bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of the availability of six commercial formulations of isoniazid
Authors: Gelber Robert , Jacobsen Peter , Levy Louis
Published: January 2016

The systemic availability of six formulations of isoniazid (INH) were compared. Each of 6 subjects ingested approximately 10 mg. per kilogram each of six formulations of INH. Plasma samples obtained at ¼, ½, ¾, 1, 1 ½, 2, 4, 6, and 8 hours after ingestion were analyzed for unmetabolized INH. In order to enable calculation of gastrointestinal absorption kinetics, subjects received an intravenous dose of isoniazid with subsequent INH plasma concentration determinations. Studies of tablet potency, disintegration time, and dissolution rate were also conducted and correlated with in vivo results. All tablets met U.S.P. standards for potency (100 ± 7 mg.) and disintegration time (30 minutes), and all tablets dissolved rapidly. No significant differences were noted among formulations in mean peak INH concentrations (range 10.3 to 11.4 µ.g per milliliter) or in the integral of INH concentration with respect to time between 1 and 8 hours (range 37.5 to 41.4 µ.g‐hr./ml.). All tablets were essentially completely absorbed by one hour, and gastrointestinal absorption rate calculations demonstrated no consistent differences among the INH formulations studied. It was concluded that the INH preparations studied were therapeutically equivalent.
The effect of organic acids on renal clearance of methotrexate in man
Authors: Liegler Donald G. , Henderson Edward S. , Hahn Mary Anne , Oliverio Vincent T.
Published: January 2016

The renal clearance of the folic acid antagonist, methotrexate, was compared with that of inulin and para‐aminohippurate in 15 patients with disseminated malignancy. The clearance of methotrexate exceeded that of inulin clearance in all cases, indicating methotrexate is not only filtered but is also actively secreted by the renal tubules. The simultaneous intravenous administration of weak organic acids resulted, generally, in suppressive effects on the clearance of methotrexate. Salicylate and high concentrations of para‐aminohippurate reduced methotrexate clearance well below the glomerular filtration rate; whereas, sulfisoxazole had only a minimal effect on total methotrexate clearance. The variations of plasma protein binding of methotrexate induced by these same drugs did not correlate with the direction or degree of methotrexate clearance. It is concluded from these studies that methotrexate is excreted by a combination of glomerular filtration and active tubular transport and that methotrexate clearance is not directly related to the level of free methotrexate presented to the kidneys. It is furthermore suggested that the alterations in plasma protein binding and renal clearance of methotrexate provoked by the simultaneous administration of other organic acids may be clinically exploitable in cancer chemotherapy.
Serum electrolyte abnormalities associated with the administration of polymyxin B in febrile leukemic patients
Authors: Rodriguez Victorio , Green Sheldon , Bodey Gerald P.
Published: January 2016

One hundred and seven courses of treatment with polymyxin B sulfate were studied retrospectively in 57 adults with acute leukemia. There was severe hyponatremia, hypochloremia, hypokalemia, and azotemia in patients with normal blood values prior to initiation of therapy. Hypocalcemia was found in most patients in whom serum calcium was determined. Excretion of electrolytes in urine was excessive and suggested that the renal tubules were a site of toxic reaction. The toxicity of polymyxin B was related to the duration of therapy and total dose of antibiotic.
A new name—and some other changes of the guard
Authors: Feinstein Alvan R.
Published: January 2016

With this issue, the regular column, "Statistical ward rounds," formerly conducted by Dr. Donald Mainland, receives a new title and a new author. Dr. Feinstein is Chief of Clinical Biostatistics and of the Eastern Research Support Center at the West Haven Veterans Administration Hospital. He is also Professor of Medicine and Epidemiology at the Yale University School of Medicine.
Clinical antidepressant activity of cyclazocine—a narcotic antagonist
Authors: Fink Max , Simeon Jovan , Itil Turan M. , Freedman Alfred M.
Published: January 2016

Cyclazocine is a benzomorphan derivative with analgesic and antinarcotic activity. During a clinical evaluation in the treatment of opiate dependence, elation, insomnia, and increased libido with administration and a “grippe‐like” syndrome on acute withdrawal were recorded as secondary effects. In the scalp‐recorded electroencephalogram (EEG), desynchronization, decreased alpha abundance, and increased fast and theta activities were recorded concurrently. Because the clinical and EEG patterns were most similar to those with the tricyclic antidepressants, a clinical trial in depressive disorders was undertaken. In an open clinical trial in severely depressed chronic mentally ill patients, improvement in depressive symptoms and in clinical evaluations occurred within 4 weeks in 8 of 10 subjects, receiving 1.0 to 3.0 mg. of cyclazocine daily. In a clinical trial in imipramine treatment failures in an outpatient mental health clinic, 10 of 19 patients improved in depressive symptoms within 8 weeks at dosages of 1.0 to 3.0 mg. daily. In both studies, secondary effects were common, suggesting a narrow therapeutic range. Cyclazocine is an active antidepressant as well as an active antinarcotic agent. The antidepressant activity is correlated with the EEG patterns and is consistent with recent EEG classifications of psychoactive drugs. The antidepressant activity does not seem to be related to the antinarcotic activity. In the treatment of opiate dependence, the efficacy of cyclazocine may be related in part to its antidepressant activity.
Modification of the effects of atropine on human heart rate by pralidoxime
Authors: Sidell Frederick R. , Magness Josephine S. , Bollen Thomas E.
Published: January 2016

