bluuebunny/crossref_metadata_2025 huggingface dataset:
Procainamide and N‐acetylprocainamide kinetics investigated simultaneously with stable isotope methodology
Authors: Dutcher John S. , Strong John M. , Lucas Samuel V. , Lee Woong-Ku , Atkinson Arthur J.
Published: January 2016

The pharmacokinetics of procainamide (PA) and N‐acetylprocainamide (NAPA) were compared in 3 normal subjects after simultaneous intravenous injection of PA and NAPA‐13C. The distribution kinetics of both compounds were modeled with a 3‐compartment mamillary system, and it was found that their steady‐state distribution volumes were not significantly different, averaging 1.41 Llkg for PA and 1.46 Llkg for NAPA. However, the intercompartmental clearances of NAPA were slower than those of PA. In these normal subjects, the average elimination tl/2 and total elimination clearance for PA were 2.5 hr and 589.8 ml/min, and for NAPA were 6.2 hr and 233.7 mllmin. Mean renal clearances of PA (346.7 ml/min) and of NAPA (199.5 mllmin) exceeded the usual rate of glomerular filtration, which suggests that both compounds are eliminated in part by renal tubular secretion. All subjects were phenotypic rapid acetylators of isoniazid and converted approximately one fourth of the administered PA dose to NAPA‐12C. The fate of 15.4% of the administered PA and 14.5% of the administered NAPA‐13C was not determined.
Plasma protein binding of basic drugs
Authors: Borgai Olof , Piafsky Kenneth M. , Nilsen Odd G.
Published: January 2016

The protein binding of a number of basic drugs has been shown to be inhibited when blood is collected in Vacutainer tubes. We found that the plasticizer tris(2‐butoxyethyl) phosphate (TBEP). present in plasma collected in Vacutainers. was a potent inhibitor of alprenolol and imipramine protein binding. Its concentration in the plasma could quantitatively explain the displacement phenomenon. Alprenolol binding to a solution of a physiologic concentration (0.67 gmlL. 0.015 mM) of α1‐acid glycoprotein (orosomucoid) was decreased from 76% to 16% by addition of 10 uglml (0.026 mM) of TBEP. while imipramine binding was decreased from 69% to 13%. Alprenolol and imipramine binding to albumin and lipoproteins was virtually unchanged by TBEP. Due to its selective effect on binding to α1‐acid glycoprotein. TBEP may be a useful tool for studying plasma protein binding of basic drugs.
Monoacetylhydrazine as a metabolite of isoniazid in man
Authors: Timbrell John A. , Wright James M. , Baillie Thomas A.
Published: January 2016

The potent hepatotoxin, acetylhydrazine (monoacetylhydrazine), has been identified by gas chromatography‐mass spectrometry as a urinary metabolite of isoniazid in man. Using a specific gas chromatographic assay procedure for acetylhydrazine, the urinary excretion of this metabolite in volunteers given a 300‐mg dose of isoniazid was found to be 1.8 ± 0.4% and 2.5 ± 0.5% of the dose in rapid and slow acetylators, respectively. In the same subjects the urinary excretion of diacetylhydrazine was significantly greater in the rapid acetylators, 23.0 ± 2.0%, than in the slow acetylators, 4.9 ± 0.9%. The results suggest that only part of the acetylhydrazine formed as a metabolite of isoniazid is excreted in the urine as acetylhydrazine and diacetylhydrazine and that a substantial proportion of the acetylhydrazine formed is further metabolized, possibly through the microsomal enzyme pathway known to be responsible for hepatotoxicity in experimental animals.
Theoretic aspects of pharmacokinetic drug interactions
Authors: Gillette James R. , Pang K. Sandy
Published: January 2016

Various nutritional and environmental factors are known to alter the rates at which drugs are absorbed, distributed, metabolized, and eliminated from the body. Some of these factors may exert their effects by changing gastrointestinal motility, blood flow rates through various organs, the activities of enzymes that catalyze the metabolism of drugs, the reversible binding of drugs to components in blood and other tissues, and the rate of elimination by the kidney. Because these physiologic and biochemical functions are interrelated, however, a given change in anyone of them mayor may not result in significant changes in the concentration of unbound drug at pharmacologic and toxicologic action sites. Indeed, whether the concentration of unbound drug at action sites is significantly changed may also depend on the principle organ of elimination, the route of administration, and the dosage schedule of the drug. In order to illustrate the effects of alterations in blood flow rates, enzyme activity, and reversible binding to blood components on the total body clearance of drugs, mathematical equations were derived for a general pharmacokinetic model that includes elimination of drugs by feces, intestinal mucosa, liver (metabolism and biliary excretion), lung, and kidney. With these equations it is possible to describe the conditions under which a change in the activities of drug‐metabolizing enzymes in a given organ or a change in the reversible binding of drugs to blood components may result in significant changes in the apparent total body clearance of drugs and thus in significant changes in the average steady‐state concentration of unbound drug at action sites after multiple doses. The fact that reversible binding of drugs to blood components may result in either increases or decreases in the half‐life of drugs in the body is noted, and a universally applicable nomogram has been designed to illustrate the conditions under which each of these events will occur.
Genetic and environmental factors affecting drug disposition in man
Authors: Vesell Elliot S.
Published: January 2016

