bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination chemotherapy of adult acute lymphocytic leukemia
Authors: Smyth A. Collier , Wiernik Peter H.
Published: January 2016

Seventeen adults with previously untreated acute lymphocytic leukemia (ALL) received thioguanine, vincristine, dexamethasone, and pyrimethamine for remission induction. Nine patients (53 %) achieved complete and 5 (30%) partial remissions. Once in complete remission patients were given two closely separated consolidation courses followed by monthly maintenance courses of the same regimen with the addition of 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU) every other month during maintenance therapy. The median duration of complete remission was 176 days (range 38 to 605). The median survival for all patients was 405 days (range 30 to 1,058+). Oral pyrimethamine and CCNU were used for their potential activity as prophylactics against meningeal leukemia. Dexamethasone was used instead of prednisone because of the potential enhancement of granulocyte mobilization by the former. Six patients (35%) developed meningeal leukemia while on initial induction or maintenance therapy, 5 within 6 months of diagnosis. Life‐threatening infections occured in 10 patients (59%) during induction. Whereas the regimen effectively induced complete remission in about half of previously untreated adults with ALL, it was not effective in maintenance. The incidence of meningealleukemia and infection during induction was high. Oral pyrimethamine was inadequate prophylaxis for meningeal leukemia; dexamethasone did not reduce the incidence of serious infection.
Plasma protein binding and placental transfer of bupivacaine
Authors: Thomas Jack , Long Geoffrey , Moore George , Morgan Denis
Published: January 2016

The maternal venous and umbilical venous plasma concentrations of bupivacaine were determined at delivery following epidural administration of the drug to 31 women in labor. In each case the umbilical venous plasma concentration of bupivacaine was lower than the maternal venous plasma concentration. There was no significant difference between the concentration of unbound bupivacaine in umbilical venous and maternal venous plasma at delivery. The difference in umbilical and maternal plasma concentrations of bupivacaine appears to be a consequence of greater bupivacaine binding to maternal than to fetal total plasma protein. The intersubject variation of the ratio of bupivacaine concentration in fetal plasma / bupivacaine concentration in maternal plasma was found to be related to individual variation in the extent of protein binding of bupivacaine in maternal and umbilical plasma and correlated positively with the variation of the ratio of total protein concentration in umbilical and maternal plasma.
Effect of lidocaine on right ventricular muscle refractoriness
Authors: Engel Toby R. , Soly Kristine L. , Meister Steven G. , Frankl William S.
Published: January 2016

The effect of clinical doses of lidocaine on ventricular refractoriness was investigated in man. Effective refractory period (ERP) and functional refractory period (FRP) were determined in 11 normokalemic patients via a catheter at the right ventricular apex using programmed extra‐stimuli and a ventricular electrogram recorded from the pacing catheter. No subject had recent ischemia or infarction. Measurements were repeated after clinical doses of lidocaine that produced therapeutic blood levels. Lidocaine caused no significant change in ERP or F RP during ventricular or atrial drive, or sinus rhythm with unchanged cycle length (CL). During sinus rhythm ERP/CL was unchanged. In 4 of 5 patients, lidocaine did not abolish echo phenomena observed during ventricular drive. This study demonstrates that ventricular refractoriness can be safely measured in man. Clinical doses of lidocaine did not alter right ventricular refractory periods. Lidocaine action is not explained by alteration of ventricular refractoriness, at least in muscle remote from the site of acute infarction.
Disposition kinetics of two oral forms of quinidine
Authors: Mahon W. A. , Mayersohn M. , Inaba T.
Published: January 2016

There are relatively few studies on the disposition properties of quinidine. We have studied in 10 normal subjects conventional quinidine sulfate and a slow‐release quinidine bisulfate. Single and repetitive doses were given; blood and urine concentrations were measured by the method of Cramer and Isaakson.5 After a single dose of two tablets of quinidine sulfate (400 mg), the average peak concentration was 2.13 ± 0.22 μg/ml (±SEM); following two tablets of the slow‐release form, the average peak concentration was 1.17 ± 0.12 μg/ml. T‐max was approximately 2 hr with quinidine sulfate and 4 hr with quinidine bisulfate. One fourth of both forms of the drug was recovered in the urine. Total body clearance was 0.36 L/kg hr and renal clearance was 117 ± 22 mllmin for both. With multiple dosing the serum quinidine concentration was higher than these predicted from the results of the single‐dose study. Based on the mean estimates of quinidine half‐life of 6 hr, a rapid method for achieving steady‐state levels of quinidine would be to give an initial dose twice that of the maintenance dose. With the slow‐release product if an equivalent dose was given every 12 hr, the mean steady‐state quinidine serum concentration would be approximately the same.
Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis
Authors: Ellard G. A.
Published: January 2016

