bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of drug therapy on the uptake of radioactive fluorine by osseous metastases
Authors: Kampffmeyer Hermann G. , Dworkin Howard , Carr Edward A. , Bull Frances E.
Published: January 2016

RadioisotopiC techniques are potentially of considerable value to clinical pharmacology. Scintigrams and uptake studies are of particular interest, as they permit one to visualize lesions in many organs and to obtain simultaneously quantitative information on the degree of abnormality in the area of the lesion. Bone metastases take up increased amounts of fluorine‐18; the present study was an investigation of the effect of therapy on this abnormal uptake. In eight patients with metastatic lesions to bone, chemotherapy or hormonal therapy produced temporary improvement in five, as ;udged by roentgenographic or clinical criteria, during the first four months after initiation of therapy. Serial scintigrams and quantitative uptake studies throughout this period showed that the abnormal ratio in fluorine uptake remained unchanged, despite the other evidence of emporary regression of metastases. Although the duration of time chosen for this study was consistent with that commonly used by physicians for evaluation of the effect of a given type of chemotherapy, our results suggest that such short‐term studies must be interpreted cautiously.
Effects of an adrenal ll‐beta, 17‐alpha hydroxylase inhibitor in juvenile‐onset diabetes mellitus
Authors: Narduzzi J. V. , Sabeh G. , Weir T. F. , Cleary W. J. , Danowski T. S.
Published: January 2016

An antiadrenal compound, 2‐{p‐aminophenyl)‐2‐phenylethylamine, which inhibited adrenocortical 17‐alpha and ll‐beta hydroxylase activity in animals, was administered for 3 week periods to 10 patients with diabetes of juvenile onset in an attempt to ameliorate the severity of the diabetes and was given for a lesser period to one patient with spontaneous Cushing's syndrome. The drug did not alter the intensity of the diabetes but it produced a partial remission of the Cushing's syndrome. In diabetes, ingestion of the dl form increased urinary 17‐ketosteroids, Porter‐Silber chromogens, and ll‐desoxycortisol metabolites in 3 and possibly 4 of 5 patients. This was observed only once in 4 trials with the d form. This suggests that the 1 form is more effective than the d form in inhibiting ll‐beta hydroxylase. Inhibition of 17‐alpha hydroxylase by the d form was either minimal or absent judging from the urinary levels of Porter‐Silber chromogens and ll‐desoxycortisol metabolites. In diabetes neither the d nor the dl preparation affected the basal plasma 17‐hydroxycorticosteroids nor the rise in this index which followed upon intravenous injection of ACTH. The basal plasma 17‐hydroxycorticosteroids were markedly lowered in Cushing's syndrome.
Accidental reserpine poisoning: Clinical and metabolic effects
Authors: Loggie Jennifer M. H. , Saito Hideya , Kahn Isaac , Fenner Axel , Gaffney Thomas E.
Published: January 2016

The effects of accidentally ingested large doses of reserpine on three children ranging in age from 2½ to 4 years are described. Coma, bradycardia, and hypothermia developed in each child. Hypertension and sinus tachycardia developed in the youngest child. There was an increase in the excretion of free norepinephrine and epinephrine in 2 of the 3 children on the first day following drug ingestion. All children recovered without sequelae.
The Bayesian approach
Authors: Mainland Donald
Published: January 2016

'The problem of diagnosis has been solved, in principle, by the Bayesian approach.' This is a remark that I heard made wo or three years ago by an operations research worker in the medical field. 'The foundation stone of the Bayesian approach is a subjective interpretation of probability'‐G. J. Glasser,5 vice chairman of a university department of business statistics.
Laboratory indices in clofibrate therapy of juvenile‐onset diabetes
Authors: Narduzzi J. V. , Danowski T. S. , Weir T. F. , Alley R. A. , Vester J. W. , Moses C.
Published: January 2016

Clofibrate, 2 Gm. per day, was ingested for 12 to 15 months by 14 adult patients with diabetes of ;uvenile onset. Slight decreases in serum total cholesterol with occasional escape and in NEFA levels tcere recorded in most patients. The total triglycerides and the alpha and beta lipoprotein triglyceride and choleoterol did not change. The serum total proteins, albumin, and creatinine increased, serum globulins decreased, platelets rose, the bleedingtime was slightly prolonged, and the coagulation time shortened at the end of 12 to 15 months of observation, but these indices did not exceed the ranges of normal. Serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were higher at one month and then mturned to pretherapy values. Lactic acid dehydrogenase (LDH) and malic acid dehydrogenase (MDH) levels decreased gradually, while aldolase and cid phosphatase increased slightly. Serum alkaline phosphatase and creatinephosphokinase(CPK) were unaffected. Bromsulphalein (BSP) retention may have increased very slightly in 3 patients. Peak hyperglycemia following a glucose load was less. Serum protein‐bound iodine (PBl), renal indices, and urinary steroids, pressor materials, and gonadotropins did not change. Many of the above changes suggest slightly altered metabolic eqUilibria during drugtherapy but they may represent changes occurring independently of the drug therapy.
Bibliographies on diseases of medical progress
Authors: Harlan Moser Robert
Published: January 2016

