bluuebunny/crossref_metadata_2025 huggingface dataset:
RENAL EFFECTS OF VERATRIDINE
Authors: CHAUDHRI KHURSHID‐UN‐NISA
Published: July 2012

Veratridine hydrochloride injected subcutaneously into unanaesthetized rats inhibited water diuresis. A linear relationship between log dose and antidiuretic effect could be established over the dose range 50 to 200 μg./100 g. of body weight. When veratridine hydrochloride was injected intravenously in doses from 10 to 30 μg./100 g., this relationship was also linear. In terms of its antidiuretic action, the alkaloid was approximately five times as effective when given intravenously. Rats anaesthetized with urethane responded to an intravenous injection with a more pronounced inhibition than unanaesthetized animals. Protoveratrine injected intravenously into unanaesthetized rats showed no clear relationship between dose and magnitude of antidiuretic effect. Veratridine hydrochloride injected intravenously had a pronounced hypotensive effect in both anaesthetized and unanaesthetized rats. Treatment with atropine did not affect this hypotensive action significantly. Atropine given subcutaneously 30 min. before an intravenous injection of veratridine hydrochloride abolished or diminished the inhibitory effect of veratridine on water diuresis. Veratridine hydrochloride injected intravenously into unanaesthetized rats caused a marked depression of the clearance of inulin and p‐aminohippurate. In unanaesthetized rats with an osmotic diuresis, veratridine hydrochloride produced its usual antidiuretic effect. The urine of rats injected with veratridine hydrochloride produced an antidiuretic effect when injected intravenously into other animals. The antidiuretic potency of such urines was not affected by treatment with thioglycollate. Animals injected with veratridine excreted small amounts of a veratridine‐like substance in the urine. These results do not suggest that veratridine in antidiuretic and hypotensive doses stimulated the neurohypophysis in the rat.
EFFECT OF VARIOUS ELECTROLYTES UPON CARDIAC AND SKELETAL MUSCULATURE
Authors: SELYE H. , BAJUSZ E.
Published: July 2012

In rats kept on a low‐potassium diet that contains only maintenance levels of magnesium, cardiac necroses and muscular cramps were readily induced by the oral administration of sodium Perchlorate or disodium hydrogen phosphate. The precipitation of these cardiac and skeletal muscle changes by sodium chlorate was prevented by the prophylactic administration of either potassium or magnesium chlorides. The protective effect of these chlorides against the cardiotoxic and convulsive effects of disodium hydrogen phosphate has already been demonstrated by our earlier experiments. Sodium sulphate produced cardiac necroses in rats maintained on the same diet, and both potassium and magnesium chlorides had a prophylactic action. Unlike sodium Perchlorate, however, sodium sulphate produced no muscular cramps under these conditions. Equimolecular amounts of sodium given in the form of sodium chloride (instead of sodium Perchlorate, sodium sulphate, or disodium hydrogen phosphate) did not cause cardiac necroses or muscular cramps in rats maintained on the potassium‐deficient diet. As the same three sodium salts, namely the Perchlorate, the sulphate, and the hydrogen phosphate, produced cardiac necroses in rats sensitized by either a potassium‐deficient diet or by certain corticoids, it seems that the anion must play a decisive rôle, since equivalent amounts of NaCl are ineffective.
MECHANISM OF ACTION OF RESERPINE IN PRODUCING GASTRIC HAEMORRHAGE AND EROSION IN THE MOUSE
Authors: BLACKMAN J. G. , CAMPION D. S. , FASTIER F. N.
Published: July 2012

Gastric haemorrhage was produced regularly in mice within 6 hours of the subcutaneous injection of a large dose (2 to 10 mg./kg.) of reserpine or of deserpidine. Rescinnamine, syrosingopine (SU‐3118), and tetrabenazine (Ro 1–9569) were less active. Gastric haemorrhage was also produced within 6 hours when 5‐hydroxytryptamine (10 mg./kg.) was injected every half‐hour. Neither reserpine nor 5‐hydroxytryptamine produced gastric haemorrhage in mice which had been vagotomized by tying the oesophagus at the cardio‐oesophageal junction or which had been pre‐treated with iproniazid. Amphetamine was less effective than iproniazid in preventing gastric haemorrhage after reserpine, and the following drugs were ineffective: cocaine, methyl phenidate (Ritalin), amarin, caffeine, nikethamide, lysergic acid diethylamide and its 2‐bromo derivative (BOL148). Gastric haemorrhage was not observed in mice which had been given substantial doses of atropine or of hexamethonium before reserpine. The incidence of haemorrhage was substantially reduced by treatment with an antacid mixture. It is concluded that reserpine‐like drugs cause gastric haemorrhage by a mechanism which has an important central component and which involves the liberation of 5‐hydroxytryptamine.
TRACER STUDIES OF THE DISTRIBUTION AND TRYPANOCIDAL ACTION OF STILBAMIDINE IN RATS
Authors: FULTON J. D. , MATHEW K. K.
Published: July 2012

[14C]Stilbamidine was used to study the distribution of the drug in the organs and tissues of rats following intravenous injection. The prophylactic action of stilbamidine was shown to depend upon the unchanged drug retained in tissues, especially the liver. Only the parent drug was extracted from trypanosomes when an infection was treated during the acute phase, as shown by the use of the fluorescent properties of stilbamidine in conjunction with scanning and chromatographic techniques. The action of stilbamidine on trypanosomes is therefore a direct one. A method for the synthesis of [14C]stilbamidine in much improved yield is also described.
DRUG RESISTANCE IN TRYPANOSOMES; SELECTIVE INTERFERENCE WITH TRYPANOCIDAL ACTION
Authors: WILLIAMSON J.
Published: July 2012