Large interindividual variations in drug response can arise from multiple genetic and environmental factors affecting drug absorption, distribution, biotransformation, excretion, interaction with receptor sites, or combinations of these. Twin and family studies disclosed that for several commonly used drugs genetic factors are predominantly responsible for large interindividual variations in drug disposition that occur in normal volunteers under basal conditions. Environmental contributions were surprisingly small. While it has been convenient in such studies to separate genetic from environmental contributions as though they were discrete, unrelated entities, the transcriptional and translational mechanisms by which genetic information is expressed require environmental participation. Conversely, many environmental factors that alter rates of drug disposition do so by affecting genetic mechanisms (for example, phenobarbital induction of human hepatic antipyrine metabolism and benzpyrene induction of aryl hydrocarbon hydroxylase [AHH] activity in cultured human lymphocytes). Environmental chemicals, such as DDT, polychlorinated biphenyls, and polycyclic hydrocarbons, can alter, through induction, basal, genetically controlled hepatic drug‐metabolizing enzyme activity. Disease states can markedly change an individual's basal, genetically controlled rate of drug elimination. Assurance of a truly basal, uninduced, or uninhibited state can never be complete but is partially attainable through repeated measurements of the rate of elimination of a particular drug and through a careful history of exposures at work and at home to potential compounds or conditions that could alter the basal rate of drug elimination. The existence and operation of numerous environmental factors, each with differing capability of altering the basal, genetically controlled level of drug metabolism, make it exceedingly difficult to attribute quantitatively different portions of the total interindividual variation to specific single environmental factors. In this regard, a major problem in man is that most populations are markedly heterogeneous with respect both to environmental and genetic factors that influence drug disposition. The task of partitioning the total interindividual variation in drug elimination of such heterogeneous populations into component parts is further complicated because some seemingly pure “environmental” factors (smoking and diet) are closely associated with other
Effects of smoking on drug action
Authors: Miller Russell R.
Published: January 2016

The effects of smoking on drug metabolism in 3 categories of cigarette smokers (nonsmokers, light smokers, and heavy smokers) were studied in patients in 22 hospitals in 7 countries in a collaborative program. The data collected by monitors along with a smoking history on consecutively admitted patients were recorded on self‐coding forms. Details were obtained on all drugs administered, and the judgment of efficacy by the prescribing physician was included. Propoxyphene was rated ineffective in 10% of nonsmokers, 15% of light smokers, and 20% of heavy smokers, the difference being statistically significant (p < 0.01). Among 835 recipients of the drug, the most common diagnoses were chronic obstructive lung disease, musculoskeletal disorders, and neoplastic diseases. Decreasing age, male sex, race other than white, and ingestion of large amounts of alcohol were other factors positively related to smoking. In patient~ receiving diazepam and chlordiazepoxide, the frequency of drowsiness was highest in nonsmokers, intermediate in light smokers, and lowest in heavy smokers. The differences among the comparison groups by chi‐square tests were statistically significant for diazepam (p < 0.05) and for chlordiazepoxide (p < 0.02). Phenobarbital data gave no evidence of an association between cigarette smoking and drowsiness attributed to the drug (p > 0.05). The relation between cigarette smoking and the benzodiazepines was evident at all dose levels; drowsiness was less common in smokers regardless of sex. The relation with smoking held for each of the diagnoses (chronic obstructive lung disease, cirrhosis of the liver, and lung cancer), and an inverse relation between drowsiness and alcohol consumption was evident at all levels of alcohol intake. Among recipients of chlorpromazine in a psychiatric population, drowsiness was highest in nonsmokers, intermediate in light smokers, and lowest in heavy smokers. Drowsiness was dose‐related but not related to smoking status; alcohol consumption correlated strongly with smoking habits and drowsiness was more frequent among nonsmokers than among light and heavy smokers in each category of alcohol consumption. The data are compatible with the hypothesis that substances in cigarette smoke induce liver microsomal enzymes which increase the metabolism of these drugs.
Phenacetin metabolism: Effect of hydrocarbons and cigarette smoking
Authors: Kuntzman R. , Pantuck E. J. , Kaplan S. A. , Conney A. H.
Published: January 2016

The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4‐benzpyrene (benzo[a]pyrene}, resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the O‐dealkylation of phenacetin to N‐acetyl‐p‐aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half‐life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first‐pass metabolism in the liver.
Toxicity to heavy metals and relationship to seizure thresholds
Authors: Adler Martin W. , Adler Charles H.
Published: January 2016

The present study was designed to provide information on the effects of lead, mercury, and nickel on lethality, body weight, and brain excitability in the adult rat. Both short‐ (2 days) and long‐term (6 wk) drug administrations were carried out in adult male albino rats (Sprague‐Dawley, Zivic‐Miller). Based on the mg/kg/day of drug given over a 2‐day period, the LD50 values were as follows: Pb(Ac)2, 215; Pb(N03)2, 65.9; MMC, 11.9; HgC12, 4.5; Ni(Ac)2, 35‐40; NiS04, 35‐40. High doses of each of the metals administered acutely caused a drop in body weight but had an inconsistent effect on fiurothyl‐induced seizure thresholds. Pb(Ac)2, 200 mg/kg/day for 2 days, produced a statistically significant anticonvulsant effect, while 50 mg /kg Pb(N03)2 resulted in afall in threshold. Both NiSO4 and Ni(Ac)2, 30 mg/kg, increased seizure threshold. Neither the organic nor inorganic mercury altered thresholds. Long‐term administration of Pb(Ac)2, MMC, or HgC12 resulted in marked effects on body weight but no significant change in brain excitability.
Environmental effects on antipyrine half‐life in man
Authors: Fraser Henry S. , Mucklow John C. , Bulpitt Christopher J. , Khan Clare , Mould Geoffrey , Dollery Colin T.
Published: January 2016

