bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential patterning of behavioral effects from three types of stimulant drugs
Authors: Dureman E. I.
Published: January 2016

The effects of the new drug 5‐phenyl‐2‐imino‐4‐oxo‐oxazolidine (PIO) in young normal subjects were compared with amphetamine and caffeine 3 and 6 hours after oral administration. The test battery included a difficult code‐tracking task performed under forced speed conditions, a needle‐threading test for assessment of fine motor coordination, flicker fusion, and the Archimedes spiral. Pulse rate was recorded as a check for undesirable circulatory effects.

The results point to the conclusion that PIO has a much more potent facilitating effect on code‐tracking performance under speed stress than amphetamine or caffeine. A slight improvement in fine motor coordination after 3 hours was observed only under amphetamine. Caffeine but not PIO caused a decrement in the same test parameter after both 3 and 6 hours. Increased duration of visual movement aftereffect was observed 3 hours after amphetamine, caffeine, and PIO, this effect being most persistent after amphetamine. The average increase in pulse rate over 6 hours after amphetamine was 4.6 beats per minute, after caffeine 1.8, and after PIO 0.7.
Effects of different dose schedules of amethopterin on serum and tissue concentrations and urinary excretion patterns
Authors: Liguori Vincent R. , Giglio Joseph J. , Miller Edward , Sullivan Robert D.
Published: January 2016

The highest serum concentration of amethopterin after single intravenous administration was present in the first specimen, which was obtained at 30 minutes. Total urinary output was greater the first 8 hours than during the next 16 hours. Tissue specimens of skin contained greater amounts of amethopterin at 5 hours than at 10 to 12 hours.

In contrast to single intravenous injection, 12 hour intravenous or intra‐arterial infusion of the same dose produced serum concentrations of the drug which were sustained until the infusion was completed. The total urinary output of the drug was less in the first 8 hours than in the remaining 16 hours. As the infusion progressed, specimens of skin tissue showed increased concentrations of the drug.

The results of this study suggest that the enhanced biologic activity of amethopterin noted clinically on continuous administration is related to sustained serum and tissue concentrations of the drug.
Effects of drugs on the performance of a task by fatigued subjects
Authors: Holliday Audrey R. , Devery William J.
Published: January 2016

This study establishes a method for differentiating between drug effects on the work performance of fatigued subjects. Sleep‐deprived subjects were assigned a boring and repetitious task of 5½ hours' duration. The work output of subjects on D‐amphetamine (10 mg.), W1206 (10 mg.), or W1206 (20 mg.) was Significantly enhanced beyond that of subjects on meprobamate (800 mg.), amitriptyline (25 mg.), or a placebo. The group on amitriptyline showed a Significant retardation of performance compared to that of all other groups. D‐Amphetamine and W1206 appear to be effective antifatigue agents whereas placebo, meprobamate, and amitriptyline do not.
Clinical experience with a new type of orally effective diuretic agent
Authors: Seller Robert H. , Fuchs Morton , Onesti Gaddo , Swartz Charles , Brest Albert N. , Moyer John H.
Published: January 2016

Of the newer diuretic agents, many are modifications of a benzothiadiazine molecule. Although a ring system (sulfur‐1, 1‐dioxide) is found in all of these benzothiadiazine drugs, it has been found that this ring is not essential for saluretic activity. A new type of drug, a member of the quinazolinone sulfonamide family (quinethazone), has been found to be a saluretic agent of the same order of potency as hydrochlorothiazide with regard to its natriuretic activity. The sodium and potassium excretion ratio is high. The duration of activity appears to be approximately 24 hours. Administration of quinethazone for 2 days induced an average Weight loss of more than 2 pounds in a group of 30 outpatients. A study of the same patients who previously had required two or more mercurial injections a week indicated that daily administration of quinethazone maintained them in an edema‐free state without significant toxic effects.
Influence of cinnarizine on the labyrinth and on vertigo
Authors: Philipszoon Adriaan J.
Published: January 2016

The effects of an antihistamine, cinnarizine, were studied in normal subjects and patients with vertigo by measuring eye movements after labyrinthine stimulation. The studies were controlled, and the effects of drugs were compared with that of placebo by means of the electronystagmograph. The effects on angular and linear accelerations were examined. Cinnarizine appeared to reduce the reaction to labyrinthine stimulation in normal subjects as well as to relieve symptoms in patients with vertigo.
Oral antifertility measures
Authors: Epstein Jeanne A. , Kupperman Herbert S.
Published: January 2016

A review of the experimental and clinical aspects of oral antifertility agents is presented. The various sites in conception and pregnancy at which contraceptive measures may act are described. It becomes apparent that at present the only practical, apparently harmless, and effective method of oral contraception is by means of gonadotropin inhibition and suppression of ovulation in women, with the use of the newer norsteroids for 20 days of the menstrual cycle. With this approach, there is neither toxic effect nor metropathic bleeding. The result of the prolonged suppression of pituitary activity is still to be evaluated; however, in the 5 years of their clinical trial, these compounds have proved harmless and without deleterious effects on subsequent fertility or endocrine function. Although highly effective, the norsteroids are by no means ideal contraceptives because of the incidence of unpleasant effects in about one‐third of the patients, because the cost of therapy is still prohibitive for use in depressed economic areas, and because the patients must be cooperative and intelligent if the medication is to be effective.

