bluuebunny/crossref_metadata_2025 huggingface dataset:
Safe new drugs and their control under law
Authors: Kessenich William H.
Published: January 2016

It has been our aim to review briefly Food and Drug Administration's methods in evaluating new drugs, and it is our hope that this will provide a better understanding of the role and function of the Food and Drug Administration in its regulation of new drugs. This will, in turn, assist physicians to meet their responsibilities in this important field.
Psychopharmacologic theories: a critical review
Authors: Callaway Enoch , Stone George C.
Published: January 2016

Understanding of the actions of the new psychopharmaeologic drugs must depend upon the development of a theory whieh relates biochemieal or pharmacologic events to behavior. On the biochemical side the problem is formidable and is aggravated by the lack of adequate behavioral referents. Theories constructed by biochemists and pharmacologists may be psychologieally naive, while those proposed by behavioral scientists may greatly oversimplify their treatment of physiologic complexities. A particular difficulty is presented by the ambiguous and subjective psychological terms used in many theories. No single theory so far is consistent with all the empiric data.

The majority of studies of the new psychotropic drugs utilize clinical ratings or descriptions on the behavioral side. These studies and those of experimental psychosis suggest some generalizations about drug effects. When specific and objective measures of behavior are used—measures like reaction times, psychophysiologic responses, and rate of conditioning—many contradictory findings emerge. The clarification of these contradictions will require a complex yet integrated theory of behavior. The new psychotropie drugs ean serve as an invaluable class of independent variables to aid in the development of such a theory.
Part III Human experimentation in medicine Moral aspects
Authors: Lynch John J.
Published: January 2016

To avoid ambiguities, a theologian generally begins a consideration of this kind by defining as precisely as possible the terms of the discussion as he understands them, for it often happens that moralists and physicians use the same terminology in somewhat divergent senses. lf these possible differences in meaning are not made initially apparent, the unfortunate result will be mutual misunderstanding.
Addiction liability of an isoquinoline analgesic, 1‐(p‐chlorophenethyl)‐2‐methyl‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline
Authors: Fraser H. F. , Martin W. R. , Wolbach A. B. , Isbell H.
Published: January 2016

The addictiveness of a new synthetic isoquinolinc. analgesic (I‐K‐1) has been compared with that of morphine, codeine, and D‐propoxyphene in former opiate addicts. Single oral doses of 600 and 1,200 mg. of I‐K‐1 (ten to seventeen times the recommended anolgesic dose) did not induce subjective or objective patterns of morphinelike effects. Intramuscularly and intravenously, I‐K‐1 was identified as an opiate, but it was not possible to give repeated doses of the drug by these routes because of its water insolubility and tissue irritant properties. When I‐K‐1 was substituted for morphine in patients addicted to morphine, it partially prevented development of withdrawal symptoms, but it was only one‐seventh as potent as codeine in this respect.

In a direct addiction test that lasted 60 days, using maximally tolerated doses (750 to 1,500 mg. orally daily), I‐K‐1 was disliked by former addicts and when it was discontinued abruptly withdrawal signs were insignificant. It is concluded that I‐K‐1 has substantially less addiction liability than morphine and codeine and even less addictiveness than D‐propoxyphene.
Clinical pharmacology of central stimulant and antidepressant drugs
Authors: Werner Gerhard
Published: January 2016

Considerations relevant to the validity of clinical psychopharmacologic studies are outlined. Thereby, criteria are established for the evaluation of the existing reports on therapeutic activity of antidepressant drugs. It is concluded that many studies, in design and interpretation, fail to do justice to the complexity of drug actions on personality functions. Nevertheless, the potential usefulness for enhancement of performance in normal subjects and for relief of symptoms of depression emerges for some of the agents reviewed. Drug effects in animal experiments involving biochemical, neurophysiologic, and behavioral parameters of actions are summarized with the view of critically discussing the current theories on mechanisms of actions.
Clinical pharmacology of antianginal drugs
Authors: Modell Walter
Published: January 2016

The problem of examining and evaluating antianginal effects is explored. Special attention is paid to the mode of action of the nitrites, which form the mainstay of the modern treatment of angina of effort. Other pharmacologic features of these drugs are also examined. Prophylactic therapy is considered, and the improbability of developing an effective long‐acting nitrite is discussed. Other drugs and therapies are also considered: alcohol, sedatives and tranquilizers, khellin, xanthines, hormones, cholesterolytic agents, tissue extracts, anticoagulants, papaverine, and antithyroid drugs. The monamine oxidase inhibitors, the probable mode of their effect in angina, and their uses and dangers are considered in some detail.
Poor drug therapy
Authors: Friend Dale G.
Published: January 2016

The striking progress in the field of drug therapy which has been taking place for the last two decades has been marked by many new substances for the treatment of disease which have greatly influenced the field of medicine and also laid the foundation for many advances to come. Twenty‐five years ago, there were very few speCific drugs available for therapy. Now, there are many preparations, and almost every year there are developed some ten to twenty agents which have distinct merit.
Part XVI. Evaluation of the safety of new drugs by means of tests in animals
Authors: Litchfield John T.
Published: January 2016