Antipyrine half‐life was studied with the use of saliva samples in healthy adult Londoners and Gambians. Of 131 Londoners, 74 were Caucasian (all but one of these were nonvegetarian) and 57 were Asian (49 of these were vegetarian). The 49 Gambians were almost complete vegetarians. Anthropometric indices, hemoglobin, and albumin were measured and a history of diet and socially used drugs obtained. The Caucasians smoked more cigarettes, drank more alcohol, coffee, and tea, and included more users of the steroid oral contraceptive (SOC) than the other ethnic groups, while the Gambians chewed cola nuts. In the Londoners four environmental factors‐diet, cigarette smoking, use of the SOC, and body weight‐were significant independent predictors of antipyrine half‐life. Together they explained 49% of the variation. A vegetarian diet prolonged the half‐life by 50% compared with a nonvegetarian diet. Use of the SOC prolonged half‐life by 40% while smoking shortened the half‐life by 25%. In the Gambians antipyrine half‐life was shorter in women and was prolonged by cola nut consumption. It decreased with an increase in height in men and increased with hemoglobin in women. Cola nut consumption and hemoglobin explained 21 % of the variation, and sex and height explained a further 15%. Our results suggest that diet and socially used drugs can have important effects on drug oxidation.
Guanabenz and methyldopa on hypertension and cardiac performance
Authors: Walker Barry R. , Shah Rajnikant S. , Ramanathan Kodangudi B. , Vanov Svetislav K. , Helfant Richard H.
Published: January 2016

In previous placebo‐controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double‐blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre‐ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.
A psychological perspective for double‐blind trials
Authors: Zifferblatt Steven M. , Wilbur Curtis S.
Published: January 2016

Blind breaking is likely to occur in a long‐term clinical trial involving subjects at risk. Double‐blind conditions require subjects to live with ambiguity regarding their health status. lt is unrealistic to expect them to tolerate this ambiguity over an extended period of time. A logical step for a subject is to break the blind and surreptitiously seek the best medical care available. Moreover, the staff assigned to monitor protocol adherence may further contribute to blind breaking because of ambiguity regarding their proper clinical role. Several steps are recommended to manage blind breaking within a trial, including improving the quality of medical care, more rigorous screening procedures, and maintaining a clinical environment that promotes accurate disclosure of blind breaking.
Diurnal variation of prednisolone binding to serum corticosteroid‐binding globulin in man
Authors: Angeli Alberto , Frajria Roberto , De Paoli Roberto , Fonzo Domenico , Ceresa Franco
Published: January 2016

Serum corticosteraid‐binding globulin (CBG, transcortin) binding capacity for prednisolone and for cortisol, and levels of the circulating cortisol were evaluated in healthy adult subjects and in patients under long‐term treatment with prednisone. Blood sampies were drawn at 4‐hr intervals throughout at least 24 hr; the prednisone administration was discontinued 24 hr before starting examination. Circadian fluctuations in the CBG‐binding capacity for prednisolone occurred in healthy subjects: maximum binding was at 12 midnight and minimum binding at 8 a.m. The diurnal pattern of prednisolone‐binding capacity was characterized by phase shifts of approximately 12 hr and 8 hr compared with those of serum cortisol and cortisol‐binding capacity, respectively. There were no diurnal variations of prednisolone‐ and cortisol‐binding capacity in the prednisone‐treated patients. Moreover, the levels of both capacities, expressed as micrograms bound steroid/100 ml, were significantly reduced with respect to normal contral subjects. Cyclic variations in serum CBG‐binding capacity may represent an additional factor accounting for temporal differences in the action of synthetic corticoids which are bound by the transport protein. Synthetic derivatives when chronically administered may interfere not only with the adrenal secretion but also with the serum transport of glucocorticoids.
Heparin: A drug of varying composition and effectiveness
Authors: Coon William W.
Published: January 2016

In the past few years concerns have been expressed by clinical investigators regarding the variable and unpredictable risk of both hemorrhage and thrombosis in patients receiving heparin. Recent observations tend to indicate that a number of elements may contribute to variability in response to heparin. Possible factors which may be responsible include differences in chemical composition and in methods of assay, variable absorption, different types and degrees of alteration in coagulation mechanism of patients, and inaccuracies or inadequacies in methods for monitoring therapy.
Cyproheptadine in levodopa‐induced dyskinesia in parkinsonism
Authors: Papavasiliou Paul S. , Cotzias George C. , McDowell Fletcher H. , Rosal Victoria L. F. , Sheehan Paul J.
Published: January 2016