Eight subiects each received atropine and pralidoxime alone, simultaneously but separately, and also mixed in the same iniection. Heart rates were counted as an indication of absorption of atropine. When the drugs were mixed before iniection, the heart rate response had a significantly longer latent period than that when they were given simultaneously but separately. The addition of pralidoxime to atropine somehow impedes the action of atropine.
Clinical evaluation of perhexiline maleate
Authors: Winsor Travis
Published: January 2016

In a crossover double‐blind study of patients with well‐documented histories of angina pectoris, perhexiline maleate, 100 mg. 4 times a day orally, significantly decreased the number of anginal attacks. The exercise heart rate was slower during perhexiline treatment than that before treatment or during placebo treatment. Occasional evidence (3 of 10 patients) of electrocardiogram improvement was noted and similar evidence (4 of 8 patients) of the exercise tolerance test was encountered. No significanct adverse effects were noted.
Increasing the usefulness of antibiotics: Treatment of infections caused by gram‐negative bacilli
Authors: Sabath Leon D. , Gerstein Deborah A. , Leaf Charles D. , Finland Maxwell
Published: January 2016

Resistance of gram‐negative bacteria to many antibiotics often necessitates the use of relatively toxic antibiotics to treat infections caused by organisms that are resistant to less toxic ones. However, some relatively nontoxic antibiotics that appear to be ineffective against many gram‐negative bacilli by conventional tests can, in some instances, be made much more active by appropriate adjunctive measures. The measures studied were: (1) the use of analogues to inhibit destruction of antibiotic by bacterial enzymes (more specifically penicillinases) and (2) adfustment of the pH of the medium to maximize antibiotic activity. Both were applied to patients with infections caused by gram‐negative bacilli. Ampicillin plus a ±‐Iactamase inhibitor, cloxacillin, were used to treat a patient with endocarditis due to Enterobacter cloacae. Gentamicin was found to be 100 or more times as active in vitro at pH 8.5 as at pH 5.0 against most strains of gram‐negative bacilli that were studied. The concomitant use of bicarbonate or acetazolamide to allcalinize the urine permitted the use of this antibiotic in a much reduced dose.
Serum lipids during oral contraceptive exposure
Authors: Corredor D. G. , Mendelsohn L. V. , Sabeh G. , Sunder J. H. , Danowski T. S.
Published: January 2016

The serum total cholesterol did not change significantly du ring 6 to 60 months of exposure to an oral contraceptive steroid combination (mestranol and norethynodrel). Alpha lipoprotein levels increased and remained slightly elevated. Serum total triglycerides increased during the sixth to eighteenth month of exposure only.
Correlation of prothrombin time tests with hemorrhage and thromboembolism in patients under long‐term anticoagulant therapy
Authors: Boyles Paul W.
Published: January 2016

The efficacy of the one‐stage prothrombin time (PT) test for control of long‐term anticoagulant therapy is similar to that of tests employing four different extrinsie thromboplastins and to the efficacy of the two‐stage prothrombin assay. For all of 10 patients who bled du ring long‐term anticoagulant therapy, the PT ratios were 2.2 or greater, whereas the values in the thrombotest and thromboplastin generation test were in a "safe" range for 30 per cent of these patients. The PT thrombotest and prothrombin assay performed for patients who hemorrhaged during treatment with anticoagulants yielded a significantly greater number of abnormal results (less than 10 per cent activity) than did the same tests performed for patients who did not bleed. During prolonged anticoagulant therapy, PT values of 1YWre than 30 seconds are not associated with recurrent myocardial infarction, thromboembolism, and death. However, when PT values are 30 seconds or greater, bleeding often occurs.
Effects of antihypertensive drugs in the spontaneously hypertensive rat
Authors: Tabei Ryo , Spector Sydney , Louis William J. , Sjoerdsma Albert
Published: January 2016

The spontaneously hypertensive rat is reported as a useful model to screen for antihypertensive drugs. Single doses of several d1"Ugs which have been useful therapeutically in man, including methyldopa and the MAO inhibitor pargyline, elicited a lowering of blood pressure in the spontaneously hypertensive animal. N ormotensive rats were generally unresponsive. For initial screening, indirect measurement of systolic blood pressure in the tail artery is recommended, but any changes observed should be validated by direct recording and possibly long‐term study.
The American Society of Clinical Pharmacology and Chemotherapy
Authors: Frohlich Edward D.
Published: January 2016

9:00 Trial of Methotrexate Riehard Gubner, M.D., State University of New York Downstate College of Medicine, Brooklyn, N. Y.
Some aspects of the pharmacology of oral anticoagulants
Authors: Coon William W. , Willis Park W.
Published: January 2016

The pharmacology of oral anticoagulants ls discussed with particular rejerence to data of value in the management of therapy. The importance of individual variability in response and drug interaction is stressed. Other effects of these agents which may have clinical utility are noted.
Kinetics of the anticoagulant effect of bishydroxycoumarin in man
Authors: O'Reilly R. A. , Levy Gerhard , Keech Geraldine M.
Published: January 2016

