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PubMed1987

Crystal structures of 1 : 1 complexes of meclofenamic acid with choline and ethanolamine.

The hydrated 1:1 complex of meclofenamic acid with choline crystallizes in the orthorhombic space group Pna2(1) with a = 9.637(1), b = 12.962(5), c = 33.099(4) A and Z = 8. Crystals of the corresponding anhydrous complex with ethanolamine are triclinic, space group P1, with a = 9.232(3), b = 12.287(5), c = 17.033(3) A, alpha = 70.21(2), beta = 76.72(2), gamma = 68.21(3) degrees and Z = 4. The structures have been solved by direct methods and refined to R values of 0.062 and 0.079, respectively for 1942 and 2852 observed reflections. The four crystallographically independent meclofenamate anions in the complexes have nearly the same molecular geometry which in turn is very similar to that found in the crystal structure of free meclofenamic acid. The choline and ethanolamine molecules assume a gauche conformation with respect to the central C-C bond. The invariant structural features observed in the crystals of the free fenamates are retained by the meclofenamate ions in the complexes. These features are the rigid coplanar geometry of the six-membered ring carrying the carboxyl group, the carboxyl group and the imino nitrogen atom, and the internal hydrogen bond connecting the imino and the carboxyl groups. The crystal structures are stabilised by ionic interactions between the carboxylate groups of meclofenamate ions and choline or ethanolamine cations, and hydrogen bonds. The choline complex exhibits pseudosymmetry and the distribution of molecules in it is nearly centrosymmetric although the space group is noncentrosymmetric. The packing of molecules in the crystals is such that the polar columns are surrounded by non-polar regions. The core of each column in the choline complex is made up of water molecules connected by hydrogen bonds involving disordered protons. The results of the X-ray structure analysis of fenamates and their crystalline complexes provide some insights into structure-function relationships in this family of drugs.

Choline↗
PubMed1990

Effect of meclofenamic acid on the response of parasite-naive lambs and adult sheep to Ostertagia circumcincta.

Meclofenamic acid was used to inhibit prostaglandin synthesis in lambs challenged with Ostertagia circumcincta. It lowered the number of parasites which established in treated animals but not significantly. In treated animals plasma pepsinogen values were elevated at the time of parasite emergence but had dropped below the values achieved in control lambs towards the end of the experiment when parasites were at the adult, lumenal dwelling stage. Meclofenamic acid administered to adult immune ewes during challenge with third stage O circumcincta larvae did not significantly affect the establishment of the parasites, nor did it affect the rise in pepsinogen concentration associated with the challenge.

Abomasum↗
PubMed1988

Plasma and synovial fluid meclofenamic acid concentrations in patients with rheumatoid arthritis of the knee.

We have measured plasma and synovial fluid concentrations of meclofenamic acid at 2, 4, 8, and 12 h during steady-state administration (100 mg three times daily for 4-7 days). Paired plasma and synovial samples were obtained pre-treatment and at one of the above times in twelve patients with a diagnosis of rheumatoid arthritis. In addition, the extent of protein binding of meclofenamic acid was assessed in vitro in the pre-treatment plasma and synovial fluid specimens. Peak total concentrations of 1.73 and 0.86 micrograms.ml-1 were observed in plasma (at 2 h) and synovial fluid (at 4 h) respectively. The extent of protein binding was 99.7 and 99.6% (not significantly different) in plasma and synovial fluid respectively. The results of this study are compared to those from similar reported studies of other nonsteroidal anti-inflamatory compounds.

Arthritis, Rheumatoid↗
PubMed1990

Effects of topical applications of meclofenamic acid and ibuprofen on bone loss, subgingival microbiota and gingival PMN response in the primate Macaca fascicularis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to alter periodontitis in both animals and humans. This study was initiated in the nonhuman primate (Nhp) model to determine the effect of two NSAIDs on preexisting gingivitis, the conversion of gingivitis to periodontitis, the associated subgingival microbiota, and the gingival PMN response. Eighteen cynomolgus monkeys were divided into three groups and treated on a blind basis with ibuprofen 8%, meclofenamic acid 5%, or placebo applied topically 5 days/week for 20 wk. After 4 wk of treatment, periodontitis was initiated in one quadrant by the placement of silk ligatures. Clinical parameters, bone loss by densitometric analysis of radiographs (CADIA), and cultural microbiology of subgingival plaque were monitored. In situ PMN chemotaxis was assessed by quantitating the PMNs which entered the sulcus in response to a challenge with n-formyl-methionyl-leucyl-phenylalanine (FMLP). No significant differences in the clinical parameters were noted by treatment groups. Radiographic bone loss was detected in all experimental sites in placebo animals as compared with 67% and 44% for ibuprofen and meclofenamic acid animals, respectively. Mean CADIA scores/animal showed a significant loss in bone density for placebo at 6 and 16 wk, no change for ibuprofen animals, and a significant increase in density for meclofenamic acid animals. The microbiota of all groups changed with ligation consistent with previous reports of disease initiation in the Nhp.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1986

Isolation of meclofenamic acid and two metabolites from equine urine--a comparison between horse and man.