The neuroendocrine properties and the beneficial effects of cyproheptadine in tardive dyskinesia led to the testing of this drug in levodopa‐induced dyskinesia. Cyproheptadine administered to 6 parkinsonian patients in doses of up to 42 mg/day was of no significant benefit in either dyskinesia or symptom control. Improvement in appetite was reported by 3 patients. These observations suggested that different mechanisms may be responsible in the pathogenesis of phenothiazine and amine‐induced dyskinesia. The failure to control levodopa‐induced dyskinesia selectively with serotonin agonists and antagonists and the accentuation of the dyskinesia in the presence of anticholinergic agents further suggest that substances that increase directly central cholinergic activity may be effective in the control of levodopa‐induced dyskinesia.
Pharmacokinetics of warfarin enantiomers: A search for intrasubject correlations
Authors: Wingard Lemuel B. , O'Reilly Robert A. , Levy Gerhard
Published: January 2016

The total body clearance of single doses of R(+)‐, S(−)‐, and racemic warfarin and the plasma concentration‐anticoagulant effect curves for these drugs were determined in 10 healthy men, 21 to 51 yr old. This information was used to calculate the steady‐state dose required to decrease prothrombin complex activity to about 30% of normal. This dose (mean ± SD in mg/70 kg/day) is 17.8 ± 9.3 for R(+)‐warfarin, 6.63 ± 2.19 for S(−)‐warfarin, and 9.4 ± 1.7 for racemic warfarin. There is a correlation between the maintenance doses of racemic and S(−)‐warfarin (r = 0.89, p < 0.01) but not between those of racemic and R(+)‐warfarin (r = 0.30, NS). According to these calculations, the maintenance dose of racemic warfarin required by an individual patient may be a useful predictor of the maintenance dose of S(−)‐warfarin which will produce a comparable degree of anticoagulation. No such predictability is evident with respect to R(+)‐warfarin. The slopes of the log plasma concentration‐anticoagulant effect curves for R(+)‐and S(−)‐warfarin differ significantly. Therefore, the potency ratio of these enantiomers is dose‐and concentration‐dependent.
Circadian variation in response to potassium infusion
Authors: Moore-Ede Martin C. , Meguid Michael M. , Fitzpatrick Garry F. , Boyden Caryl M. , Ball Margaret R.
Published: January 2016

The response of 5 normal men to an intravenous infusion of potassium chloride was compared at midday and midnight. Each subject was maintained on strict supine bedrest with oral intake limited to 100 ml distilled waterlhr for the 9 hr before and after each infusion. Potassium chloride, 37 mEq, (with an added label of 200 µCi 42KCl) in iso‐osmolar solution was administered via a central venous catheter over 1 hr starting either at midday or midnight. Plasma potassium concentration was elevated by 40% more at midnight than at midday, and plasma 42K activity also rose to a higher level at midnight. These differences were reflected by greater T wave elevations of the electrocardiogram at midnight than at midday, although urinary potassium excretion (total and 42K labeled) was higher at midday than at midnight, indicating that there was reduced renal excretory responsiveness to elevations in plasma potassium concentration at midnight compared with midday. Plasma aldosterone concentration rose during the potassium infusions at both midday and midnight by a similar amount, which suggests that the induced increments in aldosterone secretion were not a major determinant of the differing renal response. These findings indicate that circadian modulations in the physiologic mechanisms which regulate potassium homeostasis profoundly influence the response to exogenous potassium loads. Special caution must therefore be taken in administering potassium infusions at night.
Response of asthmatic patients to fenoterol inhalation: A method of quantifying the airway bronchodilator dose
Authors: Ruffin R. E. , Kenworthy M. C. , Newhouse M. T.
Published: January 2016

A radiotracer technique is described which enables direct measurement of the dose and distribution of inhaled aerosol bronchodilator in man. The mean (±SD) amounts of the B2‐adrenergic agonist, fenoterol, administered to a group of 12 asthmatic subjects in a double‐blind randomized fashion were: placebo, 0 µg; low dose, 5.6 (± 1.2) µg; medium dose, 32.7 (±7.3) µg; and high dose, 127.5 (±29.2) µg, with a mean of 86.3% of the total subject dose being deposited in the lungs. The medium and high doses of fenoterol produced similar increases above baseline in forced expired volume in 1 sec (FEV1), maximum flow at 50% of vital capacity (Vmax 50), and maximum flow at 25% of vital capacity (Vmax 25). These increases were greater than those with placebo for the entire 4‐hr study (p < 0.01). The low dose of fenoterol was more effective than placebo in increasing FEV1, Vmax 50, and Vmax 25 above baseline values (p < 0.05), but not for the entire 4‐hr study. The high‐dose fenoterol caused palpitations and tremor in 3 of the 12 subjects, and the medium‐dose fenoterol caused palpitations in one of these subjects.
Accuracy of doctors' estimates and patients' statements on adherence to a drug regimen
Authors: Roth Harold P. , Caron Herbert S.
Published: January 2016

