bluuebunny/crossref_metadata_2025 huggingface dataset:
Dicloxacillin and cloxacillin: Pharmacokinetics in healthy and hemodialysis subjects
Authors: Nauta Ernst H. , Mattie Herman
Published: January 2016

Differences in the elimination, distribution, and absorption of dicloxacillin and cloxacillin were studied in a group of healthy individuals with the use of a 2‐compartment model. In patients on chronic intermittent hemodialysis, only dicloxacillin was investigated and the results were compared with data obtained in earlier studies on cloxacillin and flucloxacillin. In healthy volunteers the bioavailability after oral administration of 2 gm dicloxacillin or 2 gm cloxacillin amounted to 48.8% and 36.9% of the dose, respectively, when calculated from the area under the serum concentration‐time curve, and to 74.1% and 48.5%, respectively, when calculated from the urinary excretion. Individual variation in bioavailability after oral administration was slightly lower for dicloxacillin than for cloxacillin. The higher serum concentrations of dicloxacillin, as compared with cloxacillin, are also attributable to slower (renal) elimination (TV½: 42 and 33 min, respectively). Analysis of serum concentrations after intravenous administration of 1 and 2 gm dicloxacillin to healthy subjects revealed concentration‐dependent kinetics with respect to renal elimination. In hemodialysis patients the elimination rate of dicloxacillin (P½: 129 min) corresponds with the extrarenal elimination rate in healthy subjects. The bioavailability after oral administration of 1 gm in patients is good (75.9% of the dose).
A model to evaluate mild analgesics in oral surgery outpatients
Authors: Cooper Stephen A. , Beaver William T.
Published: January 2016

A model was developed to evaluate mild analgesics in an oral surgery outpatient clinic population. On a reportform, patients recorded starting pain and then pain intensities, relief responses, and side effects hourly for 3 hr after drug administration. The treatments were randomly allocated to patients on a single‐dose‐only basis, and the double‐blind technique was used. The first of two studies compared codeine 30 mg, aspirin 650 mg, codeine 30 mg with aspirin 650 mg, and placebo in 128 subjects. The second study compared codeine 60 mg, acetaminophen 600 mg, and codeine 60 mg with acetaminophen 600 mg and placebo in 160 subjects. Time‐effect curves were generated for both pain reliel and pain intensity difference (PID). First‐hour scores, peak scores, and total scores were statistically analyzed by parametric and nonparametric factorial analysis. Both aspirin 650 mg and acetaminophen 600 mg proved superior to placebo (p < 0.01) for all measures of effect with both parametric or nonparametric analyses, while codeine 30 mg was not significantly superior to placebo in any analysis. Codeine 60 mg proved significantly superior to placebo for certain measures of effect when analyzed with the nonparametric model. There was no significant interaction between either aspirin or acetaminophen and codeine.
Intrasubject variation of warfarin binding to protein in serum of patients with cardiovascular disease
Authors: Vacobi Avraham , Udall John A. , Levy Gerhard
Published: January 2016

A study of 31 patients with cardiovascular disease who were taking warfarin regularly had shown pronounced intersubject differences in serum protein binding of warfarin and a highly significant correlation between the body clearance of warfarin and the free fraction of the drug in serum. Similar observations have been made in experimental animals and are consistent with predictions based on theoretical considerations. The purpose of this investigation was to determine the intrasubject variation in the free fraction of warfarin in serum. Samples of serum were obtained from 23 of the 31 patients previously studied. The time interval between the two studies was 3.4 to 5.7 mo. The daily dose of warfarin had been changed by 10.6% on the average. With two exceptions, there was no change in concurrent medications. The ratio of free fraction values of warfarin in serum, second/first study, was 0.948 ± 0.297 (mean ± S.D.), and there was a highly significant correlation (p < 0.001) between the individual free fraction values in the first and second studies.
Intramuscular butorphanol and meperidine in postoperative pain
Authors: Gilbert Malcolm S. , Hanover Rita M. , Moylan David S. , Caruso Frank S.
Published: January 2016

Butorphanol, I, 2, and 4 mg 170 kg. ami meperidine, 40 and 80 mg 170 kg, were compared for analgesic activity and side effects in 104 hospitalized postoperative patients. Butorphanol proved to he 30 to 40 times as potent as meperidine on a weight basis. Both medications prvided maximum pain relief approximately 1 hr after administration. The most common side effect in all groups was drowsiness.
Renal failure, hemodialysis, and nafcillin kinetics
Authors: Rudnick Michael , Morrison Gail , Walker Barry , Singer Irwin
Published: January 2016

