bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical trials based on patients' preferences
Authors: Acland J. D.
Published: January 2016

In many clinical trials, the relative efficacy of drugs has to be assessed by means of subjective measures based on the preferences expressed by the subjects. Patients are often unable to distinguish between two or more alternative forms of treatment, and a proportion of “no preference” decisions may consequently be recorded. Contrary to my previous argument,1 the proportion of “no preference” decisions does not affect the significance level attained in statistical tests based on the relative proportions of positive decisions only. It is maintained, however, that the proportion of sUch decisions alters the weight to be attached to a given difference between the numbers of positive choices for alternative treatments. As a consequence, it is argued that, in sequential clinical trials based on patients' preferences, different designs must be chosen according to the different proportions of “no preference” decisions which are expected to occur.
Studies with aspirin: Psychopharmacologic and methodologic considerations
Authors: Krumholz Wilhelm V. , Sheppard Charles , Merlis Sidney
Published: January 2016

The comparative tranquilizing effects of aspirin, a compound containing acetylsalicylic acid, phenacetin, and caffeine, mephenoxalone, and a placebo were measured in 20 male volunteer subjects with the Discomfort and Clyde Mood self‐rating scales. A Latin‐square design was followed with each subject regulating the daily dose of medication according to his subjective reaction. Each subject took each compound during consecutive 2 week periods. These data were subjected to a complex analysiS of variance. Significant mean differences were found for the fearfulness and depression scales. Individual subjects responded differently to each medication but APC was significantly the most effective compound in reducing feelings of depression and fearfulness. Some pitfalls in using the Latin‐square and crossover designs in psychopharmacologic research are discussed.
A comparison of the antihypertensive effect of chlorthalidone and hydrochlorthiazide
Authors: Bowlus William E. , Langford Herbert G.
Published: January 2016

Chlorthalidone, hydrochlorthiazide, and a placebo were compared in a double‐blind study. Both drugs used in this study were effective antihypertensive agents and produced similar electrolyte changes.
The doctor's bag
Authors: Southworth Hamilton
Published: January 2016

For seventeen years it has been a pleasure to me to talk to third and fourth year medical students about what the practicing intemist should carry in his bag. This is a subject often neglected in medical schools and about which surprisingly little has appeared in the literature since the Comell Conference published in 1943. There are two ways of approaching the subject, both used in the Comell Conference: first, to catch a series of practicing physicians without warning, make them open their bags, and take an inventory; and second, to sit down and reason out what are the items that the doctor might carry with him in order to be prepared for most of the situations and especially for the emergencies he might encounter in his practice.
Central facilitating and inhibiting mechanisms in the control of muscle tone
Authors: Magladery J. W.
Published: January 2016

Both facilitatory and inhibitory mechanisms, reciprocally influencing spinal motor nerve cell excitability, underlie the maintenance of muscle tone. Excitability patterns of motor nerve cells differ in normal persons and in patients with central nervous system lesions. Postsynaptic depolarization and hyperpolarization are ultimately responsible for the discharge of motoneurons, regardless of the source of excitation or inhibition, yet patients with high lesions do not differ (in the features studied) from normal persons. Only when central controlling pathways descending from mid and lower brain stem are interrupted do thresholds for motor nerve cell discharge drop precipitously. On the other hand, in upper motor neuron damage, there is diminished presynaptiC inhibition. The nature of hypertonus remains obscure until some consistent diminution in either the early short‐lived restraining mechanism or in the long‐lasting inhibitory process can be identified.
Differential peripheral nerve blockade by procaine and local cold
Authors: Herman Richard M. , Byck Robert
Published: January 2016

The muscle spindle with its gamma efferent innervation plays a major role in the regulation of muscle tone. In the decerebrate cat, dilute procaine applications to the nerve of the soleus selectively suppress the gamma fibers with little change in alpha fiber conduction, and with high concentrations of pracaine gamma blockade accurs before alpha inhibition. Similar results have been noted in man. Since selective control of the gamma efferents is difficult to maintain for any length of time, experimental pracedures are, therefare, limited to acute abservations. With the use of a cooling procedure on the saphenous and sciatic nerves isalated in situ, differential blockade was demanstrated for sustained periads af time. The results shawed that local cold completely suppressed the delta wave action potential in the saphenous nerve at 8.6° C. while the amplitude of the alpha potential was reduced to only 75 per cent. The effects af long‐term expasure to local cold remain to be studied if the method is to have therapeutic significance.
Pharmacology of muscle relaxants
Authors: Friend Dale G.
Published: January 2016

The chief Wipects of the modern concept of neuromuscular pharmacology are briefly reviewed as a basis for understanding the action of muscle‐relaxing agents. These are considered under one of two headings: (1) centrally acting, having either inhibitory action leading to diminished motor activity or facilitating action leading to increased or even uncontrolled motor activity; (2) locally acting, affecting peripheral structures. Most of the widely used muscle relaxants are of the former type, with the major effect being on polysynaptic pathways, e.g., meprobamate, carisoprodol, chlordiazepoxide, and diazepam. The advantages, limitations, and disadvantages of each are discussed. Drowsiness is a common drawback. Of these drugs, diazepam is cited as relieving muscle spasm associated with cerebral palsy and athetosis. The locally acting agents, e.g., procaine, Xylocaine, as well as toxins (diphtheria, botulism, and puffer toxin), act by interfering with nerve conduction, the release, destruction, and attachment to receptors of acetylcholine, by electrolyte alteration, and by direct action on the myofibrils, having little merit clinically. Despite the development of many centrally acting agents, a really effective and satisfactory muscle relaxant must still be sought.
Studies of analgesic drugs
Authors: Telford Jane , Keats Arthur S.
Published: January 2016

