bluuebunny/crossref_metadata_2025 huggingface dataset:
A MICROBATH
Authors: GADDUM J. H. , STEPHENSON R. P.
Published: July 2012

A microbath, with a volume of less than 50 cubic millimetres, for testing the effects of drugs on small pieces of smooth muscle, is described. Drugs are applied automatically in any desired order and the record of their effects is amplified electrically. In this apparatus the response of small pieces of rat uterus to drugs is apt to be nearly all‐or‐none. Contractions of the muscle from a single ring of guinea‐pig trachea were recorded. A fall of pH was found to reduce the effect of 5‐hydroxytryptamine on this muscle while leaving the effects of tryptamine and acetylcholine unchanged.
THE PHARMACOLOGICAL ACTIONS OF PEMPIDINE AND ITS ETHYL HOMOLOGUE
Authors: SPINKS A. , YOUNG E. H. P. , FARRINGTON J. A. , DUNLOP D.
Published: July 2012

Pempidine, and other highly active ganglion blocking agents of the polyalkylpiperidine series, were developed from tertiary alkylamines, themselves weakly active, on the hypothesis that high activity was conferred by the presence in the molecule of a sterically hindered secondary or tertiary nitrogen atom. Pempidine and its n‐ethyl homologue (26539) resembled mecamylamine qualitatively. All three drugs blocked sympathetic and parasympathetic ganglia; this action was slow in onset and protracted. They blocked neuromuscular transmission, but only about one hundredth as powerfully as ganglionic transmission. They caused a fall in amplitude and rate of the isolated heart, and reduced coronary flow. They had local anaesthetic properties in one of four tests used. They caused tremor. All were well absorbed when administered orally. Pempidine was about twice as active as mecamylamine on ganglia, but only about one half to one quarter as toxic as judged by death, growth, induction of tremor, or cardiotoxicity. Compound 26539 was also quantitatively superior to mecamylamine in respect of these safety margins, but unlike pempidine or mecamylamine damaged the pituitary gland and testis when administered daily for several months. The mode of action of the three drugs is discussed: the results give tentative support for the hypothesis that their action is intracellular.
THE NEUROMUSCULAR BLOCKING ACTION OF BENZOQUINONIUM CHLORIDE IN THE CAT AND IN THE HEN
Authors: BOWMAN W. C.
Published: July 2012

Benzoquinonium (Mytolon) has been shown to produce a curare‐like rather than a deca‐methonium‐like paralysis of neuromuscular transmission in the tibialis anterior and soleus muscle of cats and the gastrocnemius muscle of hens. In the cat, but not in the hen, benzoquinonium had an additional action in preventing both the twitch potentiating action and the anti‐curare action of edrophonium, neostigmine, eserine, and tetraethyl pyrophosphate. Paralysis produced by benzoquinonium was antagonized by injected acetylcholine and by acetylcholine liberated by tetanic stimulation of the motor nerve but, in the cat, anticholinesterases were without effect even when they were first administered in circumstances in which acetylcholine accumulation might be expected to occur. These findings suggested that inhibition of Cholinesterase played little part in the skeletal muscle effects of the anticholinesterases studied. Although anticholinesterases did not antagonize benzoquinonium paralysis in the cat, they nevertheless potentiated the antagonistic action of injected acetylcholine.
LOCAL ACTION OF SOME ANTIBACTERIAL SUBSTANCES AGAINST CORYNEBACTERIUM OVIS IN GUINEA‐PIG SKIN
Authors: COLLIER H. O. J. , GRIMSHAW J. J.
Published: July 2012

When a suspension of living Corynebacterium ovis was injected intradermally in guinea‐pigs, a lesion of roughly circular outline developed within 24 hr. Lesions of smaller diameter arose if benzylpenicillin, dequalinium, hedaquinium, cetrimide, or oxytetracycline were injected at the identical site, either before, with, or after C. ovis. Evidence has been obtained that such reductions of lesion diameter are due to direct action of drugs on bacteria and not to antitoxic or anti‐inflammatory actions. Lesion diameters became less as drug dosage increased up to a limit, and these reductions provided a measure of local antibacterial action in vivo. Intradermal injection of higher concentrations of antibacterials, without C. ovis, produced comparable but somewhat flatter lesions, diameters of which increased with increasing concentration of drug and provided a measure of intradermal toxicity.
THE ACTION OF CYSTEAMINE AND SYNKAVIT ON GASTRIC EMPTYING IN THE NORMAL AND IRRADIATED RAT
Authors: HULSE E. V.
Published: July 2012

A radiographic method for studying the delay in gastric emptying in the rat caused by whole body irradiation has been applied to the investigation of two compounds which modify the effects of irradiation. The method may be of general use in the study of the action of drugs. Synkavit, which can potentiate the lethal effects of irradiation on tumours, caused a delay in gastric emptying. When Synkavit and irradiation were combined, a simple summation of the delays produced by each of these agents occurred. Cysteamine, which gives some protection against the lethal action of x‐rays, also caused a delay in gastric emptying, it did not protect against the action of x‐rays on stomach emptying.
POTENTIATION OF THE RESPONSE OF FROG RECTUS MUSCLE TO ACETYLCHOLINE BY ISOPROPYL METHYL PHOSPHONOFLUORIDATE AND ITS MODIFICATION BY PYRIDINE‐2‐ALDOXIME METHIODIDE
Authors: FLEISHER J. H. , CORRIGAN J. P. , HOWARD J. W.
Published: July 2012

