bluuebunny/crossref_metadata_2025 huggingface dataset:
Part I. General problems in the selection of drugs for clinical trial
Authors: Zubrod C. Gordon
Published: January 2016

My task in this symposium is to raise some general questions without trespassing upon the specific data to be presented by other participants. We have been asked to emphasize “the unhackneyed, the new, the provocative, and the serious unsettled problems.” In this general essay, it is impossible for me to meet the first three of these standards, but it is easy enough to undertake the last, for I shall deal entirely with the problem of how the clinician, who has the ultimate responsibility, reaches the decision to administer a new drug to man. We are a little better off than, say, an Egyptian high priest at the bedside of a dying Pharaoh, wondering fearfully if he should take a chance on giving that new herb. Though the stakes are different, we are perhaps brothers in spirit, for we still face the same question: What is a reasonable basis for trying a new drug in a sick fellow man?
Quantitative studies in humans on the antagonism of lysergic acid diethylamide by chlorpromazine and phenoxybenzamine
Authors: Murphree Henry B.
Published: January 2016

In human volunteers, 198 trials were made to determine the threshold dose for recognition of lysergic acid diethylamide (LSD‐25) and the effect upon this of chlorpromazine and phenoxybenzamine. The threshold dose of LSD was determined to be 20 P‐g or 0.260 to 0.295 P‐g per kilogram. Chlorpromazine, in a dose of 25 mg., given 30 minutes beforehand or phenoxybenzamine, in a 10 mg. dose, given at the same time blocked recognition of this dose of LSD, i.e., raised the threshold. The same dose of chlorpromazine when given at the same time as or 30 minutes after LSD did not block this recognition. Neither chlorpromazine in this dosage nor phenoxybenzamine in doses up to 30 mg. had any significant physiologic or subjective effect. The results suggest that the mechanisms through which these compounds block the recognition of LSD are different from those producing their peripheral autonomic effects. Henry
Some metabolic aspects of tetracyclines
Authors: Shils Mauriee E.
Published: January 2016

The clinical literature is reviewed, and new data are presented concerning the increased urinary nitrogen losses which may occur in patients with tetracycline antibiotics. The nitrogen losses may be substantial enough in some to result in negative nitrogen balance. A recently reported effect of tetracycline is the increased excretion of sodium. This may be unrelated to the systemic nitrogen‐losing effect and reflect a diuretic action on the kidneys. Potassium losses are less significant, being at most those expected to accompany the nitrogen losses.
Some pharmacologic actions of yohimbine and chlorpromazine in man
Authors: Ingram Charles G.
Published: January 2016

Yohimbine was found to produce psychic and autonomic changes resembling anxiety in man. Chlorpromazine, reserpine, amobarbital and atropine modified the response to yohimbine. Both reserpine and amobarbital reduced the drug's psychic and autonomic effect, while atropine decreased the pressor response to yohimbine. Chlorpromazine acted paradoxically, potentiating both psychic and autonomic responses.
Part V. An ametric approach to bioassay
Authors: Bross Irwin D. J.
Published: January 2016

In the past decade, the controlled clinical trial has tended to become the basic instrument in clinical pharmacology and other areas of medical research. The remarkably rapid and widespread acceptance of this new instrument should not blind us to its limitations. The controlled clinical trial is a somewhat ponderous and rigid instrument, and if it should freeze in its present imperfect form, it could become an obstacle to future research progress. One way to avoid this fate is to continually add new ideas and techniques to the current ones. A relatively new approach‐the ametric approach‐I believe will be increasingly important in future research studies. In order to provide a more concrete and speCific discussion, I am going to consider the application of the ametric approach to a particular experimental situation.
Part VI. Difficulties in extrapolating data on metabolism of drugs from animal to man
Authors: Brodie Bernard B.
Published: January 2016

Numerous difficulties are met in applying data obtained from animals to man. One of the most important of these is the factor of species diHerences in the metabolism of drugs. But an additional factor, usually ignored in the design of clinical experiments, is individual variability in the rates of drug metabolism in man.
Experimental perfusion system utilizing the rabbit Vx‐2 carcinoma: II. Correlative studies of in vitro sterilization of Vx‐2 cells with results of perfusions in rabbits and in patients
Authors: Mori Shyunichi , Clarkson Bayard , O'Connor Annabel , Lawrence Waiter
Published: January 2016

The effect of exposure to six chemotherapeutic agents incubated with Vx‐2 carcinoma cells in vitro has been determined by injecting cells into rabbits. 5x‐Fluoro‐2'‐deoxyuridine, methotrexate, and cyclophosphamide failed to cause sterilization of Vx‐2 cells in vitro and had little influence on subsequent tumor growth. HN2, actinomycin D, and mitomycin C all produced sterilization of Vx‐2 cells during in vitro incubation. The minimal sterilizing concentration of each of these drugs was established.

The results of the in vitro tests were compared with the plasma concentration in the perfusion circuit during experimental rabbit hind limb perfusions as well as during pelvic perfusions in patients using these same drugs when suitable assay procedures were available (5‐fluoro‐2'‐deoxyuridine, methotrexate, actinomycin D, and mitomycin C).

