Pharmacological profile of droxicam

In Studies of anti-inflammatory activity, droxicam has shown itself to be as active as piroxicam and much more active than phenylbutazone, isoxicam and suprofen, both in acute studies such as carrageenin oedema, nystatin oedema and ultraviolet erythema, and in longer-term tests such as that of the cotton pellet. In the studies of anti-arthritic activity, which require long-term treatment, droxicam was as effective as piroxicam, both on primary and on secondary lesions. The study of analgaesic activity, conducted by means of the tests of protective activity against writhing induced by phenylbenzoquinone and acetylcholine bromide in the mouse and by acetic acid in the rat, droxicam activity was superior to that of acetylsalicylic acid, dipyrone, isoxicam and phenylbutazone. Droxicam also showed antipyretic activity in the rat, greater than that of acetylsalicylic acid, dipyrone and 4-aminoantipyrine, in the brewer's yeast and Salmonella typhi tests. Droxicam also acts as an ex vivo platelet aggregation inhibitor in the dog. In the study of inhibition of peritoneal capillary permeability in the mouse, droxicam was considerably more potent than isoxicam or phenylbutazone. Studies of general pharmacology have demonstrated that droxicam, at high doses, has no cardiovascular or respiratory effects, and that neither does it modify behaviour in rats and mice, determined by the Irwin test. Gastrointestinal tolerance of droxicam has been compared with that of piroxicam, and it has been found that droxicam is far better tolerated. The study of induction of gastrointestinal lesions in the rat demonstrated that the gastrolesive potential of droxicam is 10 times inferior to that of piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of droxicam on in vivo prostaglandin synthesis and ex vivo platelet aggregation

Droxicam, similar to piroxicam, inhibits in vivo renal synthesis of PGF2 alpha. This study was performed in rats; droxicam and piroxicam were administered orally at doses of 0.5, 1.2 and 8 mg/kg. Inhibitory activity of the two compounds was similar (40-60%) but showed no dose-effect relationship. Maximum inhibition was obtained with the 1 mg/kg dosage. In dogs droxicam has shown a clear inhibitory effect on arachidonic acid induced ex vivo platelet aggregation. Droxicam was administered orally at a dose of 2 mg/kg. Maximum inhibition (-40%) was achieved 24 hr post-administration and the effect was sustained up to 72 hr (-23%).     

The influence of gastric emptying on droxicam pharmacokinetics

Droxicam is a new nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of gastric emptying rate on droxicam pharmacokinetics has been investigated in eight healthy male volunteers. A single, 20 mg dose was administered p.o. together with 1500 mg of paracetamol. Gastric transit was experimentally modified by administration of propantheline (45 mg, p.o.) or metoclopramide (10 mg, i.v.) simultaneously with the droxicam and the paracetamol. Plasma levels of paracetamol were used as markers of gastric transit. The plasma concentrations of piroxicam, the active substance from droxicam, were determined by a high-performance liquid chromatographic method. The pharmacokinetic parameters of droxicam were: Cmax = 1.03 +/- 0.16 micrograms/mL (mean +/- SD). Tmax = 11.1 +/- 5.7 hr, AUC = 115.7 +/- 29.6 micrograms hr/mL, T 1/2 a = 2.64 +/- 0.72 hr. T 1/2 el = 73.6 +/- 16.7 hr, CL/F = 3.06 +/- 0.80 mL/min and MRT = 111.1 +/- 23.5 hr. Following modification of gastric emptying, only Tmax (droxicam + metoclopramide = 25.0 +/- 10.8 hr and droxicam + propantheline = 20.8 +/- 8.8 hr) underwent significant change (P less than 0.05). These results indicate that absorption rate of droxicam has been modified but bioavailability does not suffer modification in conditions of altered gastric emptying.     

Cross-over study of the bioavailability of a new NSAID (droxicam) versus piroxicam in healthy volunteers following single and multiple dose administration.

Droxicam is a new anti-inflammatory drug which is a pro-drug of piroxicam and possesses delayed absorption kinetics. In this study, the comparative bioavailability of the two compounds was investigated. The study was performed following a cross-over design with single (20 mg) and multiple (20 mg/day for 30 consecutive days) administration in 25 healthy volunteers. The peak plasma concentrations of piroxicam, obtained following administration of droxicam, were lower than those calculated for administration of piroxicam, and the time taken to reach these peak concentrations was increased by approximately 5-7 h. There was no significant difference in either the elimination kinetics of piroxicam or the AUC values found following administration of the two products. Bioavailability of droxicam is equal to that of piroxicam, with a slower rate of absorption.     

