Showing papers in "British journal of pharmacology and chemotherapy in 1957"

Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

Abstract: A method has been described for the study of the central effects produced by the intracerebral injection of drugs in the unanaesthetized mouse. The effects observed were in good agreement with those obtained after similar injections in cats, dogs and human beings. After intracerebral injection, drugs of diverse structure produced certain generalized effects: changes in positioning of the tail, stupor, hyperexcitability and tachypnoea. Both acetylcholine and methacholine produced an akinetic seizure and depression, but the latter compound also caused lacrimation and salivation. Atropine produced piloerection, increased sensitivity to sound and touch, clonic convulsions and scratching, whereas hexamethonium caused Parkinsonian-like muscle tremors and peripheral vasodilatation. After adrenaline, hyperexcitability, exophthalmos, stupor and death from pulmonary oedema were observed, but (+)-methylamphetamine produced only piloerection and exaggerated activity in response to sound and touch. Ergotamine caused a decreased sensitivity to sound and touch, micturition, and stupor, while ergometrine caused clonic convulsions, piloerection, defaecation and stupor.

Inhibition by morphine of the release of acetylcholine from the intestine of the guinea-pig.

Abstract: In experiments on the isolated small intestine of the guinea-pig, morphine inhibited the release of acetylcholine (ACh) into the bath fluid. Experimental evidence is presented which suggests that the reduced release of ACh could not be explained by an inhibition of the synthesis of ACh, nor by stabilization of the bound form of ACh in the tissue. Apparently morphine reduces the excitability of postganglionic structures and thereby the liberation of ACh from nerve endings during the process of excitation.

Anticonvulsant compounds and 5‐hydroxy‐tryptamine in rat brain

Abstract: In rats, a series of anticonvulsant compounds have been shown to cause a significant elevation of brain 5-hydroxytryptamine (5-HT) levels in comparison with control values. This increase in 5-HT only occurred in brain tissue and was not observed in spleen, upper small intestine or blood. Elevation of brain levels of 5-HT by iproniazid (Marsilid) or 5-hydroxytryptophan failed to give protection against the convulsant or lethal action of lept zol (75 mg./kg.).

The action of morphine on the superior cervical ganglion and on the nictitating membrane of the cat.

Abstract: The intravenous injection of 0.05 to 2.5 mg. of morphine reduced the response of the nictitating membrane in the cat to pre- and post-ganglionic stimulation. This inhibitory action of morphine was due neither to inhibition of ganglionic transmission nor to a depressant action on the smooth muscle of the nictitating membrane. It is suggested that morphine inhibits the release of the sympathetic transmitter from the postganglionic nerve endings.Small amounts of morphine (5 to 20 mug.) injected intravenously reduced or abolished the contraction of the nictitating membrane due to the injection of histamine, pilocarpine and 5-HT into the arterial blood supply of the superior cervical ganglion. This inhibitory action of morphine was due to an action on the ganglion cells, since such small amounts of morphine did not reduce the response of the nictitating membrane to postganglionic stimulation. Similar amounts of morphine did not abolish the stimulation of the ganglion by nicotine, tetramethylammonium and potassium chloride.The results provide further evidence for the view that histamine, pilocarpine, and 5-hydroxytryptamine have no "nicotine-like" properties but act on receptors of the ganglion cells different from the acetylcholine receptors.

The relationship between inhibition of phosphofructokinase activity and the mode of action of trivalent organic antimonials on Schistosoma mansoni.