There is no direct relationship between the inhibition of prothrombin complex activity at any time and the plasma bishydroxycoumarin concentration at that time. It is shown that there is an essentially linear inverse relationship between synthesis rate of prothrombin complex activity and the logarithm of plasma bishydroxycoumarin concentration. This relationship is independent of the route of administration of the anticoagulant and is not affected by pretreatment with the microsomal enzyme inducer heptabarbital. There is a similar linear relationship between synthesis rate and log plasma concentration for warfarin. In subiects who yielded approximately parallel synthesis rate versus log plasma concentration regression lines for the two anticoagulants, warfarin was 6 to 10 times as potent as bishydroxycoumarin.
Effects of short‐ and long‐term administration of pentazocine in man
Authors: Jasinski Donald R. , Martin William R. , Hoeldtke Robert D.
Published: January 2016

Pentazocine produces morphine‐like subjective effects. A dose of 60 mg. per 70 Kg. produces subjective effects which more closely resemble those of nalorphine than those of morphine. Pentazocine will not suppress abstinence symptoms in subjects dependent on either 60 or 240 mg. per day of morphine. Pentazocine is 1/50 as potent as nalorphine in precipitating abstinence symptoms in subiects dependent on 240 mg. of morphine per day. Long‐term administration of pentazocine produces dependence which has elements of both morphine and nalorphine dependence. It is concluded that pentazocine has an abuse potential which is less than that with morphine but greater than that with nalorphine.
The fate of guanethidine in two hypertensive patients
Authors: McMartin C. , Rondel R. K. , Vinter J. , Tec B. , Allan B.R. , Humberstone P.M. , Leishman A.W.D. , Sandler G. , Thirkettle J.L.
Published: January 2016

Metabolites of [3H]‐guanethidine were identified in human urine. It was found that 90 per cent of the radioactivity in urine could be accounted for as guanethidine and two metabolites which had much less antihypertensive activity. After intramuscular injection, 50 per cent of the radioactive dose was eliminated in the urine in the first 2 to 3 days and 2 to 3% in the feces. Thereafter the dose left in the body declined exponentially with a half‐life of 9 to 10 days. Plasma level measurements indicated high renal clearance for guanethidine (300 ml. per minute). The hepatic clearance of the drug was also estimated to be high. The long half‐life of the drug is therefore not due to inefficient metabolism or renal clearance and must be due to a high degree of tissue localization. After an oral dose, plasma levels of the drug stayed approximately constant from 1 to 10 hours, indicating slow but continuous absorption of the drug, while radioactivity in the urine showed that absorption was incomplete. The ratio of metabolites to unchanged guanethidine in the urine was much larger after oral than after intramuscular administration of guanethidine to the same patient, suggesting that a significant amount of the drug was metabolized while passing through the liver. The results indicate that absorption, renal clearance, metabolism, and tissue uptake of guanethidine all play important parts in determining the amount of drug in the body of patients receiving regular treatment.
Pentamidine: Clinical pharmacologic correlations in man and mice
Authors: Waalkes T. Phillip , Denham Charlene , DeVita Vincent T.
Published: January 2016

Patients with malignant disease complicated by diffuse interstitial pneumonia due to proved or suspected Pneumocystis carinii were given pentamidine in the dosage schedule recommended for this infection. By means of a sensitive method of assay, the plasma levels and urinary excretion of pentamidine during therapy were studied in these patients. Following the intramuscular administration of pentamidine, plasma levels were low and urinary excretion prolonged. After a single intraperitoneal injection in mice, the tissue distribution levels and excretion pattern for pentamidine were determined at various time intervals. There was storage of the drug in tissues and excretion was delayed. The highest concentration of pentamidine was found in the kidney. In mice pentamidine is eliminated primarily intact with little, if any, altered. The available data in man also suggested that pentamidine is retained, bound to tissues, and excreted over an extended period. Although renal abnormalities followed pentamidine, it was not possible to implicate the drug in all cases because of the seriousness of the illness and the concomitant use of other drugs. Pentamidine is useful in preventing disease due to Trypanosoma gambiense as well as effective in the treatment of diffuse interstitial pneumonia due to Pneumocystis carinii. The frequency of this type of pneumonia in cancer patients and in patients undergoing organ transplantation suggests the need for studies in animals and man.
Elderfield pyrimidine mustard in chronic lymphocytic leukemia
Authors: Louis John , Wright Thomas L. , Dessel Bert H. , Wilson Henry E. , Louis Nicholas B.
Published: January 2016

Eighty patients with chronic lymphocytic leukemia received one of 4 doses of elderfield pyrimidine mustard (EPM) orally with an antacid. Complete remissions were induced in 7 (8.7 per cent), whereas 31 others (38 per cent) developed remissions of lesser degree. The lymphocyte counts decreased to normal levels in 38 (47.5 per cent). In 26 patients (32.5 per cent) the differential leukocyte count became normal. Bone marrow suppression and gastroenteropathy were the principle toxic manifestations; these subsided promptly when EPM was discontinued. The optimum divided daily dose of EPM appears to be 0.25 mg. per kilogram.
The effect of hydrochlorothiazide on venous reactivity in hypertensive man
Authors: Ogilvie Richard I. , Schlieper Eckart
Published: January 2016