Several investigators have shown that some narcotic antagonists are potent analgesics in man, and suggested that a clinically useful nonaddicting potent analgesic could he found among the narcotic antagonists. Since these compounds are respiratory depressants as well, concern has been expressed that the use of narcotic antagonists as analgesics would be handicapped by the lack of an antagonist to its toxic effects, especially respiratory depression. This study was undertaken to demonstrate that a nonspecific analeptic could antagonize the respiratory depression induced by a narcotic antagonist. The respiratory depressant effects of pentazocine, a weak narcotic antagonist which is a potent nanaddicting analgesic in man, was used as the test object. Methylphenidate (30 mg. per 70 Kg. intravenously) significantly antagonized the respiratory depression of pentazocine (40 mg. per 70 Kg. intramuscularly) compared to a placebo in a complete crossover study of six healthy subjects. Antagonism was incomplete at 30 minutes but almost complete at 75 minutes after methylphenidate.
A clinical trial of indomethacin in rheumatoid arthritis
Authors: Katz Albert M. , Pearson Carl M. , Kennedy Joseph M.
Published: January 2016

Indomethacin, a new nonsteroidal compound, was tested as an antirheumatic drug in 97 patients. Beneficial effects were recorded as excellent in 6, good in 23, and fair in 12. The drug was discontinued in 50 patients, and 6 others were lost to follow‐up. The most common reason for discontinuation of the drug was gastrointestinal effects.1 Peptic ulcer developed in 6 patients.
Treatment of acute leukemia with methylglyoxal‐bis‐guanylhydrazone (methyl GAG)
Authors: Levin Robert H. , Henderson Edward , Karon Myron , Freireich Emil J.
Published: January 2016

Methyl GAG was administered to 83 patients with acute leukemia. Significant antileukemic activity was identified in patients with acute myeloblastic leukemia who received the drug in an average daily dose of 126 to 160 mg. per square meter (4.5 per cent complete remissions). The remission rate is higher than that reported for other agents and is reflected by the median increlMe in survival from 2.5 to 6.5 months when compared to patients with myeloblastic leukemia treated with 6‐mercaptopurine. Adverse effects of methyl GAG are severe, and include mucosal ulcerations, diarrhea, phlebitis, desquamation of feet, furunculi tis, and marrow hypoplasia. The effective dose range is quite narrow; minor alterations in dose result in either greater toxicity or decreased antileukemic effect. Leukemic cells of patients with the highest response rate to methyl GAG (72 per cent) were characterized morphologically by Auer rods and/or significant granulation. Remissions lasted 4 months (median) and 4 patients had reinduction by a subsequent course. Methyl GAG has antileukemic activity which, although associated with substantial toxicity, is unique in the treatment of acute myelohlastic leukemia.
Comparative effect in human subjects of chlordiazepoxide, diazepam, and placebo on mental and physical performance
Authors: Hughes Francis W. , Forney Robert B. , Richards Alice B.
Published: January 2016

Two tranquilizers, chlordiazepoxide and diazepam, and placebo medication were studied in 18 subjects for their effects on mental and motor performance with and without small amounts of ethanol. Attentive motor performance was measured with a pursuit meter developed by the authors. Ethanol was the only drug used alone that impaired motor performance. Over‐all drug‐alcohol interaction was not significant with diazepam or chlordiazepoxide. However, in one pattern, a synergistic effect of diazepam with alcohol occurred. Mental performance was measured with a delayed auditory feedback system. The subiects had nine verbal or arithmetical tests on six different occasions on a 6 x 6 random plan. By this procedure only alcohol effected a decrease in performance scores. No appreciable additive effect of chlordiazepoxide or diazepam with alcohol (in low blood concentration) was evident.
The physiologic disposition of dichloromethotrexate‐CI36 in man
Authors: Davidson Jack D. , Oliverio Vincent T.
Published: January 2016

Pharmacologic studies were made of the urinary and fecal excretion, blood levels, metabolism, and plasma binding of 3′,5′‐dichloromethotrexate (DCM), with a radioactive chlorine label, in patients with cancer. DCM was found to differ significantly from methotrexante in that half of both oral and intravenous doses are eliminated via the bile and feces. Approximately one third of a dose is also metabolically inactivated. The existence of these alternates to the urinary pathway of elimination suggests that DCM may be a less toxic antifolic agent than methotrexate in patients with impaired renal funcion.
The intravenous toxicity of local anesthetic agents in man
Authors: Foldes Francis F. , Davidson George M. , Duncalf Deryck , Kuwabara Shigeo
Published: January 2016