The manner in which new drugs are studied has changed drastically during the past 30 years. Certainly, the effective administration of the Food, Drug and Cosmetic Act has been a factor in this, but the importance of the gain in our basic knowledge of drug actions and the effect of intense competition in the pharmaceutic field have also played important roles. Safety evaluation has almost reached the status of a separate specialty.
Part XIX. Clinical judgment in clinical research
Authors: Ingelfinger F. J.
Published: January 2016

Some of the most difficult problems encountered in studies of the effects of drugs are related to the measurement of these effects in man. Everyone attempting to assess the effects of drugs in man would like to lean on some sort of sound and accredited yardstick, or as Dr. Bross would say, “one would at least like to hang on to some sort of strong rubber band.” Thus, in evaluating drug effects, we rely upon techniques that have enjoyed some success and acceptance. Emphasis on technique, however, may distort our basic purpose; to quote Dr. Zubrod, “I suspect that at times tactics dictate or distort strategy.” Often, the available tests are used whether or not they are strictly applicable. Certainly, good clinical judgment is necessary to determine the adequacy of any test method for a proposed clinical pharmacologic study.
A comparison of the value of 200,000 I.U. tetanus antitoxin with 50,000 I.U. in the treatment of tetanus
Authors: Vakil B. J. , Tulpule T. H. , Armitage P. , Laurence D. R.
Published: January 2016

In view of the lack of adequate data on the proper dosage of antitoxin in clinical tetanus, a comparison of two doses was undertaken. Patients were allotted at random after diagnosis to receive 200,000 I.U. or 50,000 I.U. antitoxin. Altogether 293 cases were included. Analysis of the results indicates that the lower dose is as effective as the higher.
Detoxication mechanisms in man
Authors: Williams R. T.
Published: January 2016

Many of the reactions which foreign compounds undergo in the common laboratory animals are found to occur also in man. There are exceptions to this, however, such as the glutamine coniugation of arylacetic acids, which occurs only in man and the chimpanzee and not in laboratory animals. While these exceptions are probably not the rule, they must be taken into accmmt. The main difference between man and laboratory animals probably lies in the rates of the reactions which transform drugs. These differences in rates may have profound effects on drug action. These reactions consist of various oxidations, reductions, hydrolyses, and coniugations, which are carried out by enzymes, many of which are located in the liver. Not only does man differ from laboratory animals, but various groups of people vary from one another in their ability to metabolize drugs, and as yet little is known about this variation. Variation in drug metabolism in man could be due to age, sex, genetic make‐up, the effect of one drug upon the metabolism of another, and the effect of prolonged administration of one drug upon its own metabolism. Many observations have been made on laboratory animals in these respects, but few have been made in man.
Respiratory effects of Tris (THAM) in acidosis and alkalosis
Authors: Cosby Richard S. , Swan David A. , Mayo Mary , Roberts David L. , Richardson Thomas R.
Published: January 2016

Tris is an effective, safe, rapidly acting amine buffer for the treatment of metabolic and mixed acidosis. It is useful in diminishing cardiac irritability associated with acidosis and in treating acidosis of cardiopulmonary bypass. This study reports the quantitative effects of Tris in 14 normal patients and 13 others with varying degrees of acidosis and alkalosis, primarily metabolic. In patients with a normal resting pH and in those with acidosis, the expected changes of hypoxia, hypoventilation, and hypocapnia appeared. In patients with initial alkalosis, hyperventilation and a tendency to increased pO2 were comman. In the maiority of patients, particularly those with stable initial ventilation, controlled, mild alkalosis could be produced and maintained within narrow limits. Control of shifts in pH may be of value in the therapy of cardiac irritability associated with acidosis.
Persistence of lysergic acid diethylamide in the plasma of human subjects
Authors: Aghajanian George K. , Bing Oscar H. L.
Published: January 2016

Two micrograms per kilogram of LSD‐25 was administered intravenously to five normal human subjects. The concentration of drug in plasma was determined serially over the subsequent 8 hours. LSD‐25 was found to be present in human plasma in relatively large quantities during the period of peak effect. The half‐life of LSD‐25 in human plasma was calculated to be 175 minutes.
Analgesic studies of indomethacin as analyzed by computer techniques
Authors: Sunshine Abraham , Laska Eugene , Meisner Morris , Morgan Sydney
Published: January 2016

A method of evaluating oral analgesics in a general hospital is presented. The competition between crossover studies and single dose studies has led us to compare a basic crossover design with a single dose design, and a computer program was developed from both paints of view. The patients included in this study had moderate or severe postoperative or fracture pain, and received indomethacin, aspirin, and a placebo on a random complete crossover basis. This study indicated that single dose data only yielded more reliable information and probably a more efficient design than the crossover technique. Furthermore, placebo varied in its effect, depending on its position in the study, and appeared more effective when administered as a second test medication. Fifty milligrams of indomethacin appeared to be an effective oral analgesic equivalent to approximately 600 mg. of aspirin.
Objective measurement of spasticity by light reflection
Authors: Erdman William James , Heather Arthur J.
Published: January 2016

