bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of GRAS substances on pharmacologic effects of drugs
Authors: Du Bert N. La
Published: January 2016

First, let me explain what GRAS means. GRAS is an acronym for “generally recognized as safe.” It refers to a large number of chemical compounds that the FDA considers to be safe when added to foods. The legal basis for GRAS status is rather complicated and goes back over many years to early federal regulations dealing with food additives. In 1958 the FDA solicited opinions from the scientific community about the usefulness and safety of all the substances then added to foods, and in 1959 and 1960 had lists published in the Federal Register of those that were considered GRAS and had not received adverse comments.! No further testing of the safety of these initial GRAS compounds was required, but any new additions to the list were expected to be adequately evaluated for usefulness and safety. Over the years, GRAS status was granted to other compounds by the FDA officials by letters of approval, and the present number of GRAS substances is probably in excess of 700 compounds. There are also approximately 1,200 natural and synthetic flavoring agents added to foods which are generally recognized as safe by scientific experts but listed separately in the Code of Federal Regulations.2
The construction of a pharmacokinetic model for the disposition of polychlorinated biphenyls in the rat
Authors: Anderson M. W. , Eling T. E. , Lutz R. J. , Dedrick R. L. , Matthews H. B.
Published: January 2016

The construction of a preliminary pharmacokinetic model for the distribution, long‐term storage sites, excretion, and metabolism of selected polychlorinated biphenyls (PCBs) in the rat is described. Following intravenous administration of radioactive PCBs, several metabolites of each PCB isomer were detected in urine or feces, excreted primarily as glucuronide conjugates. The relative and absolute amount of metabolites excreted depended upon the degree of chlorination and the position of the chlorine on the biphenyl molecule. Concerning long‐term storage sites, an unanticipatedjinding was accumulation in skin, as revealed by the particularly long half‐life of the 6‐CB isomer in skin. A flow diagram of the model is presented, as are the differential equations, solved by computer for a given dose schedule, for the individual mass balances on parent and metabolite in each of the compartments that represent the organs or regions in which the concentration is assumed to be uniform. Low‐level, long‐term doses of PCBs produce a variety of toxicologic symptoms which appear only after long‐time exposure. Such models should be useful in explaining and predicting the toxicities induced by exposure to PCBs and similar contaminants and the time required to reach a steady‐state tissue concentration for given long‐term doses.
Effect of Aroclor 1254, phenobarbital, and polycyclic aromatic hydrocarbons on the plasma clearance of caffeine in the rat
Authors: Welch Richard M. , Hsu Shin-yu Y. , DeAngelis Richard L.
Published: January 2016

A thin‐layer chromatographic method is described for the quantitation of caffeine and its dimethylxanthine metabolites, theophylline, theobromine, and paraxanthine. The method was used to evaluate the effect of polycyclic aromatic hydrocarbons (PCH), polychlorinated biphenyls (Aroclor 1254), or phenobarbital on the pharmacokinetics of caffeine and its dimethylxanthine metabolites. The oral administration of benzo[a] pyrene (BP) or Aroclor 1254 to rats for 3 days markedly increased the plasma clearance of caffeine and its dimethylxanthine metabolites. Similar results on the plasma clearance of caffeine were obtained with benzanthracene, dibenzanthracene, chrysene, or pyrene. Although the elimination of caffeine from plasma was increased in rats treated with phenobarbital for 3 days, it was less effective in this respect than the PCH or Aroclor 1254. In addition, phenobarbital did not significantly affect the rate of elimination of the dimethylxanthine metabolites from rat plasma following an intravenous dose of caffeine. Following the intravenous administration of caffeine to rats pretreated with Aroclor 1254 or BP, there was a marked increase in the appearance of theophylline, theobromine, and paraxanthine in plasma. The time to achieve peak plasma levels of these metabolites was reduced from 6 to 7 hr in control rats to I hr in Aroclor 1254‐treated rats and to less than 3 hr in rats treated with BP. Moreover, the plasma elimination of the dimethylxanthine metabolites formed from caffeine was greatly accelerated after pretreatment with BP or Aroclor 1254. A dose‐response study with BP indicated that as little as 1.0 mglkg of BP administered orally for 3 days markedly increased the plasma clearance of caffeine; however, pretreatment with BP did not affect the absolute bioavailability of caffeine. The area under the caffeine plasma curve after oral administration was identical to the area when the same dose was administered intravenously. The above studies indicate that the plasma clearance of caffeine is markedly increased in rats pretreated with phenobarbital, PCH, or Aroclor 1254 and suggest that the metabolism and pharmacology of caffeine may be considerably altered in human subjects exposed to these substances.
The inducing properties of polychlorinated biphenyls on hepatic monooxygenases
Authors: Alvares Alvito P. , Kappas Attallah
Published: January 2016