Over a period of two years the author observed 30 patients in whom contact dermatitis due to promethazine (Phenergan) skin cream was diagnosed. All showed a positive patch test to promethazine cream, and their dennatitis had developed or been aggravated after the use of the cream. In 5 cases the lesions were suggestive of a photodermatitis. Cross‐sensitization was identified by “polyvalent hypersensitivity tests” between paraphenylene diamine in 3 cases, sulfadiazine in 1 case, and chlorpromazine (Thorazine) in 3 cases. The last 3 patients also showed positive skin tests to trimeprazine. Other patients not included in these 30 had positive patch tests to promethazine skin cream but had no evidence of clinical dennatitis.
Respiratory and subjective effects of etomide and codeine
Authors: Bellville J. Weldon , Green Jean Haber , Forrest William H.
Published: January 2016

Etomide, a new oral analgesic, was studied to determine its respiratory depressant effects in comparison to those of codeine given orally. Respiratory and subjective effects are reported. Based on this study, it is estimated that 125 mg. etomide is equivalent to 100 mg. codeine.
Clinical and statistical methodology for cooperative clinical assays of analgesics
Authors: Bellville J. Weldon , Forrest William H. , Brown Byron W.
Published: January 2016

This paper describes a method for carrying out a cooperative clinical bioassay of analgesics. The method was developed in five Veterans Administration Hospitals. The patients were largely older men with acute postoperative pain. Procedures for collecting and recording data and for automatic data processing are discussed. Uniformity trial results with morphine are reported. These data indicate the magnitude of hospital differences, patient differences, differences due to order of administration, and differences due to morphine dose. The inherent variation in the assay is reported for various completely randomized complete‐block, crossover designs. The number of patients required for specified reliability of potency estimates is presented. Statistical techniques for analysis, particularly the pooling of results from hospitals, are discussed.
Failure of probenecid to inhibit the rate of metabolism of tolbutamide in man
Authors: Brook Robert , Schrogie John J. , Solomon Harvey M.
Published: January 2016

A variety of drugs slow the rate of metabolism of tolbutamide and thus increase its hypoglycemic effect in man. Although it has been suggested that probenecid also has this effect, the present study demonstrates that this drug does not infiuence the metabolism of tolbutamide in human subjects.
Pharmacological effects in animals and normal human subjects of the diuretic amiloride hydrochloride (MK‐870>
Authors: Baba Walten I. , Lant Ariel F. , Smith Anthony J. , Townshend Mary M. , Wilson Graham M.
Published: January 2016

Amiloride is a new diuretic drug producing moderate natriuretic effects coupled with prominent potassium retention. Though chemically distinct, this compound has some structural similaritites to triamterene, which it also resembles in its effects in normal human subjects, adrenalectomized rats, and on sodium transport across the isolated frog skin. It has no appreciable effect on the urinary concentrating mechanisms. These actions suggest a primary, direct effect upon the distal renal tubule. A dose‐response relationship in man is obtained with little increase in effect above 40 mg. At lower doses the effects are manifested within the first 10 hours after administration. Doses above 40 mg. prolong these effects to 24 hours.
Toxicity of intraperitoneal bisulfite
Authors: Wilkins James W. , Greene James A. , Weller John M.
Published: January 2016

Studies were carried out in animals to investigate the toxicity of intraperitoneal bisulfite. The LD50 (dose lethal to 50 per cent of the animals) for a single intraperitoneal injection of NaHSO3 was calculated in the mouse, rat, rabbit, and dog. Studies indicated that the LD50 dose was increased by dilution of the bisulfite. When sodium bisulfite was infused at a rate of 80 mg. of NaHSO3 per kilogram per hour in the portal vein of dogs having bilateral ureteral ligations, bisulfite did not accumulate in the serum. Autoclaving dialysis fluid substantially reduced its bisulfite concentration. These studies suggest that NaHSO3 in amounts usually added to dialysis solutions is unlikely to cause toxicity in patients undergoing peritoneal dialysis.
The local effect of morphine, nalorphine, and codeine on the diameter of the pupil of the eye
Authors: Nomof Norman , Elliott Henry W. , Parker Kenneth D.
Published: January 2016

We have demonstrated that morphine (but not codeine) when applied locally to the coniunctival sac in a solution containing polysorbate produces a small but definite degree of miosis. This is apparently a local effect, since it is significantly greater in the treated than in the untreated eye. Locally applied nalorphine may also produce miosis by direct action; but this drug appears to be absorbed more readily than morphine, and its systemic effect largely masks its local effect. Locally (but not systemically) administered nalorphine, however, antagonizes the miosis produced by local application of morphine.
To protect the American patient
Authors: Modell Walter
Published: January 2016

The wide array of medication available to the American patient is a tribute to modern science.
The respiratory effects of codeine and morphine in man
Authors: Bellville J. Weldon , Escarraga Lourdos Aguto , Wallenstein Stanley L. , Houde Raymond W.
Published: January 2016

A controlled study was carried out in human volunteers to compare the respiratory effects of codeine and morphine administered intramuscularly and codeine administered orally and intram1lScularly. Codeine intramuscularly was found to be 0.1 as potent as morphine. Oral codeine was 0.72 as potent as intramuscular codeine. These relative potency estimates are in close agreement to those published for analgesic relative potency. It is concluded that when intramuscular morphine and codeine or oral and intramuscular codeine are given in equianalgesic doses, similar degrees of respiratory depression are induced.
Effect of 5‐imino‐2,2,4,4‐tetrakis (trifluoromethyn imidazolidine (EXP 338) on spasticity: A quantitative evaluation
Authors: Levine Irving M. , Jossmann Paul B. , Friend Dale G. , DeAngelis Vincent
Published: January 2016

