bluuebunny/crossref_metadata_2025 huggingface dataset:
Broad‐spectrum screening of psychotherapeutic drugs: Thiothixene as an antipsychotic and antidepressant
Authors: Overall John E. , Hollister Leo E. , Shelton Jack , Kimbell Isham , Pennington Veronica
Published: January 2016

Thiothixene was studied simultaneously in both schizophrenic and depressed patients. Seventy‐two newly admitted schizophrenic patients and 64 depressed patients were treated for 4 weeks with relatively modest doses. As indicated by interview ratings coded on 2 psychiatric rating scales, the drug was highly efficacious in both types of patients, the degree of improvement for each general group of patients being among the highest of our series of evaluations of antipsychotic and antidepressant drugs. When the results of treatment of 5 different schizophrenic Stlbtypes were reviewed, there were no differences between the responses of various types of schizophrenic reactions. The same situation applied to 3 subtypes of depressive reactions. Side effects were chiefly related to weight gain, extrapyramidal syndromes (including akathisia), anticholinergic effects, and sedation.
Oral contraceptives: The past and future
Authors: Dodds Sir Charles
Published: January 2016

In the year 1961 I was invited to deliver the Dale Medal Lecture before the Society for Endocrinology, and I took as my subject the title: “Rime and Reason in Endocrinology.” The lecture was mainly concerned with a warning of the possible danger of the prolonged use of the progestogen‐estrogen‐type of pill. It is a common experience among gynecologists, clinicians, and general practitioners that once a woman has confidence in a method of contraception she will adhere to it for the whole of her active sexual life. This could mean that a woman might remain under the influence of this type of pill for 35 to 40 years. It would seem extremely unlikely to me, thinking as a biologist, that one could submit the delicately balanced hormone system of a woman to this violent alteration for 40 years without something serious happening. I should like to summarize very briefly this lecture and then look at the problem in the light of nearly the 9 years that have elapsed since I gave the lecture.
Phytotoxicology. I. Major problems associated with poisonous plants
Authors: Kingsbury John M.
Published: January 2016

Phytotoxicology (the study of poisoning of man and animals by plants) is an area of medical neglect in both clinical and experimental aspects. Poisonings, for the most part, are poorly investigated, poorly reported, and rarely attract appropriate experimentation. Vernacular or common names for plants are tenuous at best, and their use has led to serious errors in treatment and in medical literature. Frequently the origin of information available to the medical profession in current authoritative publications is of a prior century, or earlier, and derived from experience elsewhere than in North America. These facts often are not obvious. Figures for level of toxicity and statements of symptoms and lesions of such origin often reflect experimental conditions which should invalidate the results, as far as basing responsible present‐day treatments on them. General information from such unspecified sources ignores factors of botanical and human variability with time and place, including ecological, genetic, and nomenclatural variation, variation in human exposure, and variation with horticultural manipulation. Fact and myth are intermingled freely in what the American population believes about poisonous plants. Therefore, what colors any medical history is apt to be vastly different from reality. Induced emesis, catharsis, or gastric lavage are frequently performed when ingested plant material is entirely innocuous and none of these procedures indicated. A plant experimentally established as nontoxic, for example, is among the 10 plants most frequently reported as ingested and believed poisonous by poison control centers. Not all poisonous plants have yet been recognized as such. To establish a list of any set number of “important” poisonous plants is irresponsible on the basis of present knowledge if it results in others being overlooked when poisonings or ingestions are diagnosed.
Effect of propranolol on the duration of the Achilles tendon reflex
Authors: Waal-Manning Hendrika J.
Published: January 2016

The duration of the Achilles tendon reflex is used in the diagnosis and management of thyroid disease. Extrathyroidal factors which may increase the duration of the Achilles tendon reflex are listed. The influence of propranolol on the duration of the Achilles tendon reflex in 20 patients is reported; a considerable prolongation of the reflex occurred in 80 per cent of patients. These observations may prevent errors in diagnosis and management of thyroid disease based on timing of the Achilles tendon reflex.
Experimental designs for estimating effective doses
Authors: Ott R. Lyman , Myers Raymond H.
Published: January 2016

A particular problem in the choice of experimental designs for estimating effective doses is discussed. Several alternative approaches are considered when there is some curvature in the dose‐response relationship, but a linear approximation is still to be used. An example of one method is discussed in detail when very little information is available on the dose‐response relationship prior to experimentation. The results obtained here provide an objective technique for choosing experimental designs.
Archaic classification of barbiturates
Authors: Mark Lester C.
Published: January 2016

The classification of barbiturates as long‐, intermediate‐, short‐, or ultrashort‐acting, based on findings in animals, has been shown to be scientifically unsound when tested in carefully controlled studies in human subiects. The spectrum of barbiturate effects extends in dose‐dependent fashion from sedation to hypnosis to anesthesia to poisoning to death. Any of these effects can be achieved deliberately or accidentally by any barbiturate given in appropriate dosage, although differences in physicochemical properties and pharmacokinetic behavior do tend to confer some degree of specialization upon individual barbiturates in therapeutic usage. For clinical purposes it would be more logical to classify this family of drugs as “sedative‐hypnotic barbiturates” or “anesthetic barbiturates,” recognizing that the members can be moved from one group to the other as desired by the prescribing physician.
Perspectives in adrenergic beta‐receptor blockade
Authors: Fitzgerald J. D.
Published: January 2016

