Effect of etodolac, a new nonsteroidal anti-inflammatory drug, in MRL/lpr mice with articular lesions.

Etodolac, a new nonsteroidal anti-inflammatory drug, was administered orally at doses of 1 and 5 mg/kg to MRL/MpJ-lpr/lpr (MRL/lpr) mice, and its effect on articular lesions was compared with that of indomethacin. Both etodolac and indomethacin significantly reduced swelling of the hind paw. Histopathological examination showed that etodolac significantly reduced cartilage and bone damage, whereas indomethacin treatment did not achieve a statistically significant effect. Rheumatoid factors were not affected by either etodolac or indomethacin. These results indicate that etodolac delays the development of arthritis in MRL/lpr mice, and reduces cartilage and bone damage.     

Protective effects of polygodial on gastric mucosal lesions induced by necrotizing agents in rats and the possible mechanisms of action

The effects of polygodial isolated from the leaves of Tasmannia lanceolata on necrotizing agents-induced gastric lesions in rats were compared with capsaicin. Polygodial markedly inhibited the gastric mucosal lesions induced by several necrotizing agents, such as ethanol (ED(50)=0.029 mg/kg, p.o.), 0.6 M HCl (ED(50)=0.26 mg/kg, p.o.), and aspirin (ED(50)=0.38 mg/kg, p.o.), and partly inhibited the gastric mucosal lesions induced by indomethacin, but showed no significant effect on acid output in pylorus-ligated rats at doses of 0.05-0.5 mg/kg. The gastroprotection of polygodial was attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), N-ethylmaleimide (10 mg/kg, s.c.) and ruthenium red (3.5 mg/kg, s.c.). Polygodial (0.2 mg/kg, p.o.) increased the amount of reduced glutathione in gastric mucosa of ethanol-treated group. These results suggested that endogenous prostaglandins, nitric oxide, sulfhydryl compounds and vanilloid receptor-mediated effects are involved in the protective effect of polygodial.     

Effect of pranoprofen on sodium urate crystal-induced inflammation

Effect of a non-steroidal anti-inflammatory drug, pranoprofen (PPF), on sodium urate crystal-induced inflammation was investigated in comparison with standard drugs for treating acute gout in experimental animals. PPF inhibited sodium urate crystal-induced paw edema in both rats (1-10 mg/kg, p.o.) and mice (5-25 mg/kg, p.o.) in a dose-dependent manner. On rat sodium urate crystal-induced paw edema, PPF was found to be almost equally active as indomethacin (IM) and colchicine. In addition, PPF (2.5-10 mg/kg, p.o.) inhibited the accumulation of exudate and decreased the leucocyte numbers and the amount of prostaglandin E2 (PGE2)-like substance in sodium urate crystal-induced pleurisy in rats dose-dependently, with a potency slightly greater than that of IM. The specific anti-gout agent colchicine (5 mg/kg, p.o.) also suppressed the accumulation of exudate and decreased the leucocyte numbers, without affecting the amount of PGE2-like substance. Moreover, in mouse peritonitis, PPF (1-10 mg/kg, p.o.) suppressed the sodium urate crystal-induced increase in vascular permeability in a dose-dependent manner. Furthermore, in experimental models of articular gout, PPF inhibited the pain response (abnormal gait) of sodium urate crystal-induced arthritis in both rats (0.25 and 1 mg/kg, p.o.) and dogs (3 mg/kg, p.o.), with a potency greater than that of IM and phenylbutazone, respectively. These results indicate that as an anti-gout agent, PPF is at least as effective as other standard drugs, so that it should have good clinical potential.     

