bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐dependent changes in sulfamethazine kinetics in rapid and slow isoniazid acetylators
Authors: Olson William , Miceli Joseph , Weber Wendell
Published: January 2016

The pharmacokinetics of sulfamethazine (SMZ) was studied in 44 healthy volunteers. After an oral dose of 10 mg/kg we found the usual distribution of rapid and slow acetylators. The differences in the t½s between the phenotypes were not due to variations in renal clearance. Repeat studies at this dose showed very little intraindividual variation in t½s. After a 40 mg/kg dose there was an increase in the t½ of SMZ in every subject. The implications of these results on methods of phenotyping are discussed.
Kinetics of polythiazide
Authors: Hobbs Donald C. , Twomey Thomas M.
Published: January 2016

An assay for polythiazide, sufficiently sensitive to measure plasma concentrations of this high‐potency diuretic agent, has been developed. The assay is based on acid hydrolysis to trifluoroethylthioacetaldehyde and electron‐capture gas chromatography. Sensitivity down to 0.2 ng/ml was achieved. In a study in normal human subjects receiving single 1‐mg oral doses of polythiazide, the mean plasma half‐lives for absorption and elimination were 1.2 and 25.7 hr, respectively. The latter is consistent with the extended duration of action of polythiazide. Approximately 25% of the drug was excreted unchanged in the urine.
Rational aspirin dosage regimens
Authors: Levy Gerhard , Giacomini Kathleen M.
Published: January 2016

There has been considerable recent concern about the design of safe and effective dosage regimens of aspirin for the treatment of pain, fever, and inflammatory disease. In 1972 the Commissioner of the Food and Drug Administration appointed a special Advisory Panel on Internal Analgesic and Antirheumatic Products to prepare a report on the safety, effectiveness, and labeling (including dosage recommendations) of nonprescription internal analgesic and antirheumatic drugs. The extensive report of that Panel was submitted to the Commissioner on April 5, 1977, and was published in the Federal Register in July.3 A substantial portion of the report is concerned with the problem of safe and effective dosage regimens of aspirin for adults and children.
Effects of furosemide in the newborn
Authors: Woo Wan-Ching R. , Dupont Claire , Collinge Judith , Aranda Jacob V.
Published: January 2016

The effects of furosemide on electrolyte and water excretion were determined in 9 neonates with fluid overload states. Hourly measurements of urine volume, serum and urine Na+, K+, Cl−, creatinine, and blood urea nitrogen were done before and after the intravenous or intramuscular injection offurosemide (1 mg/kg). Mean (±SE) birth weight was 2,261.7 ± 284.4 gm; gestational age was 35.1 ± 1.4 wk, postnatal age was 13.8 ± 6.9 days, blood urea nitrogen was 10.0 ± 1.0 mg%, creatinine was 0.7 ± 0.1 mg%, and glomerular filtration rate was 21.9 ± 3.8 ml · min−1/1.73 m2. Compared with the values obtained before the administration of furosemide, there were significant increases in percent fractional Na+ excretion, percent fractional Cl− excretion, urine volume (ml · hr−1), and free water clearance (ml · hr−1), each of which peaked within 1 hr of furosemide administration and were sustained for another hour thereafter. These effects were discernible for about 5 hr and returned to baseline by 6 hr after administration of the drug. A 2.5‐fold increase in K+ excretion (µEq · hr−1) was noted I hr after furosemide; this increase was sustained for 2 hr and decreased to the predrug level in 4 hr. Although all infants showed increases in urine volume and electrolyte excretion within 1 hr of furosemide administration, the magnitude of the response exhibited remarkable variability. There is some suggestion that perinatal asphyxia may decrease the response to furosemide.
Studies on theobromine disposition in normal subjects; Alterations induced by dietary abstention from or exposure to methylxanthines
Authors: Drouillard Dennis D. , Vesell Elliot S. , Dvorchik Barry H.
Published: January 2016

Normal male volunteers on xanthine‐restricted diets had a plasma theobromine (TB) half‐life (t½) of6.1 ± 0.7 hr (mean ± SEM), a TB metabolic clearance rate (MCR) of 113.8 ± 6.8 mllmin (mean ± SEM). and an apparent volume of distribution (aVd) of 59.9 ± 7.8 L (mean ± SEM) after a single oral dose of6 mg/kg of TB. A two‐week period of dietary abstention from methylxanthines shortened the mean plasma TB t½ by 33% and increased the mean MCR ofTB by 59%; no change occurred in mean aVd of TB. In another experiment, normal male volunteers received the same oral dose of TB for each of five consecutive days. The mean plasma TB t½ measured immediately after the last TB dose was prolonged by almost two‐thirds, while the mean aVd increased 23%. Although the mean plasma TB t½ measured four days after this last TB dose was the same as that measured after a single oral dose, the mean MCR of TB increased by 34%, but this change was balanced by increased mean aVd of 35%. These results suggest that immediately after five daily doses ofTB, an impairment ofTB clearance occurs that is reversible by four days of dietary abstention from methylxanthines.
Phenobarbital pharmacokinetics in neonates
Authors: Pitlick W. , Painter M. , Pippenger C.
Published: January 2016

