Photolytic decomposition of N-(2, 6-dichloro-m-tolyl) anthranilic acid (meclofenamic acid).
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Anti-Inflammatory Agents↗
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Furosemide, fenclofenac, diclofenac, mefenamic acid and meclofenamic acid inhibit specific T3 binding in isolated rat hepatic nuclei.
Previous studies with phenytoin (DPH) show that this inhibitor of thyroid hormone binding to plasma proteins also interacts with specific nuclear T3 binding sites. In order to further define the nuclear effects of drugs that inhibit plasma protein binding of thyroid hormones, we assessed furosemide and a number of non-steroidal antiinflammatory drugs using isolated rat liver nuclei. The effects were compared with those of DPH, ipodate and amiodarone. The T3 binding site in isolated nuclei (Ka 1.2 X 10(9)M-1) showed relative affinity triac approximately equal to T3 greater than T4. Drugs were studied over the concentration range 10(-3)-10(-7)M, approximating the known therapeutic total plasma concentrations, in competition with 125I-T3 0.1 nM, expressing inhibition as the percent decrement from maximum specific binding of 125I-T3 in drug vehicle (assay buffer or thanol 1-10%). Specific T3 binding was inhibited by furosemide to 78.8 +/- 3.5% at 2 mM, by fenclofenac to 37.6 +/- 2.8% at 1 mM, by meclofenamic acid to 70.2 +/- 2.4% at 0.1 mM, by mefenamic acid to 60.6 +/- 4.6% at 0.05 mM (each p less than 0.02) and by diclofenac to 87.4 +/- 5.6% at 0.2 mM (p less than 0.05). In comparison, DPH inhibited T3 binding to only 88.1 +/- 0.6% at 0.3 mM, as did calcium ipodate (68 +/- 3.5% at 1 mM, p less than 0.02). Amiodarone (0.3 mM), sodium salicylate (1 mM) and phenylbutazone (0.1 mM) were inactive. In order to achieve a level of nuclear receptor occupancy that approaches in vivo occupancy, the concentration 125I-T3 was increased over the range 0.1-0.5 nM.2+t
Amiodarone↗
Study of the mechanisms of action of sodium meclofenamic acid (Meclomen) a "double inhibitor" of the arachidonic acid cascade.
Meclofenamic acid sodium (Meclomen) was found to inhibit both the cyclooxygenase and the lipoxygenase pathways of arachidonic acid metabolism. It inhibited both 5-lipoxygenase and 15-lipoxygenase activities. Meclomen was also shown to interfere with leukotriene receptors or possibly post-receptor mechanisms. In isolated lung parenchyma strip preparations Meclomen inhibited leukotriene C4 and D4 induced contractions, but had no effect on histamine induced contractions. Ibuprofen, naproxen and indomethacin had no effect on lipoxygenases or on leukotriene receptors but were powerful inhibitors of cyclooxygenases.
Animals↗
Development and in-vitro evaluation of sustained-release meclofenamic acid microspheres.
Meclofenamic acid (MFA) sustained-release microspheres were prepared by the solvent evaporation method using cellulose propionate (CP) polymer and acetone as the polymer solvent. Polyethylene glycol (PEG) was used as a channelling agent to improve the release properties of MFA at 1:2:1 drug to polymer to PEG ratio. The microspheres prepared at three different speeds (600, 800 and 1000 rpm) were characterized with regard to their surface morphology, average drug content, particle size distribution and release profiles in phosphate buffer, pH 8.0 at 37 degrees C. The microspheres were stored under accelerated conditions for 3 months and the effect of storage on the different characteristics was studied. Spherical particles with essentially smooth surface and few residual drug crystals on the surface were formed. Smaller particles were formed at higher agitation speeds. The release rate of MFA from these microspheres was not affected by the molecular weight of CP polymer. PEG 2000 was found to have a more enhancing effect on the rate of the release than PEG 4000. The physical properties of the microspheres and their release characteristics were not altered by storing the product at 40 degrees C/80% relative humidity (R.H.) for 3 months.
Anti-Inflammatory Agents, Non-Steroidal↗
The pharmacokinetics of meclofenamic acid in the horse.