In preclinical studies, 5‐imino‐2,2,4,4‐tetrakis (trifluoromethyl) imidazolidine (EXP 338) revealed potential muscle relaxant action at nontoxic levels in experimental animals. Our evaluation was carried out on 15 spastic multiple sclerosis patients. Eotablished methods of inducing spasticity and recording skeletal muscle hypertonia and quantitatively extracting integrated electromyogram data were used. Five patients were tested directly in the polygraph laboratory and 10 were tested at home via telephone telemetry (telemedography). Blood and urine were unaffected by the test drug. Adverse effects included muscle weakness, insomnia, paranoid reaction, sexual excitement, irritability, dry mouth, and limb pains. The alerting effect of EXP 338 suggests its trial as an antidepressant. The polygraph data revealed that a daily dose of 10 to 20 mg. of EXP 338 resulted in an average reduction of 62 per cent in skeletal muscle hypertonia in half the spastic subjects tested.
Thiothixene, thioridazine, and placebo in male chronic schizophrenic patients
Authors: Wolpert Arthur , Sheppard Charles , Merlis Sidney
Published: January 2016

The population of a male chronic schizophrenic ward was selected for treatment with thiothixene (Navane) (35 subjects), thioridazine (Mellaril) (29 subjects), and/or placebo (28 subjects). Medication was administered for seven months. During this period, the maximum daily dosage reached was 55 mg. of thiothixene and 1,100 mg. of thioridazine. Because of the high incidence of untoward effects and the absence of a marked therapeutic effect, daily dosage was titrated to an average of 10 mg. of thiothixene and 200 mg. of thioridazine during the last four months of treatment. On the basis of the fivefold criteria for determining efficacy (statistical comparisons of the behavioral ratings, psychological test data, the number of treatment failures in each medication group, and the incidence of side effects and patient status at the close of the study), thioridazine appeared slightly more effective in the treatment of schizophrenic symptomatology in this series of patients.
The Hallucinogens
Authors: Modell Walter
Published: January 2016

On this continent at least, Hoffer and Osmond pioneered in hallucinogens. In the less restrictive atmosphere of Saskatoon (Canada) Hoffer is still a very prolific worker with them, while Osmond, at Princeton, is suffeling from our restrictions. In this book they have issued what I assume is their definitive statement on hallucinogens. Hoffer and Osmond did much to open the field and stimulate others to work in it, but in their own writings they have unfortunately also done much to confuse.
Modernizing the structure of reports on drugs
Authors: de Haen Paul
Published: January 2016

At a time when about $25 billion is spent annually on research and development in this country, it is not surprising that there is a spate of writing complicated by widespread duplication. In the biomedical field the techniques of recording have not kept pace with the vast increase in reports. The format of presentation of research data has not changed essentially in 300 years, and is too often characterized by a prolixity that obscures data which should be spotlighted if the literature explosion is to be digested.
Sample size in psychiatric drug research
Authors: Rickels Karl , McLaughlin Blaine E.
Published: January 2016

Since the creation of psychopharmacology as a discipline, great strides have been made in the improvement of clinical research. Investigators have become more experienced and sophisticated, designs more appropriate, measurements more sensitive, statistical approaches to data analysis more powerful, and double‐blind and controlled procedures the accepted standard. But there is still room for improvement. Too frequently, for example, well‐designed studies, conducted by expert investigators, are carried out with inadequate samples, making conclusions drawn from the data collected questionable.
Therapy of advanced gastrointestinal cancer with 1‐3‐bis‐(2‐chlorethyl)‐l‐nitrosourea (BCNU)
Authors: Moertel Charles G. , Reitemeier Richard J. , Hahn Richard G.
Published: January 2016

1‐3‐Bis‐(2‐chlorethyl)‐1‐nitrosourea (BCNU) was administered intravenously to 72 patients with advanced gastrointestinal cancer. Total doses for each course of therapy ranged between 250 and 375 mg. per square meter, given in divided doses over periods of from 3 to 6 days. Initial toxic effects were transient nausea and vomiting. Bone‐marrow depression occurred late and involved all formed elements of the blood. Four patients had evidence of clinically significant hepatotoxicity. Courses of therapy could be repeated at 8 week intervals without significant cumulative toxicity. Objective tumor regressions were observed in 12.5 per cent of patients treated, and 19.5 per cent claimed symptomatic improvement. The mean duration of the tumor regressions was 4 months. Because of the low rate of tumor regressions and the short duration of these regressions, BCNU, as administered by the method employed in this study, does rwt seem to have a practical role in the management of advanced gastrointestinal cancer.
The Biochemistry of Foreign
Authors: Modell Walter
Published: January 2016

It is not intended to be an invidious distinction to point out that this book, with the exception of the first 20 pages on absorption, excretion, and tissue distribution, is very much a pocket version of R. T. Williams' classic, Detoxification Mechanisms. Williams was the author's mentor and has written a forward to this book (which I hope is no sign that he does not see his way clear to a third edition of his own book). The writing is clear and succinct and for those who are satisfied with the bare details on drug (in the broad sense of any foreign chemical) metabolism, this is the book. Those who want more will have to use R. T. Williams' Detoxification Mechanisms. I'm happy to have them both.
An end to the means FDA papers III
Authors: Modell Walter
Published: January 2016