Phenobarbital pharmacokinetics after intravenous injection were studied in 8 neonates with seizures. Subjects ranged in gestational age from 30 to 40 wk. Plasma concentrations of phenobarbital were measured by enzyme‐multiplied immunoassay (EMIT). The volume of distribution (Vd) of phenobarbital was 0.97 ± .15 L/kg which was independent of the dose administered. Vd and gestational age did not correlate. Phenobarbital clearance calculated from average concentrations in patients maintained on phenobarbital for 1 to 4 wks was consistent, with a decrease in t½ from 115 hr after 1 wk to 67 hr after 4 wk of therapy. The elimination of phenobarbital decreased at an exponential rate with a tVz of 4.6 days. A pharmacokinetic model with an exponentially increasing elimination rate term was used to describe the data. Average concentrations predicted with the use of the model corresponded adequately with experimental results. The increases in clearance observed are thought to be related to rates of turnover of drug‐metabolizing enzymes in the neonate.
Gentamicin binding to serum and plasma proteins
Authors: Myers Douglas R. , DeFehr Joan , Bennett William M. , Porter George A. , Olsen George D.
Published: January 2016

Gentamicin binding to serum proteins was studied by equilibrium dialysis at 37°C and pH 7.4 in the presence of both physiologic and adjusted concentrations of ionized calcium and magnesium. The percentage of bound drug was inversely related to the concentration of these two divalent cations, ranging from 27% bound with no calcium and magnesium present to 17% bound in the presence of four times physiologic concentrations. No significant difference in the extent of drug‐protein binding was noted in a comparison of sera from healthy and uremic subjects. Heparin also was found to affect gentamicin binding. Increasing heparin concentration in serum increased apparent gentamicin‐protein binding to 34% in the presence of physiologic amounts of calcium and magnesium. Buffered heparin solutions without plasma proteins bound up to 65% of total drug concentration. Gentamicin‐protein binding may have implications regarding pharmacokinetics and renal cortical uptake.
Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain
Authors: Staquet M. , Gantt C. , Machin D.
Published: January 2016

Two consecutive, randomized, double‐blind trials were performed to test the analgesic properties of a synthetic nitrogen analog of tetrahydrocannabinol (NIB). In the first trial, the test preparation was superior to placebo and approximately equivalent to 50 mg of codeine phosphate. In the second study, the tetrahydrocannabinol analog was superior to placebo and to 50 mg secobarbital. NIB is not useful clinically because of the frequency of side effects.
Clinical pharmacology: Reflections in my rear‐view mirror
Authors: Modell Walter
Published: January 2016

To be self‐propelling, a scientific discipline in medicine needs a concept, a philosophy, a special field of operation, and then a group of scientists who wish to devote themselves to such work, to communicate, discuss, report, argue, and freely exchange ideas—in short, a learned society; finally, it needs a specialty journal which published accounts of investigations, not merely for archival purposes, but to further intercourse between all scientists so as to spread the word to workers in other places and in other fields. The three may evolve serially but progress in all is facilitated by simultaneous development and operation.
Urinary excretion of µ‐aminopropionitrile and cyanoacetic acid
Authors: Fleisher Joseph H. , Peacock Erle E. , Chvapil Milos
Published: January 2016

Human serum did not convert µ‐aminopropionitrile (BAPN) to the deaminated, nonlathyrogenic metabolite, cyanoacetic acid (CAA). Instead, its enzymic activity for oxidizing benzylamine was inhibited by BAPN (I50 = 2 × 10−3 M). BAPN was found in the urine within one hour of oral administration. Oral 250 mg BAPN at 6‐hr intervals each day for 21 days resulted in urinary BAPN recoveries approximating 16% of the total dose. BAPN was not detected in urine in specimens collected later than 7 hr after cessation of BAPN dosage. Urinary CAA appeared more slowly than BAPN and increased gradually to approximately three times that of urinary BAPN. After BAPN was discontinued, there was prolonged urinary excretion of BAPN‐derived CAA. These along with earlier findings in experimental animals suggest that unexcreted BAPN is sequestered in tissues where it is metabolized to CAA before being slowly released.
Propranolol withdrawal and thyroid hormones in patients with essential hypertension
Authors: Kristensen Bent Ø. , Steiness Eva , Weeke Jørgen
Published: January 2016