The pharmacokinetics of meclofenamic acid were studied in Thoroughbred horses and in ponies. After intravenous (i.v.) administration of either 2 mg/kg or 4 mg/kg sodium meclofenamate the elimination half-life was of the order of 0.9 h while the volume of distribution was found to be 0.128 litre/kg. Elimination was in accordance with a one-compartment model. Following oral administration of either meclofenamic acid (4 mg/kg) or sodium meclofenamate (4 mg/kg) a much longer terminal half-life than that calculated for Kel from i.v. data was found. This anomaly indicated that the 'flip-flop' phenomenon was present, i.e. Ka exceeded Kel. More rapid and higher peak levels occurred following sodium meclofenamate than meclofenamic acid, although total bioavailability was similar. Studies in ponies with meclofenamic acid showed a lower absorption than that found in Thoroughbreds. Overnight fasting before meclofenamic acid administration did not alter the rate or extent of absorption. Intramuscular administration of sodium meclofenamate resulted in low plasma concentrations and after 25 h only 46% of the drug had been absorbed.
Administration, Oral↗
Use of meclofenamic acid in gynecology and obstetrics: effects on postsurgical stress.
Meclofenamic acid has been successfully used in several obstetrical and gynecological disorders sustained by a prostaglandin overproduction. A brief review of meclofenamic acid use for primary dysmenorrhea, menorrhagia, and episiotomy pain is followed by an original study of this compound in postsurgical pain and stress. Thirty gynecological patients undergoing abdominal hysterectomy and 10 pregnant women submitted to cesarean section at term were considered. In gynecological patients, meclofenamic acid suppositories (200 mg) or placebo were given every 12 h during the immediate postsurgical period; pregnant women were given the active drug only. Subjective pain was evaluated [through visual analogue scale (VAS)] in basal conditions (2 h from the end of surgery) and 2, 4, 6, 24, and 28 h from the first drug dose. At the same time, blood was drawn for the evaluation of plasma cortical levels (through coated-tube radioimmunoassay). A significant pain relief was obtained after only 4 h posttreatment both in gynecological patients and pregnant women. Meclofenamic acid was superior to placebo from 6 h after treatment and it almost suppressed subjective pain at the end of the observation period (28th h). Cortisol levels were already high at the basal evaluation and showed a further increase during the first postsurgery hours. Patients treated with meclofenamic acid had cortisol values lower than those who were treated with placebo. The former recovered normal levels after 24 h, whereas the latter already had increased values. These data demonstrate that meclofenamic acid is a safe, powerful and specific analgesic for the postsurgical period. The reduction of pain stimulation is also accompanied by a reduced activation of the neuroendocrine axis with a prompt recovery from postsurgical stress.
Adult↗
Effects of meclofenamic acid in the treatment of lesions deriving from minor traumatology.
The clinical efficacy and tolerability of topical 5% meclofenamic acid gel versus placebo and oral sodium meclofenamate versus sodium naproxen were evaluated in patients affected with minor traumatologies. Ninety patients were studied: 60 were treated with either meclofenamic acid gel or placebo for 10 days, and 30 were administered with either sodium meclofenamate capsules or sodium naproxen capsules for 7 days. The 5% meclofenamic acid gel and its sodium salt in capsules proved significantly more rapid and efficient than did the reference compounds in reducing pain symptomatology. In the patients treated with 5% meclofenamic acid gel, a greater effect was seen as regards rapidity of spontaneous movement and nocturnal pain reduction. In other variables examined, that is, surface and deep hyperalgesia, and swelling and functional restriction, there was also a significantly higher efficacy than with placebo. Confirmation of the therapeutic efficacy of meclofenamic acid (sodium salt) was obtained with the capsule formulation, that was seen to exert a significant analgesic and antiphlogistic action; the onset of this action was particularly rapid. Both formulations of meclofenamic acid (gel and capsules) were found to be well tolerated. Thus, in the examined formulations, meclofenamic acid proved to be a useful tool in the treatment of lesions in the minor traumatology category.
Administration, Oral↗
[A comparative evaluation of the remission from acute lumbar-sciatic pain following treatment with meclofenamic acid and naproxen].