Pyridine‐2‐aldoxime methiodide (P2AM) was used to study the relation between the recovery of Cholinesterase activity of isolated frog rectus abdominis muscle and the change of isotonic response to acetylcholine after previous treatment with the anticholinesterase, isopropyl methyl phosphonofluoridate (sarin). Addition of P2AM to muscle which had been incubated with sarin produced an 88% decrease in potentiation to acetylcholine. This was accompanied by 71% and 35% recoveries of the Cholinesterase activity of the intact and finely ground muscle respectively compared with controls from the contralateral muscle. Following pre‐treatment with sarin, a two‐hour rinsing with acetylcholine (3 μg./ml.) produced a 61% decrease in potentiation to acetylcholine accompanied by 24% and 4.5% recoveries of Cholinesterase activity in intact and in ground muscle respectively. Since control experiments showed absence of uncombined sarin in the muscle after rinsing with acetylcholine solution, the results indicate a greater effectiveness of P2AM and acetylcholine in reactivating superficially situated Cholinesterase of the frog rectus abdominis as compared with enzyme within the interior of the muscle.
THE INHIBITORY ACTION OF MORPHINE ON THE CONTRACTION OF THE LONGITUDINAL MUSCLE COAT OF THE ISOLATED GUINEA‐PIG ILEUM
Authors: KOSTERLITZ H. W. , ROBINSON JUDITH A.
Published: July 2012

Morphine (0.05 to 0.1 μg./ml.) markedly inhibited the contractions of the isolated guinea‐pig ileum caused by nicotine, barium, and 5‐hydroxytryptamine while the actions of acetylcholine, carbachol, and histamine were affected only a little. Atropine (0.025 to 0.05 μg./ml.) had a similar effect, in addition to its known effects on acetylcholine and carbachol contractions. Morphine had no additional effect on the inhibitory action of atropine, while in the presence of morphine, atropine had a significant additional inhibitory action only on the contraction caused by nicotine.

The action of barium was complex. It caused contractions of a rhythmic type alternating with relaxations, a pattern which is similar to that produced by the emptying phase of the peristaltic reflex; these oscillations were inhibited by hexamethonium. On the other hand, that part of the sustained barium contraction which was inhibited by morphine may be explained by an action on the nerve cells innervating the muscle fibres (motor neurones). Similarly, the morphine‐sensitive component of the 5‐hydroxytryptamine (5‐HT) contraction was probably also due to an action on the motor neurones. The morphine‐insensitive contractions of barium, 5‐HT, and nicotine were believed to be caused by a direct action on the muscle fibres.

The morphine inhibitors, nalorphine and levallorphan, had different effects with the different agonists. Their morphine‐like action was particularly pronounced on the effect of 5‐HT, which they antagonized, while their morphine‐protecting action was most strongly present on the effect of nicotine.
THE STIMULATORY ACTION OF ACETYLCHOLINE ON ISOLATED RABBIT ATRIA
Authors: JOHNSON E. A. , ROBERTSON P. A.
Published: July 2012

Quinidine (2.5 to 5 × 10−6 g./ml.) decreased the maximum rate of depolarization of the action potentials (AP) of both isolated rabbit atrial and ventricular fibres recorded with an intracellular microelectrpde and finally abolished electrical excitability and spontaneous rhythmicity. Acetylcholine (ACh) 10−6 restored these properties in the atrium (but not ventricle) without changing the membrane resting potential (MRP). Adrenaline 10−6 to 10−4 at the same time was without effect. The maximum rate of depolarization of an AP in response to an extra shock interposed between the 8th and 9th driving stimuli was increased by ACh 10−6 in atria which had received quinidine to a greater extent than that of the normal AP. It is suggested that ACh restarted atria arrested by quinidine by an action on the sodium “carrying system” (excitatory mechanism) and this was not the result of an increase in MRP. An hypothesis is put forward to explain the stimulatory and inhibitory effects of ACh on rabbit atria.
THE EFFECT OF SUBSTANCE P ON THE PERISTALTIC REFLEX OF THE ISOLATED GUINEA‐PIG ILEUM
Authors: BELESLIN D. , VARAGIĆ V.
Published: July 2012

The introduction of substance P into the lumen of the isolated guinea‐pig ileum caused an increase in the number and amplitude of the peristaltic waves. In preparations in which the peristaltic reflex was abolished, by fatigue, by external or internal application of 5‐hydroxytryptamine, or by lowering the temperature of the bath, the introduction of substance P into the lumen of the intestine restored peristalsis. This effect of substance P was absent in preparations in which the mucous membrane was removed. Hexamethonium abolished the effect of substance P on peristalsis. It is concluded that substance P acts on the afferent nervous elements of the peristaltic reflex arc, possibly on the sensory receptors.
A METHOD OF ASSAYING THE ANTI‐TETANUS POTENCY OF DRUGS ON EXPERIMENTAL LOCAL TETANUS IN THE RABBIT
Authors: LAURENCE D. R. , WEBSTER R. A.
Published: July 2012

Local tetanus was induced in rabbits by the intramuscular injection of tetanus toxin. The relative potency of drugs which abolished the muscle spasm was determined using quantitative electromyography and the accuracy of the method tested with mephenesin and thiopentone. It is suggested that the method is suitable for screening new drugs for clinical use.
ANTITHYROID ACTIVITY OF THIOHYDANTOINS
Authors: KILPATRICK R. , ELMORE D. T. , WOOD D. R.
Published: July 2012

The antithyroid activity of 2‐thiohydantoin and some derivatives has been measured in rats, after a single dose and, also, after daily administration for 6 weeks. 2‐Thiohydantoin and its 5‐alkyl derivatives from 5‐methyl to 5‐sec‐butyl‐ showed considerable antithyroid activity at a dose of 0.05 m.mole/kg. by mouth, but 5‐n‐hexyl‐2‐thiohydantoin had insignificant activity at this dose level. The presence of polar groups in the 5‐substituent was associated with reduction or complete loss of activity. By the single‐dose technique, 2‐thiohydantoin was more potent than its 5‐alkyl derivatives. The opposite result was obtained by other methods of assessment after 42 days of treatment. Some of the possible factors involved are discussed especially in relation to the difficulty of comparing results obtained by the different methods of assessment. The acute toxicity of 2‐thiohydantoin and of its 5‐methyl and 5‐ethyl derivatives is reported. No toxic effects were found after daily administration of several 2‐thiohydantoins at a dose of 50 mg./kg. for 6 weeks.
EFFECTS OF DIACETYL MONOXIME ON NEUROMUSCULAR TRANSMISSION
Authors: EDERY H.
Published: July 2012