The polychlorinated biphenyls (PCBs) represent a newly recognized and widely distributed category of environmental pollutants whose biologic impact on animals and man may be both substantial and highly detrimental. The pharmacologic effects of these agents on enzymes in the liver which metabolize drugs and other foreign compounds. such as carcinogens. are powerful and long lasting. PCBs mimic the effects produced on these enzymes by drugs. such as phenobarbital. and carcinogens. such as 3‐methylcholanthrene. They are potent inducers of cytochromes P‐450 and P‐448 and associated enzymic activities. Further. these chemicals can cross the placental barrier and be transmitted through maternal milk to the newborn infant causing marked increases in drug biotransformation enzymes in the fetus and the neonate. Studies with the use of microscope immersion oils containing PCBs show that application of minute amounts of these oils to the skin of experimental animals results in a marked induction of the drugand carcinogen‐metabolizing enzymes. These findings suggest that even trivial skin exposure to chemicals. such as PCBs. can have significant and perhaps harmful biologic effects in man.
Genetic control of interindividual variations in racemic warfarin binding to plasma and albumin of twins
Authors: Wilding George , Paigen Beverly , Vesell Elliot S.
Published: January 2016

Warfarin binding to plasma as well as to charcoal‐treated purified albumin was studied in monozygotic (MZ) and dizygotic (DZ) twins by equilibrium dialysis. The association constants of warfarin binding and the number of warfarin binding sites per molecule were more similar within MZ than within DZ twins. These data indicate that genetic factors control interindividual variations in warfarin‐albumin association constants and in the number of warfarin binding sites per albumin molecule. A heritability index of a .87 was obtained for the association constant of warfarin binding to plasma and of 0.89 for warfarin binding to albumin. Heritability indices of 0.80 and 0.85 were obtained for the number of warfarin sites per albumin molecule in plasma and albumin, respectively. When the values of Ka and n for warfarin binding to albumin are plotted for the 44 individuals in this study, the distribution of Ka as well as n appears to be trimodal. The distribution of n falls into three classes, with 19 having an average binding site of 0.9, 14 having an average binding site of 1.4, and 3 having an average binding site of 2.1. Since this distribution conforms to a Hardy‐Weinberg equilibrium with gene frequencies of 0.72 and 0.28 and since the average number of binding sites is close to integral numbers of 1 and 2, it is tempting to speculate that these data disclose for the first time a common polymorphism of the albumin molecule affecting both nand Ka such that the phenotypic variations are controlled by two alleles at a single genetic locus. Since the number of subjects is too small for this distribution analysis to be completely secure, family studies will be required to determine whether such a polymorphism exists. Ka and n, though significantly correlated, have r values that are not very high (for isolated albumin, r = 0.63 for Ka vs n in MZ twins, p < O.Ol;r = 0.34 for Ka vs n in DZ twins, p = 0.05; for whole plasma, r = 0.78 for n vs Ka in MZ twins, p < 0.01; r = 0.57 for n vs Ka in DZ twins, p < 0.0 1). With respect to avidity of warfarin binding and number of warfarin sites per albumin molecule, these results suggest that inherited structural differences in the albumin molecule may affect the transport of certain drugs within the body of
Propranolol‐induced increments in total and free serum thyroxine in patients with essential hypertension
Authors: Kristensen Bent O. , Weeke Jorgen
Published: January 2016

The effect of propranolol on serum levels of total and free thyroxine, total and free triiodothyronine, and thyroid‐stimulating hormone (TSH) was investigated in 15 clinical euthyroid patients with essential hypertension. Oral propranolol in dosages from 80 to 480 mglday for a 30‐day period induced an average increase in total serum thyroxine of 15.5 ± 2.2% (mean ± SEM, 2 p = 0.00002) and in free thyroxine of 17.7 ± 3.5% (2 p = 0.00009). The oral dose of propranolol correlated positively with serum propranolol (r = 0.70, 2 p = 0.007). No significant correlation between serum propranolol and changes in serum thyroxine could be demonstrated. Total and free triiodothyronine, as well as TSH, remained unchanged during propranolol treatment. The most likely explanation is a propranolol‐induced decreased degradation of thyroxine. A practical consequence is that in patients with an uncertain clinical picture and slightly elevated serum thyroxine, propranolol intake should be considered.
Hemodynamic correlates of prolonged thiazide therapy: Comparison of responders and non responders
Authors: de Carvalho Jose G. R. , Dunn Francis G. , Lohmoller Georg , Frohlich Edward D.
Published: January 2016

The ultimate mechanism of action of thiazide diuretics in hypertension remains to be clearly defined. The hemodynamic effects of prolonged hydrochlorothiazide therapy were determined in 14 patients with uncomplicated essential hypertension following appropriate control studies. Patients were classified according to individual therapeutic responsiveness as responders (9 patients mean arterial pressure fall. >10 mm Hg) and nonresponders (5 patients). Hydrochlorothiazide reduced mean arterial pressure (MAP) in responders by 17% (from 121 ± 2.5 to 100 ± 3.0 mm Hg) in supine studies associated with reduction in total peripheral resistance (TPR; from 25.5 ± 1.3 to 22.8 ± 1.4 TPR units. p < 0.05) and plasma volume contraction (2,769 ± 142 to 2,492 ± 152 ml; p < 0.05). Similar changes occurred during tilt studies in the absence of postural hypotension. In contrast, nonresponders demonstrated no significant hemodynamic changes during both supine and tilt studies. Neither group showed altered responses to Valsalva maneuver during treatment. Thus, by defining individual responsiveness, this study provides evidence that arterial pressure fall depends on decreased TPR associated with contracted plasma volume.
Kinetics of intravenous chlordiazepoxide: Sex differences in drug distribution
Authors: Greenblatt David J. , Shader Richard I. , Franke Kate , Maclaughlin Dean S. , Ransil Bernard J. , Weser Jan Koch
Published: January 2016