The control of fertility in men is still in the experimental stage, but the recent studies of MacLeod and Heller on the spermicidal effects of dichloracetyldiamine provide some promise.
Clinical pharmacology of antitussive agents
Authors: Bickerman Hylan A.
Published: January 2016

The cough reflex as part of an integrated protective mechanism for adequate bronchoelimination is vital in maintaining the integrity of the pulmonary parenchyma. While it is undoubtedly true that more patients have died from an inability to cough effectively than from the act of coughing itself, adequate control of useless cough is often necessary in order to preserve the health and wellȁbeing of the patient. Until recently, cough mixtures were compounded empirically and assessed clinically on the basis of subjective response. Based upon physiologic and pharmacologic studies on the mechanics and regulation of the cough reflex together with the development of new techniques for eliciting a reproducible cough with graded stimuli in animals and man, quantitative objective studies of antitussive activity are now possible. This has stimulated the search for new compounds devoid of the analgesic and narcotic properties of the opium derivatives. Some of the new synthetic compounds discussed in this review have demonstrated antitussive activity equivalent to that of codeine and are replacing the older narcotic preparations in the symptomatic management of cough.
Part VII. Correlation with potential toxicity to man of toxic effects in animals
Authors: Paget G. E.
Published: January 2016

Today, all reputable pharmaceutic organizations perform toxicity tests of varying elaboration before offering new drugs for clinical trial. Indeed, most responsible clinicians require evidence that this has been done before using a drug in man. Such an attitude is based on the belief that man will react in essentially the same way as the species used for the toxicity studies in the laboratory. This belief is usually verified by the results of the clinical trials, but laboratory experiences with the biologic actions of chemical compounds teach us that it has no logical justification. That the concept frequently forms a satisfactory basis for action is the result of good fortune rather than a law of nature. There are basically two variables involved in the extrapolation of data from laboratory animals to man which may cause vastly different reactions in humans from those found in the laboratory. These two variables are species variation and variation in the circumstances under which the drug is used.
Part X. Evaluation of antibacterial agents
Authors: Lepper Mark
Published: January 2016

In the evaluation of antibacterial agents, there are many problems which evolve from the interrelationships of drug, host, and organism and their interaction (see diagram). In the long run, we have to evaluate the entire system before we can fully understand the problem.
Some comments on the use of agents which lower serum cholesterol
Authors: Lawn Bernard , Portman Oscar W. , Stare Fredrick J.
Published: January 2016

Extensive experimental and clinical observations have associated atherosclerosis with a high serum cholesterol level. Clinical thinking has, however, been propelled beyond the mere association of the two. Cholesterol has been viewed increasingly as the bête noire of atherosclerosis. Four lines of evidence have tended to ascribe a pathogenic role to this lipid moiety, namely, the presence of cholesterol in atheromatous plaques, the production of vascular lesions in animals by incorporating large amounts of cholesterol and other serum cholesterolelevating factors in the diet, the high incidence of premature atherosclerosis in clinical conditions characterized by hypercholesterolemia, and epidemiologic studies which have related the cholesterol level of a population to mortality from coronary artery disease.
Hemodynamics during rest and exercise before and after prolonged digitalization in normal subiects
Authors: Schröder G. , Malmcrona R. , Varnauskas E. , Werkö L.
Published: January 2016

Twelve normal men were given acetyldigitoxin or digitoxin by mouth for 1 to 3 weeks. Cardiac output by dye dilution technique, intravascular arterial and right atrial pressures, heart rates with electrocardiogram, and oxygen consumption were determined during rest and at different work loads before and after digitalization. Pulse rate fell and stroke volume and left ventricular stroke work increased at rest. During the most frequently used work load, the pulse rate fell. No other hemodynamic changes were observed after digitalization.
Modified technique used in human bioassay of four butyrophenone derivatives in psychoneurotic patients
Authors: Nodine John H. , Bodi Tibor , Levy Howard A. , Siegler Peter E. , Slap Joseph W. , Mapp Yolanda , Khorsandian Rostam
Published: January 2016

