Emesis In Dogs Research Articles

PHNO, a novel dopamine agonist, in animal models of parkinsonism.

PHNO, a naphthoxazine compound, was investigated in animal models of central dopaminergic activity. The drug in doses of 5-300 micrograms/kg when administered subcutaneously, or transdermally, induced stereotypic behavior in rats which was blocked by haloperidol but not by reserpine pretreatment. In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra PHNO induced dose-dependent contralateral turnings. The drug caused emesis in dogs and hypothermia in mice. PHNO bound to D-2 dopamine receptors in the rat striatum. Chronic injection with PHNO did not induce behavioral supersensitivity or increase dopamine receptor density. These data indicate that PHNO is a direct acting dopamine agonist that is highly potent. PHNO differs from other dopaminergic drugs and may be useful in the treatment of Parkinson's disease.

Evaluation of ciladopa hydrochloride as a potential anti-parkinson drug

The effects of the putative dopamine agonist, ciladopa hydrochloride (AY 27,110), a non-ergot compound, were investigated in animal models of dopaminergic activity to evaluate its possible role in the treatment of Parkinson's disease. Ciladopa induced stereotyped behavior in both rats and guinea pigs. Unlike apomorphine, however, ciladopa did not produce a maximum behavioral response, i.e. stereotyped gnawing. Pretreatment with haloperidol and sulpiride blocked the effects induced by ciladopa. Pretreatment with reserpine and α-methyl- p-tyrosine did not alter the behavioral effects of ciladopa. Ciladopa caused contralateral rotation in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine. Ciladopa induced vomiting in dogs. Small doses of ciladopa decreased locomotor activity in rats, an effect presumably mediated by presynaptic autoreceptors. The chronic injection of both subthreshold and suprathreshold doses of ciladopa failed to induce behavioral supersensitivity. Ciladopa binds to D-2 dopamine receptors in the mammalian caudate nucleus. These data indicate that ciladopa can cause stimulation of central dopaminergic receptors and that the drug is a partial dopamine agonist with direct-acting properties. Ciladopa differs from other available dopaminergic drugs and may possess therapeutic advantages for the treatment of Parkinson's disease.

Non‐antidopaminergic, non‐cholinergic stimulation of gastric emptying with cisapride (R 51 619) in rats

AbstractThe gastrokinetic activity of cisapride, bethanechol, domperidone, and metoclopramide was tested in rats and compared with the direct cholinergic activity (induction of salivation and lacrimation in rats) and peripheral and central antidopamine activity (antagonism of apomorphine‐induced emesis in dogs and abnormal behaviour in rats, respectively) of the compounds.Cisapride showed a high dissociation between gastrokinetic activity (0.31 mg/kg) on the one hand, and direct cholinergic activity (ED50: ≥ 40 mg/kg) and peripheral and central antidopamine activity (ED50s: 3.3 and 18.6 mg/kg), on the other hand. In contrast, metoclopramide combined antidopamine effects (ED50s: 0.28 and 0.76 mg/kg for peripheral and central activity) and bethanechol direct cholinergic effects (ED50s: 2.7 and 3.6 mg/kg for lacrimation and salivation) with their gastrokinetic activity, which was obtained with bethanechol at 0.63 mg/kg and with metoclopramide at 1.25 mg/kg. Domperidone was found to be a potent and selective antagonist of peripheral dopamine receptors (ED50: 0.0071 mg/kg) but failed to stimulate gastric emptying (ED50: ≥ 10 mg/kg).The present data confirm cisapride as a potent gastrokinetic compound devoid of antidopaminergic or direct cholinergic properties.

Discrete lesions of the area postrema abolish radiation-induced emesis in the dog

Studies carried out in several mammalian species during the 1950's led to the concept of a ‘vomiting center’ located in the dorsolateral reticular formation and a ‘chemoreceptor trigger zone’ (CTZ) within or near the area postrema (AP). This early work suggested that the AP was essential for vomiting induced by a variety of chemical emetics and by ionizing radiation. However, the lesion techniques used often produced significant damage to neural tissue underlying the AP, as well as to the AP itself, making localization of function very difficult. In the present study, electrolytic lesions confined to the AP abolished both radiation- and apomorphine-induced emesis in dogs. Thus, in addition to its postulated function in osmoreception and central cardiovascular regulation, the AP also appears to have a key role in vomiting initiated by chemical emetics and by ionizing irradiation.

