bluuebunny/crossref_metadata_2025 huggingface dataset:
Titration of nicotine intake with full‐length and half‐length cigarettes
Authors: Gritz Ellen R. , Baer-Weiss Vivian , Jarvik Murray E.
Published: January 2016

Titration, the self‐regulation of nicotine intake, was studied in 12 smokers by gas chromatograph assays of urinary nicotine levels. Results demonstrated that excretion of urinary nicotine in the proximal condition (half cigarette closer to the filter) did not differ significantly from the whole cigarette condition; however, less nicotine was excreted in the distal condition (half cigarette farther from the filter) because of a rod filtration effect. Subjects extracted proportionately more nicotine from the half than from the whole cigarettes; titration was approximately the same in both half‐cigarette conditions. On scales of strength and satisfaction, full‐length cigarettes were given the highest rating, followed by proximal and then distal cigarettes.
Hemodialysis for severe procainamide toxicity: Clinical and pharmacokinetic observations
Authors: Atkinson Arthur J. , Krumlovsky Frank A. , Huang Chia M. , del Greco Francesco
Published: January 2016

A 67‐yr‐old woman who ingested approximately 7 gm procainamide developed severe hypotension, renal insufficiency, and life‐threatening cardiac toxicity, Hemodialysis doubled the rate of procainamide elimination and increased fourfold the clearance of NA PA , the N‐acetylated metabolite of procainamide. Observations of procainamide and N‐acetylprocainamide (NAPA) plasma levels during the patient's recovery suggest that lethargy and profound hypotension can be expected when these levels total 60 µg/ml and that severe cardiac toxicity should be anticipated with levels totaling 42 µg/ml or more. Hemodialysis also permitted investigation of the effects of hypotension on the pharmacokinetics of these compounds. The apparent volume of procainamide distribution was reduced from a normal value of 2 L/kg to 0.76 L/kg, and that of NAPA from 1.4 L/kg to 0.63 L/kg. The elimination t½ of procainamide was prolongedfrom the normal of 3 hr to 10.5 hr, and that of NAPA from 6 to 35.9 hr. Procainamide absorption was also slowed in this clinical setting, causing procainamide plasma levels to continue rising for some time after toxicity was first recognized.
Dose‐related sleep disturbances induced by coffee and caffeine
Authors: Karacan Ismet , Thornby John I. , Anch A. Michael , Booth Glenn H. , Williams Robert L. , Salis Patricia J.
Published: January 2016

In a 13‐night sleep laboratory study, each of 18 normal young adult males twice received 1 cup of warm water, 1‐, 2‐, and 4‐cup equivalents of regular coffee, a 4‐cup equivalent of decaffeinated coffee, and a 4vcup equivalent of caffeine. All beverages were administered 30 min before bedtime according to a balanced Latin‐square design. Regular coffee produced dose‐related changes in most standard electroencephalogram‐electrooculogram (EEG‐EOG) sleep parameters, and the 4‐cup equivalents of regular cartee and caffeine produced equivalent effects. Decaffeinated coftee had no effect. Regular coffee and cqffeine caused rapid eye movement (REM) sleep to shift to the early part of the night and stages 3 and 4 sleep to shift to the later part. Coffee also produced dose‐related changes in several subjective estimates of sleep characteristics. These results suggest that coffee and caffeine may be used in normal subjects to induce symptoms mimicking those of insomnia. Such a tool should promote further understanding of insomnia.
Analgesic efficacy of an orally administered combination of pentazocine and aspirin; With observations on the use and statistical efficiency of GLOBAL subjective efficacy ratings
Authors: Calimlim J. F. , Wardell W. M. , Davis H. T. , Lasagna Louis , Gillies A. J.
Published: January 2016

The analgesic efficacy of a combination of pentazocine and aspirin (PA) in the ratio 1:13 was compared with that of 650 mg of aspirin alone (A650) and with placebo (PBO), in 98 patients with postoperative pain. Two dose levels of the combination were compared: the lower dose (PA‐L) consisted of pentazocine 25 mg and aspirin 325 mg, while the higher dose (PA‐H) consisted of pentazocine 50 mg and aspirin 650 mg. All active treatments performed significantly better than PBO. PA‐L performed as well as A650, while PA‐H performed significantly better than A650. In addition to the usual subjective measures of analgesia, we obtained in 74 patients an evaluation of the overall (GLOBAL) performance of the treatment. This was rated on an ordinal scale of 1 (“poor”) to 5 (“excellent”). On the GLOBAL scale, PBO had a mean score of 2.4 (fair‐good); A650 and PA‐L had scores of 3.6 and 3.9, respectively (good‐very good): and PA‐H had a score of 4.5 (very good‐excellent). In five of six comparisons between treatment means, GLOBAL had the best discriminating power of all six measures. In the two comparisons of greatest interest (A650 against PBO and PA‐H against A650), GLOBAL was more than twice as efficient as the TOTAL (summed pain score) measure. In comparing the statistical efficiency of different measures of the same analgesic effect, there is a problem in determining what are “clinically equivalent differences” on the various analgesic scales employed. We propose the use of the observed sample differences and the safeguard of repeating the comparisons over several studies to minimize the effect of random‐origin bias.
Spironolactone and hydrochlorothiazide in normal‐renin and low‐renin essential hypertension
Authors: Ferguson Roger K. , Turek Diann M. , Rovner David R.
Published: January 2016