Too often, following animal and acute human pharmacologic studies, insufficient information is available for the efficient and safe design of an adequately controlled double blind study in man. The single blind human bioassay of psychopharmacologic drugs, utilizing a spectrum of clinical conditions, may provide a rough estimate of the dose‐response relationship for clinical improvement, the dose‐response relationship for toxic effects, and an estimate of diagnostic categories in which potential usefulness may be established by double blind evaluation. This procedure avoids the expense of large numbers of toxicologic studies and provides the first screening for actual rejection of a drug from more complex and expensive thorough clinical investigation. The use of the modified technique is illustrated by studies with four butyrophenone derivatives (R‐1625, R‐1647, R‐1892, and R‐2167) in 151 patients. The dose‐response curves for these drugs, including the ED50 and the TD50 of each, were obtained in psychoneurotic outpatients and were found to correlate well with the ED50 for animal conditioned avoidance behavior block and with the LD50 in mice.
Neomycin spray in the treatment of nasal carriers of staphylococcus
Authors: Hussar Allen E.
Published: January 2016

Twenty‐eight nasal carriers of coagulase‐producing Staphylococcus aureus were treated by spraying the nares and deeper nasal cavities once a day with a solution containing neomycin sulfate. The subjects received a total of forty‐four courses of treatment; in 32 instances, the culture was negative the day after the first treatment, in 7 instances after the second, and in four instances after the third. One case remained positive after the fifth spray, the only failure in the study.
Clinical pharmacology of potent analgesics
Authors: Murphree Henry B.
Published: January 2016

The object of this review is to summarize the current knowledge of morphine and morphinelike drugs. If used wisely, morphine, the oldest agent, is still one of the best. Starting in 1898 with heroin, an increasing number of morphinelike drugs have been created with the hope of improving on morphine. The array of compounds now available is made more labyrinthine by the doubtful virtuosity of trademark inventors. Whether any of the newer compounds, including meperidine, have any significant advantage over morphine or whether it is possible to separate the desired effects of these potent agents from the undesirable effects is questionable. A practical classification depends on the degree of analgesia and the duration of action. These agents can now be used more safely because of the development of such potent antagonists as nalorphine and levallorphan.
Part XV. Assay of hypoglycemic agents in man
Authors: Frawley Thomas F. , Shelley Thomas F.
Published: January 2016

The development of effective oral preparations of hypoglycemic agents has revitalized interest in the therapy of diabetes mellitus. However, the continuing supply of such agents poses problems of their assay in man and establishment of their value in comparison with compounds already available. These problems are particularly evident when one considers that the precise metabolic defect in diabetes mellitus is still unknown and, above all, that although some 40 years has passed since the discovery of insulin, its precise mode of action is still a mystery.
Variable sensitivity of assay methods of tetracycline and demethylchlortetracycline in human volunteers
Authors: Lichter Edward A. , Sobel Solomon
Published: January 2016

Evaluation of levels of serum antibacterial activity was attempted in 17 normal subjects who took a therapeutically recommended drug regimen of tetracycline or demethylchlortetracycline for 4 days. Microbiologic assay was performed by the tube dilution method with three separate test organisms, and one of these was used in a parallel cup‐plate assay method. The cup‐plate method was found to be more sensitive and more reliable than the tube dilution methods using any of the three organisms. With the dosage regimens used, serum activity accumulation could be shown for DMCT but not for TC.

Although individual subject variability in drug absorption may be noted, the average level of serum antibacterial activity was consistently higher with 150 mg. of DMCT four times daily than with 250 mg. of TC four times daily. After 4 days, the difference was found to be Significantly higher in the cup‐plate method and the tube dilution method when Bacillus cereus was the test organism but not in the tube dilution method when streptococcus 98 or staphylococcus 209P was used.

We were unable to demonstrate differences in prolongation of serum activity levels after cessation of therapy with these two drugs.
Part XVII. Physicochemical and pharmaceutic properties of drugs that influence the results of clinical trials
Authors: Nelson Eino
Published: January 2016

Despite the fact that pharmacologists and some clinicians are aware that physical, chemical, and pharmaceutic properties of a drug may influence its actions and effects, little consideration has been given to quantitating the effects of these properties. It is the aim of this article to discuss and illustrate the fact that the rate of gastrointestinal absorption of a drug is often a function of the time needed for the drug to dissolve in the fluid at the site of absorption. Clinical trials of several forms of the same drug may merely confirm a result which should have been predicted on the basis of its properties, such as specific surface area, type of salt, and the form in which it is administered.
Oral hypoglycemic agents
Authors: Boshell Buris R. , Barrett James C.
Published: January 2016

The chance observation by Janbon in 1942 that p‐aminosulfonamide caused hypoglycemia initiated an extensive search for oral hypoglycemic agents for diabetes mellitus. In the 20 years since Janbon's discovery, many agents have been studied. Some of them have been discarded after preliminary animal studies, whereas others have undergone clinical investigation in man before being abandoned. Ten oral hypoglycemic agents have been investigated in our clinic during the past 5 years; however, at the present time, only three of these drugs are currently on the market in this country. Two of these agents are sulfonylureas, and one is a diguanide.
Who killed Cock Robin? The martyred scientist
Authors: Dragstedt Carl A.
Published: January 2016