Difficulties in making objective evaluations of muscle spasticity in patients with spinal cord injury complicate rehabilitation programs. It is often difficult to predict or to judge the results of a particular regimen which in some instances may produce irreversible changes. A technique for measuring one of the components of spasticity is described. The apparatus involves two parts: a portable force recorder and a stimulator to deliver a near‐uniform stimulus. A beam of light is reflected on a calibrated ground glass for direct viewing of the force of the plantar flexion of the foot. The beam deflection is directly proportional to the force supplied by a spring‐loaded reflex hammer which may be adjusted to deliver a constant and reproducible force to the tendon. For a permanent record of the deflection, a Polaroid film may be obtained. Twelve patients with para‐ and quadriplegia and spasticity were tested while on antispasmodic medication (diazepam, 20 mg.). The premedicated forces recorded averaged 7.1 pounds, and on diazepam the force recorded was 4 pounds.
The dynamic quantitation of spasticity with automated integrals of passive motion resistance
Authors: Webster David D.
Published: January 2016

A method is described for quantitating spasticity in the forearm or lower leg. The limb is carried through passive linear motion at varying angular velocities. At high velocities forceful spasms develop opposing the direction of rotation. The degree of muscular reaction is plotted as torques with characteristic amplitudes and time durations, and the torque magnitude integrated into a meaningful work measurement. Spasticity is defined as the work output in response to angular velOcity input per 100 degree cycle (back and forth) of passive motion. A spasticity index obtained from the total work value at varying velocities may be used as a measure of drug response, and is reportable in fundamental physical units. A wide range of antispastic agents has been tested and many have proved effective for short periods when administered intravenously. Diazepam, given orally in one case, effectively reduced spasticity for 5 weeks.
Obiective measurement of muscle tone in the hand
Authors: Long Charles , Thomas Donald , Crochetiere William J.
Published: January 2016

With a device to measure the resistance offered by the middle finger to being driven externally by a D.C. servo motor running at a constant speed, the rheologic properties inherent in muscle (elasticity, viscosity, plasticity) are studied as a basis of muscle tone, independently of neurally mediated “tonus” or “postural contraction.” Provision is made for electromyographic monitoring with intramuscular electrodes and the strain gage output is recorded by an oscillograph and an oscilloscope. The resulting record appears as a Lissaious pattern on the oscilloscope with the torque (Kg.‐cm.) recorded on the vertical axis, and displacement (degrees) on the horizontal axis. By this device the stiffness of the finger is recorded in terms of torque resisting sinusoidal position change. Such data may be used to study effects of peripheral anesthesia and tension after voluntary contraction. It may also be offered as a useful tool for evaluating the effects of drugs on spasticity and rigidity.
The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents: Hydroxyurea (NSC‐32065)
Authors: Carbone Paul P. , Krant Melvin J. , Miller Sherwood P. , Hall Thomas C. , Shnider Bruce I. , Colsky Jacob , Horton John , Hosley Henry , Miller James M. , Frei Emil , Schneiderman Marvin
Published: January 2016

A randomization technique to help reduce possible bias was used in dose‐finding trials of a new cancer chemotherapeutic agent, hydroxyurea. The drug was given at fixed starting doses of 12.5, 25.0, 37.5, and 50.0 mg. per kilogram for a 6 week period by the oral and parenteral routes to 110 patients. Only downward modification of doses was allowed according to a fixed protocol. Leukopenia was the most common toxicity observed at doses of 25.0 mg. per kilogmm or more and appeared slightly more often in patients receiving the drug parenterally. The actual total dose administered was approximately the same at 25.0, 37.5, and 50.0 mg. per kilogram, and no difference in toxicity was noted between the single daily and three times daily oral administration. Recalculation of the dose by surface area indicated the biologically active dose to be about 1.4 Gm. per square meter. For hydroxyurea administered to adults, no better prediction of toxicity was noted for the dose calculated for individual patients on surface area when compared to the dose based on milligrams per kilogram. These procedures in dose‐finding trials are recommended: the usc of randomized assignment of patients, fixed nonescalating doses and the inclusion of a low (ineffective) dose (12.5 mg. per kilogram), and separation of drug toxicity from natural disease progression.
Studies of delayed‐action medication
Authors: Hollister Leo E. , Kanter Saul L.
Published: January 2016

Single 1.0 Gm. doses of aspirin were administered as uncoated tablets and as two different enteric‐coated preparations. Enteric coating of aspirin considerably delayed absorption, significant serum levels of salicylate usually not appearing until 6 hours or more. In contrast, absorption from uncoated aspirin tablets was rapid, significant serum salicylate levels being obtained by the first hour and maintained for the next 3 hours, followed by a slow fall. Absorption from the enteric‐coated sodium salicylate preparation studied resembled that from uncoated aspirin, though delayed by about 4 hours. A study of serum salicylate levels during and following four 1.0 Gm. doses of aspirin or sodium salicylate at 4 hour intervals confirmed the considerable delay in obtaining adequate serum levels from the enteric‐coated aspirin preparations. The most consistent daily curve of serum levels was obtained follOWing administration of uncoated tablets. A new tableted preparation of aspirin combined with retarding agents was found to delay absorption of the drug by about one hour without any loss in physiologic availability. If such a preparation should produce less gastric distress on further clinical trial, it might be the preferred preparation where gastric irritation is a problem. Until this is established, aspirin in dissolved form might be the best alternative if uncoated tablets cannot be tolerated because of gastric distress. Enteric‐coated aspirin should not be used in any case where an immediate analgesic or antipyretic effect is desired because of their erratic and often greatly delayed absorption.
Comparison of hyoscine‐N‐butyl bromide and atropine sulfate in man
Authors: Brownlee G. , Wilson A. B. , Birmingham A. T.
Published: January 2016