The relative blood pressure response and side effects of spironolactone (S), 400 mg/day, and hydrochlorothiazide (H), 100 mg/day, were evaluated in a double‐masked crossed comparison. Subjects were 24 essential hypertensives, 13 normal and 11 with low renin activity. Upright renin levels were determined in the am after 3 days of moderately low sodium diet (<100 mEq/day) and at the end of each drug treatment period. The values were not revealed to one investigator until completion of the study. After 4‐week placebo control periods, either S or H was given in divided doses for 6 weeks. Blood pressure measurements and side effects were evaluated at biweekly intervals. The fall in blood pressure from control was the same for each drug and was independent of renin activity. Side effects occurred more often in patients treated with S, and H was judged superior by risk/benefit analysis. We conclude that S is no more beneficial than H in hypertensive patients with either low or normal renin activity but induces a higher incidence of adverse effects in the dose used in this study. We found no evidence for a greater effectiveness of S in low‐renin essential hypertension.
Control of clofibrate toxicity in uremic hypertriglyceridemia
Authors: Goldberg Andrew P. , Sherrard Donald J. , Haas Linda B. , Brunzell John D.
Published: January 2016

A daily dose of 1.5 to 2.0 gm of clofibrate lowers serum triglyceride (TG) levels in patients with normal renal function but causes muscle toxicity and elevated creatine phosphokinase (CPK) levels in patients with long‐term renal failure. Plasma clofibrate disappearance is prolonged as much as seven times normal in severely uremic patients. A marked reduction in the standard 14 gm/wk clofibrate dose to a total dose of 1.0 to 1.5 gm/wk effectively lowered serum TG levels (−28%, p < 0.02) in hypertriglyceridemic hemodialysis patients without toxicity. The serum clofibrate level at this dose was comparable to that in hypertriglyceridemic nonuremic patients receiving 14 gm/wk of clofibrate. The dose of clofibrate administered to hemodialysis patients can be adjusted to avoid toxicity and provide the desired therapeutic effect by monitoring serum CPK and TG levels.
Prolonged delta‐9‐tetrahydrocannabinol ingestion; Effects of sympathomimetic amines and autonomic blockades
Authors: Benowitz Neal L. , Jones Reese T.
Published: January 2016

In order to evaluate the possible effects of delta‐9‐tetrahydrocannabinol (THC) on autonomic nervous system function, cardiovascular responses to intravenous isoproterenol, phenylephrine, atropine, and propranolol were compared in hospitalized volunteers before and after 14 days of THC ingestion. There was no significant alteration in responses to isoproterenol or phenylephrine, although in one subject the pressor effect of phenylephrine was considerably augmented by THC. Heart rates after parasympathetic (atropine) blockade and after combined parasympathetic and sympathetic (propranolol) blockade were significantly greater during THC ingestion. These and other data presented are consistent with the picture of reduced sympathetic and enhanced parasympathetic activity described in animals on THC. During THC ingestion, atropine had a pronounced pressor effect, which might represent a clinically significant drug interaction.
Free‐living volunteer's motivations and attitudes toward pharmacologic studies in man
Authors: Hassar M. , Pocelinko R. , Weintraub M. , Nelson Dorothy , Thomas Gordon , Lasagna L.
Published: January 2016

Two groups of volunteers who had participated in pharmacologic studies were interviewed about their motivation and their impressions of such studies. One group was from a university community, the other from the pharmaceutical industry. The differences between the two groups were correlated with their respective backgrounds. Both groups had favorable impressions about drug studies and investigators. Most were satisfied with the information given them about the nature and risks of the studies. but some believed that a written description of the study that they could consult at home would improve their understanding of the information. Financial reward was the primary reason given by both groups for volunteering, but the perceived risk of the study was the ultimate deciding factor. The volunteers disliked having their mobility restricted and for this reason might not be willing to participate in long‐term studies, such as those formerly carried out in prisons. Alternative sources of volunteers for long‐term studies will have to be found.
Spironolactone and canrenoate‐K: Relative potency at steady state
Authors: Ramsay Lawrence , Asbury Michael , Shelton John , Harrison Ian
Published: January 2016

Relative dose ratios of the mineralocorticoid antagonists spironolactone (100 mg and 200 mg daily) and canrenoate‐K (200 mg daily) at steady state were defined in six healthy subjects with fiudrocortisone as the mineralocorticoid agonist. The urine log 10 Na/K responses during spironolactone treatments were consistent with the law of mass action. The potency of canrenoate‐K was 0.68 (95% C.L. 0.53 to 0.89) that of spironolactone on a weight basis. Approximately 72% of the renal antimineralocorticoid activity of spironolactone could be attributed to the metabolite canrenone. The results at steady state are contrasted with those of a previous study comparing single doses of spironolactone and canrenoate‐K.
Variations in the fate of triamterene
Authors: Pruitt Albert W. , Winkel Joan S. , Dayton Peter G.
Published: January 2016

