bluuebunny/crossref_metadata_2025 huggingface dataset:
Trial of pipazethate as an antitussive
Authors: Vakil B. J. , Mehta A. J. , Prajapat K. D.
Published: January 2016

Pipazethate, thiophenylpyridylamine‐10‐carboxylic acid‐piperidinoethoxyethylester‐HCl, has been reported to have significant antitussive activity in clinical and experimental studies. In a double‐blind study, the drug has been compared with placebo in 70 patients with cough and in 41 healthy subjects in whom cough was artificially induced. The method of Bickerman and Barach was successfully used to induce artificial cough. The present trial suggests that results with pipazethate are no better than with placebo in experimental studies as well as in clinical studies of chronic cough.
Methysergide in migraine prophylaxis
Authors: Pedersen Ejner , Møller C. Eckardt
Published: January 2016

In a clinical trial, methysergide and placebo were compared by the double‐blind method. The study was arranged so that it was also possible to assess the effect of methysergide and that of placebo in relation to the pre‐experimental condition. A dose of 6 mg. of methysergide was given to adult patients daily. Sixty patients completed the trial satisfactorily. Analysis showed that there was significant reduction in the frequency of attacks with methysergide. In comparison with the pre‐experimental period the frequency of attacks was reduced at least 50 per cent in 57 per cent of the patients by methysergide. The corresponding figure for placebo was 27 per cent, but part of this response seemed to be due to a “carry‐over” effect. No definite correlation between the effect and the clinical data was revealed. Severe adverse effects necessitating the withdrawal of the drug occurred in 7 per cent of patients; other untoward effects were observed in about one third of the patients, mainly due to insufficient circulation. Adverse effects were more frequent in women, and especially in those who obtained good effects from the drug.
A clinical trial of oral 5‐fluorouracil
Authors: Khung Christiaan L. , Hall Thomas C. , Piro Anthony J. , Dederick Margarida M.
Published: January 2016

5‐Fluorouracil (5FU) was given orally in capsules and in solution to 75 patients with advanced cancer. Results with the drug in solution were more consistent, indicating better absorption. Predominating toxicity was gastrointestinal, and bone marrow depression was next in incidence. Ob;ective responses occurred in patients with metastatic cancer of the breast, stomach, colon, and rectum. Oral 5FU in solution is a practical form of therapy, simple, effective, safe, and as well tolerated as when given by the intravenous route.
Kinetics of intestinal absorption of sulfamethazine in man
Authors: Turco G. L. , de Filippi P. , Prinetti V. , Segre G.
Published: January 2016

The kinetics of intestinal absorption of sulfamethazine was determined in 12 normal subjects. A four compartment model was used, and the data regarding blood kinetics after intravenous injection and after oral administration were fitted to the model by a digital computer. All the transfer constants of the model (Fig. 3) were computed directly. The weighting function for the intestinal absorption is formed by two exponential terms, and the blood kinetics after intravenous injection can be accounted for by two exponential terms.
The hypocholesterolemic effect of phenyramidol
Authors: Schrogie John J. , Solomon Harvey M.
Published: January 2016

Phenyramidol, an inhibitor of the metabolism of bishydroxycoumarin, has significant hypocholesterolemic activity in rats and man. D‐thyroxine and SKF 525‐A, which also inhibit the metabolism of drugs, have potent cholesterol‐lowering effects in various animal species. Since the synthesis of cholesterol is dependent upon hepatic microsomal enzymes, drugs which inhibit these enzymes may reduce serum cholesterol.
A comparison of the effects of hydrochlorothiazide and hydrochlorothiazide in combination with triamterene on electrolyte balance
Authors: Tannenbaum Philip J. , Crosley Archer P.
Published: January 2016

A comparison of hydrochlorothiazide alone and a combination of triamterene and hydrochlorothiazide in a ratio of 2:1 was made in 9 nonedematous patients, with the use of a metabolic balance technique. The results indicated that the mixture produces a greater natriuretic effect than can be produced by hydrochlorothiazide alone. However, whereas doubling the doses of the combination of 100 mg. of triamterene and 50 mg. of hydrochlorothiazide per day had no greater natriuretic effect, the doubled quantities did result in a greater reduction of potassium loss. These findings are of value in defining the manner in which such agents exert their activity on distal tubular transport systems. The use of triameterene and hydrochlorothiazide in combination tends to eliminate the undesirable effects of each of these agents on potassium and acid‐base balance. Finally, the use of the combination as the first test agent exaggerated the difference between the ensuing natriuretic response and that produced by hydrochlorothiazide. These results indicated the importance of the order of drug administration in comparing diuretic efficacy in a crossover investigation.
Modification of urinary mucopolysaccharide excretion in patients with Hurler's syndrome
Authors: Rennert O. M. , Dekaban A. S.
Published: January 2016

