Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid (AA) and endocannabinoid substrates, placing the enzyme at a unique junction between the eicosanoid and endocannabinoid signaling pathways. COX-2 is a sequence homodimer, but the enzyme displays half-of-site reactivity, such that only one monomer of the dimer is active at a given time. Certain rapid reversible, competitive nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit COX-2 in a substrate-selective manner, with the binding of inhibitor to a single monomer sufficient to inhibit the oxygenation of endocannabinoids but not arachidonic acid. The underlying mechanism responsible for substrate-selective inhibition has remained elusive. We utilized structural and biophysical methods to evaluate flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid for their ability to act as substrate-selective inhibitors. Crystal structures of each drug in complex with human COX-2 revealed that the inhibitor binds within the cyclooxygenase channel in an inverted orientation, with the carboxylate group interacting with Tyr-385 and Ser-530 at the top of the channel. Tryptophan fluorescence quenching, continuous-wave electron spin resonance, and UV-visible spectroscopy demonstrate that flufenamic acid, mefenamic acid, and tolfenamic acid are substrate-selective inhibitors that bind rapidly to COX-2, quench tyrosyl radicals, and reduce higher oxidation states of the heme moiety. Substrate-selective inhibition was attenuated by the addition of the lipid peroxide 15-hydroperoxyeicosatertaenoic acid. Collectively, these studies implicate peroxide tone as an important mechanistic component of substrate-selective inhibition by flufenamic acid, mefenamic acid, and tolfenamic acid.
This study aimed to investigate the combined effect of magnesium oxide (MgO) as an alkalizer and polyethylene glycol (PEG) as a plasticizer and wetting agent in the presence of Kollidon® 12 PF and 17 PF polymer carriers on the release profile of mefenamic acid (MA), which was prepared via hot-melt extrusion technique. Various drug loads of MA and various ratios of the polymers, PEG 3350 and MgO were blended using a V-shell blender and extruded using a twin-screw extruder (16-mm Prism EuroLab, ThermoFisher Scientific, Carlsbad, CA) at different screw speeds and temperatures to prepare a solid dispersion system. Differential scanning calorimetry and X-ray diffraction data of the extruded material confirmed that the drug existed in the amorphous form, as evidenced by the absence of corresponding peaks. MgO and PEG altered the micro-environmental pH to be more alkaline (pH 9) and increased the hydrophilicity and dispersibility of the extrudates to enhance MA solubility and release, respectively. The in vitro release study demonstrated an immediate release for 2 h with more than 80% drug release within 45 min in matrices containing MgO and PEG in combination with polyvinylpyrrolidone when compared to the binary mixture, physical mixture and pure drug.
Television microscopy was used to observe the responses of in vivo arterioles and venules of the rat cremaster muscle to the topical application of angiotensin II (10(-8) and 10(-6) M). Neither the first- (A1) or second-order arterioles (A2) nor the first- (V1) or second-order venules (V2) constricted significantly to angiotensin II. However, after the inhibition of local prostaglandin synthesis with either mefenamic acid or indomethacin, both A1 and A2, but not the venules, gave a significant constrictor response to angiotensin II (10(-6) M). Arterioles and venules, which were preconstricted with norepinephrine, dilated to their initial baseline diameters after angiotensin II (10(-6) M), a response not observed when the microvessels were pretreated with either an angiotensin antagonist or a prostaglandin synthesis inhibitor. These observations indicate that endogenous prostaglandins exert a significant dilator influence on the larger arterioles, that this dilator influence appears to oppose the constrictor effect of angiotensin II, and that angiotensin II acts on specific receptors to induce synthesis and/or release of dilator prostaglandins in large arterioles. However, prostaglandins cannot account for the absence of a venular constriction to angiotensin.
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Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.
