Non-steroidal Anti-inflammatory Drugs Mefenamic Acid Research Articles

Structural features of nickel(II) mixed ligand complexes with mefenamic acid and nitrogen donor ligands

The reaction between Ni(NO3)2.6H2O and the non-steroidal anti-inflammatory mefenamic acid (2-[(2,3-dimethylphenyl)amino]benzoic acid), in the presence of various nitrogen donor ligands (imidazole, 2-methylimidazole, pyridine, and nicotinamide) have resulted in the formation of four novel mixed ligand mononuclear Ni(II) complexes. A direct one step metal-ligand complexation method was adopted in synthesizing the complexes under similar conditions using a solvent mixture of EtOH: H2O (2:1). The synthesized complexes have the general formula; [Ni(mef)2(L)2(EtOH)2] or [Ni(mef)2(L)2(H2O)2]·2H2O, where mef is mefenamato, L is the corresponding nitrogen donor ligand. The complexes were characterized by analytical and spectroscopic methods. FTIR studies supported the complex formation and indicated that the mefenamato ligand was coordinated as monodentate through the deprotonated carboxylate oxygen atom. Single-crystal X-ray diffraction studies show that all the complexes crystallize in the triclinic space group P-1. The complexes are isostructural, and Ni(II) lies in an octahedral geometry with NiN2O4 chromophore. Parallel stacking arrangement of the ligands, similar intramolecular N-H···O, and intermolecular O-H···O interactions between the mefenamato ligand and coordinated solvent dominated the connectivity pattern in the complexes. Also, intermolecular interactions depending on the coordinated nitrogen donor ligand further stabilized the structures of the complexes. Furthermore, density functional theory (DFT) study was done to obtain the Hirshfeld charges on different atoms.

Manganese (II)-imidazole complexes of the non-steroidal anti-inflammatory drug mefenamic acid: Synthesis, and structural studies

Two new complexes of Mn(II) have been synthesized with a non-steroidal anti-inflammatory drug, mefenamic acid, 2-[(2,3-dimethylphenyl)amino]benzoic acid (mef) and the nitrogen donor ligands; imidazole (imi) and 2-methylimidazole (mei), viz. [Mn(mef)2(imi)2(EtOH)2]; M−1 and [Mn(mef)2(mei)2(EtOH)2]; M−2. Also, when mefenamic acid interacted with MnCl2·4H2O in the presence of 2-aminopyridine (apy), a salt of ((mef)(apy)(H2O)); M−3 was isolated. The complexes were characterized using elemental analysis, FTIR, UV–Visible (M−1 and M−2), and single-crystal X-ray diffraction studies. Monodentate coordination of the mefenamate ligand in M−1 and M−2 was confirmed from the FTIR studies. The X-ray structural analysis shows that the two Mn(II) complexes and one salt crystallize in the triclinic space group P-1. M−1 consists of monomeric Mn(II) in hexacoordination with two monodentate mefenamate, two imidazoles, and two ethanol solvent ligands. M−2 consists of monomeric Mn(II) complex in octahedral geometry and coordinated to two each of monodentate mefenamate, 2-methylimidazole, and two ethanol solvent ligands. M−3 consists of salt of mefenamate anion linked to an aminopyridinium cation, with a hydrogen-bonded water molecule present in the crystal lattice which connects the cation and anion via intermolecular OH···O and NH···O interactions.

Isomorphism: 'molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid.

The non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-di-methyl-amino-pyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone-methanol (1:1) solution. That aside, a pseudopolymorph of TFA with di-methyl-formamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarity.

An insight of non-steroidal anti-inflammatory drug mefenamic acid: A review

This review focuses on the design, synthesis and pharmacological effects of non-steroidal anti-inflammatory (NSAIDs) mefenamic acid which is an anthranilic acid derivative. Mefenamic acid is a non-steroidal anti-inflammatory drug used to treat pain, including menstrual pain. Exploitation of the prodrug approach has the potential to achieve a reduction of mefenamic acid GI (gastrointestinal) intolerance, enhance its bioavailability, mask its unpleasant sensation and prolong its duration of action. Mefenamic acid, an effective NSAID has always been used as an anti-inflammatory and analgesic agent. A brief note on various marketed formulations of mefenamic acid provides an insight of the potential capability of this drug and its future scope.

An insight of non-steroidal anti-inflammatory drug mefenamic acid: A review

An insight of non-steroidal anti-inflammatory drug mefenamic acid: A review

Methacrylate-Copolymer Eudragit EPO as a Solubility-Enabling Excipient for Anionic Drugs: Investigation of Drug Solubility, Intestinal Permeability, and Their Interplay

The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 μg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility-permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility-permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.

