bluuebunny/crossref_metadata_2025 huggingface dataset:
Motivations and rewards for volunteering to be an experimental subject
Authors: Ayd Frank J.
Published: January 2016

The motives that cause volunteers to accept the risks involved in medical experimentation are intertwined and often obscure but can be broadly classified as financial, psychologic, or spiritual. In those to whom the financial rewards are not the most compelling, a mild psychopathy is a common finding, with obsessive and schizoid personality types predominant. This does not compromise their contributions: On the contrary, proper appraisal of neurotic or psychiatric traits can be of value in defining the limits and specific effects of a drug. Critics who contend that the rewards offered may constitute an undue influence upon potential volunteers, causing them to underrate the risks, are particularly concerned with such psychologic “coercion” in the prison setting. Prisoners participating in a research project enjoy greatly improved living conditions and health care and experience an increase in self‐esteem that usually triggers favorable changes in life style and behavior which are long‐lasting and possibly permanent. Prisoners are necessarily reliable subjects. They also exert pressure upon other members of the group to assure the success of the project.
For the first time in man
Authors: Blackwell Barry
Published: January 2016

A nationwide postal survey of academic and industrial clinicians engaged in early drug research has been used to discover their views concerning the study populations, experimental strategies, and value of the results obtained when a drug is given to man for the first time. The spectrum of responses provided a basis for discussion and revealed interesting differences of opinion between academic and industrial sources.
XVIII. The clofibrate trials: Another dispute about contratrophic therapy
Authors: Feinstein Alvan R.
Published: January 2016

In contratrophic therapy, the classical clinician and classical epidemiologist meet to engage in the new practice of prophylactic clinical medicine. The conventional treatment studied by clinicians is clinical and remedial. The patient is already sick, and the treatment is intended to remove or alter an existing target. An example of remedial treatment is the use of aspirin for headache. The conventional treatment studied by epidemiologists is non‐clinical and prophylactic. In such therapy, which can be called contrapathic, the patient is essentially well, and the treatment is intended to prevent the development of a target, usually a particular disease, that has not yet occurred. An example of contrapathic treatment is vaccination against poliomyelitis.
Inducibility of benzo [α] pyrene hydroxylase in human skin by polycyclic hydrocarbons
Authors: Alvares A. P. , Kappas A. , Levin W. , Conney A. H.
Published: January 2016

Neonatal human foreskin contains an enzyme system that hydroxylates the carcinogen benzol [α]pyrene (BP). The hydroxylase system requires nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen and has a pH optimum of 7.4. Exposure to carbon monoxide completely inhibits hydroxylase activity. When skins were incubated in a growth medium containing benz[α]anthracene (BA) two‐ to fivefold Increases in the amount of BP hydroxylase were observed. Maximum enzyme levels were found when the skin was incubated in the presence of BA for 16 to 24 hours. Inducibility of hydroxylase activity was greater in human skin than in neonatal rodent skin. Considerable variability in the basal levels and in the inducibility of BP hydroxylase was observed in foreskins obtained from 13 sub;ects. These studies indicate that human skin can metabolize polycyclic hydrocarbons and that the levels of the hydroxylase, as well as the inducibility of the enzyme in skin, may provide a useful means for evaluating individual differences in the capacities of humans to metabolize environmental carcinogens.
Pharmacology of orally administered Δ9‐tetrahydrocannabinol
Authors: Reyes Mario Perez , Lipton Morris A. , Timmons Martha C. , Wall Monroe E. , Brine Dolores R. , Davis Kenneth H.
Published: January 2016

A systematic study of the oral administration of 35 mg. of Δ9‐tetrahydrocannabinol (Δ9‐THC) in 5 different vehicles indicates that the speed and degree of absorption are greatly influenced by the vehicle. When the same vehicle was used, absorption of the drug varied significantly among individuals. The psychologic effects were characterized by a marihuana‐like “high” qualified by experienced sub;ects to be more intense than that associated with smoked marihuana or hashish. Predominant physiologic effects were congestion of the conjunctiva, tachycardia, and moderate increases in blood pressure. Hypotention with bradycardia occurred when the blood pressure control was challenged by a change in posture or blood volume. The biologic half‐life of the drug appears to be less than 48 hours. Thin‐layer chromatographic analysis indicates that the metabolites in the plasma are the 11‐OH‐Δ9‐THC, an unknown compound, the 8,11‐di‐OH‐Δ9‐THC, and a group of more polar substances located at the origin. Δ9‐THC and its metabolites are excreted extensively in the urine and feces. The maior urinary metabolites are the 8,1l‐di‐OH‐Δ9‐THC and polar substances where cannabinoid acids predominate. Appreciable amounts of Δ9‐THC are found in feces.
Decreased clinical efficacy of propoxyphene in cigarette smokers
Authors:   Boston Collaborative Drug Surveillance Program
Published: January 2016

In a comprehensive drug surveillance system that monitored consecutive hospitalized medical patients who received propoxyphene hydrochloride for mild or moderate pain, or for headache, the drug was rated ineffective by the attending physicians in 10.1 % of 335 nonsmokers, 15.0% of 347 patients who smoked 20 cigarettes per day or less, and 20.3% of 153 patients who smoked more than 20 cigarettes per day (p < 0.01). There was a linear increase in the proportion of ineffective ratings of about 5% for each pack of 20 cigarettes smoked per day (p < 0.005).
Drug metabolism and androgen control therapy in prostatic cancer
Authors: Sotaniemi Eero A. , Kontturi Matti J. , Larmi Teuvo K.
Published: January 2016