Triamterene is a pteridine used therapeutically as a diuretic. In order to better understand variations in effect and toxicity of triamterene in individuals, the fate of the drug in man was investigated. Both nonradioactive and 14C‐labeled forms of the drug were administered, and specific methods of analysis were used to separate the parent compoundJrom its metabolite. Individual variation in absorption, binding, and elimination was noted. The drug was excreted in bile as well as urine. Rapid and extensive metabolism of the agent occurred after oral and intravenous doses in healthy adult men. The peak plasma levels of the drug after an oral dose (200 mg) were under 0.3 µg/ml, but the concentration of the primary metabolite (2,4,7‐triamino‐6‐p‐hydroxyphenylpteridine) was higher. The urinary excretion of the metabolite was at least three times that of the parent drug.
Absorption and metabolism of lanatoside C; II. Fate after oral administration
Authors: Aldous Stephen , Thomas Richard
Published: January 2016

The absorption, metabolism, and excretion of lanatoside C were studied in hospitalized subjects following oral administration of the tritiated drug. Previous reports of an unusual double peak in plasma levels of radioactivity were confirmed. Fifty plasma samples taken from 31 patients showed that an average of 74% of the radioactive material was digoxin and its metabolites. There was little or no lanatoside C in 36 of the 50 samples of plasma. Similar results were obtained for urine radioactivity. The results confirm that lanatoside C is converted to “digoxin” in the gut prior to absorption as previously proposed by us. “Digoxin” refers to digoxin and its breakdown products, namely, digoxigenin and its mono‐ and didigitoxosides. According to these proposals, the conversion to “digoxin” takes place partly as a result of acid hydrolysis in the gut and partly by the action of bacteria in the intestine. The effects of concurrent administration of antacid therapy, anticholinergic therapy, and food on the fate of oral lanatoside C were separately studied. There were no significant differences between groups with respect to the amount of radioactive material absorbed or excreted, but there were marked qualitative differences in the plasma profiles. There was a statistically significant increase in the time to the first peak in plasma radioactivity in patients concurrently receiving either food or anticholinergic therapy and there was a significant decrease in the relative height of the first peak in patients treated concurrently with antacid.
Beta‐2 adrenoceptor blocking activity of penbutolol and propranolol at very low doses
Authors: Kulkarni Ramesh D. , DaSilva Lexley M. , Chabria Nari L. , Chadha Dev R.
Published: January 2016

The relative potency of penbutolol, a new β adrenergic receptor blocking agent, was compared with propranolol by a four‐point assay on healthy male subjects. A dose‐response relationship to intravenous doses of propranolol in the microgram range was obtained during a steady state of infusion of epinephrine. Two subjects underwent the entire assay according to the Latin square design and four others each underwent one schedule of design on different days. The potency of penbutolol thus assessed was consistent with reported results. This study emphasizes the importance of intersubject variation and differential receptor sensitivity in individuals. The use of epinephrine as a β receptor adrenergic agonist for evaluation of selective β adrenergic receptor blocking activities is discussed.
Diuretic therapies in low renin and normal renin essential hypertension
Authors: Brooks Charles S. , Johnson Curtis A. , Kotchen Jane M. , Kotchen Theodore A.
Published: January 2016

This study was designed to compare the effectiveness of spironolactone, hydrochlorothiazide, and combined spironolactone‐hydrochlorothiazide therapy in patients with low renin and those with normal renin essential hypertension. Patients with low renin hypertension had a greater hypotensive response to each regimen (p < 0.001). Low renin patients responded equally to both spironolactone and to hydrochlorothiazide, and in low renin but not in normal renin patients reduction of blood press ure correlated with weight loss. These results suggest that a volume factor, not specifically related to increased mineralocorticoid production, contributes to the pathogenesis of low renin essential hypertension.
Alteration of plasma albumin in relation to decreased drug binding in uremia
Authors: Soobis Susan W.
Published: January 2016

The binding of sulfadiazine in the plasma of normal and uremic subjects was measured by means of an ultrafiltration technique. Patients with uremia had reduced binding of sulfadiazine due to decreased albumin‐binding capacity. No conclusive evidence was found to suggest that reduced drug binding in uremia is caused by competing metabolites. Studies of purified normal and uremic albumin revealed differences in amino acid composition and variations in the protein content of the two albumin bands found on isoelectric focusing. It is suggested that decreased drug binding in uremia may be at least partly due to altered albumin composition,
Diuretic effect and metabolism of bumetanide in man
Authors: Halladay Steven C. , Sipes I. Glenn , Carter Dean E.
Published: January 2016