The toxicity of ,two hydrolyzable (meprylcaine and isobucaine) and a nonhydrolyzable (mepivacaine) local anesthetic agents was determined in man. The drugs were administered continuously, intravenously at rates proportional to concentrations commonly used in regional anesthesia. Toxicity was assumed to be inversely proportional to the tolerated length of infusion. The results of this study were compared with those obtained in a similar investigation carried out with three other hydrolyzable (procaine, 2‐chloroprocaine, and tetracaine) and a nonhydrolyzable (lidocaine) local anesthetic agents. The results of both studies indicate that, with onc exception (isobucaine), the rapidly hydrolyzable anesthetics (meprylcaine and 2‐chloroprocaine) are less toxic than the nonhydroly.wble or more slowly hydrolyzable ones. After discontinuation of infusion, signs and symptoms of systemic tOXicity disappear most rapidly with the two rapidly hydrolyzable local anesthetics.
Termination of migraine headache by a new anti‐inflammatory vasoconstrictor agent
Authors: Sicuteri F. , Michelacci S. , Anselmi B.
Published: January 2016

Indomethacin, a new nonsteroid anti‐inflammatory agent causes headache, a marked decrease in cerebrospinal fluid pressure, and an increase in retinal arterial pressure, while it produces little and inconstant change in the pressure of the carotid and brachial arteries. Despite the headache, indomethacin was investigated in sub;ects with vascular headache because of its vasoconstrictor action. Clinical improvement similar or slightly inferior to that with ergotamine was observed.
Tranquillity‐at a price
Authors: Hollister Leo E.
Published: January 2016

Following a decade of wide clinical use, psychotherapeutic drugs are firmly established as potent and useful therapeutic agents. These drugs have sparked a revolution in the treatment of major emotional disorders, such as schizophrenia. This tremendously disabling illness, which strikes at an early age and may last a lifetime, is becoming more amenable to treatment. Hospital treatment of the insane, only recently a national disgrace, has now become more humane, more energetic, and, most of all, more effective, due largely to drug therapy.7, 9 While about 20 per cent of all hospital beds in the country are still occupied by schizophrenics, the progressive increase in numbers of hospitalized patients has halted, the duration of hospitalization has been shortened, and, in many instances, hospitalization can be avoided. Surely the introduction of the antipsychotic drugs, begun with chlorpromazine (Thorazine) and reserpine and now expanded to a large number of phenothiazine derivatives, will be noted as a milestone in psychiatry.
Respiratory sensitivity of the newborn infant to meperidine and morphine
Authors: Way W. L. , Costley E. C. , Leong Way E.
Published: January 2016

An infant body plethysmograph and end‐tidal CO2, sampling were used to study respiratory CO2, response curves in newborn male infants. CO2, response curves were obtained before and after the administration of meperidine or morphine. In infants given one third the dose of each compound established to yield equivalent respiratory depression in the adult, morphine shifted the CO2, response curve to the right and downward to a greater extent than meperidine. The greater susceptibility to morphine in the infant as compared to the adult is believed to be due primarily to a greater permeability of the infant brain to morphine.
Thioridazine blood levels in patients receiving different oral forms
Authors: Mellinger Theodore J. , Mellinger E. M. , Smith W. T.
Published: January 2016

Patients taking regular sugar‐coated tablets, a liquid concentrate, and a “sustained‐release” preparation of thioridazine showed little difference in serum levels of the drug. Typical cumulation of drug in serum took place within the first 3 to 4 days, followed by a maintained drug level. Only a slight difference in the average level of the drug could be observed during day or night with all forms of their medication and whether given once daily or in divided doses. While serum levels varied with individuals, in each there was little fluctuation from the mean average level. Substantially equal drug levels, regardless of dosage schedules or medication form, pOint to the cumulation of thioridazine.
Effects of chronic chlorpromazine administration on systemic arterial pressure in schizophrenic patients: Relationship of body position to blood pressure
Authors: Korol Bernard , Lang William J. , Brown Marjorie L. , Gershon Samuel
Published: January 2016

In schizophrenic patients, mean blood pressure differed significantly when the measurements were obtained in the standing, sitting, or supine positions. Highest arterial pressure occurred in the sitting position, and the lowest pressure in the supine position. Chronic chlorpromazine (CPZ) administration produced a significant lowering of mean arterial pressures obtained from schizophrenic patients in standing or sitting, but not in supine, positions. Chronic CPZ did not produce orthostatic hypotension but did significantly reduce the postural pressor responses produced by positional changes. Male patients showed significantly greater postural blood pressure responses in the sitting position than women, but both groups demonstrated equivalent blood pressure changes produced by chronic CPZ. Determination of upright and supine body position blood pressures in the clinical evaluation of drugs is suggested and discussed.
A comparison of the value of 500,000 I.U. tetanus antitoxin (horse) with 200,000 I.U. in the treatment of tetanus
Authors: Lucas A. O. , Willis A. J. , Mohamed S. D. , Montgomery R. D. , Steiner H. , Armitage P. , Laurence D. R.
Published: January 2016

This study is one of a series designed to determine the optimum dose of antitoxin in tetanus. Each dose was allotted at random to patients after diagnosis. With sequential analysis, the trial stopped after 270 had been treated. It is concluded that the lower dose is at least as effective as the higher.
Abstracts
Authors: Moser Robert Harlan
Published: January 2016