Nafcillin (N) pharmacokinetics was studied in 27 subjects with and without renal failure (RF) (determined by endogenous creatinine clearance, CCr)' Elimination rate constants (K) were calculated from serial serum levels of N measured from 2 to 12 hr after a single 500‐mg intramuscular injection. Only 4 of 9 hemodialysis patients had measurable levels of Nat 24 hr. The K values for the groups with normal renal function, moderate RF, severe RF, and on hemodialysis were 0.477 hr−1, 0.432 hr−1, 0.369 hr−1, and 0.306 hr−1, respectively. The amounts of injected drug excreted in the urine of the normal renal function, moderate RF, and severe RF groups were 26.6 ± 1.7%, 16.1 ± 3.8%, and 2.0 ± 0.9%, respectively; the renal and nonrenal elimination rate constants for these 3 groups were 0.127 hr−1 and 0.350 hr−1, 0.069 hr−1 and 0.363 hr−1, and 0.007 hr−1 and 0.362 hr−1, respectively. Dialysis had no effect on K values; the maximum nafcillin dialysance was 13.7 ml/min, and was positive in only 5 of 12 determinations. Linear regression analysis of K vs CCr resulted in the following relationship: K = 0.347 + 0.001 CCr. The volumes of distribution for the study groups were 1.06 ± 0.1 L/kg (normals), 0.83 ± 0.07 Llkg (moderate RF), 0.70 ± 0.07 L/kg (severe RF), and 0.78 ± 0.06 Llkg (hemodialysis). We conclude that renal failure alters nafcillin pharmacokinetics only slightly and dosage alterations are not necessary in renal failure, with or without hemodialysis.
Systemic availability of orally administered meperidine
Authors: Mather L. E. , Tucker G. T.
Published: January 2016

A comparison of the areas under the plasma concentration‐time curves after intravenous and oral administration of meperidine in 4 normal subjects indicated that 48% to 56% of the oral dose avoided “first‐pass” metabolism and was systemically available. Similar estimates were obtained by applying the Loo‐Riegelman method for calculating drug absorption viz, 47% to 60%. Oral availability predicted from a knowledge of drug clearance (blood) after intravenous injection was 47% to 71%. In some subjects plasma drug concentration‐time curves after oral administration exhibited irregularities and double peaks possibly indicative of the action of meperidine on the gut or a recycling process.
Effect of oral contraceptives on platelet monoamine oxidase, monoamine excretion, and adrenocortical function
Authors: Feldman Jerome M. , Roche Joan
Published: January 2016

Studies with animals indicate that there are cyclical changes in the monoamine oxidase (MAO) activity of brain and uterus, and that these changes may be due to changes in estrogen and progesterone levels. To determine if oral contraceptives (OC) alter the tissue MAO activity of healthy women, we measured platelet MAO activity in 7 control women and in 7 women who were receiving combination estrogen‐progesterone OC. The platelet MAO of the control women and the women receiving OC did not differ with the use of tryptamine and serotonin as MA0 substrates. The two groups did not differ with respect to the following: serum serotonin, plasma tryptophan, plasma tyrosine, and the urinary excretion of tryptamine, tyramine, serotonin, 5‐hydroxyindoleacetic acid, creatinine, 17‐hydroxycorticosteroids, 17‐ketosteroids, and urinary free cortisol. The subjects receiving OC had higher plasma cortisol concentrations than the controls. Two women in the seventh month of uncomplicated pregnancy, who underwent these studies, had higher plasma cortisol and urinary 17‐ketosteroid excretion than control subjects. In the remaining tests the results of pregnant subjects did not differ from those of control subjects. We conclude that tissue MAO activity is not altered by OC or pregnancy.
Changes in serum thyroxine, triiodothyronine, and thyrotropin induced by lithium in normal subjects and in rats
Authors: Child Connie , Nolan George , Jubiz William
Published: January 2016

Serum thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were measured in 4 normal subjects before, during, and 2 wk afler administration of lithium carbonate (1,200 mg/day) for 6 wk. All subjects developed thyroid enlargement associated with increase in TSH. Serum T3 and T4 did not change significantly. In 3 hypothyroid subjects maintained on thyroxine replacement, lithium administration did not alter circulating levels of T4 or T3, suggesting no effect of lithium on the extrathyroidal metabolism of the thyroid hormones. In ratsfed a low iodine diet containing 122 mg/kg/day lithium carbonate, goiter, increased 131I uptake, and a decrease in intrathyroidal T3 and T4 with an increase in MIT, DIT, and MIT/DIT were observed at 3 wk. Serum T3 fell significantly only during the third week, while T4 did not change. Thyroid enlargement, secondary to a rise in TSH, appears to playa role in the adaptation of the thyroid gland to lithium carbonate. The exact mechanism for the elevation of TSH has not been elucidated.
Ampicillin and an ester in experimental Hemophilus influenzae meningitis
Authors: Bodine J. A. , Strausbaugh L. J. , Sande M. A.
Published: January 2016