On August 16, two months after the fact, the FDA sent us a copy of Dr. James L. Goddard's last public address before retiring as Commissioner of Food and Drugs. It was given before the American College of Legal Medicine in San Francisco in June.2 To demonstrate our devotion to the principle of freedom of speech and our abhorrence of censorship we not only print this speech in full but also take pains not to alter a word or a comma, even restraining an almost irresistible editorial itch to correct a few obvious typographical errors (and trying not to introduce any of our own). We have not printed “Modell” or “Lasagna” which were written in hand alongside the title because the words were also scratched out. We have not reprinted “circulate” which was handwritten at the top of the page because we feIt that was an order which we were duly carrying out.
Setting the record straight on “To the fullest extent”
Authors: Lasagna Louis
Published: January 2016

The passage of Dr. Goddard from the federal regulatory scene is in many ways regrettable. He brought to the FDA a vigor and excitement which‐although occasionally misdirected or injudicioushelped to shake up an agency that badly needed (and still needs) revamping.
Evaluation of butaperazine in chronic schizophrenia
Authors: Clark Mervin L. , Ray Thomas S. , Huber Wolfgang K. , Willis David , Ramsey H. Rudy
Published: January 2016

A clinical trial was conducted to evaluate butaperazine, a piperazine phenothiazine, against chlorpromazine and placebo for 16 weeks in 67 chronic schizophrenic women. Responses were made based on psychiatric and psychological interviews, general ward behavior, and psychological tests. Significant improvement of the chlorpromazine patients attested to the sensitivity of the method. Butaperazine was found to be an effective antipsychotic agent of the order of chlorpromazine. Butaperazine caused more frequent extrapyramidal and fewer orthostatic symptoms.
Comparison of tetrahydrocannabinol and synhexyl in man
Authors: Hollister Leo E. , Richards Richard K. , Gillespie H. K.
Published: January 2016

A synthetic isomer of tetrahydrocannabinol (1‐Δ'‐3,4‐transtetrahydrocannabinol), believed to be identical to the most active naturally occurring THC, was compared with a semisynthetic THC‐like compound, synhexyl. Sixteen volunteer subiects received THC in doses ranging from 341 to 946 p.g per kilo gram (median 581). Thirteen subjects received synhexyl in doses ranging from 633 to 2,666 µg per kilogram (median 1,370). Clinical syndromes tram the 2 drugs were similar, although synhexyl was slower in onset and only about one third as potent. The clinical effects resembled those of psychotomimetics such as LSD, at least at the higher doses. These drugs differed from LSD in the following respects: sedation was prominent; euphoria was langer lasting; dreamlike sequences more pronounced; and physiological and biochemical effects were somewhat different, especially in the absence of sympathomimetic effects.
Disorders produced by diphenylhydantoin
Authors: Moser Robert Harlan
Published: January 2016

Dr. Robert Moser has informed us that, due to reassignment to the Walter Reed Hospital in Washington, new duties will prevent hirn from continuing to collect material and write the abstracts for BIBLIOGRAPHIES ON DISEASES OF MEDICAL PROGRESS. It has always been a wonder to us that he was able to get all this data together under any circumstances, and it is easy to understand why new and heavy responsibilities will prevent hirn from continuing this good work. I know of no one who can replace hirn. This alone is a tribute. But I know, toD, that many of our readers will miss hirn and that the size of our JOURNAL will be reduced by this loss. I speak for the entire Editorial Board in thanking hirn for his splendid contribution to this JOURNAL since the year of its inception.
Anthelmintics, new and old
Authors: Brown Harold W.
Published: January 2016

It is estimated that over 1,100,000,000 persons the world over are infected with helminths.51 In underdeveloped countries, the burden of helminth infection, added to that of malnutrition and bacterial, protozoal, and viral infections, may be the proverbial back‐breaking straw. Well‐nourished persons often harbor helminths without apparent damage and one may question the wisdom of treating such infections, especially with chemotherapeutic agents with toxic qualities. On the other hand, if a safe and effective drug is available, treatment should be given until evidence is in hand that these helminth infections do not harm or are beneficial to man. Unfortunately, reinfection is common and prompt unless sanitary measures are instituted. Although pinworm frequently causes man little or no inconvenience, and light infections of other worms may go unnoticed, hookworm and schistosomiasis are debilitating and deadly infections. Heavy infection with many other helminths may cause very serious anemia, and the normal and aberrant wanderings of several species may be fatal.
Ephedrine mydriasis in hypertension and the response to treatment
Authors: Sneddon J. M. , Turner Paul
Published: January 2016

The responses of the human pupil to the local instillation of ephedrine have been used as a model system to investigate the pharmacology of antihypertensive drugs. No significant difference in ephedrine mydriasis in hypertensive subjects and matched normotensive controls was found. Reserpine and alpha methyldopa in antihypertensive doses significantly depressed ephedrine mydriasis, whereas guanethidine or bethanidine either slightly increased ephedrine mydriasis or had no effect. These results are discussed in terms of possible interactions occurring between the drugs at postganglionic sympathetic nerve ending during the chronic administration of small doses to man.
The effect of meperidine on the peripheral circulation
Authors: Nadasdi Miklos , Zsotér Thomas T.
Published: January 2016

