In the current-clamp mode, mefenamic acid caused a concentration-dependent hyperpolarization, which was inhibited by preapplication of 1 microm glibenclamide. In the voltage-clamp mode, mefenamic acid induced an outward current that was blocked by glibenclamide even in the presence of iberiotoxin (IbTX, 300 nm) at -50 mV. ATP-sensitive K+ channels (KATP channels) could be activated in the same patch by mefenamic acid and levcromakalim, with the same unitary amplitude and the similar opening gating at -50 mV in cell-attached configuration. In outside-out recording, external application of mefenamic acid activated intracellular Ca2+-activated IbTX-sensitive large-conductance K+ channels (BKCa channels). Mefenamic acid ( or=100 microm) increased sustained outward currents, diminishing the activity of STOCs. Over the whole voltage range, mefenamic acid caused opposite effects on the membrane currents in the absence and presence of 5 microm glibenclamide. In the presence of 10 mm 4-aminopyridine (4-AP), mefenamic acid only increased the outward currents. These results indicate that mefenamic acid increases the channel activities of two distinct types of K+ channels (i.e. BKCa channels and KATP channels) and decreased 4-AP-sensitive K+ channels in pig urethral myocytes.

Animals↗
PubMed2003

The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.

The preparation of mefenamic acid (MH)-alkanolamine [monoethanolamine, diethanolamine, triethanolamine and propanolamine] complexes was attempted to increase the transdermal flux of MH. A lipophilic enhancer system consisting of isopropyl myristate (IPM) and ethanol (9:1; EI system) produced a marked enhancement of MH flux from the alkanolamine complexes through hairless rat skin membrane. Among the alkanolamines examined, the propanolamine complex had the greatest enhancing effect on the permeation of MH. The observed permeation enhancement of MH-alkanolamine complexes by the EI system was explained by an analysis based on a two-layer diffusion model. The stratum corneum immersed in IPM forms a continuous phase of vehicle and stratum corneum and, from the phase, ethanol transport the MH-alkanolamine complexes to the epidermis and dermis, and the complexes, which are more water soluble than MH, exhibit increased partition into the epidermis and dermis, as the flux increases.

1-Octanol↗
PubMed2001

Human adult and foetal liver sulphotransferases: inhibition by mefenamic acid and salicylic acid.

1. The aim was to see whether mefenamic acid and salicylic acid had different inhibition profiles for SULT1A1 (substrate: 4-nitrophenol) and SULT1A3 (dopamine) activities and on (-)-salbutamol and minoxidil sulphation rates in the human adult and mid-gestational foetal livers. 2. The activity (pmolmin(-1) mg(-1) of SULT1A1 was 662 +/- 78 (adult) and 246 +/- 159 (foetus; p = 0.003) and that of SULT1A3 was 24 +/- 4 (adult) and 121 +/- 90 (foetus; p = 0.030). The rate (pmol min(-1) mg(-1)) of (-)-salbutamol sulphation was 109 +/- 27 (adult) and 117 +/- 34 (foetus; p = (0.144) and that of minoxidil sulphation was 202 +/- 38 (adult) and 108 +/- 44 (foetus; p = 0.001). 3. With mefenamic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 0.2 +/- 0.004 (adult) and 0.01 +/- 0.002 (foetus; p = 0.001); for SULT1A3 it was 76 +/- 6 (adult) and 77 +/- 13 (foetus; p = 0.889); for the rate of ( )-salbutamol sulphation it was 0.07 +/- 0.005 (adult) and not determinable (foetus) and for minoxidil sulphation it was 1.6 +/- 0.7 (adult) and 0.15 +/- 0.04 (foetus; p = 0.076). 4. With salicylic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 30 +/- 2 (adult) and 25 +/- 1 (foetus; p = 0.011); for SULT1A3 it was 690 +/- 36 (adult) and 570 +/- 16 (foetus; p = 0.229); for the rate of ( )-salbutamol sulphation it was 93 +/- 11 (adult) and 344 +/- 42 (foetus; p = 0.010); with minoxidil as substrate, the IC50 was not determinable. 5. In summary, SULT1A1, SULT1A3 and the sulphotransferases towards (-)-salbutamol and minoxidil had measurable activities in the mid-gestational human foetal liver. Mefenamic acid was a more potent inhibitor than salicylic acid of both human adult and foetal liver SULT1A1 and SULT1A3 activities. Foetal liver SULT1A1 was more susceptible than adult liver SULT1A1 to inhibition by mefenamic acid and salicylic acid. These results are consistent with the view that sulphotransferases develop early in the human foetal liver and drugs may inhibit their activities.