Isoniazid is the most effective and widely used antituberculosis drug. The metabolism of isoniazid is noninducible and the primary metabolie route determining the rate at which isoniazid is eliminated from the body is acetylation. There are large differences between individuals in the rates at which isoniazid and certain other hydrazides and some sulfonamides are acetylated. The acetylation of isoniazid is inherited in a simple Mendelian fashion, individuals being either slow, heterozygous rapid, or homozygous rapid acetylators . Improved methods of discriminating between the different phenotypes have recently been described that are also more convenient to use. The proportion of slow acetylators among Japanese and Eskimos is about 10%; among Chinese about 20%; among Caucasians, Negroes, and South Indians about 60%. The results of aseries of meticulously controlled clinical trials carried out in India, East Africa, Hong Kong, Singapore, Czechoslovakia, and Britain have shown the isoniazid acetylator status of tuberculosis patients treated with isoniazid‐containing regimens is of no prognostic significance when treatment is given on a daily basis. It may, however, be of significance when twice‐weekly regimens are employed, especially in circumstances in which only a short period of initial daily chemotherapy is given, and where the companion drug employed during the twice‐weekly continuation phase is relatively weak. The acetylator phenotype is, however, extremely important in once‐weekly treatment, rapid acetylators always having fared considerably worse than slow acetylators on all the regimens evaluated so far. Experimental studies of the action of isoniazid against Mycobacterium tuberculosis in vitro and in vivo have enabled these findings to be understood.
Impaired plasma protein binding of phenytoin in uremia and displacement effect of salicylic acid
Authors: Odar‐Cederlöf Ingegerd , Borgå Olof
Published: January 2016

The plasma protein binding of phenytoin (DPH) was studied by equilibrium dialysis at 37° C in plasma from uremic patients and healthy subjects. Scatchard plot analyses demonstrated a decreased association constant Kafor the DPH‐albumin interaction in the uremic plasma (mean 1.76 . 103 M−1 ± SD 0.12 and a mean 4.10 103 M−1 ± SD 0.24 in normal plasma). Studies on separated fractions of serum did not indicate any significant binding of DPH to proteins other than albumin. The nonlinear mathematical relationship between bound DPH and serum albumin could be linearized at low drug concentrations by plotting the ratio of bound/unbound DPH against albumin concentration. The displacement effect of salicylic acid at a concentration of 276 μg/ml (2mM) on DPH was considerable in plasma from normal subjects. In uremic plasma the effect was of a much smaller magnitude.
Subjective and physiologic effects of morphine, pentobarbital, and meprobamate
Authors: McClane T. K. , Martin W. R.
Published: January 2016

These studies extend previous observations on the effects of pentobarbital on subjective states and postrotational nystagmus in postaddict subjects. Pentobarbital (150 mg) induced a degree of liking and an elevation of the morphine‐benzedrine group (MBG) scale score equivalent to 24 mg of morphine. The effects of pentobarbital and meprobamate on postrotational nystagmus were studied using electro‐oculography. Both drugs increased the frequency and prolonged the duration of postrotational nystagmus in a dose‐related manner. Meprobamate was about 1/15 as potent as pentobarbital in enhancing postrotational nystagmus and producing signs of sedation.
Metaproterenol in children with chronic asthma
Authors: Hyde John S. , Yamshon Daniel , Isenberg Paul D. , Schur Samuel
Published: January 2016

Metaproterenol sulfate was given to 25 children with asthma in the form of a syrup in a continuous treatment course of 180 days. Dosage amounted to 10 to 20 mg metaproterenol four times daily. depending on the patient's age and weight. Double‐blind crossover tests of pulmonary function were run against placebo at the beginning and after 3 and 6 mo of treatment. The peak expiratory flow rate responses to metaproterenol consistently exceeded the responses to placebo, the differences proving statistically significant at several intervals after administration. Adverse reactions were limited to instances of hyperactivity in one child and of mild tremors in another; laboratory values remained normal throughout the 6‐mo period except for low normal fasting blood sugar mlues recorded in 2 patients at the end or the study. Pulse rate increases occurring after metaproterenol were not considered clinically important.
Effect of renal transplantation on protein binding of drugs in serum of donor and recipient
Authors: Levy Gerhard , Baliah Tadla , Procknal J. A.
Published: January 2016

Blood sampies were obtained periodically before and for about 3 mo after renal transplantationfrom a donor (mother) and a recipient (9‐yr‐old son with bilateral nephrectomy) for determination of serum protein binding of salicylate and sulfisoxazole. Ten days after the transplant, the recipient had an acute rejection episode which was treated successfully. The free fraction values of the drugs in serum of the recipient were considerably above normal before transplantation, decreased to normal within 2 days after transplantation, increased again several days before the rejection episode and remained elevated for about 50 days, and then returned to normal. Serum protein binding of the drugs in the serum of the donor was decreased for only a few days after transplantation and then returned to normal.
Intravenous propranolol administration: A method for rapidly achieving and sustaining desired plasma levels
Authors: McAllister R. G.
Published: January 2016

A model for the intravenous administration of propranolol by a bolus‐infusion technique designed to rapidly produce, then maintain, predicted plasma drug concentrations was derived from elimination kinetics in single‐dose studies. Prospective testing of this model in 6 adult male subjects revealed a close correlation between predicted and observed drug levels; desired plasma concentrations were achieved within 5 min and maintained over the 30‐min study period. By subtracting previously given bolus doses from the dose calculated as needed to produce a desired plasma level, progressive increases in predicted propranolol levels could be effected, with apparent maintenance of equilibrium. Correlations between the bolus doses and infosion rates and the plasma drug levels were consistent and significant, and constitute nomograms jrom which the dose of drug required to produce a desired plasma level may be approximated. The clearance of propranolol declined slightly as the drug plasma level increased, but did not significantly affect the accuracy of the model.
Clinical pharmacologic observations on atenolol, a beta‐adrenoceptor blocker
Authors: Colin Brown H. , George Carruthers S. , Dennis Johnston G. , Kelly John G. , McAinsh James , McDevitt Denis G. , Shanks Robin G.
Published: January 2016

