Showing papers in "Journal of Pharmacology and Experimental Therapeutics in 1928"

Tolerance and cross-tolerance in the human subject to the diuretic effect of caffeine, theobromine and theophylline

Abstract: We describe two women presenting with severe postpartum headache associated with hypertension but with no other signs or investigation results to suggest pre-eclampsia. In one case, the headache was associated with atypical subarachnoid haemorrhage. The variable nature of the headache and the degree of associated hypertension raised the clinical suspicion of reversible cerebral vasoconstriction syndrome, confirmed on MR angiography. Both patients took nimodipine until the cerebral vasoconstriction had resolved radiologically.

The seat of the emetic action of the digitalis bodies

Abstract: 1. The following is evidence that the digitalis bodies do not act directly on the center to induce vomiting: a. Vomiting has never been induced by the direct application of any digitalis body to the center, though it has been induced by the application of minute amounts of many drugs. b. Vomiting is not induced by the perfusion of the brain of the living animal with defibrinated blood to which a digitalis body has been added while the poison is excluded from the heart, but it is induced by the intravenous injection of the poison while the brain is perfused with defibrinated blood in such a way that none of the poison reaches the brain (1). c. The vomiting center is not stimulated for more than a few minutes by the direct application of a single dose of any drug so far as we know. Large doses cause vomiting soon followed by depression, but a single large intravenous dose of digitalis often causes prolonged nausea and vomiting. 2. The following is evidence that the digitalis bodies induce vomiting through their peripheral action. a. Nicotine (with atropine) abolishes the emetic action of an intravenous or intramuscular dose of a digitalis body, but it does not abolish that of an intraperitoneal dose of strophanthidin. b. Nicotine (with atropine) does not abolish the emetic action of apomorphine, showing that it does not depress the center markedly. 3. Experiments on intact and eviscerated animals show that the digitalis bodies do not induce emesis through any action on the gastro-intestinal tract (9). 4. The following is evidence that the digitalis bodies induce vomiting by their action on the heart: a. Cutting the cardiac nerves, or the cord above the level at which the cardiac nerves enter, abolishes the emetic action of an intravenous dose of digitalis for a time (1). b. The occurrence of nausea and vomiting associated with coronary occlusion and attacks of angina pectoris points to the heart as the seat of the vomiting reflex in such cases. c. The only published work of recent date that seemed to afford evidence that the digitalis bodies induce vomiting otherwise than by their action on the heart is shown to have no bearing on the problem so far as oral, rectal, intravenous or intramuscular administration is concerned. 5. The occurrence of vomiting following the intravenous injection of a digitalis body some weeks after the preliminary operation for denervation of the heart has been discussed.

Studies on crystalline insulin iii. further observations on the crystallization of insulin and on the nature of the sulfur linkage. the isolation of cystine and tyrosine from hydrolyzed crystalline insulin

Abstract: The method of obtaining crystalline insulin by the brucine method has been discussed and various modifications which were resorted to with some preparations have been pointed out. Crystalline insulin obtained by the brucine method has been recrystallized without the use of brucine, retaining its high activity. Insulin has been crystallized directly from crude insulin without the use of brucine. Crystalline insulin has also been obtained without the use of ammonia Cystine and tyrosine have been isolated from hydrolyzed crystalline insulin, proving the presence of these amino acids in the insulin molecule. A new method for separating cystine from tyrosine has been worked out. By means of the Sullivan method the amount of cystine has been estimated, the value obtained accounting for most of the sulfur present. Evidence has been found for the presence of another sulfur compound which gives the Folin-Looney reaction but not the Sullivan reaction. This may be an extremely difficultly hydrolysable dipeptide of cystine or another disulfide compound. The tyrosine content has been determined by the Folin-Looney colorimetric reaction.