Selective reversal of the trypanocidal action of carboxylated arsenicals by p‐aminobenzoic acid and of melaminyl arsenicals and diamidines by melamine has been demonstrated in vivo and in vitro. The structural specificity of these reversal phenomena is high, and suggests preferential adsorption of the antagonist during a reversible primary drug fixation stage. Thiols antagonize neutral, carboxylated and melaminyl aromatic arsenicals equally, but not diamidines; p‐aminobenzoic acid antagonism is specific for carboxylated arsenicals, and melamine antagonizes only the melaminyl arsenicals and the diamidines. These reversals reflect the pattern of cross‐resistance behaviour and suggest that cellular structures associated with a reversible stereospecific drug adsorption phase are modified during the development of resistance.
THE ANTAGONISM OF COCAINE TO THE ACTION OF CHOLINE 2,6‐XYLYL ETHER BROMIDE AT SYMPATHETIC NERVE ENDINGS
Authors: NASMYTH P. A. , ANDREWS W. H. H.
Published: July 2012

Choline 2,6‐xylyl ether bromide (TM10) prevents contraction of the nictitating membrane and of the spleen in response to sympathetic nerve stimulation. It was confirmed that this effect was due to prevention of the release of noradrenaline (“sympathin”) at the nerve endings. The intravenous injection of cocaine before choline xylyl ether blocked the action of the latter drug. However, when atropine was injected before the cocaine the effects of large doses of choline xylyl ether were not completely blocked. After block had been produced by choline xylyl ether the injection of cocaine partially restored both the secretion at the sympathetic nerve endings and the responses of the organs supplied by the nerves. Phenoxybenzamine did not restore the secretion at the nerve endings after it had been inhibited by choline xylyl ether, indicating that the latter did not cause an increased uptake of sympathin by the receptors.
CHOLINE ACETYLASE ACTIVITY IN THE ATRIA AND ITS POSSIBLE RELATION TO THE MAINTENANCE OF THE MEMBRANE POTENTIAL
Authors: BURN J. H. , MILTON A. S.
Published: July 2012

Choline acetylase is present in rabbit atria and forms acetylcholine continuously. It is known that the contractions of isolated atria cease when the temperature falls to a point below 20° C., and that they can be started again by acetylcholine, which causes a rise in the transmembrane potential. The question may therefore be asked whether the transmembrane potential is normally kept sufficiently high for impulses to be propagated by the acetylcholine which is formed within the atria. The effect of lowering the temperature on choline acetylase activity has therefore been studied. The activity was found to decline much more steeply below 20° C. than between 33° and 20°. The Q10 rose to 7.8. This finding is consistent with the view that one function of choline acetylase activity is to maintain the transmembrane potential.
THE ACTIONS OF BRETYLIUM: ADRENERGIC NEURONE BLOCKING AND OTHER EFFECTS
Authors: BOURA A. L. A. , GREEN A. F.
Published: July 2012

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare‐like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. Adrenergic nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5‐hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea‐pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.
THE USE OF THE GUINEA‐PIG ILEUM PREPARATION FOR TESTING THE ACTIVITY OF SUBSTANCES WHICH IMITATE OR ANTAGONIZE THE ACTIONS OF 5‐HYDROXYTRYPTAMINE AND TRYPTAMINE
Authors: BARLOW R. B. , KHAN I.
Published: July 2012

On the guinea‐pig ileum, 5‐hydroxytryptamine appeared to act in the same way as tryptamine on two types of receptor (morphine‐sensitive and phenoxybenzamine(Dibenzyline)‐sensitive). The actions of analogues of 5‐hydroxytryptamine on the phenoxybenzamine‐sensitive receptors resembled their actions on the rat uterus, and the actions on the morphine‐sensitive receptors slightly resembled those on the rat fundus strip. The guinea‐pig ileum preparation, however, did not appear to be more suitable than the rat uterus and rat fundus strip for testing the ability of compounds to imitate or antagonize 5‐hydroxytryptamine.
ASSAY OF SUXAMETHONIUM AND LAUDEXIUM ON THE FROG RECTUS ABDOMINIS
Authors: BRITTAIN R. T. , CHESHER B. G. , COLLIER H. O. J. , GRIMSHAW J. J.
Published: July 2012

Suxamethonium, like acetylcholine, causes contracture of the isolated rectus abdominis muscle of the frog, whereas laudexium antagonizes this effect. These actions may be used to assay both drugs with reasonable speed and fiducial limits, provided that changes in responsiveness of the preparation during the course of assay are met by suitable design and analysis. Small quantities of suxamethonium and laudexium may be assayed in certain body fluids.
THE COMPARATIVE TOXICITY OF ANTIBIOTICS TO SKIN
Authors: LAWRENCE J. C.
Published: July 2012

The toxicity of sixteen antibiotics to skin in vitro was investigated by a microrespirometer technique and by the histological appearance of 3‐day cultures. There was close agreement between the results obtained by the two methods and between tests with human and with guinea‐pig skin. Antibiotic concentrations which caused more than 30% respiratory damage after one day invariably produced abnormal cultures, and more than 60% respiratory damage often resulted in necrotic cultures. Dose/response curves were obtained for the effect of antibiotics upon skin respiration. Mathematical evaluation had little advantage over visually fitted dose/response curves. The ED50 provided a reproducible measure of the relative toxicity of different antibiotics to skin, but the ED30 probably provided a better comparison because this was the highest concentration of antibiotic which permitted migration of epithelium. Many antibiotics at therapeutic concentrations show little toxic effect upon skin in vitro. It is suggested that the healing of surface lesions might well be retarded if the antibiotic concentration found toxic in vitro were maintained at a similar concentration in vivo.
EFFECT OF HISTAMINE ON GANGLIONIC TRANSMISSION
Authors: GERTNER S. B. , KOHN R.
Published: July 2012