The action of diacetyl monoxime on neuromuscular transmission has been studied in frogs, chickens, and cats, and in isolated rat phrenic nerve‐diaphragm preparations. In frogs and chickens the oxime caused a flaccid paralysis; in chickens there was sometimes opisthotonos. In the indirectly stimulated rat diaphragm, diacetyl monoxime decreased the height of a single twitch, but a tetanus was well sustained. In cats, the twitch height of the indirectly excited gastrocnemius‐soleus muscle was reduced by diacetyl monoxime more than was that of the tibialis anterior muscle, but in both muscles a tetanus was well maintained. Diacetyl monoxime reduced the response to direct stimulation of both the rat diaphragm and cat muscles. Diacetyl monoxime injected intra‐arterially in the cat elicited a transient hypertension and a gasp. Diacetyl monoxime did not reverse the neuromuscular block caused by anticholinesterases either in isolated rat phrenic nerve‐diaphragm preparations or in cats.
OUABAIN‐INDUCED VENTRICULAR TACHYCARDIA AND ITS EFFECT ON THE PERFORMANCE AND METABOLISM OF THE DOG HEART
Authors: FAWAZ G. , TUTUNJI B.
Published: July 2012

At constant pressure work there was an increase in the oxygen consumption of the dog heart‐lung preparation after tachycardia due to auricular stimulation and a far greater increase in consumption after ouabain‐induced ventricular tachycardia, as compared with control hearts beating at their own sinus rhythm. In neither condition was the increase in coronary flow greater than the spontaneous increase in the controls. It is suggested that an increase in oxygen demand, under certain circumstances, may be met primarily by an increased desaturation of coronary blood. “Therapeutic” doses of ouabain did not improve the mechanical efficiency of the preparation. “Toxic” doses of ouabain which gave rise to ventricular tachycardia did not decrease the phosphocreatine or labile nucleotide phosphorus content of the heart provided there was no hypoxia of the heart muscle.
DISTRIBUTION OF [14C]BEMEGRIDE IN TISSUES AFTER INTRAVENOUS INJECTION
Authors: GRAHAM J. D. P. , NICHOLLS P. J.
Published: July 2012

The distribution and excretion of bemegride labelled at the α carbon atoms with 14C were studied in mice, rats, and guinea‐pigs. These studies were supplemented by others made by colorimetric and absorptiometric methods on unlabelled bemegride in the body fluids of rabbits and dogs. Bemegride passed rapidly from plasma to all tissues, including brain, muscle, and fat. In addition it passed readily into the cerebrospinal fluid and the aqueous humour and to the foetus. It persisted in the tissues for longer than 24 hr., to some extent preferentially in the central nervous system. Approximately two‐thirds of the dose was excreted in the bile, faeces, and urine within 24 hr. The glutarimide ring of bemegride was not completely degraded biologically.
SOME EFFECTS OF RESERPINE AND HYDRALLAZINE UPON TISSUE RESPIRATION AND THE CONCENTRATION OF ADENOSINE NUCLEOTIDES IN CERTAIN TISSUES
Authors: KIRPEKAR S. M. , LEWIS J. J.
Published: July 2012

The effects of reserpine and hydrallazine upon the oxygen uptake of preparations of rat brain, liver, and kidney and rabbit aorta have been investigated using the Warburg “Direct” method. In these tissues reserpine did not significantly stimulate respiration at any of the doses used. Concentrations of 10 or 50 μg./ml. had no significant effect upon respiration, but higher doses (330 μg./ml.) depressed it in all the tissues studied. This effect was also seen in rat brain at a reserpine concentration of 100 μg./ml. which had no significant effect in other tissues. Hydrallazine (50 or 100 μg./ml.) depressed respiration in all tissues studied. Stimulation at lower doses was not seen.

After sublethal doses of reserpine, depletion of energy rich phosphate compounds occurred in brain and liver but not in skeletal muscle and heart. Hydrallazine also depleted brain of energy rich phosphate compounds, but did not affect liver, heart, or skeletal muscle. The bearing of these results on the mode of action of reserpine and hydrallazine is discussed.
THE EFFECT OF RESERPINE ON THE ACETYLCHOLINE CONTENT OF DIFFERENT AREAS OF THE CENTRAL NERVOUS SYSTEM OF THE DOG
Authors: MALHOTRA C. L. , PUNDLIK P. G.
Published: July 2012

The acetylcholine content of the frontal and temporal lobes, hippocampus, hypothalamus, cerebellum and spinal cord was estimated in 18 dogs 3 hr. after the intravenous administration of reserpine. Another group of 7 dogs served as control. After reserpine (0.5 mg./kg. body weight) there was an increase of acetylcholine in all the areas under study except in the hippocampus. The increase was specially marked in the hypothalamus. In the hippocampus, however, reserpine caused a significant decrease of acetylcholine.
SOME PHARMACOLOGICAL PROPERTIES OF THE α‐TOXIN OF STAPHYLOCOCCUS PYOGENES
Authors: BROWN D. A. , PRICHARD B. N. C. , QUILLIAM J. P.
Published: July 2012