Studies on the toxicity of various lead compounds given intravenously

Abstract: The toxicity of lead given intravenously depends entirely upon the form of lead given. The fourteen compounds studied may be divided into four groups, when one considers the effect upon the erythrocytes. The most toxic group comprises ionic lead, colloidal lead hydroxide, metallic lead, glycerophosphate, oleate and stearate. The lead hydroxide and glycerophosphate are quite soluble. The metallic lead oxidizes to the hydroxide in the blood stream. All these compounds function potentially as ionic lead. The next most toxic group includes colloidal lead oxy chloride, oxy carbonate, and carbonate. These compounds are very insoluble and probably are removed from the blood stream before they have had a chance to react with the constituents of the blood. From two to four times the dose of the second group must be given to cause a drop in hemoglobin comparable to the first group. The third group includes tetra ethyl lead and tri ethyl lead chloride. These compounds bring about only a slight drop in hemoglobin even when the lethal dose is approached. Since the lead is linked to carbon, they are not capable of forming lead ions, until hydrolysis takes place. This hydrolysis is a slow process and is probably brought about outside the blood stream. Group four comprises tri lead phosphate, di lead phosphate and lead sulfide. These compounds have no demonstrable effect upon the red cells. The di lead phosphate probably goes over to the tri lead phosphate when it reaches the blood stream. Lead phosphate and sulfide are highly insoluble and stable compounds at the pH of the blood. The lethal dose for a compound is difficult to evaluate because of the great variation in tolerance for different rabbits. For compounds which function potentially as ionic lead the lethal dose varies from 3 to 10 mgm. of lead per kilogram. For com pounds of the type of lead oxy carbonate, 16 mgm. of lead per kilogram has been given without death, although 4 mgm. have occasionally been fatal. The lethal dose for tri ethyl lead chloride is of the same order as ionic lead and that for tetra ethyl lead the same as for lead oxy carbonate. For the pregnant animal this generalization does not hold, tetra ethyl lead being no more toxic and lead oxy carbonate being extremely toxic. This difference has been accounted for by the observation that lead oxy carbonate damages the liver, the organ burdened in pregnancy, and that tetra ethyl lead does not effect the liver. The lethal dose for lead phosphate has not been ascertained, the compound apparently being without, toxic effect. 2 The effect of lead in weakening the progeny could be demonstrated for lead phosphate, tetra ethyl lead, lead oxy chloride and lead carbonate. The effect upon the chorion was only certain in one instance. Colloidal lead phosphate and ionic lead are substantially removed from the blood stream of the rabbit in two hours. A detailed report of the preparation of suspensions of lead carbonate, lead oxy carbonate, lead oxy chloride, lead sulfide and di lead phosphate, is included. Colloidal lead phosphate and tetra ethyl lead appear to be the only lead compounds suitable for trial in intravenous cancer therapy.

Studies on crystalline insulin v. the distribution of nitrogen in crystalline insulin

Abstract: 1. The method of Van Slyke for determining the nitrogen distribution in proteins has been studied in its application to small amounts of protein material. Certain modifications in the procedure involving the use of a micromethod have been introduced. 2. The nitrogen distribution in crystalline insulin has been determined by this method. 3. The behavior in this procedure of the sulfur-containing cleavage products of insulin has also been studied.

Studies on crystalline insulin vi. further contributions to the question whether or not crystalline insulin is an adsorption product

Abstract: Starting with crystalline insulin, which had been recrystallized, and submitting it to a procedure as closely analogous as possible to that adopted by Dingemanse, we have completely failed in obtaining any evidence of fractionation or in isolating a product more active than the original crystals. Furthermore, after the adsorption on charcoal, elution with phenol, and subsequent precipitation, crystals were once more obtained from the precipitate, identical in crystalline form, behavior, and activity with the original product.

A comparative study of synthetic and natural ephedrines

Abstract: 1. Synthetic ephedrine possesses qualitatively all the characteristics of natural ephedrine: its pressor action in experimental animals following an intravenous injection and much less constandly in men after oral administration, its oxytocic action on the isolated virgin guinea pig9s uterus, its bronchodilating action after arecoline or physostigmine, its mydriatic action in rabbits and in men (definite in Caucasians but insignificant in colored races), its hyperglycemic action, and its detoxifying action in acute morphine poisoning. 2. Quantitatively, synthetic and natural ephedrines, in the form of the hydrochloride, injected intravenously, both have a M.L.D. of 60 mgm. per kilogram in white rabbits. The average ratio of the intensity of pressor action of synthetic ephedrine to that of natural ephedrine with optimal doses compared indirectly in pithed cats against epinephrine, is 1:1.33. The average ratio of the mydriatic action of synthetic ephedrine to that of natural ephedrine in Caucasians measured by the increase in the transverse diameter of the pupil, is 1:1.29. 3. Clinically, synthetic ephedrine on local application contracts the congested nasal mucous membranes and hypertrophied turbinates not unlike the action of natural ephedrine. In the treatment of bronchial asthma, synthetic ephedrine appears to have in some cases an antispasmodic but weaker action than natural ephedrine. The Abbott Laboratories, Chicago, Illinois, also courteously supplied to the author a sample of synthetic ephedrine. Their product is optically inactive, melts at 190°C, and gives with cupric hydroxide a purplish color extractable by ether. It has a pressor action in experimental animals, and shows a decrease in response of pressor action on repeated injections. No extensive work on this product was done in connection with the present investigation. One would expect, however, that it should have the same pharmacological action if it is chemically identical with synthetic ephedrine.