Histamine has been shown to depress transmission through the perfused superior cervical ganglion of the cat when doses of 150 μg. or more were administered. The intensity of the ganglionic block was related to the dose of histamine employed. In one‐third of the experiments, a slow contracture of the nictitating membrane occurred after histamine had been injected; the contracture lasted up to 10 min., and subsequent injections of histamine gave rise to progressively smaller responses. The blocking action of histamine was evident in all experiments and was the most prominent feature observed. Histamine in a sub‐depressant dose enhanced the action of the competitive blocking agents tetraethylammonium and hexamethonium, and also the depolarizing blocking agents tetramethylammonium and nicotine. The possible physiological rôle of histamine in the autonomic nervous system is discussed.
THE RELATION BETWEEN TEMPERATURE AND CHANGES IN ION CONCENTRATION ON VENTRICULAR FIBRILLATION INDUCED ELECTRICALLY
Authors: MILTON A. S.
Published: July 2012

Further observations have been made on ventricular fibrillation induced by electrical stimulation in the isolated rabbit heart, in extension of the finding that fibrillation was arrested by cooling from 37° to 32°. The observations now made suggest that at 37° the isolated rabbit heart perfused with Locke solution is on the edge of anoxia, but that at 32° the oxygen supply is adequate. At the lower temperature the proportion of hearts fibrillating at any given potassium concentration was reduced, so, although the proportion of hearts fibrillating rose as the potassium concentration fell, even when the latter was one‐quarter of the normal the proportion was not higher than 67%. The relation of the concentration of calcium ions to the proportion of hearts fibrillating changed from biphasic at 37° to almost rectilinear at 32°, the proportion increasing as the concentration of calcium ions rose. It was confirmed that a reduction in sodium concentration also raises the proportion of hearts fibrillating.
ABSORPTION, METABOLISM AND ELIMINATION OF PEMPIDINE IN THE RAT
Authors: MUGGLETON D. F. , READING H. W.
Published: July 2012

Pempidine (1,2,2,6,6‐pentamethylpiperidine) is a ganglion blocking agent introduced recently for the treatment of hypertension by oral administration of its hydrogen tartrate. It can be estimated colorimetrically by coupling with methyl orange, or fluorimetrically by reaction with eosin in xylene, the limits of sensitivity being 0. 5 μg./ml. and 0.001 μg./ml. respectively. These methods, combined with appropriate extraction techniques, were suitable for estimating pempidine in aqueous solutions of its salts, in biological fluids and the like, and for investigating the biochemical properties of the drug when given orally to rats in amounts similar to those used clinically.

When administered orally to rats pempidine was rapidly absorbed, the maximum concentration in plasma being attained after 30 min. The drug was preferentially taken up by erythrocytes and a red cell/plasma partition ratio of about 1.2 established with clinical doses. Pempidine was soon distributed throughout the body, including the cerebrospinal fluid, and the highest concentrations were found in kidney, spleen and liver. Pempidine also entered the foetus and passed thence into the amniotic fluid. Protein‐binding of the drug occurred only to a very limited extent and there was little evidence that it was metabolized. Pempidine was excreted rapidly in urine during 24 hr. following oral administration.
THE EFFECT OF MORPHINE ON VAGAL INHIBITION OF THE HEART
Authors: KOSTERLITZ H. W. , TAYLOR D. W.
Published: July 2012

The action of morphine (0.1 to 100 mg./kg.) on the cardiac slowing produced by stimulation of the right vagus nerve varied in the four species investigated. In the guinea‐pig, morphine had no inhibitory effect and in the cat the effect was small, but in the rat and the rabbit stimulation of the vagus slowed the heart much less after administration of morphine than before. Further, in the last two species morphine delayed the onset of cardiac slowing. Nalorphine, which given alone had a slight morphine‐like action, partly reversed the effect of morphine.
THE STABILITY OF ENDOGENOUS CORTICOTROPHIN IN RAT BLOOD IN VITRO
Authors: HODGES J. R. , VERNIKOS JOAN
Published: July 2012

Endogenous corticotrophin is stable in blood in vitro for periods of up to 1 hr. at 4° and 22°, and in plasma for at least 24 hr. at −15°. Estimates of plasma corticotrophin concentration provide less consistent results than assays done on whole blood. The optimal conditions for storing blood prior to the determination of its corticotrophin concentration are discussed.
EFFECTS OF CROSS‐SUTURE AND OF INJECTED ACETYLCHOLINE ON THE SUPERSENSITIVITY OF DENERVATED STRIATED MUSCLE
Authors: EMMELIN N. , NORDENFELT I.
Published: July 2012

The sensitivity of the tongue muscles to acetylcholine was examined in repeated experiments on cats anaesthetized with hexobarbitone. The supersensitivity which developed after section of the hypoglossal nerve was found to decrease when the muscles, after cross‐suture, became re‐innervated from the vagus or the chorda‐lingual nerve. The supersensitivity caused by denervation could also be reduced by injecting acetylcholine repeatedly during six hours in acute experiments.
SPECIFICITY OF AMINE OXIDASE FOR OPTICALLY ACTIVE SUBSTRATES AND INHIBITORS
Authors: PRATESI P. , BLASCHKO H.
Published: July 2012