A new methoxymethyl ester of hetacillin is highly lipid‐soluble, a property which was expected to enhance its penetration into the central nervous system (CNS). We compared the penetration of the ester and ampicillin into the cerebrospinal fluid (CSF) of normal rabbits and those with experimental Hemophilus influenzae meningitis. In normal rabbits treated by constant intravenous infusion, mean per cent penetration of the ester was four times as great as that of ampicillin (6.6 ± 3.7% against 1.6 ± 1.9%), and the difference in CSF drug levels attained was accentuated when bolus IV infusion was used. Drug concentration in brain tissue was three times as great in a rabbit treated with the ester (0.79 µg/gm against 0.26 µg/gm). In rabbits with meningitis, the ester again achieved higher CSF concentrations. Per cent penetration into CSF in infected rabbits was 23% for the ester and 13% for ampicillin. Bactericidal activity of the drugs was comparable; over 8 hr of treatment both drugs significantly reduced the CSF bacterial titers of infected animals. Our data demonstrated that the ester enters the CSF and CNS in higher concentration than ampicillin, with no loss in bactericidal activity.
Evaluation of the prison inmate as a subject in drug assessment
Authors: Schrogie John J. , Hensley Michael J. , Digiore Charles , Harris Steven
Published: January 2016

The reasons for exclusion of prisoners from research studies on drugs were based mostly on a relatively limited group of laboratory parameters which could have been detected using a simple battery of screening tests. The answers to a medical history form added little to the evaluation of either the prisoner or student groups, were probably very unreliable, and could be just as well confined to a few selected questions regarding drug history as a matter of record. Students gave appropriate responses to a mood scale measurement test while prisoners characteristically did not comply. Because of a combination of various institutional and sociological factors, prisoners probably represent a special subgroup of research volunteers whose health status may not be representative of the total “healthy” population. They are unlikely to give accurate or reliable responses in testing situations which rely upon reporting of the subjective effects of drugs with regard to tolerance or pharmacologic effect. Studies of investigational drugs where the likelihood of potential risk is significant should be avoided in such populations unless compliance has been assessed adequately.
Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers
Authors: Olsen George D. , Wendel Herbert A. , Livermore James O. , Leger Regina M. , Lynn Robert K. , Gerber Nicholas
Published: January 2016

The respiratory and pupillary effects of oral l‐, d‐, and d,l‐methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half‐life of drug in blood was 22 hr for racemic methadone, 24 hr for 1‐methadone, and 25 hr for d‐methadone. The effects of d‐methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l‐methadone and 15 mg of d,l‐methadone induced intense and sustained respiratory depression and miosis. The changes induced by l‐methadone were of longer duration than those of d,l‐methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated weil with respiratory depression and miosis for 1‐ and d,l‐methadone. The potency ratio of l‐methadone to d,l‐methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l‐methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l‐Methadone administeredfrequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.
Comparative metabolism of benzo[a]pyrene and drugs in human liver
Authors: Kapitulnik J. , Poppers P. J. , Conney A. H.
Published: January 2016

The oxidative metabolism of antipyrine, hexobarbital, coumarin, zoxazolamine, 7‐ethoxycoumarin, and the chemical carcinogen benzo[a]pyrene (BP) was studied in 32 adult human livers obtained at autopsy. When enzyme activity for one substrate was plotted against enzyme activity for a second substrate for each of the 32 livers, statistically significant correlations were found between the rates of metabolism of BP and the rates of metabolism of each of the other five drug substrates. The degree of correlation was dependent upon the substrate pair that was studied. Highly significant statistical correlations (p < 0.001) for monooxygenase activities among the different livers were observed for BP with antipyrine (r = 0.85), antipyrine with zoxazolamine (r = 0.82), antipyrine with hexobarbital (r = 0.79), zoxazolamine with 7‐ethoxycoumarin (r = 0.75), antipyrine with coumarin (r = 0.72), zoxazolamine with coumarin (r = 0.72), BP with hexobarbital (r = 0.72), hexobarbital with coumarin (r = 0.71), BP with zoxazolamine (r = 0.69), hexobarbital with zoxazolamine (r = 0.64), coumarin with 7‐ethoxycoumarin (r = 0.61), and BP with coumarin (r = 0.57). Less significant correlations were obtainedfor BP with 7‐ethoxycoumarin (r = 0.35; p = 0.05) and for hexobarbital with 7‐ethoxycoumarin (r = 0.37; p < 0.05). It is not known whether the relationships between the metabolism of the several substrates described here for autopsy livers would also occur with fresh livers. The lack of a perfect correlation for any of the substrate pairs suggests the presence in human liver of multiple monooxygenase enzyme systems for the metabolism of benzo[a]pyrene and the five other substrates studied, as weil as heterogeneity in their distribution among the 32 livers that were examined. The approach described in the present report may have significance in the study of the comparative metabolism of drugs, chemical carcinogens, and other environmental pollutants by human tissues and may help us find predictor drugs that will be useful for evaluating the drug‐ and carcinogen‐metabolizing capacity of different individuals in the human population.
Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients
Authors: Siwers Bo , Ringberger Vivi-Ann , Tuck J. Richard , Sjöqvist Folke
Published: January 2016