Adult↗
PubMed1989

Effects of the nonsteroidal anti-inflammatory drug mefenamic acid on energy metabolism in the perfused rat liver.

The action of mefenamic acid, a nonsteroidal anti-inflammatory drug, on energy metabolism in the isolated perfused rat liver was investigated. Mefenamic acid in the range between 0.1 and 1.0 mM was infused to livers from well-fed rats and from 24-hr fasted rats. The former were perfused with substrate-free Krebs/Henseleit-bicarbonate buffer, allowing the measurement of glycogenolysis and glycolysis from endogenous glycogen. The livers from 24-hr fasted rats, on the other hand, were perfused with Krebs/Henseleit-bicarbonate buffer containing fructose, thus allowing the measurement of fructolysis and glucose synthesis. Oxygen consumption was measured in both cases. When present in the range between 0.1 and 0.5 mM, mefenamic acid increased glycolysis, oxygen uptake, glycogenolysis and fructolysis. Higher concentrations, depending on the perfusion conditions, were inhibitory. Glucose production from exogenous fructose, on the other hand, was inhibited at low mefenamic acid concentrations. In general terms, the effects of mefenamic acid on energy metabolism seemed to be the primary consequence of its uncoupling action on the respiratory chain. This conclusion is supported mainly by the opposite effects on glucose synthesis (inhibition) and oxygen consumption (activation). The intracellular concentration of mefenamic acid is much higher than the extracellular one, a phenomenon which may represent binding to intracellular membrane or proteins.

Animals↗
PubMedDate not supplied

Effect of mefenamic acid on plasma protein-thyroid hormone interaction, monodeiodination of thyroxine, urinary excretion of tri-iodothyronine and thyrotropin regulation.

A single oral dose of mefenamic acid significantly depressed plasma thyroxine (T4) within 3 h in man. Similarly, mefenamic acid depressed plasma T4 within 3 h in thyroidectomized, T4-maintained rats. Plasma free fractions of T4 and tri-iodothyronine (T3) increased significantly after a single oral administration of mefenamic acid in man. In vitro addition of mefenamic acid to plasma also increased the plasma free fraction of T4. Three times more T3 was excreted into urine after an acute administration of mefenamic acid. In vitro conversion of T4 to T3 by liver homogenate was stimulated when T4 was displaced from plasma binding protein by mefenamic acid. Pituitary content of T3 increased when mefenamic acid displaced T4 and T3 from the binding protein. Simultaneously, thyrotropin (TSH) secretion in response to thyrotropin releasing hormone (TRH) was completely blocked by mefenamic acid. Prolactin release in response to TRH and luteinizing hormone (LH) and follicle stimulating hormone (FSH) release in response to luteinizing hormone releasing hormone (LH-RH) were not affected by mefenamic acid. It is concluded that mefenamic acid displaces T3 and T4 from their plasma binding protein and more T4 and T3 are available to peripheral tissues for excretion, degradation and TSH regulation.

Blood Proteins↗
PubMed1997

The bioavailability and pharmacokinetics of mefenamic acid in alloxan-diabetic rabbits.