Several variants of Hurler's syndrome can be distinguished both genetically and biochemically. All these patients excrete excess acid mucopolysaccharides in their urine, but the ratio of chondroitin sulfate B to heparitin sulfate varies in different families. When the patients are in a basic condition and are maintained on a constant diet, the amount of 24 hour urinary acid mucopolysaccharides and the ratio of chondroitin sulfate B to heparitin sulfate show little daily fluctuation. Seven children with Hurler's syndrome were studied in their basic state and consecutively while receiving corticosteroids, thyroid, human growth hormone, hydroxychloroquine, and salicylates. It was demonstrated that administration of hydroxychloroquine increases urinary excretion of acid mucopolysaccharides, while prednisone tends to decrease the excretion of urinary acid mucopolysaccharides. Thyroid and corticosteroids produced marked changes in the ratio of chondroitin sulfate B to heparitin sulfate, especially in patients who excreted predominantly heparitin sulfate in their basic state. Salicylates and human growth hormone did not induce significant changes in the pattern of urinary excretion of acid mucopolysaccharides.
Accidental therapeutic drug addiction
Authors: Friend Dale C.
Published: January 2016

A great deal is being written these days about drug addiction, and new methods of treatment of the socioeconomic deprived addict are being pursued vigorously and watched with a great deal of interest by many. While there is no doubt that addicts comprise a serious sociological problem and every effort must be made to find a way to prevent and treat them, there is another aspect of drug addiction, which, on the whole, has not received as much attention as it deserves. This is the problem of those patients with no apparent psychopathic personality or socioeconomic disadvantaged situation who have become addicted through the prescription of drugs by physicians. In this class are addicts to barbiturates, amphetamines, occasionally morphine or its derivatives and, primarily and most importantly, meperidine (Demerol). A brief discussion of this aspect of addiction, its cause and management, may be helpful to physicians.
A three‐month trial of indomethacin in rheumatoid arthritis, with special reference to analysis and inference
Authors:   The Cooperating Clinics Committee of the American Rheumatism Association
Published: January 2016

Without questioning the possibility that indomethacin benefits some patients, this 3 month, 11 clinic, blindfold trial studied arthritic symptom changes and the frequency of nonarthritic symptoms in 71 indomethacin‐treated (D) and 65 placebo‐treated (P) adult patients with peripheral rheumatoid arthritis. Salicylates were permitted to both groups. Five relatively objective measures (numbers of clinically active ioints, grip strength, morning stiffness, erythrocyte sedimentation rate, and walking time) were used, and also physicians' and patients' impressions. Corrections were made for initial levels of disease activity. The D and P groups were indistinguishable in frequency, extent and rate of change of symptoms, evaluated either singly or in combination. Undesirable symptoms, especially headache, dizziness, and light‐headedness, were more frequent in the D group than in the D group. In the week after trial medication had ceased, and before therapy assignments were revealed, physicians' and patients' impressions reported more deterioration in the D group than in the D group, and this was reflected in the morning stiffness evaluation. Six pitfalls in inferences from such trials are illustrated and discussed.
Correlation of the nalorphine test with concentration of metabolites of codeine in the urine after single doses and continuous administration of codeine
Authors: Elliott Henry W. , Nomof Norman , Parker Kenneth D.
Published: January 2016

Single doses of codeine cause miosis which is not reversed by nalorphine, as the miosis with other morphinelike drugs is. When codeine was given four times a day, most subjects gave positive nalorphine (pupil) tests on the third day. Urinalysis for codeine and its metabolite morphine revealed that subjects with the highest urine drug levels had the most strongly positive pupil tests, but the gradual development of a positive pupil test was not related to increasing concentrations of morphine in the urine. When codeine was infused continuously (30 mg. per hour) to produce “acute tolerance,” the pupil test was positive in 8 hours. In the dog, a species which forms norcodeine but not morphine from codeine, the pupil test was negative after a single injection of codeine but became positive after 2 to 3 days of intermittent injections. The data suggest that positive nalorphine tests occur only in subjects tolerant to codeine.
A quantitative evaluation of the neurospasmolytic effect of orphenadrine by direct and telemedographed electromyography
Authors: Levine Irving M. , Jossmann Paul B. , DeAngelis Vincent
Published: January 2016

Orphenfldrine was evaluated as a neurospasmolytic agent in 14 patients and as an antitremor agent in 2 patients. Response to single 100 mg. doses was measured 1 and 2 hours after medication, and the effect of maintenance therapy with 100 mg. twice a day was measured weekly for 4 weeks. Orphenadrine appeared to be highly effective in the 1 and 2 hour tests but less effective with sustained treatment. In all instances telemedography showed patients had a higher percentage of favorable responses. Orphenadrine was clearly effective in reducing intention tremor in the 2 patients tested with sustained treatment, but less so in the 1 and 2 hour observations.
Drugs and suicide in the United States
Authors: Berger F. M.
Published: January 2016

Although the suicide rate has remained constant with population growth during recent years, the pattern of methods for suicide has changed markedly. The use of drugs for suicide has increased disproportionately, while other means have fallen out of favor. The available data indicate that the increased suicide rate from drugs is not due to the use of the widely prescribed nonbarbiturate hypnotics and tranquilizers but can be accounted for entirely by the use of barbiturates.
The metabolism of uracil‐2‐14C and the granulocyte response to endotoxin as indicators of the toxicity produced in patients receiving 5‐fluorouracil
Authors: Creasey William A. , Koutras George A. , Calabresi Paul
Published: January 2016