Meperidine, 1 mg. per kilogram, given intravenously to patients with or without heart failure, significantly increased the blood flow in the forearm and the leg while arterial and venous resistance decreased. Venous tone and distensibility remained unchanged. These effects of meperidine were not mediated through histamine release or cholinergic nerves, since neither cyproheptadine nor atropine modified them. The vasodilating action of meperidine may play a part in its beneficial effect in acute pulmonary edema by decreasing arterial resistance.
A new approach to the use of histamine skin tests in the study of antihistamine drugs
Authors: Joubert L. , Gaut Z. , Abrams W. B.
Published: January 2016

Data are presented to show that the histamine skin test is more variable than previously appreciated. Dose‐response studies with the use of this test to evaluate antihistaminics should therefore include placebo and the use of the double‐blind technique. In this study the wheal alone appeared to be a sufficient discriminator of antihistamine activity.
A comparison of the behavioral effects of periodic administration of chlorpromazine and a “sustained‐release” form of chlorpromazine
Authors: Orzack Maressa Hecht , Taylor Constance L. , Kornetsky Conan
Published: January 2016

The relative efficacy of 300 mg. of chlorpromazine in a “sustained‐release” form was compared with repeated doses of regular chlorpromazine in a double‐blind crossover study. Ten sub;ects, 5 normal volunteers and 5 chronic schizophrenic patients, were given 4 psychomotor tests. Two of these, the CPT and PDS, were primarily attention tests. Performance on all the tests but the DSST indicated differences between the 2 treatments. A decrement in performance of the CPT was found 4 hours after the sustained‐release treatment; it did not persist. Decrement in performance was not found in the regular chlorpromazine program, suggesting an initial “dumping” effect of the sustained‐release capsule. Performance on the SPDT and PDS tests demonstrated latent differences between drug treatments. There were increasing decrements in performance after repeated regular chlorpromazine, suggesting a cumulative effect. This was not found after the sustained‐release treatment. While the sustained‐release treatment is as effective during the midportion of the period of observation as the repeated administration of regular chlorpromazine, the effects start to wear off between 8 to 10 hours after the administration of the sustained‐release capsule; while, after repeated doses of regular chlorpromazine, there were increasing decrements in performance.
Chlorpromazine‐procyclidine and imipramine: Effects on thyroid function in psychiatric patients
Authors: Blumberg Arnold G. , Klein Donald F.
Published: January 2016

A series of thyroid function tests were performed on 84 randomly assigned psychiatric patients receiving chlorpromazine‐procyclidine, imipramine, or placebo, before and after treatment. The rate of uptake of 1s1I and the 24 hour level of uptake of 1s1I by the thyroid gland was increased by chlorpromazine‐procyclidine but not by imipramine. Renal clearance of 1s1I was diminished by treatment with chlorpromazine‐procyclidine but not by imipramine. PBI, T3 resin uptake, and ankle jerk were not significantly altered.
Pain as a factor in the development of tolerance to morphine analgesia in man
Authors: Ferguson Roger K. , Mitchell C. L.
Published: January 2016

An experiment was designed to test the hypothesis that pain is a factor in the development of tolerance to the analgesic effect of morphine in man. Pain was induced by the submaximum‐effort tourniquet technique. Four pain ratings were recorded: mild, moderate, severe, and unbearable. Subjects were randomly divided into two major groups: (1) those tested by the tourniquet technique each day and (2) those not tested until the final day. Each major group was randomly divided into two subgroups: (1) those receiving only morphine and (2) those receiving saline for 4 days and morphine on the final day. Morphine or saline was given intravenously. The purpose of the experiment was to compare the degree of tolerance development to chronically administered morphine in the tested versus nontested groups. In the subgroups receiving morphine, analgesia was significantly less in the tested than in the nontested group at the highest pain level. Moreover, in the morphine subgroup of the tested subjects, the degree of tolerance development was proportional to the severity of pain. These findings indicate that pain can augment the development of tolerance to the analgesic effect of morphine in man.
The need to test the efficacy of the instructional aspects of clinical pharmacology
Authors: Melmon Kenneth L. , Morrelli Howard F.
Published: January 2016

During the Oslerian era, the physician par excellence was the accurate diagnostician, but today, the physician must be accomplished in therapeutics as well. Improved understanding of the pathogenesis of disease has paralleled the development of specific but toxic therapeutic agents. The hazards of drug administration became obvious as medicine abandoned homeopathy, turning to the use of potent drugs in doses that produce a therapeutic effect by altering biochemical or physiologic processes. The incidence of drug toxicity has increased as drugs are used in large patient populations, as polypharmacy with new agents continues, and as diseases are treated for prolonged periods with them.7
Cardiogenic shock: A review
Authors: Perlroth Mark G. , Harrison Donald C.
Published: January 2016