Patients were followed for 2 yr after an attack of peptic ulcer. Intake of an antacid regimen was monitored objectively. Quantitative data were obtained on error in statements about intake (i.e., “compliance”) made by 116 patients and errors in estimates of “compliance” made by 3 physicians. Although patients said their intake of antacid averaged 89% of the amount prescribed, their actual intake averaged only 47%. For patients who claimed they took 100%, intake variedfrom 2% to 130% with a mean of 59%. Patients who admitted missing only an occasional dose actually missed substantially more doses than those who claimed 100% compliance. Estimates of intake made by the 3 physicians were more accurate than patients' statements but averaged 50% higher than actual intakes. In patients with low intakes (median 13%), the median estimate by physicians was 55%—an overestimate of 400%. The correlation between actual intakes and physicians' estimates was +0.48, indicating that physicians' judgements were significantly better than chance but nevertheless low in accuracy. Physicians' accuracy did not improve as they gained familiarity with the patient. Demographic data were of limited value in estimating intake. These observations, along with others cited in the literature, indicate the importance of series of objective and quantitative measures of medicine intake. A single measurement, even though accurate, may be grossly misleading because monthly antacid intake for a given patient could vary from 80% above his mean (2 SD) to 80% below, and daily fluctuation could be even larger.
Relationship between diazepam dose, plasma level, age, and central nervous system depression
Authors: Reidenberg Marcus M. , Levy Micha , Warner Howard , Coutinho Claude B. , Schwartz Morton A. , Yu George , Cheripko Joyce
Published: January 2016

Patients undergoing elective cardioversion for treatment of arrhythmias were premedicated with diazepam. The dose was individualized to achieve a degree of central nervous system (CNS) depression characterized by response to painful but not vocal stimulation. Promptly following each cardioversion, blood was drawn and the plasma diazepam concentration was measured by gas chromatography. The plasma levels varied as widely as the diazepam doses so that there was no fixed plasma level of diazepam associated with the degree of CNS depression produced in these patients. However, both the dose of diazepam and the resulting plasma level were inversely correlated to age, indicating that age is a critical factor in the use of diazepam for cardioversion premedication; elderly are more sensitive to the depressant effects of this drug than the young.
Effect of food on kinetics of the nonsteroidal anti‐inflammative, alclofenac
Authors: Sennello Lawrence T. , Sonders Robert C. , Friedman Nadav
Published: January 2016

Two clinical studies were conducted on the kinetics of alclofenac in healthy adult male volunteers. The first involved 32 subjects, each of whom received a single oral 500‐mg dose of alclofenac as an aqueous suspension to study the oral pharmacokinetics of the drug. The second involved 19 subjects in a three‐way crossover design to compare the effect of food eaten shortly before or shortly after dosing with that under fasting conditions. Alclofenac taken as an aqueous suspension under fasting conditions had a mean absorption half‐life of 15 min and a mean elimination half‐life of 1.5 to 2.0 hr. The calculated time of maximum plasma drug concentration was about 0.8 hr, with no appreciable absorption lag time. The pharmacokinetics were better described by the one‐compartment open model with first order absorption than by the two‐compartment one. Alclofenac taken shortly before or after a meal displayed a pharmacokinetic pattern that was poorly described by a model with first‐order absorption. A model with zero‐order absorption and first‐order elimination was a better fit. Elimination half‐life was much the same as the fasting state. Although calculated peak plasma drug levels were significantly delayed and decreased by food, the total amount of drug absorbed (based upon areas under curves) was not affected. About 10% to 15% of an orally administered dose was found in the 0 to 24 hr urine as parent drug in both conditions.
Nephrotoxicity of cis‐platinum (II) dichlorodiammine
Authors: Stark James J. , Howell Stephen B.
Published: January 2016

The renal function of 15 patients receiving cis‐platinum (II) dichlorodiammine (CPDD) was examined prospectively in detail to elucidate early evidence of nephrotoxicity. Patients were given a total of 49 courses of CPDD at 20 mg/m2/day for 5 days with 1,000 ml of saline prehydration. Renal function was monitored by serial determinations of serum creatinine and glomerular filtration rate (measured as 125I‐iothalamate clearance) and by measurement of parameters of tubular function, including tubular reabsorption of phosphorus, urine‐to‐serum glucose ratio, total protein, and total free immunoglobulin light chain excretion, serum electrolytes, and urine pH and specific gravity. There was no significant change in mean serum creatinine within a course of treatment, nor was there a cumulative increase in the serum creatinine. In 9 of 19 evaluable courses there was a small transient fall in glomerular filtration rate with prompt recovery. There was no cumulative decrease in glomerular filtration rate through 3 courses of treatment. Four of the patients with preexisting renal insufficiency suffered no significant additional nephrotoxicity. There was no tubular dysfunction demonstrable in any of the patients. This study represents the first prospective detailed examination of multiple parameters of renal function in patients treated with CPDD and reveals that the only parameter to show any change with this schedule of drug administration was the glomerular filtration rate.
Tetracycline absorption in elderly patients with achlorhydria
Authors: Kramer Paul A. , Chapron Dennis J. , Benson Jay , Mercik Susan A.
Published: January 2016

Five elderly achlorhydric patients and five controls took 250 mg tetracycline as a capsule or as an oral solution. Venous blood samples drawn during the 12‐hr period following administration and urine collected for 72 hr post‐dosing were assayed fluorometrically for tetracycline. There were no differences between the two groups in either rate or extent of tetracycline absorption. The mean apparent first‐order rate constant (ka) for absorption of drug from capsules was 0.58 ± 0.17 hr−1 for patients and 0.65 ± 0.21 hr−1 for controls. The mean extent of absorption for capsule dosage forms relative to an oral solution was 1.0 ± 0.20 for patients and 1.0 ± 0.24 for controls. Concurrent administration of 2 gm of sodium bicarbonate to 2 of the normal subjects resulted in no impairment of either the rate or extent of tetracycline absorption from capsules, suggesting that the effect of elevated gastric pH on tetracycline bioavailability may relate to formulation.
Kinetic and dynamic comparison of piretanide and furosemide
Authors: Lawrence J. R. , Ansari A. F. , Elliott H. L. , Sumner D. J. , Brunton G. F. , Whiting B. , Whitesmith R.
Published: January 2016