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of aseries of single doses of atenolol reduced an exercise tachycardia. After a 200‐mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half‐life of 6.36 ± 0.55 hr: 43 ± 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a signi(icant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recoveredfrom the urine, ami the clearance was 97.3 ml/min. Comparison of AUCo→x after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half‐life, area under the plasma concentration‐time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.
Etidronate disodium in postmenopausal osteoporosis
Authors: Heaney Robert P. , Saville Paul D.
Published: January 2016

Calcium‐balance, calcium‐kinetic, and physiologic observations were made in 10 osteoporotic patients treated for 6 to 12 mo with disodium etidronate (EHDP) in oral doses of 20 mg/kg/day. Absorption of EHDP averaged 10%, and effective retained dose was approximately 1.6 mg/kg/day. Patient acceptance was excellent, and there were no detectable clinical or biochemical untoward effects of treatment. Serum phosphorus was elevated an average of 1.1 mg/100 ml, and serum calcium, 0.4 mg/100 ml. EHDP reduced bone resorption by about 50% and depressed bone mineralization by almost as much. Both the total miscible calcium pool and its component compartments were sm aller on EHDP, presumably because of a combination of interference with bone mineral reactivity and the decrease in mineralization rate. Urine calcium was increased by a small, but highly significant, amount, and gastrointestinal calcium absorption was also significantly increased. Calcium balance shifted slightly but significantly in the positive direction. The magnitude of these changes correlated with the urinary level of EHDP.
Studies on digitalis; VIII. Digitoxin metabolism on a maintenance regimen and after a single dose
Authors: Storstein Liv
Published: January 2016

The metabolic pattern of cardioactive and inactive conjugated metabolites of digitoxin on maintenance (9 patients) and after a single 0.6‐mg dose (5 patients) was studied in patients with normal renal and hepaticfunction. Serum sampies were obtained 24 hr after the last dose, and urine was collected over 24 hr. The extent or conjugation to glucuronic and sulfuric acid was 35.0% (SD, 17.4) in whole serum and 31.6% (SD, 19.3) in urine sampies. Unchanged digitoxin was the main cardioactive substance found bOlh in serum and in urine (89.7% and 87.0%) in the steady‐state group. All known cardioactive metabolites were present; digoxin represented less than 1%. All active metabolites were conjugated to glucuronic/sulfuric acid. Serum and urine patterns of metabolites were quite similar. Hydrolysis and conjugation appeared to be more important pathways than hydroxylation. Unchanged digitoxin was the most important cardioactive substance in serum and urine (80.4% and 56.5%) in the single‐dose group. Digoxin was the main cardioactive metabolite (12.5% in serum and 25.5% in urine). All active metabolites were conjugated. Hydroxylation, hydrolysis, and conjugation seemed to be equally important. The most important differences between the steady‐state and single‐dose groups were that in the steady‐state group there was signijicantly more unchanged digitoxin, far less digoxin, and less hydroxylated metabolites than in the single‐dose group. Caution is thus necessary when interpreting single‐dose datafor a drug that is usedfor maintenance.
Plasma pyridostigmine levels in patients with myasthenia gravis
Authors: Calvey T. N. , Chan K.
Published: January 2016

Plasma concentrations of pyridostigmine were measured in 7 patients with myasthenia gravis. Six subjects on oral pyridostigmine bromide were stabilized on widely different doses of the drug (60 to 660 mg/day). Nevertheless, the eoneentration of the quaternary amine in plasma was maintained within a relativeiy narrow range (usually between 20 and 60 ng/ml). In 3 myasthenic patients, the area under the plasma concentration‐time curve was relatively eonstant for 4 hr after the same oral dose of pyridostigmine (60 mg). Despite this similarity, there were in general considerable interindividual differences in the bioavailability of pyridostigmine in myasthenie patients. In 1 subject, the bioavailability of the quaternary amine was inereased sixfold by doubling the oral dose from 30 mg to 60 mg. After oral administration of pyridostigmine, the half‐life of the drug in one subject (4.25 hr) was almost three times as great as after intramuseular administration in a different patient (1.49 hr).
Clinical pharmacokinetics of lorazepam; II. Intramuscular injection
Authors: Greenblatt David J. , Joyce Thomas H. , Comer Walter H. , Knowles John A. , Shader Richard I. , Kyriakopoulos Adrian A. , MacLaughlin Dean S. , Ruelius Hans W.
Published: January 2016