Peripheral venous reactivity was measured by the occluded limb technique in 14 subjects with essential hypertension during a single‐blind trial of hydrochlorothiazide (HCT) therapy. Venoconstriction in response to deep‐breath and Valsalva maneuvers decreased during HCT 150 mg. per day with a concommitant decrease in systemic blood pressure and serum potassium concentration. Further decreases in venous reactivity occurred during treatment with HCT 450 mg. per day which doubled serum HCT concentrations from that achieved on 150 mg. per day, and there was a further decrease in systolic but not diastolic blood pressures. Venous reactivity increased during placebo therapy after HCT. The venoconstriction responses of these hypertensive subjects during placebo therapy were not significantly different from those of 9 normotensive volunteers. The results show that there was a redu.ced response of the capacitance bed to neu.rogenic stimuli during HCT therapy.
A theory of motion sickness based on pharmacological reactions
Authors: Wood Charles D. , Graybiel Ashton
Published: January 2016

A series of anti‐motion sickness drug evaluation experiments has been performed at the Naval Aerospace Medical Institute in Pensacola. Carefully controlled laboratory conditions using the slow‐rotation room were maintained. The results were confirmed by similar experiments in the air and at sea. The effective drugs fell into two categories, those that blocked acetylcholine in the central nervous system and those which activated the central sympathetic areas. A combination of drugs involving both of these mechanisms was the most effective preparation for preventing motion sickness. These results have indicated that there may be competitive neural systems involved with motion sickness, one activated by acetylcholine and one most likely mediated by norepinephrine. Motion sickness would occur when activation of the acetylcholine system disturbed this balance, and protection of the motion sickness drugs would be achieved by preventing it.
Clinical evaluation of flufenisal, a long‐acting analgesic
Authors: Bloomfield Saul S. , Barden Thomas P. , Hille Ravinna
Published: January 2016

The analgesic activity of 300 and 600 mg. of flufenisal, a fluorinated phenyl derivative of aspirin, was compared to 600 and 1,200 mg. of aspirin and to placebo under randomized double‐blind conditions in 100 patients with pain due to episiotomy. Over the 8 hours of evaluation, pain reduction greater than 50 per cent was observed in at least 60 per cent of patients treated with both doses of flufenisal, whereas it was 40 per cent with 600 mg. of aspirin, 55 per cent with 1,200 mg. of aspirin, and 26 per cent with placebo. On a time‐effect basis with the two graded doses of both flufenisal and aspirin, pain relief, as measured by pain intensity differences, was similar with respect to time of onset and maximal effect attained. However, with the flufenisal significant analgesia persisted at the eighth hour (p < 0.02), while with the aspirin there was none after the fifth hour. On the basis of these data, flufenisal at one fourth to one half the dose of aspirin appears to provide analgesia of almost double the duration of aspirin and is equivalent to aspirin in time of onset and degree of relief of episiotomy pain. This raises the possibility that in some clinical conditions flufenisal may be effective in providing prolonged pain relief.
Drug‐induced leukopenia and aplastic anemia
Authors: Pisciotta Anthony V.
Published: January 2016

Hematopoietic damage following treatment with certain medications remains a major problem of drug therapy. As long as drugs remain indispensable in the treatment of disease, this problem cannot be resolved simply by avoiding their use. Instead, development of information that pertains to the mechanism and prediction of drug‐induced blood dyscrasias must be acquired for the safe use of drugs. Forewarned is forearmed; if it were possible to identify a susceptible patient or a potentially dangerous drug, then the potential risk of producing a serious blood re action with treatment would be minimized. A precedent for this concept was established with the discovery that patients whose erythrocytes are deficient in glucose‐6‐phosphate dehydrogenase are unusually susceptible to hemolytic anemia if treated with oxidant drugs.41 For most of the other toxic blood dyscrasias, knowledge of the pathogenesis remains obscure because certain difficulties limit acquisition of such information. The mechanisms of a drug reaction produced by one drug may differ from that produced by another drug. Also, the rare incidence of druginduced blood dyscrasias has made very few patients available for studies. Few papers have appeared which deal with the mechanism of drug‐induced hematopoietic disease. In addition, the difficulties entailed in obtaining bone marrow and other specimens in sufficient quantity has restricted effective investigation. Since the technique required to study mechanisms of drug reactions may be complex and expensive, it may be logistically unsound for a laboratory to “tool up” and then sit back and wait for the first patient to arrive.
Genetic and environmental influence on halothane metabolism in twins
Authors: Cascorbi H. F. , Vesell E. S. , Blake D. A. , Helrich M.
Published: January 2016

Wehave shown that normal human volunteers convert between 5 and 25 per cent of a small intravenous dose of halothane‐C14 to a urinary metabolite.2 The large individual variations in the extent of halothane biotransformation were thought to be attributable at least in part to exposure, because anesthesiologists who used halothane had a high capacity for metabolizing it. In order to evaluate possible genetic determinants, ten pairs of (identical and fraternal) twins, in whom antipyrine half‐life had been previously measured, were studied.9, 12 For both antipyrine and halothane, intrapair difJerences were less in identical than in fraternal twins. The normalized intrapair per cent difJerences of halothane metabolite excreted in 24 hours varied from 2.4 to 17.3 per cent in identical twins and from 2.9 to 70.0 per cent in fraternal twins. In individual twins there was no correlation between capacity to metabolize halothane and antipyrine half‐life.
Emotional disturbance accompanying the treatment of parkinsonism with L‐dopa
Authors: Cheifetz David I. , Garron David C. , Leavitt Frank , Klawans Harold L. , Garvin John S.
Published: January 2016