Assertions that selected diseases are the “great killers of mankind” are common in high places. National societies promoting campaigns for funds to study those diseases contend for each death to be assigned to the disease of their special interest; thus will their claims for priority in charitable donation gain the desired weight provided by statistical evidence. Vital statisticians routinely respond in such ways as fall within their province to “fix the blame,” or, in more formal language, to secure with scientific accuracy, from the medical profession, coroners, or others, a specification of the cause of each death. Pursuit of this objective is certainly laudable from all conventional view‐points, but in so conforming one may become a victim of habit rather than an alert pursuer of well reasoned objectives. … It is a false proposition that each death is a response to a single cause. Of this we are well aware. Admission of multiple causation for each death is tacit in the [death] certificate itself. We have long striven for entry of a sequence of causes rather than a single cause. As a result of this, the selection of one cause for tabulation purposes has itself become a major problem for us, leading to much juggling of terms, rules, and instructions to the distress of the medical profession as well as the statisticians. Efforts in recent years to solve the problems of tabulation and interpretation of aSSignment of multiple causes represent an attack on a basic problem and clearly indicate that causation of death is not considered singular.
A new hormone, angiotensin
Authors: Page Irvine H. , Bumpus F. Merlin
Published: January 2016

The renin‐angiotensin system has recently received great emphasis, emerging from a position where even its existence was doubted to one where there is little question that it has powerful effects on several biologic systems. Most important in this changed status have been the determination of chemical structure and synthesis of angiotensin and improved methods of bioassay. Current work concerning the spatial orientation of the angiotensin molecule suggests that a conformation is essential for its action at the receptor site; this work should facilitate the synthesis of effective angiotensin antagonists.

The hemodynamic changes produced by angiotensin have received much recent attention. Both short‐term arullong‐term measurements of its effects on the systemic and pulmonary circulation have been made, as well as measurements of its effects on specific vascular beds and organs. The latter have included capillary and smoll arteriolar and venous beds, the carotid sinus, the heart, muscle versus splanchnic and renal vascular beds, and the adrenal gland. The effect of angiotensin on aldostemne secretion and the changed amounts of these hormones in various types of hypertension are receiving much current attention. The results of these studies may prOVide partial answers to the problem of the interaction of the various systems controlling blood pressure included in the mosaic theory of hypertension.
Clinical pharmacology of the narcotic analgesics
Authors: Vandam Leroy D.
Published: January 2016

Opium has been used for the relief of pain at least as far back as records go. Morphine was separated from the mixture of opium alkaloids in 1806, and synthesis was accomplished in 1952. From an over‐all viewpoint, morphine is still the most satisfactory narcotic analgesic, but certain untoward effects have fostered the search for a better compound, a goal still to be achieved. This review of the narcotic analgesics will deal with the clinical pharmacology of these substances with reference to morphine and meperidine, the best known substitutes, as yardsticks. A discussion of the general actions and uses of these drugs will be followed by a more detailed consideration of the commonly used compounds. It should be understood that few of the drugs have been studied satisfactorily in their entirety. This deficiency relates largely to the difficulty in determining drug effects on man under controlled conditions and to the haste in presenting new substances for clinical use before thorough study.
Proposal for a national prescription formulary
Authors: Friend Dale G.
Published: January 2016

The time is ripe for a national prescription formulary. It is utterly impossible for the practicing physician to have enough information to select the drugs he uses in the treatment of his patients wisely. The great pressures exerted on him by the drug industry through detail men, medical journal advertising, and direct mail articles, by newspaper, radio, and television publicity, and finally by patients who read or hear of such advertising often force the physician into using drugs about which he does not have full information. Furthermore, it is frequently impossible for him to get unbiased or sufficiently comprehensive data concerning a drug in order to know whether it is an effective agent or whether it is potentially harmful. At present, there is no available authoritative compendium to which he can turn for help. He is often at a loss to know just how to answer patients' questions or how to resist effectively the many pressures brought to bear on him. This leads to poor medical practice and results in serious consequences to both the patient and the physician. Many authorities in the field of drug therapy have felt that one answer to this situation is an authoritative, annually renewed compendium of truly worthwhile drugs selected by experts on which the physician could rely to guide him in his prescription needs.
The physician's legal responsibility in clinical testing of new drugs
Authors: Hatry Patricia
Published: January 2016

The physician testing a new drug has legal responsibilities to his test patients, the pharmaceutic company or other agency for whom he has agreed to do the research, and finally to the public to whom the drug is eventually to be released. The liability may be for tort or malpractice, breach of contract, assault and battery, invasion of privacy, or various criminal offenses. The usual medical malpractice policy will not cover the physician for all the possible legal repercussions. In some cases, the legal responsibility may be shifted, but in the final analysis, the physician's best insurance is his competence, integrity, and conscience.
Medical management of ascites in cirrhosis of the liver
Authors: Rivera Alfonso , Velasco Francisco , Suárez Maria Antonieta , Dies Federico
Published: January 2016