The effect of abrupt withdrawal of propranolol on serum concentrations of triiodothyronine (T3) and thyroxine (T4) was investigated in 5 patients with uncomplicated essential hypertension. The patients had been treated from 2 to 18 mo before the study was begun. Doses varied from 160 to 480 mg propranolol daily. Four of the patients studied developed tachycardia, sweating, or tremor within 2 to 6 days after withdrawal of propranolol. In 1 patient reversible ischemic ECG changes were recorded. The serum concentrations of free T3 increased in the 4 patients suffering from withdrawal symptoms. The mean increase on the day the symptoms started was 51% (range, 22 to 74, 2 p = 0.01). This increase in serum‐free T3 correlated positively with the serum propranolol concentration on the last day propranolol was given (r = 0.91, 2 p = 0.03). In the one patient, who did not develop withdrawal symptoms, the serum concentration of propranolol was very low, and the free T3 level remained unchanged. No significant changes in serum concentrations of free T4 or total thyroid hormones were found in any of the patients. We suggest that the propranolol withdrawal symptoms are, at least partially, caused by an increase in the thyroid hormone, T3.
Gastrointestinal blood loss after diflunisal and after aspirin: Effect of ethanol
Authors: DeSchepper P. J. , Tjandramaga T. B. , De Roo M. , Verhaest L. , Daurio C. , Steelman S. L. , Tempero K. F.
Published: January 2016

Fecal blood loss was evaluated in normal subjects with 51Cr‐labeled red cells. In a double‐blind parallel study in 10 subjects, 250 mg diflunisal twice daily did not significantly increase blood loss in two consecutive treatment periods, while 750 mg acetylsalicylic acid (ASA) 4 times daily did so. In a double‐blind crossover study in 2 subjects, diflunisal, 250 mg twice daily again did not significantly affect fecal blood loss during a 4‐day treatment period, and there also was no significant effect on fecal blood loss when ethanol was administered in combination with diflunisal during two additional treatment days. ASA, 600 mg 4 times daily, induced an increase in blood loss and this effect was significantly enhanced by the addition of alcohol. The difference between treatments in the way they interact with alcohol was also statistically significant.
Effects of methaqualone on blood platelet function
Authors: Mills Donald G.
Published: January 2016

To study the mechanism whereby toxic doses of methaqualone cause a bleeding tendency in humans, the effects of methaqualone, diphenhydramine, and the combination of methaqualone plus diphenhydramine on blood platelet function were investigated. Exposure of human platelets in platelet‐rich plasma in vitro to final concentrations of methaqualone ranging from 1.1 to 4.5 × 10−4 M resulted in nearly complete inhibition of the secondary phase and significant inhibition of the primary phase of adenosine diphosphate (ADP)‐induced aggregation. Both the slope and height of collagen‐induced aggregation responses were reduced significantly in vitro by the drug. When methaqualone final concentrations of 1.1, 2.3, and 4.5 × 10−4 M were studied in the presence of diphenhydramine (1.1, 2.3, and 4.5 × 10−5 M, respectively), the degree of inhibition of ADP‐induced aggregation was only slightly greater (not significant) than that observed with methaqualone. The platelets of rabbits injected intravenously with methaqualone, 10 mg/kg, demonstrated a significantly decreased ability to aggregate with ADP and collagen 30 and 60 min after administration of the drug. These results suggest that a drug‐induced defect of blood platelet function may play a role in the bleeding associated with methaqualone toxicity.
Food, splanchnic blood flow, and bioavailability of drugs subject to first‐pass metabolism
Authors: McLean Allan J. , McNamara Patrick J. , duSouich P. , Gibaldi Milo , Lalka David
Published: January 2016

There has been considerable interest in the past fifteen years in determining the influence of food and diet on gastrointestinal drug absorption. Welling21 has recently presented a comprehensive and critical review of these efforts. In general, food reduces the absorption rate of drugs from the gastrointestinal tract but in most instances has little influence on the extent of absorption. Such an effect is clinically significant for sedative‐hypnotics and for other drugs where a prompt response is desired but is probably of little concern in most other cases. On the other hand, food has been found to substantially reduce the extent of absorption of certain drugs, including many antibiotics. This type of food effect often occurs with drugs with poor permeability characteristics that are incompletely absorbed even by fasting patients. Continual administration of such drugs with meals would result in lower steady‐state drug concentrations in plasma than would be found were the drug to be given under fasting conditions.
Pharmacokinetic considerations in exchange transfusion in neonates
Authors: Yakatan Gerald J. , Smith Randall B. , Leff Richard D. , Kay Jacob L.
Published: January 2016

Neonates undergoing blood exchange often receive concomitant therapy. Questions may be raised whether dosage regimen alterations are necessary to replace drug lost as a result of the exchange procedure. Our study reports the changes in plasma concentration of kanamycin during an exchange transfusion and a pharmacokinetic analysis of the effect of the exchange on drug elimination. The relationships of the volumes of distribution, elimination rate constant, and time after dosing on the fraction of the dose eliminated in the blood exchange are developed on the basis of a one‐compartment body model. Computer simulations using the equations developed were used to estimate the fraction of a dose that might be removed as a result of an exchange transfusion. As the disposition rate constant or the apparent volume of distribution increase, i.e., the clearance of the drug increases, the fraction of the dose removed by the exchange process decreases. Thus, significant amounts of drug removal may occur in an exchange transfusion for drugs with low clearance when the exchange is initiated early in the drug dosing interval. In our study, only 3% of the kanamycin dose was removed as a result of the exchange process, and dosing adjustment would not be required. This was in part due to initiation of the exchange late in the dosing interval, although the maximum calculated percentage of the dose which could have been removed under the exchange conditions employed was only 10%.
Bumetanide‐induced rise in plasma renin activity
Authors: Velasquez Manuel T. , Wan Suk Han , Maronde Robert F.
Published: January 2016

