Inactivation of creatine kinase during the interaction of mefenamic acid with horseradish peroxidase and hydrogen peroxide: participation by the mefenamic acid radical

Creatine kinase (CK) was used as a marker molecule to examine the side effects of damage to tissues by mefenamic acid, an effective drug to treat rheumatic and arthritic diseases, with horseradish peroxidase and hydrogen peroxide (HRP-H(2)O(2)). Mefenamic acid inactivated CK during its interaction with HRP-H(2)O(2). Also, diphenylamine and flufenamic acid caused a loss of CK activity, indicating the imino group, not substituent groups, in the phenyl rings have a crucial role in CK inactivation. Rapid change in mefenamic acid spectra was detected, suggesting that mefenamic acid is efficiently oxidized by HRP-H(2)O(2). Peroxidases oxidize xenobiotics to free radicals by a one-electron transfer. However, direct detection of mefenamic acid radicals by electron spin resonance (ESR) was unsuccessful. Reduced glutathione and 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) in the reaction mixture containing mefenamic acid with HRP-H(2)O(2) produced ESR signals consistent with a DMPO-glutathionyl radical adduct. These results suggest that inactivation of CK is probably caused through formation of mefenamic acid radicals. Sulfhydryl groups and tryptophan residues of CK were diminished by mefenamic acid with HRP-H(2)O(2). Other SH enzymes, including alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, were very sensitive to mefenamic acid with HRP-H(2)O(2). Inactivation of SH enzymes may explain some deleterious actions of mefenamic acid.     

Determination of indomethacin and mefenamic acid in plasma by high-performance liquid chromatography

Indomethacin and mefenamic acid are widely used clinically as non-steroidal anti-inflammatory agents. Both drugs have also been found effective to produce closure of patent ductus arteriosus in premature neonates. A simple, rapid, sensitive and reliable HPLC method is described for the determination of indomethacin and mefenamic acid in human plasma. As these drugs are not applied together, the compounds are alternately used as analyte and internal standard. Plasma was deproteinized with acetonitrile, the supernatant fraction was evaporated to dryness and the resulting residue was reconstituted in the mobile phase and injected into the HPLC system. The chromatographic separation was performed on a C₁₈ column (250 × 4.6 mm I.D.) using 10 mM phosphoric acid—acetonitrile (40:60, v/v) as the mobile phase and both drugs were detected at 280 nm. The calibration graphs were linear with a correlation coefficient (r) of 0.999 or better from 0.1 to 10 μg/ml and the detection limits were 0.06 μg/ml for indomethacin and 0.08 μg/ml for mefenamic acid, for 50μl plasma samples. The method was not interfered with by other plasma components and has been found particularly useful for paediatric use. The within-day precision and accuracy of the method were evaluated for three concentrations in spiked plasma samples. The coefficients of variation were less than 5% and the accuracy was nearly 100% for both drugs.     

Nano-proniosomes enhancing the transdermal delivery of mefenamic acid

Mefenamic acid (MA) is a BCS II class NSAID drug. It is available only in the form of tablets, capsules, and pediatric suspensions. Oral administration of MA is associated with severe gastrointestinal side effects. The aim of this study was to develop a convenient and low-cost transdermal drug delivery system for MA using proniosome as a novel carrier without the addition of penetration enhancers. The formulation factors, such as the presence of cholesterol, types of lecithin, and surfactants were investigated for their influence on the entrapment efficiency, rate of hydration, vesicle size, and zeta potential, in vitro drug release and skin permeation in order to optimize the proniosomal formulations with the minimum dose of the drug. Furthermore, the in vivo anti-inflammatory effect was evaluated on a formalin-induced rat paw edema model. The results showed that the type of surfactants had higher impact on the entrapment efficiency than the type of lecithins, with the highest in Span 80 (82.84%). The release of MA from Span 80 proniosomal gel was significantly affected by the type of lecithin used. The addition of cholesterol significantly increased both the drug release and the skin permeation flux of MA. Zeta potential showed a stable A4 noisomal suspension. DSC revealed the molecular dispersion of MA into the loaded proniosomes. In vivo study of the treatment group with MA proniosome gel showed a significant inhibition of rat paw edema compared with the same gel without the drug (control). The results of this study suggest that proniosomes are promising nano vesicular carriers and safe alternatives to enhance the transdermal delivery of MA.     

Flufenamic acid, mefenamic acid and niflumic acid inhibit single nonselective cation channels in the rat exocrine pancreas.

The non-steroidal anti-inflammatory drugs, flufenamic acid, mefenamic acid and niflumic acid, block Ca2(+)-activated non-selective cation channels in inside-out patches from the basolateral membrane of rat exocrine pancreatic cells. Half-maximal inhibition was about 10 microM for flufenamic acid and mefenamic acid, whereas niflumic acid was less potent (IC50 about 50 microM). Indomethacin, aspirin, diltiazem and ibuprofen (100 microM) had not effect. It is concluded that the inhibitory effect of flufenamate, mefenamate and niflumate is dependent on the specific structure, consisting of two phenyl rings linked by an amino bridge.     

Neuroprotection by mefenamic acid against d-serine: Involvement of oxidative stress,inflammation and apoptosis

Abstract

Mefenamic acid, a non-steroidal antiinflammatory drug (NSAID), directly and dose-dependently exhibits neuroprotective activity. In our study, we investigated the effects of mefenamic acid against d-serine on oxidative stress in the hippocampus, cortex and cerebellum of rats. Furthermore, the potential inflammatory and apoptotic effects of d-serine and potential protective effect of mefenamic acid were determined at mRNA and protein levels of TNF-α, IL-1β, Bcl-2 and Bax. We found that d-serine significantly increased oxidative stress, levels of inflammation- and apoptosis-related molecules in a region specific manner. Mefenamic acid treatment provided significant protection against the elevation of lipid peroxidation, protein oxidation, levels of TNF-α, IL-1β and Bax. As a conclusion, we suggest that d-serine, as a potential neurodegenerative agent, may have a pivotal role in the regulation of oxidative stress, inflammation and apoptosis; and NSAIDs, such as mefenamic acid, may assist other therapeutics in treating disorders where d-serine-induced neurotoxic mechanisms are involved in.     