Case 1. A 42‐year‐old woman received 250 mg. of erythromycin estolate every 6 hours one day before and for 4 days after a stapedioplasty. Eight days after the surgical procedure she developed right upper quadrant and epigastric pain which radiated through to the back. Physical examination revealed tenderness and guarding in the right upper quadrant. Erythromycin estolate was discontinued; she improved. On the third hospital day, cholecystography revealed a nonfunctioning gallbladder; a double dose the following day permitted faint visualization.
The effect of aspirin on pain and hand blood flow responses to intra‐arterial injection of bradykinin in man
Authors: Coffman Jay D.
Published: January 2016

A new method of evoking pain by the intra‐arterial injection of bradykinin (into the brachial artery) was used in the evaluation of the analgesic activity of sodium and calcium acetylsalicylate. At the same time, hand blood flows were measured by venous occlusion plethysmography, and the plasma was analyzed for acetyl, free, and protein‐bound salicylate. The analgesic effect of aspirin appears during the second half of the first hour and continues beyond the second hour after drug administration. Bradykinin increases the hand blood flow and there is an apparent increase in flow after aspirin. No correlation could be found between the plasma salicylate level and the state of analgesia.
Acute Phospholine intoxication after intracutaneous injection
Authors: Wulfsohn Norman L. , Smith J. Crispin , Foldes Francis F.
Published: January 2016

In a healthy young male, the intracutaneous injection of 0.5 mg. echothiophate caused acute intoxication characterized by muscarinic signs and symptoms. These were severe enough to require hospitalization. They were alleviated by the administration of atropine. In a blood sample obtained 2 hours after the administration of echothiophate there was no evidence of plasma cholinesterase activity; red cell cholinesterase activity was 20 per cent of normal. In the next 19 days, there was a gradual return of plasma cholinesterase activity to near normal values. Red cell activity rose in the first few days to 60 per cent of the normal mean, dropped sharply to 20 per cent of normal between the fourth and fifth days, and remained essentially unchanged during the observation period.
Suggestions for improving drug therapy
Authors: Friend Dale G.
Published: January 2016

The increasing use of drugs and the importance of drug therapy in medicine make it important that every means possible be taken to insure that drug therapy is of the highest quality. The food and drug laws have gone far to insure drugs of proper purity for use in medicine. Only a very small percentage of drugs now on the market are not up to the accepted standards. The recent legislation signed into law by the President in July of 1965 has taken another step forward in a campaign against counterfeit or useless drugs. As enforcement becomes more adequate and proper controls are brought to bear, there will undoubtedly be a reduction in the small percentage of impure and improperly labeled drugs. For many years, responsible drug firms have taken great pride in maintaining the highest degree of purity for their products and, as anyone who has knowledge in this field knows, they are very reliable indeed. When one puts faith in a product from a responsible pharmaceutical firm, he is assured that the drug will be exactly as described. He can be sure that a satisfactory preparation will be delivered to his patients. There are, however, other aspects of drug control which have not yet been approached in a manner which insures the highest quality of drug therapy.
The effects of d‐amphetamine on errors and correct responses of human beings performing a simple intellectual task
Authors: Holliday Audrey R.
Published: January 2016

This study demonstrates that human beings performing under the treatment condition of a single dose of 10 mg. of d‐amphetamine not only solve a statistically significantly higher number of problems (adding and subtracting signed numbers) correctly than do subjects serving under a placebo treatment condition, but also make a statistically significantly lower percentage of errors. Subjects ingesting 10 mg. of d‐amphetamine do not solve more problems correctly simply because they attempt more problems. They solve more problems correctly also because they make proportionately fewer errors than do subjects ingesting a placebo. Fatigued subjects who have ingested 10 mg. of d‐amphetamine do not show the degree of decrement in performance shown by fatigued subjects who have ingested a placebo. Therefore, in comparison with the effect on the performance of the ingestion of a placebo by subjects whose performance has been degraded by a moderate amount of fatigue and who are then set to a continuous task, the effect of the ingestion of d‐amphetamine is to enhance performance. This is not to imply that d‐amphetamine enhances performance under the conditions of this study in the sense of significantly raising above the predrug level the number of problems correctly solved.
The effect of cyproheptadine on carbohydrate metabolism
Authors: Drash Allan , Elliott Jan , Langs Harold , Lavenstein A. F. , Cooke Robert E.
Published: January 2016

Cyproheptadine administration has previously been demonstrated to stimulate appetite. The present study demonstrates a depression of blood glucose by cyproheptadine. while the exact mechanism has not been determined, tentative suggestions are presented.
Penicillin G
Authors: Friend Dale G.
Published: January 2016

Penicillin is still the most important antibiotic. Even though it has been in therapeutic use for nearly a quarter of a century, it ranks as the first line of defense against many infectious diseases.
Homeopathy in the light of modern pharmacology
Authors: Guttentag Otto E.
Published: January 2016

In the light of modern pharmacology, homeopathy presents two positive aspects. It offers (1) an empirical challenge: the elaboration of the phenomenon of the inverse reaction of drugs and of a pharmacologic constitutional typology, and (2) an axiomatic reminder: the dual nature of clinical and clinical pharmacologic research.
Oral vinblastine sulfate in Hodgkin's disease
Authors: MacDonald Carlton A. , Lacher Mortimer J.
Published: January 2016