The bicyclic compound Z‐1‐(4‐bromophenyl)‐1‐(3‐pyridyl)‐3‐dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5‐hydroxytryptamine (5‐HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice dailyfor about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5‐HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawnfrom the patients; and (3) the concentrations of the main metabolites of serotonin (5‐HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5‐hydroxyindoleacetic acid (5‐HIAA), indoleacetic acid (IAA), 4‐hydroxy‐3‐methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5‐HT uptake compared to NE uptake. The inhibitory effect on 5‐HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5‐HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5‐HIAA levels. The e.fects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5‐HT uptake in central monoamine neurons and is there.fore an interesting pharmacologic tool in future central nervous system (CNS) research.
Salivary and urinary lithium clearance while recumbent and upright
Authors: Shimizu Muneo , Smith Donald F.
Published: January 2016

Excretion of lithium in urine and saliva was studied in healthy males while recumbent and while upright, walking and standing quietly. An oral dose of 24.3 mEq of Li+ was taken as three lithium carbonate tablets 13 hr before clearance tests. Urinary lithium clearance decreased when posture was changed from recumbent to upright, but salivary lithium clearance was not affected by the abrupt change in posture. A correlation was observed while recumbent between lithium clearance in urine and saliva, but not while upright. The findings are related to the extrapolation of saliva lithium excretion data to urinary lithium clearance.
Reduction in plasma norepinephrine during fenfluramine treatment
Authors: de la Vega C. E. , Slater S. , Ziegler M. G. , Lake C. R. , Murphy D. L.
Published: January 2016

Plasma norepinephrine levels were reduced to 30% of placebo levels during the administration of fenfluramine, 120 mg/day, for 10 or more days. There was also a significant reduction in plasma dopamine beta‐hydroxyl ase activity during fenfluramine treatment, suggesting that chronic administration may induce antiadrenergic effects which may be useful in the treatment of disorders affected by circulating catecholamines.
Dose‐related sleep disturbances induced by coffee and caffeine
Authors: Lasagna Louis
Published: January 2016

Karacan and co‐workers, in their article entitled “Dose‐related sleep disturbances induced by coffee and caffeine,” which appeared on pages 682–689 of the December, 1976, issue of the Journal, state their belief that “subjective assessments … should form a standard component of studies that investigate the effects of drugs on sleep.”
Studies on digitalis; IX. Some kinetic aspects of digitoxin metabolism
Authors: Storstein Liv , Amlie Jan
Published: January 2016

The metabolic pattern of cardioactive and inactive conjugated metabolites (a maximum of 24 substances) was studied in one female and one male after a single dose of 0.6 mg digitoxin intravenously. Serum samples were obtained after 24 hr, and 24‐hr urine was collected after 1, 2, 4, 6, and 8 days. With the methods used, enzymatic cleavage of conjugated bonds, thin‐layer chromatography (TLC) separation, and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. The Kendall rank correlation coefficient was used to compare the results from Subjects 1 and 2. Conjugation was the most rapid process, followed by hydrolysis and hydroxylation. Metabolism was progressive, leading to an increase in metabolites resulting from several enzymatic processes with time. Unchanged digitoxin reached minimum values on the fourth and sixth days and increased again on the eighth day. This indicated a continuous release of digitoxin from tissue stores and the enterohepatic circulation.
Greater bioavailability of digoxin solution in capsules; Studies in the postprandial state
Authors: Lindenbaum John
Published: January 2016

A liquid concentrate of digoxin administered as a capsule has recently been found to be better absorbed by normal subjects in the fasting state than a standard tablet or even a solution as such. It was not known whether the enhanced bioavailability of the encapsulated digoxin solution could also be demonstrated when given postprandially. In a crossover study single 0.4 mg doses of digoxin solution in a capsule, a solution in 10% ethanol as such, and a standard tablet were given to 12 normal volunteers immediately following a high‐fat breakfast. The mean area under the serum concentration‐time curve (AVC) and 6‐day cumulative urinary glycoside excretion (CVE) were greater after the capsule than that of either the solution or the tablet. The latter two preparations appeared to be bioequivalent. Intersubject variability in the CVE was less than with the AVC, but did not differ when the three drug formulations were compared. The bioavailability of an encapsulated liquid digoxin concentrate was thus also found to be enhanced when administered postprandially.
Frequency distribution of free warfarin and free phenytoin fraction values in serum of healthy human adults
Authors: Yacobi Avraham , Lampman Tara , Levy Gerhard
Published: January 2016

The protein binding of racemic warfarin was determined in serum from 57 normal adults (27 men and 30 women). The free fraction of warfarin (total concentration, 0.8 µg/mi) ranged from 0.0050 to 0.0186 and was log‐normally distributed. The frequency distribution differs from that in rats in which the serum free fraction values of warfarin are trimodally distributed. The protein binding of phenytoin was determined in serum from 39 of the subjects. The free fraction of phenytoin (total concentration, 15 µg/ml) ranged from 0.111 to 0.155 and was unimodally distributed. There was no apparent correlation between the extent of protein binding of warfarin and phenytoin in individual serum samples. The pronounced intersubject variation in serum free fraction of warfarin observed is consistent with our previous finding that serum protein binding is an important determinant of interindividual differences in the total clearance of warfarin in man. On the other hand, the relatively narrow distribution of free phenytoin fraction values suggests that differences in serum protein binding of phenytoin are not an important cause of the pronounced interindividual differences in the total clearance of phenytoin by subjects with normal renal function.
The disposition of sulindac
Authors: Duggan D. E. , Hare L. E. , Ditzler C. A. , Lei B. W. , Kwan K. C.
Published: January 2016

