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PubMed1989

Binding of nonsteroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin.

The binding of racemic warfarin, its enantiomers, and several nonsteroidal anti-inflammatory agents to human serum albumin was investigated by equilibrium dialysis at 4 degrees C in pH 7.4 phosphate buffer. The primary binding constant for the S(-) enantiomer of warfarin was approximately two times greater than the corresponding binding of the R(+) enantiomer. The effect of azapropazone, phenylbutazone, naproxen, ibuprofen, mefenamic acid, and tolmetin on the binding of racemic warfarin and its enantiomers was studied. Warfarin was displaced by all of the nonsteroidal anti-inflammatory agents except tolmetin. Azapropazone caused the largest displacement of warfarin (39 to 46% free warfarin versus 2.5 to 6% free warfarin without competing drug), followed by phenylbutazone (23 to 43% free warfarin), naproxen (9 to 24% free warfarin), mefenamic acid (5 to 11.5% free warfarin), and ibuprofen (5 to 9% free warfarin). Azapropazone and phenylbutazone competed with warfarin for the same primary binding site on the albumin molecule. Naproxen appeared to affect warfarin binding at both primary and secondary sites. Ibuprofen and mefenamic acid interfered with the binding of warfarin at its secondary sites. In contrast to the other drugs studied, tolmetin caused an increase in the primary binding constant of warfarin. Structural analysis indicated that a common feature of those compounds which primarily bind at the warfarin site is a hydrophobic area bearing a widely delocalized negative charge.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1995

Comparison of the effects of fenamates on Ca-activated chloride and potassium currents in rabbit portal vein smooth muscle cells.

1. The perforated patch and conventional whole-cell recording techniques were used to study the action of flufenamic, mefenamic and niflumic acid on calcium-activated chloride and potassium currents in rabbit portal vein smooth muscle cells. 2. In K-conditions at a holding potential of -77 mV flufenamic acid and mefenamic acid decreased the amplitude of spontaneous transient inward currents (STICs, calcium-activated chloride currents, ICl(Ca)) in a concentration-dependent manner. The potency sequence was niflumic > flufenamic > mefenamic acid. 3. At -77 mV 1 x 10(-5) M flufenamic acid increased the STIC exponential decay time constant (tau). At higher concentrations the STIC decay was described by 2 exponentials with an initial decay (tau f) faster than the control tau value and a second exponential (tau s) which had a time constant slower than the control tau value. Low concentrations of mefenamic acid had no effect or decreased the tau value whereas in higher concentrations biphasic currents were recorded. 4. In K-free conditions the inhibitory effect of both flufenamic and mefenamic acid on STIC amplitude was greater at +50 mV compared to -50 mV, showing that the effect of these agents was voltage-dependent. 5. In cells held at 0 mV in K-containing conditions the fenamates reduced both the frequency and amplitude of spontaneous transient outward currents (STOCs, calcium-activated potassium currents, IK(Ca)). The concentration range to produce these effects was higher than that to decrease STIC amplitude and the potency sequence was flufenamic > niflumic > or = mefenamic acid. 6. All these compounds in concentrations greater than 5 x 10(-5) M evoked a 'noisy' potassium current at 0 mV which reached a maximum after approximately 3 min. This current was readily reversible on washout of the drug and could be elicited several times in the same cell. The current-voltage relationship of the fenamate-evoked current exhibited pronounced outward rectification characteristic of IK(Ca). 7. The current evoked by 2 x 10(-4) M flufenamic acid and 5 x 10(-4) M niflumic acid was not affected by 1 x 10(-5) M glibenclamide but was markedly inhibited by 1 x 10(-3) M tetraethylammonium. Furthermore, large currents were activated by flufenamic and niflumic acid in the presence of caffeine and cyclopiazonic acid (an inhibitor of the sarcoplasmic reticulum Ca-ATPase) to deplete intracellular Ca-stores. 8. Conventional whole-cell recording was performed with pipette solutions in which the ability to buffer changes in intracellular calcium was varied by altering the concentration of the calcium chelator (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA). Flufenamic acid (2 x 10(-4) M) and niflumic acid (5 x 10(-4) M) both evoked large outward currents when recordings were made with either 1 x 10(-4) M or 1 x 10(-2) M BAPTA. Furthermore, bathing the cells in nominally calcium-free extracellular solution did not reduce the amplitude of the evoked currents. 9. It is concluded that both flufenamic and mefenamic acid inhibit ICl(Ca) by a mechanism similar to niflumic acid, possibly open channel blockade. Furthermore, at concentrations greater than 5 x 10(-5) M all three fenamates inhibited STOC activity and evoked directly an outward current which resembled IK(Ca).