Fourteen healthy subjects (7 male and 7 female) received 50 mg of chlordiazepoxide (CDX) hydrochloride by I‐hr intravenous infusion. Multiple venous blood samples drawn during the 72 hr after the infusion were assayed for whole blood concentrations of CDX and of its major metabolite, desmethylchlordiazepoxide (DMCDX). Mean (±SE) pharmacokinetic parameters, determined by weighted nonlinear least‐squares regression analysis, were: distribution half‐life, 1.3 (±0.3) hr; elimination half‐life, 17.8 (±2 .2) hr; volume of central compartment (VI), 0.27 (±0.02) Llkg; total distribution space (V.J, 0.52 (±0.03) Llkg; total clearance, 26.4 (±3.2) mllmin. Viand Vd were significantly larger among females (0.30 and 0.58 Llkg) than among males (0.22 and 0.45 Llkg), suggesting more extensive drug distribution in females. Values of half‐life and of clearance did not, however, differ significantly between sexes. A second study in three subjects compared simultaneous whole blood and plasma CDX concentrations after intravenous bolus injection and showed them to be highly correlated. Red cell :plasma partition ratios were 0, O.OJ, and 0.24, indicating limited uptake of CD X by red cells. Volumes of distribution and clearances calculated from CDX concentrations in whole blood are larger than those based on plasma concentrations.
A model for evaluation of antianxiety drugs with the use of experimentally induced stress: Comparison of nabilone and diazepam
Authors: Nakano Shigeyuki , Gillespie Hamp K. , Hollister Leo E.
Published: January 2016

Volunteer subjects were used to compare a potential antianxiety drug (nabilone, 2‐mg single doses) with a standard drug (diazepam, 5‐mg single doses). A double‐masked design with placebo control was used. Volunteer subjects were selected on the basis of high levels of trait anxiety and were tested by two anxiety‐inducing procedures—the mirror drawing test and the Stroop color‐word test. Anxiety induced by the experimental procedure was alleviated by diazepam and, to a lesser extent, by nabilone. Since doses of the two drugs may not have been equivalent, or the time courses identical, conclusions about their relative efficacy must be guarded. The experimental model is unusual in that antianxiety drugs can be tested in volunteer subjects for true antianxiety effects rather than for side effects, such as cognitive or motor impairment, sleepiness, or other signs of central nervous system depression.
Effect of pleural effusion on high‐dose methotrexate kinetics
Authors: Evans William E. , Pratt Charles B.
Published: January 2016

The kinetics of methotrexate were followed in a patient given two 6‐hr infusions of 400 mg/kg in the presence and absence of a pleural effusion. Although the decline in serum concentrations during the first 30 hr after the infusion was similar for the two treatment courses, the half‐life beginning 30 hr after the infusion was 6.7 hr without the pleural effusion and 14.4 hr with the pleural effusion. Comparison of the intercompartment distribution rate constants indicated slower movement of the drug back into the central compartment from the peripheral compartment when a pleural effusion was present. Pleural fluid methotrexate concentrations were consistently higher than serum concentrations. These data indicate that the increased risk of toxicity following high‐dose methotrexate in patients with pleural effusions is due to changes in methotrexate kinetics resulting in delayed excretion.
A clinical safety trial of stroma‐free hemoglobin
Authors: Savitsky J. Philip , Doczi John , Black Jack , Arnold John D.
Published: January 2016

A stroma‐free hemoglobin (SFH) solution was prepared which was sterile, pyrogen free, and contained only 1.2% of the stromal lipid present in unpurijied hemolysate, 250 ml of which was administered slowly intravenously to 8 healthy men. Two control subjects received 250 ml of serum albumin. The SFH infusions were generally well tolerated by 7 of the 8 men. One subject developed abdominal pain and costovertebral angle tenderness after infusion, which disappeared within 48 hr. Bradycardia and a mild increase in blood pressure was present during the SFH Infusions and for 4 to 5 hr thereafter. A decrease in urine output and endogenaus creatinine clearance appeared during the SFH infusions and for 2 to 4 hr after infusion. A mild prolongation of the activated partial thromboplastin time developed immediately after infusion. Gross hemoglobinuria appeared as expected during the SFH infusions and completely disappeared by 6 to 10 hr after infusion. All the cardiovascular, renal, and clotting changes were present for only a few hours after the SFH infusion, during the hemoglobinemia (free Hb in plasma). At 24 hr and 7 days after infusion all measurements were normal, and 6 mo follow‐up showed no abnormalities or hepatitis.
Quinidine kinetics in congestive heart failure
Authors: Ueda Clarence T. , Dzindzio Barry S.
Published: January 2016