Except for cyclophosphamide, there was generally good correlation between the results of the in vitro tests with Vx‐2 cells and the therapeutic effect of perfusions.
The analog computer and plasma drug kinetics
Authors: Taylor J. D. , Wiegand R. G.
Published: January 2016

Some uses of a general purpose analog computer are described in relation to the kinetics of drug absorption, distribution, arul disappearance as measured by plasma concentration. A study of oral sustained‐release preparations is given in detail. Some possible future uses of the computer are discussed with relation to simulation of complex models.
Part XIII. Problems in the evaluation of gastrointestinal drugs
Authors: Kirsner Joseph B. , Rubio Carlos E. , Mlynaryk Peter , Reed Peter I.
Published: January 2016

The evaluation of drugs in gastroenterology often has been characterized by the philosophy of post hoc, ergo propter hoc and by a lack of sophistication about the essentials of an objective, controlled drug testing program. Several pertinent problems in the appraisal of gastroenterologic drugs will be considered in this article.
Part XIV. Problems in the clinical evaluation of sex steroids
Authors: Kupperman Herbert S.
Published: January 2016

Frequently, the clinical pharmacologist must call forth all of his ingenuity and clinical experience to design appropriate studies to be able to evaluate objectively the effectiveness of various sex steroids in man, particularly when the clinical appraisal is based on the patient's complaints rather than on a specific end point. The patient's subjective impressions may be so nebulous that the results of clinical investigations that are dependent upon them may be widely divergent. On the other hand, when more definitive and measurable effects of the steroid can be observed, the clinical evaluation may be accomplished in the same way as a doseresponse curve in animal studies. However, even when quantitative analyses may be applied, variable results may be noted because of differences in techniques and marked biologic variations. Inconsistencies in the activity of a steroid may be observed in different laboratories even though the same preparations and doses are used. It should be emphaSized that while laboratory procedures may be used in drug evaluation, they do not automatically confer precision upon the analyses, particularly when the activity that is being analyzed may merely represent a rough measure of biologic activity or degradation.
Clinical investigation of a new phenothiazine compound, methdilazine
Authors: Taylor Cyril , Gardier Robert W. , Stoelting Vergil K. , Dallas Mary E.
Published: January 2016

The applicability of new phenothiazine compound, methdilazine, to the clinical practice of anesthesiology was examined in 527 adult patients. Methdilazine in a dose of 25 mg. by intramuscular injection, when combined with 50 mg. of meperidine, was found to be a useful drug for the preanesthetic preparation of the surgical patient. The patients who had received methdilazine were more drowsy after operation than those in the placebo group but could be readily aroused. The preanesthetic administration of the drug did not appear to offer any protection against postoperative emesis.

The use of methdilazine in the prevention of postoperative emesis was studied follOWing the intramuscular injection of 12.5 mg. at the termination of anesthesia. There was a significant decrease in emetic symptoms in the 3 hour postoperative period. Postanesthetic drowsiness and hypotension were minimal. Methdilazine was administered to patients during the first 24 hour postoperative period. These patients were given 50 mg. of meperidine whenever they requested an analgesic drug to relieve their pain. It was found that the patients who had received methdilazine had a significantly greater requirement for meperidine than those in the placebo group. It was concluded that methdilazine exhibited analgesic antagonism.
Human pharmacology of tranquilizing drugs
Authors: Domino Edward F.
Published: January 2016

The widespread confusion in the classification of various tranquilizing drugs is due to the fact that there are no specific tranquilizers at this time. All available drugs have numerous pharmacologic actions in addition to ataraxia. Some of the newer drugs used to relieve anxiety are related pharmacologically to the well‐known classic sedative and soporific compounds. Some agents, like chlorpromazine and reserpine, etc., have much less soporific effect but do have other marked pharmacologic actions. The position of the reviewer is that there are no truly specific tranquilizers and that most central nervous system depressants in proper dose or circumstance may be used clinically in man to relieve anxiety and produce tranquilization. The concept of the dose‐response relationship of these agents is discussed. Drugs with relatively flat dose‐response curves for central nervous system depression tend to be the most useful in relieving anxiety without producing too many undesirable actions.

The pharmacology of several selected agents and related congeners is discussed in detail. These include the substituted phenothiazines, the Rauwolfia alkaloids, meprobamate, and chlordiazepoxide.
Part XVIII. Data management
Authors: Roach Charles J.
Published: January 2016

Data management is the field devoted to determining how data is collected, recorded, stored, retrieved, analyzed, and displayed. In short, it is concerned with the choice and use of data processing techniques and equipment. Far too little consideration has been given to data management in medical research studies. There have been many instances in which more careful consideration of the procedures for handling data at the beginning of a study would have made a Significant difference either in the effort expended or the results achieved.
Correspondence
Authors: Fisch Solomon , DeGraff Arthur C.
Published: January 2016

In the July‐August issue, Seymour H. Rinzler contributed an article to the Symposium on Clinical Drug Evaluation and Human Pharmacology entitled “Part XII. Assessment of Antianginal Agents.” On page 508, Doctor Rinzler referred to our presentation at the 1960 meeting of the American Therapeutic Society held at Miami Beach, Florida. Doctor Rinzler's citation of our investigations bears no resemblance to the text as read nor to the abstract as published in the program of that meeting.
Acetohexamide: Comparison with other sulfonylurea compounds in the treatment of diabetes mellitus
Authors: Boshell Buris R. , Wilensky Allan S. , Barrett James C. , Almon John V.
Published: January 2016

A new oral hypoglycemic agent, acetohexamide, is compared with four other sulfonylurea drugs in 70 patients with diabetes mellitus, the majority of whom had had either primary or secondary failure with other oral hypoglycemic compounds.