The adrenergic ß‐receptor blocking drugs currently undergoing clinical evaluation are classified in relation to their pharmacological properties. Particular consideration is given to those pharmacological properties that may be of importance in the clinical application of these drugs. The present evidence on the role in the ß‐blocking action of propranolol in angina pectoris and arrhythmias is reviewed, and it is concluded that this property is of major significance in these indications. Finally, recent advances in this field are summarized and possible future areas for research described.
A retrospective study of the pharmacokinetics of heparin
Authors: Estes J. Worth , Pelikan Edward W. , Krüger‐Thiemer Ekkehard
Published: January 2016

The published data on pharmacokinetics of intravenously administered heparin were studied by computer analysis. The relative volume(s) of distribution (RVD) and plasma half‐life (t½) were calculated for men, dogs, and rabbits. All 57 log plasma heparin concentration‐time curves fitted equations for first‐order processes, even at the largest doses. In dogs, both the RVD and t½ varied with the dose and with each other, regardless of dose; in men, only the t½ varied with dose. The t½ in men increased to a greater extent per unit increment in dose than in dogs. In both species, the RVD corresponded to the plasma volume, except with very large doses. The data were consistent with the hypothesis that heparin may leave the plasma by uptake into the reticuloendothelial system. They explain some of the difficulties in devising practical and reliable clinical dose schedules for heparin.
A study of the metabolic fate of chlorpropamide in man
Authors: Brotherton P. M. , Grieveson Phillida , McMartin C.
Published: January 2016

It is shown that chlorpropamide, previously thought to be a nonmetabolized drug, undergoes metabolic transformation in man. Two of the metabolites were identified by chromatographic techniques as p‐chlorobenzenesulfonylurea and p‐chlorobenzenesulfonamide. Estimation of the quantities of these metabolites and of unchanged chlorpropamide in the urine of diabetic patients showed that a considerable quantity of an unidentified metabolite must also be excreted. The proportion of the drug converted to the two identified metabolites varies in different individuals on long‐term chlorpropamide therapy. A modified plasma assay procedure for chlorpropamide which reduces interference from metabolites is described.
Serum free fatty acids, growth hormone, and insulin during trials of ACTH and synthetic subunits
Authors: Alley R. A. , Tsai C. T. , Morgan C. R. , Robbins T. J. , Sabeh G. , Hofmann K. , Danowski T. S.
Published: January 2016

ACTH‐like molecules composed of 24 and 23 amino acid residues administered to healthy men during 3 hours of an intravenous infusion produced increases in serum nonesterified fatty acids; ACTH itself (39 amino acid residues) and molecules comprising 20 or 13 amino acid residues injected in equimolar or greater amounts were inert in this respect. These clear differences are related to the experimental conditions employed, since under other circumstances ACTH is known to increase nonesterified fatty acid levels in man and ACTH and an analogue composed of 20 amino acid residues have the same effect in animals. ln the majority of our trials in man, slow infusion of ACTH or of molecules consisting of 24, 23, or 20 amino acid residues raised the level of immunoassayable growth hormone in serum, but circulating insulin did not change.
Effect of environmental factors on drug metabolism: Decreased plasma half‐life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides
Authors: Kolmodin Birgitta , Azarnoff Daniel L. , Sjöqvist Folke
Published: January 2016

In twenty‐six men occupationally exposed to a mixture of insecticides, mainly lindane and DDT, antipyrine had a significantly shorter plasma half‐life than in 33 control sub;ects. If the mechanism is the same as that in animals, these studies indicate that insecticides can induce microsomal drug metabolism in man.
Cephalexin: Microbiological effects and pharmacologic parameters in man
Authors: Meyers Burt R. , Kaplan Kenneth , Weinstein Louis
Published: January 2016

Cephalexin (desacetoxycephaloglycin), a semisynthetic derivative of cephalosporin C, was found to have a range of antimicrobial activity similar to that of cephalothin which inhibits the in vitro growth of most gram‐positive bacteria, with the exception of the enterococci and of some gram‐negative organisms. Except for methicillin‐resistant strains, all 62 strains of Staphylococcus aureus, including penicillin‐resistant strains, were inhibited by from 0.15 to 12.5 µg per milliliter of the drug. Eleven strains of methicillin‐resistant Staph. aureus were highly resistant to cephalexin; most were inhibited by 100 µg per milliliter. Among the other susceptible species were Streptococcus pyogenes, Streptococcus viridans, Diplococcus pneumoniae, most strains of Salmonella, Shigella, and Hemophilus influenzae, approximately 50 per cent of Escherichia coli, and almost one third of Proteus isolates. Enterococci, Aerobacter aerogenes, Pseudomonas aeruginosa, Alcaligenes fecalis, and Serratia were highly resistant. In man, following ingestion of 500 mg. in the fasting state, peak levels of 18 µg per milliliter were attained in the serum at one hour, whereas after a meal the level was 12 µg per milliliter. From 75 to 100 per cent of the oral dose was excreted in the urine within the first 8 hours, producing urinary levels in some specimens of over 1,000 µg of cephalexin per milliliter of urine. The minimum inhibitory concentration of cephalexin for sensitive organisms fell within the range of serum concentrations produced by ingestion of 500 mg. of this drug.
The pH‐dependent excretion of mono methylated tricyclic antidepressants; In dog and man
Authors: Sjöqvist Folke , Berglund Fredrik , Borgå Olof , Hammer Wolfgang , Andersson Sven , Thorstrand Curt
Published: January 2016