The pharmacokinetics of quinidine was studied in cardiac patients with and without congestive heart failure. Following intravenous drug infusion, plasma and urine samples were collected at various times and analyzed for quinidine by a specific assay procedure. Although plasma quinidine concentrations varied over a wide range in both patient groups, the mean drug concentration at each time point was always higher in the congestive failure patients. In the 24‐hr postinfusion period, plasma drug disposition was biexponential with half‐life values for the fast and slow disposition processes (t½α and t½β) similar for each group. The respective values of t½α and t½β were 5.6 min and 6.8 hr in the congestive heart failure patients and 6.1 min and 6.2 hr in the control group. The volume of the central pool (Vc) and Vdarea were smaller in the congestive heart failure group (p < 0.05) with values of 0.44 ± 0.12 and 1.81 ± 0.49 L/kg, respectively, compared with those of the control group of 0.75 ± 0.31 and 2.67 ± 1.17 L/kg. Total body plasma drug clearance (Cl) was also lower in the heart failure patients (p < 0.05). The estimated Cl values were 3.16 ± 1.10 and 4.95 ± 1.36 ml/min/kg for the heart failure and control patients, respectively. Renal quinidine excretion accounted for 15% and 18% of the administered doses and corresponded to renal clearance values of 0.48 ± 0.15 and 0.95 ± 0.56 ml/min/kg in congestive heart failure and control patients, respectively. The results of this study indicate that the higher quinidine concentrations observed in congestive heart failure patients are due to a significantly smaller distribution volume for the drug.
Biological determinants of propranolol disposition in man
Authors: Kornhauser D. M. , Wood A. J. J. , Vestal R. E. , Wilkinson G. R. , Branch R. A. , Shand D. G.
Published: January 2016

Propranolol disposition has been investigated in 15 normal subjects with the use of a protocol which allowed simultaneous determination of the kinetics of the drug after both intravenous and oral administration by giving H3‐propranolol intravenously and native drug orally. In addition, plasma propranolol binding and the bloodlplasma propranolol concentration ratio (B/P) were measured. The data were used to calculate hepatic blood flow as well as systemic drug clearance from the blood and intrinsic clearance, which is an estimate of the activity of the drug‐metabolizing enzymes. Under the steady‐state conditions used, the hepatic extraction ratio was found to be 64% ± 2.5% (mean ± SE) resulting in a bioavailability of 36% ± 2.6%. Calculated liver blood flow varied from 778 to 2,162 ml/min, and, as predicted, the systemic clearance of propranolol (0.61 to 1.52 L/min) was correlated with both liver blood flow and intrinsic drug clearance (1.16 to 5.08 L/min). Variations in plasma drug binding had no effect on systemic clearance. Because of presystemic or “first‐pass” elimination, the variation in both free and total propranolol levels was greater after oral (5‐fold) than intravenous administration (2.5‐fold). We conclude that the approach described allows quantification of all of the biological determinants of propranolol disposition in subjects with normal hepatic vasculature.
Methadone maintenance: Plasma levels and therapeutic outcome
Authors: Holmstrand Jan , Änggård Erik , Gunne Lars-M.
Published: January 2016

Twenty‐one opiate‐dependent subjects were inducted into methadone maintenance treatment (MMT) in a closed metabolic ward. A daily dose of 30 mg of d,l‐methadone was given for 10 to 24 days followed by 60 mg Iday for another 10 to 24 days. Analysis of plasma levels at 4‐day intervals showed accumulation to a peak followed by a decrease to a lower level, indicative of development of dispositional tolerance. The outcome of treatment was assessed after 21 to 43 mo (median, 33 mo). The best record of rehabilitation was obtained in subjects discharged with steady‐state plasma concentrations above 200 ng/ml. Lower levels of plasma methadone were associated with higher frequency of urines containing illicit drugs and poorer psychosocial rehabilitation. This study indicates that a pharmacokinetically optimized dosage regimen would be useful in increasing the therapeutic effectiveness of MMT.
Kinetics of chlormethiazole in patients with alcohol withdrawal manifestations
Authors: Jostell K. G. , Agurell Stig , Hollister Leo E. , Wermuth Bruce
Published: January 2016

Chlormethiazole administered orally to patients in mild degrees of alcohol withdrawal was generally rapidly absorbed, showed a rapid distributive phase, and had an elimination phase t½ of 2.6 to 4.7 hr. The plasma concentrations of drug attained following higher oral doses were greater than is usually the case with augmentation of dose. Intravenously infused chlormethiazole in similar patients produced relatively high plasma concentrations of the drug, with distributive and eliminative t½ similar to those of oral doses. These pharmacokinetic patterns in alcoholic patients more closely resemble those previously reported for normal young subjects than they do for normal aged subjects.
No circadian effect on nortriptyline kinetics in man
Authors: Nakano Shigeyuki , Hollister Leo E.
Published: January 2016

Kinetics of a single 100‐mg dose of nortriptyline were studied in 10 normal men who took this dose at 9 a.m. in the morning and on another occasion at 9 p.m. Only minimal differences in kinetic parameters were observed, none enough to be of any clinical consequence. A rather high first‐pass metabolism of the drug was evident by high plasma concentrations of 10‐hydroxynortriptyline. it is thus unlikely that the recent custom of giving single daily doses of tricyclic antidepressants in the evening excludes regimens with more favorable drug kinetics.
Drug trial in rheumatoid arthritis: A new design
Authors: Arendt-Racine Eva C. , Atkinson Martin H. , Decoteau W. Earl , Flatt V. Lorraine , Varady John
Published: January 2016