To assess the potential hazards of compromised liver function and deficient granulocyte reserves during therapy with 5‐fluorouracil, the metabolism of uracil‐2‐14CO2 and the granulocyte response to a bacterial endotoxin, pyrexal, were studied in cancer patients. An inadequate response to pyrexal was invariably associated with increased toxicity, in terms of leukopenia, during therapy with 5‐fluorouracil. Severe leukopenia also occurred in subjects with normal granulocyte reserves. Other studies showed that in patients either with demonstrable liver metastases or in whom subsequent administration of 5‐fluorouracil produced particularly severe toxicity or toxic manifestations with less than average doses of the drug, the specific activity of expired 14CO2 derived from uracil‐2‐14C was lower than in other patients. The results of the more customary tests of liver function did not correlate closely with these findings. It is suggested, therefore, that the metabolism of uracil to CO2 in con;unction with determinations of the granulocyte response to endotoxin, may serve as a useful index of toxicity which may be anticipated from 5‐fluorouracil.
FDA censorship
Authors: Modell Walter
Published: January 2016

This JOURNAL has avoided criticizing the FDA for its weaknesses and its failings because we have feIt that it is charged with a virtually impossible job. Certain recent actions of the FDA, however, violate basic principles of science and education, andhere the Editor feels that in the interest of the public and of medicine he must speak.
Latency of cough response as a measure of antitussive agents
Authors: Calesnick Benjamin , Christensen Jens A.
Published: January 2016

The cough reflex was stimulated in selected healthy male subjects with a single nebulized threshold dose of citric acid. The essential components of the method were deep inhalation by the subjects and the measurement of the required time to elicit the cough reflex. Prolongation of latency was used as a measure of antitussive action. With the use of this parameter, a dose‐response curve was obtained for codeine and dextromethorphan.
Antitussive effect of ethyl dibunate in patients with chronic cough
Authors: Sevelius Hilli , Colmore John P.
Published: January 2016

Ethyl dibunate has been suggested for the suppression of eough on the basis of animal studies, eitrie aeid‐indueed eough studies on healthy humans, and by subjeetive evaluation in patients with ehronie eough. Continuous recordings on patients with chronie cough due to chronic bronchitis and obstruetive emphysema in this study failed to demonstrate that ethyl dibunate has any antitussive properties.
The role of dosage form in aspirin‐induced gastrointestinal bleeding
Authors: Leonards Jack R. , Levy Gerhard
Published: January 2016

The relationship of particle size of aspirin to gastrointestinal bleeding produced by this drug was examined in twelve healthy adults who received tablets containing the drug as fine particles, tablets containing relatively coarse particles of aspirin, and placebo tablets. Aspirin in the tablets containing the drug as fine particles dissolved and was absorbed from the gastrointestinal tract much more rapidly than aspirin in the tablets made with coarse particles. There was significantly more gastrointestinal bleeding during aspirin administration than during a control period in which no tablets were administered, but the difference in bleeding produced by the two types of aspirin tablets was not statistically significant. Placebo tablets did not cause gastrointestinal bleeding. Normal blood loss as determined du ring control periods and during placebo administration, respectively, showed a statistically significant correlation. However, subjects who bled rrwst in the control period did not necessarily bleed the most during aspirin administration.
A dinical eomparison of the analgesie effects of methadone and morphine administered intramuseularly, and oforally and parenterally administered methadone
Authors: Beaver W. T. , Wallenstein S. L. , Houde R. W. , Rogers A.
Published: January 2016

The relative analgesic potency of single graded intramuscular doses of methadone and morphine was evaluated in a double‐blind crossover study in patients with chronic pain due to cancer. If one considered either "total" or "peak" effects, the analgesic potency of methadone was estimated to be equal to or slightly greater than that of morphine. The time‐effect curves of the two drugs were similar, and there was no evidence that methadone was longer acting than morphine. Oral and intramuscular methadone were compared in a similar patient group. In terms of "total" effect, methadone was found to be approximately one half as potent orally as it was parenterally, a relatively high ratio for oral activity as compared with other narcotics. In roughly equianalgesic doses, the occurrence of side effects was qualitatively and quantitatively similar for parenteral morphine and methadone and for oral and parenteral methadone.
Phenacetin, through the looking glass
Authors: Shelley Julian H.
Published: January 2016

World literature on renal damage whieh has been attributed to phenacetin is reviewed and evaluated, together with ineidental effeets of the drug on other organ systems. Renal damage due to single drugs is found to be a rarity, and epidemiologieal, pathologieal, and elinieal data are often inadequate to provide a firm basis for the eoneept of "phenaeetin nephropathy." Partieular note is made of possible toxieity of other eommon eonstituents of analgesie mixtures and the meehanisms of renal damage. Animal experimental data is eollated and eompared, and the inadequaey of mueh experimental work is noted. More work, partieularly in the field of epidemiology, and further investigation of individual variation in metabolizing phenaeetin and other eommonly used analgesies are required. A note on existing legislation with regard to phenaeetin‐eontaining analgesies eoncludes the review.
Studies on beta‐aminopropionitrile in animals
Authors: Keiser Harry R. , Harris Edward D. , Sjoerdsma Albert
Published: January 2016