Role of kinin and prostaglandin in cutaneous thermal nociception

Involvements of kinin and prostaglandin and their interaction in noxious thermal stimuli were investigated in noninflamed and inflamed rats. The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. The escape latency in kininogens-deficient Brown Norway (B/N-) Katholiek rats was significantly longer than that in the normal strain, B/N-Kitasato rats. The latency in B/N-Kitasato rat was prolonged by administration of a bradykinin (BK) B2 receptor antagonist, FR173657 (30 mg/kg, p.o.), whereas it was shortened by pretreatment with a kininase II inhibitor, captopril (10 mg/kg, i.p.). Both agents did not affect the latency in B/N-Katholiek rats. In normal Sprague-Dawley (SD) rat, administration of indomethacin did not change the escape latency against the thermal stimuli. In contrast, administration of indomethacin or a relatively cyclooxygenase-1-selective inhibitor, mofezolac (10 mg/kg, p.o.) significantly reduced numbers of writhing reaction in mice induced by acetic acid solution. Injection of lipopolysaccharide (1 mg/kg, i.v.) resulted in shortening escape latency at 8 h after the injection in B/N-Kitasato rats. This hyperalgesia could be reversed by pretreatment of the rats with indomethacin, a cyclooxygenase-2-selective inhibitor JTE-522 (10 mg/kg, p.o.), or FR173657, but not with mofezolac. The hyperalgesia was not seen in B/N-Katholiek rats. These results indicate that kinin has major participation in peripheral skin thermal nociception under noninflamed condition, although cyclooxygenases may have little participation. Prostaglandins produced by cyclooxygenase-2 could coordinate with BK to elicit hyperalgesia during inflammation induced by lipopolysaccharide.     

Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.     

Interference of azelastine with anaphylaxis induced by ovalbumin challenge in actively sensitized rats.

The inhibition of the haematological alterations and prevention of death due to systemic anaphylaxis after antigen challenge were investigated in rats after various drug treatments. The i.v. injection of ovalbumin (250 micrograms/kg) into actively sensitized rats induced marked thrombocytopenia and haemoconcentration within 5 min and significant leukocytosis within 30 min, lasting for 2 h after the challenge. Pretreatment with meclizine or terfenadine (15-30 mg/kg i.p.) inhibited antigen-induced haemoconcentration, whereas WEB 2086 (2-10 mg/kg i.p.) and PCA 4248 (5-10 mg/kg p.o.), two platelet-activating factor (PAF) antagonists, interfered with thrombocytopenia only. Azelastine (1-20 mg/kg p.o.) dose dependently inhibited antigen-induced haemoconcentration and thrombocytopenia but failed to block leukocytosis. Azelastine also inhibited the thrombocytopenia observed after the i.v. administration of PAF (4 micrograms/kg). Administration of ovalbumin at a dose of 1.5 mg/kg resulted in a lethal anaphylactic reaction in about 85% of the rats. Pretreatment with WEB 2086 (10 mg/kg i.p.), meclizine (30 mg/kg i.p.) or both increased the survival rate from 15 to 57, 68 and 87%, respectively. Azelastine alone (20 mg/kg p.o.) completely blocked the lethal reaction. It was concluded that the ability of azelastine to antagonize histamine and PAF is important for its effectiveness against anaphylactic shock.     

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.     

Pharmacological properties of the new non-steroidal anti-inflammatory agent etodolac.

The anti-inflammatory, analgesic, antipyretic and ulcerogenic activities of etodolac (CAS 41340-25-4), a new nonsteroidal anti-inflammatory agent, were compared with those of indometacin and other anti-inflammatory drugs in experimental animals. Etodolac had a remarkable anti-inflammatory effect in various experimental models: ultraviolet erythema, carrageenin-induced edema and swelling of adjuvant arthritis. In these models, the effective dose of etodolac was several fold that of indometacin. Etodolac inhibited prostaglandin E2 formation in a concentration-dependent manner, and its inhibitory potency was about 1/5 of that of indometacin. Etodolac also caused marked inhibition of granuloma formation and leucocyte functions such as chemotaxis, lysosomal enzyme release and active oxygen generation. These effects of etodolac were observed at similar doses of indometacin. Etodolac suppressed inflammatory pain but not non-inflammatory pain, and had an antipyretic effect but did not lower normal rectal temperature. Etodolac had no effect on delayed hypersensitivity reactions and was much less ulcerogenic than indometacin. These results indicate that etodolac is a low ulcerogenic anti-inflammatory agent with suppressing activities on leucocyte functions to the same extent as indometacin and prostaglandin biosynthesis.     

Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs.

The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), superoxide and the lipopolysaccharide from luminal bacteria in non-steroidal anti-inflammatory drug-induced intestinal injury was investigated in the rat. Administration (s.c. or p.o.) of indomethacin (10 mg kg(-1)), flurbiprofen (40 mg kg(-1)) or diclofenac (40 mg kg(-1)) increased the vascular leakage of radiolabelled albumin in the jejunum, determined after 24 h, associated with the induction of iNOS, assessed by the conversion of radiolabelled L-arginine. Pre-treatment with ampicillin (200 mg kg(-1) day(-1), p.o.), metronidazole (200 mg kg(-1) day(-1), p.o.), or polymixin B (15 mg kg(-1) day(-1), s.c.), inhibited indomethacin-induced lesion formation, reduced microvascular leakage and prevented the expression of iNOS activity. Administration of the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1-iminioethylamino)-4-thiahexanoic acid; 5 mg kg(-1), s.c.), 18 h after indomethacin, likewise prevented the intestinal lesions and attenuated the microvascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and microvascular leakage, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integrity, leading to luminal bacterial translocation. This provokes iNOS induction, leading to microvascular injury involving both NO and superoxide.     

Vascular permeability and vasodilation induced by the Loxosceles intermedia venom in rats: involvement of mast cell degranulation, histamine and 5-HT receptors.

The mechanisms involved in both local and systemic effects of Loxosceles intermedia (brown spider) venom (LIV) are still poorly understood. We show using rats treated with Evans blue dye (50 mg/kg, i.v.) that small doses of the LIV (0.1, 0.3, 1 and 3 microg/site) dose-dependently increase the vascular permeability in rats, an effect unchanged by indomethacin (5mg/kg, i.p.), atropine (1mg/kg, i.p.), HOE-140 (2mg/kg, s.c.) or SR140333 (0.3mg/kg, i.p.), but fully avoided by promethazine (15 mg/kg, i.p.), methysergide (2mg/kg, i.p.) and compound 48/80 (3mg/kg/day for 3 days). Addition of cumulative concentrations of LIV (0.1-5 microg) in phenylephrine-contracted aortic rings resulted in a partial ( approximately 40%) and endothelium-dependent relaxation, inhibited by the nitric oxide synthase inhibitors L-NAME (10 microM) and L-NMMA (1mM), and the guanylate cyclase inhibitors methylene blue (100 microM) and ODQ (10 microM). LIV-induced relaxation was abolished by compound 48/80 (10 microM) and pyrilamine (a selective histamine H1 receptor antagonist; 100 microM), but not by atropine (1 microM) and indomethacin (10 microM). Our results disclose that LIV increases vascular permeability and induces vascular relaxation. These effects occur due to its ability to degranulate mast cells and release mediators such as histamine and serotonin.     

Protective effects of benidipine on arachidonic acid-induced acute cerebral ischemia in rats.