Of the 70 patients studied, 43 per cent responded to acetohexamide, maintaining fasting blood sugar levels under 160 mg. per 100 ml. Only 24 per cent of the 70 patients maintained fasting blood sugar levels under 120 mg. per 100 ml. The primary response to acetohexamide was equal to or better than that noted in the patients treated with chlorpropamide, tolbutamide, azepinamide, and cycloheptolamide. Approximately 25 per cent of patients who had failed to respond to other sulfonylurea compounds responded to acetohexamide.

Preliminary studies reveal no serious toxicity. No consistent effects on serum cholesterol levels or thyroid activity were noted.
Part I. Environmental and occupational cancer hazards
Authors: Hueper W. C.
Published: January 2016

Cancer, like all other diseases, is not a mysterious phenomenon of spontaneous creation but the result of the action of definite chemical and physical, animate and inanimate, endogenous and exogenous pathogenic agents. It should therefore be possible to eradicate cancer hazards and cancer by preventive and therapeutic measures. Although both methods will have to be applied to achieve a reasonable degree of cancer control, it is obvious that for humane and economic reasons, the use of effective preventive procedures is preferable to curative procedures.
Part V. Pharmacodynamics of carcinogenic azo dyes, aromatic amines, and nitrosamines
Authors: Weisburger John H. , Weisburger Elizabeth K.
Published: January 2016

In this review we touch upon factors affecting the carcinogenicity of three broad classes of chemicals: the carcinogenic azo dyes, the aromatic amines, and the alkyl nitrosamines. Present knowledge of their mode of action indicates that they share some points in common but differ in other respects.
Drugs and the fetus
Authors: Friend Dale G.
Published: January 2016

Although considerable information has been accumulated concerning the passage of drugs through the placenta and their effect on the fetus, unfortunately little attention is paid to this aspect of drug therapy, and, on the whole, there has not been any concerted effort to bring this type of information to the attention of physicians. However, the recent thalidomide episode has stirred up a great deal of interest in this phase of pharmacology. The excellent review by Baker2 should be read by everyone interested in the subject.
Estimating the acceptability of morphine and noracymethadol in postpartum patients
Authors: Gruber Charles M. , Baptisti Arthur
Published: January 2016

Single oral doses of morphine and noracymethadol were administered to postpartum patients for the relief of pain. Change in pain intensity was found to be directly proportional and relief of pain was found to be inversely proportional to initial pain. Effectiveness was determined by summing these two estimates of analgesia. Drug effectiveness was estimated 1, 2, 3, 4, and 6 hours after administration. The frequency and intensity of other symptoms were estimated 6 hours after drug administration. A double‐blind control was used.

Capsules containing blank were administered to 200 patients. Doses of 15, 30, 60, and 90 mg. morphine were administered to 50 patients (6 patients received 120 mg.). Doses of 2.5, 5, 10, 20, and 30 mg. noracymethadol were each administered to 50 patients (18 received 40 mg.).
Effects of addiction to intravenous heroin on patterns of physical activity in man
Authors: Fraser H. F. , Jones B. E. , Rosenberg D. E. , Thompson A. K.
Published: January 2016

Physical activity measurements were made during 30 days of placebo administration followed by 60 days of addiction to intravenous heroin. The experimental design was double‐blind. Five prisoner addicts served as subjects. The daily measures of activity selected were: (a) hours lying horizontal on the bed, (b) hours of sleep, (c) hours off the research ward, and (d) miles recorded on a pedometer.

The several activity measurements correlated well. The experiments indicate that techniques may be used to measure major daily activities which require minimal directed participation by the subject and which do not Significantly influence degree and quality of activity. Compared with placebo, heroin increased activity when given in single intravenous doses or in repeated doses for 3 or 4 days, but depressed activity when chronically administered over a longer interval. When patients chronically received heroin they showed a pronounced tendency to retreat from all forms of activity and social contacts, and to go to their rooms to lie alone on their beds, eyes closed, frequently with radios turned on, “nodding” (sedated, but usually not sleeping).