A number of optically active amines have been tested as substrates or inhibitors of amine oxidase of rabbit and guinea‐pig liver. The two stereoisomers of β‐hydroxyphenethylamine were oxidized at the same rate by rabbit liver, but the guinea‐pig liver extracts oxidized the d form more rapidly than the l form. The two stereoisomers of amphetamine were equally active as inhibitors of the rabbit liver oxidase, but with guinea‐pig liver extracts dexamphetamine, the (+) form, was more potent as an inhibitor. In both species, 2‐hydroxy‐1‐phenylethylamine was a weaker inhibitor than 1‐phenylethylamine; in the rabbit liver (+) forms of these two amines were more potent as inhibitors.
THIOPENTONE AND BUTHALITONE: THE RELATIONSHIP BETWEEN DEPTH OF ANAESTHESIA, PLASMA CONCENTRATION AND PLASMA PROTEIN BINDING
Authors: KANE P. O. , SMITH S. E.
Published: July 2012

For 24 hr. after intravenous administration of buthalitone or thiopentone, plasma concentrations in young human subjects have been followed. Buthalitone was distributed to the tissues more rapidly but was metabolized at a slower rate than thiopentone. The relationships between these findings and differences in plasma protein binding and oil/water partition coefficients were studied. It is suggested that some of the differences observed in potency between the substances is a reflection of differences in their modes of distribution. No relationship was found between speed of recovery from anaesthesia and plasma barbiturate concentrations.
UPTAKE OF INJECTED [14C]ADRENALINE IN DENERVATED AND IN NORMALLY INNERVATED SUBMAXILLARY GLANDS OF THE CAT
Authors: STRÖMBLAD B. C. R.
Published: July 2012

Radioactive adrenaline was injected into cats after one submaxillary gland had been denervated, either by section of the chorda‐lingual nerve or by excision of the superior cervical ganglion. No indication was found that the supersensitivity caused by denervation was due to a greater uptake of adrenaline in the denervated gland. Stimulation of the chorda tympani greatly increased the amounts of radioactive adrenaline taken up by normally innervated submaxillary glands.
PARALDEHYDE AND METHYLPENTYNOL AND GANGLIONIC TRANSMISSION
Authors: QUILLIAM J. P.
Published: July 2012

Paraldehyde and methylpentynol blocked transmission of nerve impulses through the superior cervical ganglion of the cat when the drugs were administered intra‐arterially to the ganglion or intravenously using the nictitating membrane as an indicator. Electrical studies showed that concentrations of methylpentynol and paraldehyde which blocked transmission in the isolated rat superior cervical ganglion were without action on the preganglionic nerve fibre. In amounts which blocked transmission in the isolated rat ganglion, paraldehyde had no depolarizing activity directly on the ganglion cells and did not interfere with the depolarizing activity of added acetylcholine. The results suggest that the block in transmission of the impulse could be accounted for by a decrease in the release of acetylcholine from the preganglionic nerve terminals. In both species the block was reversible.
PHARMACOLOGY OF METHYLPENTYNOL AND METHYLPENTYNOL CARBAMATE
Authors: MARLEY E.
Published: July 2012

The pharmacology of methylpentynol and methylpentynol carbamate has been studied. The drugs depressed monosynaptic and polysynaptic reflexes, and exerted weak ganglion and neuromuscular blocking actions. They also produced transitory hypotension, and increase of aortic blood flow. Perfusion of the coronary arteries with these drugs led to slowing of the heart, diminished systolic amplitude, dysrhythmias, and increased ccronary flow. Respiration was stimulated with small and depressed with larger doses of both drugs. The two compounds diminished the response of the isolated guinea‐pig ileum to drugs acting directly on muscle or through ganglia. The effect of the two substances was likened to that of other central nervous system depressants, particularly to that of ethanol.
THE EFFECT OF METHYLPENTYNOL AND METHYLPENTYNOL CARBAMATE ON THE PERFUSED SUPERIOR CERVICAL GANGLION OF THE CAT
Authors: MARLEY E. , PATON W. D. M.
Published: July 2012

The action of methylpentynol and methylpentynol carbamate on the perfused superior cervical ganglion of the cat was analysed. Both drugs, in doses of 1 to 5 mg., depressed the output of acetylcholine. If the acetylcholine output was reduced by more than about 50%, transmission failed. Both drugs also reduced the response of the ganglion to injected acetylcholine. The carbamate, but not methylpentynol itself, had a transient stimulant action on the ganglion, unaccompanied by acetylcholine release.
THE EFFECT OF ADRENAL STEROIDS AND CORTICOTROPHIN ON THE GROWTH OF A SARCOMA OF HUMAN ORIGIN IN SMALL LABORATORY ANIMALS
Authors: BUTTLE G. A. H. , D'ARCY P. F. , HOWARD E. M. , KELLETT D. N.
Published: July 2012

9α Fluorohydrocortisone, prednisolone, and hydrocortisone promoted the growth of the human tumour (H.S.1) in weanling rats, but deoxycortone acetate was ineffective even when injected in very high dosage; Cortrophin ZN, a long‐acting corticotrophin preparation, was just as effective as cortisone. This effect of corticotrophin on tumour growth was mediated by the adrenal cortex, and was related to the enhanced secretion of adrenocorticoids; some correlation existed between tumour size and adrenal hypertrophy in the corticotrophin‐treated rats. The action of adrenal steroids and of corticotrophin in promoting the growth of the tumour is discussed.
INTERACTION BETWEEN HISTAMINE AND DICHLOROISO‐PROTERENOL, HEXAMETHONIUM, PEMPIDINE, AND DIPHENHYDRAMINE, IN NORMAL AND RESERPINE‐TREATED HEART PREPARATIONS
Authors: MANNAIONI P. F.
Published: July 2012