The disposition of sulindac, a new nonsteroid anti‐inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half‐life of 18.2 hr, well suited to twice daily dosage of its pro‐drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti‐inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro‐drug.
Effect of long‐term lithium administration on renal phosphorus handling
Authors: Perez Guido O. , Oster James R. , Magrinat Gaston , Vaamonde Carlos A.
Published: January 2016

Renal phosphorus handling was evaluated in 12 lithium carbonate‐treated psychiatric patients. Serum phosphorus was normal and serum lithium values were within the therapeutic range in all subjects. Serum calcium concentrations measured in 6 of the patients were found to be within the normal range; in the same patients serum parathyroid hormone levels were normal in 4 and slightly elevated in 2. Phosphorus clearance (14 ± 3 [SE] ml/min) and tubular reabsorption of phosphorus (88 ± 2%) during oral sodium bicarbonate loading were not significantly different from those in 10 healthy control subjects. In a subgroup of 5 patients and 5 control subjects, phosphorus excretion did not increase after bicarbonate loading. In these subjects, phosphorus excretion rates after bicarbonate loading were not different. Although experimental studies suggest that lithium inhibits renal cortical adenylate cyclase stimulation by parathyroid hormone, our data did not indicate any striking effect of long‐term lithium administration on serum calcium and serum phosphorus or on renal phosphorus handling.
Leucovorin in combination chemotherapy of breast cancer
Authors: Corder Michael P. , Sheets Raymond F. , Stone William H. , Flannery Eugene P. , Justice Glen R. , Herbst Kenneth D.
Published: January 2016

Cyclophosphamide, 5‐fluorouracil, methotrexate, and prednisone were administered for 165, 28‐day cycles to 33 patients with metastatic breast cancer. Because of serious infections (fever ≥° F, granulocytes <1,000/mm,3 and hospitalization) and 1 drug death in the first 4 patients, oral calcium leucovorin, 20 to 30 mg/m2 orally, was given 2 days after methotrexate in subsequent treatment cycles. There were 26 cycles without calcium leucovorin and 6 serious infections; 139 cycles with calcium leucovorin and 5 serious infections (p = 0.002). Objective response was seen in 13 of 18 evaluable patients with no previous treatment and in only 2 of 11 evaluable patients with previous treatment (p = 0.0065). Equivalent doses were given to all subsets of patients. It is concluded that leucovorin added to the above combination of drugs can preserve antitumor activity while decreasing serious infections and that prior therapy significantly decreases the response rate to this combination.
Is nicotine important in tobacco smoking?
Authors: Kumar R. , Cooke E. C. , Lader M. H. , Russell M. A. H.
Published: January 2016

Tobacco smoking is generally regarded as a form of nicotine dependence, but the evidence for this is slender. Two experiments are described here which examine the hypothesis that habitual smokers need nicotine and that they regulate their intakes of this drug. A laboratory test for smoking was devised which permitted the continuous monitoring of puffing as well as of selected physiologic variables; the procedure was also designed to reduce the influence of smoking habits and rituals. In the first experiment, inhaled amounts of tobacco smoke reduced subsequent ad libitum smoking in a dose‐related way. In the second experiment comparable doses of nicotine were given intravenously to the same subjects, but they failed to affect ongoing smoking. However, both the inhaled and intravenous doses of the drug produced very similar physiologic effects. These experiments do not, therefore, support the nicotine‐dependence hypothesis; thus the ways, if any, in which this drug sustains the tobacco‐smoking habit merit further examination.
A case of deficiency of N‐hydroxylation of amobarbital
Authors: Kalow W. , Kadar D. , Inaba T. , Tang B. K.
Published: January 2016

It has been shown recently that the overall metabolism of amobarbital in man is essentially under genetic control. The drug normally undergoes two hydroxylation reactions, leading to 3′‐hydroxyamobarbital (C‐OH) and N‐hydroxyamobarbital (N‐OH). This paper describes a sibship in which two mothers who are identical twins show a gross deficiency on N‐OH elimination in urine. The whole set of sibship data suggests that this deficiency represents a recessive trait controlled by a single pair of allelic autosomal genes which regulate N‐OH formation. Several methodical approaches to assess an individual's capacity for N‐OH formation are illustrated. There was no evidence of compensatory or concordant regulation of the two hydroxylation reactions. The case of this family illustrates that the functional lack of a biotransformation reaction is almost certain to be overlooked if one measures only the disappearance of a multimetabolized drug and not the appearance of metabolites.
Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade
Authors: McDevitt Denis G. , Brown H. Colin , Carruthers S. George , Shanks Robin G.
Published: January 2016