The effect of antacid and ranitidine on droxicam pharmacokinetics.

Droxicam is a nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of concomitant administration of antacid or ranitidine on droxicam pharmacokinetics has been investigated. On three separate phases, 15 healthy volunteers received a single oral 20-mg dose of droxicam either alone, with antacid (400 mg aluminum hydroxide + 400 mg magnesium hydroxide, three times/day), or with ranitidine (300 mg, two times/day) for 6 days. Piroxicam, the active substance from droxicam, was quantified by high-performance liquid chromatography. The pharmacokinetic parameters for droxicam given alone were: maximum peak plasma concentration (Cmax) = 1.53 +/- .21 micrograms/mL (mean +/- SD), time to peak concentration (Tmax) = 7.5 +/- 2.1 hr, t1/2a = 1.38 +/- .82 hour, t1/2el = 53.3 +/- 11.9 hr, Cl/F = 2.98 +/- .71 mL/min, volume of distribution (Vd/F) = 13.2 +/- 1.8 L and area under the curve (AUC) = 117.6 +/- 26.8 micrograms/hour/mL. The subject effect was significant for all the pharmacokinetic parameters except for the absorption half-life (P < .05). Concomitant antacid or ranitidine administration had no significant effect on any of the droxicam pharmacokinetic parameters. The results of this study suggest that antacid or ranitidine do not significantly alter the oral absorption or pharmacokinetic disposition of single-dose droxicam.     

Effect of a non-steroidal anti-inflammatory agent, tolmetin sodium on exudative inflammation in experimental animals (author's transl)

Effect of tolmetin sodium(Tol) on acute and subacute exudative inflammation was tested in experimental animals. Tol had a potent inhibitory activity (ED50 = 0.75 mg/kg, p.o.) on the increased vascular permeability induced by acetic acid in mice, and the potency was about 0.4 times that of indomethacin (Ind), and 6-93 times that of ibuprofen (Ibu), phenylbutazone(Phe) and aspirin(Asp). The inhibitory activity of Tol(ED50 = 18.2 mg/kg, p.o.) on UV-induced erythema in guinea pigs was about 0.3 times that of Ind. A recovery of the hind paw edema of rats, produced by a mixture of kaolin and carrageenin, was promoted by oral administration of Tol(2.5 approximately 20 mg/kg x 5/2 days). Tol(80 mg/kg/day, p.o.) showed a significant activity in inhibiting the exudation caused by croton oil in rats, and the activity was about 0.025 times that of Ind and greater than that of Ibu, Phe and Asp. Tol(100-800 microgram/ml) inhibited in a dose-dependent manner the phytohemagglutinin-induced blast transformation of cultured lymphocytes from rat thymus, as did salicylic acid. In vitro, Tol showed a potent activity similar to that of Ibu and Phe in preventing the denaturation of bovine serum albumin and the lysis of rat erythrocytes. From these results, it is suggested that Tol has a particularly potent inhibitory activity on acute exudative inflammation, and the mode of action may be attributed to a mechanism similar to that seen with other acidic non-steroidal anti-inflammatory drugs.     

Pharmacokinetics of droxicam in rat and dog

A study was made of the oral absorption of droxicam in the rat. Five minutes after administration of 1 mg/kg droxicam, only piroxicam levels (its active metabolite) were detected at the portal vein and caudal vena cava. The transformation of droxicam into piroxicam takes place in the gastrointestional tract. A pharmacokinetic test to compare the plasma levels of piroxicam obtained in rat and dog was then made after oral administration of droxicam and piroxicam. In both animal species the oral absorption of droxicam was not dose-related. However, droxicam given at therapeutic doses (0.2-0.3 mg/kg) was bioequivalent to piroxicam. The elimination half-life of piroxicam after oral administration of droxicam and piroxicam was 8 +/- 2 h in the male rat, 27 +/- 12 h in the female rat and 38 +/- 18 h in the male dog, whilst the half-life of oral absorption of piroxicam did not vary from one animal species to another. In the case of droxicam, however, this value was higher than that after oral administration of piroxicam, as a consequence of the process of transformation of droxicam into piroxicam. It is concluded that droxicam is a prodrug of piroxicam with a slower rate of absorption, but with the same bioavailability within the range of therapeutic doses.     