This paper reports a study, using systematic observation, interview, and psychological examination, in a sample of 34 patients receiving L‐dopa for parkinsonism. Our results do not support the suggestion that disturbances of mood and behavior are to be expected. We concluded that the chances of adverse emotional side reactions to L‐dopa appear to be minimal when the dosage level does not exceed 4 Gm. per day and the subjects are emotionally stable prior to treatment.
The effect of allopurinol on the hyperuricemia of fasting
Authors: Drenick Ernst J. , Fisler Janis L. , Dennin Herbert F.
Published: January 2016

Fasting obese subjects were treated with allopurinol or probenecid in order to prevent systemic and renal complications of hyperuricemia. Allopurinol in a dose of 600 mg. per day curbed excessive urate synthesis during early fasting. Renal urate excretion in the allopurinol‐treated subjects was the same as that of untreated patients. Urinary oxypurine excretion increased 400 per cent during administration of allopurinol. When 600 mg. of allopurinol per day was given during the first month of fasting and 300 mg. per day during the second month, a uricosuric agent was not needed. Stable and near normal serum urate levels during the second month of fasting could be maintained in some subjects with the aid of uricosuric probenecid, permitting a gross estimate of a daily urate turnover rate of 480 to 500 mg. This suggests that during prolonged fasting, the initially accelerated catabolism of nucleoprotein decreases, although to a lesser degree than that of body protein in general.
The absorption and metabolism of guanethidine in hypertensive patients requiring different doses of the drug
Authors: McMartin c. , Simpson Phillida
Published: January 2016

To find out whether difJerences in absorption and metabolism are responsible for the Zarge variation in dose requirement of guanethidine, the quantities of the drug and its metabolites exereted in the urine were measured with the use of a chromatographie method for the separation and quantitative assay of basic drugs in urine. All patients were found to excrete unehanged drug and two metabolites. The percentage of the dose absorbed varied from 3 to 27 per cent, but this was not the only factor determining dose requirement of the drug because the absolute amount of drug absorbed also varied eonsiderably (6.4 to 30 mg. per day).
Effects of atropine on the electrocardiogram in different age groups
Authors: Dauchot Paul , Gravenstein J. S.
Published: January 2016

In 79 patients who had no cardiovascular disease and were scheduled for elective operations, 1 mg. of atropine sulfate per 70 Kg. was given in divided doses and electrocardiogram tracings were recorded. The patients' ages ranged from 6 weeks to 79 years. In the young, relatively more atropine was required to accelerate heart rate than was required in adults. In the oldest age group, the tachycardic response to atropine was decreased. Arrhythmias occurred in over 20 per cent of the population but particularly frequently in the young. In adults atrioventricular (A‐V) dissociation was common, and in children atrial rhythm disturbances were common. Arrhythmias were associated with small rather than large doses of atropine.
Introduction
Authors: McDowell Fletcher
Published: January 2016

One of the important developments in American medicine in the past fifteen years has been the cooperative study. These studies have been designed to gather rapidly infonnation about a therapy, a therapeutic technique, or a disease state using the facilities and information available from a large number of hospitals and medical centers.
Levodopa and parkinsonism: Clinical impressions
Authors: Yahr Melvin D.
Published: January 2016

Data are presented in support of establishing levodopa as the most efficacious pharmacologic agent available for the treatment of parkinsonism at the present time. Most of its side reactions are generally of a tolerable nature. Involuntary dyskinetic movements following longterm therapy are, however, often intolerable. One such case history of self‐imposed discontinuation of the drug is presented, and the effects of reinstitution of therapy with appropriate dose adjustment are described. Autopsy material obtained in 4 patients indicates no adverse reactions in any vital organs. Further study, however, is essential to determine its long‐term effects, both benefiCial and adverse. It is urged that those involved in the continuing collaborative study exert efforts to obtain pathologic material whenever it becomes available for such study.
The choreoathetoid movement disorder induced by levodopa
Authors: Markham Charles H.
Published: January 2016

Dyskinesia as a side effect induced by long‐term treatment with levodopa is reported on the basis of experience with 100 patients with Parkinson's disease receiving the agent for at least one year. The sex ratio of the patients was approxirrwtely 2:1 male to ferrwle, and their ages, duration of illness, and the etiologic distribution of idiopathic to postencephalic types were characteristic of a parkinsonian population. Concomitant with clinical improvement demonstrated by patients under levodopa treatment, choreoathetosis appeared as irregularly occurring involuntary movements, involVing head, face, jaw, tongue, shoulder, limbs, or trunk. These movements were usually exaggerated by voluntary movements, and the dyskinesia varied in severity throughout the day, being most severe soon after taking a regular dose of the drug. Since for most patients the dosage producing choreoathetoid movements is at or just below the effective dose of symptom control, a compromise between partial control of symptoms and disabling drug‐induced movements seems inevitable. Measures to control dyskinesia consisted mainly of lowering the dosage. No correlation was noted between the development of dyskinesia and previous stereotaxic surgery, etiology of Parkinson's disease, or its duration or severity. Choreoathetoid movements did not occur in normal control subjects receiving the drug or in patients with dystonia musculorum deformans or spastic torticollis, suggesting a strong specific predisposition in parkinsonian patients to this side effect.
Selective rise in brain dopamine by inhibition of extracerebral levodopa decarboxylation
Authors: Pletscher Alfred , Bartholini Giuseppe
Published: January 2016