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Iminodibenzyl derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine and clocapramine have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, a new iminodibenzyl derivative, were compared with those of carpipramine, clocapramine, haloperidol and sulpiride. Y-516 inhibited apomorphine (0.5 mg/kg, s.c.)-induced hyperactivity in mice, apomorphine (10 mg/kg, s.c.)-induced hypothermia in mice, apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs, methamphetamine (2 mg/kg, s.c.)-induced hyperactivity in mice and methamphetamine (50 mg/kg, i.p.)-induced mortality in grouped mice. Y-516 also suppressed both lateral hypothalamic self-stimulation behavior in rats and circling behavior induced by methamphetamine (5 mg/kg, i.p.) in rats with unilateral 6-hydroxydopamine lesions of the striatum. In these tests, Y-516 was 2--3 times more potent than clocapramine, but less potent than haloperidol. The inhibitory effect of Y-516 on apomorphine (1.25 mg/kg, i.v.)-induced gnawing behavior in rats was slightly more potent than that of clocapramine. Y-516 in combination treatment with methamphetamine (5 mg/kg, i.p.) did not induce mortality in rats; however, carpipramine and sulpiride did. The cataleptogenic action of Y-516 was almost equipotent to that of clocapramine. From these results, Y-516 possesses a post-synaptic dopamine receptor blocking action similar to that of the iminodibenzyl antipsychotic drugs, suggesting its potential usefulness as an antipsychotic drug.

Prevention of radiation emesis in dogs by combinations of drugs

Male mixed-breed dogs were used to evaluate the effectiveness of cimeddine (Cim), promethazine (Pro), and thiethylperazine (Thi), singly and in combination, to raise the threshold for radiation-induced emesis. Cim was chosen as an H 2 antihistamine, Pro as an H 1 antihistamine, and Thi as a phenothiazine derivative dopamine blocker. Doses were: 167 mg/m2 i.v. for Cim; 13.9 mg/m 2 i.m. for Pro; and 5.6 mg/m 2 i.m. for Thi. These doses were calculated on a mg/m 2 basis to approximate doses for an average human (1.8 m 2) of 300 mg Cim, 25 mg Pro, and 10 mg Thi. Exposure was to 60Co at 60 rad (midline) per min. The dogs were fed 0.4 kg canned dog food 1 hour before exposure, and injected with the appropriate drugs 30 minutes prior to exposure. Emesis onset times, number of episodes, and time to last episode were recorded. The radiation dose (midline tissue rad) to cause a 50% incidence of emesis (ED 50) was calculated using an up-and-down procedure. The ED 50 (95% confidence limits) were: 258 (212–315) for controls; 240 (151–380) for Cim; 313 (256–384) for Pro; 405 (319–514) for Thi; 334 (284–394) for Cim + Pro; 446 (365–546) for Cim + Thi; 347 (306–399) for Pro + Thi; and 478 (428–539) for Cim + Pro + Thi.

Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics

Neuroleptics such as thioxanthenes (cis( Z )-flupentixol and cis( Z )-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiapines.

Peptide-induced emesis in dogs.

Systemic administration of apomorphine, angiotensin II, neurotensin and leucine-enkephalin induces emesis in dogs in a dose-dependent fashion. Receptors for Leu-enkephalin and angiotensin II but not apomorphine show receptor desensitization, such that a second systemic administration 5 min after the first is ineffective. Domperidone blocked the emetic response to apomorphine but not to Leu-enkephalin or angiotensin II. Naloxone selectively blocked the Leu-enkephalin response, while saralasin blocked responses to both angiotensin II and Leu-enkephalin, but not apomorphine. Chlorpromazine prevented the emetic response to all agents, suggesting a dopamine receptor in the emetic pathway on the brain side of the blood-brain barrier. In dogs with ablation of the area postrema the emetic response to apomorphine and all peptides was prevented.

Altered Gastric Emptying and Prevention of Radiation-Induced Vomiting in Dogs

The relation between radiation-induced vomiting and gastric emptying is unclear and the treatment of this condition is not established. We explored, therefore, (a) the effect of cobalt 60 irradiation on gastric emptying of solids and liquids and (b) the possibility of preventing radiation-induced vomiting with the dopamine antagonist, domperidone. Twenty dogs were studied on two separate days, blindly and in random order, after i.v. injection of either a placebo or 0.06 mg/kg domperidone. On a third day, they received 8 Gy (800 rads) whole body irradiation with cobalt 60 gamma-rays after either placebo (n = 10) or domperidone (n = 10). Before each study, each dog was fed chicken liver tagged in vivo with 99mTc-sulfur colloid (solid marker), and water containing 111In-diethylenetriamine pentaacetic acid (liquid marker). Dogs were placed in a Pavlov stand for the subsequent 3 h and radionuclide imaging was performed at 10-min intervals. Irradiation produced vomiting in 9 of 10 dogs given placebo but only in 1 of 10 dogs pretreated with domperidone (p less than 0.01). Gastric emptying of liquids and solids was significantly suppressed by irradiation (p less than 0.01) after both placebo and domperidone. These results demonstrate that radiation-induced vomiting is accompanied by suppression of gastric emptying. Furthermore, domperidone prevents vomiting produced by ionizing radiation but does not alter the accompanying delay of gastric emptying.