Studies of chronic morphine poisoning tn dogs i. general symptoms and behavior during addiction and withdrawal

Abstract: Symptoms and behavior are recorded in twenty-four addictions to morphine and in twenty-two withdrawals in dogs, in which detailed observations were made over periods covering from forty to three hundred and thirty days and with doses of 30 to 230 mgm. per kilogram. Considerable variability in symptoms during chronic poisoning with morphine was observed. The severity of withdrawal symptoms varied markedly in different dogs. These differences are not related to length of addiction or size of dose at withdrawal. Two dogs showed very severe symptoms during withdrawal and in both of these the dose was relatively small. Two animals died in addiction during administration of large doses. One died on the third day of withdrawal. When the symptoms observed in this group of dogs are considered as a whole they form a composite picture that is strikingly similar to that obtained in chronic morphine poisoning in man; this is particularly true of withdrawal symptoms. We believe that the observations reported in this paper show there is marked similarity between morphine addiction and withdrawal in man and in dogs; that this similarity makes the dog a particularly suitable test object for the study of many phases of the morphine problem; that results obtained in experiments on dogs can be applied to the problems of morphine addiction with greater validity than those on any other laboratory animal.

Ii. the effect of morphine and papaverine upon the peristaltic and antiperistaltic contractions of the ureter

Abstract: 1. Morphine sulphate in high concentrations when added to the pace-maker causes increased tonus and "pendular movements" of the exposed ureter. 2. In moderate concentrations when added to the pace-maker morphine causes increased tonus and peristaltic activity if peristalsis exists and antiperistalsis if antiperistalsis is present. 3. If morphine sulphate is added to the solution bathing the dependent segment of ureter a reverse movement is quickly established, peristalsis is converted into antiperistalsis and vice versa. 4. Papaverine hydrochloride depresses both peristalsis and antiperistalsis in the ureter. 5. Papaverine hydrochloride added to the solution bathing the pace-maker quickly stops the spontaneous activity of that segment and in irritable ureters reverses the form of activity thus if peristalsis was present antiperistalsis is produced and vice versa. 6. Papaverine hydrochloride decreases the rate and height of contraction. 7. It requires about one-hundredth the quantity of papaverine hydrochloride to cause depression as it does of morphine sulphate to cause an equal stimulation of the ureters.

Studies on crystalline insulin iv. the isolation of arginine, histidine, and leucine

Abstract: Arginine, histidine and leucine have been isolated from hydrolyzed crystalline insulin, proving the presence of these amino acids in the insulin molecule. From the lysine fraction a picrate has been obtained, the properties of which indicate the presence of lysine. By means of the method of Koessler and Hanke the amount of histidine has been estimated.

The role of the liver in controlling the distribution of blood

Abstract: A large number of livers of cats, dogs, guinea pigs, and rabbits were perfused through their portal veins with sugar-free Locke9s solution to which were added various drugs: epinephrine, barium chloride, pituitary extract, and sodium nitrite. The livers of cats and dogs in every case responded to epinephrine and barium chloride with decreased outflow. Pituitary extract in very dilute concentrations also caused a decreased outflow. Sodium nitrite caused an increased outflow. In practically every case the livers of freshly killed rabbits showed a decreased outflow when perfused with epinephrine, 1:500,000. When the rabbit livers were washed free from blood, stored for some time, even thirty hours, in a cold room, the majority of them responded to epinephrine by a decreased outflow; but a number behaved in a variable manner by giving an increased outflow upon the first few trials, then responding by a decreased outflow. A few of the stored rabbit livers, upon several trials, always gave an increased outflow with epinephrine. An attempt has been made to explain the increased outflow from the stored livers, as due to autolysis with increased hydrogen ion concentration. Likewise the livers of freshly killed rabbits practically always showed decreased outflow with barium chloride and pituitary extract. Here again a few of the stored rabbit livers showed increased outflow with barium chloride. Livers of guinea pigs, when perfused immediately after death, showed decreased outflow with epinephrine and pituitary extract; with barium chloride many livers showed increased outflow upon admission of the drug but this was later followed by decreased outflow. A very few always gave an increased outflow. Livers of cats, dogs, and rabbits were perfused while sealed in an oncometer. When epinephrine and barium chloride were added to the perfusion fluid the graphic records showed decreased liver volume and a reduced outflow. From the results of the studies with the oncometer the writer considers the point of action of epinephrine upon perfused livers to be the intrahepatic portal radicles. Further studies are in progress to determine any substances capable of passing the portal radicles but causing constriction of the central and sublobular radicles of the vena cava.