In a comparative study with the use of a randomized crossover design, piretanide, a new “loop” diuretic, was given intravenously to 8 normal volunteers. Following the injection of radioiodinated human serum albumin to allow assessment of plasma volume changes, subjects were submaximally water loaded to facilitate urine collection for a period of 210 min after the intravenous injection of 12 mg piretanide, 40 mg furosemide, and placebo. Plasma piretanide concentrations, measured by a sensitive spectrofluorimetric assay, declined biexpoentially after intravenous bolus injection. The mean total body clearance was 246 ± 52 ml min−1 and the mean renal clearance was 136 ± 61 ml min−1. Significant increase in urine flow, natriuresis, and kaliuresis were evident within 15 min of piretanide injection and persisted for 90 min. A calciuric effect was also observed over this period. While a uricosuric action was observed during the first 15 min the overall effect was urate retention which became evident between 45 and 150 min. In none of these measured effects did 12 mg piretanide differ from 40 mg furosemide. Plasma volume declined linearly from the time of drug injection, a variable plateau being reached at approximately 90 min. From 15 min after injection, individual subjects showed a good linear correlation between the piretanide or furosemide urinary excretion rate and the concomitant sodium or potassium excretion rate. Corresponding concentration‐effect regression lines showed no important differences between the two diuretics. The relative potency of the drugs (piretanide : furosemide) for sodium excretion was 2.42: 1. For both piretanide and furosemide the time course of diuretic effect closely paralleled the extrapolated amount of drug in the peripheral compartment of the proposed open 2‐compartment model.
Sodium depletion and blood pressure response to 1‐sarcosine, 8‐isoleucine angiotensin II in hypertension
Authors: Ogihara Toshio , Hata Takeshi , Mikami Hiroshi , Nakamaru Mitsuaki , Maruyama Anna , Mandai Takashi , Kumahara Yuichi
Published: January 2016

The relation of sodium balance to the blood pressure response to 1‐sarcosine, 8‐isoleucine angiotensin II ([Sar1, Ile8]AII) was evaluated in patients with hypertension of various causes. Tests with [Sar1, Ile8]AII were made under the following three conditions: (1) unrestricted diet and no diuretic pretreatment, (2) unrestricted diet and 40 mg furosemide intravenously 2 hr before the test, and (3) mild salt restriction (5 gm NaCl/day) and 80 mg furosemide orally for 3 days before the test. Among patients with renovascular or malignant hypertension, 5 of 14 cases (36%) in condition 1, 3 of 6 cases (50%) in condition 2, and 7 of 7 cases (100%) in condition 3, there was a reduction of more than 10 mm Hg in the mean blood pressure. The pressor responses in essential hypertension and in primary aldosteronism were reduced by sodium depletion. All patients with pressor responses of over + 10 mm Hg in condition 3 were patients with primary aldosteronism. These results indicate that before the [Sar1, Ile8]AII test sodium depletion is useful not only for preventing an excessive pressor response in low reninemic patients but also for increasing the specificity of the test in the evaluation of renin‐dependent hypertension. Angiotensin II‐inhibiting analogues are useful in the detection of abnormally high or abnormally low renin levels.
Kinetics, salivary excretion of amphetamine isomers, and effect of urinary pH
Authors: Wan Suk Han , Matin Shaikh B. , Azarnoff Daniel L.
Published: January 2016

Amphetamine was administered to healthy subjects as the racemic mixture and as (+)‐and (−)‐isomers under conditions of urine acidification and alkalinization. Plasma and saliva concentration of each isomer was measured and the kinetics of the individual isomers were determined. (+)‐amphetamine was eliminated more rapidly than the (−)‐isomer. The difference in half‐life between isomers was maximal under basic urinary pH conditions. Saliva amphetamine levels were higher than plasma levels and in the postabsorptive phase were predictably proportional to plasma drug levels.
Kinetics of netilmicin and gentamicin
Authors: Jahre Jeffrey A. , Fu Kwung P. , Neu Harold C.
Published: January 2016

The kinetic parameters of netilmicin were studied in normal human subjects. In the intravenous study a steady‐state was obtained in 4 subjects by the constant infusion of 2 mg/kg of netilmicin during the first hour followed by 0.5 mg/kg/hr for each of three successive hours. Creatinine clearance was greater than the simultaneous serum and renal clearance of netilmicin. In the intramuscular study 6 subjects received a single injection of 1 mg/kg of netilmicin followed by the same dose of gentamicin 1 wk later. A mean peak serum levels of 3.9 µg /ml was found for both antibiotics, but the mean serum half‐life of netilmicin was shorter than that of gentamicin. Doubling the intramuscular dose of netilmicin approximately doubled the peak serum level. In both studies 75% to 90% of the netilmicin was recovered in the urine within the first 24 hr. Netilmicin appears to be primarily excreted by glomerular filtration. The apparent volume of distribution was similar to that reported for other related aminoglycosides. Netilmicin and gentamicin have similar kinetic parameters. There were wide individual differences among normal subjects with both drugs.
Bronchodilating effect of terbutaline aerosol
Authors: Chester Edward H. , Doggett William E. , Montenegro Hugo D. , Schwartz Howard J. , Jones Paul K.
Published: January 2016