Fourteen patients with Hodgkin's disease were treated with a new oral preparation of vinblastine sulfate (VLB). All had previously experienced a remission with intravenous vinblastine prior to the oral VLB administration. Eight patients were considered to have exhibited a beneficial response to oral VLB with continued stabilization of their disease. Two patients did not have an adequate drug trial. The average duration of oral VLB treatment in those who responded was 10.4 months. Until oral VLB dose schedules are better understood we recommend that it be administered to patients who have already responded favorably to intravenous VLB. The recommended starting dose of oral VLB is 8 times the weekly intravenous dose of VLB. If possible, the total dose is divided into 2 to 3 consecutive daily doses each week. A treatment‐free interval of at least 2 days a week was maintained in all cases. Toxicity observed included nausea and vomiting, diarrhea, leukopenia, paresthesias, skin rash, and aggravation of a peptic ulcer with upper gastrointestinal bleeding. Because maintenance therapy with vinblastine is necessary to sustain a remission in most patients with Hodgkin's disease, oral VLB will probably prove to be useful.
Preliminary clinical studies with ibenzmethyzin
Authors: DeVita Vincent T. , Serpick Arthur , Carbone Paul P.
Published: January 2016

Ibenzmethyzin was administered to 35 patients with neoplastic diseases. In 6 patients, daily, semiweekly, or weekly injections of 300 to 1,600 mg. per square meter were given. The adverse reactions were gastrointestinal and neurologic: nausea, vomiting, ataxia, confusion, and somnolence. When given in daily oral doses of 125 to 300 mg. per square meter, the drug caused nausea and vomiting and bone marrow depression. With oral administration, a dose of 125 mg. per square meter with interruption rather than downward modification to prevent bone marrow toxicity is recommended. Antitumor activity was seen in 5 of 10 patients with Hodgkin's disease and one with malignant melanoma. It is suggested that ibenzmethyzin metabolism or binding at the active site may be rate limiting.
The meaning and importance of drug potency in medicine
Authors: Weatherall M.
Published: January 2016

The term “potency” is ambiguous, because it may refer to the quantity of drug necessary to produce a given effect, or it may refer to the maximum response which can be achieved with the drug. In the first sense, cyclopenthiazide is more potent than frusemide, and in the second sense the reverse is true. Potency cannot be measured in precise and absolute terms without detailed specification of the method of measurement, and then it becomes an excessively arbitrary measurement. Relative potency is more easily determined, but it also is variable according to the circumstances in which it is assessed. An approximate estimate of potency is afforded by the dose ordinarily used therapeutically. For some groups of drugs, variation in effective dose is enormous and for others, quite small. The causes of such variations are not well known, but probably involve the cumulation of several separate factors. Differences in maximal effect generally indicate a different mode of action and raise doubts about the strict comparability of the drugs concerned. Such differences have definite therapeutic utility. Otherwise high potency (in the sense of small effective dosage) has some advantages and some disadvantages to a therapist and is, at best, a minor merit in most circumstances.
Myoglobinuria after intermittent administration of succinylcholine during halothane anesthesia
Authors: Airaksinen Mauno M. , Tammisto Tapani
Published: January 2016

After the intermittent administration of succinylcholine to 24 ophthalmic patients during halothane anesthesia, 2 certain (immunochemically verified) and 5 probable cases of myoglobinuria were found. In all these patients the serum activity of creatine kinase was also elevated. These findings are interpreted as signs of probable museular injury. It is recommended that intermittent administration of succinylcholine during halothane anesthesia should be abandoned.
The use of echothiophate in myasthenia gravis
Authors: Foldes F. F. , Foldes V. M. , McNall P. G.
Published: January 2016

Echothiophate is a potent inhibitor of human plasma butyrylcholinesterase and red cell acetylcholinesterase. In vitro, plasma butyrylcholinesterase was maximally inhibited within two hours, whereas maximal inhibition of red cell acetylcholinesterase occurred after eight hours. In vivo, both enzymes were maximally inhibited in about tour hours. Echothiophate was used for the treatment of subjects whose myasthenia was poorly controlled on short‐acting anticholinesterases. In most, the initial results were good. However, in about one half of the patients it subsequently became necessary to discontinue echothiophate because good control could not be maintained with it. In one third of the patients, however, it was possible to maintain good contral with the drug for over six years. In same instances pyridostigmine supplementatian was necessary to relieve bulbar symptoms. Our experience indicates that echothiophate is most useful in the treatment of severe but stable myasthenia gravis, primarily involving the skeletal muscles. After discontinuation of echothiophate therapy, plasma butyrylcholinesterase and red cell acetylcholinesterase returned to control levels in about one hundred days.
The clinical pharmacology of vasoconstrictors
Authors: Hodge R. L. , Dornhorst A. C.
Published: January 2016

