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IDPH-8261, methyl alpha-methyl-4-(3-thienyl)benzeneacetate, exhibited marked anti-inflammatory activity in acute, subacute and chronic models of inflammation. In rats, IDPH-8261 exhibited a dose related inhibition of carrageenin-induced rat paw edema and the inhibition was greater than ibuprofen, phenylbutazone, but was three times less than indomethacin. It exhibited anti-inflammatory activity in normal and adrenalectomized rats. It also exhibited the activity against various phlogistic agents. IDPH-8261 exhibited AI activity in subacute granuloma tests. In adjuvant-induced established polyarthritis. IDPH-8261 exhibited anti-arthritic effect at a very low dose (ED50 = 4 mg/kg, p.o.). Ulcerogenic liability was the lowest (UD50 = 180 mg/kg, p.o.), when compared to reference standard drugs. Low toxicity and high efficacy may make this compound a potentially useful therapeutic agent.

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IDPH-791, when injected (ip) to mice potentiated the pentobarbitone sleeping time in a dose dependent manner. Involvement of neurotransmitters and receptors in this effect was studied using various receptor blockers, enzyme inhibitors, agonist and an amine depletor. Pretreatment with high dose of yohimbine (0.5 mg/kg), haloperidol, cyproheptadine, atropine and a combination of atropine and yohimbine significantly reversed the activity. Physostigmine, diethyldithiocarbamate and high dose of apomorphine (2.5 mg/kg) potentiated the subminimal effect of IDPH-791, whereas low dose of apomorphine (0.1 mg/kg) failed to potentiate. However, reserpine significantly reversed this response. Prazosin, phenoxybenzamine, low dose of yohimbine (0.25 mg/kg), propranolol, methysergide, mepyramine and cimetidine did not produce any change, thus ruling out the involvement of adrenergic, serotonergic and histaminergic systems. There seems to be simultaneous involvement of muscarinic receptors and postsynaptic dopamine (D2) receptors in IDPH-791 induced potentiation of pentobarbitone hypnosis.

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The neuropsychopharmacological profile of a new centrally acting skeletal muscle relaxant, 2,4-dihydro[1,2,4]triazolo[3,4-c][1,4]benzothiazine-1-one (IDPH-791), an analogue of triazolobenzothiazine, has been described and compared to mephenesin, a well known centrally-acting muscle relaxant. IDPH-791 was found to be safer and of longer duration of action than mephenesin in all the tests conducted in this study. Both IDPH-791 and mephenesin caused ataxia, decrease in spontaneous activity and inhibition of pinnal reflex. IDPH-791 was 1.5 to 2.0 times more potent in exhibiting motor inco-ordination and anticonvulsant activity than mephenesin in mice and rats. IDPH-791 was twice as active in inhibiting various spinal polysynaptic reflexes, crossed extensor, flexor, and linguomandibular reflexes; however, both did not affect the typical monosynaptic reflex, patellar reflex. IDPH-791 and mephenesin did not have sedative activity. Although mephenesin exhibited haemolytic activity, IDPH-791 was devoid of this activity. It is concluded that IDPH-791 is a safe and effective centrally-acting muscle relaxant having a longer duration of action than mephenesin. IDPH-791 is also devoid of sedative and haemolytic activity.

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Carrageenin (2%) was used to produce edema and hyperalgesia; indomethacin, phenylbutazone, aspirin, ibuprofen, analgin, paracetamol and phenacetin were tested at different doses for anti-inflammatory and analgesic activity in the same rats as the peak for the edema reached at the end of 3rd hr and for the hyperalgesia at the end of 4th hr. Indomethacin, phenylbutazone and ibuprofen reduced edema and increased the pain threshold. Analgin and aspirin increased the pain threshold relatively at a low dose. Paracetamol and phenacetin were inactive in the doses tested. Carrageenin (2%) was observed to possess both phlogistic and allogenic properties.

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IDPH-791, a novel centrally acting muscle relaxant, in doses up to 500 mg/kg (po) for 14 days did not result in any appreciable adverse effect on body weight gain, food or water consumption including biochemical and haematologica parameters in rats. Variations observed in the biochemistry and haematology were either comparable to controls or were within normal limits.

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The effect of various hypotensive agents were simultaneously tested on locomotor activity and blood pressure of unanaesthetised (conscious) rats. The agents viz clonidine, prazosin, furosemide and hexamethonium were found to reduce significantly the locomotor activity as well as blood pressure, 30 min post administration. Phenoxybenzamine and alpha-methyldopa produced similar type of effect but after 60 and 120 min post administration respectively. Aminophylline and propranolol failed to reduce locomotor activity as well as blood pressure, 60 and 90 min post administration. The findings of the present study are strongly indicative that hypotensive agents reduce locomotor activity and that the reduction is sequel to the fall in blood pressure.

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The involvement of receptor subtypes in clonidine-induced hypothermia in electrically stimulated mice was studied using various alpha-adrenoceptor antagonists. Yohimbine, the selective alpha 2-adrenoceptor antagonist significantly blocked the action of low dose (50 micrograms/kg i.p.) of clonidine pretreated with Minimal Threshold Shock (12 mA, 0.2 Sec), while prazosin, selective alpha 1-adrenoceptor antagonist partially blocked the action, suggesting predominant involvement of alpha 2 and partial involvement of alpha 1-adrenoceptors. Under similar conditions when clonidine was used in higher dose (500 micrograms/kg i.p.), its action was blocked by prazosin, phenoxybenzamine and yohimbine suggesting involvement of both alpha 1 and alpha 2-adrenoceptors. In case of animals pretreated with Maximal Threshold Shock (36 mA, 0.2 Sec) the hypothermic action of clonidine in lower dose was blocked by all the three antagonists viz. prazosin, phenoxybenzamine and yohimbine, suggesting involvement of both alpha 1 and alpha 2-adrenoceptors, however, when clonidine was used in the higher dose, the action was significantly antagonised by prazosin and partially by yohimbine, suggesting predominant involvement of alpha 1 and partial involvement of alpha 2-adrenoceptors.