After intravenous administration of desmethylimipramine and nortriptyline to dogs, the excretion of unchanged drug in urine or gastric juice was found to be of little quantitative importance. The renal excretion was pH dependent, indicating nonionic diffusion between blood and urine. The urinary excretion of desmethylimipramine or nortriptyline given in therapeutic doses to depressed patients was also shown to be pH dependent. At a steady‐state plasma level of the antidepressant drugs, less than 5 per cent of the daily dose was excreted unchanged through the kidney. These data are discussed in relation to the treatment of tricyclic drug intoxications.
Plasma propranolol levels in adults With observations in four children
Authors: Shand D. G. , Nuckolls E. M. , Oates J. A.
Published: January 2016

Plasma levels of the f3‐adrenergic‐blocking drug, propranolol, have been measured fluorometrically in man after oral and intravenous administration. Following oral administration, peak plasma levels in 5 sub/ects varied sevenfold, while, after intravenous administration, levels in the same sub/ects varied only twofold, indicating considerable variability among individuals in the amount of drug reaching the systemiC circulation after oral administration. However, plasma levels were relatively constant in sub/ects given repeated, single doses. The plasma half‐life of the drug was 2.3 hours after intravenous administration. A plasma half‐life of 3.2 hours was found after oral administration; its greater duration was attributed to continuing absorption. After intravenous administration, the rate of decline of the levels of propranolol in the plasma was biexponential, and the volume of distribution during the late phase of elimination was found to be about 150 liters, indicating concentration of the drug in the tissues. The drug was administered orally to 4 children at dose levels calculated on the basis of body weight and on the basis of body surface area. It was found that a dose intermediate to the two tested would be required to obtain plasma levels approximating the average level in adults given an equivalent dose.
The diuretic action of an azido pyrimidine in man
Authors: Johnson Brian F.
Published: January 2016

SC‐16l02, an azido pyrimidine, is a potent diuretic in rats but not dogs. In 6 inpatients maintained on a constant diet, 100 mg. of SC‐16l02 orally, showed a maximum diuretic effect in the first 2 hours. Minor increases in bicarbonate excretion and uric acid clearance were noted. Blood pressure and creatinine clearance were unchanged. In 8 hours there was significant weight loss. Although no toxic effects were noted, all subjects developed a mild, temporary polymorphonuclear leukocytosis. SC‐16l02 produces a pattern of diuresis similar to that of hydrochlorothiazide. lts predominant site of action is probably the proximal tubule, and it does not appear to inhibit mic acid excretion.
Combined use of isoproterenol and propranolol in cardiogenic shock
Authors: Stubbs David , Pugh David , Bell Hubert
Published: January 2016

Nine patients with cardiogenic shock or low cardiac output following open heart surgery were treated with isoproterenol and propranolol. Isoproterenol alone was effective in increasing cardiac output in both groups. In 4 01 9 patients, isoproterenol plus propranolol caused an increased stroke volume with reduction in heart rate, while cardiac output remained elevated. Within 30 to 75 minutes cardiac output and stroke volume returned to near base‐Une values. In these patients, the antagonistic action of propranolol was seen sooner in its effect on rate than on force of contraction. Since the separation of inotropic and chronotropic effects was transient and unpredictable, it is concluded that combined isoproterenol and propranolol therapy offers no advantage in the treatment of cardiogenic shock.
Pharmacokinetic analysis of the effect of barbiturate on the anticoagulant action of warfarin in man
Authors: Levy G. , O'Reilly R. A. , Aggeler P. M. , Keech G. M.
Published: January 2016

Pretreatment with heptabarbital has no effect on prothrombin complex activity before warfarin administration and does not affect the apparent first‐order rate constant for prothrombin complex activity degradation and the relationship between plasma warfarin concentration and prothrombin complex activity synthesis rate. The decreased response to warfarin during barbiturate administration is therefore due only to the inductive effect of the barbiturate on the warfarin‐metabolizing enzyme system. There is no evidence that barbiturate affects the distribution of warfarin in the body, the inherent activity of the blood coagulation process, or the response of the appropriate receptor to warfarin.
Side effects of 6‐azauridine triacetate in rheumatoid arthritis
Authors: Elis J. , Slavik M. , Rašková H.
Published: January 2016

6‐Azauridine triacetate, a well‐tolerated antimetabolite, induces fever, erythema, joint pain, stiffness and mental depression in patients with rheumatoid arthritis in doses over 100 mg. per kilogram per day. The symptoms subside several days after discontinuation of the drug.
Digitalis
Authors: Modell Walter
Published: January 2016

Such a concise in‐depth review of one of our oldest and still important drugs as this has lang been overdue. It could easily have been twice as lang, but that would have spoiled it as a book for everybody interested in digitalis.
The clinical pharmacology and therapeutic applications of the antiarrhythmic drugs
Authors: Mason Dean T. , Spann James F. , Zelis Robert , Amsterdam Ezra A.
Published: January 2016