Acute cerebral ischemia was produced in rats by injection of arachidonic acid (AA) into the internal carotid artery. Evans blue (EB) was intravenously injected and its extravasation into the brain was determined as an indicator of disturbances in the blood-brain barrier and endothelial cells. Control animals showed severe cerebral edema and marked blue staining of the brain. Benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content and the extravasation of EB. Similarly nicardipine (100 micrograms/kg, i.p.) suppressed the elevation of water content and the extravasation of EB. Furthermore, both benidipine (30 micrograms/kg, i.p.) and nicardipine (100 micrograms/kg, i.p.) improved the neuronal injuries following AA-injection. An antiplatelet agent, ticlopidine (100 mg/kg, i.p.), and a thromboxane A2 synthetase inhibitor, OKY-1581 (3 mg/kg, i.p.), also suppressed the elevation of cerebral water content. A lipoxygenase inhibitor, AA-561 (200 mg/kg, p.o.), and a cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.p.), did not prevent the increase in cerebral water content. Neither benidipine (3-30 micrograms/kg, i.v.) nor nicardipine (100 micrograms/kg, i.v.) inhibited the AgNO3-induced thrombus formation of the abdominal aorta, whereas ticlopidine (100 mg/kg, p.o.) and OKY-1581 (3 mg/kg, i.v.) prevented the thrombus formation. From the present results, it is suggested that benidipine, as well as nicardipine, may protect against AA-induced acute cerebral infarction via a mechanism independent of antithrombotic action.     

Anti-inflammatory effect of propolis through inhibition of nitric oxide production on carrageenin-induced mouse paw edema

The anti-inflammatory effect of propolis was compared with that of diclofenac, a non-steroidal anti-inflammatory drug, and L-N(G)-nitro arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, using carrageenin-induced mouse paw edema. When administered 10 min prior to carrageenin injection, propolis (1 : 1000, 1 : 100, p.o.), diclofenac (12.5, 50 mg/kg, p.o.) and L-NAME (10, 100 mg/kg, s.c.) showed a significant anti-inflammatory effect. The anti-inflammatory effects of propolis and L-NAME were significantly inhibited by L-arginine, a precursor of nitric oxide, but not by D-arginine. In contrast, the anti-inflammatory effect produced by diclofenac was not inhibited by either D-arginine or L-arginine. These results indicate that the anti-inflammatory effect of propolis on mouse paw edema acts via the inhibition of nitric oxide production, similar to that of L-NAME but not diclofenac.     

Availability of learned helplessness test as a model of depression compared to a forced swimming test in rats

This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5-20 mg/kg), clomipramine (0.1325-1.25 mg/kg, p.o.) and fluvoxamine (0.3125-1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats.     

Immunomodulatory activity of Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid)

The in vitro and in vivo effects of the experimental immunomodulatory agent Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid) were studied in comparison with levamisole and indomethacin. Levamisole (4 mg/kg, i.v.) but not Wy-18,251 (less than or equal to 10 mg/kg, i.v.) enhanced carbon clearance rates in vivo in mice. Both Wy-18,251 and levamisole (100 mg/kg, p.o.) significantly suppressed the symptoms of experimental allergic encephalomyelitis (EAE) in rats injected with spinal cord emulsion, but neither were as effective as tilorone in this model. Wy-18,251 and levamisole (1-100 mg/kg, p.o.) suppressed the in vivo generation of plaque-forming cells (PFC) in mice immunized with sheep red blood cells while indomethacin (9 mg/kg, p.o.) enhanced PFC formation. All 3 agents (10(-5) - 10(-6) M) enhanced the in vitro ovalbumin (OA)-specific and Con A- or PHA-induced proliferative response and Con A-stimulated interleukin 2 (IL-2) synthesis of rat spleen cells. Furthermore, in vivo treatment of rats with 1-10 mg/kg (p.o.) of Wy-18,251 and levamisole but not indomethacin increased the subsequent in vitro mitogen or antigen (OA) responsiveness of spleen cells. None of the drugs (10(-5) - 10(-7) M) influenced the natural killer cell (NK) activity of rat spleen cells when incorporated directly into the 51Cr release NK assay.     