Dose‐response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized exercise test and percentage reduction in exercise heart rate (EHR) as the index of drug effect. The dose‐response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor‐blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor‐blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetic activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor‐blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprellolol was given after sotalol or oxprenoloi, or practolol was given after sotaloi or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenoiol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenoloi or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose‐response curves with exercise.
Once‐a‐day pindolol in hypertension
Authors: Traub Yehuda M. , Rosenfeld Joseph B.
Published: January 2016

The possibility of using pindolol on a once‐a‐day schedule was investigated in the treatment of mild to moderate hypertension. Eighteen patients whose blood pressure responded satisfactorily to thrice‐daily administration had a similar response to the single daily dose (p > 0.05). The advantages of once‐daily pindolol therapy as well as some of the biochemical changes produced by the drug are commented upon.
Studies on digitalis; XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas
Authors: Storstein Liv , Amlie Jan
Published: January 2016

The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty‐fourth hour and the 1‐, 2‐, 4‐, 6‐, and 8‐day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin‐layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin 18 but also changed the pattern of digitoxin metabolites in urine.
Pharmacokinetics and bioavailability of sodium valproate
Authors: Klotz U. , Antonin K. H.
Published: January 2016

The pharmacokinetics of the antiepileptic drug, sodium valproate (VPA), was investigated in 6 healthy volunteers after a single intravenous dose of 400 mg, as well as a solution and enteric‐coated tablets. The bioavailability of the enteric‐coated tablets was compared with that of normal tablets in 3 of these subjects. The bioavailability studies demonstrated that the solution was rapidly and almost completely (86% to 100%) absorbed. Peak plasma levels (66 to 196 µg/ml) were reached within 0.5 to 2 hr. Tablets had comparable bioavailabilities which varied in the different persons (68% to 100%). In some subjects VPA was found in plasma only after a lag time of 1 to 4 hr and the peak plasma concentrations of 46 to 88 µg/ml developed after 3 to 7 hr. After the intravenous dose, plasma levels declined biexponentially. The pharmacokinetic parameters were computed according to the two‐compartment open model. The half‐life of the initial phase, t½(α), could be calculated to 1.0 ± 0.86 hr (mean ± SD) and the terminal half‐life, t½(β), varied independently of the route of administration between 8.7 and 21.5 hr (12.2 ± 3.7 hr). The distribution space of the central compartment (V1) was 0.065 ± 0.010 Llkg, and both the apparent volume of distribution at steady‐state (VdSS) and Vdβ had similar values of 0.13 ± 0.04 L/kg and 0.14 ± 0.05 L/kg, respectively. These small volumes indicate that VPA distributes mainly into the extracellular space. The total plasma or blood clearance (Cl) ranged from 4.3 to 10.5 ml/min (7.8 ± 2.4 ml!min) and from 11.9 to 44.3 ml/min (30.1 ± 11.9), respectively. Therapeutic concentrations of VPA (80 µg/ml) revealed relatively strong plasma protein binding between 80% and 94%. The bloodlplasma concentration ratio ranged about 0.28 ± 0.06. Since the calculated hepatic extraction ratio of 0.02 is smaller than the free fraction, it is concluded that clearance of VPA is independent of liver blood flow and of the restrictive type. No measurable amounts of unchanged VPA were excreted during the 2 days of observation. Approximately 10% to 30% of a single dose was eliminated as VPA conjugates which could be hydrolyzed by 2 N HCl and β‐glucuronidase/aryl‐sulfatase.
Call for abstracts
Authors: Aagaard George N.
Published: January 2016

Call for abstracts of papers for Scientific Program, Seventy‐ninth Annual Meeting, Peachtree Plaza Hotel, Atlanta, Georgia, March 29–31, 1978.
Enhancement of hydralazine bioavailability by food
Authors: Melander A. , Danielson K. , Hanson A. , Rudell B. , Scherstén B. , Thulin T. , Wåhlin E.
Published: January 2016

The influence of food on the bioavailability of hydralazine in noncoated and coated tablets was examined in 5 healthy males. Each subject received an oral 50‐mg dose on four different occasions: two 25‐mg noncoated tablets with and without food and one 50‐mg coated tablet with and without food. The meal was a standardized breakfast of 440 calories. Venous blood samples were obtained during a 6‐hr period, and the plasma concentrations of unmetabolized hydralazine were assessed by a selective and sensitive gas chromatographic method. The results indicate that food enhances the bioavailability of hydralazine 2‐ to 3‐fold both when noncoated and coated tablets are used.
Elimination of furosemide in healthy subjects and in those with renal failure
Authors: Beermann Björn , Dalen Elisabet , Lindström Björn
Published: January 2016