The drug metabolizing capacity during androgen control therapy was determined in 12 patients with prostatic cancer, using plasma antipyrine half‐life as an index. In general, drug metabolizing capacity seemed impaired; the disappearance rate of the test dmg decreased in 8 of the patients. In 1 the half‐life was unchanged, and in 3 there was shortening. The results suggest that many factors simultaneously affect the drug metabolizing enzymes, and the total effect may be stimulated in the face of therapy known to inhibit these enzymes.
Positive inotropic effect of oral esproquin in normal subjects
Authors: Kotelanski Bernardo , Grozmann Roberto J. , Cohn Jay N.
Published: January 2016

The Hypertension and Glinical Hemodynamics Section, Veterans Administratian Hospital, and the Department of Medicine, Georgetown University School of Medicine An isoquinoline derivative, esproquin (NG 7197), was administered in single oral doses of 100, 200, or 300 mg to 15 normal volunteers. A dose‐related positive inotropic effect was characterized by an increase in cardiac output and stroke volume that persisted for about 4 hours without a significant change in heart rate associated with areduction in pre‐ejection period and an increase in mean systolic ejection rate. Arterial pressure rose with the lower doses, but diastolic press ure fell and forearm blood flow increased with the highest dose. These data indicate that oral administration of esproquin produces a sustained positive inotropic effect and that in Zarger doses peripheral vasodilatation results either from adrenergic blockade or a direct vascular effect. The drug deserves evaluation for the treatment of chronic heart failure.
XXI. A primer of concepts, phrases, and procedures in the statistical analysis of multiple variables
Authors: Feinstein Alvan R.
Published: January 2016

The analysis of multiple variables probably received little or no attention when contemporary clinicians were taught about statistical methods. The topic is either absent from most textbooks of elementary statistics and biostatistics; or, if present, it is saved for advanced instruction in which a medical student seldom participates. Multivariate analysis has nevertheless become a frequent event in the literature that now confronts a clinical reader. Such multivariate procedures as discriminant functions, multiple regression, factor analysis, and cluster analysis regularly occur among the methods used in reports that appear not only in specialty medical journals, but also in journals intended for a general clinical audience.
Drugs and fetal metabolism
Authors: Rane Anders , Sίöqvist Folke , Orrenius Sten
Published: January 2016

Biochemical mechanisms related to oxidative and conjugative drug biotransformation are outlined, and the present knowledge about the development of the capacity of the human fetal liver to catalyze these reactions is summarized. The possible importance of extrahepatic drug metabolism in the human fetus is also discussed.
Effects of drugs and environmental chemicals on steroid metabolism
Authors: Conney A.H. , Levin W. , Jacobson M. , Kuntzman R.
Published: January 2016

Drugs and steroids are hydroxylated by a common enzyme system in rat liver microsomes. In accord with this concept, treatment of rats with drugs or environmental chemicals that stimulate or inhibit hepatic drug metabolism can alter the hydroxylation of steroid hormones. Examples of compounds that stimulate the microsomal hydroxylation of drugs and steroids include phenobarbital, phenylbutazone, DDT, and chlordane; inhibitors of microsomal hydroxylation include SKF 525–A, chlorthion, carbon tetrachloride, ami carbon monoxide. Treatment of rats or guinea pigs with phenobarbital induces the synthesis of liver microsomal enzymes that hydroxylate progesterone, estradiol, estrone, deoxycorticosterone, testosterone, Δ4‐androstene‐3,17‐dione and cortisol, whereas treatment of rats with SKF 525‐A or carbon tetrachloride inhibits the activity of microsomal enzymes that hydroxylate steroids. The stimulatory or inhibitory effect of drugs on the enzymatic metabolism of steroids is reflected in vivo by an altered metabolism and action of steroids. Accordingly, pretreatment of rats with phenobarbital decreases the uterotropic action of estradiol and estrone, the growth‐promoting effect of testosterone on the seminal vesicles, and the anesthetic action of progesterone and deoxycorticosterone. Pretreatment of rats with SKF 525‐A or carbon tetrachloride enhances the uterotropic action of estrone. Drugs that stimulate steroid hydroxylation in animals also influence steroid metabolism in man. Phenobarbital, N‐phenylbarbital, diphenylhydantoin, phenylbutazone, o,p'‐DDD and DDT are potent stimulators of microsomal hydroxylation in animals, and these compounds stimulate the urinary excretion of 6β‐hydroxycortisol in man. In addition, treatment of humans with phenobarbital alters the proportion of testosterone metabolites excreted in the urine and decreases the action of prednisone in steriod‐dependent asthmatics. Since the human fetus, placenta, and mother hydroxylate steroids in many positions, the influence of drugs or environmental chemicals on these metabolic pathways should be studied during pregnancy.
Introduction of new therapeutic drugs in the United States and Great Britain: An international comparison
Authors: Wardell William M.
Published: January 2016