Studies were conducted in patients with cirrhosis of the liver and ascites, in one with peritoneal carcinomatosis and ascites, and in one normal subject. Spironolactone, 16α, 17α‐dihydroxyprogesterone and diuretics were administered. It was observed that spironolactone alone produced significant increases in urinary volume and in sodium and chloride excretion. When spironolactone was combined with diuretics, the effect was potentiated and excessive potassium excretion was prevented. It is concluded that aldosterone participates in the sodium retention of the cirrhotic patient with ascites and that aldosterone is, at least in part, a cause of the rebound that follows the withdrawal of diuretics. 16α, 17α‐dihydroxyprogesterone was found to have no antialdosterone activity.
Hypotensive effect of some antihypertensive drugs
Authors: Grenfell Raymond F. , Briggs Arthur H. , Holland William C.
Published: January 2016

Chlorothiazide consistently caused a significant decrease in systolic and diastolic blood pressure, the onset of the former appearing before the latter. Hydrochlorothiazide caused comparable decreases. Reserpine in combination with hydrochlorothiazide caused slightly greater decreases than hydrochlorothiazide alone. Hydrogenated ergot alkaloids given in combination with hydrochlorothiazide caused a decrease in systolic and diastolic blood pressure comparable to that of chlorothiazide and reserpine. In the sitting position, guanethidine caused a decrease in systolic and diastolic blood pressure not significantly different from the pressure obtained by the administration of an oral placebo. However, when the patient was in the standing position, the drug induced significantly greater reduction in diastolic blood pressure than did the oral placebo. α‐Methyldopa caused a significant decrease in the systolic blood pressure and a more variable reduction in diastolic blood pressure.

In a group of patients with blood pressure over 200/120 mm. Hg, there was a significant decrease in the systolic and diastolic blood pressure after an oral placebo. On the other hand, a group of patients with blood pressure under 200/120 mm. Hg did not have a decrease in systolic or diastolic blood pressure after oral placebo.
The similarities and differences between meprobamate and barbiturates
Authors: Berger F. M.
Published: January 2016

The literature comparing meprobamate and the barbiturates is extensively reviewed, and the differences between these agents are found to be significant, from both pharmacological and clinical standpoints. These include major differences in site and mode of action, effects on conditioned responses and other animal behavior, primary indications for use in human beings, and effects on normal human behavior. The barbiturates are shown to be useful primarily as hypnotics which, in clinical doses, produce motor and intellectual impairment. Meprobamate is shown to be a specific antianxiety agent which produces no significant behavioral impairment at clinical dosage. A critique of this review follows.
Commentary on preceding article
Authors: Domino E. F.
Published: January 2016

The Editorial Board of this JOURNAL has established the policy that where there is an interesting and sharp difference of opinion between an author and a reviewer, if it appeared to be more valuable to publish a statement of the differences than to attempt to make one of the disputants agree with the other, this would be done with the permission of both parties. In this way interesting as well as educational material which would otherwise be lost is published. The publication of a reviewer's commentary should make his contribution a more substantial one, to the reader as well as to the author. It is for this reason that we publish a commentary on Dr. Berger's paper and leave it to the reader to come to his own conclusions. Editor.
Difficulties and opportunities in clinical pharmacology
Authors: Wilson G. M.
Published: January 2016

The rapid introduction of new drugs effective in modifying the natural course and symptoms of disease has not yet been accompanied by a parallel development of clinical pharmacology in many medical schools. Medical education has too often emphasized the animal experimental aspects of pharmacology and methods of clinical diagnosis, with relative neglect of the scientific aspects of drug therapy. As a result, many doctors are inadequately trained in clinical pharmacology and therapeutics, particularly with respect to the critical assessment of new remedies. There are presently too many new drugs to be evaluated and too few physicians qualified to carry out this work. The development or expansion of departments of clinical pharmacology is urgently required so that more research can be directed to problems arising from the use of drugs in the treatment of human disease. Particular attention should be given to the improvement of methods of conducting therapeutic trials and of comparing the relative merits of new drugs, to the proper recognition of injurious toxic effects, and to the study of the mechanism of action of drugs in human disease.
Effects in human volunteers of subparalytic doses of dihydro‐β‐erythroidine
Authors: Murphree Henry B.
Published: January 2016

Dihydro‐β‐erythroidine is a curariform alkaloid of interest to neuropharmacologists because unlike curare it is a tertiary amine. Hence, it can be given orally and may cross the blood‐brain barriers. In the studies described here, this compound was given in single oral doses of 200 mg. total dose and 6 mg. per kilogram to trained human volunteers. At 200 mg. the effects were bradycardia and visual difficulty most often described as blurring of vision or double vision. The 6 mg. per kilogram dose produced these effects plus hypotension and reduction in grip strength with accompanying feelings of sedation. Visual effects, reduction in grip strength, and recognition of the drug were highly correlated. Dihydro‐β‐erythroidine appears to be reliably absorbed by the oral route, but its skeletal muscle effect is not reliable and does not appear until much larger doses are given than those which produce visual effects and bradycardia.
The protean control of clinical pharmacology
Authors: Modell WaIter
Published: January 2016