The anuran in bio-titration of pituitrin

Abstract: 1. The anuran perfusion preparation equals or surpasses in delicacy any present method detecting presumptive posterior hypophysial lobe principle; it is however slow, needs careful attention to buffering, and requires larger amounts of test substances than the oxytocic titration. A quick method of making the preparation is described, some anomalous discrepancies in absolute amounts determined by different methods are considered, and qualitative results on canine sera and cerebrospinal fluids are reported. 2. The state of melanophore expansion in anuran skin is in part heavily determined by the hydrogen ion concentration of the circulating fluid. 3. Intact hypophysectomized tadpoles immersed in fluid are only crude indicators of presumptive posterior hypophysial lobe principle.

The renal blood-flow of the bird

Abstract: 1. The renal blood flow of the fowl may exceed the figure of 10 cc. per gram minute. 2. The blood flow under the experimental conditions appears to vary directly with the general circulatory changes. 3. The blood pressure is not in itself an indication of the rate of blood flow. 4. The functional activity of the organ appears to depend neither on the amount of blood flow, nor the pressure, but may vary with these. 5. There appears to be a dissociation between the secretion of water and the removal of uric acid from the blood. 6. The kidney can remove 30 per cent of the uric acid from the blood circulating through it, and this removal is independant of the rate of blood flow. The figure of 30 per cent may not necessarily be the highest obtainable. 7. The action of adrenalin, ergotoxin, amyl nitrite, choline, acetyl choline, pituitrin, histamine, Ringer, sulphate and uric acid solutions, also the effect of poisoning with carbon dioxide, and stimulating the vagus, are discussed in relation to the blood flow and urinary secretion.

Clinical and experimental studies on phototherapy in pernicious anemia

Abstract: 1. The toxic reaction of pernicious anemia blood serum as studied by phytopharmacological methods is diminished when such serum is irradiated by ultraviolet rays in a quartz tube outside the body. 2. Such detoxification of the blood serum also occurs as shown by the same test after exposure of pernicious anemia patients to ultraviolet rays. 3. A comparative study of the detoxifying power in this respect of various monochromatic ultraviolet rays on different samples of the same pernicious anemia serum indicate that the wave lengths 3130 and 2967 are the most efficient in this respect. 4. The addition of a photosensitizing drug, sodium tetrabromfluorescein in small quantities to the pernicious anemia serum increases the detoxifying efficiency of the ultraviolet rays. 5. A comparative study of monochromatic, polarized and non-polarized ultraviolet rays indicates that in respect to their effect on pernicious anemia toxin the ordinary or non-polarized waves are more efficient. 6. The penetration of ultraviolet rays through living animal tissues is shown to be much greater than has been generally supposed. 7. The influence of ultraviolet irradiation with or without addition of photosensitizing drugs on a series of pernicious anemia cases so far studied by the authors has been followed by a definite improvement in their general condition. 8. This improvement is indicated not only by the subjective and objective amelioration of symptoms and a marked improvement in the "anemia" or morphological blood picture, but also goes hand in hand with a diminution of the toxicity of the blood and therefore seems to point to a destruction or inhibition of the causative factor in the disease. 9. In view of the scientific experimental basis for the effect of ultraviolet rays on pernicious anemia toxin and in view of the penetration of ultraviolet rays through living tissues, demonstrated by the authors, and also in view of the favorable results obtained in the preliminary clinical series here described it is hoped that a further and more extensive clinical therapeutic study of phototherapy in pernicious anemia will be carried on by qualified physicians.

Physiological reactions induced by alpha-lobelin i. intravenous injections during anesthesia and certain other forms of depression

Abstract: 1. Alpha-lobelin is one of four alkaloids of Lobelia-inflata which have been isolated and whose chemical composition seems well established. 2. The work here reported deals with the action of intravenous injections of alpha-lobelin in the dog, cat, monkey, rabbit and man, in conditions of depression due to amytal, morphine, veronal, ether, carbon monoxide (illuminating gas), carbon dioxide and increased intracranial pressure. 3. The action of alpha-lobelin on the respiration and on arterial pressure as reported by previous investigators is in the main confirmed. 4. The respiration can be markedly, even tremendously, increased in the intact animal or in man, in light and in moderate anesthesia. Marked individual differences in the degree of response are seen. The respiratory effects are of brief duration. 5. Arterial pressure can also be raised in a striking manner and maintained at a level above the original one for as long as six minutes or more in animals depressed to certain degrees. 6. In deeply depressed animals, arterial pressure can be lowered by doses of alpha-lobelin which in lesser degrees of depression stimulate respiration and raise the pressure. In these animals the respiratory stimulation is likely to be slight or to fail altogether. 7. The extent and duration of the pressure fall vary with the size of the dose of lobelin and depth of anesthesia. A fall of pressure that is fatal can easily be obtained. 8. The reactions responsible for this effect are discussed and the danger of intravenous injections of alpha-lobelin is emphasized. 9. There is a striking similarity between the action of alpha-lobelin and adrenine as regards (a) the respiration, (b) the blood pressure effects of the two substances, and (c) their hyperglucemic effects, which have not been hitherto described in relation to lobelin. The relation of these various actions of adrenine and lobein are discussed. 10. The side actions and toxicity of alpha-lobelin are briefly considered.