The pattern of introduction of new therapeutic drugs in the United States during the decade 1962 to 1971 has been compared with that in Great Britain. Nearly four times as many new drugs became exclusively available in Great Britain as in the United States. Where differences occurred in the introduction dates of mutually introduced drugs, about twice as many were introduced first in Great Britain as introduced first in the United States. When examined by therapeutic category, the drug lag was found to be most marked in cardiovascular, gastrointestinal, respiratory, diuretic, and antibacterial drugs.
Formation of a 16,17‐trans‐glycolic metabolite from a 16‐dehydro‐androgen in human fetal liver microsomes
Authors: Rane Anders , Gustafsson Jan-Åke
Published: January 2016

This study aimed to investigate if the human fetus can form epoxides during the oxidation ot double bonds. Indirect evidence for this was obtained using 4,16‐androstadien‐3‐one as substrate of the liver microsomal drug oxidation enzyme system. Human fetal liver microsomes were shown to catalyze the formation of the corresponding 16,17‐glycol, a reaction that is thought to proceed via an intermediary 16,17‐epoxide. The findings may imply that the human fetus is also capable of forming epoxides from certain drugs that contain double bonds.
Comparison of activities of drug‐metabolizing enzymes in human fetal and adult livers
Authors: Pelkonen Olavi , Kaltiala Eero H. , Larmi Teuvo K. I. , Kärki Niilo T.
Published: January 2016

The in vitro capacity of human fetal liver to metabolize 3,4‐benzpyrene, aniline, aminopyrine, and hexobarbital was lower than that of human adult liver from patients with uncomplicated cholelithiasis. Fetal liver drug‐metabolizing capacity, expressed as percentages of adult values, was 2.4, 27.8, 32.0, and 36.1 per cent, respectively, for the four substrates studied. Cytochrome P‐450 content and nicotinamide adenine dinucleotide phosphate (NADPH)—cytochrome c reductase activity in fetal liver microsomes also reflected the lower drug‐metabolizing activity, being 27.4 and 49.2 per cent, respectively, of adult values. Microsomal protein content was about 26 mg per gram wet weight in fetal liver and about 35 mg per gram in adult liver. Recovery of microsomes was 40% to 60% in both fetal and adult livers. All parameters studied exhibited considerable variation, which ranged from three‐ to elevenfold. Fetal drug metabolism, although generally lower than in the adult, may, in some cases, be higher than maternal drug metabolism.
Urinary corticosteriod and diphenylhydantoin metabolite patterns in neonates exposed to anticonvulsant drugs in utero
Authors: Reynolds John W. , Mirkin Bernard L.
Published: January 2016

Five newborn infants, whose mothers had received anticonvulsant therapy throughout gestation (diphenylhydantoin and a barbiturate [4] or diphenylhydantoin alone [1]), were studied. Urinary steroids (6β‐OH‐cortisol, tetrahydrocortisone, 16α‐OH‐pregnenolone, and 16α‐OH‐dehydroepiandrosterone) and urinary 5‐parahydroxyphenyl, 5‐phenylhydantoin (HPPH, conjugated and unconjugated) were quantitatively assayed during the early neonatal period. The urinary steroid excretions were found not to be significantly different from those of normal full‐term newborn infants. Total HPPH excretion and the unconjugated/total metabolite ratios showed no correlation with urinary steroid excretion. Thus, the enhanced 6β‐hydroxylation of cortisol seen in adults after barbiturate or diphenylhydantoin was not observed in newborns exposed to these drugs in utero.
British usage and American awareness of some new therapeutic drugs
Authors: Wardell William M.
Published: January 2016

British experts were surveyed to determine their use of, and attitudes toward, certain newer drugs available in Britain but not in the United States. The survey was conducted by mail at 20 British teachillg hospitals and covered 5 therapeutic areas: angina, hypertension, asthma, pyelonephritis, and gastric ulcer. Responses concerning the newer drugs were compared with those cOllcerning older dmgs mutually available in both Britain and the United States. A second survey was conducted at an American university medical center to determine the level of knowledge American physicians possess about these and other drugs currently unavailable to them. In the therapeutic areas described, certain dmgs unavailable in the United States had made large impacts on the prescribing habits of British experts, whose therapy was likely to be substantially different from that which could be prescribed by Americans. This included use of salbutamol in asthma, the beta blockers in angina, co‐trimoxazole in pyelonephritis, carbenoxolone in gastric ulcer, and, to a lesser but still important degree, beta blockers and bethanidine in hypertension. By contrast, most of the American physicians surveyed had a very low level of knowledge about these and other new drugs. Those Americans who were aware of a drug's properties usually wished to have that drug available in the United States.
Therapeutic implications of the drug lag
Authors: Wardell William M.
Published: January 2016

The American lag with respect to Britain in the introduction of new therapeutic drugs over the past decade was analyzed to determine whether, in therapeutic terms, Britain has gained or lost from adopting the more permissive policy. The therapeutic impact of a new drug on the whole community is difficult to assess, mainly because there are few methods or data available for measuring benefit. On the evidence currently available, Britain probably did not lose appreciably from the introduction of ineffective drugs, nor from the fact that a greater number of new drugs were made available. The main deleterious effect was that Britain suffered more tOXicity due to new drugs than did the United States, as could have been anticipated from the fact that mare new drugs were marketed there. However, considering the size of the total burden of drug tOXicity, the portion due to new drugs was extremely small, and would in any case be at least partially offset by the adverse effects of older alternative drugs had the latter been used instead. Conversely, Britain experienced clearly discernible gains by introducing useful new drugs, either sooner than the United States or exclusively. On balance, Britain appears to have gained in comparison from its more permissive policy toward the marketing of new drugs coupled with a more rigorous program of postmarketing surveillance. Wider issues raised by this study include the desirability of further intensifying postmarketing surveillance, particularly in the case of new drugs; the conflict between the presently conceived public health role of a regulatory agency and the desire of a physician to choose optimal therapy for particular patients; the therapeutic and social implications of the control of drug utilization as distinct from marketing; and the significance of the latter controls for the future of medicine.
Serum gold levels during chrysotherapy with relation to urinary and fecal excretion
Authors: Harth Manfred
Published: January 2016