A single dose of 4 mg of lorazepam was injected into the deltoid muscles of six healthy male volunteers. Multiple venous blood sampies were drawn during 48 hr after the dose and all urine was collected for 24 hr after the dose. Concentrations of lorazepam and its major metabolite, lorazepam glucuronide, were determined by electron‐capture gas‐liquid chromatography. Lorazepam was rapidly absorbed from the injection sire, reaching peak concentrations within 3 hr. Mean pharmacokinetic pamrameters for unchanged lorazepam were: apparent absorption half‐life: 21.2 min: elimination half‐life: 13.6 hr; volume of distribution: 0.9 L/kg; total clearance: 58.2 ml/min. Lorazepam glucuronide rapidly appeared in plasma, reached peak concentrations within 12 hr of the dose, then was eliminated approximately in parallel with the parent drug. Within 24 hr a mean of 47.6% of the dose was recovered in the urine as lorazepam glucuronide and less than 0.5% was recovered as unchanged lorazepam.
Kinetic model for gentamicin dosing with the use of individual patient parameters
Authors: Sawchuk Ronald J. , Zaske Darwin E. , Cipolle Robert J. , Wargin William A. , Strate Richard G.
Published: January 2016

Multiple‐infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level‐time data obtained after a single infusion were used to determine the patient's gentamicin half‐life (t½) and distribution volume. Patients with serum creatinine (Cr) <1.2 mg per 100 ml had t½s (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr ≥1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patient's kinetic parameters and desired steady‐state peaks and nadirs, assumed a one‐compartment model with first‐order elimination and 1‐hr constant‐rate input at fixed intervals. Follow‐up steady‐state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged ‐0.05 µg/ml with 60% of the measured values falling within 1 µg/ml of that predicted. Predicted‐measured nadir differences averaged −0.62 µg/ml (significantly different from zero) indicating slight bias in the model. Fifty‐six percent of these nadirs were within 1 µg/ml of that predicted.
XXXIX. The haze of Bayes, the aerial palaces of decision analysis, and the computerized Ouija board
Authors: Feinstein Alvan R.
Published: January 2016

Most people prefer to avoid complicated problems. Politicians confronted with a complex, multi‐faceted dilemma will usually try to satisfy their constituents, rather than struggle with basic solutions to the dilemma. Judges asked to settle a major legal controversy will often make their decisions not by directly resolving the substantive issue, but by evading it, to reach a conclusion based on matters of technical procedure.
Digoxin kinetics during furosemide administration
Authors: Malcolm Alasdair D. , Leung Fred Y. , Fuchs James C. A. , Duarte James E.
Published: January 2016

The urinary excretion of a 0.75‐mg oral dose of digoxin was assessed in 8 healthy men during a control 5‐day period and then, after a washout period of at least 2 wk, during a 5‐day period when the subjects also took oral furosemide, 40 mg daily. Analysis of the raw data by a paired Student's t test and analysis of variance of log‐transformed urinary digoxin excretion data revealed no significant difference attributable to the addition of furosemide (F = 1.16; df = 1,21). The treatment by day interaction showed the slopes to be consistent between the two treatments. It seems that in the presence of normal renal function there is no need to alter loading or maintenance doses of digoxin when furosemide is also given. Analysis of variance with log transformation of data is suggested as a practical approach to handling digoxin urinary excretion results when the transformation linearizes the data through examination by the method of orthogonal polynomials.
Influence of alprenolol on hemodynamic and metabolic responses to prolonged exercise in subjects with hypertension
Authors: Frisk-Holmberg Marianne , Jorfeldt Lennart , Juhlin-Dannfeldt Anders
Published: January 2016

In 7 young men with essential hypertension, central and regional hemodynamics and leg metabolism were studied at rest, during and after a prolonged exercise, and with and without long‐term alprenolol treatment. Alprenolol (200 mg twice daily) lowered arterial blood pressure. Heart rate decreased in relation to plasma levels during and after exercise. Cardiac output was not significantly influenced, but leg blood flow was reduced at rest. Lipolysis was also attenuated by treatment both at rest and during exercise, and the increment in plasma insulin after exercise was decreased. A reduction in the release of leg muscle lactate was noted during exercise.
Kinetics of a sulfadiazine‐trimethoprim combination
Authors: Bergan Tom , Mo Harald Vik , Anstad Unni
Published: January 2016

The pharmacokinetics of a combination of sulfadiazine and trimethoprim has been studied in 16 patients with varying degrees of reduced renal [unction, In normal renal function, the serum half‐life (t½) of active sulfadiazine, total sulfadiazine, and trimethoprim were quite close: 7.7, 9.6, and 12.1 hr, respectively . There was a gradual increase in serum t½ witlt reduction in renal function for both active and total sulfadiazine andJor trimethoprim. With accurate determinations of endogenous renal clearane, t½ estimates may be made Jrom regression curves presented. The relative distribution in the body was unrelated to renal function. It was similar Jor the two fractions of sulfonamide and higher for trimethoprim. The means were 0.371,0.176, and 1.104 Llkg, respectively, [or active and total sulfudiazine, and trimethoprim.
Pharmacokinetics and pharmacodynamics of ethanol, whiskey, and ethanol with n‐propyl, n‐butyl, and iso‐amyl alcohols
Authors: Auty Richard M. , Branch Robert A.
Published: January 2016