Furosemide was administered intravenously to 5 healthy volunteers and 15 patients with various degrees of renal failure. Two patients were given the drug orally, The plasma half‐life offurosemide averaged 0.79 hr in the healthy subjects, Although most patients with kidney disease had a prolonged half‐life (t½), up 10 24.58 hr, some with advanced renalfailure had an almost normal t½. The plasma clearance of furosemide, which in the normal subjects averaged 194 ml/min, decreased proportionally with decreasing creatinine clearance, as did the renal clearance, which in the healthy subjects averaged 95 ml/min. There was no correlation between kidney function and the apparent volume of distribution or of non renal clearance. One patient was given 35S‐labeled furosemide intravenously. Although the furosemide plasma t½ was essentially normal, the elimination rate of metabolites was decreased. Unlike that of healthy subjects, the main route of excretion of label was in the feces.
Commentary
Authors: Haynes R. Brian , Sackett David L. , Taylor D. Wayne , Roberts Robin S. , Johnson Arnold L.
Published: January 2016

Lack of patient compliance with prescribed regimens is an important and fascinating problem in medical care. Its distressing magnitude in virtually all outpatient senings33 makes consideration of noncompliance mandatory for all serious medical conditions for which efficacious self‐administered treatments are available. Unfortunately, attempts to understand noncompliance (the better to contral it) have revealed its complexity without yielding much useful information about its management. To make matters worse, the complexity to which we have alluded seems to have resulted in both confusion about or inattention to what is actually known and misleading or inaccurate claims about that which is not. This has certainly been the case with respect to the relationship of the therapeutic regimen to compliance. One can hardly avoid encountering a manufacturer's claim that a product will promote compliance
Alterations in drug metabolism in workers exposed to polychlorinated biphenyls
Authors: Alvares Alvito P. , Fischbein Alf , Anderson Karl E. , Kappas Attallah
Published: January 2016

Administration of the polychlorinated biphenyls (PCRs) mixture, Aroclor 1016, to rats elicited a barbiturate type of inducing effeet on the hepatic microsomal oxidative enzyme system. Aroclor 1016 eaused significant increases in liver eytoehrome P‐450 eontent, microsomal protein, and ethylmorphine N‐demethylase activity; its effeet on benzoiaipyrene hydroxylase activity was minimal. Unlike the widely studied PCRs mixture, Aroclor 1254, Aroclor 1016 did not induce eytoehrome P‐448 in liver microsomes. Five workers occupationally exposed to Aroclor 1016 in a capacitor‐manufacturing plant showed a significantly lower mean antipyrine half‐life (10.8 hr) than the mean half‐life of 15.6 hr in non‐PCRs‐‐exposed normal subjeets. These differenees in half‐life were aeeompanied by increased metabolie clearanee rates in workers exposed to the PCRs, whieh strongly suggests that PCRs accelerate the rate of drug metabolism in man. Dur studies show that Aroclor 10/6 elicits the barbiturate type of inducing effeets on drug metabolism in man as weil as animals.
Prolongation of gastric emptying by oral propantheline
Authors: Hurwitz Aryeh , Robinson Ralph G. , Herrin William F.
Published: January 2016

The present study shows that a single oral recommended dose of propantheline bromide normally doubles the mean gastric half‐emptying time in man. In a prospective, double‐blind, randomized crossover design 13 normal subjects were given 30 mg propantheline or placebo 90 min before taking a l l Sm‐indium‐labeled liquid test meal, the volume of which was adjusted to body weight . The disappearance of radioisotope from the area of the stomach was determined by external gamma counting . After placebo the mean half‐emptying time was 68 min and after propantheline it was 135 min (p < 0.005). Although salivary fiow decreased and pulse rate increased there were no visual disturbances . In studies already reported maximally tolerated oral doses of quaternary ammonium anticholinergic drugs have not consistently retarded gastric emptying in man.
Clinical consequences of polymorphic acetylation of basic drugs
Authors: Drayer Dennis E. , Reidenberg Marcus M.
Published: January 2016

The clinic'al consequences (therapeutic and toxic) of drug acetylation polymorphism are reviewedfor procainamide, hydralazine, phenelzine, isoniazid, and salicylazosulJapyridine. Genetic slow acetylators are more likely than rapid acetylators to experience the following adverse drug reactions: (1) earlier development of procainamide‐induced antinuclear antibody; (2) earlier and more frequent development of procainamide‐induced systemic lupus erythematosus (SLE); (3) hydralazine‐induced SLE; (4) spontaneous SLE; (5) drowsiness and nausea from phenelzine; (6) cyanosis, hemolysis, and transient reticulocytosis from salicylazosulJapyridine; and (7) polyneuropathy after isoniazid therapy. The incidence of isoniazid hepatitis may, however, be more common in rapid than in slow acetylators. Genetic slow acetylators are also more likely than rapid acetylators to experience greater therapeutic responses from similar doses of the following: phenelzine, hydralazine provided beta blockers are concurrently used, and isoniazid if once weekly therapy is used. Thus, knowledge of the acetylator phenotype of a patient can help determine the relative risk for some drug‐related toxic and therapeutic responses.
Protriptyline plasma levels and antidepressant response
Authors: Biggs John T. , Ziegler Vincent E.
Published: January 2016