Animals↗

PubMed1995

Calcium-and G-protein-related spasmolytic effects of nonsteroidal anti-inflammatory drugs on rat uterus contractions in vitro.

The effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) acetylsalicylic acid, metamizole, phenylbutazone, indometacin, piroxicam, naproxen, tolmetin, diclofenac, and mefenamic acid on methacholine (10 mumol/l), prostaglandin F2 alpha (1 mumol/l), and KCl (60 mmol/l) induced contractions of isolated rat uterus were assayed. All of these cause a concentration-dependent inhibition of methacholine and prostaglandin F2 alpha-induced contractions with the exception of acetylsalicylic acid, metamizole, and naproxen. All except acetylsalicylic acid and metamizole relaxed in a concentration-dependent manner the tonic contractions induced by KCl. CaCl2 (0.1-10 mmol/l) totally counteracted the relaxant effects of naproxen and tolmetin, but not those of the other NSAIDs. Bay K8644 did not revert the effect of the NSAIDs. Pertussis toxin (50 micrograms/l) did not modify the effect of indometacin, mefenamic acid, and tolmetin, but partially antagonized the effects of diclofenac and naproxen and increased the effect of phenylbutazone and piroxicam. These results suggest that some of the NSAIDs assayed induce smooth muscle relaxation by mechanisms independent of prostaglandin synthesis inhibition, but related to the inhibition of extracellular calcium influx through mechanisms related or unrelated to pertussis toxin sensible G proteins.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1979

Drug therapy reviews: antirheumatic agents.

The pathophysiology, symptoms and drug treatment of rheumatic disease are reviewed. Antirheumatic drugs reviewed are salicylates (including aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate, salsalate), phenylpropionic acid derivatives (fenoprofen, ibuprofen, naproxen), indole derivatives (sulindac, tolmetin and indomethacin), pyrazolone derivatives (phenylbutazone, oxyphenbutazone), gold compounds, penicillamine, antimalarials mefenamic acid, corticosteroids and immunosuppressives. Simple analgesic therapy (acetaminophen, aspirin, propoxyphene) is used in the early stage of the disease. As the disease progresses, aspirin remains the drug of choice for antiinflammatory activity but the phenylpropionic acid or indole derivatives may be preferred in patients unable to tolerate salicylates. If such nonsteroidal antiinflammatory agents are not effective, parenteral therapy with gold compounds or oral penicillamine usually is indicated. Indomethacin or phenylbutazone, then antimalarials, are resorted to next. Corticosteroids or immunosuppressives are reserved for patients who are unsuccessfully controlled or who have major side effects with the other drugs. Mefenamic acid occupies a very secondary place in rheumatoid arthritis treatment.

Anti-Inflammatory Agents↗

PubMed1981

[Significance of prostaglandins (PGs) in ovulation (author's transl)].

In order to investigate involvement of prostaglandins (PGs) in ovulation, it was examined whether inhibitors of cyclooxygenase, such as indomethacin and mefenamic acid, and the antiserum to cyclooxygenase were able to inhibit superovulation in immature female rats and gilts. Indomethacin and mefenamic acid were dose-dependently effective in inhibition of superovulation in the two animals. The antiserum to cyclooxygenase was raised in rabbits using the solubilized cyclooxygenase extracted and purified from bovine seminal vesicle as antigen. The in vivo administration of the antiserum inhibited superovulation in female rats dose-dependently at the doses of 0.1, 0.2 and 0.4 ml but did not influence production of progesterone. Inhibition of cyclooxygenase in the follicular cells by the antiserum with no effect on steroidogenesis was observed in organ culture of the follicles excised from the rats primed with PMS and the antiserum. On the contrary, no inhibition of cyclooxygenase was detected in case of the addition of the antiserum to the culture medium. The present study showed PG is one of the indispensable factors in ovulation as steroids are.