Abstract: The addition of purified mammalian phosphofructokinase to homogenates of schistosoma mansoni increased the rate of lactic acid production from glucose and reversed the inhibition of glycolysis produced by low concentrations of trivalent organic antimonials. Neither mammalian phosphofructokinase nor trivalent antimonials affected the rate of lactic acid production from fructose-1:6-diphosphate (HDP) by schistosome homogenates. Accordingly, in the schistosome, the rate of glycolysis of glucose is determined by the activity of phosphofructokinase. The aldolase of S. mansoni has a high requirement for HDP; relatively slight reductions in the concentration of this substrate below the optimum resulted in a sharp decline of aldolase activity. Therefore, decreased formation of HDP, due to inhibition of schistosome phosphofructokinase activity by antimonials, reduced the activity of aldolase and resulted in an inhibition of glycolysis of schistosome homogenates. Kinetic data revealed differences in the nature of the phosphofructokinase of S. mansoni and that of the enzyme catalysing the same reaction in the host. Exposure of schistosomes to low concentrations of potassium antimonyl tartrate or administration of subcurative doses of stibophen to the host resulted in an accumulation of the substrate (fructose-6-phosphate), and a reduction of the product (HDP) of the phosphofructokinase reaction, indicating that the activity of this enzyme was inhibited by antimonials in the intact parasite. It is concluded that inhibition of phosphofructokinase activity can account for the mechanism of the chemotherapeutic action of trivalent organic antimonials in schistosomiasis.

A comparative study of kinin, kallidin, and bradykinin

Abstract: Partially purified kinin, a polypeptide in wasp venom, has been found to be a potent smooth-muscle stimulating and hypotensive agent. Such a preparation was 10 to 100 times more effective than histamine in enhancing capillary permeability on intradermal injection, and 10 times more effective than acetylcholine in evoking pain on a cutaneous blister base. Some differences between the actions of salivary kallikrein and trypsin in releasing kallidin or bradykinin have been observed, and some modifications of previous methods of preparing crude kallidin and bradykinin are suggested. Kallidin and bradykinin are effective enhancers of capillary permeability in the guinea-pig and rabbit. Chemical and pharmacological tests failed to differentiate between kallidin and bradykinin which must be, therefore, closely similar compounds. The possible role of kallidin and bradykinin in physiological or pathological conditions is discussed.

Protection against the lethal effects of organo‐phosphates by pyridine‐2‐aldoxime methiodide

Abstract: The mechanism responsible for the protection against lethal organophosphate poisoning by pyridine-2-aldoxime methiodide (P-2-AM) was studied in the mouse. Two types of organophosphates were used: ethyl pyrophosphate (TEPP), E 600, Ro 3-0340, and Ro 3-0422 which form with true cholinesterase a diethylphosphoryl enzyme (1) and DFP, D 600, and Ro 3-0351 which form with true cholinesterase a diisopropylphosphoryl enzyme (2).In vitro and under the experimental conditions used more than 50% reactivation of (1) was obtained within 1 hr. by concentrations of P-2-AM ranging from 0.5 to 1x10(-5) M; 30 times higher concentrations of the oxime were required to achieve the same effect with (2). In vivo reactivation of phosphorylated true cholinesterases in blood amounted to 10 to 24% within the first 30 min. if 25 mg./kg. P-2-AM was injected (i.p.) 5 min. before a sublethal dose of TEPP, E 600, Ro 3-0340, or Ro 3-0422 and reactivation reached a maximum within 1 to 2 hr. after the injection of the oxime. P-2-AM was more effective when given 30 min. after the organophosphate. The effect of 25 mg./kg. P-2-AM on the phosphorylated true cholinesterase in brain (experiments with TEPP and E 600) was negligible. A dose of 25 mg./kg. P-2-AM had no consistent effect on the phosphorylated true cholinesterases in blood and brain of mice injected with sublethal doses of DFP, D 600, or Ro 3-0351.The protection by 25 mg./kg. P-2-AM against lethal doses of TEPP, E 600, Ro 3-0422, and Ro 3-0340 was greater than that obtained with 50 mg./kg. atropine sulphate, but the degree of protection was determined by the organophosphate itself and not its dialkylphosphoryl group. Protection by 25 mg./kg. P-2-AM against lethal doses of DFP, D 600, and Ro 3-0351 was negligible. The antidotal effect of P-2-AM was potentiated by atropine. Mice which were injected with atropine and P-2-AM were protected to a greater extent against DFP than against Ro 3-0422, and protection against DFP was only slightly less than protection against TEPP. This is difficult to reconcile with a specific action of P-2-AM on phosphorylated cholinesterases.

Action of anaphylactic shock and anaphylatoxin on mast cells and histamine in rats.