Clinical observations and pursuit rotor tests indicate that the depressant effects on activity observed during chronic heroin administration were not due to debility or to psychomotor impairment but rather suggest a reduced responsiveness of the patient to ambient stimuli.
Pharmaceuticals for prolonged action
Authors: Nelson Eino
Published: January 2016

During about the last ten years the pharmaceutical industry both here and abroad has become increasingly active in the fabrication of dosage forms intended to impart prolonged, sustained, or long‐acting effect from their contained drug. A large number of papers concerned with their evaluation continue to appear in both the clinical and the scientific literature.
Poison control centers: Their purpose and operation
Authors: Adams William Curtis
Published: January 2016

Poison control center activity is a coordinated community effort the scope of which is dependent upon interest and the financial support available. Prevention and treatment are equally important aspects of every program. There is a tremendous need for research to improve treatment techniques, to develop appropriate experimental models, to improve data‐collecting techniques, and to find more effective methods for teaching preventive measures.
Clinical pharmacologic observations of the effects of ajmaline in chronic atrial fibrillation
Authors: Dick H. Lenox H. , McCawley Elton L.
Published: January 2016

AjmaTine, an alkaloid which contains the quinuclidine ring, is closely related to quinidine; in quinidine, the quinuclidine ring is joined to quinoline, while in ajmaline, which is derived from a species of Rauwolfia, it is combined with the reputedly less toxic indole nucleus. Ajmaline was administered by slow intravenous drip to patients with chronic, sustained atrial fibrillation, some of whom also had frequent premature ventricular sY5toles. Small doses of ajmaline eliminated the premature ventricular systoles although the atrial arrhythmia persisted. Larger doses of ajmaline restored normal P wave activity, but complete A‐V block developed. When A‐V block was prevented by small doses of procaine amide, ajmaline converted atrial fibrillation to regular sinus rhythm for short periods.
Human cardiopulmonary effects of doxapram, a respiratory stimulant
Authors: Wasserman Albert J. , Richardson David W.
Published: January 2016

In the experimental animal, doxapram (l‐ethyl‐4‐(2 morpholinoethyl)‐3,3‐diphenyl‐2‐ pyrrolidinone hydrochloride hydrate) was a potent, centrally acting respiratory stimulant. Doxapram was infused intravenously in closes of 23 to 320 mg. in 13 humans (11 with obstructive pulmonary emphysema and 2 with severe cerebral vascular disease). In each, minute ventilation increased within a few seconds after beginning the infusion. In 12, arterial oxygen tension increased, and in 11, arterial carbon dioxide tension decreased. Mean brachial arterial pressure increased in 12. Mean pulmonary arterial pressure rose in 2 subiects with pulmonary emphysema and in 3 anesthetized dogs. Oxygen consumption and cardiac output did not change significantly. There was a greater improvement in oxygen tension than in carbon dioxide tension, suggesting that doxapram not only increases alveolar ventilation but also improves centilation‐perfusion relationships in subiects with emphysema. Doxapram may be useful in the treatment of respiratory depression associated with chronic pulmonary disease. The systemic and pulmonary pressor effects and the development of dyspnea when larger doses are administered are limiting factors.
Hemolytic effects of drugs and chemical agents
Authors: Prankerd T. A. J.
Published: January 2016

Three different modes of action may be envisaged by which red cells are destroyed in the body by chemical agents. In the first instance there may be a direct interaction between cell and drug, in the second the cell may be predisposed to damage by its own inherent chemical abnormality, whereas, in the third, cell destruction is brought about by the formation of a red cell antibody. These different mechanisms are discussed and, where possible, chemical agents known to produce hemolytic reactions are considered as illustrations of these mechanisms. Since our knowledge of pathogenesis must succeed our knowledge of the occurrence of disease, it is impossible in many instances to ascribe a particular mechanism to a particular agent.

The rapid growth of knowledge in this field has revealed chemical bases for individual susceptibility to several groups of drugs and has had wide repercussions in other scientific fields.
What does the laboratory worker expect from clinical trials?
Authors: Bloch Hubert
Published: January 2016

Methods of preliminary exploration of drugs are analyzed. There are serious limitations to preliminary testing in the animal and to the preclinical testing in man. Some acute drug effects cannot be determined by animal experimentation: unpleasant taste, slight nausea, color vision disturbance, tinnitus, dizziness, etc. Some chronic effects on the liver, bone marrow, and other organs cannot be detected in the animal because they are characteristically human and often are not detected in man until the drug is given to hundreds of thousands of patients. It is suggested that greater "buyer resistance" by physician and patient would lead to reduction in the number of new drugs and greater concentration on aspects of drug development and application that would make for greater safety in their use.
Metabolism of barbiturates in man
Authors: Mark Lester C.
Published: January 2016

Barbiturate effeets in man are limited by various proeesses. These include redistribution of unehanged drug within the body, development of toleranee, renal exeretion, and metabolie transformation. Biotransformation of barbiturates is mediated primarily by mierosomal enzyme systems residing in the liver. Yet, beeause of the abundant reserve eapacity of this organ, barbiturates need rwt be withheld from patients with liver disease unless the aeeompanying funetional impairment is extreme. Side ehain oxidation is the major meehanism of inactivation of barbiturates in vivo; 5‐dealkylation has also been deseribed. Ring cleavage, of theoretieal import, has still to be demonstrated in man. The products of other metabolie pathways sueh as N‐demethylation, desulfuration and (if verified) N‐methylation retain pharmacologic activity; these are not mechanisms for termination of barbiturate effect. Barbiturates may conveniently be divided into two groups according to whether their rate of metabolism is measured in days (long‐ and medium‐acting barbiturates) or in hours (anesthetie and short‐acting barbiturates). None is metabolized rapidly. Aeeeleration of mierosomal enzyme activity indueed by drugs and other eompounds, amply documented in animals, may ultimately prove a signifieant factor in barbiturate metabolism in man, whose drug history is often complex.
Observations on the human pharmacology and addictiveness of methotrimeprazine
Authors: Fraser H. F. , Rosenberg D. E.
Published: January 2016