Animals↗

PubMed1994

Cyclooxygenase inhibitors depress norepinephrine constriction of rat abdominal, but not thoracic, aorta.

Experiments were done on aortic rings (thoracic and abdominal) from young and retired breeder Lewis and Sprague-Dawley male rats. Constriction responses to norepinephrine, 5-hydroxytryptamine (5-HT), and prostaglandin F2 alpha, were done +/- the cyclooxygenase blockers, indomethacin or mefenamic acid. Indomethacin significantly depressed norepinephrine constriction in abdominal (but not thoracic) aorta of all groups. In additional studies of abdominal aorta from Lewis retired breeders, indomethacin and mefenamic acid depressed norepinephrine (but not 5-HT or prostaglandin F2 alpha) construction. Furthermore, indomethacin depressed norepinephrine constriction in vessels denuded of endothelial cells. The thromboxane receptor antagonist SQ 29548 did not alter norepinephrine constriction. Thus, in rat abdominal aorta, norepinephrine constriction is mediated by a constrictor prostanoid of vascular smooth muscle origin that is not thromboxane A2.

Adrenergic alpha-Antagonists↗

PubMed1986

Measured menstrual blood loss in women with menorrhagia associated with pelvic disease or coagulation disorder.

Fifty-five women with a convincing clinical history of menorrhagia associated with recognizable pelvic disease (40 women) or a confirmed coagulation disorder (15 women) were studied through one or more cycles with measurements of menstrual blood loss volume by a modified alkaline hematin method. Women with leiomyomata almost always exhibited large volumes of menstrual bleeding, which was invariably reduced by myomectomy and sometimes helped by mefenamic acid. Women with other pelvic disease such as endometriosis, adenomyosis, and myometrial hyperplasia also often exhibited genuine menorrhagia that responded to mefenamic acid, whereas others were found to have normal blood loss even when the history was convincing. Some women with coagulation disorders due to platelet dysfunction exhibited gross menorrhagia but others had blood loss within normal limits.

Blood Coagulation Disorders↗

PubMed1985

Effect of inhibition of prostaglandin synthesis on cervical softening and uterine activity during ovine parturition resulting from progesterone withdrawal induced by epostane.

The effects of an inhibitor of 3 beta-hydroxysteroid dehydrogenase (epostane) on uterine activity and cervical softening have been studied in eight sheep during late pregnancy. Treatment with epostane led to a rapid decline in the concentration of progesterone measured in utero-ovarian venous plasma, to less than 10% of the pretreatment value within 30 min of bolus injection. This was followed by a significant (P less than 0.02) increase in the concentrations of metabolites of prostaglandins E and F in utero-ovarian venous plasma and uterine activity similar to that seen in the final stages of normal labour. Measurements of cervical tissue extensibility made ex vivo showed the cervix to have softened considerably. These changes occurred without any significant change in the concentration of oestradiol-17 beta in utero-ovarian venous plasma. Infusion of mefenamic acid, an inhibitor of prostaglandin synthesis, prevented the changes in uterine activity and cervical softening that occurred after injection of epostane alone. Mefenamic acid also reduced the increase in concentrations of metabolites of prostaglandins E and F in plasma, although the concentration of progesterone in these animals showed the same abrupt fall which occurred in sheep after injection of epostane alone. These results suggest that progesterone withdrawal, in the absence of any subsequent rise in circulating oestrogen concentrations, is sufficient stimulus to induce cervical softening in the ewe. Cervical softening following progesterone withdrawal can be prevented by inhibition of prostaglandin synthesis.

3-Hydroxysteroid Dehydrogenases↗

PubMed1987

Endometrial prostaglandins and menorrhagia: influence of a prostaglandin synthetase inhibitor in vivo.