Effects of a new 1,4-dihydropyridine, lacidipine, on gastrointestinal motility and other gastrointestinal functions

Lacidipine is a new 1,4-dihydropyridine calcium entry blocker endowed with slow onset of action and potent and long-lasting antihypertensive activity. This study investigated the effect of lacidipine on some gastrointestinal functions, mainly gastrointestinal motility, in rats and dogs. In fasting conscious dogs chronically fitted with electrodes and strain gauges along the small bowel, lacidipine (12 micrograms/kg i.v. bolus or 10 micrograms/kg/h for 3 h) did not modify the migrating motor complex pattern or intestinal spike activity. In the rat, lacidipine proved less active (ED 50 greater than 100 mg/kg p.o.) than nitrendipine (ED 50 = 31 mg/kg p.o.) in inhibiting gastric emptying of a liquid meal, whereas the opposite was true after a solid meal (ED 50 = 10.9 and 35.0 mg/kg p.o., respectively). Lacidipine inhibited fecal pellet output at lower doses (ED 50 = 14.8 mg/kg p.o.) than nitrendipine (ED 50 = 40.1 mg/kg p.o.). On histamine-induced gastric acid secretion, the effect of 100 micrograms/kg i.v. lacidipine was moderate (maximum inhibition 45%). The gastrointestinal effects displayed by lacidipine appear at doses at least 5 and 50 times as high as those affecting blood pressure after intravenous and oral administration, respectively. Thus, lacidipine is unlikely to cause noteworthy unwanted effects on the gastrointestinal tract.     

Pharmacological studies of loperamide, an anti-diarrheal agent. I. Effects on diarrhea induced by castor oil and prostaglandin E. (author's transl)]

Effects of loperamide on diarrhea induced by castor oil and prostaglandin E1 were investigated in rats and mice and compared with those of narcotic analgesics, atropine, mecamylamine and local anesthetics. The following results were obtained. Loperamide markedly suppressed the appearance of diarrhea induced by oral administration of castor oil in rats and the ED50 values for 1 and 2 hr protection was 0.082 and 0.42 mg/kg p.o., respectively. Loperamide markedly suppressed the appearance of diarrhea induced by i.v. administration of prostaglandin E1 and the ED50 value for 2 hr protection was 0.24 mg/kg p.o. in rats. The ID120 min value of loperamide which was calculated on the basis of the dose producing a 20% or more inhibition of the charcoal transport in the small intestine for 120 min was 0.8 mg/kg p.o. in mice and this activity was 9.2 times more potent than that of morphine. The analgesic ED50 value (Haffner's method) and LD50 value of loperamide was 149 and 249 mg/kg p.o., respectively. These results suggest that loperamide has a potent anti-diarrheal activity and specificity to the gastrointestinal tract and inhibits the effect of prostaglandin E1 and ricinoleic acid on the intestinal tract in rats.     

Pharmacological properties of the anti-inflammatory agent pyridyl-biphenylyl-acetamide (diphenpyramide).

Pyridyl-biphenylyl-acetamide (diphenpyramide, Z-876) is a new bisphenylalcanoic derivative with marked anti-inflammatory, analgesic, antipyretic and uricosuric properties. It is more active than phenylbutazone in the adjuvant polyarthritis in the rat when given prophylactically or therapeutically. It is thrice as active as phenylbutazone and ten times as active as acetylsalicylic acid (ASA) on the carrageenin-induced edema of the hind-paw. Diphenpyramide is characterized by low acute toxicity and by weak ulcerogenic activity. On the carrageenin-induced edema the therapeutic index of diphenpyramide is 30 times higher than that of indometacin and the ratio between the ED50 and the UD50 (ulcerogenic dose in 50% of the treated rats) is 39 times higher than that of ASA.     

Analgesic activity of a non-steroidal anti-inflammatory agent, tolmetin sodium in experimental animals (author's transl)