The action of Ro 4‐4602 on decarboxylase of aromatic amino acids (DC) was studied in homogenates of both brain and heart to which the drug had been added and in intact rats after parenteral administration of the compound. Furthermore, investigations on the effect of Ro 4‐4602 on the metabolism of levodopa were carried out in extracerebral tissues as well as in brain of intact rats. In vivo, Ro 4‐4602 preferentially inhibits DC of extracerebral tissues including the brain capillaries. The inhibitor markedly enhances the accumulation of levodopa in the blood. As a consequence, increased amounts of levodopa penetrate through the brain capillaries into the cerebral parenchyma where decarboxylation to dopamine occurs. The newly formed amine is preferentially localized in the extrapyramidal brain centers. Concomitantly, the endogenous 5‐hydroxytryptamine (5‐HT) of the brain decreases. Potential advantages of the combination inhibitor plus levodopa over levodopa alone are: enhanced intestinal absorption of levodopa, decrease of the required levodopa dose, decrease of the peripheral side effects of levodopa, and enhanced selectivity of action of levodopa in the central nervous system.
Levodopa: Alterations in behavior
Authors: Goodwin Frederick K. , Murphy Dennis L. , Brodie H. Keith H. , Bunney William E.
Published: January 2016

Results on the use of sustained high doses of levodopa in depressed patients are presented, and the psychiatric side effects encountered during the therapeutic use of the drug in Parkinson's disease are discussed against the background of the hypothesized role of catecholamines in the pathogenesis of affective disorders. One half of the patients were treated with smaller doses of levodopa in combination with a peripheral decarboxylase inhibitor (MK‐485). Only 6 of 21 depressed patients consistently improved on levodopa, with relapse following placebo substitution and remission on restoration of the drug. A statistically significant increase in anger rating following 5 days of maximal dose of levodopa was noted as compared with that prior to treatment; others who previously experienced manic episodes manifested hypomanic behavior during treatment. Doses large enough to produce hypomania did not reverse depression. It is concluded that: (1) Amine depletion does not explain the pathophysiology of depression in most patients. (2) Hypomania occurs almost exclusively in affectively labile individuals. (3) The catecholamine hypothesis for depression may be an oversimplification in that mania and depression do not appear to represent the opposite poles of a single biochemical continuum. (4) Many factors contribute to psychiatric side effects—the pre‐dopa psychiatric state being the most important variable, levodopa often serving to unmask pre‐existing psychopathology.
Sleep in patients with Parkinson's disease and normal subiects prior to and following levodopa administration
Authors: Kales Anthony , Ansel Robert D. , Markham Charles H. , Scharf Martin B. , Tan Tjiauw-Ling
Published: January 2016

Six patients with parkinsonism and 4 spouse control subjects were studied in the sleep laboratory prior to administration of levodopa and during initial, short‐term, long‐term, and chronic usage. The parkinsonian patients had a significant amount of sleeping difficulty, taking much longer to fall asleep and awakening frequently for long periods during the night, as compared with spouse control subjects and a normal, elderly control group. Values for rapid eye movement (REM) sleep were similar to those of both control groups, while Stage 3 sleep was decreased. Three of the 6 patients showed a decrease in REM sleep with initial drug administration at the 1.0 Gm. per day dosage level. One had a marked increase in REM sleep for about the first 2 weeks of drug administration. However, REM sleep values for all patients with long‐term and chronic drug administration were similar to base‐line values. In the spouse control subjects, other than a slight increase in REM sleep with initial drug administration which was not maintained with long‐term use, no changes were noted in REM sleep, even during withdrawal of the drug. In both patients and control subjects, values for sleep induction and sleep maintenance were essentially unaltered by the administration of levodopa. Biochemical implications of these data are discussed. In addition, the clinical implications in terms of evaluating and treating the moderately severe insomnia in parkinsonian patients are described.
Where do we go from here?
Authors: Udenfriend Sidney , Cotzias George C. , Duvoisin Roger C. , Goldberg Leon I. , Du Bert N. La , Pletscher Alfred
Published: January 2016

DR. UDENFRIEND. One thing quite clear from the foregoing discussion, not directly related to parkinsonism and the treatment with levodopa, is that scientists and clinicians are developing a sophistication in the application of biochemistry to pharmacology and therapeutics to a degree they had not realized before. This, I think, is probably one of the best examples of the continuing use of esoteric biochemical information in clinical medicine.
Clinical pharmacology—Old wine in new bottles?
Authors: Moran Neil C.
Published: January 2016

I think a word is in order about the title, at least the second part of it, i.e., “Old wine in new botttles?” When I was asked to give this lecture, my first impulse was to say yes and to run to my slide file and write a lecture about my favorite topic in pharmacology, beta adrenergic receptors. However, it was suggested that a less scientific topic would be more in keeping with the concept of a Distinguished Guest Lecture, perhaps something such as a pharmacologist's view of clinical pharmacology might be appropriate. Since my second favorite topic in pharmacology is clinical pharmacology, I agreed.
A rapid method for the estimation of drug‐albumin affinity constants in human plasma
Authors: Solomon Harvey M. , Thomas Gordon B.
Published: January 2016