Prostaglandin levels in the human endometrium were determined on day 2 of the menstrual cycle in eumenorrheic subjects and in patients with menorrhagia, dysmenorrhea, or both. Menorrhagic subjects had significantly higher levels of endometrial prostaglandins of the E and F series when compared with eumenorrheics. Prostaglandin E levels were markedly higher than prostaglandin F. In 10 menorrhagic subjects who completed a double-blind clinical study on the effectiveness of mefenamic acid in lowering menstrual blood loss, 9 exhibited statistically significant reduction in endometrial prostaglandin levels. A decrease in menstrual blood loss was also noted during mefenamic acid treatment in these patients. These findings are consistent with the concept that abnormally high uterine prostaglandin levels may be an important etiologic factor in menorrhagia and support the notion that one of the mechanisms of action of nonsteroidal anti-inflammatory agents in the treatment of this menstrual disorder is inhibition of endometrial prostaglandin production.

Adult↗

PubMed1983

Influence of certain prostaglandin synthetase inhibitors on cytoplasmic estrogen receptors in the uterus.

Prostaglandin synthetase inhibitors are widely used in the treatment of primary dysmenorrhea. They are thought to act by inhibiting endometrial synthesis of prostaglandins and subsequently altering endometrial receptor concentration. Since prostaglandins are known to vary with the menstrual cycle in women, implicating an effect associated with sex steroid hormones, we examined the influence of certain prostaglandin synthetase inhibitors on specific estrogen binding capacity of uteri from rats. Ibuprofen (Motrin), 25 mg/kg, indomethacin (Indocin), 15 mg/kg, mefenamic acid (Ponstel), 25 mg/kg, and sulindac (Clinoril), 40 mg/kg, were evaluated at 6 and 24 hours after injection. Specific estrogen-binding capacity was elevated twofold by mefenamic acid; the other agents showed no statistically significant effect. No alteration in the dissociation constant values of the estrogen receptors was observed with these agents. These data suggest that prostaglandin synthetase inhibitors do not influence the estrogen response mechanism in rodents.

Animals↗

PubMed1989

Effect of centrally administered prostaglandin D2 and some prostaglandin synthesis inhibitors on carrageenan-induced paw oedema in rats.

The putative modulatory role of central prostaglandins (PGs) on peripheral inflammation has been explored by investigating the effects of intracerebroventricularly (i.c.v.) administered PGD2, the major rodent brain PG, hydrocortisone, a phospholipase A2 inhibitor, and the cyclo-oxygenase inhibitors, paracetamol and mefenamic acid, on carrageenan-induced paw inflammation in rats. PGD2 produced a dose-related inflammation-augmenting effect, whereas hydrocortisone and the PG synthesis inhibitors, paracetamol and mefenamic acid, induced attenuation of the peripheral oedema. These findings confirm an earlier report from this laboratory which had indicated that central PGs may modulate peripheral inflammation and that conventional anti-inflammatory agents exert at least part of their effect by inhibiting central PG synthesis.

Acetaminophen↗

PubMed1996

Role of prostaglandins and nitric oxide on halothane-induced arteriolar dilatation in rat diaphragm.

The effects of anaesthetics on the microcirculation of the diaphragm are incompletely understood. Therefore, we assessed by in vivo intravital microscopy in rats the action of halothane on diaphragmatic arteriolar diameter and the role of nitric oxide and prostaglandins on halothane-induced diaphragmatic arteriolar diameter. We studied 54 rats anaesthetized with thiopentone. Dose-response curves to topically applied Krebs' solution saturated with halothane at increasing concentrations of 0%, 1%, 3% and 5% were carried out in the presence of an inhibitor of nitric oxide synthesis (N omega-nitro-L-arginine (LNA), 300 mumol litre-1) or inhibitors of prostaglandin synthesis (mefenamic acid 20 mumol litre-1 or indomethacin 20 mol litre-1) or in the absence of any inhibitor. We found dose-dependent arteriolar dilatation which was abolished by mefenamic acid and indomethacin. In contrast, the effect of halothane was not modified by LNA. These data demonstrated that halothane-induced arteriolar dilatation in the diaphragm of the rat was mediated by prostaglandins but not by nitric oxide.

Anesthetics, Inhalation↗

PubMed2000

Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum.