Manganese coordination compounds of mefenamic acid: In vitro screening and in silico prediction of biological activity

The in vitro and in silico biological properties of two manganese complexes with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) in the presence or absence of salicylaldoxime (Η2sao), i.e. [Μn6(O)2(mef)2(sao)6(CH3OH)4] 1, and [Μn(mef)2(CH3OH)4] 2, respectively, are presented in the present contribution. More specifically, the in vitro biological activity of the complexes was investigated by studying their affinity to calf-thymus DNA (by diverse spectroscopic and physicochemical techniques) and their binding towards bovine (BSA) or human serum albumin (HSA) (by fluorescence emission spectroscopy). Molecular docking simulations on the crystal structures of HSA and DNA, exploring in silico the ability of the complexes to bind to these macromolecules, were also employed in order to explain the described in vitro activity of the compounds. Furthermore, in silico predictive tools have been employed to study the properties of the most active complex 2 to act as anticancer agent, in continuation of the previously reported cytotoxic activity. It is adopted in silico studies on a multitude of proteins involved in cancer growth, as well as prediction of drug-induced changes of gene expression profile, protein- and mRNA-based prediction results, prediction of sites of metabolism, quantitative prediction of antitarget interaction profiles etc.

Enhancement in sensitivity of non-steroidal anti-inflammatory drug mefenamic acid at carbon nanostructured sensor

This article describes the selective and sensitive determination of mefenamic acid on single walled carbon nanotubes modified glassy carbon electrode (GCE) employing square wave voltammetry for the first time. The developed sensor exhibited amelioration in the peak current response with a negative shift in the peak potential in comparison to multi walled carbon nanotubes modified GCE and bare GCE. A good linear relationship has been found between the anodic peak current and mefenamic acid concentration in the range of 0.1–35μM with limits of quantification and detection as 44.7 and 13.4nM, respectively. The interfering effects of the commonly existing metabolites in the biological fluids have been investigated on the current response of the drug. The developed sensor was successfully applied for the assay of mefenamic acid in pharmaceutical formulations. Furthermore, the applicability of the proposed method to determine mefenamic acid in human urine samples obtained from healthy volunteer and patient after 4h of administration of the drug is illustrated.

A novel bioactive Cd(II) polymeric complex with mefenamic acid: Synthesis, crystal structure and biological evaluations

A novel complex [Cd(mef)2(CH3OH)]n, 1, has been synthesized by the interaction of Cd(II) with the non-steroidal antiinflammatory drug mefenamic acid, mef, which has been structurally characterized by spectral (IR, UV–Vis) and X-ray crystallography. This complex is a 1D polymer, consisting of hepta-coordinated Cd atoms connected by six oxygen atoms from four different mef ligands and one oxygen atom from a methanol molecule. The coordination geometry around each metal ion is distorted by the bulky mef ligand. Binding of the synthesized complex with calf thymus DNA (CT-DNA) was investigated by spectroscopic methods (UV–Vis, fluorescence, CD spectroscopy) and viscosity measurements. The complex partially intercalated to DNA with high affinity. The antioxidant activities of ligand mef and complex 1 show this complex has better antioxidant activity than the free ligand. The antimicrobial activities of complex 1 are higher against both bacteria and fungi than free Cd2+ or mef. The cytotoxic effect of compound 1 on the human breast cancer cell line (MCF-7) and the bladder cancer cell line (T24) was also much higher than free Cd2+ or mef.

Synthesis, structure and biological activity of nickel(II) complexes with mefenamato and nitrogen-donor ligands

Six novel nickel(II) complexes with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) with the nitrogen-donor heterocyclic ligands 2,2′-bipyridine (bipy), 2,2′-bipyridylamine (bipyam), 1,10-phenanthroline (phen), 2,2′-dipyridylketone oxime (Hpko) or pyridine (py) and/or the oxygen-donor ligands CH3OH or H2O were synthesized and characterized by physicochemical and spectroscopic techniques. The crystal structures of [Ni(mef-O)2(bipy)(CH3OH)2] (1), [Ni(mef-O)2(phen)(CH3OH)2] (2), [Ni(mef-O,O′)2(bipyam)] (3) and [Ni(mef-O)2(Hpko)2]∙CH3OH (4·CH3OH) were determined by X-ray crystallography. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals was investigated and the in vitro inhibitory activity against soybean lipoxygenase was evaluated; complexes 3 and 4 were the most active compounds. Spectroscopic (UV and fluorescence), electrochemical (cyclic voltammetry) and physicochemical (viscosity measurements) techniques were employed in order to study the binding mode of the complexes to calf-thymus (CT) DNA and to calculate the corresponding binding constants; for all complexes, intercalation was the most possible mode of DNA-binding. The interaction of the complexes with serum albumins was studied by fluorescence emission spectroscopy and the values of the albumin-binding constants were determined.