Twenty‐one depressed outpatients were treated for 4 wk with 20 mg Iday of protriptyline. Protriptyline plasma levels in individuals after 4 wk ranged from 22 nglml to 167 nglml. There was a negative correlation (‐0.50, p < 0.05) between the severity of depression measured by the Hamilton Rating Scale (HRS) and the wk 4 protriptyline concentration. Patients with plasma levels above 70 ng Iml (wk 4) had better outcomes measured by the HRS (p < 0.05) and the Zung Self‐Rating Depression Scale (p < 0.05) and had greater percent decreases on both scales (p < 0.05) during treatment than those with lower plasma levels. An upper limit to the therapeutic plasma level range beyond which response to treatment was less satisfactory was not demonstrated in this study.
Effect of beta adrenoceptor antagonists on baroreceptor reflex sensitivity in hypertension
Authors: Simon Geza , Kiowski Wolfgang , Julius Stevo
Published: January 2016

High‐pressure baroreceptor reflex sensitivity (BRS) was estimated by measuring the reflex heart rate response to pharmacologic elevation olblood pressure (phenylephrine, 150 to 200 f.Lg intravenously) in 18 patients with essential hypertension on two occasions: after a 4‐wk placebo period and after 9 wk of incremental doses of oral timolol (20, 40, and 60 mg daily). On placebo, measurements were pelformed both before and after propranolol (0.2 mglkg intravenously). The level of cardiac vagal inhibition, estimated by the heart rate change alter atropine (0.04 mglkg intravenously), was similar on placebo and on timolol, thereby permitting comparisons of BRS. BRS on placebo (belore and after propranolol) correlated with BRS on timolol (r = 0.87 and 0.90, p < 0.001), attesting to the reproducibility of BRS measurements. BRS was unchanged by either short‐term (propranolol) or long‐term (timolof) beta adrenoceptor inhibition. Results were similar in responders (n = 10), whose mean arterial blood pressure on timolol fell by 10 mm Hg or more, and in nonresponders. The findings do not provide evidence for a change in gain of the baroreceptor reflex arc under conditions of short‐ or long‐term beta adrenoceptor inhibition.
Effect of antacids on absorption of clorazepate
Authors: Chun A. H. C. , Carrigan P. J. , Hoffman D. J. , Kershner R. P. , Stuart J. D.
Published: January 2016

The effect of a magnesia and alumina antacid suspension on the absorption of clorazepate dipotassium was studied in 15 normal healthy adult subjects who ingested a 15‐mg dose of clorazepate alone or with single or multiple doses of antacid. The results of this three‐period randomized complete crossover study showed a trend of initially slower absorption and lower peak nordiazepam plasma levels when administered with the antacid suspension. However, there were no significant differences among treatments in the extent of absorption as measured by the area under the plasma level‐time curves. Clorazepate plasma levels were of relatively short duration and similar for all treatments. The urinary excretion pattern was likewise comparable with conjugated oxazepam, the major species measured. Plasma elimination half‐lives of nordiazepam and clorazepate were not affected by the antacid treatments.
A multicenter trial of sulindac in osteoarthritis of the hip
Authors: Calabro John J. , Andelman Sumner V. , Caldwell Jacques R. , Gerber Robert C. , Hamaty Daniel , Kaplan Herbert , Maltz Bertram A. , Parsons James L. , Saville Paul , Tretbar Harold C. , Ward John R.
Published: January 2016

Sulindac (cis‐5‐fluoro‐2‐methyl‐I‐[ (p‐methyl‐sulfinyl )‐benzylidene J‐indene‐3 ‐acetic acid) is a new nonsteroidal antirheumatic drug recently evaluated in a double‐blind trial of 91 patients with hip osteoarthritis. Consecutive patients with documented flare following previous drug withdrawal were randomly assigned to one of 3 treatment groups: (I) sulindac given twice daily, (2) sulindac given 4 times daily, and (3) placebo. The dosage of sulindac, 100 to 300 mg daily, was adjusted according to patient global response and tolerance at 3‐ to 7‐day intervals over 3 wk. Of 15 efficacy measurements evaluated, there was no difference between sulindac given 2 or 4 times daily, but differences were disclosed between one or both sulindac treatment groups and placebo in II of the 15 efficacy measurements (p < 0.05, < 0.01). The frequency of adverse reactions was of the same order for each treatment group. These included gastrointestinal upset, rash, and dizziness, usually transient and mild to moderate in severity. Serial laboratory studies revealed no evidence of renal, hepatic, or hematopoietic toxicity.
Effects of urine acidification on plasma and urine phencyclidine levels in overdosage
Authors: Domino Edward F. , Wilson Ann E.
Published: January 2016

A gas chromatography‐mass Jragmentography‐electron impact (GC‐MS‐EI) assay of phencyclidine (PCP) was adapted for human plasma and urine. This assay is specific for PCP and very sensitive (approximately I ng/ml). Patients with the putative diagnosis of PCP overdosage were studied to correlate plasma and urinary levels with clinical state. Urinary PCP levels were enhanced in an acid urine, which suggests that acidification of the urine is an adjunct in the therapy of PCP overdosage.