Methotrimeprazine, a derivative of chlorpromazine, has been evaluated for addictiveness by subcutaneous administration to former opiate addicts. It does not induce morphinelike effects when given in single doses, and only partially suppresses abstinence from morphine. When given chronically its effects were disliked and it did not induce physical dependence. Therefore, it does not possess morphinelike addictiveness.

Sedation and postural hypotension are conspicuous pharmacologic effects of methotrimeprazine, and may greatly impair its clinical usefulness. Insofar as evaluated, rectal body temperature, respiratory rate, and systolic blood pressure (horizontal) were not affected by methotrimeprazine. No extrapyramidal symptoms were observed. All subjects retained a good appetite, and showed a moderate gain in body weight while receiving methotrimeprazine chronically.
III. Pentobarbital sodium in prolonged‐action form compared with conventional capsules: Serum levels of drug and clinical effects following acute doses
Authors: Hollister Leo E. , Kanter Saul L. , Clyde Dean J.
Published: January 2016

Twelve subjects were given acute 200 mg. doses of pentobarbital sodium in four trials at weekly inteTIJals. Two doses were administered as conventional capsules; two as proprietary prolonged‐action preparations (Gradumet). The order of administration was randomized.

Mean serum levels of pentobarbital sodium were cOnsistently higher following the capsules, although only significantly greater than from the prolonged‐action medication at 2 hours. First trials of the capsules showed significantly higher levels of the drug than second trials at 4, 8, and 24 hours. No significant differences were found between successive trials of prolonged action medications; however, the range of serum levels was COnsiderable, with much variation within as well as between subjects. Global estimates of the effects indicated that for most subjects the capsule dose had greater intensity and duration. Capsules also appeared to have appreciably more effect as determined by the Clyde mood scale at 2 and 4 hours, but less at 8 hours.

No advantage could be found for the prolonged‐action form, which appeared slightly less efficient than the capsules. Biologic variability between trials using the same subject may supersede any advantages of specific pharmaceutical preparations of drug.
Evaluation of actinospectacin in urinary tract infections
Authors: Vineyard John P. , Mays Benita M. , Sanford Jay P.
Published: January 2016

Actinospectacin is a broad‐spectrum antibiotic which has been demonstrated to be effective in vitro against a variety of gram‐negative bacteria.

A comparison of the in vitro activity of actinospectacin with other antibiotics against 827 recent clinical isolates of gram‐negative bacteria demomtrated that 41.6 per cent were inhibited by 20 I‐'g per milliliter or less of antinospectacin; this activity was intermediate in comparison to that of agents now in use. Sixteen patients with urinary tract infectiom were treated and clinical improvement occurred in all, with bacteriologic cure in 9. The occurrence of actinospectacin‐resistant organisms in 5 patients suggests that the in vivo development of resistance will limit the usefulness of this drug as the sole antimicrobial agent in the therapy of urinary tract infections.
The effects of drugs used in labor on the fetus and newborn
Authors: Moya F. , Thorndike V.
Published: January 2016

In his response to drugs, the newborn infant is qualitatively arul quantitatively different from the mother arul even the same infant several months hence. The newborn shows marked susceptibility to the depressant effects of drugs used in labor. This heightened sensitivity is related in part to increased permeability of the blood‐brain barrier, inefficient renal function, absence of microsomal enzymes necessary for drug metabolism, arul asphyxia and physical trauma associated with the delivery process. Drugs used during labor arul delivery are considered in terms of their transmission across the placenta arul pharmacologic effects on the fetus and newborn.
Drugs for travelers
Authors: Hoskins Donald W. , Kean B. H.
Published: January 2016

Physicians are increasingly being called upon to prepare their patients medically for international travel. Assuming appropriate immunoprophylaxis, this paper discusses the relative merits of the drugs employed in the chemoprophylaxis of tropical diseases such as malaria, African trypanosomiasis, and amebiasis. In addition, drugs useful for the prevention or relief of motion sickness and the diarrhea of travelers are also considered. It is hoped that a review of the pharmacology and clinical application of such drugs will aid the physician in the medical preparation of prospective travelers.
Legal considerations in drug research
Authors: Smith Austin
Published: January 2016

Legal questions and their answers can be provided by lawyers more factually and more revealingly than by me. In fact, in the literature there are many papers that bear'to some extent on this subject. So in fairness to the members of this audience I should suggest that the writings of experts on this subject be read. For whatever assistance it may provide I would be glad to furnish on request a bibliography even though it may not be complete.
The effect of the new F.D.A. regulations on the drug industry
Authors: Beyer Karl H.
Published: January 2016