The α‐toxin of Staphylococcus pyogenes produced a slowly developing contracture of isolated preparations of rabbit jejunum and of guinea‐pig ileum which persisted after thorough washing and left the gut unresponsive to further doses of α‐toxin or of acetylcholine. After incubation with antitoxin, the α‐toxin no longer produced a contracture. Antitoxin only prevented the α‐toxin response if added to the bath fluid before but not after the α‐toxin. Certain drugs reduced the α‐toxin contracture when added to the bath fluid before or after the α‐toxin, but the contracture reappeared on washing. Papaverine abolished the contracture and pethidine was only slightly less active. Mepyramine, amyl nitrite, caffeine, aminophylline, adrenaline and ephedrine partly reduced the contracture. Hexamethonium, cocaine, tubocurarine and gallamine had no effect. The effect of atropine was only small. The gut‐stimulant activity/haemolytic unit of two α‐toxin samples differed greatly; this difference did not appear to be due to activity of impurities. The implications of these observations are discussed.
STUDIES OF A PROTEOLYTIC ENZYME FROM SCHISTOSOMA MANSONI
Authors: TIMMS A. R. , BUEDING E.
Published: July 2012

The presence of a proteolytic enzyme has been demonstrated in ground‐up preparations of Schistosoma mansoni. A twenty‐fold purification has been achieved by ultracentrifugation at pH 3.0; the enzyme has an optimum pH of 3.9 and a marked substrate specificity for haemoglobin. No significant proteolysis was observed either with whole serum at pH values of 3.9, 6.0 or 8.0, or with isolated serum proteins at pH ranges between 2.5 and 7.7. The evidence is discussed that this enzyme may be located in the intestine of the schistosomes and that it is, at least in part, responsible for the supply of amino acids to the organisms.
THE EXTRACTION OF HUMAN URINARY KININ (SUBSTANCE Z) AND ITS RELATION TO THE PLASMA KININS
Authors: GADDUM J. H. , HORTON E. W.
Published: July 2012

Human urinary kinin (substance Z) has been extracted by modifications of the methods previously described by Gomes (1955) and Jensen (1958). The separation of two oxytocic fractions from such extracts by paper pulp chromatography (Walaszek, 1957; Jensen, 1958) could not be confirmed. Substance Z could not be distinguished from kallidin, bradykinin or glass‐activated kinin by parallel quantitative assays, thus confirming that these four substances are very closely related.
THE BIOLOGICAL ACTIVITY OF A NEW ANALOGUE OF OXYTOCIN IN WHICH THE TYROSYL GROUP IS REPLACED BY PHENYLALANYL
Authors: KONZETT H. , BERDE B.
Published: July 2012

A new synthetic analogue of oxytocin with a phenylalanyl group instead of a tyrosyl group has been investigated. The most prominent biological properties of this peptide were its oxytocic activity on the rat or cat uterus in vivo and on milk‐ejection pressure in the rabbit. Another remarkable feature was the striking difference in pressor activity measured in spinal cats and in anaesthetized rats. The presence of the phenylalanyl group in the molecule in the above‐mentioned position did not increase the antidiuretic potency in unanaesthetized rats. The authors propose a nomenclature for the peptides related to oxytocin and vasopressin.
INCREASED URINARY EXCRETION OF ADRENALINE AND NORADRENALINE AFTER PHENOXYBENZAMINE
Authors: BENFEY B. G. , LEDOUX G. , MELVILLE K. I.
Published: July 2012

In dogs anaesthetized with pentobarbitone sodium phenoxybenzamine greatly increased the urinary excretion of adrenaline and noradrenaline. This was associated with a transient increase in the volume of urine excreted and a fall in blood pressure. Hexamethonium prevented the effects on the urinary amines and on the blood pressure. Methacholine hypotension induced an increased adrenaline excretion, but no change in noradrenaline. The excretion of adrenaline released following ganglionic stimulation by acetylcholine did not appear to be affected by phenoxybenzamine, but that of noradrenaline was increased. During infusions of adrenaline or noradrenaline, phenoxybenzamine increased the excretion of both adrenaline and noradrenaline.
DRUG ANTAGONISM AND AUDIOGENIC SEIZURES IN MICE
Authors: WILSON C. W. M.
Published: July 2012

The occurrence of audiogenic seizures in mice has been used as the basis of a method for measuring the antagonism between sodium thiopentone and bemegride or leptazol. Thiopentone in doses of 8 and 16 mg./kg. protected all the mice against the occurrence of audiogenic seizures. Bemegride and leptazol were administered in doses having molecular concentrations which bore a simple relationship to the doses of thiopentone. Bemegride was four times as powerful as leptazol in antagonizing the protective effect of thiopentone, and comparison of their regression lines showed that both analeptics acted in the same way. The antagonistic effect of bemegride occurred with doses less than its normal convulsant dose, but the doses of leptazol needed to antagonize thiopentone were within the convulsant range, and it increased the severity of any audiogenic seizures.
THE INEFFECTIVENESS OF (±)‐CARNITINE PREVENTING THE TWITCHINGS OF STRIATED FROG MUSCLE IN 0.7% SODIUM CHLORIDE SOLUTION
Authors: FRIEBEL H.
Published: July 2012

The spontaneous twitchings of isolated frog sartorius muscles in 0.7% NaCl solution have been studied. Addition of 1 mg./ml. of (±)‐carnitine hydrochloride, or of (±)‐carnitine base, to the bath fluid had no influence on the spontaneous activity of the muscles, their excitability or their ability to liberate potassium. This indicates that carnitine is not a natural inhibitor of striated frog muscle. Fluids enriched with potassium either from twitching muscle or by addition of KCl inhibited the activity of muscles reversibly.
ANTIPHLOGISTIC ACTIVITY OF IPRONIAZID
Authors: SETNIKAR I. , SALVATERRA M. , TEMELCOU O.
Published: July 2012

Iproniazid was found to inhibit formalin‐induced oedema of the foot, dextran‐induced oedema and cotton‐pellet‐induced granulomatous tissue in the rat. The presence of the adrenals was essential for the antiphlogistic activity. The antiphlogistic action was not accompanied by any antipyretic effect. Inhibition of formalin‐induced oedema was also observed with phenylbutazone and with salicylamide.
EXPERIMENTAL HEPATIC AMOEBIASIS AND ITS APPLICATION TO CHEMOTHERAPEUTIC STUDIES
Authors: WILLIAMS G. A. H.
Published: July 2012