The effects of mefenamic acid on postprandial intestinal carbohydrate metabolism

The effects of mefenamic acid on the food-induced changes in intestinal carbohydrate metabolism were determined in an attempt to elucidate the mechanism(s) by which inhibition of prostaglandin synthesis enhances the postprandial increases in intestinal blood flow and oxygen consumption. The data show that when the luminal perfusate was was changed from saline to a nutrient/bile solution, there was an increase in carbohydrate utilization, which was offset by absorption of glucose from the lumen. Intravenous administration of mefenamic acid significantly increased both carbohydrate absorption and metabolism when food was placed in the lumen. Changes in carbohydrate absorption and metabolism have been shown to play an important role in determining the magnitude of glucose induced changes in intestinal blood flow and oxygen consumption. Therefore, it is possible that the ability of mefenamic acid to enhance significantly the food-induced increases in blood flow and oxygen consumption may be due in part to its effects on intestinal carbohydrate absorption and utilization.     

The effects of mefenamic acid on postprandial intestinal carbohydrate metabolism

The effects of mefenamic acid on the food-induced changes in intestinal carbohydrate metabolism were determined in an attempt to elucidate the mechanism(s) by which inhibition of prostaglandin synthesis enhances the postprandial increases in intestinal blood flow and oxygen consumption. The data show that when the luminal perfusate was changed from saline to a nutrient/bile solution, there was an increase in carbohydrate utilization, which was offset by absorption of glucose from the lumen. Intravenous administration of mefenamic acid significantly increased both carbohydrate absorption and metabolism when food was placed in the lumen. Changes in carbohydrate absorption and metabolism have been shown to play and important role in determining the magnitude of glucose induced changes in intestinal blood flow and oxygen consumption. Therefore, it is possible that the ability of mefenamic acid to enhance significantly the food-induced increases in blood flow and oxygen consumption may be due in part to its effects on intestinal carbohydrate absorption and utilization.     

Neuroprotection by mefenamic acid against D-serine: involvement of oxidative stress, inflammation and apoptosis

Mefenamic acid, a non-steroidal antiinflammatory drug (NSAID), directly and dose-dependently exhibits neuroprotective activity. In our study, we investigated the effects of mefenamic acid against d-serine on oxidative stress in the hippocampus, cortex and cerebellum of rats. Furthermore, the potential inflammatory and apoptotic effects of d-serine and potential protective effect of mefenamic acid were determined at mRNA and protein levels of TNF-α, IL-1β, Bcl-2 and Bax. We found that d-serine significantly increased oxidative stress, levels of inflammation- and apoptosis-related molecules in a region specific manner. Mefenamic acid treatment provided significant protection against the elevation of lipid peroxidation, protein oxidation, levels of TNF-α, IL-1β and Bax. As a conclusion, we suggest that d-serine, as a potential neurodegenerative agent, may have a pivotal role in the regulation of oxidative stress, inflammation and apoptosis; and NSAIDs, such as mefenamic acid, may assist other therapeutics in treating disorders where d-serine-induced neurotoxic mechanisms are involved in.     

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.     

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%.     

Embryolethality in rats caused by retinoic acid

Retinoic acid (25 mg/kg) administered by gavage to rats at 216 hours of gestation killed almost all conceptuses by 288 hours and all by full term. The embryolethal dose50 was 12.3 mg/kg. Embryos died from damage to the allantois leading to agenesis or hypogenesis of the chorioallantoic placenta. Suppression of cell division in, disturbed fluid entry into, and impaired normal vascularization of the allantois underlay the abnormality, the predominant element depending principally on when exposure occurred. Hydremia (Br. J. Exp. Pathol., 57:525-541, '76) affected over 50% of the sacs. Relating data from the literature to resorption patterns suggested that 25 mg/kg of retinoic acid raised a lethotoxic level (approximately 2 micrograms/ml) of retinoate in the plasma for about 5 hours. This, together with asynchronous development, was used to help explain why groups of embryos responded to the teratogen for 18 hours longer than single embryos and why exposure 18 hours before the allantois on average appears, killed some young. Comparison showed that retinoic acid was 4.8 times as embryolethal as retinol. Otherwise, each behaved qualitatively similarly, suggesting that either retinol acts through retinoic acid or via a common path entered independently by each. Placental agenesis is well documented in Soviet literature. It is almost unknown in Western teratology even though it is probably the most important cause of embryonal death following teratogenic procedures around the time of placentation.     

Voltammetric determination of mefenamic acid at lanthanum hydroxide nanowires modified carbon paste electrodes

Lanthanum hydroxide nanowires modified carbon paste electrode (LNW/CPE) exhibiting an electrocatalytic response toward the oxidation of mefenamic acid (MFA) is described. The catalytic action of the LNW/CPE on the oxidation of MFA via one-electron and one-proton transfer is attributed to the formation of the porous construction and the increase of efficient surface of the electrode due to the adulteration of LNW with carbon powders. Using the LNW/CPE, a linear sweep voltammetric method for the determination of MFA and other drugs with diphenylamine parent is proposed. A linear range of 2.0 x 10(-11) to 4.0 x 10(-9)mol L(-1) is obtained along with a detection limit of 6.0 x 10(-12)mol L(-1).