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New glutarimide compounds were synthesized by incorporating piperidine (compounds 1 to 7), diethylamine (8 and 9), morpholine moities (10 to 13), and alkyl derivatives of 3,5 dicyanoglutarimide (14 to 20) at position -1 of the nitrogen atom. Only compounds 1 to 7 at a dose of 8 mg/kg i.p. caused hypermotility, ataxia, tachypnoea and mild tremors in mice. At higher doses (32 mg/kg i.p.), all compounds induced tonic and clonic convulsions, respiratory paralysis and death. The LD50 values of compounds 1 to 20 in mice range from 152 to 488 mg/kg i.p. and for compounds 21 to 23, the p.o. values are 484, 500 and 525 mg/kg. The relative toxicity of compounds 1 to 7 and 14 to 20 showed inverse ratio in their numbers. Basic compounds 21 to 23 at high dose levels (64 mg/kg i.p.) induced only hypnotic depression. No change was observed in organ-wise histopathological study except patchy necrosis at the site of injection of basic compounds. The CNS pharmacological studies were negative with reference to anti-convulsion, analgesic, antipyretic tests by conventional methods except at higher doses (32 or 64 mg/kg i.p.), which exhibited synergistic effects in mice and rats.

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In the present study, augmentation of contractile responses to acetylcholine, potassium chloride and caffeine by prostaglandin F2 alpha on frog rectus abdominis muscle is documented. The PG-induced responses to ACh was restricted to brief exposure of the tissue to PG. Prolonged exposure resulted in disappearance of the enhancing effect and depression of ACh responses. The augmentation of ACh response was unaltered in presence of physostigmine and the pA2-value of d-tubocurarine was not changed by PGF2 alpha ruling out the involvement of a cholinergic mechanism. In potassium depolarized muscle, PGF2 alpha abolished the contractile response to caffeine, indicating an action at the trigger calcium site. PGF2 alpha also permitted reactivation contracture during repolarization.

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Newly synthesized glutarimide compounds (Table 1) at doses of 4, 8 and 16 mg/kg (IP) reduced the duration of sleep induced by pentobarbitone in mice. Compounds 1 to 7 and 21 were more potent than the other compounds and their activity was comparable to the reference drug, bemegride. The structure activity relationship for the decrease in duration of barbiturate anaesthesia caused by the various groups of these compounds was mainly found to be inversely related to the length of the alkyl side chain at position 4 of the beta carbon atom. It was also shown that the presence of piperidine, diethylamine and morpholine moieties attached to 3,5-dicyanoglutarimide was partly responsible for the reduction in barbiturate anaesthesia by these compounds.

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Muscarinic action of acetylcholine was demonstrated in the human isolated appendix. Histamine-induced contractions seemed to the mediated by H1 receptors. Nicotine and DMPP-induced contractions were mediated through their action on ganglion cells. Experiments with adrenergic drugs suggested the presence of beta receptors.

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1 Isolated duodenum of the rat, exposed to ultraviolet (u.v.) light in the presence of NO2 ions, responded with reversible relaxation. 2 The photorelaxation response did not seem to involve any known receptor mechanisms and was independent of any ganglionic or neuronal influences. 3 Changes in the ionic environment of the tissue showed that NA+ and Ca2+ were essential for the photorelaxation. K+ depolarized-tissue did not show the photoresponse. 4 The presence of the metabolic inhibitors, iodoacetic acid, 2,4-dinitrophenol, sodium fluoride, sodium azide or potassium cyanide, abolished the photorelaxation response. 5 It is proposed that the photorelaxation of the tissue resulted from the liberation of metabolic energy following NO2 ion-dependent absorption of u.v. light energy, which in turn, interfered with the Na+ ion movement across the cell membrane.

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Responses of isolated tissue preparations to ultraviolet (UV) light were studied with and without the presence of photosensitizers like eosin, fluorescein and sodium nitrite. Exposure to UV light in the presence of sodium nitrite induced consistent relaxation of rat duodenum. The photorelaxation was found to be related to the concentration of sodium nitrite. Adrenergic or cholinergic mechanisms do not seem to be involved. The isolated rat duodenum preparation exhibited quantitatively consistent photoresponse for 3 to 4 hr at its normal tone obviating the need for additional spasmogens as needed with other preparations. The preparation is a suitable test model for the study of photobiologic response evoked by UV light.