We compared the efficacy of terbutaline with that of metaproterenol, isoproterenol, and placebo aerosols in 16 asthmatic patients. Terbutaline, metaproterenol, and isoproterenol produced equivalent improvements in flow rates. At 5 hr, the effect of terbutaline on tests of small airways, FEF25%–75% and FEF50%, was greater (p < 0.05) than that of metaproterenol and isoproterenol. Terbutaline produced no significant change of heart rate or blood pressure.
Furosemide kinetics in renal failure
Authors: Tilstone William J. , Fine Adrian
Published: January 2016

Furosemide kinetics were studied in normal volunteers and patients with renal failure. Comparison of results from intravenous bolus and intravenous infusion in normal subjects showed no significant model dependency of estimations of furosemide clearance, although the average clearance by fitting to a one‐compartment model was 16% higher than that obtained by fitting to a two‐compartment model. Normal subjects had a total body clearance offurosemide of 1.53 ± 0.11 (SE) ml/min/kg, a volume of the central compartment of 2.61 ± 0.37 L, a volume of the peripheral compartment of 2.48 ± 0.24 L, and a half‐life of 0.8 ± 0.06 hr and they absorbed 68.9% ± 7.1 % of a solution of furosemide given by mouth. The corresponding values in patients with renal failure were 0.27 ± 0.03 ml/min/kg, 8.02 ± 0.96 L, 14.1 ± 3.57 L, 14.2 ± 2.30 hr, and 43.4% ± 8.0%, all differing significantly different from the normal. The bioavailability of 500‐mg tablets of furosemide in the renal failure patients was 43.4% ± 7.4%, equivalent to the absorption of the dose given to the same patients in the form of a solution.
Para‐aminosalicylic acid as a lipid‐lowering agent
Authors: Vessby B. , Lithell H. , Boberg J. , Hellsing K.
Published: January 2016

The capacity of para‐aminosalicylic acid (PAS) to lower initially high serum lipoprotein lipid concentrations was tested in a double‐blind crossover study. Thirty patients who were on a lipid‐lowering diet were treated with PAS (6 gm daily) for 4 wk. There was an average reduction of the serum triglyceride concentration of 28% (p < 0.001) and of 12% of the serum cholesterol concentration (p < 0.001) corresponding to a reduction of very low density lipoprotein (VLDL) triglycerides of 40% (p < 0.001) and low density lipoprotein (LDL) cholesterol of 6% (p < 0.05). In hypercholesterolemic patients, the WL cholesterol reduction was 14% (p < 0.001). In patients with hypertriglyceridemia type IV, the mean reduction of the VWL triglyceride concentration was 47% (p < 0.01), corresponding to a serum triglyceride reduction by 37% (p < 0.01). In spite of the decrease of VWL concentration, there was an unexpected reduction of the lipoprotein lipase activity in adipose tissue of 16% (p < 0.02). The glucose tolerance and the serum insulin concentrations at fasting and after glucose injection were not changed.
Kinetics of netilmicin in man
Authors: Pechere Jean-Claude , Dugal Robert , Pechere Marie-Madeleine
Published: January 2016

The kinetics of netilmicin (N‐ethyl‐sisomicin), an investigational aminoglycoside, have been determined in man following intravenous and intramuscular administration of a dose of 2 mg/kg. After intravenous injection the serum elimination of the antibiotic obeys two‐compartment open model kinetics. Distribution and elimination constants are in the range reported for other aminoglycosides, with the exception of the volume of distribution at the steady‐state, which appears to be greater than that of sisomicin and of tobramycin. Urinary excretion data suggest that this antibiotic undergoes some degree of tubular reabsorption and appears to be cleared partially by extrarenal processes. After intramuscular administration, the absorption of netilmicin follows first‐order kinetics and its physiologic availability is complete.
Effect of glucocorticoids and ACTH on antipyrine clearance in children
Authors: Saenger Paul , Rifkind Arleen B. , Pareira Judy
Published: January 2016

Administration of dexamethasone and infusion of adrenocorticotropic hormone (ACTH) to children for periods up to 4 days did not alter the half‐life, apparent volume of distribution, or metabolic clearance rate of antipyrine, a drug principally metabolized by the mixed‐function oxidase system of the liver. We conclude that the short‐term administration of glucocorticoids and ACTH with ensuing stimulation of endogenous glucocorticoid production is unlikely to produce clinically significant changes in the rate of drug metabolism.
Ticrynafen: Kinetics, protein binding, and effects on serum and urinary uric acid
Authors: Wood Alan J. , Bolli Peter , Waal-Manning Hendrika J. , Simpson F. Olaf
Published: January 2016