Pharmacological characterization of standard analgesics on mechanical allodynia in streptozotocin-induced diabetic rats

The present study was designed to investigate the anti-allodynic effects of current analgesic agents, such as pregabalin, amitriptyline, mexiletine, morphine, and diclofenac, in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Diabetic rats developed a sustained decrease in withdrawal threshold response to the von Frey test within 8 weeks after a single injection of STZ (45 mg/kg, i.v.). The anti-allodynic effects of analgesic agents were examined after a single oral or subcutaneous administration at 3 and 7 weeks after beginning of STZ-treatment. Pregabalin (3-30 mg/kg, p.o.), an antiepileptic agent, dose-dependently blocked the mechanical allodynia in rats treated both at 3 and 7 weeks. Mexiletine (10-100 mg/kg, p.o.), a sodium channel blocker, dose-dependently ameliorated mechanical allodynia in rats treated at 3 weeks; however, the efficacy was diminished at 7 weeks. Morphine (1-10 mg/kg, s.c.) was effective in rats treated at 3 weeks; however, it was ineffective at 7 weeks. Conversely, an antidepressant amitriptyline (0.3-3 mg/kg, p.o.) improved mechanical allodynia in rats treated at 7 weeks, whereas it was ineffective at 3 weeks. Diclofenac, a non-steroidal anti-inflammatory drug, was ineffective at both time points. These results demonstrate that, except for diclofenac, the standard analgesic agents tested can effectively alleviate the mechanical allodynia seen in STZ-induced diabetic neuropathy. Their efficacies varied depending on the duration of the diabetic condition, suggesting that temporal changes in pharmacodynamic factors could affect the responsiveness of this model to analgesic agents.     

Effect of etodolac on the prostaglandin concentrations in the kidney of the normal rat

The effect of acute and subchronic dosing with etodolac on the renal PGE₂ and 6-keto-PGF_1α concentrations in the normal rat were studied. Etodolac and other nonsteroidal antiinflammatory drugs (NSAIDs) were administered orally, at equieffective antiinflammatory doses, to normal rats either as a single dose or as seven daily doses. Whole kidney prostaglandin (PG) concentrations were measured. In the acute study, etodolac (3 mg/kg) did not significantly lower the PGE₂ levels for up to 4 hr postdosing. In contrast, naproxen (3 mg/kg) and piroxicam (0.5 mg/kg) significantly decreased the PGE₂ levels to about 20% and 60% of control, respectively. Similar reductions in 6-keto-PGF_1α concentrations were observed. In the subchronic study, etodolac (3 mg/kg/day) did not lower either PGF₂ or 6-keto-PGF_1α concentrations whereas naproxen (3 mg/kg/day), piroxicam (0.5 mg/kg/day), indomethacin (1 mg/kg/day), and aspirin (300 mg/kg/day) significantlydecreased both PGs. In both studies, the effect of etodolac was significantly different from that of the NSAIDs. It is concluded that etodolac possesses only a very weak capacity to lower renal PGs, and therefore is unlikely to cause any renal complications related to PG biosynthesis inhibition.     

Effects of Y-20811, a specific thromboxane A2 synthetase inhibitor, on chemical mediator-induced bronchoconstriction in guinea pigs

We investigated the effects of Y-20811 on chemical mediator-induced bronchoconstriction and the release of chemical mediators into lung perfusion fluid during arachidonic acid (AA)-induced bronchoconstriction in guinea pigs. Y-20811 (0.01-1 mg/kg, i.v.), like acetylsalicylic acid or indomethacin, dose-dependently suppressed arachidonic acid- and LTD4-induced bronchoconstriction, and it (1 mg/kg, i.v.) also inhibited PAF-induced bronchoconstriction in guinea pigs. However, at a dose of 1 mg/kg, i.v., it was inactive against the bronchoconstriction induced by histamine, serotonin and acetylcholine in guinea pigs. Y-20811 (0.3-10 mg/kg) administered orally also prevented the LTD4-induced bronchoconstriction in a dose-dependent manner. This protective effect of Y-20811 (10 mg/kg, p.o.) persisted for at least 24 hr. Y-20811 (10 mg/kg, p.o.) also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti-ovalbumin guinea pig serum and pretreated with mepyramine. In the perfused and ventilated guinea pig lungs, Y-20811 inhibited AA-induced bronchoconstriction, decreased the release of TXA2 (estimated as TXB2) and increased the release of PGE2 into the perfused lung fluid, significantly (TXB2 and PGE2 were measured by HPLC). Therefore, Y-20811 suppressed various stimulant-induced bronchoconstrictions through the decrease of TXA2 production and the increase of PGE2 production. Thus, Y-20811 should prove useful as an anti-asthmatic drug.     