Abstract: Anaphylactic shock in rats produces disruption of mast cells. These cells are also disrupted when rat mesentery is incubated with antigen in vitro. The plasma histamine reaches a maximum about 5 min. after injection of the antigen. Though antihistamines protect rats against anaphylactic shock, they do not prevent mast cell disruption. Previous depletion by compound 48/80 of the histamine bound to the mast cells prevents anaphylactic shock and the increase in plasma histamine. Anaphylatoxin produces no mast cell alterations or plasma histamine increase, and thus does not seem to act as a histamine-releasing agent in rats. Probably nearly all the histamine liberated in anaphylaxis in rats comes from the mast cells.

The effect of lysergic acid diethylamide, 5-hydroxytryptamine, and related compounds on the liver fluke, Fasciola hepatica.

Abstract: The rhythmical activity of the liver fluke, Fasciola hepatica, was stimulated by 5-hydroxytryptamine and by lysergic acid diethylamide at very low concentrations. The effect was peripheral and was not mediated through the central ganglion. Other amines also stimulated rhythmical activity, the most potent being the indolamines. Bromolysergic acid diethylamide, and other analogues such as yohimbine, harmine, and dopamine depressed rhythmical movement and antagonized the stimulant action of 5-hydroxytryptamine and lysergic acid diethylamide. Evidence which suggests the presence of tryptamine receptors in the trematode is discussed.

The relation between sedation and body temperature in the mouse

Abstract: Chlorpromazine and reserpine reduce locomotor activity and prolong pentobarbitone hypnosis in mice. Both these effects are shown to be proportional to the fall in body temperature produced by these drugs. Other agents are shown to reduce body temperature and potentiate pentobarbitone. At ambient temperatures of 32° C. neither chlorpromazine nor reserpine is hypothermic or sedative. It is concluded that sedative effects in the mouse at ordinary room temperatures are related to the hypothermic properties of these drugs. At 36° C., while reserpine fails to potentiate pentobarbitone, chlorpromazine still does so.

The blocking action of choline 2:6‐xylyl ether bromide on adrenergic nerves

Abstract: Choline 2:6-xylyl ether bromide (TM 10), given systemically to cats in doses of 5 to 15 mg./kg., abolishes the effects of adrenergic nerve stimulation whilst leaving the reactions of the effector organs to adrenaline unimpaired. The effects of a single dose may take up to one hour to become fully established and last for more than twenty-four hours. Apart from transitory ganglionic blockade, cholinergic autonomic nerves are unaffected even by large doses of TM 10. Doses of TM 10 which produce effective blockade do not impair conduction along adrenergic nerve trunks; the drug must, therefore, act at, or close to, the nerve terminals. TM 10 prevents the output of noradrenaline from the spleen on stimulating the splenic nerves; but, in acute experiments, it does not influence the liberation of pressor amines from the stimulated suprarenals. Examination of some ethers related to TM 10 revealed no correlation between TM 10-like adrenergic blocking activity and local anaesthetic activity. The action of TM 10 on adrenergic nerves does not, therefore, seem to be accounted for by axonal block.

The interaction between edrophonium (tensilon) and acetylcholine at the motor end-plate.

Abstract: The effect of edrophonium (3-hydroxy-phenyl-dimethylethylammonium chloride) on the motor end-plate and its interaction with acetylcholine and carbachol has been investigated. Use was made of intracellular recording of membrane potential and of ionophoretic micro-application of drugs from single and twin-pipettes. Small doses of edrophonium potentiate the depolarizing effect of acetylcholine, but not that of carbachol. This action can be observed with doses of edrophonium which have no depolarizing effect by themselves. Large doses of edrophonium have some depolarizing action and, at the same time, inhibit depolarizations produced by carbachol. After treatment with neostigmine, edrophonium fails to potentiate the acetylcholine response. The observations are in agreement with the view that the principal action of edrophonium on the neuromuscular junction is that of a potent and rapidly acting anticholinesterase.

The effects of nicotine, hexamethonium and ethanol on the secretion of the antidiuretic and oxytocic hormones of the rat.