1. Resveratrol, a polyphenolic compound present in grapes and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. It is present in the diet, and the hepatic and duodenal sulphation might limit the bioavailability of this compound. The aim was to study the sulphation of resveratrol in the human liver and duodenum. 2. A simple and reproducible radiometric assay for resveratrol sulphation was developed. It employed 3'-phosphoadenosine-5'-phosphosulphate-[35S] as the sulphate donor and the rates of resveratrol sulphation (mean +/- SD, pmol/min/mg cytosolic protein) were 90 +/- 21 (liver, n = 10) and 74 +/- 60 (duodenum, n = 10, p = 0.082). 3. Resveratrol sulphotransferase followed Michaelis-Menten kinetics and Km (mean +/- SD; microM) was 0.63 +/- 0.03 (liver, n = 5) and 0.50 +/- 0.26 (duodenum, n = 5, p = 0.39) and Vmax (mean +/- SD, pmol/min/mg cytosolic protein) were 125 +/- 31 (liver, n = 5) and 129 +/- 85 (duodenum, n = 5, p = 0.62). 4. Resveratrol sulphation was inhibited by the flavonoid quercetin, by mefenamic acid and salicylic acid, two commonly used non-steroidal anti-inflammatory drugs. IC50 of resveratrol sulphation for quercetin was 12 +/- 2 pM (liver) and 15 +/- 2 pM (duodenum), those for mefenamic acid were 24 +/- 3 nM (liver) and 11 +/- 0.6 nM (duodenum), and those for salicylic acid were 53 +/- 9 microM (liver) and 66 +/- 4 microM (duodenum). 5. The potent inhibition of resveratrol sulphation by quercetin, a flavonoid present in wine, fruits and vegetables, suggests that compounds present in the diet may inhibit the sulphation of resveratrol, thus improving its bioavailability.

Adult↗

PubMed2002

Bioactivity studies on beta-sitosterol and its glucoside.

Beta-sitosterol and beta-sitosteryl-beta-D-glucoside were isolated as analgesic constituents from the leaves of Mentha cordifolia Opiz. The acetic acid-induced writhing test showed that beta-sitosterol and beta-sitosteryl-beta-D-glucoside decreased the number of squirms induced by acetic acid by 70.0% and 73.0%, respectively, at a dose of 100 mg / kg mouse. Statistical analysis using the Kruskall Wallis one-way analysis of variance by ranks showed that these isolates approximate the analgesic activity of mefenamic acid at a 0.001 level of significance. The hot plate method confirmed their analgesic activities, as beta-sitosterol and beta-sitosteryl-beta-D-glucoside exhibited a 300% and 157% increase in pain tolerance, respectively, while mefenamic acid, a known analgesic, showed a 171% increase. Neither isolate exhibited antiinflammatory activity using the carrageenan-induced mouse paw oedema assay. Beta-sitosterol also exhibited anthelminthic and antimutagenic activities. In vitro tests using live Ascaris suum as test animals showed that the behaviour of worms treated with beta-sitosterol approximated that of the positive controls, Combantrin and Antiox. An in vivo micronucleus test showed that beta-sitosterol inhibited the mutagenicity of tetracycline by 65.3% at a dose of 0.5 mg /kg mouse. At the same dose, it did not exhibit chromosome-breaking activity.

Acetic Acid↗

PubMed1982

An early mitosis-determining event in regenerating rat liver and its possible mediation by prostaglandins or thromboxane.

Inhibitors of prostaglandin and thromboxane production such as mefenamic acid, hydrocortisone, and dexamethasone prevented a large proportion of the parenchymal cells of rat liver, proliferatively activated by a two-thirds partial hepatectomy, from entering mitosis without preventing them from initiating or completing DNA synthesis. This specific mitosis-inhibiting action was maximum when the drugs were present during the first few hours after partial hepatectomy. In contrast, indomethacin, another inhibitor of prostaglandin and thromboxane production, maximally inhibited both DNA synthetic and mitotic activities when present during the same early period of prereplicative development, which showed that it had an action not shared by the other inhibitors. Arachidonic acid completely reversed the hydrocortisone- or dexamethasone-induced inhibition of mitotic activity, but it did so only when it was injected between 2 and 3 hours after partial hepatectomy and glucocorticoid injection. Arachidonate's reversal of the hydrocortisone-induced inhibition did not occur in the presence of mefenamic acid. These observations indicate that there is an early, prostaglandin- or thromboxane-mediated, prereplicative process in proliferatively activated hepatocytes which determines their later entry into mitosis and which is separate from the early events leading to DNA synthesis.