The effects of hyoscine‐N‐butyl bromide (20 mg. subcutaneously) and of atropine sulfate (0.6 mg. subcutaneously) were compared in a controlled, double‐blind study in man. Both drugs caused statistically significant increases in heart rate and decreases in salivation, but the extents and the time courses of the changes were difJerent for the two drugs. Changes in pupil diameter, near point of vision, and sweat gland activity were not statistically significant. The experiments were made by medical students as part of their training in pharmacology.
Clinical experiences with thalidomide in patients with cancer
Authors: Grabstald Harry , Golbey Robert
Published: January 2016

Thalidomide (N‐phthaloylglutamimide) was used as a screening agent in the treatment of 71 patients with a wide spectrum of cancers. The production of embryonic defects by this compound prompted us to use it as an anticancer agent. There was no evidence of ob;ective response in any except one patient with renal cell cancer whose pulmonary lesions disappeared after treatment. This patient had also had nephrectomy, and it is highly possible that this response represented spontaneous regression of pulmonary metastases after operation, an event preViously observed with this tumor.
Metabolic effects and site of action of ethacrynic acid
Authors: Ledingham J. G. G. , Bayliss R. I. S.
Published: January 2016

The response in terms of urinary electrolyte excretion in a group of eight normal subjects to increasing doses of oral ethacrynic acid has been determined. The changes in urine acid excretion, and in plasma volume and electrolyte content have been assessed on another normal subfect and an edematous patient. The effects of ethacrynic acid upon renal concentrating and diluting mechanisms have been demonstrated in a dog. In normal subfects the maximum effective oral dose of ethacrynic acid is 150 mg. The natriuresis la8ts for 6 to 8 hours and reaches its peak 2 hours after the drug is taken. Ethacrynic acid provides greater excretion of chloride than of sodium ions and increases hydrogen ion and potassium loss. This pattern of urinary electrolyte excretion is unique and may induce metabolic alkalosis, in the persistence of which chloride depleUon is more important than potassium deficiency. The dmg probably inhibits sodium reabsorption in the proximal renal tubules and in the ascending limb of Henle's loop.
Tranylcypromine: A review
Authors: Atkinson Roland M. , Ditman Keith S.
Published: January 2016

In the six years since it was added to the antidepressant agents, tranylcypromine has attracted wide attention because of toxic side reactions and disputed efficacy. It was the first clinically important nonhydrazine monoamine oxidase inhibitor, and it remains Widely used. This review attempts fully to present the history, pharmacology, clinical toxicology, and evidence for the degree of clinical value of the drug in the treatment of depression. The hypertensive syndrome most notable among the drug's adverse reactions probably occurs very infrequently but is largely an unpredictable phenomenon. Fifty‐four of the fifty‐six published clinical trials have been assessed. Many were uncontrolled, encumbered by other concurrent treatments and heterogeneous patient samples, or inadequately reported. Assessment of trials indicated that the drug alone was beneficial in reactive and psychoneurotic depressions, while it tended not to influence agitated, psychotic, or endogenous depressions. Where the drug was compared to other treatments for depreSsion, it was found equivalent or superior to other monoamine oxidase inhibitors in several trials, while it was generally inferior to iminodibenzyl compounds and to electroshock treatment. The findings support a view that tranylcypromine is not the treatment of choice for depression but that it may be indicated where other drugs or ECT have failed.
Abstracts
Authors: Moser Robert Harlan
Published: January 2016

A 31‐year‐old white woman with a urinary tract infection was given sulfisoxazol (dose undisclosed). After 9 days pyuria persisted. She was then given nitrofurantoin, 100 mg. 4 times a day. After 6 days she developed fatigue, nausea, cough, and fever to 102.2° F. The subject also complained of headache, myalgia, and thirst. Physical examination showed respirations 40 per minute and bilateral expiratory wheezes. A chest radiograph showed that prominent hilar shadows and bilateral patchy infiltration were more marked in the right. Pertinent laboratory data included white blood cells 17,200 per cubic millimeter; urine sediment showed 2 to 5 white blood cells and 1 to 3 red blood cells. Oxygen was administered followed by a reduction of tachypnea. Clinical and radiographic improvement permitted her discharge from the hospital after 4 days. Approximately 3 weeks after discharge the subject complained of feeling “feverish.” A urine specimen showed pyuria. She was given three doses of 50 mg. of nitrofurantoin. On the evening after the third dose there was recurrence of nausea, fever, and dyspnea. The patient responded rapidly to oxygen. Chest radiograph showed fluid in the minor fissure and major fissure on the right, increase in the bilateral infiltrates, and hilar enlargement. There was clinical and radiographic improvement over the next 2 months without specific treatment.
The cardiovascular effects of digitalis in normal man
Authors: Mason Dean T.
Published: January 2016