Multimedia fate modeling and comparative impact on freshwater ecosystems of pharmaceuticals from biosolids-amended soils

This study modeled the impact on freshwater ecosystems of pharmaceuticals detected in biosolids following application on agricultural soils. The detected sulfonamides and hydrochlorothiazide displayed comparatively moderate retention in solid matrices and, therefore, higher transfer fractions from biosolids to the freshwater compartment. However, the residence times of these pharmaceuticals in freshwater were estimated to be short due to abiotic degradation processes. The non-steroidal anti-inflammatory mefenamic acid had the highest environmental impact on aquatic ecosystems and warrants further investigation. The estimation of the solid-water partitioning coefficient was generally the most influential parameter of the probabilistic comparative impact assessment. These results and the modeling approach used in this study serve to prioritize pharmaceuticals in the research effort to assess the risks and the environmental impacts on aquatic biota of these emerging pollutants.

Polymorph Control of Micro/Nano-Sized Mefenamic Acid Crystals on Patterned Self-Assembled Monolayer Islands

The nucleation of organic molecular compounds is a stochastic process and is difficult to control. The problem becomes even more complex when the compound has two or more polymorphic forms that can concomitantly nucleate. In this work, patterned self-assembled monolayers (SAMs) are employed, on which a large number of identical experiments can be conducted. SAMs can be an effective way to induce heterogeneous nucleation and were used in this work to generate the desired polymorphic form based on the chemical interactions. Seven different self-assembled monolayers were employed to study the nucleation behavior of the nonsteroidal anti-inflammatory drug mefenamic acid [MA, N-(2,3-xylyl)anthranilic acid]. The results show that SAMs forming a strong interaction with the −COOH group of MA molecules preferably produced form II. The effects of temperature, solvent, droplet size, and concentration on the nucleation kinetics of MA were also explored. The ability to prepare crystalline MA as small as ∼300 nm while ...

Conformational Polymorphism in a Non-steroidal Anti-inflammatory Drug, Mefenamic Acid

For several years, the non-steroidal anti-inflammatory drug mefenamic acid, MA, has been known to exist as dimorphs (I and II). We report a new metastable polymorph (III) of MA obtained during attempted co-crystallization experiments and establish its stability relationship with existing forms. At elevated temperatures I and III convert to II, as evident from DSC experiments. On the basis of the lattice energy calculations in conjunction with thermal analysis, the stability order is proposed to be I > II > III at ambient conditions, whereas at elevated temperature the order is II > I > III. In either condition III is a metastable form and hence transforms to I at ambient conditions and to II at higher temperatures. Also we report the structural studies of a DMF solvate and a cytosine complex.

Non-steroidal antiinflammatory drug–copper(ii) complexes: Structure and biological perspectives

Copper(II) complexes with the non-steroidal antiinflammatory drug mefenamic acid in the presence of aqua or nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline, 2,2'-bipyridylamine or pyridine) have been synthesized and characterized. The crystal structures of [(2,2'-bipyridine)bis(mefenamato)copper(II)], 2, [(2,2'-bipyridylamine)bis(mefenamato)copper(II)], 4, and [bis(pyridine)bis(methanol)bis(mefenamato)copper(II)], 5, have been determined by X-ray crystallography. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and [bis(aqua)tetrakis(mefenamato)dicopper(II)] exhibits the highest binding constant to CT DNA. The cyclic voltammograms of the complexes in the presence of CT DNA solution have shown that the complexes can bind to CT DNA by the intercalative binding mode verified also by DNA solution viscosity measurements. Competitive studies with ethidium bromide (EB) indicate that the complexes can displace the DNA-bound EB suggesting strong competition with EB. Mefenamic acid and its complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. All the compounds have been tested for their antioxidant and free radical scavenging activity as well as for their in vitro inhibitory activity against soybean lipoxygenase showing significant activity.