Abstract: The actions of nicotine, hexamethonium, and ethanol on the hypothalamo-hypophysial system have been investigated in the rat. The antidiuretic action of nicotine was not inhibited by ethanol, nor by doses of hexamethonium which were sufficient to block both its pressor and convulsant actions. Hexamethonium itself had an antidiuretic action the mechanism of which has been investigated. Nicotine caused a release of oxytocin into the blood which was not blocked by ethanol nor significantly reduced by hexamethonium. The results suggest that any synapse which exists at the supraoptic nuclei is dissimilar in its pharmacological properties to synapses at autonomic ganglia.

Digoxin, ouabain and potassium movements in rabbit auricles.

Abstract: Movements of potassium have been observed in isolated right and left auricles of rabbits by means of radioactive tracer. The tissues have been immersed in a modified Krebs saline at 37 degrees , and in these conditions showed only small changes in ionic content over periods up to 6 hr. The extracellular volume, determined with inulin and with (24)Na, was large (44.1 ml./100 g. tissue), and accounted for about 3.8% of the tissue potassium. Left auricles exchanged without gross inhomogeneity: the rate of exchange was about 1.5% of the total tissue potassium/min., though it was probably higher in the first half-hour or hour after preparation. In right auricles the exchange was less homogeneous and included a faster component than that observed in left auricles. Digoxin and ouabain reduced the influx and had no appreciable effect on the efflux of potassium, so that the auricles lost potassium. The threshold concentrations which produced effects within 20 min. were of the order of 10(-6) for ouabain and somewhat higher for digoxin. Irregularities or failure of contraction occurred when the tissue potassium was reduced by about 15%. Loss of potassium was accompanied by gain of sodium, but the tissue appeared unsuitable for making estimations of the rate of sodium movement.

The action of triethylenemelamine on the fertility of male rats

Abstract: Small doses of triethylenemelamine (TEM) had a selective action on the fertility of male rats. One dose (0.2 mg./kg., i.p.) produced effects ranging from subfertility to sterility during the next 3 weeks. In the fourth week sterility was the rule, but normal fertility was restored in the fifth week. A short course of the drug (5 daily doses, 0.2 mg./kg., i.p.) resulted in sterility lasting about 5 weeks, after which fertility was rapidly regained. Daily doses (0.05 mg./kg., i.p.) caused infertility in about a week which was maintained throughout treatment (7 weeks), and persisted for several weeks after the drug was discontinued. Sexual activity of infertile animals seemed normal and sperm production appeared to continue. Spermatozoa from infertile animals were able to reach and penetrate ova. The results suggest that TEM acts directly on the germinal epithelium. An attempt has been made to provide some explanation for these results and correlate them with the time required for spermatogenesis.

The effect of eserine and neostigmine on the blood pressure of conscious rats

Abstract: Small amounts of eserine salicylate (10 to 20 mug.) regularly caused a rise of blood pressure in non-anaesthetized rats. Neostigmine methylsulphate in doses from 1 to 10 mug./animal usually caused a fall of blood pressure, or no change was observed; only in a few experiments was a rise of blood pressure noted. The pressor effect of eserine was abolished by atropine and reduced or abolished by yohimbine and phentolamine. Adrenalectomy did not change the response to eserine. The present experiments do not contradict earlier statements that the pressor effect of eserine was due to the discharge of impulses from a centre or centres in the central nervous system.

The pharmacological actions of murexine (urocanylcholine).

Abstract: Murexine or urocanylcholine is a naturally occurring choline ester of urocanic acid which was found in very large amounts in the hypobranchial body of Murex trunculus and other prosobranchiate molluscs. In vertebrates and invertebrates, it was found to possess marked neuromuscular blocking and nicotinic actions, but was almost devoid of muscarinic effects. The blocking action of murexine was considered, on the basis of experimental and clinical evidence, to be of the “depolarizing” type. It was weaker than, but qualitatively very similar to, that produced by suxamethonium. The nicotinic action of murexine was stronger than that of suxamethonium in both experimental animals and human beings.

Oximes and atropine in sarin poisoning

Abstract: Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.

Some pharmacological actions of four synthetic analogues of oxytocin.