The effect of bumetanide on renal function, plasma renin activity (PRA), and electrolyte excretion was investigated in seven normal men who had been on a daily diet containing 120 mEq sodium and 80 mEq potassium for three days. A single oral dose of 2 mg bumetanide induced substantial diuresis and variable but significant increases in PRA. Diuresis occurred promptly, reached a peak at 1 to 2 hr, and abated almost completely at 6 hr. The PRA increase began at 1 hr but, unlike the diuretic effect, it persisted for up to 12 hr. Peak effects occurred between 4 to 12 hr. The initial rise in PRA during early diuresis was associated with a significant increase in creatinine clearance, but further rises in PRA during later diuresis were accompanied by a fall in creatinine clearance. At maximal diuresis, sodium excretion increased 16‐fold while potassium excretion tripled. Chloride excretion, which increased 20‐fold, represented the largest increase in electrolyte excretion. Plasma levels of bumetanide measured by radioimmunoassay were detected as early as 30 min and peak concentrations were noted at 1 hr. Levels declined thereafter with a mean half‐life of 2.0 hr. The hourly excretion of bumetanide in the urine was greatest at 1 to 2 hr and correlated with sodium excretion (r = 0.94, p < 0.001).
Effects of an oral contraceptive on hepatic size and antipyrine metabolism in premenopausal women
Authors: Homeida Mamoun , Halliwell Michael , Branch Robert A.
Published: January 2016

Liver volume and antipyrine disposition have been investigated in healthy premenopausal women who received 30 µg ethinyl oestradiol + 500 µg dl‐norgesterol as an oral contraceptive. Six months‐ treatment was associated with a 17% increase in liver volume while no change occurred in age‐matched control subjects. In the same subjects the contraceptive decreased antipyrine clearance by 21%. Thus the contraceptive markedly reduced drug‐metabolizing activity per unit volume of liver by 33%. In additional subjects, discontinuation of the contraceptive resulted in a 30% increase in antipyrine clearance. These observations confirm that conventional oral contraceptive therapy to premenopausal women increases hepatic size and that it is a potent inhibitor of drug‐metabolizing activity.
Minocycline and doxycycline kinetics in chronic renal failure
Authors: Heaney David , Eknoyan Garabed
Published: January 2016

Half‐lives and urinary excretion rates of minocycline (MINO) and doxycycline (DOXY) were compared in 8 normal volunteers and in 8 patients with chronic renal failure. Each drug was given as a single, 200‐mg intravenous infusion with a 7‐day period between doses. Blood sampies for serum levels were taken just prior to and at the completion of infusion (0 hr) and then I, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hr later. Urine sampies were collected every 6 hr on day 1, every 12 hr on day 2, and every 24 hr on day 3. Peak serum levels occurred at 0 hr immediately upon completion of the infusion with both drugs. Mean serum levels for MINO were consistently lower than those for DOXY in both groups. Mean serum half‐lives (t½) increased from 14.6 hr (MINO) and 13.8 hr (DOXY) in normal subjects to 17.3 hr (MINO) and 20.6 hr (DOXY) in renal failure patients. Although there was not a statistically significant difference between the mean areas under the serum level curves (AUC) of the normal and the renal failure groups for either drug, the AUC was identical for both groups receiving minocycline and 37% higher than normal for the renal failure group receiving doxycycline. At 72 hr, the normal group had excreted 11% (MINO) and 57% (DOXY) of the dose whereas the renal failure group excreted 0.7% (MINO) and 2.0% (DOXY). These differences between normal and renal failure groups were significant (p < 0.01). Overall, excretion of minocycline was virtually independent of renal function, whereas doxycycline appeared to accumulate to some degree in the renal failure patients.
Assessing the subjective effects of stimulants in casual users; A methodology and preliminary results
Authors: Cole Jonathan O. , Pope Harrison G. , LaBrie Richard , Ionescu-Pioggia Martin
Published: January 2016

In order to assess the subjective effects of nefopam, a new non‐opiate analgesic, a study was designed using highly educated, young, middle‐to‐upper dass subjects in a naturalistic setting. Results suggest that the design is capable of differentiating variations in subjective drug effects. On a number of measures, 10 mg of d‐amphetamine, a modest dosage, could be distinguished from placebo, showing changes in the direction expected for stimulant drugs. Nefopam (90 mg), on the other hand, showed few differences from placebo or caffeine (300 mg). Nefopam appeared mildly dysphoric, rather than stimulant, in subjective effects.
Doses and dosage intervals of drugs—clinical practice and pharmacokinetic principles
Authors: Boëthius Göran , Sjöqvist Folke
Published: January 2016