The comparative efficacy and safety of naproxen and ibuprofen were studied in 64 patients with rheumatoid arthritis. A new trial design with three aspirin periods interspersed during the study was used. By passing a smooth curve through the values obtained for the various measures of disease activity during the aspirin periods, one could calculate the difference between what would have been expected on aspirin therapy and what was found during therapy with the two trial drugs. These differences, or “incremental values,” allowed each patient's variations to be analyzed individually, thus eliminating the necessity of assuming that a patient's disease was constant. Naproxen and ibuprofen were comparable in efficacy to each other and to aspirin, but both drugs caused significantly less severe side effects than aspirin. Although analysis of the incremental values showed essentially the same results as a standard analysis of the raw data with only a modest increase in sensitivity in this particular study, the novel trial design may prove useful in future drug studies in patients with rheumatoid arthritis and other chronic but fluctuating diseases.
Concurrent antagonism of isoproterenol and norepinephrine after labetalol
Authors: Richards D. A. , Prichard B. N. C.
Published: January 2016

Labetalol reduces blood pressure in normotensive and hypertensive subjects. The effects of a therapeutic dose of intravenous labetalol upon the cardiovascular responses to intravenous isoproterenol and norepinephrine in 6 normotensive subjects were studied in order to investigate the drug's mode of action. Before labetalol, intravenous isoproterenol increased heart rate and reduced diastolic blood pressure in a dose‐dependant manner; likewise, intravenous norepinephrine increased both systolic and diastolic pressure. The order of administration of these agonists was randomized between the subjects before and after labetalol. Following labetalol (1.5 mg/kg intravenously) the effects of isoproterenol were antagonized such that cumulative log‐dose response curves of mean isoproterenol‐induced increases in heart rate and reductions in diastolic pressure were shifted to the right in a parallel manner to approximately the same extent. At the same time, the mean norepinephrine‐induced increases in systolic and diastolic blood pressure were also antagonized in a competitive manner. These responses were compared with others in the same subjects under the same conditions and it was concluded that the antihypertensive effect of labetalol is explained by concurrent blockade of α‐and β‐adrenoceptors.
Physiologic disposition of lergotrile
Authors: Rubin Alan , Lemberger Louis , Dhahir Patricia , Warrick Patricia , Crabtree Ross E. , Obermeyer Boyd D. , Wolen Robert L. , Rowe Howard
Published: January 2016

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea‐amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinson's disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N‐14CH3‐lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was allributed to the presence of circulating metabolites of lergOlrile. Lergotrile metabolites were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13‐OH‐lergotrile (up 10 30% of the dose). A metabolite in urine was formed by conversion of the C8‐acetonitrile group of lergotrile to a carboxyl group (aboUl /0% of the dose). The presence of 14CO2 in the expired air after administering N‐14C‐methyl‐lergotrile indicated that the drug was N‐demethylated to form norlergotrile.
Nortriptyline in depressed patients with high plasma levels. II
Authors: Braithwaite Robin , Montgomery Stuart , Dawling Sheila
Published: January 2016

Eighteen depressed patients were routinely treated with 100 mg nonriptyline nightly for 4 wk. Steady‐state plasma nortriptyline concentrations were measured at weekly intervals for each patient at the same time as clinical assessments were carried out. Steady‐state nonriptyline levels ranged between 120 µg/L and 681 µg/L (mean, 293 µg/L), which represents a 6‐fold interindividual variation. A single oral dose of 100 mg nonriptyline was given to 17 of the 18 patients prior to treatment. Plasma nortriptyline concentrations were obtained at regular intervals over a 3‐day period. Several kinetic parameters were calculated for each patient. The plasma nonriptyline half‐life (t½) ranged from 22 to 88 hr and the plasma clearance ranged between 8 and 55 L/hr. Highly significant correlations were obtained between steady‐state nortriptyline levels and both t½ (p < 0.01) and clearance (p < 0.0001). A high correlation (p < 0.0001) was also obtained between single‐dose 48‐hr nonriptyline levels and steady‐state nonriptyline levels. We have been able to demonstrate a strong relationship between individual patient differences in nonriptyline kinetics and steady‐state plasma concentrations and associated therapeutic effects. The pharmacokinetic data obtained in the patients appear to be different to those reponed in studies carried out in normal healthy volunteers. Reasons for this are discussed. The use of simple kinetic parameters in predicting the high nonriptyline levels is also discussed.
Effect of a standard breakfast on digoxin absorption in normal subjects
Authors: Johnson B. F. , O'Grady J. , Sabey G. A. , Bye Carole
Published: January 2016

The influence of food on absorption of digoxin was studied in 6 healthy volunteers who received 1.0 mg digoxin as 4 tablets of Lanoxin either after an overnight fast, immediately after a standard breakfast, or 90 min after a standard breakfast. There was no significant difference between the three regimens in terms of area under the plasma concentration‐time curve for 79 hr or in the 10‐day cumulative urinary excretion. The mean peak plasma concentration was higher (p < 0.05) when digoxin was given fasting (4.2 ± 0.46 ng/ml) than immediately after food (2.8 ± 0.24 ng/ml). The mean peak plasma concentration when digoxin was administered 90 min after food (3.3 ± 0.30 ng/ml) was intermediate but not significantly different from either of the other mean peak concentrations. The results demonstrate that ingestion of food decreases rate but not extent of absorption of concurrently administered digoxin.
Hemoperfusion for methotrexate removal
Authors: Gibson Thomas P. , Reich Steven D. , Krumlovsky Frank A. , Ivanovich Peter , Gonczy Constance
Published: January 2016