Vasoconstrictors are mainly used in acute hypotensive states, and they often succeed in bringing about at least a temporary increase in arterial pressure. Pressure is easy to measure, whereas tissue perfusion is not; but it is the latter that is the important variable, and a rise in pressure does not necessarily imply an improved circulation. In this review the human pharmacology of a variety of constrictors is surveyed. Abrief account of the abnormal physiology of hypotensive states is followed by an attempt to assess the contribution of vasoconstrictors to their management. It is concluded that, where benefit follows the use of a vasoconstrictor, it often comes from the cardiac stimulatory action of the drug rather than from a rise in blood pressure resulting from vasoconstrictor action.
Advances in control of viral infections by nonspecific measures and by vaccines, with special reference to live mumps and rubella virus vaccines
Authors: Hilleman M. R.
Published: January 2016

Vaccines have been most rewarding in their contribution to the safe and effective control of many acute infectious diseases. Additional new vaccines, such as for mumps and rubella, which are reported here for the first time, and for multiple combined forms, will be developed. Application of safe and effective immunologic adjuvants shows promise of decreasing cost and dosage and of improving immunizing performance of killed virus vaccines. Antiviral chemotherapy has shown its first successes and gives special hope to chemoprophylaxis in infections such as those caused by rhino viruses, which are of such antigenic diversity as to be beyond the scope of present hope for effective vaccination. Finally, the door has been opened to possible utilization of natural host resistance mechanisms for combating viral disease by the discovery of interferon, and this approach, in the long run, may offer more than chemotherapy. These approaches, if judiciously used, together provide a real basis for eventual control of the remaining viral diseases of significance to man.
Failure of urethane to influence early steps of pyrimidine biosynthesis in man
Authors: Ohnuma Takao , Holland James F.
Published: January 2016

The orotidylic‐decarboxylase activity in leukocytes and the urinary excretion of orotidine, orotic acid, and uric acid were determined in three patients with advanced cancer before, during, and after administration of urethane and 6‐azauridine. No influence of urethane on the biochemical changes induced by azauridine was noted. These findings cast doubt on the influence of urethane on carbamylaspartate biosynthesis in man.
The long‐acting thyroid stimulator
Authors: Dorrington Keith J. , Munro Donald S.
Published: January 2016

When iniected into suitably prepared guinea pigs or mice, the serum of some patients with thyrotoxicosis causes a prolonged discharge of radioiodine from the thyroid. There is chemical and immunological evidence that the long‐acting thyroid stimulator (LATS) responsible for this effect is distinct from pituitary thyroid‐stimulating hormone, and that the activity is inherent in specific immunoglobulin G molecules. The distribution of thyroid‐stimulating activity in the polypeptide chains of the IgG parallels antigen‐binding activity in known antibodies. As a result of these findings and the specific absorption of LATS by human thyroid endoplasmic reticulum, it has been suggested that LATS is an autoantibody to a thyroid component. This hypothesis is discussed. Using suitable concentration methods LATS can be detected in the serum of 85 per cent of thyrotoxic patients, and the level correlates with several parameters of thyroid activity. High levels of LATS are also frequently associated with localized myxedema, but the relation of LATS to the eye signs associated with thyrotoxicosis is less clear.
Pharmacological effects of drugs on the pulmonary circulation in man
Authors: Dollery C. T. , Glazier J. B.
Published: January 2016

The effect of drugs on the human pulmonary circulation has been reviewed in light of newer physiological mechanisms shown to regulate that vascular bed. If one takes the measurement of pulmonary vascular resistance (PVR) as the basic information required, surprisingly few drugs have been adequately evaluated in man. Even PVR may be affected by changes other than those produced by active vasomotion, often making its interpretation difficult. The effects of the hydrostatic gradients of pulmonary arterial and venous pressures on PVR have been discussed. Most of the evaluations of vasodilator drugs have been made in patients with pulmonary hypertension due to mitral stenosis. The suitability of these patients for such studies has lately been questioned by the finding that the increased PVR may be due to perivascular edema rather than active vasoconstriction. Most information is available on the effects of acetylcholine, although an adequate literature exists for isoproterenol, aminophylline, and bradykinin. Studies of vasoconstrictor agents have been made in subjects with normal pulmonary circulation. Although serotonin produces an unequivocal rise of PVR in animals, it does nat do so in man. The effects of the commonly used drug, norepinephrine, is still unsettled, while angiotensin and bretylium tosylate cause a clear increase in PVR.
Statistical ward rounds—1
Authors: Mainland Donald
Published: January 2016

Dr. Mainland's statistical “Notes” have heretofore been sent from time to time to a select group who have enjoyed and benefited from them. In this issue we welcome Dr. Mainland's “Statistical Ward Rounds” to CLINICAL PHARMACOLOGY AND THERAPEUTICS, for now the select group is being expanded to include the readership of this JOURNAL. The JOURNAL will be all the more useful for this additional feature which will appear in each issue. We hope that the “Rounds” will stimulate correspondence. While Dr. Mainland is not offering a consultation service, some letters will be reproduced and answered in these columns, some directly. Please write to Dr. Mainland's unit.
The hypnotic efficacy of doxylamine
Authors: Sjöqvist Folke , Lasagna Louis
Published: January 2016