Plasma ethanol concentration, reaction time, and electroencephalogram (EEG) were recorded in 6 normal men after ingestion of ethanol alone (Group I), whiskey (Group 2), or a mixture of ethanol, n‐propanol, n‐butanol, and iso‐amyl alcohol (Group 3). The peak plasma ethanol concentration and the total area under the plasma concentration: time curve of ethanol did not depend upon the type of drink given, but the half‐life of the terminal exponential phase of ethanol elimination was longer in Group 3. In each study period reaction time increased, there was a relative increase in delta activity (2 to 3 Hz) and a fall in mean dominant jrequency in EEG activity. The extent of increase in reaction time depended on the rate of increase in plasma ethanol concentration and correlated with the concentration of ethanol while the plasma concentration of ethanol was falling. Differences in the effects of ethanol between study periods were minimal.
Comparative pharmacodynamics of betamethyl digoxin and digoxin in man
Authors: Das Gopal , Talmers Frederick N. , Weissler Arnold M.
Published: January 2016

The positive inotropic effects and serum glycoside levels following intravenous and oral administration of betamethyl digoxin (BMD) were measured and compared with those of digoxin in normal adults. The cardiac inotropy was assessed noninvasively in the abbreviation of the electromechanical systolic index (QS2l) obtained by serial measurements of systolic time intervals. Following 0.8 mg BMD intravenously, the QS2l abbreviation occurred within 3 min and reached a maximum at 4 hr. The time‐course and the magnitude of the response were essentially the same as those obtained with 0.8 mg digoxin given intravenously in the same subjects. The serum glycoside levels were also similar for both drugs. When administered orally the QS2l abbreviation to 0.8 mg BMD appeared at 40 min and reached a maximum at 4 hr. The time‐course and the magnitude of the effects were similar to those observed following oral digoxin. The blood digitalis levels following the drug ingestion, however, were significantly higher for BMD than for digoxin which suggests greater gastrointestinal absorption of BMD. Based on our observations, the inotropic effects of BMD are similar to those of digoxin. Our results, however, do not demonstrate greater cardiac activity after oral administration of BMD despite higher blood levels.
Patterns of plasma concentrations and urinary excretion of salicylate in rheumatoid arthritis
Authors: Graham G. G. , Champion G. D. , Day R. O. , Paull P. D.
Published: January 2016

lntersubject differences in the volume of distribution, whole body clearance, and steady‐state plasma concentrations of salicylic acid (SA) were studied in a series of patients with rheumatoid arthritis and healthy control subjects. The measurement of the plasma concentration of SA 12 hr after an oral dose of 1.2 gm aspirin appears predictive of the success of long‐term dosage of aspirin. Concentrations below 5 u‐g/ml in this single‐dose test were associated with failure to achieve therapeutic plasma concentrations of SA (above 150 u‐g/ml) during long‐term therapy with approximately 4.8 gm aspirin per day. Conversely, plasma concentrations above 10 u‐g/ml in the single‐dose test were associated with levels above 150 u‐g/ml during long‐term therapy. The volume of distribution of SA correlated poorly with body weight (r = 0.51, P < 0.01) and did not correlate significantly with plasma albumin levels. Corticosteroids appear to induce the metabolism of SA and most subjects dosed with oral corticosteroids and aspirin 4.8 gm/day did not attain plasma levels of SA above 150 u‐g/ml. The clearance of SA was greater in male than in female patients. The difference appears to be of clinical significance since fewer men than women achieved therapeutic plasma concentrations of SA.
Metabolism of l‐bunolol
Authors: Carlo Frederick J. Di , Leinweber Franz-Josef , Szpiech Joseph M. , Davidson Ivan W. F.
Published: January 2016

The metabolism of I‐bunolol, a new f3‐blocking drug, was studied in man after single oral 3‐mg doses of W‐labeled compound. Absorption from the gut was rapid and virtually complete. Peak levels of bunolol and of dihydrobunolol, an active metabolite, were observed at I hr. Excretion of the administered radioactivity was mainly into the urine (78% in 4 days), with only 3% appearing in the feces. Bunolol, bunolol glucuronide, bunolol sulfate, dihydrobunolol, and dihydrobunolol glucuronide were identified and quantified in the plasma. These compounds represented 82% of the radioactivity in plasma at 30 min and 55% at 24 hr. Plasma half‐lives (± S.D.) were estimated to be 6.1 ± 0.3 hr for bunolol, 9.1 ± 1.9 hr for bunolol glucuronide, 17.4 ± 2.5 hr for bunolol sulfate, 7.1 ± 0.5 hr for dihydrobunolol, and 7.7 ± 0.8 hr for dihydrobunolol glucuronide.
Bioavailability and first‐pass metabolism of oral pentazocine in man
Authors: Ehrnebo Mats , Boreus Lars O. , Lonroth Ulla
Published: January 2016

The bioavailability of oral pentazocine was studied in 5 healthy volunteers. Plasma concentrations were determined from 30 min up to 6 hr following oral administration (two 50‐mg tablets) and, at other occasions, after intravenous injection of 30 mg pentazocine. The average bioavailability was found to be 18.4 ± 7.8% (SD, n = 5). It is shown that this low bioavailability depend almost entirely on the first‐pass metabolism of pentazocine following oral administration by application of intravenous clearance concepts. The average beta‐phase half‐life was about the same following intravenous administration, 203 ± 71 (SD, n = 5) min as following oral administration, 177 ± 34 (SD, n = 5) min, with a total volume of distribution of 5.56 ± 1.63 (SD, n = 5) Llkg. It is suggested that the variations in bioavailability of orally administered pentazocine have the potential to contribute to variations in pharmacologic effects in patients.
Metabolic disposition of cephalothin and deacetylcephalothin in children and adults: Comparison of high‐performance liquid chromatographic and microbial assay procedures
Authors: Rolewicz T. F. , Mirkin B. L. , Cooper M. J. , Anders M. W.
Published: January 2016