Removal of methotrexate by Amberlite XAD‐4 hemoperfusion was determined in a patient with metastatic breast carcinoma. During 4 hr of hemoperfusion the plasma concentration of methotrexate fell from 5.5 × 10−7 M to 3.1 × 10−7 M. After hemoperfusion methotrexate concentration increased as a consequence of multicompartmental pharmacokinetics to 5.5 × 10−7 M and then slowly declined. Plasma methotrexate clearance decreased from 79 mllmin 30 min into hemoperfusion to 28 mllmin at the conclusion. In vitro clearance of methotrexate by 17 artificial kidneys. Amberlite XAD‐4. and uncoated charcoal was determined. Uncoated charcoal had the greatest clearance of methotrexate of all the devices tested. We conclude that: (1) Amberlite XAD‐4 transiently reduces plasma methotrexate concentration; (2) in vitro. charcoal hemoperfusion is more effective than XAD‐4 in removing methotrexate; (3) as a consequence of the multicompartmental pharmacokinetics of methotrexate a postperfusion rebound in plasma methotrexate concentration is to be expected.
Correlation between plasma diphenhydramine level and sedative and antihistamine effects
Authors: Carruthers S. George , Shoeman Don W. , Hignite Charles E. , Azarnoff Daniel L.
Published: January 2016

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t½ was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 mllmin. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subjects. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.
Analgesic activity of floctafenine after cholecystectomy
Authors: Morris Marilyn E. , Henderson Ian W. D.
Published: January 2016

In a double‐blind. crossover study involving 40 post‐cholecystectomy patients. the analgesic activity of a new oral nonnarcotic agent, floctafenine, was compared with that of oral meperidine and oral propoxyphene. A behavioral approach to the measurement of pain relief. i.e., the measurement of pain on movement or coughing, was used in addition to the accepted subjective method. Floctafenine 200 mg was found to have analgesic activity intermediate between that of meperidine 75 mg and propoxyphene 65 mg. Patients reported the fewest side effects after floctafenine. Initial pain level was found to affect the final pain score. Effects on pain relief due to age, sex, time of the day, and carryover effects were also examined and not found to be significant.
Fendosal and aspirin in postpartum uterine pain
Authors: Bloomfield Saul S. , Barden Tom P. , Mitchell Jeanette
Published: January 2016

The analgesic efficacy of fendosal, a new nonsteroidal anti‐inflammatory agent structurally related to salicylic acid, was compared with that of aspirin and placebo in 100 patients with postpartum uterine pain in a single oral dose, parallel, stratified, randomized, double‐blind design. With 650 mg aspirin and with 200 or 400 mg fendosal, but not with 100 mg, analgesic effects, as measured subjectively by mean pain intensity scores, began within 1 hr and had similar time‐effect patterns for the first 4 or 5 hr. Thereafter with the 2 higher doses of fendosal analgesia continued to increase, reaching a peak at 6 hr (p < 0.05) and persisting beyond 7 hr (p < 0.01), whereas there was no aspirin analgesia after the fifth hour. With 100 mg fendosal time of onset tended to be delayed 2 hr or more, and duration was short. The most effective treatment (largest mean 7‐hr sum of pain intensity difference [SPID] score) was 400 mg fendosal (p < 0.01); 200 mg fendosal was rated second (p < 0.01), 650 mg aspirin, third (p < 0.05), 100 mg fendosal, fourth, and placebo, fifth. There were no significant side effects. These results demonstrate the efficacy of single doses of fendosal as well as the dose‐dependent magnitude and time course of effect on postpartum uterine pain.
Effect of charcoal‐broiled beef on antipyrine and theophylline metabolism
Authors: Kappas Attallah , Alvares Alvito P. , Anderson K. E. , Pantuck Eugene J. , Pantuck Carol B. , Chang R. , Conney A. H.
Published: January 2016

Eight healthy volunteers were sequentially fed a control diet, a charcoal‐broiled beef‐containing diet, and the control diet a second time. The mean plasma half‐lives (t½) of antipyrine and theophylline were each decreased by 22% after the subjects were fed the charcoal‐broiled beef‐containing diet. The mean plasma t½s for these drugs returned to control values when the subjects were fed the control diet for a second time. Considerable individuality occurred in the responsiveness of the subjects to the charcoal‐broiled beef‐containing diet. The decreases in antipyrine plasma t½s among the 8 subjects ranged from 5% to 39%, and the decreases in theophylline t½S ranged from 0% to 42%.
Effect of lithium on plasma chlorpromazine levels
Authors: Rivera-Calimlim Leonor , Kerzner Boris , Karch Fred E.
Published: January 2016