Acyl glucuronides have been implicated in the toxicity of many xenobiotics and marketed drugs. These toxicities are hypothesized to be a consequence of covalent binding of the reactive forms of the acyl glucuronide to proteins. Reactive intermediates of the acyl glucuronide arise from the migration of the aglycone leading to other positional and stereoisomers under physiological conditions. In order to screen for the potential liabilities of these metabolites during the early phase of pharmaceutical development, an NMR method based on the disappearance of the anomeric resonance of the O-1-acyl glucuronide was used to monitor the degradation kinetics of 11 structurally diverse acyl glucuronides, including those produced from the known nonsteroidal anti-inflammatory drugs (NSAIDs). The acyl glucuronides were either chemically synthesized or were isolated from biological matrices (bile, urine, and liver microsomal extracts). The half-lives attained utilizing this method were found to be comparable to those reported in the literature. NMR analysis also enabled the delineation of the two possible pathways of degradation: acyl migration and hydrolytic cleavage. The previously characterized 1H resonances of acyl migrated products are quite distinguishable from those that arise from hydrolysis. The NMR method described here could be used to rank order acyl glucuronide forming discovery compounds based on the potential reactivity of the conjugates and their routes of decomposition under physiological conditions. Furthermore, we have shown that in vitro systems such as liver microsomal preparations can be used to generate sufficient quantities of acyl glucuronides from early discovery compounds for NMR characterization. This is particularly important, as we often have limited supply of early discovery compounds to conduct in vivo studies to generate sufficient quantities of acyl glucuronides for further characterization.
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Three fenamates (flufenamate, meclofenamate and mefenamate) were examined for their protective effect on neurons under ischemic (glucose/oxygen deprivation) or excitotoxic conditions, using the isolated retina of chick embryo as a model. Retinal damage was evaluated by histology and lactate dehydrogenase assay. Whole-cell recording was used to examine the direct effect of the fenamates on glutamate receptor-mediated currents. The fenamates protected the retina against the ischemic or excitotoxic insult. Part of the neuroprotection by the fenamates derived from inhibition of N-methyl-D-aspartate receptor-mediated currents. However, kainate receptor-mediated currents were not blocked by the fenamates, which nonetheless reduced kainate receptor-mediated retinal damage. Our results raise the possibility that fenamates may serve as lead structures in the development of novel therapeutic agents against brain ischemia.
The diagnosis of DUB is made by the exclusion of organic disease as a cause of the abnormal menses; the condition accounts for about 80% of cases of menorrhagia. Of these, over 80% will have no abnormality of the hypothalamo-pituitary-ovarian axis, and it is likely that the disorder is the result of local endometrial factors. There appears to be not only a preponderance of vasodilatory prostaglandins in the endometrium of women with menorrhagia, but also an excessive increase in fibrinolytic activity within the uterine cavity. Once a diagnosis has been reached with the aid of history, examination, haematological and endocrine investigations, and dilatation and curettage when appropriate, medical treatment is the usual first line approach. Non-steroidal anti-inflammatory drugs such as mefenamic acid, or antifibrinolytic agents such as tranexamic or epsilon aminocaproic acids, will reduce blood loss by between 25 and 50%. Though the former drugs are relatively free from side-effects in healthy women, intracranial thrombosis has been reported with the latter (Agnelli et al, 1982). Medications which suppress ovarian function, such as danazol or gonadotrophin releasing hormone analogues, are highly effective in lessening, or inhibiting, menstrual loss, but at the expense of side-effects and convenience respectively. The combined contraceptive pill may reduce blood loss by 50% but is not appropriate for older women. Cyclical gestagens such as norethisterone have been widely employed, particularly for the treatment of anovulatory cycles, but their place in the management of ovulatory DUB is less clear. If medical treatment fails hysterectomy should be considered, though less invasive surgical methods of endometrial ablation are being developed. Finally, it should be remembered that in the absence of associated signs or symptoms of iron-deficiency anaemia, heavy menstrual bleeding is a subjective complaint and up to 50% of women describing menorrhagia will have a measured monthly blood loss within normal limits.
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The use of a zinc supplement in combination with mefenamic acid was superior in reducing primary dysmenorrhea compared to mefenamic acid alone.
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There are no studies verifying that mefenamic acid is more effective than other NSAID (= non-steroidal anti-inflammatory drugs). However, there are several notions in the literature that this drug is less well-tolerated than other NSAID because over a prolonged period of application more lesions of the upper gastro-intestinal tract are induced as well as occasionally renal insufficiency. Compared to other NSAID the systemic toxicity starts already with relatively low doses above the maximal daily dose. Considering current knowledge there is no reason to prefer mefenamic acid to other NSAID.
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There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin.
To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE).