Induction of hepatic amoebiasis with two strains of Entamoeba histolytica has been attempted by direct inoculation of trophozoites into the livers of rats, hamsters, and guinea‐pigs, and by intravenous injection into guinea‐pigs. A high incidence of amoebic abscesses was obtained in hamsters. Rats and guinea‐pigs were relatively less susceptible. The two strains of Entamoeba histolytica differed in virulence. Serial liver passage increased their virulence for the hamster liver, and also increased invasiveness to the rat caecum. The chemotherapeutic effects of chloroquine, emetine, and some anilides were determined. The procedure finally adopted was based on mean survival times of treated and untreated animals. Chloroquine and emetine were effective under conditions which greatly favoured the drugs, but the anilides showed little effect.
THE INHIBITION OF AMINE OXIDASE AND THE CENTRAL STIMULATING ACTION OF THE STEREOISOMERIC AMPHETAMINES AND 1‐PHENYLETHYLAMINES
Authors: GRANA E. , LILLA L.
Published: July 2012

The stereoisomers of amphetamine and 1‐phenylethylamine have been studied in the rat both as central stimulants and as inhibitors of amine oxidase from brain, liver, and kidney. There was no correlation between these two effects; thus it is unlikely that the central stimulating action of amphetamine is due to inhibition of amine oxidase.
CONSISTENT DIFFERENCES IN INDIVIDUAL REACTIONS TO DRUGS AND DUMMIES
Authors: JOYCE C. R. B.
Published: July 2012

The tendency of some individuals to report changes of physical and mental state after taking pharmacologically inert substances has been investigated experimentally. In a class of healthy medical students, those individuals who reported symptoms and those who did not made significantly different scores on a number of behavioural tests. The likely reactions of the members of a second class (containing none of the previous participants) to dummies were then predicted from their scores on the same tests, some of which were found to be much more efficient predictors than would have been expected by chance. Some implications for further research and for clinical medicine are discussed.
PHARMACOLOGICAL PROPERTIES OF PHENYLDIGUANIDE AND OTHER AMIDINE DERIVATIVES IN RELATION TO THOSE OF 5‐HYDROXYTRYPTAMINE
Authors: FASTIER F. N. , McDOWALL M. A. , WAAL HENDRIEKA
Published: July 2012

Cats in which the coronary and allied chemoreflexes could not be obtained with small intravenous doses of 5‐hydroxytryptamine were insensitive also to phenyldiguanide. In cats which responded to phenyldiguanide with reflex falls of blood pressure and heart rate, abolished by vagotomy, the effects of graded doses (5 to 150 μg./kg.) of phenyldiguanide bore a striking resemblance to those produced initially by 5‐hydroxytryptamine in somewhat smaller doses. Differences in the cardiovascular responses to the two drugs are attributed to additional (non‐reflex) actions of 5‐hydroxytryptamine. The reflex actions of both drugs were blocked reversibly also by 2‐naphthylguanidine (500 μg.). Certain other drugs (bufotenine, procaine,S‐decylisothiourea) antagonized the depressor action of phenyldiguanide as well as the reflex depressor action of 5‐hydroxytryptamine. Like 5‐hydroxytryptamine, phenyldiguanide and certain other amidine derivatives caused pain when applied to the base of blisters in human subjects. Unlike 5‐hydroxytryptamine, phenyldiguanide did not constrict perfused rat blood vessels or increase the tone of the rat fundal strip preparation of Vane (1957). Phenyldiguanide did not affect the sensitivity of these smooth muscle preparations to 5‐hydroxytryptamine, but other amidine derivatives proved to be moderately strong antagonists of the vasoconstrictor actions of 5‐hydroxytryptamine and of adrenaline. Unlike 5‐hydroxytryptamine, phenyldiguanide did not produce gastric haemorrhage in the mouse. Phenyldiguanide did not prolong chloral hydrate sleeping time in mice by the same mechanism as did 5‐hydroxytryptamine. Phenyldiguanide was not highly toxic to mice (LD50 being 240 mg./kg.). It is concluded that phenyldiguanide and certain other amidine derivatives act on sensory receptors which respond to 5‐hydroxytryptamine, but that they show little pharmacological resemblance to 5‐hydroxytryptamine in other respects.
KININS PRODUCED FROM BOVINE COLOSTRUM BY KALLIKREIN AND SALIVA
Authors: GUTH PAUL S.
Published: July 2012

Substances capable of stimulating smooth muscle are produced on the incubation of bovine colostrum with urinary kallikrein or calf saliva. These substances, called urine‐ and saliva‐colostrokinin, have been differentiated from kallidin, substance A and similar smooth muscle activating agents. Saliva‐colostrokinin is likely to be formed in the suckling calf. Further, as colostrum became milk, the ability to form colostrokinin diminished. A function for saliva‐colostrokinin in the newborn is suggested.
THE EFFECTS OF SODIUM SALICYLATE ON THE OXYGEN CONSUMPTION OF RATS
Authors: HSIEH A. C. L. , CHIU C. C.
Published: July 2012

The effects of sodium salicylate on oxygen consumption of intact rats and rats treated with tubocurarine have been studied. Intraperitoneal injections of sodium salicylate in untreated rats produced varying results which depended on both the dose and the concentration used. Intravenous injections in rats treated with curare gave rise to an increase in oxygen consumption which was proportional to the log dose over a range of 0.0625 mg./g. to 0.5 mg./g. body weight. It was concluded that sodium salicylate stimulated the oxygen consumption of rats when the concentration of the drug in the plasma was high.
THE EFFECT OF TREATMENT WITH A LARGE DOSE OF ISONIAZID ON AN ESTABLISHED TUBERCULOUS INFECTION IN MICE
Authors: ROBSON J. M. , SULLIVAN F. M.
Published: July 2012