Abstract: Four structural analogues of oxytocin were investigated with regard to their oxytocic, milk-ejecting, pressor and diuretic/antidiuretic effects. In three of them the isoleucyl group of oxytocin was replaced by a phenylalanyl, leucyl, or valyl residue; in the fourth the asparaginyl group was replaced by a glutaminyl residue. Synthetic oxytocin and the international standard pituitary (posterior lobe) powder were used for comparison. Although the analogues showed marked differences in their oxytocic effects, there was a fairly good agreement between the results obtained on the isolated rat uterus and the blood pressure of the chicken for each polypeptide. The milk-ejection pressure test gave much higher values throughout. The pressor and antidiuretic activities of the four analogues showed no obvious correlation with the values obtained in the other tests. The valyl and the leucyl analogues also had a diuretic effect. The phenylalanyl analogue was remarkable for the close correspondence between its oxytocic and antidiuretic effects: practically identical values were obtained for the potency, whether measured on the rat uterus in vitro, the blood pressure in the chicken, the cat uterus in situ or water diuresis in the rat. The leucyl analogue showed an oxytocic activity on the cat uterus in situ or the rabbit mammary gland roughly 7 to 9 times as high as that measured by means of the conventional bioassay methods, such as the blood pressure of the chicken or the rat uterus in vitro. The glutaminyl analogue, the weakest of the whole series, had only a modest effect on the mammary gland. The valyl analogue was the most interesting of the new polypeptides. Its oxytocic action on the cat uterus in situ and its milk-ejecting effect were greater than that of synthetic oxytocin, whereas its antidiuretic and pressor effects were less. In cats and rats, the uterine effect was stronger in situ than in vitro. There were also distinct species differences between cats, rabbits, and rats in their sensitivity to valyl-oxytocin.

Prolongation of chloral hydrate sleeping time by 5-hydroxytryptamine and by certain other drugs.

Abstract: Various drugs have been tested for a capacity to prolong the hypnotic effect of chloral hydrate in mice. Amongst the compounds which, when injected subcutaneously in substantial amount shortly before the chloral hydrate (250 mg./kg. intraperitoneally), increased sleeping time significantly were adrenaline, noradrenaline, phenylephrine, methoxamine, 5-hydroxytryptamine (serotonin), histamine, ergotamine, yohimbine, and atropine. The ability of these drugs to prolong chloral hydrate sleeping time could not be related to any common circulatory property, but most of the active drugs are known to lower body temperature under comparable conditions. It was found that mice which have been pre-treated with 5-hydroxytryptamine or adrenaline suffer a much greater fall of body temperature when chloral hydrate is given subsequently than do mice which have been given chloral hydrate alone. It is suggested that some, at least, of the drugs which prolong the effects of hypnotics do so by virtue of a hypothermic action.

A method of estimating histamine in plasma.

Abstract: The method is intended for the estimation of minute quantities of histamine in blood plasma. A neutralized trichloracetic acid extract of plasma is adsorbed at pH 8 on a column prepared by mixing a quantity of the cationic exchange resin Amberlite XE-64 with powdered cellulose as a supporting medium. Histamine is adsorbed but N-acetylnistamine is not: the amines can therefore be estimated independently. Elution of the histamine is by displacement with HCl. The eluate is converted into the solution for bioassay on the superfused guinea-pig ileum. In recovery experiments histamine was added in the range 25 to 100 ng. to solutions of known composition and to plasma (5 ml.) obtained from man and the cat. The mean recovery in this range for histamine added to plasma was 82.5% ±2 S.E. (17 estimations). It was possible by this method to follow the concentration of histamine in the arterial plasma of the cat when histamine was infused intravenously at a rate of 330 ng./kg./min. There was no perceptible change in the arterial blood pressure during the infusion, but the plasma histamine rose from <0.3 ng./ml. to 3.4 ng./ml. (mean of 2 estimations). The histamine equivalent of human plasma obtained from the antecubital vein was found to be less than 1 ng./ml.

Effect of chain length of aliphatic amines on histamine potentiation and release.