The decline of gold in serum and its excretion in urine and feces were studied in the first week following an iniection of sodium aurothiomalate in 10 patients with rheumatoid arthritis. Changes in the renal clearance of gold were also observed over a period of 25 weeks in 13 patients on chrysotherapy. The urinary excretion of gold in the first 24 hours was higher than in the second 24 hours, whereas fecal excretion of gold was greater in the second than in the first clay. The serum gold levels showed a biphasic decline with a rapid early phase and a slow late phase. The latter was assumed to represent the excretion of gold in urine and possibly in feces. The difference over 24 hours between gold levels declining along the slow phase was multiplied by the estimated plasma volume for each patient to give an expected excretion value. These calculated values correlated substantially with the observed urinary excretion values in both the first and second 24 hour periods. There was a gradual increase of renal clearance of gold over a period of 25 weeks in 13 patients. These results suggest that the slow phase of decline of gold may be due to excretion and the rapid phase to tissue absorption. The increase in renal clearance of gold may be due to increased excretion of gold from deposits in body tissue.
Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving
Authors: Linnoila M. , Häkkinen S.
Published: January 2016

Effects of single oral doses of codeine, diazepam (Valium), and alcohol on simulated driving were investigated by using a modification of the English Sim‐L‐car. The driving time was 40 minutes, subjects were told to adapt speed to surroundings and traffic. Placebo increased the inaccuracy of speed estimations. Alcohol increased the numbers of steering wheel reversals and neglected instructions. Diazepam 10 mg increased the number of collisions and neglected instructions, but the greatest increase in collisions was after codeine 50 mg. Diazepam generally enchanced the effect of alcohol.
Studies on digitalis; II. The influence of impaired renal function on the renal excretion of digitoxin and its cardioactive metabolites
Authors: Storstein Liv
Published: January 2016

Simultaneous serum and urine measurements of digitoxin and its cardioactive metabolites were performed in patients with impaired renal function, after a single dose and during maintenance therapy. A modified 86Rb method was used. Comparison of serum levels after intravenous and peroral dosage of digitoxin in 5 patients with severe uremia showed that absorption was complete. After an intravenous dose, the serum‐tissue eqUilibration T/2 in renal failure had a mean value of 150 minutes, while it was 71 minutes in the control subjects. Mean T/2 of serum elimination was 3.9 days and 8.1 days in 5 control subjects (p < 0.01). The urine digitoxin concentration T/2 with a mean value of 8.0 days did not differ significantly from the control subjects (7.2 days). The urine levels were, however, lower in uremics with lower cumulative excretion during an 8 day period. Eleven patients with slightly impaired renal function (creatinine clearance 50 to 80 ml per minute) on maintenance dosage did not differ Significantly from a control group of 22 patients. Twelve patients with uremia (mean serum creatinine 12.2 mg per 100 ml) had serum levels in the same range as the control subjects, but significantly lower urine levels, renal excretion, and digitoxin clearance. They excreted 13.6% of the daily dose compared to the 32.9% of the controls. The results indicate that compensatory mechanisms are operative in uremia as increased excretion through other pathways or as changes in hepatic metabolism of digitoxin.
Erythrocyte uptake and plasma binding of di phenyl hydantoin
Authors: Kurata Douglas , Wilkinson Grant R.
Published: January 2016

The human erythrocyte (RBC) uptake of diphenylhydantoin (DPH) from pH 7.4 buffer solution was proportional to the buffer concentration of drug; a constant RBClbuffer concentration ratio of 4.83 ± 0.16 was observed. Plasma reduced the uptake as a linear function of the unhound fraction of DPH; in nomlOl plasma, 5.34 ± 0.18% of the drug was unhound, and an RBClplasma concentration ratio of 0.22 ± 0.03 was determined. Perturbations of binding seen in uremia anel cirrhosis and proeluced by competitive binding displacement caused changes in the concentration ratio consistent with, anel predicted by, the above linear relationship. Binding and erythrocyte uptake were essentially constant over the therapeutic plasma level range (5 to 50 /lg per milliliter) and were also unaffected by the concomitant presence of other commollly used anticonvulsants. It is suggested that determination of the RBClplasma concentration ratio may seme as a simple and rapid technique for the large‐scale screening of abnormal plasma binding in routine clinical blood sampies, thereby facilitating individualization of drug therapy.
Antihypertensive effects of practolol and sotalol
Authors: Sundquist Hannu , Anttila Markku , Arstila Matti
Published: January 2016