This study was performed to assess the analgesic effect and the onset of action of meclofenamic acid compared with naproxene in patients affected by acute lumbar-sciatic pain. Thirty patients of both sexes were randomly allocated to 2 groups of 15 patients each; the first group was treated with meclofenamic acid (200 mg b.i.d.) and the second with naproxene (500 mg b.i.d.). Both drugs were administered as suppositories for a week. The intensity of pain, both at rest and after movement, was assessed by means of analogic scales at basal time and 15, 30, 60, 180, 360 minutes, 4 and 8 days after the first administration. Both types of pain were significantly decreased with respect to basal values in meclofenamic acid group (P < 0.01), 60 minutes after onset of treatment, while in the naproxene group the effect was later. Moreover the analgesic effect was significantly greater in the meclofenamic acid group with respect to the naproxene group, after 15 minutes for pain at rest (P < 0.05) and after 30 minutes for pain after movement (P < 0.02). Similarly, after 4 and 8 days, both types of pain improved to a larger extent in the meclofenamic acid group with respect to the naproxene group (P < 0.05 after four days and P < 0.01 after eight days). This study has shown that meclofenamic acid has greater efficacy and faster analgesic effect than naproxene. Meclofenamic acid has proved to be a drug of choice in the treatment of slight to moderate musculo-skeletal pain syndromes.
Acute Disease↗
Prostaglandin biosynthesis in rabbit kidney medulla: inhibition in-vitro vs. in-vivo by aspirin, indomethacin and meclofenamic acid.
The non-steroidal anti-inflammatory drugs aspirin, indomethacin and meclofenamic acid were compared for their potency and duration of inhibition of prostaglandin biosynthesis in rabbit kidney medulla. Indomethacin and meclofenamic acid showed equal potency of inhibition in-vitro (IC50 0.88 micron and 0.85 micron respectively) while aspiring was a much weaker inhibitor (IC50 120 micron). In-vivo, indomethacin was the most powerful inhibitor (ID50 0.034 mg/kg) followed by meclofenamic acid (0.45 mg/kg) and aspirin (2.35 mg/kg). Studies on the duration of in-vivo inhibition by these compounds showed the effect of indomethacin and meclofenamic acid to be completely reversed within 4-6 hours. In contrast, return of kidney prostaglandin biosynthetic activity following aspirin inhibition is very slow and significant inhibition is still present 48 hours after a single aspiring injection. The inhibitory effect of aspirin in-vivo could be blocked by pretreatment with indomethacin, indicating that both drugs interact with related sites on the cyclo-oxygenase enzyme. The irreversible inhibition of the cyclo-oxygenase by aspirin as demonstrated in studies of other investigators suggests that the return of kidney prostaglandin synthetase activity after aspirin inhibition represents synthesis of new cyclo-oxygenase protein.
Animals↗
Comparison of the kinetics of sodium meclofenamate versus meclofenamic acid after oral administration to sheep.
Meclofenamates are non-steroidal anti-inflammatory agents used in ruminants for the prevention and the treatment of anaphylactic processes. The objective of the present work was to study possible kinetic variations due to the chemical form of meclofenamates administered by the oral route to adult sheep. Six Rubia del Molar female sheep (2-3 years old, 47-57 kg) were used. Initially, an intravenous administration of sodium meclofenamate (2.2 mg/kg bwt) was given; the obtained kinetic results were in agreement with data from other authors. Oral administrations (20 mg/kg bwt) of sodium meclofenamate and meclofenamic acid were then given. When the reticular groove was opened, both drug forms showed a single meclofenamate plasma peak; t2max were 60.0 +/- 10.61 min and 127.50 +/- 22.5 min for the sodium and acid form, respectively. The elimination rate constants (beta) were not significantly different, but the absorption half-lives were (14.69 +/- 3.21 min for the sodium form and 61.07 +/- 21.7 min for the acid form). The bioavailability was 48.6 +/- 4.3% for sodium meclofenamate and 65.1 +/- 2.8% for meclofenamic acid. Thus, the chemical form (sodium versus acid) alters the oral bioavailability and tmax of meclofenamates in adult sheep. These findings agree with the behaviour of meclofenamates in man.
Administration, Oral↗
Inhibition of hKv2.1, a major human neuronal voltage-gated K+ channel, by meclofenamic acid.
Using the standard patch clamp whole cell recording method, we assessed the pharmacological activity of four fenamate nonsteroidal anti-inflammatory drugs, meclofenamic acid, flufenamic acid, mefenamic acid and niflumic acid, on hKv2.1, a major human neuronal voltage-gated potassium channel stably expressed heterologously in Chinese hamster ovary cells. Meclofenamic acid inhibited hKv2.1 in a concentration-dependent manner whereas the other three fenamates had weaker or no effect on these channels at a concentration of 100 microM. The estimated IC50 of meclofenamic acid was 56.0 microM for hKv2.1 compared an IC50 of 155.9 microM for another human neuronal K channel (hKv1.1). Meclofenamic acid reached its maximum inhibition within 5 min of bath application and its effect was readily reversed upon wash. Kinetic analysis revealed that this drug did not alter the channel activation or deactivation time courses. Moreover, the effect of meclofenamic acid on hKv2.1 channels was not voltage-dependent. Indomethacin, another inhibitor of the cyclooxygenase that catalyses the synthesis of prostaglandin from arachidonic acid, had no effect on either hKv2.1 or hKv1.1. These results indicate that meclofenamic acid inhibits hKv2.1 more potently than hKv1.1 and it is likely that this compound acts directly on the channel proteins.