Histamine stimulated the isolated auricles and heart of the guinea‐pig. The effect was best seen in auricles which had been previously depressed by treatment with reserpine. Ganglionic blocking drugs (hexamethonium and pempidine), applied to auricles which had been previously treated with reserpine, abolished the diphasic effect of nicotine, but did not alter the response to histamine. Dichloroisoproterenol did not modify the stimulant action of histamine in isolated auricles, either before or after treatment with reserpine; nor did it alter the response of the isolated heart. Diphenhydramine reduced or blocked the stimulant action of histamine in auricles which had been previously treated with reserpine. The results support the hypothesis that histamine stimulates the myocardium by a direct action on specific receptors.
SOME PHARMACOLOGICAL ACTIONS OF SYNTHETIC ANALOGUES OF ANGIOTENSINAMIDE
Authors: PAIVA THEREZINHA B. , PAIVA A. C. M.
Published: July 2012

In order to evaluate the importance of some structural features of asparagyl1‐valyl5‐angiotensin II (angiotensinamide) for its pharmacological actions, the relative potencies of angiotensinamide and five peptide analogues were studied on the blood pressure of the rat, the isolated rat uterus and the isolated guinea‐pig ileum. All the modifications of the angiotensinamide structure that were studied led to a decrease of potency which, however, was not the same on all three preparations. The importance of the guanido group, the phenolic group and the length of the peptide chain for the pharmacological activities of these peptides is discussed.
THE TRYPANOCIDAL ACTION OF HOMIDIUM, QUINAPYRAMINE AND SURAMIN
Authors: HAWKING F. , SEN AMIYA BHUSHAN
Published: July 2012

Homidium, quinapyramine, and suramin (Group II compounds) produce their trypanocidal effect in vivo only after a latent period of 24 hr. or more, during which time the trypanosomes may continue to multiply; this is in contrast to trivalent arsenical and diamidine compounds (Group I compounds), which begin to act immediately. Group II compounds also differ from Group I compounds in that (a) they have only a slight tendency to combine with trypanosomes, (b) they have little trypanocidal action in vitro, but (c) they make trypanosomes non‐infective to fresh subinoculated mice. To explain these features it is postulated that homidium, quinapyramine, and suramin first combine in small amounts with some receptor on the trypanosome and then block some biochemical system which produces a hypothetical substance X which is needed for cell division of the trypanosome; the trypanosome is supposed to contain a preformed store of this substance X sufficient for several divisions to take place; and it is only when this store is exhausted that cell division is prevented and the trypanosome eventually dies.
THE EFFECT OF PRECURSORS OF NORADRENALINE ON THE RESPONSE TO TYRAMINE AND SYMPATHETIC STIMULATION
Authors: BURN J. H. , RAND M. J.
Published: July 2012

Previous observations have shown that the effects of sympathetic stimulation and of tyramine were absent in the organs of animals treated with reserpine, but that they were restored by an infusion of noradrenaline. Observations are described showing that an infusion of adrenaline did not restore the pressor action of tyramine in the cat or in the rat, but that in the rat the pressor action was restored by an infusion of dopamine, or of (—)‐dopa, or of m‐tyrosine, or of phenylalanine. Observations are also described showing that the effect of postganglionic stimulation of the fibres to the nictitating membrane and to the iris was restored by an infusion of dopamine or of (‐)‐dopa; it was restored less well by an infusion of noradrenaline. An infusion of noradrenaline did not restore the action of tyramine on the denervated iris or on the denervated vessels of the cat's foreleg. An infusion of noradrenaline appeared to increase the effect of sympathetic stimulation of the hypogastric nerves to the uterus of the virgin cat about as much as an infusion of adrenaline. An infusion of noradrenaline restored the constrictor action of nicotine on the perfused vessels of the rabbit ear.
INHIBITION OF MAST CELL DISRUPTION AND HISTAMINE RELEASE IN RAT ANAPHYLAXIS IN VITRO. COMPARISON WITH COMPOUND 48/80
Authors: MOTA I. , ISHII TISUE
Published: July 2012

In vitro anaphylactic reaction causes mast cell damage and histamine release from rat tissue. Histamine release is correlated with mast cell damage and both phenomena are simultaneously inhibited by various metabolic inhibitors, antipyretics, calcium lack and previous heating of the tissue at 45°. The mast cell damage produced by antigen in sensitized rat tissues is morphologically similar to that caused by compound 48/80, both agents causing extrusion of granules. Mast cell damage and histamine release induced by antigen or by compound 48/80 are inhibited alike by several substances and conditions. It is suggested that in rats the histamine‐releasing mechanism of the antigen‐antibody reaction in anaphylaxis is very similar to that of compound 48/80.
ACTION OF TWO ETHYL THIOL ESTERS AGAINST EXPERIMENTAL TUBERCULOSIS IN THE GUINEA‐PIG
Authors: DAVIES G. E. , DRIVER G. W.
Published: July 2012

Two thiol esters, ethyl dithiolterephthalate (Compound 13,130) and ditophal (ethyl dithiolisophthalate; Etisul), have been tested for their antituberculosis activity in guinea‐pigs. Compound 13,130 was active at a dose of 100 mg./kg. twice daily by mouth in animals infected subcutaneously, but was inactive against an intracerebral infection at 50 mg./kg. Ditophal was active in the subcutaneously infected animals at 200 mg./kg. orally or 50 mg./kg. subcutaneously. Higher doses subcutaneously were irritant.
THE 5‐HYDROXYTRYPTAMINE CONTENT OF MOUSE BRAIN AND WHOLE MICE AFTER TREATMENT WITH SOME DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM
Authors: BARTLET A. L.
Published: July 2012