Bumetanide (3‐N‐butylamino‐4‐phenoxy‐5‐sulfamyl‐benzoic acid) is a sulfonamide congener with potent diuretic activity in man. Oral administration of 14[;‐bumetanide (2 mg, 22 t‐LCi) to 4 adult male volunteers was rapidly and almost completely absorbed (>95%). Its average apparent volume of distribution was 25 L. Bumetanide induced a ceiling diuresis at 1 hr, with loss of Na+ and water for 4 to 5 hr. Loss ofK+was minimal. Bumetanide was quickly eliminated by metabolism and urinary excretion with a plasma half‐life of 1.5 hr. The administered radioactivity was almost completely recovered (96%),81% appearing in the urine and the remainder in thefeces. In one subject with biliary T tube, 14.4% of the dose was excreted in the bile which suggested that the radioactivity of the feces came from the bile. Thin‐layer chromatography analysis ofpooled urine, bile, and fecal samples showed the elimination of bumetanide could be explained by excretion oI unchanged drug and side chain oxidative metabolism and conjugation.
Metabolism of flurazepam by the small intestine
Authors: Mahon W. A. , Inaba T. , Stone R. M.
Published: January 2016

The metabolism offiurazepam‐5‐14C has been studied in man following catheterization of the portal and hepatic veins. Flurazepam was administered through a tube into the stomach in one patient and into the duodenum in two patients. Thin‐layer chromatographs of portal vein blood showed that there was a rapid and early appearance of metabolites offiurazepam consistent with the metabolism of the flurazepam by the intestinal mucosa and at times when the concentrations in the hepatic vein and peripheral blood were very much lower than those in the portal vein. The major metabolites identified in portal vein blood were the mono‐ and didesethyl metabolites offiurazepam. Considerable hepatic uptake offlurazepam and its metabolites occurred, as evidenced by the lower concentrations of the parent compound and metabolites in the hepatic vein. Thus, “first‐pass” metabolism offiurazepam following oral administration occurs in the small bowel mucosa of man as well as in the liver.
Leukocyte cyclic adenosine monophosphate in asthmatic children Effects of adrenergic therapy
Authors: Morris Helen G. , Rusnak Stuart A. , Barzens Kathy
Published: January 2016

Blood specimens for measurement of leukocyte cyclic adenosine monophosphate (AMP) were obtained at weekly intervals from asthmatic children who were participating in a double‐blind, crossover study to compare the effects of two adrenergic agents and a placebo. When patients were treated with the placebo, the basal measurements and the cyclic AMP responses of leukocytes to in vitro stimulation with epinephrine (10‐ 4 M) were similar to those of normal subjects but within one week after initiation of treatment with an adrenergic bronchodilator, leukocyte cyclic AMP responses to adrenergic stimulation in vitro decreased and remained low during the remainder of the treatment period. Within one week after discontinuation of adrenergic therapy, leukocyte cyclic AMP responses returned to the control level. Our results indicate that the alterations in leukocyte cyclic AMP metabolism which have been observed previously in asthmatic patients may result from medications used for treatment of asthma.
Renal clearance and tissue accumulation of gentamicin
Authors: Schentag Jerome J. , Jusko William J.
Published: January 2016

Multiple‐dose studies of gentamicin pharmacokinetics were performed in 2 treated patients. After the final dose, serum and urine concentration declined in biphasic fashion with beta ha(f‐lives of 87 and 173 hr. Recovery of the total dose administered required urine collection for at least 10 to 20 days after the last dose. A two‐compartment model was used to describe the biphasic decline in serum concentrations, to simulate all measured concentrations during treatment, and to predict the amount of gentamicin in the tissue compartment. Analysis of autopsy tissues yielded the predicted amount of drug. A linear two‐compartment model adequately quantitates gentamicin disposition until about 4 days after cessation of therapy when gentamicin renal clearance begins to decline because of tubular reabsorption.
The pharmacokinetics of [3H]‐vincristine in man
Authors: Bender Richard A. , Castle Manford C. , Margileth David A. , Oliverio Vincent T.
Published: January 2016

The pharmacokinetics, metabolism, and excretion of aromatically labeled tritiated vincristine (VCR) was examined in 4 patients. Clearance of radioactivity from the blood was triphasic with half‐life tV2 values of 0.85, 7.4, and 164 min. The initial phases probably represent distribution and binding to formed blood elements which exceeded 50% of the administered dose by 20 min. Excretion of radioactivity was principally fecal, with 33% recovered in the feces by 24 hr and 69% by 72 hr. Considerably less radioactivity (12%) was excreted in the urine over the 72‐hr period. Approximately 40% of fecally excreted and 46% of urinary excreted radiolabel represented metabolites, which suggests that at least 34% of the VCR dose was excreted as metabolites. Plasma metabolites represented from less than 1 % to 30% or more of radioactivity in plasma. Ultraviolet spectral analysis of all metabolites revealed preservation of the intact VCR dimer, which suggests that metabolism involves alteration of side groups.
Antihypertensive and biochemical effects of chlorthalidone
Authors: Tweeddale Martin G. , Ogilvie Richard I. , Ruedy John
Published: January 2016