The relation between concentration, and action of adrenaline

Abstract: 1. The isometric and isotonic response of strips of sheep9s carotid artery to varying concentrations of adrenaline are shown to agree satisfactorily with the formula [See formula in the PDF File] where x = concentration, y = action as per cent of maximum action ( A ), and K = constant. 2. When the frog9s aorta is perfused with varying concentrations of adrenaline the relation between concentration and out-flow approximates to the formula given above over a wide range of concentrations. This partial coincidence is surprising because when the pressure is constant the outflow from a tube varies as (radius) 4 . 3. The relations between dosage of adrenaline and rise of blood pressure in the pithed cat follows the formula given above. This agreement is partly explained by the fact that the relation between adrenaline dosage and increase in cardiac frequency follows the formula fairly exactly. 4. An important consequence of the relation that has been shown to exist between the concentration of adrenaline and the action it produces is that when physiological concentrations are present the effect produced varies almost directly as the concentration, whereas when higher toxic concentrations are present, the effect varies as the logarithm of the concentration.

Studies in chronic morphine poisoning in dogs iii. blood sugar during tolerance and withdrawal

Abstract: During the first half of a long addiction to morphine the general level of blood sugar, as shown by estimations made before the injection of the daily dose, is somewhat higher than during the control period before addiction started. During the second half of a long addiction the general level of blood sugar is lower than during the first half and either approaches or is slightly below the normal level. The hyperglycemia that occurs immediately after the injection of morphine in a normal dog, rapidly disappears during addiction. The fall in temperature that occurs simultaneously with the hyperglycemia decreases very slowly and does not entirely disappear during addiction. When the drug is withheld for two to four days during addiction, the hyperglycemia recurs to approximately the same degree as after the first dose, when administration is resumed; the fall in temperature is not as great proportionately as the hyperglycemia. The blood sugar curve shows a distinct increase during the first week of withdrawal. Later in withdrawal, after withdrawal symptoms have subsided, the blood sugar curve falls somewhat below normal, in some cases.

Studies in chronic morphine poisoning in dogs ii. changes in blood cells and hemoglobin during addiction and withdrawal

Abstract: Studies of red and white cells and hemoglobin were made on 16 dogs during addiction to morphine and after sudden withdrawal; differential counts of white cells were made on 8 dogs. Red blood cells are normally more numerous in dog9s blood than in human blood; during addiction to morphine the number of red cells is not materially altered; following abrupt withdrawal the number is decreased. White blood cells are normally more numerous in dog9s blood than in human blood; during addiction neither the number nor the relative amounts of the various forms of white cells show any consistent change; during withdrawal there is a marked leucocytosis and during the leucocytosis the percentage of polynuclear neutrophiles is increased. The hemoglobin content of dog9s blood is not altered during addiction to morphine; during withdrawal the hemoglobin is usually decreased, the fall being parallel to the decrease in red cells.

Further experiments on the effects of small doses of vaso-constrictor substances on the kidney

Abstract: Results are here presented which confirm the report of Richards and Plant in that minute doses of certain vasoconstrictor drugs may produce simultaneously a rise in blood pressure, an increase in kidney volume, a decrease in volume flow of blood through the kidney and diuresis. This coincidence is regarded as evidence in favor of glomerular filtration.

A comparison of the pharmacological action of diacetone alcohol and acetone

Abstract: 1. The comparison of the toxicity and pharmacological action of diacetone alcohol and acetone is of industrial importance since both are in wide use as commercial solvents. Their study is of interest because they offer an opportunity to compare a substance with its simplest polymer. 2. Diacetone alcohol is somewhat more toxic than acetone. Its soporific action develops more rapidly and a more constant depressant effect is noted upon the respiration. 3. Both substances produce a fall in blood pressure which is probably due to decreased cardiac output and which is independent of the vagal center.