Since the proposed regulations regarding clinical investigation of new drugs were published in the Federal Register, the pharmaceutical industry, the clinical investigator, the Food and Drug Administration itself have been plunged into a tremendously disruptive and costly activity. The Food and Drug Administration may not have realized all the problems that the new regulatioru have created. However, without their gUidance on policy and a mutual sense of trust and helpfulness, the industry cannot effectively approach some of the problems relating to the delineation of authority and responsibility of clinical investigators, the role of clinical pharmacologists in the initial assessment of new drugs, the basis for assessment of utility of numerous prescription drugs cleared by the F.D.A. on the basis of safety prior to Oct. 10, 1962, and the reporting and collation of adverse reactioru. Wisely and efficiently administered, the new regulations can go a long way toward raising the standards of drug research, but it is clear that the pharmaceutical companies will be called on for still greater total research capability and expenditures if we are to maintain, in this new environment, the tremendous strides that have been made in the advancements of therapy in our generation.
Thyroid analogues and coronary insufficiency
Authors: Winsor Travis , Poole John , Trotter Donald
Published: January 2016

Studies with certain dextro‐ and levorotatory forms of thyroid show a definite lowering of blood cholesterol in euthyroid cardiac patients with angina pectoris. However, all of these agents aggravated angina pectoris in some patients and necessitated stopping the drug or reducing the dose. Large doses of DT 4 increased pulse rate, widened pulse pressure, increased muscle circulation, and increased the circulation index.
The modern treatment of shock based on physiologic principles
Authors: Lillehei Richard C. , Longerbeam Jerrold K. , Bloch Jack H. , Manax William G.
Published: January 2016

The hemodynamic disturbances resulting from shock due to hemorrhage or endotoxins and the results of several methods of treatment are presented. The experimental data indicate that vasopressors intensify the visceral vasoconstriction, ischemia, and loss of capillary integrity characteristic of severe shock. The benefical effects of corticosteroids or phenoxybenzamine combined with volume replacement are indicated.

The hemodynamics of shock appear to be similar in man and animals, although the visceral organ which suffers the greatest insult varies among the species. This concept of a basic hemodynamic mechanism of shock gains further support from the fact that the same therapy in dog and man produces similar results.

In treating patients with actual or suspected bacterial shock, we prefer a regimen of hydrocortisone, plasma to replace volume loss, specific antibiotic therapy, and surgical intervention when necessary to eliminate the source of infection. Hydrocortisone is used in preference to phenoxybenzamine because it has a more subtle effect on vascular tone and is less likely to cause further hypotension. Plasma is preferred to low molecular dextran because of our concern over the combined effects of endotoxin shock and dextran on basic blood clotting mechanisms in man.
The usefulness of useless knowledge
Authors: Modell Walter
Published: January 2016

My title is taken from an address given by Abraham Flexner 25 years ago at the opening of the Squibb Institute for Medical Research. I admit the plagiarism without embarrassment because I knew Dr. Flexner well for most of my life and felt the depth of his concern for true learning, so that I am confident he would have given his approval to the use to which I am going to put his paradox. In his address he concluded that we should “continue our quest for the useless as well as the useful, confident that in the long run both will inure to the benefit of humanity, as they have already done. …” He felt that true scholarship was irresistible and, in addition, could be profitable. As an example, he used the abstruse and remote calculations of Clerk Maxwell on magnetism, made with no concern for their utility, which were absolutely essential to the practical invention of wireless telegraphy by Marconi. Though not in the apocalyptic terms now justifiable, in 1938 Flexner had the foresight to predict that the researches into atomic structure of Rutherford, Bohr, Millikan, and Einstein, made out of sheer curiosity, would have revolutionary effects on modern life, just as the discoveries of Ehrlich, Pasteur, Koch, and Theobald Smith, who were following only their noses, led to veritable revolutions in medicine. That this is a fundamental and continuing truth is demonstrated by the effects of the nonutilitarian researches of Fleming, Dubos, and Waksman, which provided the basis for the modern revolution in the treatment of infectious disease.
Reduction of the central effects of tryptophan by a decarboxylase inhibitor
Authors: Hodge James V. , Oates John A. , Sjoerdsma Albert
Published: January 2016

Administration of L‐tryptophan to animals and man following monoamine oxidase inhibition produced characteristic neurological abnormalities which were chiefly excitatory in nature. Large doses of tryptophan in gUinea pigs also produced hyperpyrexia, and death followed in over 80 per cent of the animals. Pretreatment with a potent, centrally active decarboxylase inhibitor, Ro 4‐4602, diminished or prevented the neurological abnormalities abolished the hyperpyrexia in gUinea pigs, and reduced the animal mortality rate to below 10 per cent. Serotonin levels rose in the brains of guinea pigs after tryptophan but failed to do so when the tryptophan followed treatment with Ro 4‐4602. These results favor the conclusion that the effects seen after tryptophan administration are caused by its amine metabolites and not by the amino acid itself. The administration of L‐tryptophan to man under proper conditions provides a useful means of evaluating decarboxylase inhibition within the central nervous system in vivo and is the first such method to be described.
Pargyline hydrochloride, a new antihypertensive agent
Authors: Sutnick Alton I. , Fewell J. William , Esbenshade John H. , Soloff Louis A.
Published: January 2016