Practolol and sotalol were found to differ qualitatively in their effects on blood pressure (BP). The reductions in both systolic and diastolic BP and in heart rate were largely unrelated to differences in dosage and serum concentrations of practolol in 22 patients with mild‐to‐moderate hypertension. On the other hand, when due to sotalol, these effects were dose related in 12 patients. From 200 to 800 mg of both drugs were given daily in two doses. The differences from the posttreatment of placebo systolic/diastolic BP were at a maximum at 400 mg of practolol: 22/6, 18/9, and 18/6 mm Hg in a standing, sitting, and supine position. In 8 patients who tolerated 600 mg of sotalol, the differences were, respectively, 29/14, 22/18, and 27/18 mm Hg. Side effects with sotalol were numerous when the heart rate fell below the critical level of about 48. The highest tolerated serum concentration of sotalol was about 5.1 mg/1. A 600 mg dose of sotalol was tolerated as well and as often as 800 mg of practolol. The serum concentrations of both drugs were closely related to the dose per kilogram of body weight.
Effect of antacids on pH of urine
Authors: Gibaldi Milo , Grundhofer Barbara , Levy Gerhard
Published: January 2016

To determine the effect of regular administration of usual doses of several antacids for 7 day periods on urine pH, measurements of urine pH were carried out daily on 11 healthy subjects during regular use of antacids and during control periods. On the average, suspensions of aluminum hydrOXide and dihydroxyaluminum glycinate had no significant effect on urine pH. Magnesium hydroxide and calcium carbonate‐glycine suspension increased urine pH by 0.4 to 0.5 U, while aluminum and magnesium hydroxide suspension increased pH by 0.9 U. The increase in urine pH was inversely proportional to the urine pH during the control periods. Regular administration of certain antacids can increase urine pH sufficiently to have pronounced effects on the kinetics of elimination of certain acidic and basic drugs.
Clinical biostatistics
Authors: Feinstein Alvan R.
Published: January 2016

Clinical investigators who undertake the study of mechanisms of biology and human disease usually begin to read the appropriate non‐medical journals. Among such publications are the Journal of Biological Chemistry, Journal of General Physiology, Journal of Microbiology, Journal of Molecular Biology and Biophysics, etc. Although these publications rarely contain papers on specifically medical topics, clinical investigators read the journals to learn about the biochemical, physiologic, microbial, or molecular advances that augment basic medical knowledge and that provide better basic methods for application in biomedical research.
Plasma nortriptyline and clinical response
Authors: Burrows Graham , Scoggins Bruce A. , Turecek L. R. , Davies Brian
Published: January 2016

The relationship of plasma nortriptyline levels to the clinical response of 80 depressed patients was studied. Plasma nortriptyline levels were estimated 4 weeks after commencing treatment. Percentage change in the Hamilton Depression Rating Scale was used to measure clinical response. There was no simple relationship between these two measures. Twelve of the 80 patients were studied further. Clinical response to variations of plasma nortriptyline levels was studied. Calculation of regression coefficients showed a positive relationship between clinical change and plasma nortriptyline levels in all. Comparison of the regression coefficients showed that they differed significantly among themselves and were not related to age or sex.
Dopa, 3‐0‐methyldopa, and metabolites in urine during oral l‐3‐0‐methyldopa therapy
Authors: Sharpless Nansie S. , Tyee Gertrude M. , Muenter Manfred D. , Dinapoli Robert P.
Published: January 2016

The metabolic fate of orally administered l‐3‐0‐methyldopa, given alone or with levodopa, was studied during a therapeutic trial in 5 patients with Parkinson's disease. During administration of 3‐0‐methyldopa alone, dopa was excreted in urine almost exclusively as a confugate hydrolyzable by Glusulase (mixture of sulfatase and β‐glucuronidase). Small increases in dopamine excretion confirmed that there had been some demethylation of 32‐0‐methyldopa. The small increase in 3‐methoxytyramine (3‐MT) excretion was greater than that of dopamine (DA), suggesting some direct decarboxylation of 3‐0‐methyldopa. Excretion of norepinephrine (NE) and epinephrine (E) and of their O‐methyl derivatives (normetanephrine [NM] and metanephrine [M]) was marginally affected by 3‐0‐methyldopa. Only small amounts of homovanillic acid (HVA) appeared in urine (2.3% of the dose), indicating that both decarboxylation and demethylation were minor routes of 3‐0‐methyldopa metabolism. Most of the 3‐0‐methyldopa dose was excreted unchanged or as vani/lactic acid (VLA). The proportion of the dose excreted as VLA increased linearly with increase in 3‐0‐methyldopa dosage, suggesting induction of transaminase. A paradoxic increase in vanilmandelic acid (VMA) excretion was observed during 3‐0‐methyldopa administration. Relative to the dose, the amount of VMA in urine was 7 times as great during administration of 3‐0‐methyldopa as during administration of levodopa.
Serum concentration of rifampin after oral administration
Authors: Virtanen Simo , Tala Eero
Published: January 2016

The serum levels of rifampin after single 450 mg doses were much the same when taken as 3 gelatin capsules and 1 sugar‐coated tablet. The concentrations of rifampin in the serum of pulmonary tuberculosis patients on prolonged rifampin‐containing regimens were lower than the levels in control sub;ects and patients on a drug regimen Without rifampin. The difference is significant after 4 hours. The increased elimination of the drug should be taken into account in planning long‐term therapy with rifampin.
Pharmacokinetics; Pharmacokinetic factors affecting epidermal penetration and percutaneous absorption
Authors: Riegelman Sidney
Published: January 2016