Antivertigo agents. IV. Synthesis and antivertigo activity of 6-[omega-(4-aryl-1-piperazinyl)alkyl]-5,6,7,8-tetrahydro-1,6-naphth yridines.

A series of novel 6-[ω-(4-aryl-1-piperazinyl) alkyl]-5, 6, 7, 8-tetrahydro-1, 6-naphthyridines was synthesized and evaluated for antivertigo activity by testing their ability to inhibit spontaneous nystagmus in cats. Structure-activity relationships are discussed. Many of the compounds having the 4-(2-alkoxyphenyl) piperazine group as the 4-arylpiperazine moiety showed more potent antivertigo activity than diphenidol. Among them, 2-{2-[4-(2-ethoxyphenyl)-1-piperazinyl] ethyl}-1, 2, 3, 4, 6, 7, 8, 9-octahydrobenzo [b] [1, 6] naphthyridine (NK 422, 41) was selected as a promising antivertigo agent. NK 422 also exhibited a more potent inhibitory effect on apomorphine-induced vomiting in dogs than diphenidol.

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers.

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological properties of Y-516, a new antipsychotic drug

Iminodibenzy1 derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine (CPP) and clocapramine (CCP) have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, which also has an iminodibenzy1 nucleus, were compared with those of CPP, CCP, chlorpromazine (CPZ), haloperidol and sulpiride (SPR). Y-516 inhibited apomorphine (0.5 mg/kg s.c.)-induced hyperactivity in mice, apomorphine (1.25 mg/kg i.v.)-induced gnawing behavior in rats, methamphetamine (2 mg/kg s.c.)-induced hyperactivity in mice and methamphetamine (50 mg/kg i.ρ.)-induced mortality in grouped mice. Except for SPR,the other drugs tested also had similar inhibitory activity. Y-516 was more potent than CCP,but slightly less potent than CPZ in these tests. The antagonistic effect of Y-516 on apomorphine (0.1 mg/kg s.c.)-induced vomiting in dogs was 7 times more potent than that of CPZ. The other drugs tested also showed antagonistic activity in this test. Y-516 antagonized apomorphine (10 mg/kg s.c.)-induced hypothermia in mice. CPZ, on the other hand, potentiated this effect. When combined with methamphetamine (5 mg/kg i.p.) in rats, Y-516 did not induce mortality, but CPP and SPR did. From these results, it would appear that the central antidopaminergic activity of Y-516 differs from that of the other drugs tested.

Pharmacological effects of Ro 22-1319: a new antipsychotic agent.

Ro 22-1319, a novel pyrroloisoquinoline compound, was identified as a potential antipsychotic agent in a rat discrete avoidance procedure that is highly specific for such agents. Results in this test are highly correlated with the clinical potency of all types of antipsychotic agents. The avoidance-blocking potency of Ro 22-1319 (0.7 mg/kg) in this procedure approached that of haloperidol (0.4 mg/kg) and was 7- and 12-times greater than that of chlorpromazine and clozapine, respectively. Ro 22-1319 exhibited similar high potency in other rat and monkey avoidance procedures, rat motor activity, and antagonism of apomorphine emesis in dogs. High potency and antipsychotic-like activity have been demonstrated in monkey EEG and in an in vivo 3H-spiroperidol binding assay. Although studies of amphetamine antagonism in rats indicate antidopaminergic activity at nigrostriatal sites, Ro 22-1319 exhibited relatively weaker cataleptogenic and antistereotypic activity than haloperidol, and had minimal activity in a rat chronic stereotypy model of receptor supersensitivity. This profile suggests that Ro 22-1319 is an efficacious antipsychotic compound, almost as potent as haloperidol, with fewer or less intense extrapyramidal effects and low potential for tardive dyskinesia.