Studies are reported that were designed to elucidate the actions of digitalis on the force of contraction of the normal human heart and on the peripheral circulation in intact, unanesthetized man. The drug, administered in clinically important doses to normal sub;ects, resulted in a greater rate of rise of intraventricular pressure, in a shorter duration of time from the onset of contraction to peak myocardial tension, and in an improvement in the force‐velocity relationship of the contractile element of cardiac muscle. These findings indicate that the glycoside stimulates the contractile force of the normal heart. In normal subjects, digitalis resulted in direct arterial and venoconstriction of the systemic beds. In patients with heart failure, digitalis stimulated the contractile state of the heart, but, in contrast to the normal subjects, the glycoside elevated the reduced forearm blood flow and lowered the elevated forearm vascular resistance and venous tone. It was postulated that this vasodilatory action was indirect, that it overrode the direct stimulating effect on the peripheral vascular beds, and resulted from the augmentation of the lowered cardiac output in the heart failure state. Thus, the effects of the glycoside on the peripheral vasculature were dependent on the circulatory state of the patient at the time the drug was administered. These observations indicate that the digitalis glycosides have both cardiac and extracardiac actions and that these actions occur in normal subjects as well as in patients with congestive heart failure.
6‐Azauridine‐induced changes of the trophoblast in early human pregnancy
Authors: Vojta Miroslav , Jirásek Miroslav
Published: January 2016

6‐Azauridine was given intravenously in single doses of 7.5 to 15 Gm. to 15 pregnant women preceding legal abortion. Pregnancies of 1 ½ to 2 ½ months (amenorrhea of 49 to 90 days) were interrupted 24 hours to 8 days afterward. In 3 cases of advanced pregnancy which were interrupted after 24 houTs, no changes of the trophoblast could be detected. In 10 cases, diffuse micromolar degeneration of the chorion was found and, in one case, focal degeneration of the chorion. In 4 cases, there was striking proliferation of trophoblast syncytial lamellae.
On the clinical evaluation of diuretics with particular reference to a new phthalimidine diuretic, clorexolone
Authors: Lant Ariel F. , Baba Walten I. , Wilson Graham M.
Published: January 2016

A standardized technique suitable for clinical evaluation of diuretic drugs in hospitalized patients with fiuid retention is described. The sensitivity and reliability of the method have been explored. Urinary excretion of sodium, potassum, and fiuid, as well as acute weight loss have been employed as response parameters. The assay has been applied to yield data on the absolute and comparative efficacies of a newly introduced phthalimidine diuretic, clorexolone, in a group of fifty patients. Clorexolone was found to be a potent diuretic producing a pattern of water and electrolyte excretion similar to that caused by the benzothiadiazine group of diuretics. Its natriuretic action persisted for at least 48 hours after oral administration. A comparison of maximally effective doses of clorexolone and a standard benzothiadiazine derivative, hydrofiumethiazide, showed the two drugs to be essentially eqUipotent. Except for a rise in serum uric acid levels, no potentially adverse effects were observed during prolonged therapy with clorexolone and potassium supplements.
Some clinical effects of guanoxan
Authors: Frohlieh Edward D. , Dustan Harriet P. , Page Irvine H.
Published: January 2016

Same clinical effects of guanoxan, an adrenergic neuron blocking agent, were studied in ten hypertensive patients. Although the drug lowered blood pressure, abnormal hepatic function in three patients indicated that this drug should not be used as an antihypertensive drug.
II. The effect of D‐thyroxine, clofibrate, and norethandrolone
Authors: Schrogie John J. , Solomon Harvey M.
Published: January 2016

D‐thyroxine, clofibrate, and norethandrolone influence the pharmacologic effect of bishydroxycoumarin. In mice, D‐thyroxine inhibits the metabolism of bishydroxycoumarin as well as that of meperidine and pentobarbital; in man, the anticoagulant response to bishydroxycoumarin is increased at doses which do not change the rate of metabolism of the drug. Clofibrate does not affect bishydroxycoumarin metabolism in mice or in man but does increase the anticoagulant response to the drug in man. Norethandrolone also increases the anticoagulant response to bishydroxycoumarin in man without affecting the rate of metabolism of the drug. Since clinically effective doses of these three drugs do not decrease the concentration of vitamin K‐dependent clotting factors or affect the absorption, distribution, or metabolism of bishydroxycoumarin in man, it seems likely that they potentiate the pharmacologic effect of bishydroxycoumarin by increasing the affinity of the receptor site for the anticoagulant.
Circulatory responses to angiotensin in man
Authors: Nolan John P. , Cobb Leonard A. , Thompson James J.
Published: January 2016

This report presents hemodynamic responses to the intravenous administration of synthetic angiotensin II in thirty‐nine subjects with normal and abnormal cardiovascular systems. Small doses of angiotensin produced no significant change in mean cardiac output; large doses of angiotensin consistently reduced cardiac output. Significant reductions in splanchnic and renal blood flow were produced by all doses tested. The fall in splanchnic blood flow was found to be a dose‐related phenomenon, with reductions of greater than 50 per cent of the control measurements recorded at high rates of infusion. Pretreatment with atropine lessened or prevented the reduction of cardiac output by large doses of angiotensin, but it did not alter the splanchnic‐flow responses nor prevent the reduction in renal blood flow. The regional effects were, therefore, not explained by reductions in total blood flow but by increased vascttlar resistance in these specific areas. When cardiac output is maintained, angiotensin may produce a significant augmentation of blood flow to regions other than the splanchnic and renal.
Statistical ward rounds—3
Authors: Mainland Donald
Published: January 2016