A highly specific method utilizing ion‐pair extraction and high‐pressure liquid chromatography has been developed for the analysis of cephalothin and deacetylcephalothin in biological specimens. Kinetic data obtained in children and adults were used to compare this method of analysis with microbial assay procedures. In this study serum elimination curves were developed following the intravenous administration of cephalothin to adults (5 to 37.5 mg/kg) and children (10 to 25 mg/kg). The elimination half‐life (t½ of cephalothin from serum was 13.5 ± 3.2 min in adults and 18.6 ± 4.6 min in children (p < 0.05). The mean KEL in adults was 3.15 ± 0.2 hr‐1 and 2.35 ± 0.51 hr‐1 in children; the specific VD in adults was 0.21 ± 0.03 Llkg as compared to 0.93 ± 0.15 Llkg in children. The primary metabolite of cephalothin, deacetylcephalothin, was present in sera and urine obtained from adult subjects. Approximately 25% of the cephalothin dose administered was eliminated in urine as deacetylcephalothin. Significant differences were observed between microbial and high‐pressure liquid chromatographic assay procedures in that the former estimated higher concentrations of cephalothin in urine specimens, probably due to the presence of high concentrations of deacetylcephalothin or other active metabolites. The rapid plasma clearance of cephalothin suggests that clinical regimens using 4‐to 6‐hr dosage intervals may result in drug levels which are below the minimum inhibitory concentration of most susceptible organisms for approximately 50% of each treatment period.
Differential effects of morphine on forearm blood flow: Attenuation of sympathetic control of the cutaneous circulation
Authors: Flaim Stephen F. , Zelis Robert , Eisele John H.
Published: January 2016

Morphine sulfate (MS) induces net peripheral arteriolar dilation due to reduction in alpha adrenergic control. In order to determine the relative effects of this action on cutaneous and skeletal muscle circulations, forearm bloodfiow (FBF) and mean arterial pressure (BP) were measured and forearm vascular resistance (FVR) was calculated in 7 normal male subjects before (C) and after the intravenous administration of 15 mg of MS. In each subject, FBF was determined plethysmographically in an intact forearm and in a forearm subjected to epinephrine iontophoresis, a technique which specifically arrests only the cutaneous circulation. Cutaneous FBF was calculated from the difference between the FBF of the intact and the iontophoresed arms. No change in BP occurred with MS (C: 74; MS: 74 mm Hg, p > 0.5). Intact FBF increased with MS (C: 1.8; MS:3.9 ml/min × 100 ml, p < 0.05) while FVR was reduced (C:49.3; MS:27.9 mm Hg/ml/min × 100 ml, p < 0.01). Skeletal muscle FBF and FVR did not change with MS (FBF, C: 1.2, MS: 1.3, p > 0.5; FVR, C: 74.1; MS: 77.3, p > 0.5). Cutaneous FBF increased with MS while cutaneous FVR was reduced (FBF, C :0.7, MS: 2.4, p < 0.05; FVR, C:93.3, MS:43.0, p < 0.025). These data indicate that clinical doses of morphine cause net limb vasodilation limited to the cutaneous circulatory bed.
Metabolism of cocaine in man
Authors: Inaba T. , Stewart D. J. , Kalow W.
Published: January 2016

Following ingestion of [N‐14CH3]cocaine (10 mg, 2.3 µCi) by 2 healthy subjects, breath, saliva, serum, and urine samples were collected serially. Labeled CO2 production was monitored as a measure of N‐demethylation of cocaine. The cumulative excretion of 14CO2 in 5 hr was 2.4% and 6.2% of the administered dose with half‐lives of 2.3 and 1.4 hr, respectively. The greater N‐demethylation was found in a subject with lower plasma cholinesterase activity. Radioactivity excreted in 0 to 28 hr urine reached 65% to 75% of the dose. Ecgonine methyl ester, a product of cocaine hydrolysis by plasma cholinesterase, was identified as a major metabolite in the urine of both subjects and accounted for 32% to 49% of the urinary metabolites.
Trimethoprim/sulfamethoxazole and renal function in transplant patients
Authors: Caterson Robyn J. , Collett P. V. , Hood Virginia L. , Duggin G. G. , Horvath J. S. , Johnson J. R. , Sampson Jan , Tiller D. J.
Published: January 2016

Twenty‐two patients with functioning renal allografts took part in a double‐blind crossover trial during which placebo, sulfamethoxazole, and trimethoprimlsulfamethoxazole were given for periods of 14 days. The patients were divided into 2 groups. The first group consisting of 12 patients had serum creatinine levels less than 0.18 mmol/L and the second group of 10 patients had serum creatinine levels between 0.18 mmol/L and 0.35 mmol/L. Renal function at the end of each period was assessed by clearance of inulin (CIn), p‐aminohippurate (CPAH) and endogenous creatinine (CCr). The second group also had a pitressin concentration test as a measure of distal tubule function. There was no change in inulin or creatinine clearance or in maximum concentration after pitressin in any of the patients in any of the phases. In the first group there was an increase in PAH clearance during the sulfonamide and trimethroprimlsulfamethoxazole phases. This change was not seen in the second group of patients with significantly impaired renal function.
Effect of plasma protein and tissue binding on the biologic half‐life of drugs
Authors: Gibaldi Milo , Levy Gerhard , McNamara Patrick J.
Published: January 2016