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Differences in the inhibitory potentials against UDP-glucuronosyltransferase (UGT) between species have been reported only rarely, even though the information would be useful for the precise characterization of drug candidates. In this study, the inhibition potentials of nonsteroidal anti-inflammatory drugs (NSAIDs) against UGT-catalyzed estradiol 3beta-glucuronidation (E3G) in the liver microsomes of rats, dogs, and humans were compared. Rat liver microsomes (RLMs) and human liver microsomes (HLMs) exhibited homotropic activation kinetics with S(50) values of 22 and 12 microM, respectively. However, dog liver microsomes (DLMs), exhibited Michaelis-Menten kinetics with no activation. Among the NSAIDs investigated (diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, niflumic acid, and sulindac), only niflumic acid and mefenamic acid inhibited E3G potently in all three species. The IC(50) values of NSAIDs against E3G in RLMs and HLMs were within a threefold difference of each other, while those in DLMs was more than three times higher than the other two. In conclusion, RLMs showed an inhibitory pattern similar to that of HLMs, whereas DLMs presented a distinct pattern. These results indicate that a rat animal model would be useful for evaluating the inhibitory potentials of drugs against estradiol glucuronidation, but a dog model would not.
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Thiopurine S-methyltransferase (TPMT) is a biotransformation phase II enzyme responsible for the metabolic inactivation of thiopurine drugs. The present study was carried out to investigate the inhibitory potential of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) on human TPMT activity in vitro. TPMT activity was measured in pooled human erythrocytes in the absence and presence of various NSAIDs using the previously published high-performance liquid chromatography-UV method. To determine the inhibition type and K(i) value for each compound, we performed kinetic analysis at five different inhibitor concentrations close to the IC(50) value obtained in preliminary experiments. Naproxen (K(i) = 52 microM), mefenamic acid (K(i) = 39 microM), and tolfenamic acid (K(i) = 50 microM) inhibited TPMT activity in a noncompetitive manner. The estimated K(i) values for the inhibition of TPMT by ketoprofen (K(i) = 172 microM) and ibuprofen (K(i) = 1043 microM) indicated that the propionic acid derivatives were relatively weak inhibitors of TPMT. Our results suggest that coadministration of thiopurines and various NSAIDs may lead to drug interactions.
We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched April 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2007), MEDLINE (1966 to April 2007), EMBASE (1985 to April 2007), CINAHL (1982 to April 2007), Current Contents (1993 to April 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field.
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Mefenamic acid (MA) is a nonsteroidal anti-inflammatory drug used as analgesic and antipyretic drug. Available conventional pharmaceutical forms are capsules and film-coated tablets given three times a day (t.t.d.). Natural polymers such as sodium alginate, pectin, chitosan and carregeenan, used as barriers to effect the drug release, are those of the main interest of researchers. The aim of the present study was to formulate sustained release MA-beads based on kappa-carrageenan in order to reduce daily dose and to minimize gastrointestinal disturbances caused by the drug.
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The effect of prostaglandin synthesis inhibition on the postprandial intestinal hyperemia was examined in the jejunum of anesthetized dogs. Both intravenous and intra-arterial infusion of the cyclooxygenase inhibitors indomethacin and mefenamic acid reduced resting jejunal blood flow and markedly enhanced the food-induced jejunal hyperemia. The jejunal vascular response to food did not change after either intravenous or intra-arterial infusion of the carrier solutions or intra-arterial infusion of angiotensin II. The enhancement of the jejunal hyperemia was associated with an increase in the food-induced increase in jejunal oxygen consumption. Infusion of the cyclooxygenase inhibitors increased the mean amplitude of the monophasic intestinal contractions; however, this did not appear to play a role in the enhancement of the food-induced hyperemia. The study indicates that inhibition of prostaglandin synthesis has a marked effect on the postprandial intestinal hyperemia and that this may be due to its enhancement of the jejunal metabolic response to food. The prostaglandins involved and their mechanism of action are unknown.
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A number of nonsteroidal anti-inflammatory drugs (NSAIDs) are subject to glucuronidation in humans, and UDP-glucuronosyltransferase (UGT) 2B7 is involved in the glucuronidation of many NSAIDs. The objective of this study was to identify a NSAID with potent inhibitory potential against UGT2B7 using liquid chromatography with tandem mass spectrometry (LC-MS/MS).
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Prospective, randomized, controlled, single-blinded, clinical trial.
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GABA(A) receptor (R) positive allosteric modulators that selectively modulate GABA(A)Rs containing beta(2)- and/or beta(3)- over beta(1)-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"beta(2/3)-selective" GABA(A)R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show alpha-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA(A)R positive allosteric modulators that demonstrate differential beta-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other beta(2/3)-subunit selective, alpha-subunit isoform-selective, BZ and nonBZ GABA(A) positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at beta(1)-subunit-containing GABA(A)Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA(A)R with BZ-like anxiolytic efficacy by reducing or eliminating activity at beta(1)-subunit-containing GABA(A)Rs.