A number of drugs were examined for their ability to change the concentration of 5‐hydroxytryptamine in mouse brain and in whole mice treated with 5‐hydroxytryptophan. After β‐phenyl‐isopropylhydrazine or iproniazid, two inhibitors of monoamine oxidase, the brain 5‐hydroxytrypt‐amine rose to a maximum value in 8 hr., after which it declined, although a slight rise remained for as long as 6 days. Dose‐effect relationships, determined 6 hr. after administration, showed β‐phenyl‐isopropylhydrazine to be approximately 60 times as effective as iproniazid in raising the brain 5‐hydroxytryptamine. When mice were given 5‐hydroxytryptophan and the amine content of the whole mice estimated, pretreatment with β‐phenylisopropylhydrazine increased their 5‐hydroxytryptamine content whereas pretreatment with iproniazid did not change it. The concentration of the amine in mouse brain and in whole mice was lower after reserpine, but was raised when reserpine and β‐phenylisopropylhydrazine were given together. A small rise in brain 5‐hydroxytryptamine was found after chlorpromazine; when chlorpromazine was given with iproniazid, however, the resulting increase was less than that found after iproniazid alone. Brain 5‐hydroxytryptamine was unaltered after prolonged treatment with morphine.
THE EFFECTS OF INTRACISTERNAL SARIN AND PYRIDINE‐2‐ALDOXIME METHYL METHANESULPHONATE IN ANAESTHETIZED DOGS
Authors: BROWN R. V.
Published: July 2012

Dogs poisoned by the anticholinesterase sarin could be saved by intravenous administration of atropine sulphate together with a suitable oxime. The central effects of intracisternal sarin were respiratory paralysis and vasomotor stimulation. The problem arose as to whether the oxime, being a quaternary nitrogen compound, could enter the brain from the blood, and could have a central action on the paralysed respiration. The methyl methanesulphonate of pyridine‐2‐aldoxime administered intracisternally, after sarin poisoning by the same route, was ineffective; atropine, given intravenously, was effective. The central and peripheral effects of sarin were thus reversed by the atropine‐oxime therapy, the central effects by atropine, the peripheral by the oxime.
A COMPARISON OF THE KALLIKREIN‐KININ SYSTEM IN SHEEP AND DOGS
Authors: GADDUM J. H. , GUTH P. S.
Published: July 2012

Three preparations of kallikrein, made from the urine of man, dog and sheep, all formed active kinins when incubated with the plasma of sheep or dogs. The six kinins could not be distinguished from one another by parallel assays on guinea‐pig ileum, rat uterus and rat duodenum; they are thought to be identical, or nearly so. As judged by the amount of kinin produced, a sample of dog plasma appeared to contain about 4·3 times as much substrate as a sample of sheep plasma. This ratio did not depend on the kallikrein used. Attempts to compare the three kallikreins gave inconsistent results which may be due to the presence in the preparations of kallikrein of other enzymes acting on the same substrate. Sheep plasma does not form kinins on contact with glass.
UNSPECIFIC DRUG ACTION. THE EFFECTS OF A HOMOLOGOUS SERIES OF PRIMARY ALCOHOLS
Authors: RANG H. P.
Published: July 2012

Experimental results relating to the unspecific depressant action of normal primary alcohols from methanol to octanol on four separate biological systems are presented. It was found that the log‐concentration action curves of alcohols on all four systems were straight over most of their range and, for any one system, parallel throughout the series. With arithmetic increase in the alcohol chainlength the concentration required to produce a given effect diminished logarithmically. The rate of this decrease varied in different biological systems, and was always less than the rate of decrease of solubility with chainlength. In two of the systems investigated alcohols beyond octanol failed to show any activity (cut‐off phenomenon). The implications of these findings are discussed, with reference to the mechanism of action of unspecific depressants. Ferguson's principle of using thermodynamic activity instead of concentration as an index of activity was applied to the present results. In an appendix, the results are compared with predictions according to Mullins' hypothesis of narcotic action, and found not to agree well.
A GANGLION‐STIMULATING PRINCIPLE PRESENT IN PEPTONE
Authors: BERALDO W. T. , ZANOTTO A.
Published: July 2012

One of us (W. T. B.) has previously described a pressor effect of peptone in the rat. This effect was considered secondary to a release of sympathin by the stimulation of sympathetic ganglia. The present experiments show that peptone causes contraction of guinea‐pig ileum and inferior eyelid of the rat which is antagonized by hexamethonium. Atropine inhibits equiactive doses of peptone and acetylcholine on the guinea‐pig ileum and eserine potentiates them. Boiling peptone in concentrated hydrochloric acid or n sodium hydroxide destroys its activity; incubation with proteolytic enzymes (trypsin, pepsin, and chymotrypsin) has no effect on its activity. It is concluded that peptone acts upon the intramural ganglia of the guinea‐pig ileum and on sympathetic ganglia which supply the inferior eyelid of the rat.
THE ABSORPTION, DISTRIBUTION AND EXCRETION OF PROTHIDIUM IN RATS, RABBITS AND CATTLE
Authors: TAYLOR ANGELA E. R.
Published: July 2012