Mice were infected intracorneally with Mycobacterium tuberculosis var.bovis and the infection allowed to develop for a period of 2 weeks. At this stage the animals were divided into two main groups; one received no treatment, the other was treated with large doses of isoniazid (3.0 mg./mouse/day). The effect of treatment on the primary lesion, the viability of the bacilli, the systemic spread of infection, and the production of immunity were observed. Treatment was continued for 11 months, after which the animals were observed for another 8 months. Within a few days of starting isoniazid treatment the primary lesion stopped increasing in size, regressed slightly and stabilized at a size of about one‐third of that of the controls. There was little evidence of any clearing of the bacilli from the lesions; they remained strongly acid‐fast and morphologically normal for many months after infection, although by 13 months about half of the organisms in both groups had become very granular. The evidence suggests that in control and treated animals the bacilli in the cornea had usually all died within 8 months after infection. In two treated corneas, living virulent bacilli were demonstrated 15 months after inoculation. In the untreated animals, the disease spread systemically to involve the lungs, liver, and spleen, and by one year after inoculation the systemic tuberculous infection was very heavy, though not enough to kill the animals. The lesions in these animals contained many acid‐fast bacilli. In the treated group, systemic spread of infection as judged by the development of small macroscopic lung foci was slight; acid‐fast bacilli were found in only one animal. In the treated animals, practically no immunity could be detected 5 months after inoculation and had not reappeared 2 months after cessation of treatment; in the untreated animals immunity was present.
NICOTINE AND THE EFFECT OF ANTISYMPATHOMIMETIC AGENTS ON THE AORTA OF THE RABBIT
Authors: MILLSON D. R.
Published: July 2012

The responses of strips of rabbit aorta to almost maximal doses of nicotine were less readily antagonized by five antisympathomimetic agents than were comparable responses to noradrenaline. The effect was most marked with dibenamine, ergotamine, and tolazoline: approximately twice the dose of noradrenaline was required to match the test dose of nicotine after treatment with the antagonists. Dose/response curves for nicotine before and after phentolamine 10−7 indicate that the phenomenon may be reversed with low doses of nicotine and that the release of noradrenaline by nicotine within the tissues is probably a graded response. The pattern of nicotine/phentolamine antagonism in this preparation is consistent with the view that nicotine acts indirectly by releasing a noradrenaline‐like substance, and the difficulty found in antagonizing responses to nicotine with antisympathomimetic agents is probably similar to that responsible for failure of atropine to block some parasympathomimetic responses to nicotine.
THE ANTITUBERCULAR ACTIVITY OF 3‐ACETYLTHIO‐PROPYLENE SULPHIDE AND 3‐(2‐FUROYLTHIO)PROPYLENE SULPHIDE
Authors: ACRED P. , BROWN D. M. , WRIGHT D.
Published: July 2012

Two derivatives of 3‐mercaptopropylene sulphide (B.R.L. 482), 3‐acetylthiopropylene sulphide (B.R.L. 459) and 3‐(2‐furoylthio)propylene sulphide (B.R.L. 658), have been tested in mice for antitubercular activity. The compounds were administered daily in arachis oil by the subcutaneous route. When tested by a prolongation in survival time B.R.L. 459 was less active than streptomycin, while B.R.L. 658 was of the same order of activity. When assessed by the lesions present in the lungs after 14 days' treatment B.R.L. 658 was as active as isoniazid and B.R.L. 459 was of the same order of activity as streptomycin. Neither compound, however, cured an established infection and resistance developed rapidly to both compounds, both in vitro and in vivo. It is concluded that, in view of their adverse physical and pharmacological properties, the compounds are unsuitable for clinical use.
NEUROMUSCULAR BLOCKADE BY STREPTOMYCIN AND DIHYDROSTREPTOMYCIN
Authors: JINDAL M. N. , DESHPANDE V. R.
Published: July 2012

Both streptomycin and dihydrostreptomycin in large doses produced neuromuscular blockade in different types of skeletal nerve‐muscle preparations. Streptomycin had a quicker, more marked and a longer‐lasting action than dihydrostreptomycin. Neostigmine reversed a partial block of streptomycin, but a complete neuromuscular block remained unaffected. Calcium ions antagonized the neuromuscular block of streptomycin rapidly but incompletely.
THE ANTICHOLINESTERASE ACTIVITY OF SOME ANTIADRENALINE AGENTS
Authors: BOYD HELEN , CHANG V. , RAND M. J.
Published: July 2012

The contractions of the isolated guinea‐pig vas deferens in response to stimulation of the sympathetic hypogastric nerve were potentiated by low concentrations and inhibited by high concentrations of the antiadrenaline agents tolazoline, yohimbine, ergotamine, phenoxybenzamine and piperoxan. Eserine potentiated the contractions of the vas deferens produced by hypogastric nerve stimulation. The cholinesterase activity of an extract of vas deferens was decreased by the antiadrenaline agents. The potentiation of responses to sympathetic stimulation by antiadrenaline drugs, which also possess anticholinesterase activity, can be explained on the basis of a cholinergic sympathetic mechanism.
THE ANATOMICAL BASIS OF THE STRAUB PHENOMENON
Authors: BILBEY D. L. J. , SALEM H. , GROSSMAN M. H.
Published: July 2012