The bioavailability and pharmacokinetics of mefenamic acid was studied in alloxan-diabetic rabbits. Mefenamic acid in plasma was assayed by high performance liquid chromatography. A paired t-test for normal and alloxan treated rabbits revealed a significant decrease in all the bioavailability and disposition kinetic parameters of mefenamic acid during diabetes was observed in the present study. The altered bioavailability and disposition of mefenamic acid in the diabetic state will require adjustment of the dosage regimen prescribed for diabetics in a clinical setting.

Animals↗
PubMed1983

Long-term treatment of menorrhagia with mefenamic acid.

Thirty-six women with menorrhagia were treated with mefenamic acid during all menstrual periods for more than 1 year. These women had experienced objective and subjective benefit--menstrual blood loss was reduced and other menstrual symptoms improved during a preliminary 4-cycle double-blind placebo-controlled trial with mefenamic acid (placebo cycles: 65.6 +/- 5.3 ml; mefenamic acid cycles: 45.3 +/- 5.1 ml, mean +/- SEM). This reduction in menstrual blood loss was maintained at 6 to 9 months (49.2 +/- 9.9 ml) and at 12 to 15 months (42.8 +/- 4.8 ml) after the trial. These reductions were significant at the 6- to 9-month (paired t test = 2.18; P less than .05) and the 12- to 15-month interval (paired t test =- 4.40; P less than .001). Significant sustained reductions in blood loss were seen in the women with menorrhagia due to ovulatory dysfunctional bleeding and in those who had undergone tubal sterilization. Significant reductions were also seen in dysmenorrhea, headache, nausea, diarrhea, depression, number of sanitary towels used, and number of mefenamic acid capsules taken. A significant increase in serum ferritin was found between admission and completion of the follow-up trial in 11 women (P less than .01).

Clinical Trials as Topic↗
PubMed1980

Hemodialysis of mefenamic acid in uremic patients.

The effect of hemodialysis on plasma mefenamic acid levels was studied in four patients on long-term hemodialysis. A 500-mg oral dose of mefenamic acid was administered to the fasting patients two hours before hemodialysis. Arterial and venous blood samples taken before dialysis, at 30-minute intervals during a three-hour dialysis, and immediately before termination of dialysis were assayed by high-performance liquid chromatography. Mefenamic acid half-life on hemodialysis was not reduced substantially compared with that reported for normal patients. The extraction efficiency of the hollow-fiber kidneys averaged 6.4%. The mean drug recovery was 1.03 mg or 0.2% of the administered dose. The extensive plasma protein binding (range: 85-97%) accounted for the poor recovery. The study suggests that adjustment of mefenamic acid dosage is not necessary in patients undergoing hemodialysis and that hemodialysis is of minimal value in the management of mefenamate overdose.

Adult↗
PubMed1993

Structures of mefenamic acid metabolites from human urine.

Three major metabolites of mefenamic acid were isolated from the urine of a normal adult man receiving mefenamic acid orally. The structures of those metabolites were determined as glucuronides of mefenamic acid, its hydroxymethyl derivative, and its carboxylic acid derivative on the basis of spectral data.

Adult↗
PubMed2006

The effects of mefenamic acid on hematocrit of the lizard, Uromastix hardwickii.

Mefenamic acid is an analgesic, antipyretic and anti-inflammatory agent. In addition induces several hematological disturbances. Present study was conducted to determine the alterations in blood PCV of the lizard Uromastix hardwickii after the administration of 7.1 mg/ml; 10.5 mg/ml and 14.0 mg/ml mefenamic acid per individual per day for 12 days to 3 test groups. The mean values of PCV were 15.5+/-0.81%, 14.5+/-0.25% and 12.0+/-0.25% for 3 test groups respectively in comparison to 23.5+/-0.40% for control. Thus a significant dose dependant reduction in mean PCV per cent following the administration of mefenamic acid for 12 days indicates the extra vascular hemolysis due to destructive change in the red cell membrane through autoantibody mechanism.

Anemia, Hemolytic, Autoimmune↗
PubMed1996

Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid.