The interaction of lithium and chlorpromazine (CPZ) was studied in healthy volunteers in a randomized crossover study. Each subject ingested two doses of CPZ (l00 mg) as the liquid concentrate: (1) without concurrent lithium therapy and (2) after a 7‐day treatment with lithium carbonate (900 mg/day). When CPZ was administered with lithium, peak plasma CPZ levels were 40.3% (mean) lower than those without lithium (p = 0.006), and the area under the CPZ plasma concentration time curve was 26.6% smaller (p = 0.08). The time to reach peak plasma CPZ levels was similar in both groups. All subjects slept for 4 to 6 hr after oral CPZ and had a maximum fall in both systolic (8 to 32 mg Hg) and diastolic (5 to 23 mg Hg) blood pressure at the time of peak plasma CPZ concentration. This lithium‐CPZ interaction may explain the low plasma CPZ levels reported previously in psychiatric patients taking both lithium and CPZ.
Ticrynafen, a uricosuric antihypertensive diuretic
Authors: Stote Robert M. , Dubb Jeffrey W. , Familiar Robert G. , Alexander Fred
Published: January 2016

Ticrynafen, a diuretic‐uricosuric also effective as an antihypertensive, was compared in single doses with several other diuretics. Over an 8‐hr period, a 250‐mg dose exerted natriuretic activity comparable to that of 25 mg of chlorthalidone and 50 mg of ethacrynic acid; a 500‐mg dose was comparable to 50 mg chlorthalidone and 50 mg hydrochlorothiazide. Ticrynafen combined with furosemide had an additive effect, whereas a combination with hydrochlorothiazide was not additive. In both doses ticrynafen was a uricosuric and this effect was maintained when given with furosemide and hydrochlorothiazide, both of which individually were slightly antiuricosuric. Ticrynafen may be useful in patients requiring a diuretic in whom it is desirable to avoid hyperuricemia.
Cefamandole kinetics during cardiopulmonary bypass
Authors: Polk Ron E. , Archer Gordon L. , Lower Richard
Published: January 2016

The kinetics of cefamandole during cardiac surgery was studied in 16 adult patients given a single intravenous infusion of 20 mg/kg at the time of anesthesia induction. Five normal volunteers who received the same dose served as controls. Cardiopulmonary bypass (CPB) was found to significantly increase the half‐life (t½) of cefamandole. The mean t½ during CP B (113.2 min) was longer than the terminal t½ in normal volunteers (52.0 min; p < 0.005). Throughout CPB (maximum, 3.7 hr), cefamandole plasma levels were maintained above the minimum inhibitory concentration for those organisms most likely to cause postoperative infections. We conclude that if 20 mg/kg of cefamandole is given within an hour of the beginning of cardiovascular surgery, a supplemental dose is not needed until the patient has been on CPB for at least four hours.
XLIII. The architecture of cross‐sectional research (conclusion)
Authors: Feinstein Alvan R.
Published: January 2016

The previous essay8 of this series was concerned with the ‘anatomy’ and ‘physiology’ of the architecture used in cross‐sectional research. Cross‐sectional structures can serve either as direct descriptions of the characteristics found in groups of patients, or as surrogates for the longitudinal (cohort) structures needed to investigate the etiology, pathogenesis, or outcome effects of diverse diseases. The descriptive and surrogate functions of crosssectional architecture allow abundant opportunity for the development of many forms of scientific ‘pathology’, which will be discussed in the current essay. The discussion will also include suggestions for the prevention and treatment of the scientific ‘lesions’.
Hexobarbital disposition in compensated and decompensated cirrhosis of the liver
Authors: Zilly W. , Breimer D. D. , Richter E.
Published: January 2016

Hexobarbital disposition after intravenous infusion in 8 patients with compensated and 22 patients with decompensated liver cirrhosis was compared with that in 17 young healthy and 5 elderly subjects with normal liver function. The postinfusion plasma concentrations showed a rapid initial decay (a‐phase) and subsequently a slower decrease (β‐phase). The half‐life of this phase was 340 ± 110 min for the healthy volunteers, 509 ± 174 min for the patients with compensated liver cirrhosis, and 1,017 ± 450 min for the decompensated group. Clearance values were 3.32 ± 0.99, 1.88 ± 0.70, and 1.26 ± 0.49 ml · min−1 · kg−1, respectively. The mean value for the steady‐state volume of distribution in decompensated cirrhosis appeared larger than in compensated cirrhosis and healthy volunteers, whereas the central compartment volume was reduced in compensated cirrhosis. The binding of 3H‐hexobarbital by plasma proteins in cirrhotic patients and healthy controls did not differ. In one patient hexobarbital concentrations were also measured in ascites, which appeared to be identical to those in plasma after a relatively slow equilibrium period. In patients hexobarbital clearance appeared to be correlated with serum albumin concentration. For the patients with decompensated liver cirrhosis serum albumin has some predictive value with respect to drug clearance, whereas compensated liver cirrhosis is generally associated with normal or near normal albumin concentration despite reduced hexobarbital clearance.
Protriptyline kinetics
Authors: Ziegler Vincent E. , Biggs John T. , Wylie Laurence T. , Coryell William H. , Hanifl Kathleen M. , Hawf Donald J. , Rosen Samuel H.
Published: January 2016