Dermal pharmacokinetics has to do with the rate processes involved in dissolution, diffusion, and/or release of the drug substance from its vehicle, transit to the absorption site, penetration through the limiting barrier to the site of action, and subsequent elimination of that compound. Dermatology is almost exclusively interested in the pharmacologic and therapeutic effects of drugs within the skin. Emphasis will be primarily made in this presentation to the epidermal penetration of drugs so as to induce no local responses. However, comments will be made later related to percutaneous absorption with the intent to elicit systemic response.
XXXI. On the sensitivity, specificity, and discrimination of diagnostic tests
Authors: Feinstein Alvan R.
Published: January 2016

In 1947, Yerushalmy18 introduced the terms sensitivity and specificity as statistical indexes of the efficiency of a diagnostic test. The sensitivity of the test would indicate its capacity for making a correct diagnosis in confirmed positive cases of the disease. The specificity would indicate the capacity for correct diagnosis in confirmed negative cases.
Altered plasma half‐lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction
Authors: Vesell Elliot S. , Shapiro Jay R. , Passananti G. Thomas , Jorgensen Hildegarde , Shively Carol A.
Published: January 2016

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half‐lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half‐lives ± S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 ± 1.4 hr, 6.7 ± 1.0 hr, and 9.3 ± 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 ± 1.2 hr, 4.3 ± 0.7 hr, and 6.9 ± 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half‐lives of these drugs were prolonged to 26.4 ± 4.0 hr, 24.7 ± 34.5 hr, and 13.6 ± 4.8 hr, respectively. Return to the euthyroid state restored plasma half‐lives to or toward normal. Alterations in plasma drug half‐lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.
Neurologic and electroencephalographic correlates in glutethimide intoxication
Authors: Myers Robert R. , Stockard James J.
Published: January 2016

Neurologic and electroencephalographic (EEG) examinations were performed every two hours during a case of severe glutethimide intoxication resulting from the acute ingestion of at least 15 grams of glutethimide. Neurologic data were reduced to 10 measurements of brainstem function and plotted as an index that varied cyclically in amplitude during the clinical course. Electroencephalographic data were computer‐processed by power spectral methods and related to the brainstem function index. Good positive correlation existed between the frequency and reactivity of EEG activity and the level of brainstem function as reflected in the index. The cyclic and, sometimes, unilateral nature of the clinical findings previously reported in glutethimide coma was confirmed and seen to be reflected in the EEG. The present case also indicates that, in the absence of cerebral ischemia or hypoxemia secondary to cardiopulmonary depression, complete clinical recovery from glutethimide‐induced coma is possible no matter how severe the presenting neurologic and EEG signs.
Influence of congestive heart failure on blood levels of lidocaine and its active monodeethylated metabolite
Authors: Halkin Hillel , Meffin Peter , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

The blood concentrations of lidocaine and its active monodeethylated metabolite, monoethylglycinexylidide (MEGX), were measured in 31 patients who were receiving infusions of lidocaine intravenously. In 3 patients who were studied intensively, the elimination half‐life of MEGX was 120 min, which was similar to the elimination half‐life of lidocaine (139 min). An additional 3 patients demonstrated a higher ratio of the concentration in blood of MEGX to lidocaine, and the MEGX may have contributed, in 1 patient, to the central nervous system toxicity that occurred during the infusion. Elevated concentrations of MEGX in blood were associated with congestive heart failure (r = 0.5, p = 0.004). Our data suggest that the elimination of MEGX may be decreased in patients with depressed cardiac output and sympathomimetic compensation.
Morphine and phenytoin binding to plasma proteins in renal and hepatic failure
Authors: Olsen George D. , Bennett William M. , Porter George A.
Published: January 2016

The binding of morphine and phenytoin to plasma proteins was examined in healthy subjects and in patients with renal and hepatic failure. In the uremic patients without hepatic failure, morphine binding was dependent on the concentration of total serum proteins and albumin, but not the severity of renal failure as measured by creatinine clearance. Binding of phenytoin, however, was dependent on the degree of renal failure and albumin concentration, but not on total serum protein concentration. Renal transplant in 1 patient restored the binding of both drugs to a value within the normal range. The combination of hypoalbuminemia and hyperbilirubinemia resulted in the greatest impairment of binding for both drugs. It is concluded that patients with uremia, jaundice, hypoalbuminemia, particularly in combination, are sensitive to usual clinical doses of morphine, at least in part, because of decreased binding to plasma proteins.
Comparison of cardiac effects of timolol and propranolol
Authors: Achong Michael R. , Piafsky Kenneth M. , Ogilvie Richard I.
Published: January 2016

The cardiac effects of the β‐adrenergic blocking agent, timolol, were compared to those of propranolol after intravenous administration in 6 healthy male subjects. The effects of timolol and propranolol on maximal exercise‐induced tachycardia were measured. Timolol was about ten times as potent as propranolol in antagonizing exercise‐induced tachycardia. Dose‐response curves to intravenous infusions of isoproterenol were obtained after three doses of each β‐antagonist. Changes in myocardial contractility were assessed by cardiac systolic time intervals and were compared to the simultaneous changes in heart rate elicited by isoproterenol. For the 6 subjects, the mean potency ratios of timolol to propranolol as an antagonist of the chronotropic and inotropic effects of isoproterenol were 13.8 (±0.8) and 12.7 (±1.0), respectively. Neither timolol nor propranolol acted more selectively on β‐receptors affecting heart rate than on those influencing contractility.
Temporal variations in acetaminophen and phenacetin half‐life in man
Authors: Shively Carol A. , Vesell Elliot S.
Published: January 2016