Examination of the problems involved in the design of investigations of drugs in man indicates that there is no routine approach which provides meaningful answers in all cases. Appropriate control of the experiment in man is especially elusive. Each case has to be considered separately. It is suggested that with the increasing recognition of the need for controlled studies in man, some aspects of the problems involved have been generally recognized and better handled than previously, hut that the problems inherent in the selection of the most appropriate subject are often ignored.
Patient selection and stratification in therapeutic trials
Authors: Laurence D. R.
Published: January 2016

As drug therapy improves, it will become more and more important to be able to detect small differences in therapeutic effect. This can be done only on groups and, if such small effects are not to be obscured, the groups must be themselves wholly homogeneous, or else divided into homogeneous subgroups, either at the outset or at the end of the trial. This requires careful definition and discriminating selection of patients, matters the importance of which it would be difficult to overstress.
Abstracts
Authors: Moser Robert Harlan
Published: January 2016

[Because of the considerable interest in the putative connection between abuse of acetophenetidin and renal complications and anemia, it was thought desirable to bring together some of the papers which have been important in calling attention to this possibility as well as to an editorial which advises a conservative view. Ed.]
Problems in the development and use of oral poliovirus vaccine
Authors: Sabin Albert B.
Published: January 2016

I am highly honored to be one of the recipients of the Oscar B. Hunter Memorial Award. The esteem of one's colleagues is the greatest reward for a scientist. For the scientist realizes, as Aristotle pointed out long ago, that each one at best can add but a little to our knowledge of Nature, and that the real grandeur arises only from all the assembled facts.
The significance of "nonsignificance"
Authors: Mainland Donald
Published: January 2016

Although statistical textbooks have for a long time asserted that "not significant" merely implies "not proven," investigators still display confusion regarding the interpretation of the verdict. This appears to be due to the ambiguity of the term "significance," to inadequate exposition, and especially to the behavior of textbook writers who in the analysis of data act as if "nat significant" means "nonexistent" or "unimportant."

Appropriate action after a verdict of "nonsignificance" depends on many circumstances and requires much thought.

"Significance" tests often could be, and in some instances should be, avoided; then "nonsignificance" would cease to he a serious problem.
Clinical evaluation of a new anabolic agent 7 α, 17 α‐dimethyltestosterone (bolasterone)
Authors: Korst Donald R. , Bowers Cyril Y. , Flokstra John H. , McMahon F. Gilbert
Published: January 2016

The anabolic effects of bolasterone have been compared with other such agents and with a placebo by the use of a twin crossover method. By expressing human metabolic balance effects as differences between pretreatment and posttreatment nitrogen excretion values, the steroid was found to be 25 times as potent as fluoxymesterone, 80 times as effective as norethandrolone, and twice as effective as methandrostenolone. The anabolic effect of bolasterone was confirmed by a weight gain study which compared a placebo, a standard anabolic agent, and the test drug. Androgenic effects of bolasterone were not observed in these studies.
The interaction of morphine and d‐tubocurarine on respiration and grip strength in man
Authors: Bellville J. Weldon , Cohen Ellis N. , Hamilton Joan
Published: January 2016

In healthy male volunteers, morphine in combination with d‐tubocurarine produces a greater decrease in responsiveness to end expiratory carbon dioxide than does morphine alone.

We believe this represents a central respiratory depressant effect of morphine plus an additive peripheral effect of d‐tubocurare on the respiratory musculature. In these subjects, morphine caused a significant increase in grip strength while d‐tubocurarine caused a significant decrease in grip strength.
Some pharmacologic effects of intravenous chlordiazepoxide
Authors: Steen Stephen N. , Martinez Leonardo R.
Published: January 2016

Effects of intravenous chlordiazepoxide at three dose levels (0.5 mg. per kilogram, 1.0 mg. per kilogram, and 1.5 mg. per kilogram) were studied in 7 conscious volunteers. Meperidine (0.5 mg. per kilogram), pentobarbital sodium (1.0 mg. per kilogram), promethazine (0.5 mg. per kilogram), and a placebo were included for comparison in the study. Evaluation of responses in the postinjection period indicated that (1) promethazine caused the most severe subjective effects, (2) subjects receiving 1.0 mg. per kilogram of chlordiazepoxide appeared to behave as though they had received meperidine or pentobarbital, and (3) there was rw hypotension even at the highest dose level of chlordiazepoxide.
The comparative ineffectiveness of Nafcillin (a new antistaphylococcal drug) against beta hemolytic streptococcal infections in children
Authors: Breese B. B. , Disney F. A. , Talpey W. B.
Published: January 2016