Thirty‐seven patients with mild to moderate essential hypertension completed a dose‐finding study in which daily doses of 25, 50, 100, and 200 mg of chlorthalidone were administered in random order for 8 wk. Active treatment periods were double‐blind and were interspersed with single‐blind placebo intervals which lasted until control blood pressure values were regained. The four doses of chlorthalidone produced similar hypotensive effects, but changes in serum potassium, chloride, and uric acid were clearly related to the dose of chlorthalidone. The reduction in blood pressure was maximal in 25 of the patients on a dose of 25 or 50 mg of chlorthalidone, while maximal reduction was observed in the remaining 12 patients on doses of 100 or 200 mg. The response of an individual to chlorthalidone could not be predicted. Chlorthalidone was well tolerated as evidenced by an acceptable level of compliance and by the relative infrequency with which side effects were reported. On the basis of this study approximately two thirds of patients with mild to moderate hypertension can be expected to respond to 50 mg or less chlorthalidone daily. Such doses are associated with minimal biochemical changes. Some patients failing to respond to low doses of chlorthalidone may respond to higher doses, but these frequently induce biochemical disturbances.
Nifedipine, a new antihypertensive with rapid action
Authors: Guazzi Maurizio , Olivari Maria T. , Polese Alvise , Fiorentini Cesare , Magrini Fabio , Moruzzi Paolo
Published: January 2016

Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered sublingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176189 and to 47/19 mm Hg by an additional 10 mg.
Mechanisms of inhibition of tolbutamide metabolism: Phenylbutazone, oxyphenbutazone, sulfaphenazole
Authors: Pond Susan M. , Birkett Donald J. , Wade Denis N.
Published: January 2016

Tolbutamide half‐life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n =2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within I to 2 hr of a single dose of sulJaphenazole and the tolbutamide half‐life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing a form of cytochrome P‐450 with low activity for tolbutamide hydroxylation. whereas sulJaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.
Effect of malnutrition on the metabolism of sex hormones in man
Authors: Fishman Jack , Bradlow H. Leon
Published: January 2016

The effects of caloric deprivation and accompanying body weight loss on gonadal hormone metabolism were studied in young women with anorexia nervosa. In these patients serving as models of uncomplicated malnutrition, the biotransformation of labeled testosterone and estradiol was followed after intravenous injection of these hormones. The metabolite distribution pattern is affected by thyroid status. All of 8 anorexia nervosa patients in whom testosterone metabolism was studied had low plasma Ta and borderline T4 levels, along with substantial deviation from normal body weight. The androsterone to etiocholanolone (A/E) ratio was greatly diminished, precisely as expected from a hypothyroid state, although these patients, lacking classic symptomatology, were not hypothyroid. Three of these patients restudied after administration of T3 showed a reversal of direction of testosterone metabolism, i.e., more than a doubling of the 5a to 5β ratio. During spontaneous remission from the disease and progressive weight gain, the plasma T3 rose and the AlE ratio increased. In 7 patients with anorexia nervosa, the metabolism of estradiol was compared with that of normal weight control subjects and of 4 obese patients. In the malnourished patients the formation of 2‐hydroxyestrone was markedly greater than in the other 2 groups, while estriol production was significantly diminished. In the obese subjects estriol formation increased and catecholestrogen production decreased. These opposite trends in anorexic and obese patients suggest that the metabolic alteration of estradiol is a consequence of low body weight and food intake and not the result of other factors specific to anorexia nervosa. It is concluded that the changed estradiol metabolism in anorexia nervosa is not the result of the thyroid status in these subjects, and it is speculated that the distortion of estradiol metabolism is attenuated by the biochemical hypothyroidism accompanying malnutrition. This results in a diminution of estrogenic activity of the endogenous estradiol which may accentuate the consequences of the decreased production of the hormone in this disease.
Obesity and fasting—effects on drug metabolism and drug action in man
Authors: Reidenberg Marcus M.
Published: January 2016

Drug metabolism and distribution were studied in severely obese subjects who underwent a 2‐wk fast as part of a weight reduction program. Drug studies were done before fasting and repeated during the fast after ketoacidosis had developed and weight loss had occurred. The half‐life values of 5 drugs—antipyrine and tolbutamide metabolized by the microsomal oxidation pathway, sulfisoxazole and isoniazid by acetylation, and procaine by the pseudocholinesterase hydrolysis pathway—were found to be normal in the obese but otherwise healthy subjects when allowance was made for the body weight. The dose‐response curve, as demonstrated by the effect of atropine, 0.24 mg every 4 min given intravenously, on the heart rate was the same in obese as in normal weight subjects when the dose was calculated on a weight basis. The apparent volumes of distribution of antipyrine and tolbutamide and the metabolic clearance rates were normal, again if corrected for body size. In some patients (those with edema) a discontinuity was noted in the plasma elimination curve of tolbutamide, apparently because of a decrease in the volume of distribution of this protein‐bound drug when the subjects changed from the recumbent to the sitting position. The same effect had been reported by others with protein‐bound sulfonamides and benzylpenicillin during change from the recumbent to the upright posture, an effect to be considered in interpreting pharmacokinetic data. Fasting for 7 to 10 days decreased the volume of distribution in proportion to the loss of weight and body water. The excretion rate of sulfisoxazole was decreased by fasting, one reason being that fasting caused a decrease in urine flow rate and a fall in pH, both favoring nonionic diffusion of the drug from the renal tubule back to the blood. Regardless of the different transformation pathways, the rate of metabolism of the drugs studied remained unchanged by fasting. This observation is in sharp contrast to changes seen in laboratory animals, varying with the species, sex, and drug substrate used among other factors. Extrapolations of data from species to species concerning the effects of fasting on drug metabolism may, therefore, lead to erroneous conclusions.
Drug metabolism in heavy consumers of ethyl alcohol
Authors: Iber F. L.
Published: January 2016