A great expansion of interest has occurred in the syndrome of circulatory shock. The measurement of hemodynamic and metabolic variables in human beings and experimental animals now allows an orderly and integrated approach to the ill patient. In cardiogenic shock the minute output of the acutely iniured heart abruptly decreases with attendant fall in arterial blood pressure, tissue perfusion, and pH. Effective venous return to the right and left heart may be monitored by central venous pressure and pulmonary artery diastolic pressure. If low, infusion of volume expanders alone may be sufficient to reverse the shock syndrome. If drugs are required, a variety of catecholamines with alpha and beta stimulating properties are available, as well as inotropic agents such as digitalis and glucagon. Principles for their selection are discussed. The potential roles and hazards of alpha‐ and beta‐adrenergic blocking agents and steroids are also considered. When limits of pharmacologic resuscitation have been reached, mechanical aid and surgical assistance to the cardiovascular system are available. The latter promises to pe of greater importance in the future.
Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee
Authors: Goldstein Avram , Kaizer Sophia , Whitby Owen
Published: January 2016

Caffeine (150 and 300 mg.) and placebo were administered in decaffeinated coffee on 9 successive mornings (each treatment 3 times) to 18 housewives who were not coffee drinkers and to 38 who habitually drank 5 cups or more daily. The design was blind. The criteria of caffeine effects were 11 clusters of adjectives on a self‐rating form, used at 30 minute intervals for 2 hours. Major differences between effects of caffeine on abstainers and on users were revealed. The abstainers felt quite normal when placebo was administered but reacted negatively to caffeine; principal complaints were jitteriness, nervousness, and "upset stomach." The users complained of sleepiness and also of dysphoric symptoms such as irritability when placebo was administered or before caffeine was administered. The users reacted positively to caffeine, reporting increased alertness, decreased irritability, and a feeling of contentedness. These findings are entirely consistent with those obtained by a questionnaire survey in the same and other women, reported in the preceding paper. The possible implications for understanding the genesis of drug‐seeking behavior in man are discussed.
The relationship between kanamycin pharmacokinetics: Distribution and renal function
Authors: Orme Burton M. , Cutler Ralph E.
Published: January 2016

In thirty‐four patients with either normal renal function or varying degrees of renal failure, simultaneous determinations of the renal clearance of inulin, para‐aminohippurate, creatinine, and kanamycin were made. In addition the volume of distribution of inulin and kanamycin was determined in 18 patients. No evidence for protein binding of kanamycin was found . .Although the exact tubular transport mechanisms are not clear, it is evident that net reabsorption occurs since the kanamycin clearance averaged 76 per cent of the inulin clearance and 60.4 per cent of the creatinine clearance. Kanamycin was distributed in a volume averaging 18.9 per cent of the body weight which closely approximated the inulin space. A formula for the serum half‐life of kanamycin is given.
Clinical trial of bitoscanate in hookworm disease
Authors: Mutalik Gururaj S. , Gulati Ravindra B.
Published: January 2016

Bitoscanate was examined for clinical efficacy and safety in 30 hospitalized patients with hookworm infection due to Necator americanus. With 2 doses of 100 mg., each administered 12 hours apart after food, cure was obtained in 16 out of 30 patients. Egg reduction of over 95 per cent occurred in 90 per cent of the patients. The untoward effects observed were mild and limited to the gastrointestinal tract. There was no significant alteration of any of the laboratory tests performed.
A controlled clinical study of metopimazine and perphenazine in treatment of radiation nausea and vomiting
Authors: Chu Florence C.H. , Paulshock Marvin , Wallenstein Stanley L. , Houde Raymond W. , Phillips Ralph
Published: January 2016

A total of 252 outpatients receiving radiotherapy were started on a single‐blind placebo medication "for prevention of nausea and vomiting." Those who developed nausea or vomiting participated in a double‐blind study to compare the relative antiemetic efficacy of metopimazine at two dose levels (2.5 mg. and 5.0 mg.) with perphenazine at two dose levels (4.0 mg. and 8.0 mg.) and with inert placebo. The results were analyzed in a variety of ways. The analysis of paired responses in the same patients showed that metopimazine in doses of 10 to 20 mg. per day and perphenazine in doses of 8 to 32 mg. per day were effective antinauseant‐antiemetics significantly super or to placebo but not significantly different from one another. There were no significant differences in side effects among the test medications except for drowsiness, which occurred with a significantly higher frequency in patients receiving the higher dose of perphenazine. A method of population selection was proposed. A preliminary screening of patients by radiotherapists would el:minate from studies of antiemetics a large number of patients unlikely to develop nausea or vomiting after radiotherapy.
Comparison of antihypertensive efficacy, intestinal absorption, and excretion of guanethidine in hypertensive patients
Authors: Rahn K. Heinz , Goldberg Leon I.
Published: January 2016

Intestinal absorption and urinary excretion of guanethidine was determined in 6 patients with essential hypertension. Three of the patients had adequate reductions of standing diastolic blood pressure with 25 mg. per day of guanethidine (Group 1); the other 3 patients did not respond to 150 mg. per day of the drug (Group II). All patients also received a single oral dose of 41.6 mg. guanethidine‐14C (5 pc). There was no significant difference between the two groups of patients with respect to rate of urinary excretion of radioactivity or the total amount of radioactivity excreted in the urine. The amount of radioactivity in the feces (reflecting unabsorbed drug) was similar in both groups. There was also no consistent difference noted in the urinary excretion of guanethidine metabolic fractions. These data indicate that poor intestinal absorption was not the cause of inadequate response to guanethidine in these patients.
The evaluation of anticancer drugs in dogs and monkeys for the prediction of qualitative toxicities in man
Authors: Schein P. S. , Davis R. D. , Carter S. , Newman J. , Schein D. R. , Rall D. P.
Published: January 2016