The administration of morphine was followed in white mice by a typical Straub reaction which consisted of the tail becoming rigid and erected across the back of the animal in an S‐shaped curve. This reaction was accompanied by restlessness, excitability, extension rigidity of the hindlimbs, forcible viodance of faeces and prominence of the perineum. The Straub reaction was abolished by general anaesthesia with pentobarbitone or ether, by administration of tubocurarine, by bilateral section of the muscles causing extension to the tail, and by the removal of the circulation to the lower extremity. The reaction was modified by unilateral section of the extensor muscles of the tail. Section of the spinal cord, decortication, division of the anal sphincter and perineal floor, or ablation of the pelvic splanchnic nerves did not suppress the appearance of the Straub response. It was concluded that the phenomenon described by Straub (1911) was produced mainly by the action of the sacro‐coccygeus dorsalis muscle, and that it was also necessary that the lumbo‐sacral cord with its peripheral nervous outflow should be intact and that these functioning units should have an adequate circulation.
A STUDY OF POTENTIAL HISTIDINE DECARBOXYLASE INHIBITORS
Authors: MACKAY D. , SHEPHERD D. M.
Published: July 2012

A series of compounds has been examined for ability to inhibit histidine decarboxylase. Histidine analogues having substituents in the imidazole ring showed a wide variation in potency, but these were all much less active than α‐methyldopa [β‐(3,4‐dihydroxyphenyl)‐α‐methylalanine], the most potent known inhibitor of histidine decarboxylase. Some tentative conclusions are drawn regarding the relationship between chemical structure and inhibitory activity.
THE EXCRETION OF SODIUM 6‐(2,6‐DIMETHOXYBENZ‐AMIDOPENICILLANATE) MONOHYDRATE IN RATS
Authors: HARRISON PATRICIA M. , WHITE JEAN A. , STEWART G. T.
Published: July 2012

The excretion of sodium 6‐(2: 6 dimethoxybenzamido) penicillanate monohydrate has been studied. When injected intramuscularly it was rapidly excreted in the bile and urine of rats, but only in trace amounts in the faeces. The excretion products in the bile (2 to 3% of the dose) and urine (26–84% of the dose) are microbiologically active. The product in the bile may be in conjugated form.
THE MECHANISM OF THE INHIBITORY EFFECT OF GLUTEN FRACTIONS ON THE PERISTALTIC REFLEX
Authors: SCHNEIDER R. , BISHOP HILARY
Published: July 2012

The mechanism of the inhibitory effect of gluten fractions on the peristaltic reflex was studied using, first, a filtrate of the autoclaved peptic‐tryptic digest of gluten (fraction III A.F.) and, second, the ultrafiltrate of an aqueous extract of gluten (fraction G.U.F.). The fractions did not act as antagonists to naturally‐occurring agents such as acetylcholine or substance P, but they did depress the twitch response of the isolated guinea‐pig jejunum preparation stimulated coaxially. The output of acetylcholine from cholinergic nerve endings in gut was decreased during rest as well as during electrical stimulation. In large amounts, the gluten fractions depressed acetylcholine synthesis in vitro. It was concluded that the mechanism of inhibition of the peristaltic reflex gluten fractions was chiefly by decreasing acetylcholine release.
A COMPARATIVE STUDY OF HYDROXYINDOLE OXIDASES
Authors: BLASCHKO H. , LEVINE W. G.
Published: July 2012

A comparative study has been carried out of the oxidation of 5‐hydroxytryptamine and related compounds by the oxidase present in the gill plates of Mytilus edulis and of caeruloplasmin, the copper containing oxidase of mammalian plasma. Both preparations oxidized indole derivatives carrying a hydroxyl group in the 4‐, 5‐, 6‐, or 7‐ position. The oxidation of bufotenine was compared with that of its 4‐ and 6‐hydroxy analogues; the 4‐hydroxy analogue is psil ocine, a naturally occurring hallucinogenic compound. Bufotenine and the 6‐hydroxy analogue were oxidized by both preparations with the formation of brown pigments; psilocine was more rapidly oxidized with the appearance of a blue colour. 4‐Hydroxytryptamine and 7‐hydroxytryptamine were also oxidized, the former with the formation of a blue compound. The N‐1‐methyl derivatives of both bufotenine and psilocine were also oxidized. The Mytilus preparation acted also on 4‐, 5‐, and 7‐hydroxytryptophan and on 5‐hydroxyindole, none of which was oxidized by caeruloplasmin. The Mytilus enzyme also oxidized 5‐hydroxyindoleacetic acid. Paraphenylenediamine, a very good substrate of caeruloplasmin, was much more slowly oxidized by the gill plate enzyme. The evidence suggests that the two enzymes catalyse the same reactions, but that the substrate specificity of the mammalian oxidase is somewhat more restricted. Both enzymes are “hydroxyindole oxidases,” not specific for 5‐hydroxyindoles alone. Inhibitors of the Mytilus oxidase included inhibitors of copper enzymes but not edetate or carbon monoxide. The action of pig serum on 5‐hydroxytryptamine was due to caeruloplasmin and not to amine oxidase.
SYMPATHETIC POSTGANGLIONIC CHOLINERGIC FIBRES
Authors: BURN J. H. , RAND M. J.
Published: July 2012

When the postganglionic fibres to the nictitating membrane are stimulated in a cat treated with reserpine, the membrane contracts. The contraction is increased after the injection of eserine and is abolished with atropine. Thus the fibres stimulated appear to be cholinergic. When the splenic nerve is stimulated in a cat treated with reserpine there is similar evidence of the presence of cholinergic fibres; the spleen dilates, the dilatation is greater in the presence of eserine and is abolished by atropine. The hypogastric nerves when stimulated cause inhibition of the uterus of the virgin cat. When the cat is treated with reserpine, stimulation then causes contraction which is increased in the presence of eserine and abolished by atropine. There is also evidence of cholinergic fibres in the postganglionic supply to the vessels of the rabbit's ear. From this and other evidence it is suggested that a form of adrenergic mechanism may exist such that cholinergic fibres in the postganglionic sympathetic supply liberate acetylcholine; this in turn liberates noradrenaline from a store around the sympathetic nerve ending.
ANOXIA AND VENTRICULAR FIBRILLATION; WITH A SUMMARY OF EVIDENCE ON THE CAUSE OF FIBRILLATION
Authors: BURN J. H. , HUKOVIĆ S.
Published: July 2012