Single doses of f3‐aminopropionitrile (BAPN) were found to be relatively nontoxic in mice and rats and almost completely excreted in the urine, chiefly as cyanoacetic acid. Importance of oxidative deamination in the drug's metabolism was also indicated by delayed disappearance of the compound in mice pretreated with a monoamine oxidase inhibitor. When BAPN was administered repeatedly to rats, urinary hydroxyproline increased when there were onlyminimal signs of osteolathyrism. These findings provided the basis for prospective clinical trials.
A bioassay computer program for analgesic clinical trials
Authors: Laska E. , Gormley M. , Sunshine A. , Bellville J. W. , Kantor T. G. , Forrest W. H. , Siegel C. , Meisner M.
Published: January 2016

A Fortran program to calculate estimates of relative potency of a test to a standard analgesic is described. The program considers, at the option of the users, four distinct populations: completers, all of those patients who have completed a full crossover round of medication; two‐rounders, patients who have completed two or more rounds of medication; incompleters, patients who have not completed one or more rounds of medication; and first dose only patients, the initial administration received by all patients in the study whether or not they have dropped out. Up to six observations plus the initial reading for pain intensity scores and pain relief scores may be processed separately. The program also creates several summary variables including: SPID, an estimate of the area under the reciprocal of the pain intensity curve; TOTAL, an estimate of the area under the pain relief curve; and estimates of onset and duration as measured by relief scores and by pain intenSity scores. The program automatically performs calculations‐ for the analysis of variance and produces F values when appropriate for testing linearity of the log dose relationship, parallelism of the two curves for test and standard, and so forth. The paper discusses the rationale behind the approach adopted in the program.
An analysis of the placebo effect in hospitalized hypertensive patients
Authors: Moutsos Spero E. , Sapira Joseph D. , Scheib Eileen T. , Shapiro Alvin P.
Published: January 2016

A study was done in which six patients with moderately severe essential hypertension without significant end‐organ disease were hospitalized and treated with placebo only. Placebo was administered in gradually increasing doses and then discontinued in the reverse order. A significant fall in blood pressure from that seen in the outpatient clinic and that on admission to the hospital was demonstrated in all patients. Analyses of these data indicated that the major component to the decline was the hospitalization per se and not the administration of the placebo. Cumulative drug effects and dose‐response patterns were not noted with the placebo to any significant extent. A major component of the effect of hospitalization appears to be the removal of pressor stimuli of psychological origin including the procedure of the blood pressure measurement itself, in addition to physical inactivity. The data also demonstrated a striking difference between blood pressure readings taken by nurses and doctors, primarily in the systolic component. Following discharge from the hospital and initiation of specific drug therapy, blood pressure levels returned toward their original levels but did not rise as high as they had been preViously.
Oxygen therapy
Authors: Hedley-Whyte J. , Winter P. M.
Published: January 2016

Mea'iurements of abnormalities in the interrelationship of pulmonary ventilation and perfusion have become common in oxygen therapy. The techniques by which these measurements are now made and their value in guiding oxygen therapy are discussed. Each phase of oxygen transport to the tissues can be infiuenced by properly regulated oxygen therapy. Oxygen is a poison when given in too high a dose. Pulmonary oxygen toxicity occurs at tensions well below one atmosphere, and at higher tensions almost every cell in the body is affected. The results of hyperbaric oxygen therapy are frequently questionable, and the physiologic rationale often obscure; however, hyperbaric treatment, when properly regulated, will probably continue to have therapeutic application. Likely area‐i of usefulness for hyperbaric medicine are outlined.
The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid
Authors: Lucchesi B. R. , Schuster C. R. , Emley G. S.
Published: January 2016

The effect of intravenously administered nicotine upon smoking behavior was studied in smokers who were unaware of the nature of the administered drug and the true purpose of the study. Smoking behavior was not altered significantly when nicotine was administered in a dose of 1 mg. per hour for 6 hours. A significant decrease in smoking frequency was obtained when nicotine was administered at the rate of 2 to 4 mg. per hour. Recordings of systolic blood pressure, heart rate, and the elect1"Ocardiogram indicate that the physiological alterations in these parameters produced by smoking can be reproduced by parenteral nicotine.
Time‐series analysis of the effects of barbiturates on the electroencephalograms of psychotic and non psychotic men
Authors: Murphree Henry B. , Pfeiffer Carl C. , Goldstein Leonide , Sugerman A. Arthur , Jenney Elizabeth H.
Published: January 2016

Quantitative electroencephalography was used to determine differential neuropharmacological effects of barbiturates in chronic schizophrenic men and nonpsychotic male volunteers. The effects of oral pentobarbital and intravenous thiopental were compared in the two groups. The schizophrenic patients were relatively refractory to the sleep‐inducing effect ot the pentobarbital and showed attenuated responses to this drug in their electroencephalograms in comparison with the nonpsychotic subjects. The patients also showed quantitative electroencephalographic changes consistent with the clinical definition of greater !activation" after the thiopental. Both of these findings suggest that these patients, at least in the experimental setting, tend to be more !alerted" or !overstimulated" than the nonpsychotic subjects.
Pharmacology of animal venoms
Authors: Russell Findlay E.
Published: January 2016