Acetaminophen (AP AP) and phenacetin mean plasma half‐lives were approximately 15% longer in normal male volunteers at 6 A.M. than at 2 P.M. as determined after oral administration of each drug at 6 A.M. and 2 P.M. Concentrations of plasma 11‐hydroxycorticoids (11‐0 HCS) in these volunteers were approximately 42% higher at 6 A.M. than at 2 P.M. The mean apparent volume of distribution (aVd) of APAP decreased by approximately 13% from 6 A.M. to 2 P.M., whereas the mean metabolic clearance rate (MCR) of APAP did not change significantly. Neither the mean aVd nor the mean MC R of phenacetin changed significantly from 6 A.M. to 2 P.M. Measurement of urinary metabolites showed no alteration in APAP glucuronidation in the 8‐hr period following AP AP administration at 6 A.M. or 2 P.M., but indicated that after phenacetin administration 10% more of the dose was oxidatively metabolized to APAP during a 24‐hr period beginning at 2 P.M. than at 6 A.M. Within each subject, plasma acetaminophen or phenacetin half‐life at 2 P.M. or 6 A.M. was highly reproducible, but large interindividual variations occurred in the extent of temporal variation during this period.
Effect of hemodialysis on kinetics of acetaminophen elimination by anephric patients
Authors: Øie S. , Lowenthal D. T. , Briggs W. A. , Levy G.
Published: January 2016

The pharmacokinetics of acetaminophen elimination were determined in 4 anephric patients during hemodialysis and on an interdialysis day. The biologic half‐life of acetaminophen ranged from 119 to 147 min on an interdialysis day and was decreased by 42% to 53% during hemodialysis. Individual mean dialyzer extraction ratios, based on assay of plasma samples from blood flowing into and out of the dialysis unit, were 0.46 to 0.78for acetaminophen, 0.53 to 0.57 for acetaminophen glucuronide, 0.13 to 0.60 for acetaminophen sulfate, and 0.70 to 0.87 for urea nitrogen. There was a strong correlation between the extraction ratios of acetaminophen and urea nitrogen. Hemodialysis was the major or sole route of elimination of acetaminophen glucuronide and sulfate in the anephric patients.
Clinical pharmacology of nabilone, a cannabinol derivative
Authors: Lemberger Louis , Rowe Howard
Published: January 2016

Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose‐related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5‐mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5‐mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7‐day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.
The efficacy of carbamazepine combinations in epilepsy
Authors: Cereghino James J. , Brock Joseph T. , Van Meter John C. , Penry J. Kiffin , Smith Lawrence D. , White Billy G.
Published: January 2016

The efficacy and bioavailability, and tolerance to carbamazepine when administered with phenobarbital or phenytoin or with both drugs were evaluated in a prospective, double‐blind study of patients whose seizures were not completely controlled by currently available antiepileptic drugs in usually therapeutic dosages as determined by serum levels. During each of four 21‐day treatment periods, one fourth of the patients received daily doses of: (1) carbamazepine (1,200 mg) and phenytoin (300 mg); (2) carbamazepine (1,200 mg) and phenobarbital (300 mg); (3) phenytoin (300 mg) and phenobarbital (300 mg); or (4) carbamazepine (1,200 mg), with phenytoin (300 mg) and phenobarbital (300 mg). The treatment periods were separated by 2 wk of each patient's usual pre study medication. Treatment with all three drugs was the most efficacious for seizure control. Serum carbamazepine concentration was significantly decreased when the drug was administered with either phenytoin or phenobarbital or both.
Pharrnacokinetics of nalidixinic acid and oxolinic acid in healthy wornen
Authors: Männistö P. T.
Published: January 2016

The pharmacokinetics of oral nalidixinic acid (NA, 1 gm 4 times a day) and oxolinic acid (OA, 750 mg 2 times a day) administeredfor 7 days were studied in the same 10 healthy women on the first, third, and seventh days of the treatment. The peak concentrations of NA + OH‐NA (hydroxynalidixinic acid) in serum at 2 to 3 hr were 34 µg/ml (total) and 23 µg/ml (unconjugated) on the first day and nearly two times higher on the third and seventh days; 82% to 85% of these amounts were NA. The protein‐free fraction of NA + OH‐NA was 8.8% to 18.3%. The total concentration of NA + OH‐NA in urine was 1,220 to 2,700 µg/ml, the unconjugated concentration, 250 to 350 µg/ml, and the chemotherapeutically active concentration, 55 to 75 µg/ml. In steady state the 24‐hr recovery of the total drug was 79% of the daily dose. The excretion rate in urine was 591 to 853 mg 16 hr. The OA concentration in serum was very low on the first day of the treatment, but increased to 4‐ to 5‐fold on the third and seventh days: 6.2 to 6.4 µg/ml (total) and 3.3 to 3.6 µg/ml (unconjugated). The protein‐free OA represented 19% to 23% of the total amount. The modest initial serum concentrations of OA were conjirmed by the low urine concentrations on thefirst day. In steady state the OA concentration in urine was 570 µg/ml (total) and 35 µg/ml (unconjugated), and the 24‐hr recovery, 49% and 3%, respectively. The microbiologic assay gave somewhat higher concentrations of the active drug than did the chemical assay. When taken with food, the excretion of OA in urine was retarded by 6 hr but the 48‐hr recovery was not decreased.
Absorption and excretion of tolmetin in man
Authors: Cressman William A. , Wortham G. Forrest , Plostnieks Janis
Published: January 2016