The mechanisms of action and therapeutic applications of the commonly employed and new antiarrhythmic agents are best understood by consideration of the basic electrophysiologic properties of heart muscle affected by these drugs. Thus, each of these agents depresses disorders of impulse formation by reducing diastolic depolarization and thereby diminishing automaticity and inhibits disorders of impulse conduction by altering conduction velocity and refractory period and thereby disrupting re‐entry mechanisms. Accompanying these antiarrhythmic actions, quinidine, procaine amide (Pronestyl), propranolol (Inderal), and potassium worsen atrioventricular block; whereas lidocaine (Xylocaine) usually does not influence nodal conduction velocity, and diphenylhydantoin accelerates this property in the atrioventricular node. Quinidine and procaine amide directly prolong refractory period; in contrast, lidocaine, diphenylhydantoin, and propranolol directly reduce this period. Quinidine and procaine amide are useful in most types of supraventricular and ventricular tachyarrhythmias. Propranolol is particularly effective against supraventricular arrhythmias; however, lidocaine is only moderately effective in disorders of atrial rhythm but markedly suppresses ventricular tachyarrhythmias. Diphenylhydantoin (Dilantin) and bretylium (Darenthin) are most beneficial in terminating disorders of ventricular rhythm and, in the case of bretylium, particularly those due to re‐entry mechanisms. Diphenylhydantoin, propranolol, and lidocaine possess electrophysiologic properties that are particularly salutary in the treatment of digitalis toxicity. In general, antiarrhythmic agents have depressant effects on cardiac contractility which are related to dose, speed of administration, and extent of myocardial disease. In contrast, bretylium possesses positive inotropic actions, and potassium within normal serum concentrations has no effect on contractile state. It is suggested that the fundamental subcellular actions of antiarrhythmic agents occur as a consequence of their binding to the cell membrane; in this manner, altered transmembrane fluxes of sodium and potassium ions underlie the electrophysiologic effects, and those of calcium ions underlie the contractile properties of these agents. From these observations, the thorough understanding of basic and applied pharmacology of the antiarrhythmic agents prOVides for their more iudicious use in patients.
Inhibition of apomorphine‐induced vomiting by benzquinamide
Authors: Klein Rogelr L. , Graves Constance L. , Kim Yong , Blatnick Richard
Published: January 2016

Benzquinamide was compared to prochlorperazine in apomorphine‐induced vomiting in healthy male volunteers. The antiemetic activity of benzquinamide by the oral route was significantly greater than that of 10 mg. of prochlorperazine. On the other hand, duration of action of benzquinamide was much shorter than that of prochlorperazine. Vomiting was not prevented except in a small percentage of the subjects 6 to 12 hours after oral administration of benzquinamide, while prochlorperazine was still effective. There were no adverse effects after benzquinamide. Benzquinamide is an effective antiemetic with rapid onset of action that deserves further clinical trial.
ButcJbarbital sodium and chlordiazepoxide in anxious neulrotic outpatients: A collaborative conl'rolled study
Authors: Rickels Karl , Clark Edward L. , Etezady Mohammad H. , Sachs licu , Sapra Ravi K. , Vee Robert
Published: January 2016

Butabarbitual sodium, a barbiturate rather widely used in the symptomatic treatment of anxiety, particularly in nonpsychiatric practice, was compared with chlordiazepoxide, a standard antianxiety agent, and placebo in 138 psychiatric and nonpsychiatric patients suffering from anxiety. Data on the 95 patients who completed the 4 week doubleblind study were analyzed with the use of a factorial analysis of covariance design, and the main findings were as follows: (1) Butabarbital sodium and chlordiazepoxide produced significantly more clinical improvement than placebo. (2) General practice patients improved the most, private psychiatric patients somewhat less, and medical and psychiatric clinic patients the least. (3) Both private practice populations improved the most on active drugs and the least on placebo, leading to significant drug‐placebo differences only in these 2 populations. Factorial covariance analyses testing for the effect of initial level of anxiety on clinical improvement consistently indicated that, within all 4 populations, “high” anxious patients responded less well to placebo and better to drug than “low” anxious patients. Several global improvement measures indicated chlordiazepoxide to be superior to butabarbital sodium irrespective of population, while more circumscribed measures showed butabarbital sodium to be particularly effective in general practice patients, with chlordiazepoxide slightly favored in private psychiatric patients. An explanation of these somewhat conflicting findings is not presently available, and further research on butabarbital sodium is suggested.
Inhibition of cigarette smoking by orally administered nicotine
Authors: Jarvik M.E.. , Glick S.D. , Nakamura R. K.
Published: January 2016

Five doses per day of 10 mg. per kilogram of nicotine tartrate were orally administered to 17 volunteers smoking cigarettes ad libitum. Nicotine administration was found to produce a small but significant decrease in the number of cigarettes smoked.
The role of plasma protein binding in the inhibitory effect of nortriptyline on the neuronal uptake of norepinephrine
Authors: Borgå Olof , Hamberger Bertil , Malmfors Torbjörn , Sjöqvist Folke
Published: January 2016

The inhibitory effect of nortriptyline (NT) on the neuronal uptake of radio labeled norepinephrine (NE) was studied with the use of the rat iris preparation in Krebs‐Ringer solution or human plasma. When added to the incubation medium, NT inhibited the uptake of NE approximately ten times as effectively in buffer as in human plasma within the tested concentration range of NT (10−8 to 10−6M). This result is in good agreement with the 94 per cent binding (at NT concentration of 1.1 10−6M) obtained by the ultrafiltration method. Plasma from patients treated with NT also inhibited the uptake of NE. Correlation between the inhibitory effect and the “endogenous” plasma level of NT in the 14 patients studied was significant (p < 0.001). When NT was added in different concentrations to control plasma the inhibitory effect observed was close to that obtained with patient plasma containing the same “endogenous” concentration of NT.
IV. The architecture of clinical research (continued)
Authors: Feinstein Alvan R.
Published: January 2016