Many drugs are bound to a single site on human albumin, and the extent to which they bind may markedly infiuence their pharmacologic activities. The extent of binding of a drug to albumin depends, in part, upon the affinity of the protein for the drug (KAP). A method is described for the rapid and accurate determination of the KAP of a drug from a single value of its concentration in plasma and extent of binding to albumin.
Diabetes in patients treated with asparaginase
Authors: Gailani Salman , Nussbaum Annie , Ohnuma Takao , Freeman Arnold
Published: January 2016

In 5 patients treated with L‐asparaginase, plasma insulin response to intravenous glucose injection was measured by radioimmunoassay. Two of the patients developed a diabetic state (2 and 4 days) after a single dose of L‐asparaginase, while a third patient developed diabetes 2 days after the fourth dose of L‐asparaginase. Plasma insulin was not detectable by radioimmunoassay during the diabetic state in each of them. The normal pattern of insulin response returned completely in one of the 3 patients within 23 days, whereas suboptimal response persisted for 2 weeks and 9 months in the remaining 2 patients. The two remaining patients were studied prior to and 6 days after a single dose of L‐asparaginase; neither developed a diabetic state.
Effect of benzodiazepines upon saccadic eye movements in man
Authors: Gentles W. , Thomos E. Llewellyn
Published: January 2016

The saccade or ;ump which the eye makes as it goes from one fixation point to another is the most common type of eye movement, but little is known about the factors which affect the velocity of the [ump, In this study a model of the eye movement‐eontrol system developed by Cook and Stark was used to predict the effect of muscle‐relaxant drugs upon the peak velocity and the magnitude of the saccade in man. It was found that 30 mg. of chlordiazepoxide and 5 mg. of diazepam reduced the peak saccadic velocity by about 11 per cent. Further studies with diazepam in oarious doses have shown this effect to be stable and reproducible in uulioiduals. These findings may have potential value as a method of bioassau in the intact human being and they exemplify how drugs may affect psychomotor performance.
Cytosine arabinoside in acute granulocytic leukemia
Authors: Goodell Brian , Leventhal Brigid , Henderson Edward
Published: January 2016

Gytosine arabinoside (Ara‐G) is an antimetabolite of demonstrated activity in acute granulocytic leukemia (AGL). Between 1966 and 1969, 49 patients with AGL received remission induction chemotherapy with this drug at the National Gancer Institute. Ara‐G was given by 4 hour infusion at a dose of 70 to 150 mg. per square meter per day in repeated 4 day courses. Gomplete remissions were achieved in 42 per cent of patients. Of patients receiving Ara‐G as initial chemotherapy, 25 per cent died during attempted induction and 25 per cent attained complete remission; of patients who had received prior chemotherapy (irrespective of response), 67 per cent achieved complete remission (p<0.02). Infection (73 per cent} and hepatic dysfunction (44 per cent) were common complications of therapy. Median duration of remission in 21 patients receiving weekly Ara‐G at 75 mg. per square meter subcutaneously as maintenance chemotherapy was 5 months. Median survival in patients achieving remission with Ara‐G was 17 months; patients failing induction with this drug lived a median of 6 months. Ara‐G is an effective and well‐tolerated chemotherapeutic agent in AGL.
Dose‐response analysis of the efJects of tetrahydrocannabinol in man
Authors: Kiplinger Glenn F. , Manno Joseph E. , Rodda Bruce E. , Forney Robert B.
Published: January 2016

Fifteen volunteers smoked marihuana cigarettes under controlled laboratory conditions on five occasions. The cigarettes were calibrated to deliver doses of 0, 6.25, 12.5, 25, and 50 εg per kilogram of Δ‐9‐tetrahydrocannabinol(THC). A randomized block, double‐blind design was used. It was found that motor and mental performance as well as stability of stance deteriorated in a linearly dose‐dependent fashion. Heart rate and corüunctioal redness increased with dose as did scores on sensation and mood questionnaires.
Commentary, The Washington Conference on Clinical Pharmacology
Authors: Carr Edward A.
Published: January 2016

The Drug Research Board of the National Academy of Sciences‐National Research Council convened a Conference on Clinical PhannacoIogy in Washington, D. C., on December 3 and 4, 1970. For two days the participants reviewed the status and future possibilities of Clinical Pharmacology. In some instances the viewpoints of several individuals blended wen in support of an idea, while a clear separation occurred on the other occasions The Conference thus afforded an opportunity to gauge the state of opinion on many important issues related to clinical pharmacology.
Actions and metabolism of heroin administered by continuous intravenous infusion to man
Authors: Elliott H. W. , Parke K. D. , Wright J. A. , Nomof N.
Published: January 2016

The effects of heroin given to human subjects by continuous intravenous infusion are described. Progressive CNS depression eventually required reversal with levallorphan. There was no indication of development of acute tolerance to the depressant effects of heroin. Blood and urine specimens were collected for analysis of metabolites and analyzed for morphine, 6‐monoacetylmorphine, and heroin by gas‐liquid chromatography. Blood concentrations were too low to identify any heroin or metabolites, but about fifty per cent of the dose was recovered in the urine mostly as bound morphine with small amounts of 6‐monoacetylmorphine and heroin present in some specimens. Rate of excretion of total morphine indicated that man can metabolize about 6 mg. per 93 Kg. per hour of heroin.
Disposition of glutethimide in man
Authors: Curry S. H. , Riddall D. , Gordon J. S. , Simpson P. , Binns T. B. , Rondel R. K. , McMartin C.
Published: January 2016