2 ‐ Amino‐7 ‐ (2‐amino‐6‐methylpyrimidin‐4‐ylamino)‐9‐p‐aminophenylphenanthridine 10,1′ ‐ dimethobromide (Prothidium), a prophylactic drug against cattle trypanosomiasis, was concentrated in the liver and kidneys of rats and rabbits after intraperitoneal or intracardial injection; it was detectable in these organs for 7 days in rats and 10 days in rabbits. The drug protected adult rats against Trypanosoma vivax for 8 weeks. Histological examination of the organs of rats treated with Prothidium indicated that no damage had been incurred from the treatment. When cattle were treated subcutaneously, elongated swellings appeared at the site of injection which disappeared within 6 weeks. Excretion of unchanged Prothidium occurred via the bile in rats and the drug was detectable in the bile for 9 days, but no Prothidium could be detected in the faeces or urine of rats or rabbits. No metabolic products of the Prothidium were found in the tissues or plasma of rats, rabbits, or cattle. In rat liver perfused for 6 hours with Prothidium only the unchanged drug was recovered. A depot of Prothidium was formed at the site of subcutaneous injection in cattle and this remained for at least 3 months. The prolonged prophylactic action was probably due to the formation of this depot since Prothidium injected intraperitoneally into a calf was excreted at a similar rate to that observed in rats and rabbits.
THE ANTIMICROBIAL PROPERTIES OF SOME α‐AMINO‐OXY‐ACIDS, α‐AMINO‐OXY‐HYDRAZIDES, ALKOXYAMINES, ALKOXYDIGUANIDES AND THEIR DERIVATIVES
Authors: PRICE S. A. , MAMALIS P. , McHALE D. , GREEN J.
Published: July 2012

A series of compounds containing an amino‐oxy‐group has been examined for antibacterial and antifungal activity. The amino‐oxy‐acids and the alkoxyamines showed little activity, but the hydrazides, notably the amino‐oxydodecyl and the amino‐oxytetradecyl compounds, had appreciable activity against Staphylococcus aureus. The alkoxydiguanides showed considerable bactericidal activity in vitro against Gram‐positive and Gram‐negative organisms and some activity against Mycobacterium tuberculosis. The most active compounds were those with a chain containing 10 to 14 carbon atoms, but the activity was considerably reduced in the presence of serum. They were also active against the few fungi tested. The most active compound, decyloxydiguanide, was moderately toxic when administered intraperitoneally to mice and no therapeutic activity could be demonstrated against an intraperitoneal injection of Streptococcus pyogenes administered 15 min. previously.
THE EXCRETION AND STABILITY TO METABOLISM OF BRETYLIUM
Authors: DUNCOMBE W. G. , McCOUBREY A.
Published: July 2012

Bretylium (o‐bromobenzylethyldimethylammonium) is a new type of hypotensive drug. It was estimated in extracts of human urine as the methyl orange complex. From 7 to 45% of a single oral dose was found in human urine within 9 hr. The [14C] labelled drug was used to investigate excretion by cats. A minor proportion of a subcutaneous dose was eliminated by cats in the faeces, probably after secretion into the bile. Most of the dose was excreted unchanged in the urine. No products of metabolism were found in either human or cat urine. The drug suffered negligible change when incubated with rat liver tissue in vitro.
A NOTE ON THE DEMYELINATION PRODUCED IN HENS BY DIALKYLFLUORIDATES
Authors: LANCASTER M. C.
Published: July 2012

Hens were treated with organophosphorus compounds until signs of neurotoxicity developed. The sciatic nerves, spinal cord, and medulla were then examined histologically by the Marchi method, to determine the extent and distribution of demyelination. The lesions were proportional to the dose of compound injected, and the spinal cord was more sensitive than the sciatic nerves. It is suggested that the spinal cord, and not the sciatic nerves, is the main site of damage in clinical paralysis following dyflos poisoning.
THE INFLUENCE OF THIOPENTONE ANAESTHESIA ON THE BLOOD LIPID AND BLOOD SUGAR LEVEL
Authors: FODOR J. , GRAFNETTER D.
Published: July 2012

Thiopentone anaesthesia in dogs and rats was accompanied by a sharp fall in blood non‐esterified fatty acids and a small increase in blood sugar. No pronounced changes in the blood concentrations of cholesterol, phospholipids or fatty acid esters were observed. Ether anaesthesia had no effect on the blood non‐esterified fatty acids in rats. The fall in non‐esterified fatty acids during thiopentone anaesthesia is therefore not related to the state of anaesthesia itself.
POTENTIATION OF SULPHADIMIDINE BY 2,4‐DIAMINO‐6,7‐DI‐ISOPROPYLPTERIDINE AND OTHER 6,7‐DISUBSTITUTED 2,4‐DIAMINOPTERIDINES AGAINST EIMERIA INFECTIONS OF CHICKS
Authors: HORTON‐SMITH C. , LONG P. L. , COLLIER H. O. J.
Published: July 2012

Six 2,4‐diaminopteridines substituted in the 6 and 7 positions were tested as potentiators of sulphadimidine against Eimeria tenella. 2,4‐Diamino‐6,7‐di‐isopropylpteridine and 2,4‐diamino‐1′‐propylindolo(2′,3′: 6,7)pteridine were selected for further study. Both potentiated sulphadimidine against E. tenella and the di‐isopropylpteridine potentiated it against E. necatrix. A 10% mixture of the di‐isopropylpteridine with sulphadimidine (or other sulphonamides) appears to offer advantages in the treatment of E. tenella and still more of E. necatrix.
EFFECT OF DENERVATION AND OF COCAINE ON THE ACTION OF SYMPATHOMIMETIC AMINES
Authors: STRÖMBLAD B. C. R.
Published: July 2012