The kinetics and acute effects of ticrynafen, a new diuretic and uricosuric, have been studied in 4 normal subjects. In 3 of the 4 subjects given a 250‐mg tablet, peak plasma ticrynafen concentrations of 15 to 35 µg/ml were achieved at 1 to 2 hr; in the fourth subject a peak concentration of 10 µg/ml was attained at 6 hr. Elimination half‐life was 2.0 to 3.3 hr. Bioavailability covered a 2.5‐fold range (61.7–154.6 µg · hr · ml−1). Administration of the same dose as quarter doses at 2 hr intervals produced a progressive rise in plasma ticrynafen concentration to 5.5 to 12.9 µg/ml at 8 hr and thereafter a decline at a similar rate to that seen with the single dose. The hypouricemic effect was similar for the single‐ and divided‐dose treatments: uric acid concentration began to fall within 1 hr, reached a minimum of 53% to 77% of the pre‐drug value at 7 to 10 hr, and had returned to approximately pre‐drug values at 24 hr. Urinary uric acid excretion was significantly increased for up to 12 hr with both treatments. The diuretic effect of the single dose lasted 4 to 8 hr, while that of the divided dose lasted 8 to 12 hr.
Phase I studies on chlorozotocin
Authors: Hoth Daniel , Woolley Paul , Green Dianna , Macdonald John , Schein Philip
Published: January 2016

A phase I investigation of chlorozotocin, a new‐water soluble chloroethylnitrosourea, was undertaken to define its pharmacologic effects in man. Forty‐three patients received single intravenous doses ranging from 5 to 175 mg/m2 every 6 wk. No signs of toxicity were observed at doses of under 120 mg/m2, but thrombocytopenia occurred at higher doses. The thrombocytopenic nadir appeared to be dose‐dependent and occurred 4 wk after treatment. Platelet transfusions were required in 2 patients who had previously received intensive chemotherapy. No significant leukopenia occurred. A mild reversible and delayed elevation of hepatic transaminases was found in 25% of courses of 120 mg/m2 or more. No renal toxicity was observed and gastrointestinal toxicity was mild. Investigation of clinical pharmacology revealed a rapid triphasic plasma clearance with initial t½s of 3, 15, and 30 min. The concentration of N‐nitroso intact drug at 1 hr was 10% of the initial peak level. Renal excretion accounted for half of the dose. No significant concentration of N‐nitroso intact or radiolabeled drug was detected in the cerebrospinal fluid of 2 patients in whom it was examined. There were objective signs of therapeutic activity in 5 patients, 3 of whom had melanoma. Based on these studies, the recommended dose for phase II investigation of chlorozotocin is 120 mg/m2 every 6 wk.
Steady‐state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function
Authors: Drayer Dennis E. , Lowenthal David T. , Restivo Kathleen M. , Schwartz Allan , Cook Clarence E. , Reidenberg Marcus M.
Published: January 2016

The concentrations of quinidine, (3S)‐3‐hydroxyquinidine (3‐0H), and 2′‐oxoquinidinone (2′‐OXO) in serum samples from 25 patients on long‐term quinidine therapy were determined by a high‐pressure liquid chromatography assay. Large individual variation in the levels of each of the compounds measured was observed. After correcting for differences in protein binding, the ratio of 3‐OH/quinidine in serum water is 0.61 ± 0.31 (SD) and the ratio of 2′‐OXO/quinidine is 0.39 ± 0.44. Seven of the 25 patients had serum water levels of one of these metabolites similar to or greater than that of quinidine. The quinidine levels, after normalizing for dose, are significantly higher in hemodialysis patients (about twice) than in nonazotemic patients; azotemic patients have mean values intermediate between them. Quinidine, 3‐OH, and 2′‐OXO are equally potent antiarrhythmic drugs (ED50 = 0.18,0.17, and 0.21 mmoles/kg, respectively) when tested against chloroform‐ and hypoxia‐induced ventricular fibrillation in mice. O‐Desmethylquinidine, a new metabolite detected in urine of quinidine‐treated patients, is less active. Quinidine and vOXO are equally potent (ED50 = 0.010 mmoles/kg), while 3‐OH seems less potent and more toxic when tested against BaCl2‐induced ventricular arrhythmias in rabbits. Thus, these metabolites appear to contribute to the effects of quinidine and may make a significant contribution in some cases.
Effect of smoking on caffeine clearance
Authors: Parsons William D. , Neims Allen H.
Published: January 2016

The elimination of caffeine from saliva was compared in groups of healthy smokers (n = 13) and nonsmokers (n = 13). Mean caffeine t½ in smokers (3.5 hr) was shorter than that in the nonsmokers (6.0 hr). The body clearance of caffeine in the smokers (155 ± 16 ml · kg−1 · hr−1) was greater than that in the nonsmokers (94 ± 18 ml · kg−1 · hr−1) (p < 0.05). No significant difference was noted in the apparent volume of distribution in smokers (720 ± 67 ml . kg‐I) and nonsmokers (610 ± 80 ml · kg−1). These differences probably reflect the induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity in smokers. The increased clearance of caffeine by smokers may contribute to the higher consumption of coffee reported to occur in this group.
Effect of cimetidine on renal function in normal man
Authors: Dubb Jeffrey W. , Stote Robert M. , Familiar Robert G. , Lee Kenward , Alexander Fred
Published: January 2016

To evaluate the effect of acute histamine H2‐receptor blockade on renal function, renal function studies were performed in a control state and after cimetidine. Studies included acid excretion in response to acid loading, bicarbonate reabsorption during bicarbonate infusion, and urinary concentrating ability. Cimetidine produced no significant effect on any of these functions. During bicarbonate infusion, inulin clearance remained constant while creatinine clearance fell, possibly because of an effect on tubular creatinine secretion.