Data are presented on the rate of removal of tolbutamide from the blood from studies in heavy drinking, unemployed, male alcoholic subjects. In such subjects tolbutamide was removed faster than it was in normal subjects and faster than in patients with cirrhosis who are not drinking. This rapid removal rate persists for 4 to 9 wk after hospitalization and is reproduced with 400 gm of pure ethanol in 2 or 3 wk but cannot be reproduced with lesser amounts of beverage alcohol taken outside of the experimental study. Similar acceleration of the clearance rates was observed for warfarin and for phenytoin but could not be demonstrated for aminopyrine.
Noninvasive monitoring of β‐adrenergic tone during isoproterenol infusions
Authors: Easley Ronald B. , Rodbard David
Published: January 2016

Sphygmo‐Recording is a simple, noninvasive technique for analysis of pulse wave contour and timing which has been used to evaluate the change in cardiac dynamics during isoproterenol infusion. The QKd interval, i.e., the time interval between the onset of the QRS complex and the onset of the KorotkojJ sound at the brachial artery when the sphygmomanometer cuff is at diastolic pressure, is normally 205 ± 15 msec. Continuous intravenous infusion of isoproterenol at 0.01, 0.02, and 0.03 ug /kg /min into 12 euthyroia normotensive adult volunteers for 10‐min intervals resulted in decreases of 55, 79, and 89 msec in QKd and increases of heart rate of 14, 27, and 43 beats/min, respectively. The corresponding changes in dP/dt, i.e., slope of the pulse wave upstroke at the brachial artery determined noninvasively from the same records, were 0.65, 1.47, and 2.26 mm Hg/msec. These results confirm previous studies which indicate that the chronotropic response of normal subjects to isoproterenol infusion is comparable to that previously reported in patients with the putative “hyperdynamic β‐adrenergic state.”
Amitriptyline plasma levels and clinical response in primary depression
Authors: Kupfer David J. , Hanin Israel , Spiker Duane G. , Grau Thomas , Coble Patricia
Published: January 2016

Sixteen patients with primary depression were treated for 4 wk with amitriptyline. After clinical diagnoses were determined, patients entered a double‐blind protocol (amitriptyline or placebo) and their clinical status was determined with the Hamilton Depression Rating Scale by raters blind to the drug type, its dosage and plasma levels. Amitriptyline (AT) and nortriptyline (NT) plasma levels were assayed twice weekly by gas chromatography‐mass spectrometry. In the 16 patients, a negative correlation between the Hamilton Score and the mean total tricyclic level (p < 0.01), as well as with individual plasma levels, was found at the end of the treatment period. When the group was divided into clinical responders and nonresponders, the mean total tricyclic (AT + NT) levels discriminated the two groups by day 12 (p < 0.001) as well as at the end of the protocol (day 26, 88% of the patients were classified correctly if an arbitrary level of200 ng/ml total tricyclic plasma level was chosen). These results strongly suggest the presence of a positive correlation between plasma levels and clinical improvement in patients with primary depression.
Salivary excretion and pharmacokinetics of sulfapyridine after sulfasalazine
Authors: Bates Theodore R. , Blumenthal H. Peter , Pieniaszek Henry J.
Published: January 2016

The concentrations of sulJapyridine (SP) and N4‐acetylsulJapyridine (AcSP) in the plasma and saliva of 5 healthy male adults (3 slow and 2 rapid acetylators) were determined as a function of time after a single 2.0‐gm oral dose of sulJasalazine (salicylazosulJapyridine). SP absorption commenced 3.5 to 6 hr after sulJasalazine administration and occurred slowly (apparent absorption tlhs rangedfrom 1.6 to 5 hr) irrespective of acetyl at or phenotype. Appreciable differences existed between slow and rapid acetylators with respect to the biologic tlh and total body clearance of SP. SP concentrations in the saliva correlated well with those in the plasma. The saliva: plasma concentration ratio for SP was 0.559 ± 0.027 (mean of 5 subjects ± SE) and was independent of plasma concentration and saliva pH. The mean saliva: plasma concentration ratio for AcSP was lower (0.246 ± 0.056), consistent with the pH‐partition hypothesis, and showed considerably more intrasubject and intersubject variation than the ratio for SP. These findings suggest that measurement of SP concentrations in the saliva may be a convenient, noninvasive method for monitoring indirectly the steady‐state plasma (serum) concentrations of SP in patients with ulcerative colitis or Crohn's disease who are receiving sulJasalazine.
Antihypertensive and β‐adrenoceptor antagonist action of timolol
Authors: Simon Geza , Kiowski Wolfgang , Julius Stevo
Published: January 2016