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The pain intensity in the mefenamic and ginger group was 39.01 ± 17.77 and 43.49 ± 19.99, respectively, in the first month, and 33.75 ± 17.71 and 38.19 ± 20.47, respectively, in the second month (p > 0.05). The severity of dysmenorrhea, pain duration, cycle duration and bleeding volume was not significantly different between groups during the study. The menstrual days were more in the ginger group in the first (p = 0.01) and second cycle (p = 0.04). Repeated measurement showed a significant difference in pain intensity within the groups by time, but not between groups.
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Based on the studies carried out so far, the efficacy of aspirin, steroid and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.
A swelling-activated, background K(+) current in the corneal epithelium is characteristically activated by fenamates and inhibited by diltiazem. Fatty acids also stimulate this current, indicating that its origin is a lipid-sensitive mechano-gated 2P domain K(+) channel. In the present study, modulation of TREK-1, TREK-2, and TRAAK channels by fenamates and diltiazem was examined. TREK-1, TREK-2, and TRAAK currents transiently expressed in COS-7 cells were recorded by the perforated-patch configuration. As previously reported, arachidonic acid (20 microM) stimulated all of these channels, and a volatile anesthetic, halothane (1 mM) augmented TREK-1 and TREK-2 but not TRAAK. Flufenamic acid (FA, 100 microM), niflumic acid (NA, 100 microM), and mefenamic acid (MA, 100 microM) markedly stimulated TREK-1, TREK-2, and TRAAK. The potency sequence for the activation of TREK-1 and TREK-2 was FA > NA = MA, and the potency sequence for the activation of TRAAK was FA = NA > MA. Diltiazem (1 mM) inhibited TREK-1 and TREK-2, but not TRAAK. In conclusion, fenamates are openers of the lipid-sensitive mechano-gated 2P domain K(+) channels, and diltiazem may be a specific blocker for TREK. These novel findings could help to further understand channel functions of the mechano-gated 2P domain K(+) channels.
Thirty patients suffering from the premenstrual syndrome were studied for five consecutive menstrual cycles. An untreated baseline cycle without medication was followed by four treatment cycles. Mefenamic acid or placebo was taken on days 11-26 of the cycle in a prospectively randomized double-blind cross-over manner, with each patient acting as her own control. On subjective assessment, there was a significant overall improvement on mefenamic acid compared with placebo. With the exception of gastro-intestinal symptoms, mefenamic acid was not significantly better than placebo for any of the individual symptoms assessed on the patients daily symptom checklists.
All the commonly used non-steriodal anti-inflammatory drugs (NSAIDs), except mefenamic acid, when extracted from the pharmaceutical dosage forms or the urines of users, and derivatized by silylation and then analysed by GC/MS, gave the mono- or the di-trimethylsilyl derivatives (depending on the number of derivatized groups in the drug) as the sole products. Mefenamic acid gave a mixture of products. When extracted from pharmaceutical dosage froms or from the urines of users, and analysed by GC/MS without derivatization, some of the NSAIDs were separated and detected as the unchanged molecules as the sole products, while others were separated and detected in altered forms as sole products or mixtures, depending on: (a) the solvent in which the extract was dissolved for injection into GC/MS, (b) the chemical structure of the drug, and (c) specifically for diflunisal, the presence or absence of potential methylating and/or acetylating agents on the GC column and/or septum. The main thermally-induced reactions of the underivatized NSAIDs included (i) methyl ester formation at the COOH group when the extract was dissolved in methanol, (ii) decarboxylation (i.e., loss of CO2), (iii) dehydration (i.e., loss of H2O) when the chemical structure permitted, such as for diclofenac, and (iv) cleavage at a carbon-heterocyclic nitrogen bond when one is present in an NSAID. Heating the urine in approximately 2 M HCl at 100 degrees C for 30 min, has been found to be a satisfactory means for effecting hydrolysis of the NSAIDs glucuronide conjugates. No metabolites, resulting from aromatic-ring hydroxylation, have been detected in urine for any of the NSAIDs studied.
Ginger was as effective as mefenamic acid and ibuprofen in relieving pain in women with primary dysmenorrhea. Further studies regarding the effects of ginger on other symptoms associated with dysmenorrhea and efficacy and safety of various doses and treatment durations of ginger are warranted.