In the biostatistical architecture of clinical research, the first operational principle is to specify the components and choose the logic of the objective of the research. As discussed in the previous paper of this series,11 the components consist of a sequence of initial state, maneuver, and subsequent state. The logic consists of suitable scientific judgment in the decisions made to demarcate the diagnostic and prognostic conditions of the initial state of the population; to identify, differentiate, and prognostically correlate the diverse targets of the subsequent state; and to choose maneuvers that are satisfactory in potency, comparison, multiplicity, and concurrency.
Aspirin absorption
Authors: Nosaquo Norman De
Published: January 2016

The article, “Inhibition of aspirin absorption by activated charcoal and apomorphine” which appeared in CLINICAL PHARMACOLOGY AND THERAPEUTICS, September‐October, 1969, raises several interesting questions. First, the study of 12 adults represents a small sample, and no information is provided regarding the relation of meals and time of ingestion of aspirin, etc., or the weight or age of the subjects. As a result, I am curious about the validity of the conclusion that the study showed “. . . conclusively . . . consistent adsorption of aspirin by activated charcoal takes place in the gastrointestinal tract of man.” Second, since the subjects were all adults and most aspirin accidents occur among children, I wonder whether this is a true picture of what happens.
Effect of amphetamine on the pressor response to tyramine: Formation of p‐hydroxynorephedrine from amphetamine in man
Authors: Cavanaugh John H. , Griffith John D. , Oates John A.
Published: January 2016

The effect of amphetamine on the pressor sensitivity to the indirectly acting amine, tyramine, and to norepinephrine was determined in 6 male patients. Acute intravenous administration of amphetamine increased the sensitivity to both tyramine and norepinephrine to 200 to 300 per cent of control. In contrast, long‐term administration reduced the sensitivity to tyramine to 60 to 70 per cent of control, while the sensitivity to norepinephrine was still enhanced. A likely explanation for the diminished response to the indirectly acting amine is depletion of norepinephrine. In this study it was demonstrated that human sub;ects metabolize 8H‐amphetamine to p‐hydroxynorephedrine, an amine known to displace norepinephrine from the neuron terminal.
An improved method of estimating digoxin in human plasma
Authors: Bertler åke , Redfors Arne
Published: January 2016

A clinically useful method for determination of digoxin in plasma is described. It is based on the ability of digitalis glycosides to inhibit the transport of 86Rb into erythrocytes. The different steps of the method are critically examined. The lower limit of sensitivity seems to be between 0.3 and 0.5 mμg of digoxin per milliliter of plasma. Some clinical findings are presented.
Molindone in chronic schizophrenia
Authors: Clark Mervin L. , Huber Wolfgang K. , Sakata Kenneth , Fowles Don C. , Serafetinides Eustace A.
Published: January 2016

Molindone, a new indole derivative, was evaluated as an antipsychotic agent with the use of a double‐blind placebo‐controlled technique. Antipsychotic activity relative to placebo was apparent, although it did not appear as impressive as that of the standard drug, chlorpromazine. A possible alerting effect associated with molindone was not apparent with chlorpromazine. Side effects were no more frequent than those seen with the usual psychotropic drugs.
Trials of Ro 5–3350 and diazepam for anxiety symptoms
Authors: Mcleod William R. , Mowbray Robert M. , Davies Brian
Published: January 2016

Problems of assessment of antianxiety drugs are discussed and the use of small‐scale controlled preliminary clinical trials is suggested. Two such trials are described. In each the effects of the active substance were compared with placebo in persistently anxious patients with the use of a partially balanced design. In the first trial no differences wem found between Ro 5–3350 at 5 and 10 mg. 3 times a day and placebo. In the second trial conducted with similar patients and for the same length of time, different ratings of change were used, and diazepam was found to be superior to placebo.
Unwanted effects of pentagastrin
Authors: Barrowman J. A. , Herxheimer A. , Kits T. P.
Published: January 2016

The nature and incidence of the unwanted effects of an injection of pentagastrin 6 μg per kilogram subcutaneously in 15 students were compared with those of a control injection in 9 students. The incidence of subjective effects with pentagastrin in this study was higher than that reported in most other studies. Almost all of the volunteers given pentagastrin had mild transient subjective effects. These effects and their time course were then examined in detail in a double‐blind crossover study in 10 more students. Evidence is provided that the nausea experienced during a pentagastrin acid‐secretion test is caused by the drug rather than by the presence of a stomach tube.
Comparative stimulant and diuretic actions of caffeine and theobromine in man
Authors: Dorfman L. J. , Jarvik M. E.
Published: January 2016

Human subiects ingested measured quantities of caffeine and theobromine, separately and together, at random. The double‐blind technique was used. Caffeine altered self‐estimates of sleep latency and sleep quality in a dose‐dependent fashion and increased overnight urinary sodium excretion. Theobromine in equivalent doses had no detectable effect on sleep parameters or on urine composition, nor did it interact significantly with caffeine when the two were ingested together. Theobromine is much weaker than caffeine or entirely inert in these situations.
Evaluation of methods for determining antibacterial activity of serum and urine after colistimethate injection
Authors: Sande Merle A. , Kaye Donald
Published: January 2016