Outpatient prescriptions dispensed to 17,000 individuals in the county of Jämtland, Sweden, have been analyzed with regard to doses and dosage schedules. Two groups of drugs were studied; one group with marked interindividual variability in metabolism (antidepressants, beta receptor blockers, and phenytoin), the other group excreted unchanged in the urine (digoxin, nitrofurantoin, sulfonamides, and tetracycline). A 25‐fold—15‐fold variability in daily doses wasfoundfor amitriptyline and nortriptyline, respectively. Four‐Jifths ofthe prescriptions were for doses between 30 and 75 mg, making the mean dose remarkably low—58 and 48 mg, respectively. The variability in doses was high er for the beta receptor blockers propranolol and alprenolol. Daily doses of phenytoin varied between 0.1 and 0.6 gm, 93% of the doses falling between 0.2 and 0.4 gm. Generally, doses of sulfonamides and nitrofurantoin prescribed to children were correctly reduced. In the elderly the doses of these drugs and of tetracycline and digoxin were only moderately reduced in discrepancy with the physiologic impairment of kidney function. The clinical significance of these findings has not been evaluated. The effect of drug information programs on dosage intervals prescribed for procainamide, phenytoin, and beta receptor blocking drugs is demonstrated. It is suggested that more emphasis be given to general pharmacokinetic principles in drug information programs.
Racial differences in drug metabolizing ability: A study with antipyrine in the Sudan
Authors: Branch R. A. , Salih S. Y. , Homeida M.
Published: January 2016

The kinetic disposition of antipyrine following oral administration of 1,200 mg has been investigated in 11 normal Sudanese subjects living in Sudan, 9 Sudanese subjects living in England for al least 2 yr, and 19 normal English subjects living in England. Sudanese subjects living in Sudan had significantly lower mean antipyrine clearance and higher volume of distribution than the English group (−28% and +30%, respectively). There was no significant difference for antipyrine clearance between English and Sudanese subjects living in England, but the volume of distribution of antipyrine was higher (16%) in the Sudanese subjects. The mean half‐lives of the three groups difJered significantly. We conclude that differences in disposition of antipyrine between native English and Sudanese populations was predominantly due to environmental factors.
Adjustment of smokers to dilution of tobacco smoke by ventilated cigarette holders
Authors: Sutton S. R. , Feyerabend C. , Cole P. V. , Russell M. A. H.
Published: January 2016

This study was designed to examine the extent to which smokers would compensate for the dilution of smoke produced by ventilated cigarette holders. Peak plasma nicotine and carboxyhemoglobin levels were measured in 18 smokers when they had been smoking normally and when they had been using holders which dilute the smoke by about 20% (holder 1) and 60% (holder 2) for periods of 2 days and 7 days. Comparison of the observed blood levels with the “expected” levels estimated from the dilution factors of the holders showed that subjects partially compensated on holder 2 but showed little or no compensation on holder 1. There were no changes in the number of cigarettes smoked when using the holders so any compensation achieved must have been due to increasing the intake from each cigarette. There was wide individual variation in the amount of compensation with about 50% of subjects compensating fairly consistently on both holders. Degree of compensation was not significantly associated with usual cigarette consumption, plasma nicotine and carboxyhemoglobin levels when smoking without a holder, the nicotine yields of the subjects' cigarettes, or the experience of withdrawal symptoms and the degree of satisfaction when using the holders. It cannot be determined from this study whether the compensation observed was mediated by a need to regulate the intake of nicotine rather than some other factor.
Digoxin concentration in choroid plexus, brain, and myocardium in old age
Authors: Krakauer R. , Steiness E.
Published: January 2016

Thirteen aged persons receiving digoxin until the time of death were examined by autopsy, and digoxin concentrations were determined in samples from various tissues (the choroid plexus, grey and white brain matter, left and right ventricular and left atrial myocardium, diaphragm, and musculus psoas major). These concentrations were related to the digoxin dose and duration of treatment. No significant difference was found between the concentration of digoxin in the choroid plexus and left ventricular myocardium, whereas there were significantly lower concentrations in the right ventricular myocardium and still lower concentrations in the other tissues analyzed. Independent of the digoxin dose, the digoxin concentrations in the choroid plexus tended to be lower in persons treated for a short time before death than in those treated for longer periods of time. Similar differences were not observed in the other tissues, suggesting a slower rate of digoxin uptake in the choroid plexus compared with the myocardium and other tissues. The implications of these findings for the effect of digoxin treatment on the production of cerebrospinal fluid are discussed.
Dose‐dependent acebutolol disposition after oral administration
Authors: Meffin Peter J. , Winkle Roger A. , Peters Flora A. , Harrison Donald C. , Harapat Sandra R. , Yee Yin-Gail
Published: January 2016

The relationship between dose and area under the blood concentration‐time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.
Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients
Authors: Mcintyre Barbara A. , Philp Richard B. , Inwood Martin J.
Published: January 2016