It is now generally appreciated that there can be pronounced interindividual differences in plasma protein binding of many drugs because of genetic,13 environmental (drug interaction),11 and pathologic7 factors and aging.1 Pharmacokinetic theory has been developed to relate quantitatively the effect of changes in plasma protein binding to changes in the elimination kinetics of drugs.8,14 In the case of drugs that are eliminated almost entirely by hepatic biotransformation with linear (apparently nonsaturable) kinetics not limited by organ perfusion rate, it has been shown that the total clearance (Cl) is directly proportional to the free fraction of drug in plasma (fp), i.e.,
Clorazepate kinetics in treated epileptics
Authors: Wilensky Alan J. , Levy René H. , Troupin Allan S. , Moretti-Ojemann Linda , Friel Patrick
Published: January 2016

Clorazepate is decarboxylated to form desmethyldiazepam and is a convenient way of administering it. Its kinetics were investigated in epileptic patients after single oral and multiple oral doses. Peak serum concentrations of demethyldiazepam occurred in 0.5 to 1 hr. There appeared to be a brief lag before rapid absorption. Because of the rapid absorption with resulting high serum levels. daily doses should be divided. Serum concentration/time curves were best fitted by the two‐compartment open model. The apparent t½ of the distribution phase was 1.28 ± 0.44 hr and the t½ of the disposition phase was 40.8 ± 9.96 hr. Serum concentrations rose after meals. Whole body apparent volume of distribution (VB/F) was 1.63 ± 0.24 Llkg. Total plasma clearance was 34.4 ± 7.2 ml/min. which is greater than clearance levels for desmethyldiazepam in normals and reflects the greater hepatic metabolism which occurs in treated epileptics. The discrepancy illustrates the hazards of extrapolating data collected in normals to patients with multiple drug exposures.
Dose response to chlorthalidone in patients with mild hypertension; Efficacy of a lower dose
Authors: Materson Barry J. , Oster James R. , Michael Ulrich F. , Bolton Sanford M. , Burton Zeb C. , Stambaugh John E. , Morledge John
Published: January 2016

A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4‐wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5‐, 25‐, 50‐, or 75‐mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50‐ and 75‐mg groups but not significantly in the 25‐mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smalter initial diuretic doses may provide equal efficacy with fewer side effects for many patients.
Placental transfer of furosemide
Authors: Beermann Björn , Groschinsky-Grind Margaretha , Fåhraeus Lars , Lindström Björn
Published: January 2016

After oral administration of furosemide to 18 pregnant women on the day of delivery, substantial concentrations of the drug were detected in umbilical cord vein plasma as well as in amniotic fluid. The ratio between the furosemide concentrations in maternal vein plasma and in umbilical cord plasma increased with time and approximated unity at 8 to 10 hr after administration of the drug. The plasma half‐life offurosemide appeared to be longer in the mothers than in nonpregnant healthy volunteers. In one patient the plasma level of furosemide was constant during 5 hr of observation.
Parotid and whole saliva in the prediction of serum total and free phenytoin concentrations
Authors: Anavekar Sadanand N. , Saunders Ralph H. , Wardell William M. , Shoulson Ira , Emmings Fred G. , Cook Clarence E. , Gringeri Anthony J.
Published: January 2016

Epileptic outpatients (22 male and 12 female) participated in this study. All were taking phenytoin and 20 were taking one or more additional antiepileptic drugs. The mean percent free phenytoin in serum was 11.0% whether the patient was taking phenytoin alone or in combination with other antiepileptic drugs. There was a strong linear relationship between the serum total and ultrafiltrate phenytoin concentrations, the slope of the regression line being 0.109. There was also a strong relationship between the phenytoin concentrations in serum ultra filtrate and each of four salivary fractions, but each salivary fraction significantly underestimated the mean serum ultrafiltrate phenytoin concentration. It should be noted, however, that in this study the saliva fractions collected were relatively large (7 ml), and it is possible that collection conditions such as these may influence the salivary phenytoin concentration. The supernatant of whole saliva had a significantly lower concentration of phenytoin than whole saliva itself (due to binding of the drug to the mucoid sediment). Parotid saliva appears to be the best predictor of serum ultrafiltrate phenytoin concentrations. Contrary to expectation, gingivitis, at least as defined here, appeared to have no effect on the predictability of serum ultrafiltrate phenytoin concentrations by the salivary fractions, but this conclusion is a qualified one.
Serum and urine phosphate during short‐term β‐adrenergic blockade in healthy men
Authors: Lindsay R. , Ramsay L. E. , Hettiarrachchi J. , Davies D. L. , Beastall G. H.
Published: January 2016

Treatment of 6 healthy adult men with a β‐blocker, timolol, resulted in a rise in serum phosphate which was maintained for the 5 days of therapy. This rise was accompanied by a transient fall in urine phosphate and a rise in the tubular maximum for phosphate reabsorption per unit glomerular filtration rate (TmPO4/GFR). No change in circulating parathyroid hormone or growth hormone could be demonstrated.
XLVI. What are the criteria for criteria?
Authors: Feinstein Alvan R.
Published: January 2016