The usefulness of dogs and monkeys in predicting potential qualitative drug toxicity in man was examined retrospectively for twenty‐five anticancer compounds of diverse chemical and functional classification. It was found that the large animal screen served to alert the physician to a significant proportion of the total spectrum of drug effects, which were encountered during the clinical use of a new toxic compound. The dog and monkey correctly predicted bone marrow depression, gastrointestinal disturbance, and hepatotoxicity for each drug producing these effects in the clinic; in the case of renal, cardiovascular, and neuromuscular toxicity, however, the large animal screen failed in each instance to predict one drug that produced these toxicities in man. The correct predictions were accomplished at the expense of a high percentage of false positives, which resulted from the necessity of using severely toxic dose levels in order to demonstrate all potential toxicities inherent in any compound. While organ system toxicity observed during an animal study can never be disregarded, it should be viewed with an understanding of certain limitations of animal toxicologic data. While toxicity may develop in man in an organ system predicted susceptible by an animal, a different specific clinical or chemical parameter may be involved. The adverse reaction may appear in man at a greater or lesser dose level or may follow a different order of appearance in relationship to the total spectrum of qualitative toxicity inherent in the compound.
Studies of delayed‐action medication V. Plasma levels and urinary excretion of four different dosage forms of chlorpromazine
Authors: Hollister Leo E. , Curry Stephen H. , Derr Julia E. , Kanter Saul L.
Published: January 2016

The physiological availability of chlorpromazine administered as three oral preparations (tablets, liquid, and long‐acting capsules) and by intramuscular iniection was measured in 13 psychiatric patients under steady‐state conditions and 8 previously untreated sub;ects given single doses. Determinations of plasma levels of chlorpromazine, as well as urinary excretion of con;ugated and uncon;ugated metabolites, were used as the criteria of physiological availability. Under each condition, the availability of drug followed the same order in regard to the oral preparations: liquid, tablets, and long‐acting capsules. Differences were far more apparent in plasma levels than in urinary excretion. None of the oral dosage forms was completely reliable, but in steady‐state conditions, all tended to produce sustained plasma levels. On the other hand, intramuscular injection of drug, even in doses approximating one third of the same oral dose, led to rapid and regular appearance of significant plasma levels of drug and a consistently higher per cent of the administered dose in the urine. The use of the long‐acting oral dosage form does not seem warranted for a drug such as chlorpromazine; liquid or tablet dosage forms were more reliable and satisfied the claims made for long‐acting dosage forms in chronic treatment.
Lithium in mania
Authors: Gershon Samuel
Published: January 2016

Lithium was discovered in 1818 by Arfwedson.6 Its chemie al individuality was the key to its discovery as the unaccOlmted for percentage composition of the newly found mineral petalite. Arfwedson demonstrated that the mysterious element resembled sodium and potassium in some reactions but not in others. Bunsen disclosed the presence of lithium in tobacco, sugar cane, and seaweed which belied the exclusive occurrence of this element in minerals. Its salts were later detected in the spa waters of England and Germany, and thus lithium was launched on its medical and therapeutic career. It was believed that the reputed efIects of these spas on rheumatoid arthritis and gout were due to the presence of lithium. The mineral waters contain about 1 mEq. per liter of lithium.
Guanadrel and guanethidine in hypertension
Authors: Bloomfield Daniel K. , Cangiano Jose L.
Published: January 2016

A modified double‐blind study was carried out in 40 patients with moderate to severe hypertensive disease. Twenty patients were treated with guanadrel in oral doses of 30 to 400 mg. daily for 17 weeks; the other 20 patients were treated with guanethidine in oral doses of 10 to 200 mg. daily for 14 weeks. Hypotensive actions were similar, but on a weight basis gttanadrel was only one third as potent as guanethidine. With gttanadrel there were positive responses in 60 per cent of patients in the supine position and 75 per cent of paUents in the erect position; with guanethidine there were positive responses in 55 per cent of patients in the supine position and 70 per cent of patients in the erect position.
Clinical biostatistics
Authors: Feinstein Alvan R.
Published: January 2016

The design of experiments has been a favorite concern of statisticians ever since R. A. Fisher,16 after emphasizing the importance of statistics in research, published a second book in 1935, entitled The Design of Experiments,17 and stated that a clear grasp of simple and standardized statistical procedures will … go far to elucidate the principles of experimentation. Fisher's book, now in its eighth edition,l8 has been followed by many other statistical texts and papers on this topic. With minimal effort, I was able to find 16 current statistical books,l 3‐7, 15, 18, 24, 26, 28, 30, 31, 35‐37 written in English, with experimental design or some congener in their titles. In arecent bibliographie review23 of the topic, the authors cited about 800 items published since 1957.
Penicillin allergy
Authors: Stewart G. T.
Published: January 2016