New propionic acid derivatives are claimed to induce a lower incidence of gastrointestinal bleeding and hemostatic disturbance than older anti‐inflammatory analgesics such as aspirin. One of these (ibuprofen, Motrin) was given (600 mg orally) to normal subjects and hemophiliac subjects on a random, double‐blind basis (lactose placebo). Platelet adhesiveness, aggregation, platelet and red cell counts, percent packed cells, percent hemoglobin, serum ibuprofen levels, and modified Ivy bleeding time were measured before and 2 and 24 hr after drug. Predrug and 24‐hr postdrug values were normal, but at 2 hr after drug, adenosine diphosphate, epinephrine, and collagen aggregations were inhibited and bleeding times were slightly but significantly prolonged in the ibuprofen‐treated normal subjects. The other parameters tested remained unchanged. Similar results were obtained in the ibuprofen‐treated hemophiliac patients, although bleeding time was not prolonged. The results suggest that ibuprofen may be given to hemophiliac subjects with greater safety than some of the older anti‐inflammatory drugs.
(−)‐2‐Hydroxy‐N‐cyclopropylmethylmorphinan: Radioimmunoassay and pharmacokinetic profile
Authors: Dixon Ross , Young Richard , Mohacsi Erno , Holazo Alice , Malarek David , Boxenbaum Harold , Moore James , Parsonnet Mia , Kaplan Stanley
Published: January 2016

The pharmacokinetic profile of (−)‐2‐hydroxy‐N‐cyclopropylmethylmorphinan (HCMM), a narcotic antagonist and analgesic, has been evaulated in man following administration of 25 to 50 mg of the drug orally and 10 to 15 mg intramuscularly. A specific radioimmunoassay procedure was developed for the determination of HCMM in plasma and urine. The drug had a mean “apparent” elimination half‐life in plasma of about 11 hr following both routes of administration. A mean of 47% of the oral dose was excreted in the urine as unconjugated and conjugated HCMM and only 5% of the dose was excreted as intact HCMM. In one subject studied, the plasma levels of conjugated HCMM were as much as 5‐fold higher than the levels of un conjugated drug. Although there was considerable intersubject variability following both routes of administration, the overall pharmacokinetic parameters suggest that oral and intramuscular doses are bioequivalent.
Disposition of metformin (N,N‐dimethylbiguanide) in man
Authors: Sirtori Cesare R. , Franceschini Guido , Galli-Kienle Marzia , Cighetti Giuliana , Galli Gianni , Bondioli Alighiero , Conti Franco
Published: January 2016

Kinetic parameters ol metformin (N,N‐dimethylbiguanide), an anti‐diabetic reported to be associated with a lower number of episodes of lactic acidosis than phenformin, were determined in volunteers with normal renal function and in patients with different degrees ol renal impairment. Drug in body fluids was measured by a highly specific and sensitive mass fragmentographic method, alter the formation of a triazine derivative, obtained with heptafluorobutyric anhydride. The half‐life (t½) for the elimination ol drug from plasma after intravenous injection in 5 normal subjects (1.52 ± 0.3 hr) (mean ± SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr). The mean t½ in 5 renal patients was 4.94 ± 1.11 hr, and a correlation was observed between t½ of drug from plasma and creatinine clearance. After oral administration of metlormin tablets, drug recovery in urines was only 37.6%, possibly not as a consequence of low bioavailability (a similar low recovery was found after oral administration of the metformin solution usedlor the intravenous studies), but of binding to the intestinal wall, as shown in animal and clinical studies with metformin and other biguanides. Metformin is rapidly eliminated through active secretion by the kidney (mean renal clearance, 440.8 ml/min)—it is neither metabolized nor protein‐bound in plasma. The very brief plasma t½ makes significant cumulation, with a standard tid regimen, unlikely. These findings may help explain the lower incidence of toxic effects, particularly lactic acidosis, than after phenformin.
Effects of hypothermia on propranolol kinetics
Authors: McAllister R. G. , Bourne David W. , Tan Tiong G. , Erickson John L. , Wachtel Claire C. , Todd Edward P.
Published: January 2016

Propranolol may be uniquely useful in cardiac surgical procedures, since beta adrenergic blockade can prevent the hypokalemia and associated arrhythmias which result from systemic hypothermia. To determine the effects of hypothermic cardiopulmonary bypass (HCPB) on the in vivo handling of propranolol, serial drug plasma concentrations (Cp) were measured during HCPB in 12 patients who had been treated chronically with propranolol prior to surgery. Although no further propranolol was given during the procedure, Cp values (corrected for plasma volume dilution) were higher during hypothermia than in the preoperative period, falling to or below control levels after rewarming. Due to the variables inherent in patient surgery, meaningful kinetic analysis could not be carried out. Therefore, intravenous propranolol (1 mg/kg) was given twice to each of 5 dogs, first after anesthesia only, then after anesthesia and systemic cooling to 26° in a water bath. Cp values measured serially over 2 hr afler drug administration were consistently higher during hypothermia. Compared with the paired normothermic control studies, hypothermia markedly reduced the apparent volume of distribution (6.78 ± 1.65 vs 2.08 ± 0.58 L/kg; p < 0.001) and the total body clearance of propranolol (64.4 ± 11.0 vs 52.8 ± 7.2 ml/kglmin; p <? 0.005). These data show that hypothermia substantially alters the pharmacokinetics of propranolol, resulting in plasma drug levels higher than those predicted from kinetic patterns derived under normothermic conditions.
Hydrochlorothiazide and spironolactone in hypertension
Authors: Schrijver G. , Weinberger M. H.
Published: January 2016