After a 4‐wk placebo period, 20 patients with essential hypertension received incremental doses of timolol (20, 40, and 60 mg daily) during three consecutive 3‐wk treatment periods. Throughout the study, home blood pressures (BP) were obtained twice daily. At the end of each study period, plasma renin activity (PRA), the maximum heart rate (RR) response to isoproterenol (30 ng/kg/min) and to ergometric exercise (750 to 1,050 kgm/min), and serum timolol levels were measured. Average weekly home BP of 150/100 on placebo fell to 139193 on 20 mg of timolol (p < 0.01). An additional fall in diastolic BP (4 mm Hg, p < 0.01) occurred as the dose was increased to 60 mg. PRA, 2.6 ng/ml/hr on placebo decreased to 1.2 on 20 mg of timolol (p < 0.05); thereafter it did not change. The mean maximum heart rates in response to isoproterenol and exercise were 117 and 158 beats/min on placebo; the maximum rates were 64 and 112 when the patients were receiving 20 mg of timolol (p < 0.001). On 60 mg, mean maximum heart rates decreased to 57 with isoproterenol and to 104 with exercise (p < 0.02). Timolol, 20, 40, and 60 mg daily, resulted in a wide range but increasing serum concentrations of the drug. The antihypertensive effect of timolol did not correlate with the fall in PRA. PRA and the maximum HR response to isoproterenol on placebo did not predict the BP response to timolol. That PRA was not predictive of the BP response cannot be taken as conclusive because of small number of low renin patients (3) in our series.
Optimal phenytoin therapy: A new technique for individualizing dosage
Authors: Mullen Peter W.
Published: January 2016

A simple, new technique (the direct linear plot) for predicting steady‐state serum phenytoin concentrations is described. Although no calculations are required, reliable estimates (comparable with those derived by computer) of the Michaelis‐Menten parameters can be readily determined and used graphically to predict the individualized dose required to achieve a desired serum concentration.
Hemodynamic and respiratory effects of morphine and butorphanol
Authors: Popio Kenneth A. , Jackson Donald H. , Ross Andrew M. , Schreiner Bernard F. , Yu Paul N.
Published: January 2016

The hemodynamic effects of butorphanol, a potent synthetic narcotic‐antagonist analgesic, were investigated and compared with those of morphine. A total of 20 patients were studied (8 butorphanol, 12 morphine) at the time of diagnostic cardiac catheterization. Butorphanol decreased pH, PCO2, and systemic artery pressure and increased PCO2, cardiac index, and pulmonary artery pressure. Morphine caused similar changes in pH, PO2, systemic artery pressure, and PCO2 but much smaller changes in cardiac index and no change in pulmonary artery pressure. The clinical implications and possible mechanisms are discussed.
High plasma nortriptyline levels in the treatment of depression. I
Authors: Montgomery Stuart , Braithwaite Robin , Dawling Sheila , McAuley Rosanna
Published: January 2016

Following a 3‐day single‐dose kinetic study, 21 moderate to severely depressed inpatients were treated with 100 mg of nortriptyline nightly. Eighteen patients completed the 4‐wk trial. The severity of depression was measured by weekly Hamilton Rating Scale and global rating. Blood for plasma nortriptyline estimation was taken at weekly intervals 12 hr following the nighttime dose. There was a 610ld variation in mean plasma nortriptyline levels, ranging from 120 µg/L to 681 µg/L. Patients with high plasma levels (<200 µg/L) showed significantly poorer clinical responses than those with levels below this limit. This study provides very strong support for the view that, in routine treatment, high plasma nortriptyline levels are significantly less effective than intermediate levels. Single‐dose pharmacokinetic data obtained on the same patients showed a highly significant correlation with mean steady‐state plasma levels obtained, which themselves correlated with clinical response. The value of predicting high plasma nortriptyline levels which are associated with poor response is discussed.
Kinetics of carbamazepine and carbamazepine‐epoxide, determined by use of plasma and saliva
Authors: Westenberg Herman G. M. , van der Kleijn Eppo , Oei Tiauw T. , de Zeeuw Rokus A.
Published: January 2016

The concentration‐time curves of carbamazepine (CBZ) and its metabolite (carbamazepine‐10,11‐epoxide; CBZ‐epoxide) were determined in patients undergoing long‐term antiepileptic drug treatment with the use of plasma and saliva data. Plasma and saliva samples were assayed concurrently for each patient by liquid chromatography. There was excellent linear correlation between CBZ levels in saliva and plasma (r = 0.991, p < 0.001) over a large concentration range. The saliva/plasma ratio for CBZ concentration was 0.26 ± 0.01 (SD). Since CBZ binding to plasma proteins is in the order of 76%, saliva CBZ concentration seems to reflect the unbound fraction of the drug in plasma. CBZ‐epoxide has not been detected in saliva. The pharmacokinetic parameters of CBZ‐epoxide were determined in 6 patients. The pharmacokinetic parameters of CBZ obtained from saliva concentrations were in excellent agreement with those obtained from plasma concentrations. Thus, CBZ determination in saliva is convenient for controlling blood levels in patients as well as for studying pharmacokinetics. The half‐life, the relative body clearance of CBZ, and the metabolite concentration during steady‐state, expressed as percent the parent compound, appear to be significantly different in patients on single and combined drug therapy.
Fluoride bioavailability after intravenous and oral administration: Importance of renal clearance and urine flow
Authors: Ekstrand Jan , Ehrnebo Mats , Boréus Lars O.
Published: January 2016