The purpose of this study was to evaluate methods for determining antibacterial activity in serum and urine following intramuscular administration of colistimethate sodium to man. The levels of actual antibacterial activity were determined by a serial dilution technique with the use of 30 minutes of incubation, and the results were compared with levels determined by an agar diffusion method and a serial dilution technique with 18 hours of incubation. The results indicate that colistimethate sodium itself has little antibacterial activity but that activation occurs rapidly in vivo. Antibacterial activity in serum was sustained for up to 12 hours after injection of colistimethate sodium. Levels derived with serial dilution methods with 18 hour incubation periods were falsely elevated, and levels obtained from agar diffusion techniques were falsely low. The inaccuracy of the agar diffusion results was, at least in part, related to a decrease in diffusibility of colistimethate sodium that occurs as the material is activated.
The effect of chlorpromazine on serum cholesterol in chronic schizophrenic patients
Authors: Clark Mervin , Dubowski Kurt , Colmore John
Published: January 2016

In a series of 6 separate controlled clinical trials of antipsychotic agents in chronic schizophrenic patients, it was shown repeatedly that chlorpromazine (CPZ) exhibited hypercholesterolemic activity. In the analysis of covariance, the adjusted final mean difference in serum cholesterol concentrations between the placebo and CPZ groups ranged from 14 to 28 mg. per 100 ml. This activity was dose related in that it occurred with a fixed daily dose of 600 mg. administered for 24 weeks, but not with a fixed daily dose of 150 mg. or 300 mg. over the same period of time. The serum concentration of triglycerides remained unaffected under similar experimental conditions. This action of CPZ appeared unrelated to thyroid function and liver function as presently measured in the clinical laboratory. A consistent relationship to body weight changes could not be demonstrated even though increased body weight was noted to be a consistent result of CPZ therapy. In view of its extensive use as long‐term therapy, the possible role of CPZ as an atherogenic agent deserves consideration.
Prazepam metabolism by man
Authors: DiCarlo Frederick J. , Viau Jean‐Paul , Epps Joyce E. , Haynes Lloyd J.
Published: January 2016

The absorption, excretion, and biotransformation of 14C‐labeled prazepam were studied in man. Slow, sustained absorption followed the administration of a single oral dose. The peak level of the blood radioactivity was observed after 6 hours. Clearance from the blood was also slow, particularly with respect to the unconjugated forms of the drug. Unlike diazepam, the major phase 1 reaction for prazepam was hydroxylation at carbon‐3 rather than dealkylation. Initially, the principal urinary metabolite was 3‐hydroxyprazepam glucuronide. Oxazepam glucuronide was excreted in increasing quantities over the 48 hour study period so that its total excretion approached that of 3 ‐hydroxyprazepam glucuronide. No unaltered prazepam was detected in the urine and the level of desalkylprazepam was low. Several unidentified radioactive glucuronides and sulfates were also excreted in the urine.
Flumethasone pivalate (Locorten); Anti‐inflammatory, antipruritic
Authors:   Ciba Pharmaceutical Company
Published: January 2016

Locorten is a new topical coricosteroid. Locorten Cream is 0.03% flumethasone pivalate in a water‐washable base, containing cetyl alcohol, sodium lauryl sulfate, propylene glycol, methyl and propyl parabens and water.
Pharmacokinetics of lidocaine in man
Authors: Boyes R. N. , Scott D. B. , Jebson P. J. , Godman M. J. , Julian D. G.
Published: January 2016

Plasma levels of lidocaine were measured in 5 normal male volunteers following both intravenous and oral administration of the drug. Each subject received a constant‐rate intravenous infusion lasting for 60 minutes and an exponential intravenous infusion which allowed administration of the drug at an ever‐decreasing rate having a half‐life of 50 minutes. In each case the total dose of lidocaine was 250 mg. The subjects also received a 250 mg. and a 500 mg. oral dose administered in tablet form. The plasma level data were subjected to pharmacokinetic analysis with the use of a two‐compartment open model to describe the lidocaine disposition. These calculations suggest that approximately 5 to 7 hours of constant intravenous infusion would be required to approach steady‐state plasma levels in human subfects. The plasma level data after oral administration indicate that approximately 35 per cent of the 250 and 500 mg. oral doses reached the systemic circulation. Subfective symptoms typical of lidocaine were noted in some cases after the 500 mg. oral doses. Since these symptoms were noted when the blood levels of lidocaine were lower than those following intravenous administration, it is suggested that they may, in part, be due to a metabolite formed during the first passage of the drug through the liver.
Hypolipidemic and thyroid hormone effects of sodium dextrotriiodothyronine
Authors: Danowski T. S. , Sunder J. H. , Corredor D. G. , Jung Y. , Vester J. W. , Khurana R. C. , Wingert J. P.
Published: January 2016