The efficacy of doxylamine succinate as a nighttime hypnotic was compared with that of placebo and a standard drug, secobarbital sodium, using a double‐blind, randomized block design and replicate observations. The study was performed in 22 hospitalized patients with chronic disease who were accustomed to taking nightly hypnotics. Doxylamine, in doses of 25 and 50 mg., was found to be an effective hypnotic drug, with little difference in the performance of the two doses. Doxylamine performed generally better than secobarbital, 100 mg., but was somewhat inferior to secobarbital, 200 mg. Although the active treatments were Significantly better than placebo, 50 per cent of the patients reported satisfactory sleep on dummy medication. Side effects were mild with little difference between the different drugs and placebo except for “hangover,” which occurred more often after doxylamine and secobarbital.
The anticoagulant response to bishydroxycoumarin: I. The role of individual variation
Authors: Solomon Harvey M. , Schrogie John J.
Published: January 2016

Marked variation in anticoagulant response was observed when healthy human volunteers were given 150 mg. of bishydroxycoumarin. This variation in response could not be accounted for by individual differences in the rate of metabolism of bishydroxycoumarin since there was no correlation between the half‐life of the drug and the magnitude of the anticoagulant effect. Differences in the affinity of the receptor site for bishydroxycoumarin may be responsible for the variation in biological response observed among individuals who absorb and metabolize the drug similarly. A clinical example of marked sensitivity to coumarin anticoagulants presumably caused by increased affinity of the receptor site for the drug is presented.
General principles of computer systems
Authors: Harless William G.
Published: January 2016

Computers are machines which accept, process, and display information. Depending upon certain characteristics they are categorized as being either analogue or digital. The central processing unit for a digital computer comprises a memory section, a control section, and an arithmetic and logical unit. Extremely fast internal speeds and the many‐place accuracy of arithmetic calculations are trademarks, but the real power of a digital computer lies in its ability to take advantage of the "stored‐program concept." The fact that an analogue computer is particularly adept at solving ordinary differential equations has made it an efficient simulator of many physiological phenomena. Compared to its digital cousin the cast of this computer is low and it is a relatively simple machine from an engineering point of view. These and other factars are responsible for its popularity as a special‐purpose computer in a laboratory. It has become obvious that the virtues of both of these types of computers are important in the biomedical sciences. This need is responsible for a third type of computer called the hybrid computer. An interface is used between the analogue computer and the digital computer as a controlling facility in the hybrid system. In a true hybrid environment, either of the two types of computers may control the other at a given time.
Molindone: An indole derivative with antipsychotic activity
Authors: Sugerman A. Arthur , Herrmann Jane
Published: January 2016

In the first clinical pharmacological trial of EN‐1733A, an oxygenated indole derivative not closely related to other antipsychotic drugs, it was given to 11 chronic schizophrenic men in doses increasing from 5 to 200 mg. daily. The maximum period of administration was 13 weeks. Independent global ratings of clinical change by 2 investigators showed some improvement in at least 7 patients. Behavioral rating scales showed most improvement in the second month of therapy, at a dose level of 50 to 125 mg. daily; especially notable were improvements in disorientation, thinking and perceptual distortion, schizophrenic disorganization, and social competence. Unusual euphoria was also observed. Improvement in appetite and gain in weight occurred late in the study. Side effects included an early marked drowsiness and moderate extrapyramidal effects, mainly of an akathisic kind, with occasional tremor and dystonia.
Hypotensive Peptides
Authors: Modell Walter
Published: January 2016

The vasoactive peptides have received considerable recognition and, as a consequence, symposia on the group as a whole are common. Here is one dealing only with the hypotensive or vasodilating peptides, whose role as a group is much less well established than that of oxytocin, vasopressin, and angiotensin (Hypertensin). The book presents the proceedings of an international symposium held in October, 1965, in Florence. It consists of some 60 papers and some desultory discussion. The papers are brief and informative, yet one ends up still wondering where the hypotensive peptides stand.
The effect of formulation on phenmetrazine plasma levels in man studied by a sensitive analytic method
Authors: Quinn G. P. , Cohn M. M. , Reid M. B. , Greengard P. , Weiner M.
Published: January 2016

A sensitive method for estimating phenmetrazine concentration in plasma is described. Phenmetrazine is weil absorbed, with average peak plasma levels ab out 2 hours after ingestion and a half‐Ufe in plasma of about 8 hours. A single oral dose of 75 mg. regular tablets results in significant plasma levels for over 12 hours, with highest levels at 2 and 5 hours. A sustained‐release formulation containing the same dose pro duces lower early levels without significantly altering the subsequent blood level pattern.
Changes in serum potassium levels occurring in patients treated with triamterene and a triamterene‐hydrochlorothiazide combination
Authors: Hansen Karl B. , Bender A. Douglas
Published: January 2016

This report summarizes the changes in serum potassium levels in 583 patients treated with triamterene alone, 484 treated with a combination of triamterene and hydrochlorothiazide, and 82 treated with hydrochlorothiazide. The incidence of hypokalemia <3.5 mEq. per liter) in patients treated with a combination of triamterene and hydrochlorothiazide was 6 per cent. Hyperkalemia (>5.4 mEq. per liter) developed in 7.5 per cent of subfects to whom the combination was given, in 12 to 19 per cent of subfects treated with triamterene, and in 4 per cent of patients, especially the severely ill, treated with hydrochlorothiazide.
Effects of antibiotics on the gastrointestinal tract
Authors: Kunin Calvin M.
Published: January 2016