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Acetic acid administered to mice resulted in post-writhing incoordination and a subsequent fall in the rota-rod test. This fall from rota-rod induced by 3% acetic acid was dose-dependently protected by the non-narcotic analgesics. While suprofen was found to be the most potent (ED50 = 15.29 mg/kg), aspirin was found to be the least potent (ED50 = 81.54 mg/kg). The model appears to be more sensitive than the conventional methods for testing non-narcotic analgesics.

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Dimethylformamide (DMF) is widely used as a drug solvent. We found DMF to have wide-spread pharmacological effects including depressant effect on CNS evidenced by a decrease in locomotor activity, body and limb tone and rectal temperature, and potentiation of pentobarbitone sleep. A dose-dependent hypotensive effect was seen in cats and rats. In rats, it was partially blocked by atropine and was associated with bradycardia. DMF antagonised the contractions of smooth muscle induced by many agonists. An atropine sensitive spasmogenic effect was observed on rabbit ileum at 20 ml/l and a direct relaxant effect at 50 ml/l. A positive inotropic effect on guinea pig atria was observed with 5 ml/l. The results indicate DMF concentrations that may not perhaps produce 'solvent artifacts' when used as a solvent.

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Clonidine produced dose-dependent inhibition of pinna reflex in rats, the ED50 being 1.20 +/- 0.28 mg/kg. The effect of agents affecting adrenergic, tryptaminergic and histaminergic systems were evaluated on clonidine-induced inhibition of pinna reflex. All these agents had no effect on pinna reflex. Phentolamine, phenoxybenzamine, prazosin, propranolol, haloperidol, cyproheptadine and mepyramine did not affect significantly the action of clonidine. However, reserpine, alpha-methyl-p-tyrosine, alpha-methyldopa, diethyldithiocarbamate, 6-hydroxydopamine, yohimbine and cimetidine significantly blocked clonidine-induced inhibition of pinna reflex, indicating the involvement of central adrenergic-histaminergic systems.

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Polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween 80), a surfactant, has been widely used as a solvent for pharmacological experiments. In the present study, polysorbate 80 was found to have toxicity of a low order in both the mice and rats when given by i.p. and p.o. routes. It produced mild to moderate depression of the central nervous system with a marked reduction in locomotor activity and rectal temperature, exhibited ataxia and paralytic activity and potentiated the pentobarbital sleeping time. On intravenous administration in dogs, it had a dose-dependent hypotensive effect. Polysorbate 80 did not have a direct stimulant or relaxant effect on either guinea pig ileum or rat uterus, however, it antagonised the contractions induced by acetylcholine, histamine, barium, 5-hydroxytryptamine and carbachol in a dose-dependent manner. A direct relaxant effect was observed on rabbit jejunum. A dose-dependent myocardial depressant effect was observed on guinea pig and rabbit paired atrial preparations. On the electrically-driven guinea pig left atrial preparation, polysorbate 80 exhibited a dose-dependent negative inotropic action. Polysorbate 80 did not induce diuresis in rats upto a dose of 2.5 ml/kg. The results of the present study indicate that polysorbate 80 can neither be used as a solvent for isolated tissue experiments nor when considered for intravenous administration. However, polysorbate 80 can be employed safely as a vehicle for neuropsychopharmacological experiments in doses not exceeding 1 ml/kg.

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Studies were planned to establish the dose-effect relationship with both acetic acid and phenylquinone and to find out suitable concentrations for these two chemicals for pre- and post screening. The LD50 of acetic acid and phenylquinone were found to be 3.16% and 0.23%, respectively. Based on the studies conducted, the prescreening and postscreening concentrations of 0.5% is recommended for acetic acid, while for phenylquinone, prescreening concentration of 0.005% and postscreening concentration of 0.02% is advocated. Using this criterion in the acetic acid writhing test, analgin was the most potent analgesic while aspirin was the least. However, suprofen was most potent and paracetamol least among analgesics employed against phenylquinone induced writhing.

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Propane-1,2-diol (propylene glycol, PG), considered to be a safe solvent and commonly used as a vehicle in pharmacological and toxicological investigations, showed various neuropsychopharmacological activity in albino mice and rats. In lower concentrations (10-20%), at dose level of 10 ml/kg, PG did not show any significant neuropsychopharmacological activity either by i.p. or p.o. routes. But higher concentrations (50-100%), at same dose level by i.p. route, were found to have moderate to marked effect. There was decrease in locomotor activity, body and limb tone, respiration, rectal temperature and suppression of secondary conditioned responses. Significant potentiation of pentobarbitone (pentobarbital) hypnosis, slight increase in d-amphetamine toxicity in aggregated mice and pronounced analgesic and anti-inflammatory activity were also observed. Most of the above effects were also observed on p.o. treatment but the effects were of lesser degree. PG did not produce any effect on dog or cat blood pressure up to 100% concentration at the dose level 0.5 ml/kg. However, it potentiated the adrenaline (epinephrine) and noradrenaline (norepinephrine) response. On isolated smooth muscle preparations, in 50-100% concentrations, a dose-dependent non-specific blockade was observed against agonists viz. acetylcholine, histamine, 5-HT and barium chloride. No effect was seen on cardiac tissue preparation. On the basis of present findings, it is suggested that propylene glycol as a solvent be used only in low concentration of not more than 10% for pharmacological and toxicological investigations.

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