The kinetics of protriptyline were examined in 8 subjects after a single oral dose of 30 mg protriptyline hydrochloride. Peak protriptyline levels ranged from 10.4 to 22.3 ng/ml and were reached 6 to 12 hr after the oral dose. The mean protriptyline half‐life (t½) was 74.3 hr and ranged from 53.6 to 91.7 hr in individual subjects, confirming the long t½ of protriptyline reported by Moody and associates. The estimated first‐pass metabolism of protriptyline was relatively small, ranging from 10% to 25% of the oral dose, assuming complete absorption. The mean volume of distribution was 22.5 L/kg and ranged from 15.0 to 31.2 L/kg. No relationship was found between the kinetics of protriptyline and those of doxepin studied previously in 7 of the 8 subjects.
Timolol kinetics in chronic renal insufficiency
Authors: Lowenthal David T. , Pitone Joseph M. , Affrime Melton B. , Shirk Jane , Busby Patricia , Kim Kwan E. , Nancarrow John , Swartz Charles D. , Onesti Gaddo
Published: January 2016

A single‐dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function—(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; Ccn 20 to 50 ml/min); (3) 4 patients with end‐stage renal disease (ESRD)—to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (Cmax) was 84.3 ± 44.8 ng/ml at 0.8 ± 0.4 hr for N and 87.1 ± 22.8 ng/ml at 1.7 ± 1.2 hr (p, NS) for MCRI. Nand MCRI mean half‐lives (5.2 ± 2.6 hr and 4.0 ± 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 Nand 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration oftimolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.
Error dependent on renal function when monoexponential equation assumed
Authors: Reidenberg Marcus M.
Published: January 2016

The recent paper by MacKichan and coworkers, which appeared in the November, 1977, issue of the Journal, states that there is an important error dependent on renal function when a one‐compartment model is used to calculate drug clearance values from data better fitted to a more complex model. This error is related to the magnitude of the ratios of the exponents and constants of the two‐compartment model and is independent of the pathway of elimination of the drug. Lidocaine, a drug with a rapid metabolism rate, shows an error when a one‐compartment model is used, but this error is independent of renal function.4,5 Even for lidocaine, dosage recommendations calculated from a one‐compartment model are not significantly different from those calculated from a two‐compartment model.4 Thus the general conclusion of MacKichan and coworkers that “the clinical importance of this error cannot be overlooked” requires qualification. MacKichan and co‐workers imply that a one‐compartment model is inappropriate for calculating clearance values for antipyrine, tolbutamide, and pentobarbital in man. The literature documents that there are very small differences in clearance values calculated for these drugs when the one‐compartment model is compared to the two‐compartment model.1–3
Biliary excretion of vincristine
Authors: Jackson Don V. , Castle Manford C. , Bender Richard A.
Published: January 2016

A patient with pancreatic carcinoma and a choledochal T tube was given tritiated vincristine sulfate ([3H]‐VCR) intravenously. Peak biliary excretion occurred in 2 to 4 hr and this sample contained 9.7% of the injected radioactivity. The first 24‐hr bile sample contained 21.7% of the dose and 76.4% of the cumulative 72‐hr biliary excretion. During a 3‐day period of observation, 4.2%, 45.6%, and 49.6% of the excreted radiolabel was present in the feces, urine, and bile, respectively. Products of VCR metabolism and decomposition appeared in the bile rapidly; only 46.5% of the drug was present in the parent form in the 2‐hr collection. Since significant amounts of these products were also identified in control specimens of bile, blood, plasma, and buffer alone after brief periods of incubation, the origin and nature of the species appearing in the bile remain unclear. Observing the fecal route to be the major source of elimination of radio label following intravenous injection of [3H]‐VCR in our patients previously, we now conclude the biliary system to be the principal route of excretion of VCR and its products. Hepatic dysfunction might therefore alter elimination kinetics and increase the exposure to VCR and its products which might augment toxicity and require dose modification.
Kinetics of mezlocillin and carbenicillin
Authors: Pancoast Stephen J. , Neu Harold C.
Published: January 2016

The kinetics of mezlocillin, a semisynthetic acylureido penicillin, more active than carbenicillin against many gram‐negative bacteria, were compared with those of carbenicillin. Following an intravenous infusion of 4 gm in 5 min to 8 normal men there was an average serum level of 294 µg/ml for mezlocillin and 365 µg/ml for carbenicillin. The t½ for mezlocillin was 47 min and that for carbenicillin was 70 min. The apparent volume of distribution was 13.4 L for mezlocillin and 14.4 Lfor carbenicillin. The mean urinary recovery of mezlocillin was 72% and that for carbenicillin was 92 %. Constant infusion of 5 mg of mezlocillin over 2 hr gave steady‐state levels of 234 µg/ml. Half‐life, apparent volume of distribution, and serum and renal clearance of mezlocillin after constant infusion were in the same range as those after rapid infusion.
Oral clonidine loading for rapid control of hypertension
Authors: Cohen Irvin M. , Katz Murray A.
Published: January 2016

In order to determine the efficacy and safety of oral clonidine loading to control hypertension rapidly, 15 patients received 0.1 or 0.2 mg clonidine initially followed by hourly doses of 0.1 mg until the blood pressure was substantially reduced or until a total of 0.5 mg had been given. Twelve (80%) responded with a reduction in mean blood pressure of 33 ± 3 (SE) mm Hg in an average time of 2.25 hr. Side effects were minimal. Four of the 5 patients hospitalized solely for purposes of blood pressure control responded to clonidine loading and were discharged the next day. Clonidine loading proved to be safe and effective for rapid control of hypertension and may be preferred to intravenous antihypertensives for some indications.