It will be shown in this brief review that antimicrobial agents do have a powerful and varied effect upon the entire gastrointestinal tract. Untoward complications of therapy due either to ecologic changes in the microflora or to direct toxicity are best treated by adherence to the following classic principles of antimicrobial therapy: (a) restrict treatment to specific susceptible infections, (b) use the minimum curative dose, (c) avoid the use of the drug in patients with particularly high risk of secondary reactions, (d) do not unnecessarily prolong therapy, and (e) when you suspect a drug reaction, discontinue use of the drug whenever possible rather than try to mask the effect by nonspecific adiunct therapy, and do not try to prevent it with agents which sound good in theory but whose beneficial effect has never been proved.
Pain and analgesia evaluated by the intraperitoneal bradykinin‐evoked pain method in man
Authors: Lim R. K. S. , Miller D. G. , Guzman F. , Rodgers D. W. , Rogers R. W. , Wang S. K. , Chao P. Y. , Shih T. Y.
Published: January 2016

Synthetic bradykinin WCM in;ected intraperitoneally to produce pain. The optimal individual dose of bradykinin was given every 15 minutes for 120 minutes after analgesic administration. experiments were performed double blind on groups of 16 sub;ects (4 per drug) in a random block design. The pain response WCM recorded by the sub;ect pressing one of four buttons on a pain signal box. Each button registered on a counter at a rate per second corresponding to the button number; the sum of the counts gave the weighted pain score (WPS). The latent period was recorded; it triggered a cutoff timer limiting pain responses to 4 minutes. To evaluate the effect of drugs, the WPS was expressed as a percentage of the individual control WPS and was compared by analysis of variance with the corresponding placebo or other data. Given orally, 650 mg. of aspirin, 20 mg. of dl‐amphetamine, and 100 mg. of meperidine were each analgesic, but half these doses had no such effect. The intraperitoneal in;ection of 20 to 40 mg. of Na‐CMpirin blocks the pain response to subsequent intraperitoneal in;ection of bradykinin, while the same dose given intravenously is ineffective. This suggests that aspirinanalgesia in man may be due to blockade of pain receptors at the periphery.
Studies in patients with diabetes insipidus
Authors: Ramos Guadalupe , Rivera Alfonso , Peña Jose Carlos , Dies Federico
Published: January 2016

In patients with diabetes insipidus who remained on a low salt diet, antidiuresis following the administration of saluretic drugs persisted long after the drugs were discontinued. Sodium repletion terminated the antidiuresis. The antidiuretic phenomenon occurred with mercurial diuretics, several thiazide derivatives, quinethazone, and ethacrynic acid. Antidiuresis was partially or totally inhibited by prevention of sodium or potassium losses during saluretic therapy. There was a significant correlation between antidiuresis and body fluid volume contraction. Urine was transiently concentrated by acute administration of vasopressin to a greater extent during poly thiazide therapy than during a control period. This is taken as evidence that the medullary interstitium is more hypertonic after diuretic treatment. The observed antidiuresis appeared to be secondary to the contraction of body fluid volume. The renal mechanism for antidiuresis seems to be related to enhanced proximal sodium and water reabsorption in the renal tubules and to increased medullary hypertonicity, with a larger tubular clearance of free water. The formation of free water in the urine is an important phYSiological phenomenon, which is regulated by several ontrol mechanisms and not ;ust by antidiuretic hormone activity.
Coronary disease—45 years ago and now
Authors: Master Arthur M. , Kuhn Leslie A.
Published: January 2016

That coronary thrombosis was in the past, and is now, perhaps our most important and serious disease is unquestioned. Improved diagnostic techniques, better clinical acumen, with resultant earlier recognition of the attack, more complete understanding of the disease by both physicians and the laity, and a more rational treatment have all helped to improve the outlook. Continued research can be expected to improve still further the immediate and long‐term prognosis of patients with coronary thrombosis. The remarkable accomplishments in biochemical research and imaginative operations support optimism for the future. The ultimate and probably reasonable hope is that arteriosclerosis, which is a disease entity and not an "inevitable result of aging," may be effectively prevented, and that angina pectoris, subendocardial ischemia or infarction (coronary insufficiency), and acute myocardial infarction (coronary thrombosis) will become rare clinical experiences.
Modern oral diuretics
Authors: Moser Robert Harlan
Published: January 2016

Complications of diuretic therapy in hepatic cirrhosis, by S. Sherlock, B. Senewiratne, A. Scott, and J. C. Walker. Lancet 1: 1049‐1052, 1966.
Change in receptor site affinity: A proposed explanation for the potentiating effect of D‐thyroxine on the anticoagulant response to warfarin
Authors: Solomon Harvey M. , Schrogie John J.
Published: January 2016

A healthy female volunteer was given a series of doses of warfarin before and after treatment with D‐thyroxine. A marked potentiation of the anticoagulant effect of warfarin was noted during treatment. A nalysis of the data according to the method of Lineweaver and Burk demonstrated that D‐thyroxine increased the affinity constant (Km) of warfarin for its receptor. It is suggested that this increased affinity of the drug for its receptor site is responsible for the potentiation of the pharmacologic effect.