Animals↗
Influence of meclofenamic acid on the initiation of parturition and lactation in the sow.
The effect of inhibition of prostaglandin (PG) synthesis on the initiation of parturition was studied in 4 groups of 16 sows each. Oral administration of meclofenamic acid (5.0 mg/kg body weight/day) on Days 112, 113 and 114 of pregnancy significantly delayed parturition compared to controls (P less than 0.001). Exogenous PGF-2 alpha after meclofenamic acid treatment synchronized parturition 20.4 +/- 1 h later. Functional luteolysis as indicated by a decline in maternal progesterone levels began during meclofenamic acid treatment; the fall in progesterone was then arrested in sows treated only with meclofenamic acid. Meclofenamic acid treatment in late pregnancy modified the normal initiation of lactation, as indicated by the high concentration of lactose and low concentrations of protein and Na+ in colostrum in treated sows compared to controls. We suggest that PG synthesis is required for the initiation of parturition in the sow and that luteal regression may involve two stages: the first which may be independent of prostaglandin, and the second, dependent on prostaglandin.
Animals↗
Use of meclofenamic acid to investigate the role of prostaglandin biosynthesis during induced parturition in sheep.
The maternal administration of meclofenamic acid (a prostaglandin synthetase inhibitor) to pregnant sheep prevented the dexamethasone-induced delivery of live lambs and delayed delivery after foetal death in utero. Administration of meclofenamic acid had no effect on the changes in the levels of progesterone and oestrogen in the plasma which occur before lambing in response to foetal glucocorticoid. Despite normal maternal endocrine changes, increased uterine activity did not occur at the expected time, although it could be elicited by vaginal distension or by administration of oxytocin. The rates of cervical ripening and dilatation were reduced by meclofenamic acid and lambing was frequently associated with some degree of cervical dystocia. Withdrawal of meclofenamic acid did not immediately result in an increase in the level of prostaglandin F in the plasma despite the appearance of co-ordinated uterine contractions; the concentration of prostaglandin in the plasma was not raised until vaginal passage of the lambs. It is concluded that the synthesis or release of prostaglandins mediates the effects of changes in the levels of steroids in the maternal plasma on uterine contractility in sheep.
Animals↗
Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties.
The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel alpha subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC(50) = 25 microM) and diclofenac (EC(50) = 2.6 microM) resulted in the activation of KCNQ2/Q3 K(+) currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 and -15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel alpha subunits. In contrast, they did not enhance KCNQ1 K(+) currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED(50) = 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.
Action Potentials↗
Meclofenamic acid for inhibition of human vascular smooth muscle cell proliferation and migration: an in vitro study.
PURPOSE: The aim of the study was to examine the effects of meclofenamic acid on proliferation, clonogenic activity, migratory ability, cell cycle distribution and p44/42 MAPK (mitogen activated protein kinase) expression in serum-stimulated human aortic smooth muscle cells (haSMCs). METHODS: haSMCs were treated with meclofenamic acid in three different concentrations (10 mM, 100 mM, 200 mM) for 4 days. Then meclofenamic acid-free culture medium was supplemented until day 20. Growth kinetics were assessed. Cell cycle analysis was performed by flow cytometry. Clonogenic activity was evaluated with colony formation assays. Migratory ability was investigated by stimulation with platelet-derived growth factor (PDGF-BB) in 24-well plates with 8 mm pores membrane inserts. p44/42 MAPK was detected by Western blot technique. RESULTS: Meclofenamic acid inhibited the proliferation, clonogenic activity and migratory ability of haSMCs in a dose-dependent manner. Cell cycle analysis revealed a G2/M-phase block. The p44/42 MAPK was significantly reduced. CONCLUSION: Meclofenamic acid inhibits the proliferation and migration of haSMCs. If a sufficient dose of meclofenamic acid can be applied systemically or by local drug delivery it could be a valuable substance to prevent restenosis after angioplasty.