The animal venoms are the most complex of all the poisons. The study of their physiopharmacological activities and the autopharmacological responses they produce is one of the most important new fields in toxicology. The value of venoms as tools in biochemistry and perhaps their use in the treatment of disease is also becoming apparent. Finally, the injuries produced by venomous animals are of considerable medical importance. Some 35,000 to 50,000 persons a year die from the bites or stings of these animals, and perhaps some 10 million persons are poisoned by them each year. With these things in mind, the author has attempted to review some of the more important chemical and pharmacological properties of the toxins of representative poisonous species from the marine fauna, terrestrial snakes and arthropods. Some consideration has also been given to the venom apparatus of several species and to the medical problem of envenomation.
Statistical ward rounds—6
Authors: Mainland Donald
Published: January 2016

In most of the preceding rounds we have, somewhat to my surprise, hardly moved around the ward at all, because there seemed to be so much to say about individual cases. In this round I propose to mention briefly many cases, hoping to return to them later, if readers will help.
Polypharmacy in twentieth century America
Authors: Hudson Robert P.
Published: January 2016

The medical practitioner of today is schooled in the scientific method. Yet in therapeutics he persists in curiously unscientific attitudes and practices. How will the social historian of a century hence reconstruct this apparent discrepancy between the physician's education and what he does with it? This piece attempts a partially fanciful analysis of the origins of a problem that is bound to loom more serious as the full story of iatrogenic disease is appreciated by the physician, who should already know, and the man in the street, who soon will.
Treatment of angina pectoris with chromonar hydrochloride
Authors: Bell Hubert , Azarnoff Daniel L. , Dunn Marvin
Published: January 2016

Forty‐one patients with angina pectoris were evaluated in a clinical study of the treatment of this disorder with chromonar hydrochloride. The study employed a placebo and a double‐blind crossover technique. A significant number of patients showed over‐all improvement when receiving 675 mg. of chromonar hydrochloride daily. Whereas there was no over‐all reduction in the quantity of nitroglycerin tablets required nor in the number of anginal attacks, the severity of anginal attacks was reduced and the number of weeks with improvement in exercise tolerance was significantly greater. Arthralgia and back pain were observed more frequently during the administration of the drug, and three patients refused to continue in the study because of this symptom.
The diuretic effect of desmethyl‐pipazuroyl‐guanidine (MK‐870) in man
Authors: Hitzenberger Gerhart , Kampffmeyer Hermann , Conway James
Published: January 2016

The diuretic properties of desmethyl‐pipazuroyl‐guanidine (MK) have been investigated in man and compared with hydrochlorothiazide (HC). In single‐dose studies MK (30 mg.) had a slower onset of action and lower peak response than H C. It caused K + retention and did not affect Cl output. When administered daily for five days, MK again had a lower peak response than HC, but its effect was maintained for a longer period and after five days the natriuresis produced by each drug was approximately the same. When MK and HC were given together, there was a greater natriuresis and the K loss produced by HC was reduced. Both diuretics lowered blood pressure, but MK appeared to be less effective than HC.
Indomethacin: A survey of clinical trials
Authors: O'Brien William M.
Published: January 2016

Clinical trials of indomethacin in rheumatic diseases are reviewed. In treating rheumatoid arthritis, the good results observed in uncontrolled subjective and objective evaluations have not been confirmed in recent controlled double‐blind trials. Failure to account for natural remission and cyclic variation in disease activity in uncontrolled trials probably explains these differences. There is no clear reason for preferring this drug over aspirin in treating rheumatoid arthritis. Indomethacin may be useful in treating other nonrheumatoid rheumatic diseases, but as yet few comparisons with standard therapies have been made. The drug has severe side effects and should be used with caution. Problems encountered in collecting information about this drug and its toxicity are discussed. The controlled double‐blind trial appears to be the only feasible method for assessing both the efficacy and the toxicity of drugs used in treating rheumatoid arthritis.
Effects of angiotensin and norepinephrine infusions on total plasma volume and extracellular fluid space in man
Authors: Werner Mario , Bock Klaus Dietrich , Brandenburger Juergen , Sack Horst
Published: January 2016

Pressor doses of angiotensin and norepinephrine were infused into normal subjects for 5 to 6 hours. 125I‐human serum albumin space, 82Br space, serum protein concentration, venous hematocrit, blood pressure, and pulse rate were determined at half‐hour intervals before, during, and after the infusions. There were no significant changes in the sizes of 125I‐human serum albumin space, 82Br space, and serum protein concentration during and after the administration of the pressor substances. It is concluded that under the conditions of these experiments angiotensin and norepinephrine cause no detectable water movements into or from the intravascular and extracellular space.
Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside
Authors: Loo Ti Li , Luce James K. , Sullivan Margaret P. , Frei Emil
Published: January 2016