Animals↗

PubMed2003

Effectiveness and mechanism of action of desmopressin in the treatment of copper intrauterine device-related menorrhagia: a pilot study.

BACKGROUND: Desmopressin, a synthetic analogue of the natural hormone vasopressin, stimulates endogenous haemostasis and exerts a powerful myometrial and vasoconstrictor action in a variety of pharmacological preparations. Both mechanisms of action may have therapeutic value for the treatment of intrauterine device (IUD)-related menorrhagia, which is believed to be caused not only by altered local haemostasis but also-according to a new hypothesis-by decreased vascular uterine resistance. The aim of this prospective study was to evaluate the effect of vasopressin drug on menstrual blood loss and on changes, if any, in uterine flow impedance. Mefenamic acid, which is commonly used to treat IUD-related menorrhagia, was administered as a comparison. METHODS: Twenty-four women with IUD-induced menorrhagia were recruited and randomly allocated to treatment with either desmopressin or mefenamic acid. Menstrual blood loss (measured by pictorial blood loss assessment chart) and uterine artery resistance (measured with transvaginal colour Doppler) performed in two pretreatment periods were compared with 3-month treatment periods. RESULTS: Menstrual blood loss was significantly reduced in both treatment groups. In the desmopressin group, the effect was clinically useful in all subjects, but in the mefenamic group menstrual blood loss was consistently menorrhagic in two patients. No significant differences were observed in the uterine artery pulsatility index before and during treatment. CONCLUSIONS: Desmopressin may be a useful therapeutic tool for many women with IUD-related menorrhagia. Its mechanism of action lies in an ability to enhance local haemostasis, without affecting uterine blood flow.

Adult↗

PubMed1988

The influence of extracellular calcium on microvascular tone in the rat cremaster muscle.

In vivo responses of arterioles and venules to changes in bath calcium concentrations were observed in the cremaster muscle of male Sprague-Dawley rats. Small arterioles (2A, 3A) initially exposed to a solution containing calcium (2.55 mM) significantly dilated in response to a 0-calcium bath. Reexposure to calcium (greater than 0.65 mM) caused 2A and 3A arterioles to constrict to diameters similar to the initial control values. In contrast, large arterioles (1A) and all venules (1V, 2V, 3V) were unresponsive to exposure to a 0-calcium solution or to reexposure to calcium (0.65-5.10 mM). Treatment with mefenamic acid (10 micrograms/ml), a prostaglandin synthesis inhibitor, produced marked constriction of arterioles but not of venules, suggesting the involvement of endogenous vasodilator prostaglandins in the regulation of resting diameters of arterioles. In the presence of mefenamic acid, 1A arterioles dilated when exposed to a 0-calcium solution and constricted back to control diameters following reintroduction of calcium into the bath. These data demonstrate heterogeneity in the responsiveness of cremasteric microvessels to changes in extracellular calcium. The small arterioles were most responsive to calcium. The lack of response by the largest arterioles appears to be due to the dilator influences of endogenous prostaglandins.

Animals↗

PubMed1982

Intrauterine pressure changes during dysmenorrhea therapy.

The treatment of primary spasmodic dysmenorrhea with prostaglandin synthetase/receptor site inhibitors such as mefenamic acid (Ponstel) is becoming accepted. Recent improvements in intrauterine pressure recording have made the acquisition of reliable, physiologic data possible. These data have been used to provide objective evaluation of the effectiveness of drug therapy as part of a larger subjective investigation. Analysis of these data shows that mefenamic aid causes rapid, dramatic reductions in parameters of uterine pressure and work. Complete loss of uterine contractile activity was found in 46.2% of patients. Subjective relief was obtained in all patients receiving mefenamic acid in this sample.

Cyclooxygenase Inhibitors↗