Nootropic candidates inhibit head-twitches induced by mescaline in mice.

The effects of various nootropic candidates on mescaline-induced head-twitches were studied in mice. The number of head-twitches induced by mescaline (100 mg/kg, s.c.) was significantly reduced by idebenone (32 and 100 mg/kg, i.p.), minaprine (0.32-10 mg/kg, p.o.) and nebracetam (100 mg/kg, p.o.). Cholinesterase inhibitors such as tetrahydroaminoacridine (1 and 10 mg/kg, p.o.), NIK-247 (10 and 18 mg/kg, p.o.) and physostigmine (0.32 mg/kg, i.p.) also suppressed the head-twitch response to mescaline. These results suggest that the direct or indirect cholinergic-activating effects of these drugs may be involved in inhibiting mescaline-induced head-twitches.     

Cytoprotective activity of tiquizium bromide (HSR-902) and its mechanism

The effects of HSR-902, an antimuscarinic agent, on acute gastric mucosal lesions induced by various necrotizing agents, gastric mucus secretion and gastric HCO3- secretion in rats were compared with those of pirenzepine.2HCl (pirenzepine), an antiulcer agent. 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently prevented the gastric mucosal lesions induced by ethanol-HCl (60% ethanol in 150 mM HCl), aspirin-HCl (150 mg/kg of aspirin in 150 mM HCl), 0.6 N HCl and 0.2 N NaOH; and the cytoprotective effects of HSR-902 were almost equal or somewhat more potent than those of pirenzepine. 2) HSR-902 (30 mg/kg, p.o.), like pirenzepine, increased the alcian blue binding to gastric mucosa and both hexosamine and N-acetylneuramic acid in gastric juice and reversed the decrease of alcian blue binding to gastric mucosa in water-immersion stress. 3) HSR-902 (30 mg/kg, p.o.), unlike pirenzepine and atropine sulfate, increased the gastric HCO3- secretion in the pylorus-ligated preparations. 4) The cytoprotective effect of HSR-902 (30 mg/kg, p.o.), when examined using gastric mucosal lesion induced by aspirin-HCl, was not abolished by the pretreatment with indomethacin (10 mg/kg, s.c.) or N-ethylmaleimide (10 mg/kg, s.c.). 5) HSR-902 (30 mg/kg, p.o.) did not influence the gastric mucosal potential difference. These results suggest that HSR-902 is a promising drug for the treatment of gastritis and peptic ulcers.     

Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats

Involvement of the serotonergic system in tail tremor induced by repeated administration of nicotine was investigated in rats. Tail tremor induced by nicotine (0.5 mg/kg, s.c.) was suppressed by a 5-HT(1A) receptor antagonist, N-?2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyl?-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride (WAY-100635; 0.3-3 mg/kg, i.p.), but not by a 5-HT(2) receptor antagonist, ketanserin (0.1-0.3 mg/kg, i.p). The 5-HT(1A) receptor agonists, buspirone (1-20 mg/kg, i.p.), gepirone (1-10 mg/kg, i.p.), tandospirone (1-10 mg/kg, i.p.) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.01-0.1 mg/kg, s.c.), enhanced the tail tremor. The enhancement of tail tremor by buspirone (10 mg/kg, i.p.) was blocked by WAY-100635 (0.3-3 mg/kg, i.p.). These findings suggest that nicotine-induced tail tremor is mediated by 5-HT(1A) receptors and that 5-HT(1A) receptor antagonists are effective in the treatment of tremor.