Two metabolites of meclofenamic acid have been isolated from equine urine. Both metabolites are found to be monohydroxylated forms of meclofenamic acid by gas chromatography-mass spectrometry after extractive alkylation. The parent drug and the metabolites are separated by reversed-phase liquid chromatography on a Spherisorb ODS column, using methanol-phosphate buffer eluents and UV detection at 280 nm. The structure of the metabolites is discussed on the basis of LC, TLC and GC-MS data.

Journal Article↗
PubMed1976

Inhibition of prostaglandin F2alpha-induced reflex bradycardia and hypotension by meclofenamic acid.

Intravenous injection of prostaglandin F2alpha (4-15 mug/kg, i.v.) produces an increase in pulmonary arterial pressure in conjunction with reflex bradycardia and hypotension in the anesthetized cat. Meclofenamic acid (30 mg/kg, i.v.) inhibited the bradycardia and the reflex contribution to the systemic hypotension. Neither the PGF2alpha-induced pulmonary vasoconstriction nor the direct systemic vasodilator actions of PGF2alpha were blocked by meclofenamate. In addition, the reflex responses caused by i.v. veratrine and 5-HT were not inhibited by meclofenamate. These results suggest that meclofenamic acid selectively blocks the afferent mechanism by which PGF2alpha induces reflex bradycardia and hypotension in the cat.

Animals↗
PubMed1987

The topical anti-inflammatory effects of a topical preparation of meclofenamic acid on carrageenan-induced footpad swelling in mice.

A topical preparation of meclofenamic acid (Meclomen) was tested for anti-inflammatory activity in a murine model of carrageenan footpad oedema. The preparation significantly inhibited swelling when applied to the carrageenan-injected paw. Maximum inhibition was observed 4-5 h after carrageenan injection. The topical effects could not be attributed to systemic absorption because the preparation was more inhibitory when applied topically to the carrageenan-injected paw than to a distant site or orally.

Administration, Oral↗
PubMed1994

Pentoxifylline and meclofenamic acid treatment reduces clinical manifestations in a murine model of AIDS.

C57/BL/6 mice infected with LP-BM5 MuLV virus developed an AIDS-like disease (MAIDS) with splenomegaly, leukopenia, thrombocytopenia, anemia, decreased numbers of helper/inducer and suppressor/cytotoxic T-cells and decreased production of interferon alpha. We have shown previously that HIV-associated Kaposi's sarcoma tissue contains high levels of prostaglandin E2 (PgE2), and this inhibits interferon synthesis through a cAMP-dependent second-messenger process. In this study we treated groups of MAIDS-infected mice with combinations of pentoxifylline, an agent which increases cAMP and inhibits phosphodiesterases, and sodium meclofenamic acid, a PgE2 inhibitor. Treated mice showed: 1) significantly higher total leukocyte and platelet counts, 2) higher total L3T4+ (helper/inducer) and Lyt-2+ (suppressor-cytotoxic) T-cell population. Pathologic examination also showed significantly less hepatosplenomegaly and lymphadenopathy in animals treated with pentoxifylline and meclofenamic acid. Partly, PgE2-induced suppression of interferon alpha production may mediate expression of retrovirus infection in this murine model of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1980

Effect of oral meclofenamic acid on uterine motility and reactivity to oxytocin in goats.

Spontaneous uterine motility and reactivity to intravenous oxytocin were recorded in eight ovariectomised, oestrogen-primed goats before and after oral meclofenamic acid treatment. Spontaneous motility was completely abolished within 50 to 100 min of meclofenamate administration. However, although uterine reactivity to oxytocin was significantly reduced, the sensitivity was not altered. It is suggested that, in the goat, oxytocin has two effects on the uterus: it increases myometrial activity and also stimulates prostaglandin synthesis.

Administration, Oral↗
PubMed1989

Uterine cavity and the location of IUDs following administration of meclofenamic acid to menorrhagic women. A pilot study.