Gastrointestinal absorption of 6‐mercaptopurine (MP) was incomplete and variable. After a single intravenous iniection, its plasma half‐life was 21 minutes in children and 47 minutes in adults. However, in 6 hours the cumulative urinary excretion of MP in each was about 20 per cent of the administered dose. The passage of MP into the red blood cells and into the cerebrospinal fluid was minimal. MP was 19 per cent bound to plasma protein. In contrast, the study on 6‐methylthiopurine ribonucleoside (MMPR) showed that the highest plasma level of radioactivity in patients on MMPR‐S35 occurred at 1 to 2 days following both oral and intravenous routes. Gastrointestinal absorption was complete. The half‐life of plasma radioactivity was 5 days. Radioactivity was concentrated within human red blood cells to a 40 to 1 concentration gradient over plasma; the radioactivity was in the form of MMPR 5'‐monophosphate. This anabolite persisted in the red cells for as long as 6 weeks. Excretion of radioactivity was slow and sustained, about 10 per cent daily of the MMPR dose. Only unchanged MMPR was detected in urine during the first day; in later urine samples, principally the 5'‐monophosphate was found. MMPR was largely excluded from the cerebrospinal fluid. It was 39 per cent bound to plasma protein.
Drug responses in hyperthyroid children suggesting an endogenous false transmitter
Authors: Prange Arthur J. , French Frank S. , McCurdy R. Layton , Van Wyk Judson J. , Lipton Morris A.
Published: January 2016

Alpha methyl dopa (AMD) is ineffective as a treatment for increased cardiovascular activity in hyperthyroid children. Reserpine produces some vascular improvement, but is less effective than thyroidectomy or propylthiouracil. During periods of AMD treatment, reserpine treatment, and no treatment, hyperthyroid patients were infused with norepinephrine (NE) and tyramine and their systolic blood pressure (BP) responses were measured. These infusions were repeated when the patients were euthyroid. AMD increased responses to tyramine in hyperthyroidism, as it does in normal and hypertensive states, but it did not affect response to NE. Reserpine treatment diminished responses to tyramine in hyperthyroidism and increased responses to NE, as it does in other conditions. In the untreated hyperthyroid state, as compared to the euthyroid state, responses to both tyramine and NE were increased. These clinical observations and evoked drug responses in hyperthyroidism can be explained by postulating the accumulation of the false transmitter octopamine in sympathetic nerves. The conditions which lead to octopamine accumulation in animals‐monoamine oxidase inhibition and tyramine increase‐are present in hyperthyroid human beings. We suggest that AMD has no beneficial effect on cardiovascular dynamics in hyperthyroidism because the AMD metabolite, alpha methyl NE, though a weak transmitter, is a more potent one than the false transmitter, octopamine, already present, which it partly replaces. The finding that BP response to tyramine (as well as to NE) is enhanced in untreated hyperthyroidism suggests increased total NE storage in nerve ends. This is consistent with the postulated accumulation of octopamine.
Blood levels of pentobarbital sodium, meprobamate, and tybamate in relation to clinical effects
Authors: Hollister Leo E. , Clyde Dean J.
Published: January 2016

Experiments are reported in which single therapeutic doses of central depressant drugs were given to normal volunteers with simultaneous measurement of blood levels of drug and clinical effects. In the case of pentobarbital, only one of nine possible correlations was significant; after eight hours, high serum levels of pentobarbital were correlated with high aggressive scores on a mood scale. In the case of meprobamate, none of six possible correlations at two time periods was significant, although the relationship between sleepy scores and high plasma levels approached significance both times. This relationship was confirmed for meprobamate in a third study, in which the presence of sleepiness as a symptom was associated with significantly higher levels of drug than its absence. Similar findings applied to tybamate in regard to the symptom of drowsiness. The relatively poor correlation between blood levels of central depressant drugs and clinical symptoms may be related in part to the difficulty of measuring relevant effects in normal men. In larger part, however, it may be due to the fact that social and personal factors more strongly influence the appearance of clinical effects from mild central depressants than do serum levels of the drugs.
How to HEW the FDA into shape
Authors: Modell Walter
Published: January 2016

Shortly before announcing his resignation from the Department of Health, Education, and Welfare, Secretary Gardner privately outlined plans for its reorganization, the result of about two years' study. Enough reliable information has leaked so that those interested have a good picture of what he wanted to do. What is most surprising is that this extraordinarily gifted public servant proposed no important help, significant internal changes, or fundamental improvement in the structure of the Food and Drug Administration itself, but as part of a new larger division it will continue to operate in the shadows of the enormous structure that is HEW. It is shocking to learn that improvement in this very important but inefficient administrative machine was not thought to be urgently needed. But it is urgently needed.
Doxycycline monohydrate and hyclate (Vibramycin Monohydrate and Hyclate)
Authors:   Pfizer Laboratories
Published: January 2016

Vibramycin ( doxycycline) is a new broad‐spectrum antibiotic synthetically derived from methacycline, available as Vibramycin Monohydrate (doxycycline monohydrate) and Vibramycin Hyclate (doxycycline hydrochloride hemiethanolate hemihydrate). The chemical designation of this light‐yellow crystalline powder is α‐6‐deoxy‐5‐oxytetracycline. Vibramycin ( doxycycline) possesses the following useful properties not observed with previously available tetracyclines: its greater absorption from the gastrointestinal tract and its capability for once‐a‐day maintenance dosage.
A comparison of the respiratory depressant effects of dextropropoxyphene and codeine in man
Authors: Bellville J. Weldon , Seed John C.
Published: January 2016