When the causes of penicillin allergy are fully understood, they might well offer answers to a number of immunochemical and biologie conundrums. Supperficially, there is no mystery in the fact that penicillin causes allergy‐lots of simple substances cause allergy‐the mystery comes when one considers that, of the millions of people who receive penicillin, only a few, perhaps 3 per cent, develop allergy at one time or another, In most of these, the allergy is short‐lived or inconstant: A person who has reacted adversely to penicillin on one occasion may tolerate it subsequently, and vice versa. In a very small minority of allergie subjects, fewer than 0.1 per cent of the total, the dangerous state of anaphylaxis develops; to persons in this state, a milligram of penicillin, or less, can cause shock, collapse, and even death. One encounters individuals who are so sensitive that by merely handling a tablet of penicillin or by receiving a skin test dose of 10 to 100 units, they suffer an immediate reaction. Some subjects manifest this extreme sensitivity in the form of contact dermatitis, while in others the reaction may be remote from the site of contact or may be systemic. More so than with other specific allergies, the manifestations of penicillin allergy are extremely diverse; each of several organs may bear the shock, and the symptomatology of response is correspondingly varied (Table 1). To add to the mystery, it is on record that some persons (e.g., in 1944) who had never received penicillin have reacted violently to a first dose.
The effects of urban air pollution on health
Authors: Ayres Stephen M. , Buehler Meta E.
Published: January 2016

An impressive body of scientific information points to the inescapable conclusion that the levels of pollutant contamination existing today in many American cities are sufficient to produce profound health consequences. This review describes the relationship between pollutant emission, atmospheric cleansing processes, and ambient air pollutant concentrations. Toxicologic studies involving the administration of sulfur dioxide, nitrogen dioxide, carbon monoxide and particulate suspensions to both animals and man are reviewed and demonstrate that single pollutants cannot explain the irritant potential of the urban atmosphere. A number of important epidemiologic studies are presented which emphasize the relationship between human illness and atmospheric pollution, Synthesis of both toxicologic and epidemologic studies leads to the conclusion that the noxious nature of the environment is due to a complicated "mix" of pollutant and meteorologic factors.
Clinical pharmacologic studies of L‐asparaginase
Authors: Ho D. H. W. , Thetford Beverly , Carter Carol J. K. , Frei Emil
Published: January 2016

Studies were performed with L‐asparaginase in patients with metastatic cancer and leukemia. The enzyme in human plasma had a broad optimal pH range and was stable in plasma at 40° C. for at least 40 days and at −10° C. for more than 4 months. Frequent freezing and thawing had no effect on the enzyme activity. The activity was not affected in vitro by the addition of 2 × 10−3M L‐aspartic acid, NH4C1, or (NH4)2 SO4. The initial plasma level following a single intravenous infection was dose related. The enzyme decrease in the plasma was exponential with half‐times varying among patients from 8 to 30 hours. In 15 patients who received daily doses there was a cumulative increase in plasma enzyme levels, but the half‐time did not change and rapid immune clearance was not observed. Plasma half‐time was not affected by age, sex, diagnosis, extent of disease, plasma lactic dehydrogenase levels, or hepatic or renal function. The apparent volume of distribution of the enzyme was slightly greater than the plasma volume. In a patient with a thoracic duct fistula it was found that the enzyme entered the extravascular space slowly and attained a concentration of 20 per cent the plasma level. Only a trace of L‐asparaginase activity was present in the cerebrospinal fluid and urine of patients after treatment.
III. The architecture of clinical research
Authors: Feinstein Alvan R.
Published: January 2016

Because the scientific fundamentals of clinical research are omitted in most statistical discussions of the “design of experiments,”5 a new scientific architecture must be developed as a methodologic discipline for planning clinical investigations. These investigations can be constructed in several different ways, according to the events, problems, and challenges contained in the clinical experiments of nature and of man. In the previous paper of this series,5 I outlined those diverse investigative structures, which include the following: surveys of nature's activities in preserving health, or in creating and evolving human disease; surveys and experimental trials of man's therapeutic attempts to intervene in the course of nature; explanatory experiments that probe a maneuver of nature or delineate a maneuver of man; and exploratory efforts to assess and improve the methodology used in the foregoing research activities.
A short course in clinical pharmacology
Authors: Carr Edward A.
Published: January 2016

The public, its representatives in government, and its practicing physicians have a well‐known and well‐documented interest in the opportunities and problems created by changes in drug therapy during the past twenty‐five years. Their interest does not require further documentation here. The topic of the present report is the response of academe to these opportunities, problems, and widespread interest.
Thalidomide in the treatment of erythema nodosum leprosum
Authors: Hastings Robert C. , Trautman John R. , Enna Carl D. , Jacobson Robert R.
Published: January 2016

Forty‐four trials of thalidomide or an identical placebo have been conducted in 22 patients with active lepromatous leprosy and chronic erythema nodosum leprosum (ENL) reactions. Thalidomide is significantly superior to placebo in completely alleviating the two principal signs of ENL, fever and skin lesions. Selected serial laboratory determinations during the study demonstrate an acute anemia occurring in and immediately after EN L and an acute rise in circulating leukocytes with a shift to the left in the differential count. There is an acute increase in both direct and indirect serum bilirubin associated with ENL and a fall in total serum cholesterol. The suggestion is made that ENL has some characteristics of the disseminated intravascular coagulation syndrome. Despite its teratogenic effect, thalidomide is less toxic than corticosteroids and therefore seems to represent a major advance in the management of ENL. Its mechanism of action in ENL is unknown.