Nafcillin, one of the newer penicillins designed for use against penicillin‐resistant staphylococci, was compared with buffered penicillin G in the oral treatment of beta hemolytic streptococcal infections in children. Although usually effective, occasionally it was not, nor was it as reliable as buffered penicillin G for this purpose.
Drug‐induced respiratory depression in man: A method of assessment
Authors: Campbell D. , Lister R. E. , McNicol G. W.
Published: January 2016

It is generally agreed that the precise quantitative assessment of drug‐induced respiratory depression presents many difficulties whether the measurements are attempted in animals or man. There has been considerable divergence between the claims made by manufacturers of narcotic analgesics and clinicians' experience with these drugs in practice. An attempt has been made to devise a simple and reliable technique which can be used in man to compare the respiratory depression produced by novel narcotic drugs and the standard drugs such as morphine and pethidine. To this end a modification of the carbon dioxide “challenge” test was used in this investigation, and four possible measures were considered. The best indices of respiratory depression were shown to be (a) the absolute value of the alveolar ventilation while a 95 per cent O2/5 per cent CO2 mixture is breathed and (b) the change in the arterial carbon dioxide tension from the control level during carbon dioxide stimulation to respiration. Both measurements were made 10 to 20 minutes following intravenous injection of the test drug.
Methysergide in the migraine syndrome
Authors: Shekelle R. B. , Ostfeld A. M.
Published: January 2016

Methysergide and a placebo were compared under double‐blind conditions for prophylactic effect in patients exhibiting the migraine syndrome. Each patient received in randomized order 2 mg. methysergide, three times a day orally for 5 consecutive weeks, and an identical placebo taken in the same way during another period of 5 weeks. The number of headache days reported by each patient during the last 4 weeks of the methysergide period was subtracted from the number reported during the last 4 weeks of the placebo period. These observations were analyzed sequentially with Rushton's t test. After 13 patients had completed both treatment periods, the data were sufficient to conclude that methysergide was significantly (P < .05) more helpful than the placebo in reducing the frequency of migraine headache attacks. No serious toxic effects of methysergide were noted.
The effects of preanesthetic, anesthetic, and postoperative drugs on renal function
Authors: Papper Solomon , Papper E. M.
Published: January 2016

Morphine produces a decrease in urine flow in certain animals and man. There is evidence in animals that this antidiuresis may be attributed to a release of antidiuretic hormone (ADH). In man, morphine may result in decreased urine flow that is attributable to decreased renal hemodynamics in the absence of increased ADH. Although the evidence is less clear, the situation is apparently similar for meperidine and barbiturates.

General anesthetic agents result in decreased renal blood flow, filtration rate, and excretion of water and electrolytes. It is possible that these renal effects are the result of some as yet undetermined consequences of the anesthetic state rather than of a specific drug action.
Abstracts
Authors: Moser Robert Harlan
Published: January 2016

A 38‐year‐old man stationed in a known endemic malaria area took 500 mg. chloroquine once a week for a period of 6 months; there were no immediate ill effects. Upon leaving this region, he was given primaquine diphosphate (26.3 mg., equivalent to 15 mg. of primaquine base) once daily for 12 days. After this, chloroquine was resumed. One week later, he noted scaly, erythematous lesions developing on his legs, which soon spread to other areas. Six weeks later, new lesions continued to appear (chloroquine was still being taken once each week). Typical psoriatic lesions appeared on the scalp, face, trunk, palms, legs, and penis. Nail pitting and lesions of the elbows, knees, and intergluteal cleft region were not present.
Information on New Drug Regulations
Authors: Larrick Geo. P.
Published: January 2016

The Committee on Investigational Drugs has suggested changes in the investigational drug regulations to facilitate clinical investigations of new drugs without jeopardy to the public health. The suggestions would permit the shipment of chemicals to be administered to human beings as research tools to be exempt from the other provisions of the investigational drug regulations, provided a brief report is submitted to the Food and Drug Administration justifying the exemption; and allow pharmaceutical companies to prepare and distribute for use, solely as controls in clinical investigations, new dosage forms of drugs already commercially available without filing claims for exemption for these controls.
Training program in Clinical Pediatric Pharmacology
Authors: Modell Walter
Published: January 2016

A Clinical Pediatric Pharmacology unit has been established in the Department of Pediatrics, Children's Memorial Hospital, University of Oklahoma Medical Center. Fellowships for training in clinical pediatric pharmacology in the unit are now being offered. The program is designed especially for those interested in a career in academic medicine or in intensive clinical investigation relating to drug metabolism.
The extraordinary side effects of drugs
Authors: Modell Waiter
Published: January 2016