The nonhydrazine monoamine oxidase inhibitor, pargyline, was evaluated for antihypertensive response in 25 outpatients. Twenty‐one subjects (84 per cent) demonstrated an orthostatic fall in blood pressure, while a supine response was noted in only 12 (48 per cent). The most common and serious complication of treatment involved signs and symptoms of coronary, cerebral, and renal insufficiency. This occurred to some degree in 16 subjects (64 per cent), but in 13 merely involved symptoms of postural hypotension. In 6 of these patients the symptoms were extremely mild. Other side effects included weight gain resulting from fluid retention, increase in appetite, urinary frequency, nervousness, dryness of the mouth, and mild constipation. This agent is a potent antihypertensive drug, but is primarily effective in the erect position. Great care must be exercised in its administration because of ease of overdosage. The possibility of long‐term tolerance to the drug has not yet been evaluated.
Report of the subcommittee on position and status of the clinical pharmacologist in drug research
Authors: Modell Walter , Beecher Henry K. , Lasagna Louis , Maren Thomas , Pfeiffer Carl , Richards R. K.
Published: January 2016

The new F. D. A. regulations direct attention to the clinical pharmacologist and have suddenly created a broad demand for his services. Yet there is no clear‐cut de:6.nition of a clinical pharmacologist or of clinical pharmacology; there are no generally accepted standards for the education and training of clinical pharmacologists and, though a journal with such a title is now in its fourth annual volume, there exists no collected body of literature or any textbook. If only for the legal considerations, an authoritative statement on the meaning and scope of clinical pharmacology is urgently needed. Since an important public function is involved, this subcommittee puts forward the statement which follows in the hope it will lead to the establishment of appropriately high standards for clinical pharmacology and clinical pharmacologists.
Clinical Principles and Drugs in the Aging
Authors: Modell Walter , Kuperman Albert , Van Posnak Alan
Published: January 2016

If this book stayed strictly with its subject, it would be no more than half its present size. Most of its chapters do not explore the specific problems of geriatric pharmacology and therapeutics, but merely pay it lip service by providing a general resume and citing a few exceptions or indicating that it differs little in the aged from that in others. Much that is said seems to be based on reasonableness rather than on proved differences.
The uncontrolled variable
Authors: Aldous J. G.
Published: January 2016

Several weeks ago I had the privilege of hearing a practitioner of some fifty years' experience lecture to a group of medical students on the art of practicing medicine. His general theme was that despite the great increase in scientific knowledge that had taken place during his lifetime, the doctor‐patient relationship had not diminished in importance. He was not a therapeutic nihilist and neither am I.
Effects of carbon dioxide inhalation upon cerebral blood flow
Authors: Kuhn Robert A.
Published: January 2016

A method of coupling indirect brachial artery injection with high‐speed film changing in order to investigate the effects of inhaled CO2 on cerebral blood flow is described. Inhalation of 95 per cent oxygen and 5 per cent carbon dioxide results in increased arterial flow and increased numbers of visible vessels. The site of this effect is thought to be the arteriole‐capillary network.
The use of metyrapone as an aldosterone antagonist
Authors: Davies M. S. , Hetzel B. S. , Kearney G. M. E. , Wilson G. M.
Published: January 2016

The use of metyrapone as an aldosterone antagonist was studied in 11 salt‐depleted normal subjects and 8 patients with resistant edema. Studies in normal subjects showed that to achieve natriuresis with metyrapone, a large dose of a glucocorticoid (prednisolone) must be administered along with it to suppress corticotrophin. Metyrapone and prednisolone alone had no diuretic action. A diuretic effect was obtained in edematous subjects when metyrapone with prednisolone was added to the thiazide diuretic, but these drugs were not clearly shown to have an advantage over spironolactone. Metyrapone produced undesirable effects, nausea and dizziness, but none was noted with prednisolone or spironolactone. It is concluded that metyrapone with prednisolone is not suitable as a long‐term adjunct to diuretic therapy, but may be useful as a short‐term, intensive therapy in enhancing the diuretic effect of spironolactone
Complications from psychotherapeutic drugs‐1964
Authors: Hollister Leo E.
Published: January 2016

After a decade of use, the indications and abuses of psychotherapeutic drugs have become evident. The antipsychotic drugs, chiefiy the phenothiazine derivatives but also Rauwolfia alkaloids, have had a profound impact on the management of severe mental illnesses. Tranquilizing or antianxiety drugs, some of new chemical structure, others old, offer the physician a wider choice of agents for managing the difficult patients with minor emotional disorders, but have not enhanced the total therapeutic results a great deal. Antidepressant drugs still have questionable value, though very likely some are helpful for selected patients. As is the case with all therapeutic agents with pharmacodynamic actions, side reactions and complications can develop from each of these classes of drugs. They Occur often enough so that none should be used for trivial reasons. On the other hand, when clearly indicated, these drugs may be used with an acceptable amount of risk. Until more is known about the interactions between different psychotherapeutic drugs, the trend toward polypharmacy is to be deplored. Drug combinotions often produce new and unexpected complications. Fortunately, most important side reactions and complications of these drugs appear early in treatment, there being little evidence of chronic toxicity. A few complications are preventable and most are treatable.
Quantitation of stress by catecholamine analysis
Authors: von Euler U. S.
Published: January 2016