Twelve volunteers were given placebo and graded doses of codeine and dextropropoxyphene to determine the relative respiratory potency of oral dextropropoxyphene and oral codeine. Carbon dioxide response curves were prepared from data accumulated with a rebreathing technique. The relative respiratory potency, p, was calculated as 0.33. According to this calculation, 180 mg. of dextropropoxyphene administered orally produces respiratory depression equal to that of 60 mg. of codeine orally.
Pharmacology of amino acids
Authors: Milne M. D.
Published: January 2016

In a review of the pharmacology of amino acids twenty years ago,16 it was stated that “simple amino‐acids do not show startling drug reactions.” This statement is basically true today, but in the intervening years amino acids which are not constituents of protein have been discovered at an average rate of about ten per year.157 In addition, there has been an awakening of interest in the effects of general and specific amino acid excess and deficiency, and a realization that chronic amino acid imbalance, found in one of the most common of human diseases, malnutrition, and in the rare but instructive inborn errors of amino acid metabolism, gives important information of the pharmacology of amino acids in man. In a discussion of the pharmacology of important natural products the boundaries between physiology and pharmacology become blurred, but in this review the latter aspect will naturally be emphasized.
A comparative clinical trial of metaproterenol and isoproterenol as bronchodilator aerosols
Authors: Holmes Thomas H. , Morgan Beverley
Published: January 2016

A double blind cross‐over trial of the responses of asthmatic patients to 2 microaerosol bronchodilators, isoproterenol and metaproterenol, was conducted. Drug effects were followed for 6 hours, with the use of 3 indices of pulmonary function. Effects on blood pressure, pulse rate, and subjective sensations were monitored. The results indicated significantly greater duration of action following administration of metaproterenol. Although this drug was given in higher dosage by weight, fewer side effects appeared than after inhalation of metaproterenol. The mean improvement in lung function was not significantly different, but the peak effect of metaproterenol inhalation occurred somewhat later than that of the isoproterenol.
Phenylalanine tolerance tests in patients receiving chloramphenicol
Authors: Weksler Marc E. , Bourke Edmund , Schreiner George E.
Published: January 2016

Chloramphenicol has been shown to inhibit the intestinal transport of phenylalanine in animals. Phenylalanine tolerance tests were performed on 22 patients receiving chloramphenicol. Serum phenylalanine levels were depressed in patients with chloramphenicol‐induced hematopoietic toxicity. This alteration in phenylalanine tolerance did not precede the development of hematopoietic toxicity. Impaired intestinal transport of phenylalanine is the most likely explanation for the reduced blood levels. Defective transport of phenylalanine is another manifestation of chloramphenicol toxicity in man.
Mortality of bereavement
Authors: Mainland Donald
Published: January 2016

This is the title of a report12 by a medical practitioner and a statistician on a study of the mortality among persons who had recently lost a close relative by death. The summary ends thus: “People who die following a bereavement are on average slightly younger than the relatives who predeceased them, and they die at an earlier age than is usual for the community in which they live.” It was this sentence that prompted the Editor of this JOURNAL to send me a copy of the report with the following comment: “The last sentence floored me. However I look at it, it means that either (1) an overwhelming number of persons die without anyone caring at all, or (2) there is a progressive and inevitable downward trend in the lifespan of communities sharing this phenomenon. What is the flaw?”
Fentanyl (Sublimaze)
Authors:   McNeil Laboratories, Inc.
Published: January 2016

Sublimaze (fentanyl) is a piperidine derivative with the following chemical name: N‐(1‐phenethyl‐4‐piperidyl) propionanilide. It is a potent narcotic analgesic with a rapid onset and short duration of activity.
To the fullest extent
Authors: Goddard James L.
Published: January 2016

Through the accidenee of history, I find that one of my last presentations as Commissioner of Food and Drugs is here before an audienee of doctors and lawyers. Of all professions, I suspeet that those of medicine and law have been represented most often around my conference table in Washington during the past 29 months.
Liver disease in narcotic addicts I. The role of the drug
Authors: Gorodetzky C. W. , Sapira J. D. , Jasinski D. R. , Martin W. R.
Published: January 2016

Liver function tests were performed on 20 human volunteers before, during, and after the long‐term administration of morphine. No significant differences in the serum glutamic‐oxaloacetic tramaminase, serum glutamic‐pyruvic tramminase, thymol turbidity, or cephalin flocculation were found. It is concluded that the high incidence of abnormal liver function tests observed in morphine and heroin addicts is not due to a direct hepatotoxic effect of the drug.
Evaluation of a synthetic 25 amino acid corticotrophin in normal man
Authors: Rose Leslie I. , Williams Gordon H. , Jagger Paul I. , Lauler David P.
Published: January 2016

A synthetic 25 amino acid corticotrophin was evaluated in normal man. Graded doses of the corticotrophin (DW‐75) were administered intramuscularly to 4 subjects and intravenously to 4 subjects. Urinary 17‐ketosteroids and 17‐hydroxycorticosteroids and plasma cortisol responses were measured. The intramuscular route of administration resulted in little change from the control periods in the parameters monitored. The drug had a potent adrenocortical‐stimulating effect when administered intravenously. No side effects were encountered during the study.
Impaired water excretion following diuretic therapy
Authors: Peña José Carlos , Ruíz Francisco , Abraham Juan
Published: January 2016