Effect of tolmetin sodium on the pain-like responses caused by various nociceptive stimuli was examined in experimental animals. Tolmetin sodium showed a potent inhibitory activity on the acetic acid-induced writhing in mice and rats, and its potency, (ED50 = 23.4 and 3.01 mg/kg, p.o.) was about 2.4--10.3 times that of ibuprofen and aspirin. The hypertension induced by intraarterial injection of bradykinin toward the spleen of dogs was inhibited by tolmetin sodium (ED50 = 80 mg/kg, i.v.), but the hypertension by a simultaneous injection of bradykinin and PGE1 was not inhibited by tolmetin sodium and sulpyrine, though pentazocine inhibited both hypertensions. The pain-like response caused by pressing mechanically the inflamed paws or joints of rats induced by kaolin-carrageenin or adjuvant was inhibited by tolmetin sodium (30--100 or 20--40 mg/kg, p.o., respectively), and the potency was approximately equal that of ibuprofen and phenylbutazone. Tolmetin sodium produced a significant inhibition of the pain-like response induced by electrical stimulation of tooth pulp of dogs, but showed no effect when the methods of Haffner and D'Amour-Smith were applied to mice. Anti-writhing action of tolmetin sodium was not antagonized by naloxone. From these results, it was concluded that tolmetin sodium has a potent inhibitory activity on the pain-like responses induced by the chemical nociceptive stimuli and by the mechanical pressure stimulus of the inflamed tissue, especially on the writhing. The analgesic activity probably involves a peripheral mechanism.     

Comparison in rats of the anti-inflammatory and gastric irritant effects of etodolac with several clinically effective anti-inflammatory drugs

The anti-inflammatory and gastric effects of etodolac were compared in the rat with those of seven clinically established nonsteroidal anti-inflammatory drugs. The anti-inflammatory potency of etodolac was found to lie between that of sulindac and piroxicam. Etodolac was 2.8 times more active than sulindac and 2.2 times less active than piroxicam. Compared to phenylbutazone it was 12.5 times more potent. The irritation produced on the gastric mucosa was less than that of sulindac, although this difference did not reach statistical significance. However, etodolac was significantly (p less than 0.05) less irritant than piroxicam. Of the drugs studied, etodolac showed the highest ratio between the irritant ED50 and the dose which inhibited inflammation by 50%. From these results etodolac is predicted to be a potent anti-inflammatory drug with a high gastric tolerance. Clinical trials appear to confirm these predictions.     

A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity

The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.     

Lacidipine: a calcium antagonist with potent and long-lasting antihypertensive effects in animal studies.

Lacidipine, currently being evaluated as a once-daily antihypertensive agent, acted as a calcium entry blocker on rabbit ear artery (pA2 = 9.4) with a markedly slower onset of action than that of nitrendipine; this effect was not reversed after 9 h of drug washout. Calcium entry blocker activity was also evaluated on nonvascular smooth muscles: Lacidipine showed a more pronounced vascular selectivity than nitrendipine; for both drugs, concentrations required to induce negative inotropic effects in guinea pig ventricular strip were approximately 100 times higher than concentrations needed to antagonize calcium contraction in vascular smooth muscle. In spontaneously hypertensive rats (SHR), by the tail-cuff method, lacidipine (ED25 = 0.35 mg/kg orally, p.o.) proved approximately 30 times more potent, slower in onset, and longer-acting than nitrendipine in reducing blood pressure. These features were confirmed in chronically implanted SHR after oral and intravenous (i.v.) administration (ED25 = 0.19 mg/kg p.o. and 0.006 mg/kg i.v.). A short-lasting tachycardia was detected with both drugs. No evidence of acquired tolerance emerged after repeated oral administrations over a 3-week period. Lacidipine induced a natriuretic effect in saline-loaded SHR at antihypertensive doses. In renal hypertensive dogs, lacidipine proved more potent (three to seven times), slower in onset, and longer-lasting than nitrendipine after p.o. (ED25 = 0.22 mg/kg) and i.v. (ED25 = 0.004 mg/kg) administrations.     

Comparative light and electron microscopic observations of the lesive effects of two non-steroid anti-inflammatory drugs plus stress on rat gastric mucosa

In this histological study it has been demonstrated that a single-dose administration of piroxicam, at the same dosage (4 mg/kg) as droxicam, has a greater erosive potential on the gastric mucosa of rats later exposed to cold stress. For this purpose the depth of all lesions found was evaluated by light microscopy and results showed that piroxicam produces lesions deeper and more numerous than those of droxicam. The transmission and scanning electron microscopic studies showed that the lesive mechanism was very similar for both drugs and that both local and general factors induced by these drugs and stress come into play. Absorption or penetration and uptake by the cells of the mucosa have been considered among the most important local factors in the development of erosive gastric lesions caused by non-steroid anti-inflammtaory drugs. As this absorption is in direct relation to the depth of the lesions, it can be considered from the results of this study that the lesser lesive effect of droxicam on the gastric mucosa when compared to that of piroxicam is due to the fact that, owing to its hydrolysis to piroxicam the absorption rate is slower.     