The relationships between various kinds of physical and mental stress and the activity of the sympathoadrenal system, as measured by the urinary excretion of epinephrine and norepinephrine, are briefly reviewed. Gravitational stress and exposure to cold are mainly associated with an increase in the norepinephrine excretion, indicating the importance of this hormone in circulatory and temperature controlling homeostatic mechanisms. Mental stress involving exhilarating or aggressive reactions is also associated with an increase in the norepinephrine excretion. The types of emotional stress which are moinly characterized by apprehension, anxiety, pain, or general discomfort are regularly accompanied by an increase in the epinephrine excretion. The possibility of obtaining a graded response from the adrenal medulla suggests that mental stress situations may be quantitatively evaluated by urine catecholamine analysis. The importance of obtaining an objective measure of the occurrence and degree of stress in individual subjects is emphasized.
Comparison of the nalorphine test and urinary analysis in the detection of narcotic use
Authors: Elliott Henry W. , Nomof Norman , Parker Kenneth , Dewey Marjorie L. , Leong Way E.
Published: January 2016

Several parameters of the nalorphine test for narcotic use were evaluated in prisoners with histories of prior narcotic use. Measurement of changes in pupillary diameter caused by narcotics alone or in combination with narcotic antagonists was correlated with chemical analysis of the urine for narcotics or metabolites. After one dose of morphine, the pupillary test remained positive about 4 hours, while urinalysis usually detected a single dose for as long as 36 hours. However, when morphine was administered every 6 hours for 5 days, some sub;ects gave positive pupillary tests 20 hours after the last dose. Negative pupillary tests were obtained after as many as three doses of codeine, but when codeine was given every 6 hours for 5 days more positive tests were obtained each day. Positive pupillary tests were obtained 2 to 4 hours after single in;ections of meperidine, heroin, and oxycodone, and 6 hours after methadone. The pupillary test is a useful method of screening for narcotic use, which might well be combined with chemical tests for narcotics in the urine.
Comparative effect of three antihistaminics and ethanol on mental and motor performance
Authors: Hughes Francis W. , Forney Robert B.
Published: January 2016

The effect of three antihistaminics, alone and with ethanol, on mental and motor performance has been measured. Alcohol consistently effected a significant impairment of both mental and motor performance. No significant mental impairment was observed when the antihistaminic drugs were given alone, nor was the effect of ethanol potentiated by them significantly. When motor performance was measured, none of the antihistaminics alone produced significant effects. In the presence of ethanol, the action of diphenhydramine was potentiated in two tests. The depressant property of the antihistaminics studied was much more apparent to the subjects than that of alcohol, and, yet, significant impairment was observed only with alcohol.
Developmental pharmacology
Authors: Done Alan K.
Published: January 2016

A review of basic research on immaturity and its influences on the effects and disposition of drugs, together with a consideration of known drug hazards in human infants, indicates how important may be the practical therapeutic implications of immaturity and how desparately further research and the development of testing procedures in infant animals are needed.
Evaluation of the teratogenicity of drugs
Authors: Cohen Raymond L.
Published: January 2016

The detection of the teratogenic effect of drugs remains a challenge. The sudden appearance of the problem has baffled pharmacologists. The testing of the teratogenic action of a new drttg requires a systematic and complete investigation, without bias, based on the chemical s1rttctttre or pharmacologic action. The absence of consistent sensitivity in animal species and of a valid reference standard has slowed up progress in solving the problem. We hope, however, that with research, the exchange of pharmacologic information, and the continuation of cooperation between pharmacologists, biochemists, geneticists, and clinicians, the teratogenic effect of a new drug will eventually become a calculable risk.
Self‐medication
Authors: Friend Dale G.
Published: January 2016

Man's desire to practice self‐medication is a deep and cherished trait. It is evident from historical records and extensive present‐day surveys that man has tried nearly every known natural material in the search for medicines for his ailments. Except for the antibiotics, no new natural medicine of importance has been discovered in many years. OccaSionally, an old agent is rediscovered and through improved techniques is put to better use.
The problem of the toxicologic examination of drugs in animals and their safety in man
Authors: Zbinden Gerhard
Published: January 2016

I am grateful for the opportunity to review for you and the members of the Subcommittee some of the many problems of drug toxiCity as they appear to one not only responSible for the development and initial clinical trials of new therapeutic agents, but also interested in the continued safe use of the compounds by the medical profeSSion at large. In my discussion, I will emphaSize the great variety of adverse reactions to medicaments and the multiplicity of mechanisms by which toxic drug effects are caused. It will be shown that the chance to recognize or predict harmful side effects of drugs during preclinical evaluation in animals and clinical trials in man depends on the nature and mechanism of drug action.