Cell Cycle↗
Meclofenamic acid extends donor-recipient asynchrony in equine embryo transfer.
REASONS FOR PERFORMING STUDY: A level of synchrony between embryo and uterine environment is essential for the establishment of pregnancy when performing embryo transfer. The ability to extend the acceptable degree of asynchrony would allow more efficient use of recipient mares. OBJECTIVES: To establish if administration of the prostaglandin synthetase inhibitor, meclofenamic acid, to asynchronous recipient mares could widen the acceptable window of asynchrony for embryo transfer. HYPOTHESIS: The prostaglandin synthetase inhibitory action of meclofenamic acid may act to suppress luteolysis and thereby allow for a greater degree of asynchrony between donor and recipient mares. METHODS: A total of 72 Grade 1 horse embryos were transferred nonsurgically into the uteri of recipient mares that had ovulated 2 (n = 20), 3 (n = 20), 4 (n = 16) or 5 (n = 16) days before the donor. Half of the mares in each group were treated orally with 1 g meclofenamic acid, beginning on Day 9 after ovulation and continuing for 7 days after embryo transfer. RESULTS: Comparison of recipient:donor asynchrony between treated and untreated mares was: +2 days, 9/10 pregnancies vs. 8/10 (P= 1.00); by +3 days, 8/10 vs. 2/10 (P= 0.025); by +4 days, 5/8 vs. 1/8 (P = 0.121); and by +5 days 3/8 vs. 0/8 (P = 0.20). In 10/11 meclofenamic acid-treated and 23/25 untreated recipient mares that failed to become pregnant, luteolysis occurred at the normal time (14-19 days) after ovulation. CONCLUSION: Treatment with meclofenamic acid supported the establishment of pregnancy in recipient mares that ovulated before the donors. However, meclofenamic acid appeared to provide this support in a manner other than by suppression of luteolysis. POTENTIAL RELEVANCE: Pregnancy rates can be increased in recipient mares that ovulate 3 days before the donor by administration of meclofenamic acid.
Animals↗
Studies of meclofenamic acid and two metabolites in horses--pharmacokinetics and effects on exercise tolerance.
The pharmacokinetics and the effects on treadmill exercise of the anti-inflammatory drug meclofenamic acid were studied in seven Standardbred horses after single intravenous and/or oral doses. The decline in plasma concentration after a single intravenous dose of meclofenamic acid (2.2 mg/kg b.wt) was described by a two-compartment open model. The average elimination half-life was 1.4 h, the apparent volume of distribution 0.14 l/kg and the plasma clearance 0.12 l/h kg. Absorption was the rate-limiting step after oral administration. Non-compartmental analysis showed a mean absorption time of 4.3 h. The pharmacokinetics of two metabolites of meclofenamic acid were also studied in two of the horses. The elimination half-lives of the two metabolites were virtually the same in each horse (3.0 h and 3.4 h). The blood lactate response to exercise was significantly decreased after treatment with meclofenamic acid, indicating a lower utilization of the glycolytic ('anaerobic') energy contribution during exercise. Circulatory capacity was apparently unaffected with an unchanged heart rate response to exercise.
Absorption↗
Protein binding and in vitro serum thromboxane B2 inhibition by flunixin meglumine and meclofenamic acid in dog, goat and horse blood.
Flunixin was highly protein bound in the serum of dogs (92.2 per cent), goats (84.8 per cent) and horses (86.9 per cent). Meclofenamic acid was also highly protein bound, although there were larger differences between the extent of the binding in dogs (90.3 per cent), goats (84.7 per cent) and horses (99.8 per cent). Both flunixin and meclofenamic acid were potent inhibitors of the in vitro generation of thromboxane (Tx) B2 in blood. Flunixin inhibited the generation of TxB2 by 50 per cent of the maximum response (IC50) in dog, goat and horse blood at concentrations of 0.10, 0.02 and 0.04 microM respectively and by 100 per cent (Imax) at 2.07, 0.14 and 2.07 microM respectively. The IC50 values of meclofenamic acid in dogs, goats and horses were 0.77, 0.80 and 0.30 microM respectively and the Imax values were 3.93, 3.63 and 3.56 microM respectively. When the concentrations of flunixin were corrected for protein binding, it was estimated that the IC50 of the unbound fractions in dogs, goats and horses were 0.008, 0.003 and 0.005 microM, respectively. Similarly corrected values for meclofenamic acid were 0.075, 0.122 and 0.001 microM respectively.
Animals↗