The disposition of glutethimide in man was studied by measurement of drug concentrations in plasma, whole blood, urine, and breast milk after oral doses. In vitro, plasma protein binding and ionization constants were measured. Wide variations in absorption of the drug were observed, the peak plasma concentration varying from 2.85 to 7.05 μg per milliliter and occurring at any time from one to 6 hours after administration of 500 mg. doses. Decline of the concentration after the peak lwd been reached occurred in one phase in 2 subjects and in two phases in 4 subjects. The earlier of the two phases was the one of more rapid decline. Higher concentrations were recorded after the higher of two doses (250 and 500 mg.). Concentrations in whole blood and plasma were similar and an average of 54.2 per cent of the plasma content of the drug was bound to protein in vitro. Concentrations in urine were lower than those in plasma, and it was estimated thot less than 2 per cent of a dose was excreted as unchanged drug in 24 hours by this route. Mean concentrations of the drug in breast milk were also very low. Maternal and neonatal plasma concentrations of the drug were similar. These fondings were examined in relation to other observations of glutethimide kinetics, to treatment of patients with glutethimide poisoning, and to duration and intensity of central depressant effects.
Commentary Relationships among medical and nonmedical uses of pharmacologically active agents
Authors: Estes J. Worth , Johnson Malcolm
Published: January 2016

Psychoactive drug use was admitted by 14 per cent of 328 high school students (a 22 per cent sample) in a suburban town. The incidences of alcohol use, intoxication, smoking, and self‐medication with aspirin were severalfold greater. The frequency of nonmedical psychoactive drug use by the students was associated with the frequency with which they took aspirin.
The binding of sulfaphenazole to fetal, neonatal, and adult human plasma albumin
Authors: Chignell Colin F. , Vesell Elliot S. , Starkweather Donnas K. , Berlin Cheston M.
Published: January 2016

In man, sulfaphenazole has a lower affinity for the albumin of the fetus and neonate than for that of the adult. Removal of bound endogenous anions from neonatal albumin by treatment with charcoal at pH 3.0 restored the affinity of the protein for sulfaphenazole to the adult level. Prior treatment of adult albumin with bilirubin reduced the affinity of the protein for sulfaphenazole to that observed in fetal and neonatal albumins. Thus the reduced affinity of su1faphenazole for fetal and neonatal albumin compared to that for adult albumin probably is the result of the presence of a tightly bound endogenous ligand, such as bilirubin, on fetal and neonatal albumin.
Lead as an environmental poison
Authors: Hardy Harriet L. , Chamberlin Richard I. , Maloof Clarence C. , Boylen George W. , Howell Mary C.
Published: January 2016

After some years of assuming lead poisoning to be either a phenomenon of past history63 or confined to children eating paint, an American geochemist (Patterson) challenged the complacency of industry, physicians, and public health officials on this subject. A symposium was called in 1965 by the Department of Health, Education, and Welfare as the result of the reaction to Patterson's angry conclusions. The timing of this symposium marked the upsurge of activity and attention in the United States to potential harm to all of us from contamination of air with products of industry and heavy auto traffic. One of us presented a paper at the 1965 session entitled, “What is the status of knowledge of the toxic effect of lead on identifiable groups in the population,” which was later published in this JOURNAL.39 Further discussion in the press and in medical and industrial hygiene literature led to the knowledge that updated and new data on sources of lead in the environment are needed. The present paper attempts to supply this need. In addition, means of identifying toxic lead effect not readily recognized by clinicians are discussed. A crowded and old city (Boston), with heavy traffic flow but without large lead‐using industries, and its suburbs have been studied over the years 1965 to 1970. Using the skills of the chemist and engineer trained to assess the risk of industrial disease, a number of environmental sources of lead have been measured. Collaboration with public health staff and hospital residents and physicians utilizing these so‐called industrial hygiene techniques revealed their value in case finding and identifying the source of damaging lead. The role of inhaled lead in risk to urban children needs emphasis. Ingestion plays little part in adult poisoning. Due to poor absorption of lead through the gut, the role of lead by mouth may be not as great as thought in childhood disease. Absorption through the skin is a problem in industrial exposure to organic lead compounds only. Failure of most physicians to recognize any form of lead intoxication other than severe acute disease, and under‐utilization of chelating agents for diagnosis and therapy is discussed. Possible methods of changing the bleak picture of risk of lead poisoning in the United States are enumerated.
Delay of erythema of human skin by anti‐inflammatory drugs after ultraviolet irradiation
Authors: Gruber Charles M. , Ridolfo Anthony S. , Nickander Rodney , Mikulaschek Walter M.
Published: January 2016

Nonsteroidal, anti‐inflammatory, antipyretic analgesics have been demonstrated to delay the onset of the erythemic response to high‐intensity ultraviolet irradiation in albino guinea pigs. A similar phenomenon has been demonstrated in male Caucasian sub;ects and is used as a clinical screen for anti‐inflammatory activity. Single oral doses of aspirin, indomethacin, and fenoprofen (dl‐2‐[3‐phenoxyphenyl] propionic acid) have been evaluated. A sequential experimental design demonstrated activity for all three drugs. It is suggested that the method may be useful in evaluating anti‐inflammatory drugs.