Abstract: Diamines in the series NH(2).(CH(2))(n).NH(2) specifically potentiate histamine contractions of the guinea-pig ileum and inhibit the enzymatic destruction of histamine. These activities are greatest with short-chain compounds (n approximately 5). Diamines also release histamine from isolated tissues and depress the contractility of plain muscle and the motility of paramecia. These activities increase with chain-length and are probably limited only by solubility. The parallelism between histamine-releasing activity and toxicity also extends to the monoamines in the series CH(3).(CH(2))(n-1).NH(2). Histamine-releasing activity of both series increases with increase of pH and can mainly be attributed to the non-ionized base.From the results on the effect of chain-length and ionization on activity, it is suggested that aliphatic amines release histamine by penetration of the cell membrane in the non-ionized form, followed by exchange in the ionic form with intracellular histamine.

The influence of potassium concentration on the action of quinidine and of some antimalarial substances on cardiac muscle.

Abstract: The action of quinidine and some other antimalarial substances on cardiac muscle has been shown to be closely related to the K+ concentration of the surrounding medium. The depression of the amplitude and rate of the contractions of the isolated perfused rabbit heart and of the isolated rabbit atria which the antimalarial substances produced seems to be due to a diminution of the permeability of the membrane to K+, since it can be reversed by lowering the external K+ concentration. During exposure to any of the antimalarial compounds tested, the normal inhibitory action of acetylcholine was converted to a stimulant action. This stimulant action of acetylcholine is probably due to its effect in increasing the permeability of the membrane to K+. There were slight differences in behaviour between proguanil and quinidine on the one hand, and chloroquine, mepacrine and pyrimethamine on the other. The observations may explain the action of quinidine-like substances in abolishing fibrillation.

The release of adrenaline and noradrenaline from the adrenal gland of the cat by acetylcholine

Abstract: The adrenal glands of atropinized cats were depleted of their content of adrenaline and noradrenaline by repeated intravenous doses of acetylcholine. In each experiment there was a similar percentage loss of both amines. This was irrespective of the degree of depletion, which ranged from 7.1% to 86.5%. In some experiments, adrenal blood was collected and it was found that the percentage of noradrenaline in the adrenal venous effluent (mean 62.0%) was similar to that in the amine lost from the depleted gland (mean 63.7%). In some experiments, the adrenaline and noradrenaline lost from the gland could be recovered quantitatively in the adrenal blood. The results indicate that, under these experimental conditions, synthesis is not taking place concurrently with the liberation of amines or that it is taking place so slowly as not to be detected.

The adrenaline and noradrenaline content of the adrenal gland of the cat following depletion by acetylcholine

Abstract: This paper describes the attempts that were made to obtain a replacement of adrenaline and noradrenaline in the adrenal gland of the atropinized cat, subsequent to the depletion of the gland by repeated intravenous doses of acetylcholine. In the anaesthetized animal, there was no replacement of adrenal amines within 15 hours of the depletion. The further loss of amine that occurred during this time was prevented by the de nervation of the gland. If the animal was allowed to recover from the anaesthetic there was some replacement of amines within 2 to 3 days, provided that the condition of the animal was satisfactory. By 6 to 7 days the total amine content had returned to its initial level, but there was now an alteration in the relative proportions of the two amines. Although the adrenaline was still well below the resting level, the noradrenaline was several times its initial value. By one month, the noradrenaline had decreased and the adrenaline had increased to their initial amounts and proportions. Thus this work gives evidence for the formation of adrenaline from noradrenaline.

The concentration of adrenaline in the plasma of rabbits treated with reserpine.

Abstract: Doses of 1 to 2.3 mg./kg. of reserpine given intravenously to rabbits raised the plasma adrenaline. The noradrenaline concentrations were too near the threshold of the method to decide whether any alterations followed the injection of reserpine. Control experiments, in which blood samples were taken from rabbits but no drug was given, showed only a very slight rise in adrenaline concentration after the first bleeding.

Pharmacological actions of pure muscarine chloride.