The cases in this round are intended to illustrate two related topics: "Randomfrequency tests‐reason or automatism?" and "Card shuffiing, the 'exact' test and chi‐square."
Sequential trials‐why do not more people use them?
Authors: Mainland Donald
Published: January 2016

About two years ago that question was asked at a meeting of the Editorial Board of this JOURNAL. I undertook to try to find some answers, if other members of the Board would help by suggesting sources of information among workers who had more abundant and more varied experience with the method than myself. I thereby obtained a few brief comments from two investigators. At the same time I put the question to the readers of the mimeographed "Notes from a Laboratory of Medical Statistics" and asked for opinions based on personal experience. I recall only one reply—from a clinical pharmacologist who described a variant of the sequential design that he had used. This represented a response rate of less than 0.3 per cent of those who might have been expected to contribute, because a 20 per cent randomsample survey of recipients of the Notes in the United States gave an estimated otal of about 360 research workers in internal medicine and pharmacology, and this did not include workers in the same categories in foreign countries. The explanation of the low response rate might be that recipients were not necessarily readers; but investigators in those classes repeatedly showed their interest in the Notes and wrote frequently about other topics.
A comparison of chlormezanone, meprobamate, and placebo
Authors: Champlin F. B. , Cotter C. F. , Moskowitz M. D. , Rossman M. , Sheppard C. , Merlis S.
Published: January 2016

A double‐blind, comparative survey was conducted on a combined sample of inpatients and outpatients presenting moderate degrees of anxiety, depression, somatic concern, and tension. Patients were randomly assigned to therapy. Twenty‐one patients received chlormezanone averaging 500 mg. (200 to 800 mg.) daily, for a maximum of 6 weeks. Twenty‐one patients were treated with an average of 500 mg. of meprobamate (400 to 600 mg.) daily. Twenty‐four patients were treated with an average of 3 placebo capsules (2 to 8) daily, for a maximum of 6 weeks. Ratings were conducted prior to and 2 weeks following medication, 6 weeks after the start of medication, and 2 weeks after medication stopped. Based upon the dual criteria of symptom reduction and frequency and intensity of untoward reactions, meprobamate was the more effective drug in this study.
Thiabendazole (Mintezol) suspension
Authors:   Merck Sharp & Dohme
Published: January 2016

MINTEZOL (thiabendazole) is a unique, highly effective anthelmintic with a broad spectrum of activity. It has been used extensively in man since 1961 (more than 300,000 patientdays of world‐wide experience). Since it is not a dye, it will not stain the stool, the teeth, clothing, or bed linen.
An evaluation of the absorption characteristics of different chloramphenicol preparations in normal human subjects
Authors: Glazko A. J. , Kinkel A. W. , Alegnani W. C. , Holmes E. L.
Published: January 2016

The absorption characteristics of four different chloramphenicol preparations were compared in normal adult volunteers by means of blood level measurements and urinary excretion of chloramphenicol and its metabolites following administration of single 0.5 Gm. oral doses. Products of two manufacturers were compared in the first two studies, while a third study involved a compaTison of four commercial lots of chloramphenicol. Product A produced colorimetric and microbiologic plasma levels which were nearly double those of B; the area under the mean time‐concentration curve was nearly twice as great, and peak blood levels were reached earlier. Product C showed absorption characteristics similar to those of B. Product D showed a greatly extended period of absorption with maximum plasma levels about one quarter those of A. In vitro dissolution tests indicated that products B, C, and D went into solution more slowly than A. These observations emphasize the need for caution in assuming that absorption characteristics are the same for different chloramphenicol preparations containing identical amounts of drug.
Statistical ward rounds‐l0
Authors: Mainland Donald
Published: January 2016

There is probably no disease in which symptoms, and even laboratory values, do not fluctuate to some extent, and in some diseases, such as rheumatoid arthritis, wide and unpredictable variations are a well‐known characteristic. Let us visualize a drug trial in which the patient but not the ph~sician is blindfold. When a patient is domg well on the drug he is transferred to the placebo, or when he is doing poorly on the placebo he is transferred to the drug, or both maneuvers are practiced. A statistical test is applied to the data and if the patients, reckoned either by a majority frequency or by an average of measured differences, did “significantly” better on the drug than on the placebo, the verdict is proclaimed in favor of the drug.
The comparative metabolism of phenacetin and N‐acetyl‐p‐aminophenol in man, with particular reference to effects on the kidney
Authors: Prescott L. F. , Sansur M. , Levin W. , Conney A. H.
Published: January 2016