The previous essay10 of this series was concerned with the purposes, functions, and basic architecture of criteria. In purpose, criteria are used to outline the performance of a procedure, or to set standards of identification, correctness, or desirability. The criteria are called operational if they contain suitably detailed rules and instructions to describe the way the procedure is done or the way a decision is reached about the standard.
Prazosin in hypertension with and without methyldopa
Authors: Kochar Mahendr S. , Zeller James R. , Itskovitz Harold D.
Published: January 2016

The efficacy of prazosin was assessed in 21 patients with essential hypertension who failed to respond adequately to a combination of methyldopa and hydrochlorothiazide. The patients were divided randomly into two groups; in the first group prazosin was substituted for methyldopa and in the second group prazosin was added to the combination. In group 1, the average blood pressure (BP) fell from 144/102 mmHg (sitting) and 142/105 mmHg (standing) to 136/91 mmHg (sitting) and 129/91 mmHg (standing) after prazosin (17 mg) was substituted for methyldopa. The fall in the diastolic BP was statistically significant (p < 0.01). In group 2, BP fell from 146/101 mmHg (sitting) and 143/103 mmHg (standing) to 126/87 mmHg (sitting) and 118/86 mmHg (standing) when prazosin 14 mg was added to methyldopa and hydrochlorothiazide. The reductions in systolic and diastolic pressures were statistically significant (p < 0.001).
Judgments of trained observers on adverse drug reactions
Authors: Blanc Sylviane , Leuenberger Philippe , Berger Jean-Pierre , Brooke Eileen M. , Schelling Jean-Louis
Published: January 2016

Patients (672) admitted to a department of medicine during five consecutive months were followed by an investigator who identified 110 clinical manifestations which could have been considered adverse drug reactions. From these, 42 were excluded because they did not correspond to the definition of adverse reaction or they were inadequately documented. The remaining 68 cases were submitted to three independent observers who had to reply to a series of questions; from these replies five degrees of probability for the reaction itself were deduced. Reactions (54; 49% of the manifestations reported) were considered as certain or probable by at least two observers, but only 27 reactions of these (25%) were attributed to the same drug by all three observers. There was a low level of agreement between any two observers (paired agreement ratio: 0.6 to 0.7) and little difference of agreement between any one observer and each of the others (personal agreement ratio: 0.6 to 0.7).
Aerosol fenoterol by intermittent positive pressure breathing in asthmatic patients
Authors: Ruffin R. E. , Montgomery J. M. , Newhouse M. T.
Published: January 2016

Ten subjects with mild to moderately severe asthma participated in a study of the bronchodilator activity and incidence of side effects of fenoterol aerosol administered by intermittent positive pressure breathing (IPPB). The doses of fenoterol used in the Bird micronebulizer were 0, 0.25 mg, 0.5 mg. 1.0 mg, and 2.5 mg, and these were administered in a randomized, double‐blind fashion. The bronchodilator response, assessed by the area under the FEV1 curve, showed mean (±SE) values of 1.44 ± 0.53 1 hr for 0.25 mg of fenoterol to 1.66 ± 0.56 1 hr for 2.5 mg of fenoterol (p > 0.05), longer (p < 0.01) than the mean placebo response of 0.06 ± 0.38 1 hr. A dose‐dependent increase in tremor was observed for each of the doses of fenoterol. The 0.25‐mg dose of fenoterol solution is an appropriate starting dose for the treatment of moderately severe asthma.
Effect of neuroleptic drugs on lithium uptake by the human erythrocyte
Authors: Pandey Ghanshyam N. , Goel Indra , Davis John M.
Published: January 2016

We studied the effects of neuroleptic and antidepressant drugs on Li+ uptake in human red cells to examine the reported neurotoxicity reported for lithium‐neuroleptic combination treatment and its relationship to altered tissue Li+ levels. All the phenothiazines increased Li+ influx in red cells and steady‐state Li+ distribution ratio in vitro. This effect was not observed with other drugs studied. It is suggested that increased levels of Li+ in the tissue caused by phenothiazines may be related to neurotoxic effects observed during Li+‐phenothiazine therapy.
Presystemic and systemic glucuronidation of propranolol
Authors: Walle Thomas , Fagan Timothy C. , Conradi Edward C. , Walle U. Kristina , Gaffney Thomas E.
Published: January 2016

The relative importance of presystemic and systemic glucuronidation of propranolol was examined in normal subjects given single oral and intravenous doses of propranolol. The areas under the plasma concentration‐time curves (AUCs) of propranolol glucuronide (PG), 41 ± 15 ng · hr/ml, and propranolol, 48 ± 15 ng · hr/ml, were of the same order after the intravenous dose (0.05 mglkg). After oral doses of 20 and 80 mg, the AUCs of PG were 302 ± 105 and 1,398 ± 409 ng · hr/ml; these were 7 times the AUCs of propranolol, 44 ± 15 and 220 ± 38 ng · hr/ml. The time lapse to peak concentration, 1.5 to 3.0 hr, and the plasma half‐life, 3.2 to 3.7 hr, were the same for PG and propranolol. These results demonstrate glucuronidation as an important determinant of propranolol bioavailability.