Abstract: The action of chromatographically pure crystalline muscarine chloride, prepared from Amanita muscaria, has been compared with acetylcholine chloride (ACh) on a number of different organs from a variety of species. Muscarine caused spasm in vivo and in vitro of muscles of the gut, uterus, urinary bladder, and bronchus. It also caused contraction of the horse ureter and carotid artery chain in vitro and slowed the isolated auricles of the guinea-pig and rabbit, and the frog heart. Muscarine caused a drop in blood pressure, although in vitro it produced either constriction or dilatation of the blood vessels of the rabbit ear. All these actions resembled those of acetylcholine, though muscarine was usually more potent. Muscarine effects were readily prevented by atropine sulphate. It had a slight action on the frog rectus abdominis muscle, causing a contracture at high concentrations. Muscarine was destroyed neither by pepsin nor by boiling at any pH. It was inactive by mouth in a monkey in a quantity many times that which would cause poisoning by ingestion of Amanita muscaria in the human being. Muscarine neither inhibited nor was hydrolysed by either true- or pseudo-cholinesterase. Muscarine chloride did not cause paralysis of the neuromuscular junctions of the rat diaphragm or of the cat gastrocnemius.

The action of 5-hydroxytryptamine and some of its antagonists on the umbilical vessels of the human placenta.

Abstract: The vasoconstrictor action of 5-hydroxytryptamine (5-HT) in the human placental preparation is about 10 times stronger than that of adrenaline and is antagonized by anti-adrenaline compounds like phentolamine. Both 5-HT and adrenaline are antagonized by yohimbine and chlorpromazine. Specific and strong anti-5-HT action is demonstrated for lysergic acid diethylamide (LSD) and tryptamine. Both LSD and tryptamine in larger doses have a vasoconstrictor action. Mescaline has no certain modifying effect on the action of 5-HT, but itself causes vasoconstriction in large doses. The antihistamine drug phenbenzamine in histamine blocking doses abolishes the action of 5-HT in half the preparations tested. The ganglionic blocking agent trimetaphan in large doses antagonizes the action of 5-HT added subsequently, and also, to a lesser degree, the effect of adrenaline. Hexamethonium and tetraethylammonium bromides are ineffective in this preparation. No certain modifying action of reserpine on subsequently added 5-HT could be demonstrated, and the same was true for heparin even in very high concentrations.

Local effects and mechanism of absorption of iron preparations administered intramuscularly.

Abstract: An attempt has been made to correlate factors involved in the absorption of iron-polysaccharide complexes administered intramuscularly. Different complexes varied greatly in degree of retention in muscle and in diffusibility in agar; these two characteristics were not closely related. The local changes in the muscle produced by the iron complexes consisted of an acute inflammatory reaction at the site of injection, with degenerative changes. Subsequent regeneration was rapid and complete. The major proportion of the absorption occurred during the initial 72 hr. and appeared to be mediated partly by the inflammatory reaction evoked, with enhancement of lymphatic transport of the iron complex. Rapid fixation by tissue macrophages impeded absorption and, with some complexes, this factor may make much of the injection inaccessible.

The inhibitory action of some antimalarial drugs and related compounds on the hexokinase of yeast and of Plasmodium berghei.

Abstract: Of various antimalarial compounds tested, only proguanil failed to inhibit yeast hexokinase. The metabolite of proguanil, 10,580, was an effective inhibitor. Some compounds tested which were without antimalarial activity were potent inhibitors of yeast hexokinase. The degree of inhibition increased as the time during which the enzyme had been in contact with the drug increased, and the inhibitory action of mepacrine was reduced when the concentration of ATP was raised. The inhibition of yeast hexokinase by 10,732 was independent of the concentration of ATP. The hexokinase of haemolysates of the reticulocytes of mouse or rat blood was not appreciably higher than that of similar haemolysates of normal erythrocytes. Preparations of mouse or rat erythrocytes parasitized with P. berghei possessed a much higher hexokinase activity. The inhibiting action of various compounds on the hexokinase of P. berghei closely resembled those with yeast hexokinase. Again all antimalarial compounds (apart from proguanil) inhibited the enzyme, but some of the most potent inhibitors were devoid of antimalarial action. Amongst the chemotherapeutically active compounds, there appeared to be an approximate parallelism between antimalarial activity and potency as inhibitors of plasmodial hexokinase. The action of mepacrine on plasmodial hexokinase was reduced by raising the concentration of ATP, but, as with yeast hexokinase, the inhibition by 10,732 was independent of the ATP concentration. From a consideration of the results, it seems doubtful whether this type of inhibitory effect plays more than a minor part in the mechanism of antimalarial action in vivo.