Sodium dextrotriiodothyronine (Na‐DT3) at a dosage of 1 mg. per day for 24 weeks produced an approximately 75 mg. per cent decrease in serum total cholesterol in hyper‐and normolipidemic subjects. Na‐DT3 usually lowered the level of serum leva‐thyroxine (LT4) to the myxedema range, but the subjects remained euthyroid, suggesting that Na‐DT3 was exerting a thyroid hormone‐replacement effect. The failure to observe the changes to be expected in the in vitro levo‐triiodothyronine (LT3) uptake by blood cells when the serum protein‐bound iodine (PBI) had increased indicates that perhaps Na‐DT3 occupies binding sites other than those used by LT3 that Na‐DT3 is loosely bound to plasma proteins and is readily displaced by LT3, or both. An unexplained rise in urine total protein was observed during the first 6 weeks of Na‐DT3 therapy but not at 12 weeks. Serum total globulins were increased in the twenty‐fourth week. Minor changes within the normal range were recorded in plasma 11(OH)‐corticosteroids and in urine Porter‐Silber chromogens. All other indices remained within the pretherapy range.
Hemodynamic and therapeutic effects of guancydine in hypertension
Authors: Hammer Jan , Ulrych Milos , Freis Edward D.
Published: January 2016

Guancydine, a new vasodilator and antihypertensive agent, increased cardiac output and lowered total peripheral resistance in hypertensive patients. Sympathetic reflexes were not blocked and there was no symptomatic orthostatic hypotension. Renal blood flow and glomerular filtration rate did not decrease. Although guancydine effectively reduced blood pressure, the side effects of fluid retention and sinus tachycardia preclude its long‐term use as a single agent. Fluid retention was prevented by giving a diuretic in conjunction with guancydine; tachycardia was considerably attenuated by the addition of reserpine. The following reductions in blood pressure occurred during a crossover trial in 14 outpatients who had an average control supine blood pressure of 185/119 mm. Hg: guancydine alone, 25/16; diuretic alone, 22/9; reserpine alone, 7/5; diuretic and guancydine, 42/32; reserpine and guancydine, 43/33; diuretic and reserpine, 23/15; and diuretic, reserpine, and a moderately redueed dose of guancydine, 40/31 mm. Hg. The last combination of antihypertensive agents resulted in an effective control of blood pressure with minimal side effects.
Safety of kanamycin aerosol
Authors: Lifschitz Martin I. , Denning Carolyn R.
Published: January 2016

Three aspects of the pharmacology of kanamycin aerosol were investigated in normal subjects and in patients with cystic fibrosis. Absorption of kanamycin from the tracheobronchial tree was found to be so low that doses of 250 mg. per treatment appear safe, even in children. Aerosols containing 125 mg. per milliliter of kanamycin caused no greater decrease in the one‐second forced expiratory volume than did aerosols of saline alone. In vitro studies with cystic fibrosis sputum revealed that kanamycin had a viscosity reducing effect greater than that of water or saline.
Clinical biostatistics‐VIII; An analytic appraisal of the University Group Diabetes Program (UGDP) study
Authors: Feinstein Alvan R.
Published: January 2016

The Eastern Research Support Center and the Department of Medicine of the West Haven Veterans Administration Hospital, and the Departments of Medicine and Epidemiology of the Yale University School of Medicine
Catecholamines and mania: The effect of alpha‐methyl‐para‐tyrosine on manic behavior and catecholamine metabolism
Authors: Brodie H. Keith H. , Murphy Dennis L. , Goodwin Frederick K. , Bunney William E.
Published: January 2016

Alpha‐methyl‐para‐tyrosine (AMPT), an inhibitor of catecholamine biosynthesis, was given to 7 manic and 3 depressed patients under double‐blind conditions. Five of the 7 manic patients became less manic, while the three depressed patients became more depressed. Urinary excretion of catecholamine metabolites and dopamine was significantly decreased in all. These behavioral and biochemical changes confirm previous indirect evidence implicating catecholamines in affective disorders.
Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man
Authors: Martin W. R. , Sloan J. W. , Sapira J. D. , Jasinski D. R.
Published: January 2016

Five centrally acting sympathomimetic amines, d‐amphetamine, d‐methamphetamine, ephedrine, phenmetrazine, and methylphenidate, were studied in man. All of these agents increased blood pressure and respiratory rate, produced similar types of subiective changes, and increased the excretion of epinephrine. With regard to these parameters, there was a high concordance between estimates of their relative potencies. The concordance between the potency estimates for the different parameters suggests, but does not prove, that these five agents share a common mode of central action. Further, if the peripheral modes of action as elucidated by animal studies are true for man, this study suggests that it is unlikely that their central actions in man are a consequence of the release of norepinephrine in the brain.
Mithramycin (Mithracin)
Authors:   Pfizer Laboratories
Published: January 2016

It is recommended that Mithracin (mithramycin) be administered only to hospitalized patients by or under the supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents, because of the possibility of severe reactions. Facilities for the determination of necessary laboratory studies must be available.

Severe thrombocytopenia, a hemorrhagic tendency and even death may result from the use of Mithracin. Although severe toxicity is more apt to occur in patients who have far‐advanced disease or are otherwise considered poor risks for therapy, serious toxicity may also occasionally occur even in patients who are in relatively good condition.