Tolmetin, a nonsteroidal anti‐inflammatory drug, is rapidly absorbed (10 to 20 min) and rapidly excreted (T½ ≃ 60 min) and shows a linear dose‐plasma level response in the therapeutic dose range. Tolmetin does not affect its own metabolism on chronic administration. Tolmetin is displaced, in vitro, from plasma proteins by salicylic acid. This effect is reflected in minor changes in plasma levels and pharmacokinetic parameters when aspirin and tolmetin are coadministered.
Cardiovascular effects of a new inotropic drug in dog and normal man
Authors: Follath F. , Kersting F. , Lewis G. R. J. , Walden R. J. , Woolhouse N. M. , Dollery C. T.
Published: January 2016

Cardiovascular effects of 1‐butyl‐3(1‐(6, 7‐dimethoxyquinazolin‐4‐yl) piperidin‐4‐yl urea) (BDPU) were studied in 16 anesthetized dogs and in 7 healthy male volunteers. In animal experiments intravenous doses of 100, 250, and 500 μ‐g/kg/min produced dose‐related, significant increases in cardiac output and peak left ventricular dpldt. No changes in heart rate and blood pressure occurred at 100 μ‐g/kg/min, whereas higher doses caused falls in both systolic and diastolic blood pressures, accompanied by significant rises in heart rate. Inotropic effects could also be demonstrated in man. Changes of the systolic time intervals were dose‐related and began at 64 μg/kg/min. At 250 μg/kg/min, the highest dose administered, the pre‐ejection period decreased by 14.8 ± 4.42 msec and its ratio with left ventricular ejection time by 0.049 ± 0.017 against their respective control values (p < 0.01). In contrast to animal experiments, no hypotension or tachycardia was observed in any subject. Pharmacokinetic studies showed a plasma elimination half‐life of 76 ± 3 min (mean ± SE). There were no subjective side effects and standard laboratory tests were not altered, but there was a slight but significant rise in the urinary enzymes, lactic dehydrogenase (WH) and glutamic oxaloacetic transaminase (GOT), which persisted up to 7 days.
Antihypertensive effects of oxprenolol and propranolol
Authors: Materson Barry J. , Michael Ulrich F. , Oster James R. , Perez‐Stable Eliseo C. , Hernandez Alba , Smith Mary
Published: January 2016

The antihypertensive effects of the beta blockers oxprenolol and propranolol were compared in a randomized double‐blind study of patients with standing diastolic pressures (SDP) exceeding 99 mm Hg when receiving hydrochlorothiazide alone. After 3 wk of hydrochlorothiazide with placebo, the latter was replaced with oxprenolol (n = 12) or propranolol (n = 12), 20 mg three times daily. Beta blocker was increased subsequently to 40 and 80 mg three times daily if SDP exceeded 89 mm Hg. Nine oxprenolol and 7 propranolol subjects were hospitalized for 24‐hr monitoring. With oxprenolol, standing pressure declined from 135 ± 2 (S£)/104 ± 1 mm Hg to 128 ± 3/90 ± 2. SDP declined to under 91 mm Hg in 7 of 12 subjects, and to from 91 to 95 in 3 subjects. With propranolol, findings were 138 ± 3/106 ± 2 to 123 ± 3/89 ± 3; in 7 of 12 to less than 91 mm Hg and from 91 to 95 in 4 subjects. Decrements in supine and SDP were slightly (4 mm Hg) greater for propranolol than for oxprenolol. Both drugs gave similar 24‐hr blood pressure control. We conclude that oxprenolol and propranolol used to supplement hydrochlorothiazide provide comparable reductions in blood pressure and smooth control over a 24‐hr period in most patients with hypertension.
Digoxin bioavailability: Formulations and rates of infusions
Authors: Marcus Frank I. , Dickerson Janet , Pippin Susan , Stafford Marvin , Bressler Rubin
Published: January 2016

The bioavailability of digoxin (Lanoxin) tablets, oral aqueous solution of digoxin, and capsules containing a solution of digoxin was compared with digoxin given intravenously over J and 3 hr. The mean peak serum concentration of digoxin after the 1‐hr intravenous infusion was 5 nglml, after the 3‐hr infusion, 3.5 nglml, and after the oral solution, 2.0 ng Iml. There was an equivalent bioavailability of the oral solution and reference tablets of digoxin. The digoxin in capsules tended to be better absorbed than the reference tablets. There was 21% more digoxin excreted over 6 days after the 3‐hr iv i'lfusion than after the J hr iv infusion. This indicates that the calculated bioavailability of an orally administered dose of digoxin may vary with the rapidity of injection of the intravenous standard. It is estimated that an oral tablet of digoxin of 0.5 mg has about the same bioavailability as 0.35 mg of digoxin given by slow intravenous infusion (or 0.4 mg if calculated against a rapid intravenous injection).