The secretory effect of sympathomimetic amines on the submaxillary gland of cats was increased after section of the chorda tympani (preganglionic, parasympathetic supply). After sympathetic denervation of the gland the secretory response to tyramine and phenylethylamine was absent, the response to dopamine and ephedrine decreased and the response to adrenaline and noradrenaline increased. Large doses of cocaine, given locally into the gland, produced changes similar to those observed after sympathetic denervation. The sensitization towards adrenaline and noradrenaline was obtained with smaller doses. Tyramine did not cause a release of catechols from the suprarenal glands of the cat.
THE EFFECT OF TEMPERATURE ON THE DIRECT MUSCLE TWITCH RESPONSE AND THE ACTION OF DRUGS ON THE ISOLATED DENERVATED RAT DIAPHRAGM
Authors: LETLEY E.
Published: July 2012

The effect of temperature on the direct twitch response of the normal and denervated rat diaphragm, and the sensitivity of the contractural response of the denervated muscle to acetylcholine, suxamethonium, decamethonium, and potassium salts, was studied. Cooling the normal diaphragm from 39 to 20° increased the size of the direct twitch, but below this temperature the twitch response of the muscle was progressively depressed. The denervated muscle twitch was, by contrast, maximal at 39° and decreased as the temperature was lowered. This property of the denervated muscle first appeared about the third day after denervation. The contractural response of the denervated diaphragm to applied acetylcholine was enhanced by cooling, while the response to potassium salts was depressed. The depression of the contracture induced by potassium followed closely the depression of the direct muscle twitch of the denervated muscle over the same temperature range.
SUPERSENSITIVITY OF THE SUBMAXILLARY GLAND FOLLOWING EXCLUSION OF THE POSTGANGLIONIC PARASYMPATHETIC NEURONE
Authors: EMMELIN N.
Published: July 2012

The repeated subcutaneous injection of four different parasympatholytic agents into cats has been found to cause a supersensitivity of the submaxillary glands to adrenaline. The fact that the level of sensitivity reached is the same with all four drugs is taken as evidence that the supersensitivity is due to the absence of an action of acetylcholine on the gland cells. This acetylcholine can only in part be that released by the secretory impulse, for the supersensitivity produced is more marked than that caused by preganglionic parasympathetic denervation. It is assumed that the postganglionic cholinergic neurone exerts some action of its own on the gland cell. Sensitization above the level reached after decentralization ensues when such an action is abolished by parasympatholytic agents. Degenerative section of the postganglionic fibres would also exclude this action, but for anatomical reasons this cannot be made complete. The supersensitivity which follows this operation is greater than after decentralization but less than that produced by treatment with atropine‐like drugs.
THE RESPONSES OF THE VENUS HEART TO CATECHOL AMINES AND HIGH CONCENTRATIONS OF 5‐HYDROXYTRYPTAMINE
Authors: GREENBERG M. J.
Published: July 2012

The catechol amines excite the isolated heart of Venus mercenaria in a characteristic manner. This response was not obtained with phenethylamine, tyramine, ephedrine, or mescaline, nor with histamine, nor with the basic n‐alkylamines. 5‐Hydroxytryptamine had a distinctive effect at high concentrations (above 3 × 10−6 m) different from that at lower doses. The response to high concentrations was dominated by an increase in muscle tone. Hearts exposed to high concentrations of 5‐hydroxytryptamine and other tryptamine analogues for long periods became tachyphylactic to low doses of these substances. However, high doses of 5‐hydroxytryptamine (about 2 × 10−5 m) still excited the tachyphylactic heart, but the response was then like that to the catechol amines. When high bath temperatures rendered the heart insensitive to 5‐hydroxytryptamine, high concentrations of this compound again had the catechol amine effect. The possibility of a physiological role for the catechol amines or high 5‐hydroxytryptamine concentrations is discussed.
PHARMACOLOGICAL ACTIVITY OF AN AQUEOUS EXTRACT OF THE LEAVES OF THE MALAYAN RENGAS TREE GLUTA RENGHAS
Authors: LIN R. C. Y. , WHITTOW G. C.
Published: July 2012

A pharmacological analysis of an aqueous extract of the leaves of Gluta renghas has been carried out. It has been shown that the extract contained a heat‐stable, anticholinesterase agent. A heart‐stimulating substance was also shown to be present in the extract. Intravenous injection of the extract into the anaesthetized cat produced changes of arterial blood pressure, venous pressure and respiration which were reduced or abolished by vagotomy. The leaves contained approximately 0.1 μg./g. of 5‐hydroxytryptamine‐like activity.
PERIPHERAL VASCULAR EFFECTS OF BRETYLIUM TOSYLATE IN MAN
Authors: BLAIR D. A. , GLOVER W. E. , KIDD B. S. L. , RODDIE I. C.
Published: July 2012

After intra‐arterial infusion of bretylium tosylate (12.5 mg.), the reflex changes in vasoconstrictor tone which normally occur in the forearm with body cooling, positive pressure breathing, the Valsalva manœuvre and postural change were greatly reduced or abolished. Reflex vasodilatation mediated by cholinergic fibres in response to body heating or to emotional stress was little affected. It was concluded that bretylium can selectively block the activity of sympathetic noradrenergic fibres without causing a similar block of sympathetic cholinergic fibres. As the responses to intravenous or intra‐arterial infusions of adrenaline or noradrenaline were not reduced after bretylium, it was concluded that bretylium interferes with the activity of noradrenergic fibres rather than with the activity of the noradrenaline released at the nerve ending. After bretylium infusion, forearm and hand blood flow did not often rise to levels characteristic of full release of vasoconstrictor tone. As infusion of bretylium into a nerve‐blocked forearm resulted in a pronounced reduction in flow, it is concluded that bretylium also has a constrictor effect on blood vessels. The state of the vessels following an infusion of bretylium appears to depend on the balance between this constrictor action and the longer‐acting sympathetic blocking effect.