In the treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit versus the risk of toxicity which may occur with Mithracin therapy. The following data concerning the use of Mithracin in the treatment of testicular tumors, hypercalcemic and/or hypercalciuric conditions associated with various advanced malignancies, should be thoroughly reviewed before administering this compound.
Parkinsonism and levodopa
Authors: Colzias George C. , Papavasiliou Paul S. , Sleek Andreas , Düby Simone
Published: January 2016

Based on the chemical constitution and metabolism of levodopa as well as on the effects of long‐term therapy in patients with parkinsonism, a hypothesis of pharmacologic activity which clearly differentiates it from conventional antiparkinsonian drugs is proposed. Unlike the latter which tend to lose their therapeutic effect with time, levodopa continues to be effective with prolonged therapy, controlling the parkinsonian symptoms, including the characteristic tremor. Also, the troublesome involuntary movements that develop in some patients have been emerging as a function of levodopa consumed cumulatively up to about one year of continuous treatment. It is postulated that levodopa may play a dual role in parkinsonism: It does supply the consumable dopamine lacking in the brain of these patients, but it may also damage the synthesis of certain proteins, possibly those containing methionine, thereby affecting the macromolecular composition of brain tissue. A possible mechanism by which levodopa can function in changing protein synthesis is transmethylation: “Siphoning off” of labile methyl groups from methionine, the chief methyl source in tissues, is a necessary accompaniment of levodopa therapy. That further study of levodopa activity may lead to better understanding of other neurological disorders is suggested.
Glucagon: Present status in cardiovascular disease
Authors: Kones Richard J. , Phillips John H.
Published: January 2016

The actions of pancreatic glucagon, a known hyperglycemic, hypoaminoacidemic, and lipolytic agent, have received recent attention because of a variety of effects mediated by increases in cyclic AMP concentrations. Studies in the dog demonstrated the positive inotropic and chronotropic actions of glucagon, unaltered by reserpine, insulin, or propranolol. Enhanced contractility was additive with that of the digitalis preparations but did not produce undesirable arrhythmias. The ability of glucagon to increase contractility was attenuated with longer duration of experimental congestive heart failure, thus implying greater effectiveness in acute pathology. In man, variables dependent upon contractility are correspondingly enhanced with the use of glucagon. Current evidence suggests glucagon is a secondary coronary vasodilator and lowers renal vascular resistance as well. Restored blood pressure and urine output accompanying clinical improvement have been noted as a result of continuous glucagon therapy in patients with early congestive heart failure, cardiogenic shock, myocardial infarction, and in low output syndromes following open heart surgery. Glucagon appears to activate adenyl cyclase to increase cycliC AMP levels, which in tum enlarges the intracellular calcium pool. Thus, according to current excitation‐contraction theories, an increase in contractility results.
A new method for assessing the clinical effects of oral analgesic drugs
Authors: Jick Hershel , Slone Dennis , Shapiro Samuel , Lewis George P. , Siskind Victor
Published: January 2016

A randomized double‐blind trial comparing aspirin and a placebo in the treatment of mild to moderate pain was introduced into a comprehensive drug surveillance program. The program's standard methods of data collection were judgments of attending physicians on the efficacy and adverse effects of drugs. The napsylate and hydrochloride salts of propoxyphene were also compared. The already established effectiveness of aspirin was demonstrated. No evidence of a difference in efficacy between the two salts of propoxyphene was found. A randomized, double‐blind, large‐scale evaluation of certain marketed and unmarketed drugs within a comprehensive drug surveillance program is feasible and can be of considerable value in their clinical assessment.
Mechanism of the lack of a beneficial response to inotropic drugs in hemorrhagic shock
Authors: Lefer Allan M. , Glenn Thomas M. , Rasi Alfredo M. Lopez , Kiechel Stephen F. , Ferguson Wayne W. , Wangensteen Stephen L.
Published: January 2016

Lanatoside C, glucagon, and isoproterenol, three inotropic agents were found to be ineffective in prolonging survival or in improving the over‐all circulatory status of dogs in hemorrhagic shock, despite their temporary effectiveness as inotropic agents. Lanatoside C constricted the splanchnic circulation leading to lysosomal disruption, release of cathepsin D, and production of a myocardial depressant factor (MDF). Glucagon dilated the splanchnic circulation only transiently but directly disrupted splanchnic lysosomes and thus MDF was produced. Isoproterenol dilated the peripheral vasculature to such an extent that circulatory collapse ensued. Other inotropic agents may be of value in the treatment of postoligemic shock, but potentially deleterious side effects must be considered when they are administered in circulatory shock.
Hypolipidemic, uricosuric, and thyroxine‐displacing effects of MK‐185 (halofenate)
Authors: Morgan John P. , Bianchine Joseph R. , Hsu Tah-Hsiung , Margolis Simeon
Published: January 2016

MK‐185, an ester structurally related to clofibrate, was given to hypertriglyceridemic patients for 6 week periods in a controlled double‐blind crossover trial. Serum triglycerides decreased an average of 50 per cent during the trial, but little change was noted in serum cholesterol. An average decrease of 30 per cent was noted in the serum uric acid, and 5 patients showed a uricosuric effect of the drug independent of the glomerular filtration rate. Plasma thyroxine (T4) showed a significant increase while patients were taking MK‐185. Further studies showed a decrease in protein‐bound iodine and T4 by column. An increase in the dialyzable fraction of T, in vivo suggested a thyroxine‐displacing effect from thyroid‐binding proteins. This hypothesis was confirmed by in vitro displacement by MK‐185 free acid of 131I‐labeled T4 bound to thyrOid‐binding globulin.