Effects of putative dopamine autoreceptor agonists in pharmacological models related to dopaminergic and neuroleptic activity

The pharmacological profile of 2 proposed selective dopamine (DA) autoreceptor agonists 3-PPP and 3-phenethyl-PP was compared with that of apomorphine in test systems for detection of dopaminergic and antidopaminergic activity. In vitro 3-PPP and 3-phenethyl-PP showed preferential affinity for D-2 DA receptors and only very low affinity for D-1 DA receptors. Accordingly, and in contrast to apomorphine, no stimulation of DA-sensitive adenylate cyclase was observed. A weak to moderate inhibitory activity of all 3 compounds was shown in uptake systems for DA, NA and 5-HT. A weak or no effect on α 1-or α 2-adrenergic receptors was observed. 3-PPP, 3-phenethyl-PP and apomorphine inhibited spontaneous locomotor activity in mice and rats, induced contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and induced emesis in dogs. The DA involvement in these effects was confirmed by antagonistic effects of neuroleptics in all three test systems. Apomorphine was the only compound inducing stereotyped behaviour in normal rats and neuroleptically induced supersensitive mice and inducing ipsilateral circling behaviour in hemitransected rats. 3-PPP did not show activity in several tests for neuroleptic effects in vivo, including inhibition of apomorphine- and methylphenidate-induced stereotyped gnawing, cataleptogenic effect, inhibition of conditioned avoidance response and inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. In contrast 3-PPP and 3-phenethyl-PP antagonized d-amphetamine-induced stereotyped licking/gnawing and hyperactivity. 3-PPP did not influence the cateleptogenic or methylphenidate antagonistic effect of cis-(Z)-flupentixol or haloperidol. 3-PPP increased the methylphenidate antagonistic effect of spiroperidol and the apomorphine antagonistic effect of cis-(Z)-flupentixol, cis-(Z)-clopenthixol and spiroperidol. It is concluded that 3-PPP and its more potent derivative 3-phenethyl-PP show high selectivity for DA receptors mediating sedation in rodents but that these compounds activate DA receptors mediating emesis and activate denervation supersensitive DA receptors, while not affecting neuroleptic supersensitive DA receptors. The neuroleptic-like activity of 3-PPP and 3-phenethyl-PP is only shown as a d-amphetamine antagonistic effect, indicating a presynaptic site of action. The increase of some neuroleptic effects may have clinical relevance for treatment of diseases associated with DA hyperactivity.

Antiemetic specificity of dopamine antagonists.

Twelve antagonists of apomorphine-induced emesis in dogs were studied in different tests to evaluate their antiemetic specificity. Ten of these antagonists were neuroleptics: benzquinamide, clebopride, bromopride, prochlorperazine, haloperidol, chlorpromazine, thiethylperazine, metoclopramide, droperidol, and pimozide blocked conditioned responding in dogs and apomorphine-induced stereotyped behavior in rats. The use of these compounds as anti-emetics entails a risk of neurological side effects. Metopimazine and domperidone were devoid of neuroleptic activity. Metopimazine, however, showed potent alpha-adrenergic blocking activity, showed histamine H1 antagonism, and induced palpebral ptosis. Therapeutic doses of metopimazine are, therefore, likely to produce sedation and side-effects related to autonomic blockade, Domperidone showed potent antiemetic activity and, up to high doses, no other central or peripheral effects. Therefore, domperidone is the only specific antiemetic known.

Determining the effective emetic dosage of tetrapotassium pyrophosphate (TKPP) in dogs.

The effect of TKPP on emesis was examined in adult "conditioned random source" mongrel dogs. Only dogs that exhibited emesis with CuSO4, were used. The effect of dosage and concentration of TKPP on emesis was highly significant. The effective combinations of dose and concentration were 4,800, 2,400, or 1,200 mg/head at 5, 10, or 20%. In all the tested dogs, 4,800 mg of 20% TKPP was effective inducing emesis. The mean latency of emesis in dogs was 7 min, 33 sec (95% confidence limits: 5 min, 58 sec 9 min, 7 sec).

Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog.