A double‐blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild‐to‐moderate essential hypertension after a 4‐wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of ≤107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty‐nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.
Atenolol and three nonselective β‐blockers in hypertension
Authors: Waal-Manning Hendrika J.
Published: January 2016

The object of this study was to establish whether cardioselectivity of atenolol confers any advantage over noncardioselective β‐blockade in the treatment of hypertension. A dose of atenolol was established on the basis of morning mean systolic blood pressure (mean of 5 readings) in 27 long‐standing hypertensive patients previously controlled on one of three nonselective β‐blockers: propranolol, oxprenolol, or pindolol. Most patients were also taking a diuretic. A crossover trial was then conducted of atenolol and the previous nonselective β‐blocker, each drug being given for 8 wk in randomized order. Other drugs were kept constant. At the end of each 8‐wk period a morning test of blood pressure and pulse rate was done, an 11:30 a.m. blood sample was taken for estimation of drug concentration, and spirometry was performed. During the eighth week a glucose tolerance test, fasting lipids, and other biochemical and hematologic estimations were done. On a separate occasion a late morning study was done on the response of blood pressure and pulse rate to three kinds of stress: bicycle ergometer, mental arithmetic, and handgrip. At dosage levels of atenolol giving a mean resting systolic blood pressure equal to that during nonselective β‐blockade, diastolic levels on atenolol tended to be lower at rest and during the mental and handgrip forms of stress. Serum creatinine levels on atenolol were lower than during nonselective β‐blockade. Anti‐dioxyribonucleic acid (DNA) titers remained normal in all patients. There was no difference in lung function. There was little difference in glucose and insulin levels during glucose tolerance tests in these patients, half of whom were diabetic. There were no serious side effects but there were a few surprising ones such as vivid dreams in three and muscle cramps in one patient.
Kinetics of gallium nitrate, a new anticancer agent
Authors: Hall Stephen W. , Yeung Katherine , Benjamin Robert S. , Stewart David , Valdivieso Manuel , Bedikian Agop Y. , Loo Ti Li
Published: January 2016

Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half‐life (t½) of 0.5 to 1.8 hr (mean 1.0) and a terminal t½ of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 12% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.
Acebutolol in supraventricular arrhythmias
Authors: Aronow Wilbert S. , Van Camp Steven , Turbow Marvin , Whittaker Kenneth , Lurie Mark
Published: January 2016

The effect of intravenous acebutolol on supraventricular arrhythmias was evaluated in 20 patients, 5 with chronic obstructive pulmonary disease. A rapid ventricular rate in atrial fibrillation was slowed >15% in all of 10 patients by acebutolol and in none of 5 patients by saline. A rapid ventricular rate in atrial flutter was slowed >15% in all of 6 patients by acebutolol and in none of 3 patients by saline. Frequent premature atrial beats were abolished or reduced by >75% in each of 2 patients by acebutolol and not in a patient by saline. Acebutolol converted multifocal atrial tachycardia to sinus rhythm in a patient. Digitalis‐induced nonparoxysmal atrioventricular junctional tachycardia was not affected by saline but was abolished by acebutolol in a patient. Acebutolol was well tolerated in each of 5 patients with chronic obstructive pulmonary disease. Acebutolol is useful in the treatment of supraventricular arrhythmias.
Effect of food on kinetics of 8‐methoxsalen
Authors: Ehrsson Hans , Nilsson Sten-Ove , Ehrnebo Mats , Wallin Inger , Wennersten Göran
Published: January 2016

Kinetics of 8‐methoxsalen were studied in 5 healthy subjects under fasting and nonfasting conditions. The plasma concentration‐time data could be fitted to a zero order absorption one‐compartment model. The area under the curve (AUC) values were higher (p < 0.05) under nonfasting compared to fasting conditions, indicating higher relative bioavailability of the drug in the presence of food. No significant differences were observed in the lag‐time for the start of the absorption, the apparent zero‐order absorption rate constant, or the elimination rate constant. It is suggested that the drug should be taken in a standardized way in relation to food during the ultraviolet (UV) light treatment.
Acetaminophen kinetics in acutely poisoned patients
Authors: Slattery John T. , Levy Gerhard
Published: January 2016