OBJECTIVE: To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia. DESIGN: Randomised controlled trial. SETTING: A university department of obstetrics and gynaecology. SUBJECTS: 76 women with dysfunctional uterine bleeding. INTERVENTIONS: Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly. MAIN OUTCOMES MEASURES: Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient's estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events. RESULTS: Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid. CONCLUSIONS: Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery.

Adult↗
PubMed2005

Synthesis and analgesic activity of N-Arylhydrazone derivatives of mefenamic acid.

PURPOSE: A series of N-Arylhydrazone derivatives of mefenamic acid (a known non-steroidal anti-inflammatory drug) were synthesized in order to obtain new compounds with potential analgesic and anti-inflammatory activity. METHODS: The structures of all synthesized compounds were confirmed by means of infrared, proton magnetic resonance and mass spectroscopy. All compounds were evaluated for their analgesic and anti-inflammatory activities by abdominal constriction test (writhing test) and carrageenan-induced rat paw edema test respectively. RESULTS: Most of the synthesized compounds induced significant reduction in the writhing response when compared to control. Among them, compounds 11, 12, 15, 16, 19, 20, and 21 were significantly more potent than mefenamic acid in the writhing test. The anti-inflammatory activity of these 7 compounds were evaluated and compounds 11, 12, 16, 19 and 20 showed significant anti-inflammatory activity in comparison to control but their effect was weaker than mefenamic acid. CONCLUSIONS: The antinociceptive relative activity of some of these newly synthesized compounds is greater than mefenamic acid but they are not potent anti-inflammatory agents.

Analgesics, Non-Narcotic↗
PubMed2004

Liquid chromatography method for determination of mefenamic acid in human serum.

A simple, rapid and specific method for analysis of mefenamic acid (I) in serum by a sensitive high-performance liquid chromatography is described. Only 70 microl of serum and a little sample work-up is required. A simple procedure of extraction by dichloromethane followed by evaporation to dryness under gentle stream of nitrogen and dissolving the dried residue in mobile phase was used. The mefenamic acid peak was separated from endogenous peaks on a C(8) column by a mobile phase of acetonitrile-water (50:50, v/v, pH 3). Mefenamic acid and internal standard (IS) (diclofenac) were eluted at 7.4 and 5.4 min, respectively. The limit of quantitation of mefenamic acid in serum was 25 ng/ml at 280 nm. The method was linear over the range of 25-2000 ng/ml with r(2) of 0.998. Mean recovery for mefenamic acid was 110%.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Differential inhibition of hepatic and duodenal sulfation of (-)-salbutamol and minoxidil by mefenamic acid.

OBJECTIVE: The aim of this investigation was to determine whether mefenamic acid and salicylic acid inhibit the sulfation of (-)-salbutamol and minoxidil in the human liver and duodenum, and if so, to ascertain whether the 50% inhibitory concentration (IC50) estimates are different in the two tissues. METHODS: Sulfotransferase activities were measured for 10 mM (-)-salbutamol and 5 mM minoxidil, and the concentration of 3'-phosphoadenosine-5'-phosphosulphate-[35S] was 0.4 microM. RESULTS: The IC50 estimates for (-)-salbutamol and minoxidil sulfation of mefenamic acid were 72 +/- 5.4 nM and 1.5 +/- 0.6 microM (liver), respectively, and 161 + 23 microM and 420 +/- 18 microM (duodenum), respectively. The figures for the liver were significantly lower (P < 0.0001) than those for the duodenum. The IC50 estimates for (-)-salbutamol sulfation of salicylic acid were 93 +/- 11 microM (liver) and 705 +/- 19 microM (duodenum, P < 0.0001). Salicylic acid was a poor inhibitor of minoxidil sulfation. CONCLUSION: The IC50 estimates for (-)-salbutamol sulfation of mefenamic acid and salicylic acid are lower than their unbound plasma concentrations after standard dosing, suggesting that mefenamic acid and salicylic acid should inhibit the hepatic sulfation of (-)-salbutamol in vivo.

Adrenergic beta-Agonists↗