1 The emetic action of Met-enkephalin, morphine and naloxone was studied following their administration into the cerebral ventricles of dogs through chronically implanted cannulae and the effect on the responses of ablating the chemorceptor trigger zone (CTZ) was investigated. The opiate antagonist, naloxone, was used to determine the role of enkephalin receptors in emetic responses.2 Administration of Met-enkephalin (1.0 mug/kg) into the IVth ventricle regularly evoked emesis with an average latency of 35 s. A dose of morphine (2.5 mug/kg) which was five times larger was required for a consistent emetic response when introduced into the lateral cerebral ventricle (i.c.v.) as compared to the dose required by the IVth ventricular route. The latency of emetic responses by the latter route of injection of morphine was shorter. This is in accord with an action of morphine on the emetic CTZ.3 After bilateral ablation of the CTZ, intraventricular injections of Met-enkephalin and morphine failed to produce emesis even when given in doses that were 5 to 10 times the dose which regularly elicited emesis in animals with intact CTZ. The emesis produced in dogs by intraventricular Met-enkephalin and morphine is thus fully accounted for by an action on the CTZ.4 Naloxone (i.c.v.) in doses up to 10.0 mug/kg did not cause emesis. However, higher doses of naloxone elicited dose-dependent emesis in dogs. The 100% emetic dose of naloxone was found to be 160 mug/kg and the latency of emesis was 180 s. Unlike Met-enkephalin and morphine, naloxone continued to elicit emesis in CTZ-ablated animals.5 Pretreatment with intraventricular naloxone (1 to 8 mug/kg) blocked the emetic responses induced by intraventricular Met-enkephalin and morphine but not that to apomorphine. The selective protective action of the opiate antagonist against Met-enkephalin and morphine supports the presence of enkephalin receptors in the emetic CTZ.

Biphasic effects of pimozide on sleep-wakefulness in dogs

Sleep-wakefulness patterns in dogs were studied using computerized on-line power spectral analysis and off-line automatic stage-classification during control recordings and after oral treatment with three doses of the specific dopamine blocker pimozide. A biphasic effect on sleep-wakefulness patterns was found. At 0.016 mg/kg (the ED 50-value for the antagonism of apomorphine-induced vomiting in dogs), pimozide significantly increased the time spent awake, and significantly decreased slow wave sleep and REM sleep. No significant effects were obtained with a four times higher dose of pimozide. At 0.16 mg/kg, pimozide significantly decreased the time spent awake and significantly increased slow wave sleep and REM sleep. The effects appear the opposite of those described for apomorphine and suggest that dopamine plays a role in the physiology of sleep-wakefulness regulation.

The pharmacological evaluation of pergolide mesylate as a potential anti-parkinson agent.

Abstract The effects of the putative dopamine agonist, pergolide mesylate, a substituted propylergoline, were investigated in several animal models of dopamine-related behavior in an attempt to evaluate its possible role in the treatment of Parkinsonism. Pergolide induced intense stereotypic behavior in both rats and guinea-pigs. The stereotypy was immediate in onset, of prolonged duration, and was blocked by non-sedating doses of haloperidol but not by clozapine. In rats, pergolide reversed reserpine-induced effects even in animals pretreated with the dopamine depletor, α-methyl-para-tyrosine. Pergolide induced vomiting in dogs which could be inhibited by pretreatment with haloperidol. In animals with unilateral 6-hydroxydopamine lesions of the substantia nigra, pergolide produced contralateral rotation. Behavioral subsensitivity to apomorphine developed after 4 weeks of chronic administration of a low (subthreshold) dose of pergolide that did not induce steroetyped behavior, while supersensitivity to apomorphine was observed when animals were chronically treated with a suprathreshold dose of pergolide. These data indicate that pergolide can cause stimulation of central dopaminergic receptors and possesses direct agonist properties. However pergolide does have effects which are different from those of other available dopaminergic drugs and may be advantageous in the treatment of Parkinson's disease.

The anti-inflammatory and analgesic profile of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (tiopinac).

Tiopinac displayed marked anti-inflammatory activity when given p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (40 x phenylbutazone), and cotton-pellet-induced granuloma (0.8 x indomethacin). In an 18-day test, tiopinac prevented the development of adjuvant-induced arthritis (10-15 x naproxen) and had similar activity versus pre-induced arthritis. Tiopinac exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. Depending upon the type of analgesic test used, the potency of tiopinac varied. When given p.o. it inhibited phenylquinone-induced writhing in the mouse and rat (respectively 16 and 10 x aspirin). In contrast, tiopinac had approximately 10 times the potency of indomethacin in increasing the pain threshold when yeast-inflamed paws were compressed. The pain threshold of the noninflamed paw was not increased. Tiopinac was highly active versus pain induced by flexing the adjuvant arthritic-inflamed paw (greater than or equal to 1000 x aspirin). It was inactive in the mouse hot-plate test in which opiate-like agents are active. Tiopinac, p.o., lowered yeast-induced pyrexia (130 x aspirin). Tiopinac did not have significant cardiovascular or CNS activity. Whereas the Ed50 versus adjuvant arthritis in rats was 0.1 mg/kg/day p.o., rats tolerated up to 20 mg/kg/day p.o. in the 8-day cotton-pellet test. Lack of anorexia and emesis in dogs with up to 30 mg/kg p.o. and mild oral activity in producing gastric erosion in acute and subacute studies in rats suggests that tiopinac may have relatively little gastrointestinal irritating activity.