Defined in its strict pharmacologic sense, side effect is any effect of a drug, desirable or undesirable, other than the one sought for a particular therapeutic purpose. Thus, the therapeutic effect of a drug for one case can be the side effect of another. This presentation deals with extraordinary side effects: side effects due to drug interaction, nutrition, age, enzyme abnormality, ecologic disturbance, drug resistance, social problems, and inferior therapy. The best way to limit the side effect of drugs is by basic understanding of drug action obtainable only by well‐controlled, well‐designed experiments in man. Otherwise, drugs will be used without this vital information until, in clinical use by trial‐and‐error method, sufficient data are haphazardly collected to provide conclusive evidence of drug effects. This is the common medical experiment in man, a mass experiment of a retrospective type in which the patient plays the role of the unwitting subject and the phYSician is the unwitting observer. It is inefficient, exposes more patients to poorly understood drugs than necessary, and, until the necessary information is obtained, is marked by avoidable catastrophe.
Sodium retention following diuretic therapy
Authors: Rivera Alfonso , Flores Alejandro , Suárez Ma. Antonieta , Chávez José Ma.
Published: January 2016

Thirty‐three experiments were carried out to investigate the period of sodium retention which follows sodium diuresis in a group of patients with cirrhosis, a patient with Addison's disease, and a normal control. Four experimental schemes were employed under strict metabolic conditions: a normal sodium intake without an aldosterone antagonist, a normal sodium intake with an aldosterone antagonist, a low‐sodium intake without an aldosterone antagonist, and a low‐sodium intake with an aldosterone antagonist. It was shown that in patients with cirrhosis, or normal controls with a “normal sodium intake,” the postdiuretic weight regain was greater than the diuretic‐induced weight loss. That aldosterone participates in this phenomenon was demonstrated in the experiments with an aldosterone antagonist in which the period of sodium retention was reduced and was altogether absent in the patient with Addison's disease, but reappeared when this patient received desoxycorticosterone acetate.
Bone marrow depression due to methicillin, a semisynthetic penicillin
Authors: Levitt Barrie H. , Gottlieb Arian J. , Rosenberg J. Richard , Klein Jerome J.
Published: January 2016

Methicillin, 1,6 dimethoxyphenyl penicillin, is the first of the commercial semisynthetic penicillin analogues derived from the 6‐amino penicillanic acid nucleus1 resistant to destruction by penicillinase. These new antimicrobial substances have already proved their clinical effectiveness, but clinical experience with them is not yet extensive enough to establish how toxic they are. This is a report of bone marrow depression in two patients treated with methicillin. In both cases there was complete hematologic recovery following withdrawal of methicillin. It is noted that such reactions have not been reported after two decades of use of penicillin G.
Synthetic lysine vasopressin nasal spray in the treatment of diabetes insipidus
Authors: Moses Arnold M.
Published: January 2016

Thirteen patients with diabetes insipidus have been satisfactorily and conveniently treated with synthetic lysine vasopressin nasal spray, the material being administered 3 to 5 times per day in a total daily dosage ranging from 35 to 125 units. A transient decrease in effectiveness has been nated during periods of upper respiratory infection or allergic rhinitis. The only adverse effects of the nasal spray have consisted of minor nasal irritation in 3 patients and increased frequency of bowel movements in 1 child after he increased the dose in an effort to concentrate and restrict urine volume. In hydrated normal subjects, lysine vasopressin administered subcutaneously is 7.4 times as effective as the nasal spray preparation.
Hyperventilation syndrome
Authors: Aronson Philip R.
Published: January 2016

The effects of five drugs‐diazepam, triflupromazine, butabarbital sodium; meprobamate, and chlordiazepoxide‐upon the electrocardiograms of 4 subjects with chronic hyperventilation were compared at rest and after 2 minutes of forced hyperpnea. Chlordiazepoxide was the only one which consistently appeared to inhibit the electrocardiographic alterations consisting of ST segment depression, and less frequently influenced the T wave lowering or inversion. The importance of avoiding the error of misdiagnosing coronary heart disease is emphasized. Exact mechanisms for the hyperventilation‐produced electrocardiographic distortions are not yet fully understood. A “blocking effect” by chlordiazepoxide upon certain areas of the central nervous system may postulate one factor. This medication may be useful in differentiating the electrocardiographic patterns of hyperventilations from those of organic cardiac origin. Similar additional applications of chlordiazepoxide and other psychotropiC agents merit further study.
Absorption efficiency and excretion profile of a prolonged‐action form of chlorpromazine
Authors: Sugerman A. Arthur , Rosen Earl
Published: January 2016

In a rigidly controlled study, equal dosage regimens of chlorpromaZine (CPZ) tablets and sustained release capsules were compared to determine whether one dosage form was more efficient than the other in delivering the drug for absorption. Comparisons were made by determining the levels of CPZ metabolites recovered from the urine of 15 schizophrenic patients taking the two dosage forms in successive courses. Determinations were made at selected intervals during drug administration over an 11 day period and for 2 days after the drug was discontinued. The determinations showed that the two forms are equally efficient, that CPZ is as available for absorption from sustained release capsules as from tablets. They also showed that CPZ from the capsules is absorbed over a longer period than from the tablets. The pattern of urinary recovery from the sustained release capsule paralleled that from the standard tablet regimen. Variation in urinary recovery from subject to subject was no greater with the sustained release capsule than with the standard tablet regimen it is intended to replace.