The relationship between the uterus and the IUD was studied selectively with hysterosalpingograms in 18 menorrhagic women previously treated with Meclofenamic acid (M Ac.), a well known anti-inflammatory drug. Major anomalies (embedding, perforation, rotation) were found in 28.6% of those patients who responded positively to M Ac. In contrast, major anomalies were found in 63.6% of those patients who responded negatively to the drug. It is proposed that the negative response to M Ac. might be due to severe macroscopic disturbances of the uterine wall-IUD relationship. The degree of response to M Ac. might contribute to the decision to remove the IUD from menorrhagic women. In addition, 84.7% anomalies (deformities, embedding, perforation) in the uterine-IUD relationship were found in 13 women with a T-shape IUD device. The fact that those anomalies are related to the tip of the horizontal arm justifies future studies using shortened arms to diminish hypermenorrhea induced by T-shape devices or attempts to use IUDs which do not have the conventional plastic frame, as in the Cu-Fix IUD which has been mentioned as particularly useful to prevent bleeding side effects and pain induced by conventional IUDs. The Cu-Fix IUD consists of 6 sleeves made of pure (99.99%) copper, each sleeve with a length of 5 mm and an outer diameter of approximately 2.2 mm, threaded on surgical 00 monofilament polypropylene (ProleneR, Ethicon). The total area of exposed copper is approximately 390 mm2. The sleeves are prevented from sliding off the suture by 2 smaller copper tubules crushed on the thread in both ends of the IUD structure. This thread-type, copper-bearing device has been designed to overcome the most common IUD-related problems, bleeding and pain.

Adolescent↗
PubMed1991

Recent acquisitions in pain therapy: meclofenamic acid.

A better utilization of nonsteroidal anti-inflammatory drugs (NSAIDs) is possible today based on recent pharmacodynamic and pharmacokinetic studies. The analgesic action of these drugs may take place in the central nervous system (CNS). The analgesic action with a lower dose occurs earlier than the anti-inflammatory action. Some NSAIDs cause an increased level of plasmatic bendorphines in humans. NSAIDs not only have antiprostaglandin action, but also may block the release of substance P. The NSAIDs may be useful for headache, dysmenorrhea, rheumatic disease and in cancer pain therapy. For the safe use of NSAIDs the previous anamnestic and clinical features of the patient must be considered, and a high therapeutic level must be satisfied. Considering this goal, the authors examine pharmacologic and clinical behavior of meclofenamic acid.

Animals↗
PubMed2005

QSAR analysis of meclofenamic acid analogues as selective COX-2 inhibitors.

The use of quantitative structure-activity relationships, since its advent, has become increasingly helpful in understanding many aspects of biochemical interactions in drug research. This approach was utilized to explain the relationship of structure with biological activity of selective COX-2 inhibitors. The enormity of the COX-2 discovery is reflected in the unprecedented speed at which research laboratories have sought to validate its clinical implications. Presented herein is a series of 21 derivatives of meclofenamic acid with selective COX-2 inhibitory activity. Several statistically significant regression expressions were obtained for both COX-1 and COX-2 inhibition using sequential multiple linear regression analysis method. Two of these models were selected and validated further, which revealed the importance of Kier molecular flexibility index for COX-2 inhibitory activity and the number of hydrogen bond donor atoms for COX-1 inhibitory activity. Additionally, linear correlation of molecular flexibility with COX-1 and COX-2 inhibitory activities revealed that flexibility of molecules at COX-2 active site can improve the selectivity of COX-2 inhibitors.

Cyclooxygenase 2↗
PubMed1991

Interactions between oleic acid and drug competitors influence specific binding of thyroxine in serum.

Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T4 could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on drug-induced inhibition of [125I]T4 binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilution-related artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T4, but this concentration augmented the inhibitory effects on T4 binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T4-displacing effect of fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum. Increments in added oleic acid (0.5-2.0 mmol/L) progressively increased the mean unbound fractions of [14C]aspirin, [14C] diflunisal, and [14C]furosemide, but did not displace [14C]fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T4 were concordant in the order: meclofenamic acid greater than aspirin greater than mefenamic acid greater than diflunisal greater than furosemide greater than fenclofenac. In contrast, drug-induced increases in the unbound fraction of [14C]oleic acid did not correlate with augmentation of T4 displacement. We conclude that synergistic effects of oleic acid and drugs on T4 binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T4-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1985

Experimental diabetes: reduction of serotonin-induced vasoconstriction by meclofenamic acid in vitro.

In diabetes the sensitivity of isolated rat aortae to serotonin is greatly diminished and the dose-response curve is shifted to the right. The maximal response is reduced to 37% of control, the threshold dose is approximately tenfold greater, and the ED50 is about fourfold greater than control. This decrease in sensitivity may be due, in part, to a reduction in the synthesis of prostaglandins because serotonin-induced responses in normal and diabetic arteries treated with meclofenamate are also significantly diminished. In addition, there is evidence that both receptor-operated Ca2+ and potential-operated Ca2+ channels may be impaired because the responses to norepinephrine and KCl are both dampened in diabetic aortae. The greatly diminished effect of serotonin may be a sensitive tool to study the nature of diabetes better and to monitor its development.

Animals↗