Biological evaluation of non-steroidal anti-inflammatory drugs-cobalt(ii) complexes

Cobalt(II) complexes with the non-steroidal anti-inflammatory drug mefenamic acid in the presence or absence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine) have been synthesized and characterized with physicochemical and spectroscopic techniques. The experimental data suggest that mefenamic acid acts as deprotonated monodentate ligand coordinated to Co(II) ion through a carboxylato oxygen. The crystal structures of tetrakis(methanol)bis-(mefenamato)cobalt(II), 1 and (2,2'-bipyridine)bis(methanol)bis(mefenamato)cobalt(II), 2 have been determined by X-ray crystallography. The EPR spectra of complexes 1 and 2 in frozen solution reveal that they retain their structures. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and bis(methanol)bis(pyridine)bis-(mefenamato)cobalt(II) exhibits the highest binding constant. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The cyclic voltammograms of the complexes recorded in dmso solution and in the presence of CT DNA in 1 : 2 dmso : buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode. Mefenamic acid and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The antioxidant activity of the compounds has been evaluated indicating their high scavenging activity against hydroxyl free radicals and superoxide radicals.

Status febrilis, pneumonisches Infiltrat und Eosinophilie

We present the case of a 71-year old man with acute eosinophilic pneumonia. By ruling out other common etiologies and by a positive lymphocyte transformation test the non-steroidal anti-inflammatory drug mefenamic acid was identified as the possible causative agent or this potentially life threatening lung disease. The clinical presentation, diagnosis, and treatment of acute eosinophilic pneumonia as a pulmonary manifestation of a drug-induced allergic reaction are discussed.

Environmental photodegradation of mefenamic acid

Pharmaceuticals and personal care products are an emerging class of environmental pollutants. Photolysis is expected to be a major loss process for many of these compounds in surface waters, including the common non-steroidal anti-inflammatory drug mefenamic acid. The direct photolysis solar quantum yield of mefenamic acid was observed to be 1.5 ± 0.3 × 10 −4. Significant photosensitization was observed in solutions of Suwanee River fulvic acid and Mississippi River water, as well as for the model photosensitization compounds 3′-methoxyacetophenone, 2-acetonaphthone and perinaphthenone. Quenching, sparging and light-filtering experiments suggested a direct reaction of mefenamic acid with excited triplet-state dissolved organic matter as the major photosensitization process. The persistence of the model photosensitizer suggests that the photosensitization by perinaphthenone occurs either by triplet-energy transfer or an electron transfer followed by rapid regeneration of the sensitizer. Due to its low quantum yield, the loss of mefenamic acid in sunlit natural waters is expected to depend on both direct and indirect photodegradation processes.

Sulfation of R(--)-apomorphine in the human liver and duodenum, and its inhibition by mefenamic acid, salicylic acid and quercetin

1. The aims were to study the sulfation of R-(--)-apomorphine (hereafter apomorphine) in the human liver and duodenum, and to study the rate of inhibition of apomorphine sulphation by mefenamic acid, salicylic acid and quercetin also in the human liver and duodenum. 2. A rapid and sensitive method was developed to measure the sulfation rate of apomorphine in the human liver and duodenum. The method was based on the use of 0.4 µM 3'-phosphoadenosine-5'-phosphosulfate- [35 S] (PAPS) and 50µM apomorphine. The unreacted PAPS was precipitated with barium hydroxide, barium acetate and zinc sulfate. 3. The rate of apomorphine sulfation (mean ± SD and median) was 261 ± 82 and 242 pmol min -1 mg -1, respectively (liver), and 433 ± 157 and 443 pmol min -1 mg -1, respectively (duodenum). The apomorphine sulfation rate was higher in the duodenum than in the liver (p = 0.0005). 4. Apomorphine sulfation was correlated with SULT1A1 activity in the liver (r 2 = 0.363, p = 0.005) and duodenum (r 2 = 0.494, p = 0.0005), but it did not correlate with SULT1A3 activity both in the liver and duodenum. 5. The K m estimate of apomorphine sulfation rate was 20 ± 3.6 (liver) and 6.5 ± 0.2 µM (duodenum, p = 0.024), and the V max estimate was 248 ± 99 (liver) and 636 ± 104 pmol min -1 mg -1 (duodenum, p = 0.018). 6. Mefenamic acid, salicylic acid and quercetin were potent inhibitors of apomorphine sulfation rate in the liver, and the IC 50 estimates were 16 ± 0.2 nM, 54 ± 8.6 µM and 18 ± 2.8 nM, respectively. These compounds were poor inhibitors of apomorphine sulfation in the duodenum. 7. Apomorphine is sulfated by the human liver and duodenum, the highest activity being associated with the duodenum. The K m of apomorphine sulfotransferase is in the order of µM both in the liver and duodenum. The non-steroidal anti-inflammatory drug mefenamic acid and the natural flavonoid quercetin inhibit the hepatic sulfation of apomorphine with an IC 50 in the order of nM.

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.