Water excretion in normal subjects during water loading was impaired after the administration of the short‐acting diuretics, mannitol, quinethazone, furosemide, and ethacrynic acid. Correlation between antidiuresis and body‐fluid‐volume depletion was established. Minimum contraction of body‐fluid volume is postulated as the cause of the antidiuresis. It is postulated that free water formation in the urine is regulated by several intra‐ and extrarenal factors; the role of the antidiuretic hormone is uncertain.
Kinetics of pharmacologic effects in man: The anticoagulant action of warfarin
Authors: Nagashima R. , O'Reilly R. A. , Levy G.
Published: January 2016

The kinetics of many pharmacologic effects of drugs in man can be described by mathematical expressions that are based on apparent first‐order elimination of the drug and on an essentially linear relationship (over the clinically significant range) between the intensity of the elicited effect and the logarithm of the dose or concentration of the drug in the blood. The maximum prothrombinopenic response to the coumarin anticoagulant drug, warfarin, appears 2 to 4 days after the administration of a single dose of the drug and the occurrence of the peak plasma levels. However, it is shown in the present study that the pharmacologic effect of warfarin, when expressed in terms of the degree of inhibition of “prothrombin complex activity synthesis rate,” follows the classical relationship previously described. Thus, there is a linear relationship between the logarithm of drug concentration in plasma at a given time and the pharmacologic effect at that time, and the pharmacologic effect declines at a constant rate following cessation of therapy. The prothrombinopenic effect of warfarin as a function of time after drug administration can now be predicted effectively by use of a mathematical relationship based on the dose or the initial concentration of the drug, the rate constants for warfarin elimination and for prothrombin complex activity decline, and the slope of the log‐plasma concentration‐response plot for the drug. The pharmacokinetic approach used in this study may also be applicable in principle to the kinetic analysis of other types of apparently delayed pharmacologic effects.
Clinical evaluation of amiloride, a potassium‐sparing diuretic
Authors: Lant Ariel F. , Smith Anthony J. , Wilson Graham M.
Published: January 2016

Amiloride (MK 870), a new potassium‐sparing diuretic belonging to the pyrazine carboxamide class was evaluated in 34 hospitalized patients with fluid retention. The drug increased the excretion of sodium, chloride, and water but decreased potassium excretion. The major natriuretic effects of the drug were complete within 24 hours but in a few patients some potassium‐sparing lasted longer. The therapeutic efficacy of amiloride was compared with that of triamterene at ceiling dosages selected from the early portion of the dose‐response plateaus of the 2 drugs. The natriuretic and potassium‐sparing efficacies of 40 mg. amiloride were significantly greater than those of 200 mg. triamterene. At submaximal dosages, amiloride potentiated the natriuresis and reduced the potassium loss evoked by ethacrynic acid. The potassium‐retaining action of amiloride was apparent even in the presence of full doses of spironolactone.
The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man
Authors: MacDonald Murdo G. , Robinson Donald S. , Sylwester David , Jaffe Julian J.
Published: January 2016

Ten male volunteers received phenobarbital, glutethimide, chloral betaine, and a placebo at bedtime for 3 week periods. Plasma warfarin levels and prothrombin times were determined after a single oral dose of warfarin prior to and immediately following placebo or hypnotic drug treatment. Glutethimide and phenobarbital lowered the plasma warfarin concentration and reduced the half‐life of warfarin by nearly 50 per cent. Chloral betaine had less effect but differed significantly from control values. Phenobarbital and glutethimide interfered with the hypoprothrombinemic effect of warfarin; chloral betaine and placebo did not. The findings suggest increased metabolic inactivation of warfarin by induction of liver microsomal enzymes.
Quinine, pyrimethamine, and sulphorthodimethoxine: Clinical response, plasma levels, and urinary excretion during the initial attack of naturally acquired falciparum malaria
Authors: Brooks Marion H. , Malloy John P. , Bartelloni Peter J. , Sheehy Thomas W. , Barry Kevin G.
Published: January 2016

Plasma concentrations and urinary excretion rates of antimalarial drugs were studied during acute illness in 15 patients with naturally acquired falciparum malaria despite chloroquine‐primaquine prophylaxis. The therapeutic regimen included single oral doses of sulphorthodimethoxine and pyrimethamine in combination with a 14 day course of quinine. The plasma half‐life of a 1 Gm. dose of sulphorthodimethoxine was 200 hours with levels exceeding 8 mg. per 100 ml. for 4 days. Plasma‐pyrimethamine concentrations remained relatively stable during the 14 day study. For both drugs a slow rate of urinary elimination accounts for sustained plasma levels following single doses. Doses of 650 mg. of quinine every 8 hours produced mean plasma levels in excess of 11 mg. per liter during the first 5 days. Thereafter the concentration gradually declined to levels observed in patients receiving quinine during relapse and experimental infections. Transient hepatic dysfunction during the acute phase of the illness may account for the initial elevation and subsequent decline during continued administration. In all patients the clinical illness was promptly controlled and no toxicity developed. There were no relapses. The advantages of single‐dose oral therapy, the promising clinical results, and low incidence of toxicity suggest that sulphorthodimethoxine may be an important antimalarial drug and that further clinical and pharmacological investigation is warranted.