Experiments are described showing that ventricular fibrillation is more readily produced in isolated rabbit hearts by electrical stimulation when the oxygen supply to the heart is reduced. This evidence completes investigations which have been made into factors affecting the production of fibrillation. These investigations have shown that factors which shorten the duration of the action potential, particularly those which cause the “plateau” to disappear, facilitate fibrillation, and those which lengthen the duration of the action potential prevent fibrillation. The reason for the length of the cardiac action potential may therefore be to prevent fibrillation. When the action potential is of normal length the fact that two adjacent fibres are out of phase does not matter; the one which is first to contract is not re‐excited by the one which is second to contract, because at that moment the first is inexcitable. If the action potential is short, then the first may be already repolarized and may be excited by spread of excitation from the second. Factors which inhibit metabolism shorten the action potential.
THE STRUCTURE‐ACTIVITY RELATIONSHIPS OF THE ANTIVIRAL CHEMOTHERAPEUTIC ACTIVITY OF ISATIN β‐THIOSEMICARBAZONE
Authors: BAUER D. J. , SADLER P. W.
Published: July 2012

As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure‐activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin β‐thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4‐point parallel‐line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin β‐thiosemicarbazone as a standard. The overall dimensions of the isatin β‐thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as ill substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the −CS.NH2 group in relation to the ring nitrogen was found to be critical, as the α‐thiosemicarbazone was inactive. A number of modifications of the side‐chain were investigated: all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1‐ethylisatin β‐thiosemicarbazone, with an activity of 286 (isatin β‐thiosemicarbazone≡100). Isatin β‐thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed no activity against ectromelia.
PHARMACOLOGICALLY ACTIVE PEPTIDES IN THE BLOOD AND URINE OF ANIMALS INFECTED WITH BABESIA RODHAINI AND OTHER PATHOGENIC ORGANISMS
Authors: GOODWIN L. G. , RICHARDS W. H. G.
Published: July 2012

The blood and urine of mice and rats infected with Babesia rodhaini contain substances which stimulate the isolated guinea‐pig ileum and rat duodenum. The amount of active material excreted increases as the infection increases. The active substances are stable to boiling with hydrochloric acid but not with alkali; they pass through a cellophane membrane and are soluble in hot ethanol. They are destroyed rapidly by papain and less rapidly by chymotrypsin, but are unaffected by trypsin or pepsin. Their action on smooth muscle is not affected by atropine, eserine, antihistamines, iproniazid, bretylium or by lysergic acid diethylamide. The active substances are probably peptides and there is evidence that the urine contains a mixture of peptides, some of which relax and some of which contract the rat duodenum. Similar active peptides appear in the urine of mice infected with Plasmodium berghei, Trypanosoma rhodesiense, Streptococcus pyogenes and Rift Valley fever virus.
DEPLETION OF PITUITARY CORTICOTROPHIN BY RESERPINE AND BY A NITROGEN MUSTARD
Authors: SAFFRAN M. , VOGT MARTHE
Published: July 2012

A single intraperitoneal injection of reserpine (2.5 mg./kg.) into rats produced a fall in the corticotrophin concentration of the pituitary to 30% of the resting value; recovery was not far from complete at 40 hr. A single injection of a nitrogen mustard caused an even greater loss of pituitary corticotrophin; 24 hr. after the injection the concentration was 10% of the resting value. There is no reason to assume that the effect of reserpine is due to an interference with storage of ACTH in the tissue and is not simply due to the fact that the drug acts as a stressing agent. The shape of the curve representing the fall in pituitary ACTH during the early phases of a sudden stress may be very similar to that of the fall in adrenal ascorbic acid produced by the released ACTH. This suggests that, under these circumstances, resynthesis is slow and the diminishing stores of ACTH in the pituitary reflect mainly the release of the hormone.
THE ACTION OF LOCAL ANAESTHETICS ON THE SPINAL CORD OF THE CAT
Authors: TAVERNER D.
Published: July 2012

The effects of intravenously injected lignocaine, procaine and amethocaine on the monosynaptic and polysynaptic reflexes and the cord dorsum potentials elicited by selective electrical stimulation of appropriate afferent fibres have been investigated in decerebrate cats before and after strychnine. The three drugs depress the amplitude of the reflex responses in the basal preparation for 40 to 50 min. Smaller doses eliminate the reflex augmentation produced by strychnine for comparable periods. Very small doses selectively abolish the augmentation of the P component of the cord dorsum response induced by strychnine. The drugs have no effect on post‐tetanic potentiation of the monosynaptic reflex response evoked from the gastrocnemius muscle in the cat. Their activity on the spinal cord is roughly proportional to their local anaesthetic potency. The ratios of the doses which produce the same central activity are amethocaine 3: lignocaine 10: procaine 20.
CENTRAL VASOMOTOR EFFECTS OF A NEW GANGLION‐BLOCKING AGENT—–1 : 2 : 2 : 6 : 6‐PENTAMETHYL PIPERIDINE (PEMPIDINE)
Authors: DHAWAN K. N. , BHARGAVA K. P.
Published: July 2012

The central vasomotor effects of pempidine were studied in dogs and cats anaesthetized with pentobarbitone sodium, and in spinal cats. Pempidine lowered the threshold of electrical stimulation of the medulla oblongata to evoke a pressor response when given intravenously to cats in a dose insufficient to block autonomic ganglia. Injection of a small dose into the cerebral ventricles of dogs produced an increase in the pressor responses to occlusion of the carotid artery and to electrical stimulation of the central end of the cut vagus. In the spinal cat small doses of pempidine, given either intravenously or intrathecally, augmented the rise in blood pressure resulting from compression of the spinal cord. Since all these effects were produced by pempidine in doses insufficient to cause ganglionic block, the observed effects are attributed to central facilitation of the vasomotor responses. Thus pempidine has a stimulant action on the spinal and supraspinal centres.