A kinetic model of acetaminophen elimination over a wide dose range has been developed on the basis of (1) kinetic data from normal adults who received a usual dose (up to 2 gm) of the drug and (2) the composition of urinary metabolites of acetaminophen excreted within 24 hr by 29 patients who had ingested up to 26 gm of acetaminophen in suicide attempts (including 2 that were fatal and 5 with evidence of severe intoxication). The model consists of the following parallel pathways: conjugation with glucuronide by Michaelis‐Menten kinetics, conjugation with sulfate by Michaelis‐Menten kinetics, renal excretion of acetaminophen by apparent first‐order kinetics, and formation of an oxidative metabolite (which is responsible for the hepatotoxicity of acetaminophen) by apparent first‐order kinetics. There is good agreement between the model‐predicted and actual urinary excretion of individual acetaminophen metabolites for doses of 0.8 to 26 gm and between model‐predicted and actual plasma acetaminophen concentrations in both the low (normal subjects) and high (intoxicated subjects) concentration ranges. Computer simulations indicate that unsaturation of acetaminophen sulfate formation, previously shown to be feasible in vivo, should decrease the formation of the hepatotoxic metabolite. This prediction is consistent with experimental data obtained in preliminary studies on mice.
Long‐term antiarrhythmic therapy with N‐acetylprocainamide
Authors: Lertora Juan J. L. , Atkinson Arthur J. , Kushner William , Nevin Mary Jane , Lee Woong-Ku , Jones Charles , Schmid Frank R.
Published: January 2016

The effects of long‐term NAPA therapy were evaluated in 6 patients with chronic PVCs known to respond to this drug during a previous placebo‐controlled, dose‐ranging trial. Underlying cardiac status was evaluated every six months by switching each patient from NAPA to placebo. Placebo period PVC frequency after one year of NAPA therapy was reduced, compared to baseline placebo values. Mean PEP/LVET, measured while the patients received placebo, was elevated at the beginning of the study but was normal after one year of NAPA therapy. Comparison of NAPA and placebo period observations indicated a reduction in PEP/LVET when NAPA therapy was begun. This effect, however, could not be demonstrated one year later when mean placebo period PEP/LVET was normal. The apparent dependence of this effect on underlying status of left ventricular function suggests that the initial reduction in PEP/LVET represents an indirect effect of NAPA rather than a direct inotropic action. NAPA therapy was well tolerated by the 6 patients and ANA titers became abnormal in only one, in marked contrast to reported experience with procainamide.
Atenolol and chlorthalidone on blood pressure, heart rate, and plasma renin activity in hypertension
Authors: Teeuw A. H. , Leenen F. H. H. , Geyskes G. G. , Boer P.
Published: January 2016

The antihypertensive effect of atenolol, with and without chlorthalidone, on hypertension was assessed in an outpatient as well as in an inpatient study. In the outpatient study atenolol alone induced decreases in systolic and diastolic BP amounting to 20 and 15 mm Hg. Maximal response of BP and HR developed within a week at the lowest dose used (100 mg twice daily). Combined atenolol‐chlorthalidone treatment decreased lying and standing systolic BP by 7 and 14 mm Hg more than atenolol alone, but diastolic BP was decreased little more. In the inpatient study the addition of atenolol to chlorthalidone therapy in a dose of 100 mg twice daily resulted in a maximal decrease in BP within 3 days. At this dose PRA was lowered only slightly. Larger doses did not lead to any significant further decrease in BP, whereas PRA fell progressively. Our results indicate that, in contrast to nonselective blockade, specific beta‐1‐adrenoceptor blockade by atenolol is capable of inducing a distinct antihypertensive effect, unrelated to suppression of PRA. The decrease in PRA after larger doses of atenolol was not accompanied by a further decrease in BP. Because diuretic‐induced renin release plays a role in the maintenance of the BP, our findings suggest that at higher dosages a hypertensive effect of the beta blocker compensated for the hypotensive effect of the decrease in PRA.
Effect of d‐ and dl‐propranolol on glucose‐stimulated insulin release
Authors: Myers Martin G. , Hope-Gill Herbert F.
Published: January 2016

The effect of intravenous d‐ and dl‐propranolol on serum insulin levels has been examined before and after the administration of glucose orally to 10 normal subjects. The increase in serum insulin 45 to 90 min after glucose ingestion was reduced during the infusion of either d‐or dl‐propranolol. The insulin suppression was not accompanied by any alteration in the glucose curves. The insulin/glucose ratios were reduced by both d‐ and dl‐propranolol during the time of maximum glucose and insulin responses. Neither d‐ nor dl‐propranolol induced any significant change in basal glucose or insulin levels before glucose administration. Since d‐propranolol has no appreciable beta adrenoceptor blocking activity, it appears that the suppression of glucose‐stimulated insulin release by propranolol may be due primarily to local anesthetic properties which are exerted equally by both isomers.
Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d‐tubocurarine
Authors: Sheiner Lewis B. , Stanski Donald R. , Vozeh Samuel , Miller Ronald D. , Ham Jay
Published: January 2016

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time‐independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non‐equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first‐order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least‐squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d‐tubocurarine (dTC). In 7 normal subjects, the (mean ± SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 ± 0.04 min−1 and the (mean ± SD) steady‐state Cp required to produce 50% paralysis is 0.37 ± 0.05 µg/ml.