Action of piroxicam on allergic inflammation

Effects of piroxicam on allergic inflammation were investigated with allergic air pouch inflammation and antigen-induced arthritis in rats. In allergic air pouch inflammation, piroxicam exerted a dose-dependent inhibition (1-10 mg/kg, p.o.) of the exudate production, the migration of leukocytes and the release of lysosomal enzyme into the exudate; and its potency was superior to that of indomethacin and equivalent to that observed with prednisolone. In contrast with this, the suppressive effect of piroxicam on non-allergic air pouch inflammation was as weak as indomethacin. Prednisolone showed a similar effect on both types of air pouch inflammation. In antigen-induced arthritis, piroxicam showed a dose-dependent (0.3-3 mg/kg, p.o.) inhibitory effect on knee joint swelling and an improving action on the functional disorder of the inflamed joint. On this model, piroxicam was 3 to 4 times more active than both indomethacin and prednisolone. In non-allergic joint inflammation induced with croton oil in rats, however, the anti-inflammatory potency of piroxicam was almost equal to those of indomethacin and prednisolone. Piroxicam showed more potent inhibition than indomethacin on heterologous passive cutaneous anaphylaxis in rats, but showed only a slight inhibition on the increased vascular permeability caused by histamine and bradykinin. Piroxicam had no influence upon the plaque-forming cell response and the delayed hypersensitivity reaction in mice; furthermore, the hemolytic activity of complement in guinea-pig serum was scarcely affected by piroxicam in vitro. These results indicate that piroxicam possesses prominent efficiency on allergic inflammation and may function on several activities of inflammatory cells.     

Anti-inflammatory activity of orpanoxin administered orally and topically to rodents

Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID) lacking gastric ulcerogenic effects in the therapeutic dose range in rats, was compared with six reference NSAIDs for oral activity in the rat paw carrageenin-induced edema assay. Tested NSAIDs were ranked on the basis of oral mg/kg ED50 values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6; benoxaprofen, greater than 300; tolmetin sodium, greater than 300; and sulindac, greater than 300. Zomepirac sodium was inactive. Only the three most potent compounds produced greater than 60% inhibition of edema. Inhibition was generally greater at 4 h than at 6 h post carrageenin for all compounds. Oral activity of orpanoxin was also demonstrated in the guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o. when given 1 h before irradiation) and in the mouse ear croton oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical activity of orpanoxin was assessed in both the guinea-pig and mouse models. In the guinea-pig u.v.-induced erythema model, application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin creams (containing 10% urea) significantly inhibited erythema at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid, and indomethacin as 1% creams inhibited total erythema scores 70, 92 and 74%, respectively. Evidence for topical activity in the mouse ear assay was also obtained for orpanoxin in diethyl ether or 10% urea cream, but not in dimethylsulfoxide. It was concluded that orpanoxin has anti-inflammatory activity comparable to reference NSAIDs in the rat paw edema test, is active orally in rat, mouse, and guinea-pig models, and shows topical activity in the guinea-pig and the mouse.     

Preclinical evaluation of CHF3381 as a novel antiepileptic agent

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.     

Mechanism of anti-inflammatory action of etodolac.

The effect of etodolac (CAS 41340-25-4) on the inflammatory reactions induced by histamine and bradykinin was compared with that of indomethacin and other nonsteroidal anti-inflammatory drugs. Etodolac (50 mg/kg p.o.), indomethacin (20 mg/kg p.o.), diclofenac Na (20 mg/kg p.o.) and acetylsalicylic acid (200 mg/kg p.o.) had no effect on the increase of vascular permeability induced by histamine or bradykinin and on passive cutaneous anaphylaxis in rats. Etodolac (5, 10 and 20 mg/kg p.o.) suppressed concanavalin A-induced paw edema in rats. Etodolac (10 mg/kg p.o.) and bromelain (10 mg/kg i.v.) significantly suppressed the heat-induced elevation of bradykinin in perfusates of rat paws, but indomethacin (20 mg/kg p.o.) and diclofenac Na (20 mg/kg p.o.) did not. Etodolac inhibited bradykinin-forming enzyme activity in a concentration-dependent manner (IC50 = 1.5 x 10[-4) mol/l). These results suggest that etodolac is a unique nonsteroidal anti-inflammatory drug which can inhibit bradykinin formation, unlike indomethacin or diclofenac Na.     

The antinociceptive effects of prostaglandin antagonists in the rat

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.