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20 newly synthesized glutarimide compounds and their organic bases were investigated for their action on the autonomic ganglion in cats. Compounds 1 to 7 having piperidine moiety showed mainly ganglionic stimulant activity as evidenced by rise in blood pressure, contraction of nictitating membrane and rise in urinary bladder pressure of cats, which was completely blocked by C6 and partly by atropine. Compound 8 and 9 having diethylamine moiety showed initial stimulation--followed by blockade of the autonomic ganglia. Compounds 10 to 13 having morpholine moiety showed stimulation of both sympathetic and parasympathetic autonomic nervous system. The responses were due to effect partly on ganglia and partly on the receptors. Compounds 14 to 20, which have alkyl substitution chain at position 4 of beta-carbon atom, showed depressor action. The ganglionic activity of the glutarimide compounds in various groups was found to be in inverse ratio to the length of the alkyl side chain at position 4 of the beta-carbon atom.

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Diphenylhydantoin (DPH) (20 x 10(-6) to 80 x 10(-6) M/kg) blocked the depressor responses to isoproterenol in spinal, bilaterally vagotomized and atropine pretreated cats; depressor responses to histamine were unaffected; DPH shifted the isoproterenol concentration-response curve to the right in isolated guinea pig tracheal chain preparation, isolated rabbit ileum and isolated perfused heart of frog. The results suggest that DPH has a specific beta-adrenoceptor blocking action and the blockade appears to be competitive in nature as shown by PA2 and PA10 values.

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The effects of a new series of glutarimide compounds have been studied in acetylcholine induced auricular fibrillation in anaesthetized cats and epinephrine induced ventricular arrhythmmias in conscious pigeons. Some of the compounds showed varying degree of protective action against experimental arrhythmias. However these compounds were found to be less potent than quinidine. The mechanism of antiarrhythmic action has been discussed.

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Effects of four antiepileptic drugs, viz., diphenylhydantoin, trimethadione, phenobarbitone and ethosuximide, were studied on different in vitro and in vivo skeletal muscle preparations which consisted of frog rectus, rat phrenic nerve diaphragm and cat gastrocnemius sciatic nerve preparations. A dose related blockade of neuromuscular transmission was seen with all the compounds tested. The blockade was mainly confined to the neuromuscular junction, although direct stimulation of muscle was slightly affected. The blockade was partially antagonized by physostigmine, adrenaline, succinylcholine, choline, tetraethylammonium and KCl and was additive to that due to tubocurarine. Moreover, the drugs were found to possess moderate local anaesthetic activity. The blockade was therefore considered to be partly due to curariform activity and partly due to their local anaesthetic activity.

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The effect of three recently introduced beta-adrenoceptor blockers practolol, USVC 6524 and Inpea was studied on various skeletal muscle preparations. Practoloo, USVC 6524 and Inpea produced a dose related inhibition of acetylcholine induced contractions of rectus abdominis muscle of frog. These drugs also blocked neuromuscular transmission when tested on in vitro rat phrenic nerve diaphragm preparation; the blockade was partially reversed by physotigmine, KCl and adrenaline and was potentiated by d-tubocurarine. In gastrocnemius sciatic muscle-nerve preparation only Inpea exhibited neuromuscular blocking activity, while practolol and USVC 6524 did not show any effect up to a dose of 10 mg/kg (intraarterially). The apparent discrepancies between the results of in vitro and in vivo experiments could not be adequately explained. It has been discussed that the neuromuscular blockade caused by presently investigated beta-adrenoceptor blocking agents is essentially due to curare-like activity and to a small extent may be due to local anaesthetic activity.

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1 Metallic mercury (0.04 ml) injected into the foot pad of rats induced a consistent inflammatory reaction, which at 4 h showed oedema but no cellular infiltration or vascular changes. The lesions exhibited lymphocytic infiltration, vasodilatation and haemorrhages at 24 and 48 h, and often became cystic after 2-3 weeks, before healing. The oedema volume at 4 h was used to test anti-inflammatory activity of drugs.2 Cortisone, phenylbutazone, indomethacin, acetylsalicylic acid, flufenamic acid and propranolol exhibited potent, dose-related anti-inflammatory activity. Aminopyrine, chloroquine and chlorpromazine were only moderately effective. Dimercaprol, adrenaline, and to some extent, mepyramine also inhibited mercury-induced oedema.3 This simple model of acute inflammation may be useful for preliminary tests of anti-inflammatory activity.

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