The metabolism of phenacetin and N‐acetyl‐p‐aminophenol (APAP) was investigated in con;unction with studies of renal tubular cell excretion. A significant increase in renal tubular cell excretion was observed in 2 of 9 healthy volunteers receiving a total of 13.5 Gm. of phenacetin in 5 days and in 1 of 8 volunteers receiving the same dose of APAP. Following oral doses of 1.8 Gm., the maximum plasma concentrations of phenacetin varied from 1.3 to 24.8 P,g per milliliter, and there were often marked differences in the same individual during repeated studies. There was less variation in the plasma concentrations of free AP AP following administration of phenacetin or AP AP and the half‐life of both drugs in the plasma was relatively constant in a given individual. Approximately 78 per cent of the dose of phenacetin and 85 per cent of the APAP was recovered as free and con;ugated APAP in the urine in 24 hours. Many pigmented bands were observed on thin layer chromatograms of hydrolyzed urine extracts from sub;ects receiving phenacetin. In contrast, negligible amounts of pigment were present when APAP was taken. It was not possible to demonstrate differences in the absorption, excretion, or metabolism of phenacetin or AP AP in volunteers showing a marked renal tubular cell response compared with those who did not.
Azathioprine (Imuran) 50 mg. scored tablets: An adjunct for the prevention of rejection in renal homotransplantation
Authors:   Burroughs Wellcome & Co. (U.S.A.), Inc.
Published: January 2016

Caution: Imuran brand Azathioprine is a potent drug. In view of its hematopoietic toxicity, complete blood counts, including platelets, should be performed frequently. See below under Warnings.
A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man
Authors: Hammer Wolfgang , Mårtens Sten , Sjöqvist Folke
Published: January 2016

The steady‐state plasma levels of desmethylimipramine and nortriptyline were compared with the half‐life of oxyphenylbutazone in 5 psychiatric patients, previously treated with various psychotropic drugs. The data showed large interindividual differences, but individuals who achieved a relatively high (or low) steady‐state plasma level (a long or short half‐life) with one drug, also achieved a high (or low) steady‐state plasma level (a long or short half‐life) with the other drugs tested. The findings suggest nonspecificity of the drug hydroxylating enzymes in man. Simultaneous administration of desmethylimipramine did not affect the half‐life of oxyphenylbutazone.
Tobacco cigarette smoking and patellar reflex depression
Authors: Domino Edward F. , von Baumgarten Alona M.
Published: January 2016

One hundred fifteen young men served as subjects to determine the effects of smoking cigarettes of differing nicotine content on the patellar reflex. Each volunteer smoked 2 of the same kind of cigarettes in a 4 minute period with an interval of 25 minutes between. The patellar reflex was elicited automatically every 2 seconds by a reflex hammer attached to a solenoid. The reflex was recorded with the use of a strain gauge transducer and the electromyogram of the ipsilateral quadriceps femoris muscle. A negligible depression was produced by smoking a nicotine‐free lettuce cigarette. A low‐nicotine tobacco cigarette showed approximately 45 per cent depression within 5 minutes compared with a 67 per cent depression after smoking a high‐nicotine cigarette. The depression caused by the second cigarette was comparable in degree and duration to the effect of the first cigarette. No accumulative or tachyphylactic effect was observed. It is concluded that tobacco smoking produces a remarkable, short‐term depression of the human skeletal‐motor system. The depression of the patellar reflex seems to be related to the nicotine content of the cigarette smoked.
Topical therapy of the burn wound: Present status
Authors: Moncrief John A.
Published: January 2016

Invasive infection of the burn wound has long been the primary cause of death in thermal infury. Recent understanding of the pathogenesis of this “burn wound sepsis” has led to the successful control of the infection. The avascular nature of the burn wound precludes successful use of systemic antibacterial agents, but topical use has been found to be effective in reducing the numbers of bacteria to more manageable proportions. While all drugs are not effective, two rather old ones, silver nitrate and p‐aminomethylbenzenesulfonamide, are enfoying a renewed popularity due to their effectiveness in the burn patient. Wounds are more easily cared for, septic complications are lessened, and survival rates, particularly in children, are greatly increased. Significant side effects of drug use occur with both, but these are readily controlled with intelligent use. Other agents are being introduced, but experience with them is too limited. However, the success with the drugs currently utilized has firmly established the principle of effective topical therapy in the control of burn wound sepsis.
A look at some previous cases
Authors: Mainland Donald
Published: January 2016

It is often salutary, although sometimes disconcerting, for a physician to look through his records of previous patients and see whether he would treat them, or even diagnose their conditions, exactly as he did when they were in his care. Whether he would make any changes or not, the records can be instructive to him and to others. I have just been looking through the series of mimeographed "Notes from a laboratory of medical statistics," distributed from 1959 to 1966, which were the progenitors of the Ward Rounds. I was searching for "cases" that have not been mentioned in the Rounds or in the current "Notes on biometry in medical research"—especially for readers' contributions, many of which were to me the most valuable items in the series. They were often contained in informal letters, and in many instances I did not receive permission to mention the writers by name; but I feel that it would be a pity not to let them have a broader and longer, although still anonymous, existence by offering them to readers of the Ward Rounds. This Round will present three of them.
Comparison of cephaloglycin and penicillin in streptococcal pharyngitis
Authors: Stillerman Maxwell
Published: January 2016

Cephaloglycin, 0.5 Gm. orally daily for 10 days (Regimen 1); K phenoxymethyl penicillin, 0.5 Gm. orally daily for 10 days (Regimen 2); K phenoxymethyl penicillin, 1.0 Gm. orally daily for 7 days (Regimen 3); and benzathine penicillin G, 0.5 Gm. once intramuscularly (Regimen 4) were compared in 180 patients with group A streptococcal pharyngitis. The regimens were assigned randomly. Bacterial failure rates for primary treatments were: Regimen 1, 10 per cent; 2, 17 per cent; 3, 28 per cent; and 4, 9 per cent. Bacterial failure rates for retreatments were: Regimen 1, 29 per cent; 2, 67 per cent; and 4, 75 per cent. Possible side efJects of Regimen 1 were generalized maculopapular rashes in 11, other rashes in 2, and mild diarrheas in one third. The minimal inhibitory concentrations of cephaloglycin and penicillin G for 98 group A streptococci averaged 0.2 P,g per milliliter and 0.01 P,g per milliliter, respectively. Cephaloglycin concentrations showed a mean average of 0.8 P,g per milliliter in 30 sera obtained 1 to 2 hours after ingestion of 125 mg. doses during therapy.
Measuring intake of a prescribed medication A bottle count and a tracer technique compared
Authors: Roth Harold P. , Caron Herbert S. , Hsi Bartholomew P.
Published: January 2016

The adequacy of bottle or pill counts for assessing patients' intake of medication has not been established. A bottle count was evaluated in this 2 year follow‐up of 105 patients with peptic ulcer. We added a trace of sodium bromide to a liquid antacid which enabled us to measure intake. There were 1,445 counts of empty bottles and 1,364 blood bromide level determinations. For 10 patients, the bottle counts did not appear to provide an accurate measure of medicine intake. These patients consistently turned in more empty bottles than iustified by their blood bromide levels. For the group as a whole, individual observations (covering time periods ranging from 1 to 3 months) showed only moderate correspondence between bottle counts and their matched bromide levels (r = 0.51). The correspondence was particularly poor when 7 or more bottles were "missing" (r = 0.22) or when the period of observation exceeded 35 days. Despite the inclusion of some erraneous observations, however, when a 12 or 24 month series of observations was pooled for each patient, the bottle count appeared to be moderately accurate (r = 0.80). A correlation of this magnitude stillleaves an errar of up to 36 per cent (i.e., 1 to 0.802 ), and the errar might be even larger if it were not possible to have the rigorous controls used in this study.
Increased response and tolerance to the dibutyryl derivative
Authors: levine Robert A.
Published: January 2016

Cardiovascular and metabolie responses to parenteral administration of the dibutyryl derivative of cyclic adenosine 3',5'‐monophosphate (DBC) in 5 fasting subjects were compared with those in 8 volunteers receiving cyclic adenosine 3',5'‐monophosphate (3',5'‐AMP). The responses to DBC infusion (0.2 mg. per kilo gram per minute for 1 to 1% ho urs) were significantly greater than those to a larger infusion of 3',5'‐AMP (0.3 to 0.5 mg. per kilo gram per minute for 1 to 2 hours), and fewer reactions were induced. Single intravenous injections of DBC (1 to 2 mg. per kilogram) also increased blood glucose and cardiac rate, while doses of the parent compound of 3 mg. per kilo gram produced no effects and stilllarger doses (10 mg. per kilogram) produced responses always accompanied by side effects. Pretreatment with aminophylline did not significantly increase the effects of 3',5'‐AMP alone. Simultaneous intravenous injection of 3',5'‐AMP with aminophylline or caffeine failed to induce any biochemical changes or uncomfortable reactions, presumably because of a chemical antagonism between 3',5' ‐AMP and the methyl xanthine. These studies indicate that DBC is well tolerated by man and may be used in investigations on the role of cyclic 3',5'‐AMP.
Psychotomimetic Drugs : Workshop Series of Pharmacology Section, National Institutes of Mental Health, No.4
Authors: Modell Walter
Published: January 2016

There is a fascinating quality about hallucinogenic drugs which, I am certain, accounts not only for their cultural and ritual use and their social abuse but also for endless discussions, meetings, and symposia on their effects, mechanisms, contributions to psychiatric understanding, and possible uses. Although the sum total of the last two is unhappily small, one always looks hopefully to yet another printed account of a two‐day talkfest on the subject for new light and new insights.
Disposition of bretylium in man and rat; A sensitive chemical method for its estimation in plasma and urine
Authors: Kuntzman R. , Tsai I. , Chang R. , Conney A. H.
Published: January 2016

A gas chromatographic method is described which allows estimation of bretylium, a quarternary ammonium compound, in plasma and urine at drug concentrations as low as 0.07 μg per milliliter. This sensitivity allows the measurement of plasma levels of bretylium in patients receiving therapeutic doses. The plasma level of bretylium in man does not decrease as a first‐order function. During the first 24 hours after drug administration the half‐life increased from 1 to 5.5 hours. In man, 70 to 80 per cent of an intramuscular dose of bretylium was excreted unchanged in the urine within 24 hours and an additional 10 per cent was excreted during the next 3 days. In the rat, 63 per cent of an intramuscular dose was excreted unchanged in the urine; 31 per cent was excreted unchanged in the feces. Excretion into the bile probably accounts for the bretylium found in rat feces.