Fluoride (3 mg) was administered as a continous intravenous infusion during 30 min to 6 healthy subjects. Plasma concentrations and urinary excretion of fluoride in these experiments were compared with those obtained following oral administration of 2.82 mg, 4.50 mg, 5.64 mg, and 9.40 mg in the form of tablets and capsules. There were large day‐to‐day variations in the renal clearance of fluoride. This was shown to be due to differences in the urinary flow, an increase in flow causing an increase in renal clearance. The mean value of renal clearance from all experiments was 66.2 ± 27.8 (SD; n = 16) mllmin. The extrarenal clearance, suggested to represent mainly the clearance to the bone pool, showed less interindividual variation: mean 110.3 ± 32.3 (SD; n = 6) ml/min; the fraction remaining in the bone pool was highly consistent: 0.579 ± 0.049 (SD; n = 6). When apparent bioavailability was calculated from plasma and from urinary data, there was a great intra‐ and intersubject variation, as well as poor agreement between the two methods of calculations. This was found to be due to the day‐to‐day variation in renal clearance, which, in turn, varied with urinary flow. By use of equations that corrected for these variations, it was found that the bioavailability of sodium fluoride tablets is approximately 100%.
Gastrointestinal microbleeding after aspirin and naproxen
Authors: Lussier André , Arsenault André , Varady John
Published: January 2016

Gastrointestinal bleeding is the most serious side effect encountered with the anti‐inflammatory antirheumatic drugs. Using the 51Cr labeling technique, the comparative quantity of blood loss with aspirin or naproxen has been previously done on normal volunteers. With the present study, 12 rheumatoid arthritic patients were controlled in a double‐blind crossover study with the same radioactive technique. There is a difference in favor of naproxen. The difference between the baseline period and naproxen administration was not statistically significant.
Theophylline disposition in obesity
Authors: Gal Peter , Jusko William J. , Yurchak Anthony M. , Franklin Barry A.
Published: January 2016

Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high‐pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on lBW in normal and obese subjects indicates that lBW should be used to calculate maintenance doses for theophylline. Mean half‐lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.
Effect of aspirin on exercise‐induced angina
Authors: Davis James W. , Lewis H. Daniel , Phillips Phyllis E. , Schwegler Raymond A. , Yue Kenneth T. N. , Hassanein Khatab R.
Published: January 2016

Suspecting that platelet thromboemboli could playa role in the pathogenesis of myocardial ischemia, we did a random‐order, double‐blind, crossover study of the effect of the platelet aggregation inhibitor, aspirin, on treadmill exercise‐induced angina in 13 men with coronary artery disease. Although collagen‐induced platelet aggregation and the second phase of adenosine diphosphate (ADP)‐induced platelet aggregation were significantly decreased and the rate of disaggregation of ADP‐induced platelet aggregates was significantly increased after 650 mg aspirin in buffered solution, there was no delay in onset of exercise‐induced angina, change in heart rate‐blood pressure product at onset of angina, or change in S‐T segment depression at onset of angina. Regardless of whether the patients had received placebo or aspirin on the preceding day, treadmill exercise until angina was followed by no changes in platelet aggregation or disaggregation, platelet count in blood or platelet‐rich plasma, or of the plasma concentration of nonesterified fatty acids.
Suppression of renal excretion of digoxin in hypokalemic patients
Authors: Steiness Eva
Published: January 2016

Inulin and digoxin clearances were simultaneously measured in 19 normokalemic and 4 hypokalemic patients. In normokalemia the renal digoxin clearance exceeded the inulin clearance, indicating both glomerular filtration and active tubular secretion of digoxin. The tubular secretion increased with increasing plasma digoxin concentration. In hypokalemia, however, the tubular secretion of digoxin was significantly reduced but increased after the plasma potassium level was raised to normal.
Allopurinol kinetics
Authors: Hande Kenneth , Reed Eddie , Chabner Bruce
Published: January 2016

A spectrophotometric assay for measuring allopurinol and oxipurinol has been developed which can detect as little as 5 × 10−8 M of each in serum and urine. With this assay, serum disappearance characteristics of intravenous and orally administered allopurinol have been investigated in man. Serum concentrations of both allopurinol and oxipurinol reach levels above 1 × 10−5 M within minutes of intravenous administration and within 1 or 2 hr of oral administration of 300 mg allopurinol. Patients receiving 300 mg allopurinol daily show a mean serum concentration of 3 × 10−5 M oxipurinol (range, 0.9 to 9 × 10−5 M). Serum half‐lives of allopurinol and oxipurinol were 39 ± 11 min and 13.6 ± 2.8 hr, respectively. Estimates of renal clearance were 13.6 and 18.9 mllminfor allopurinol and 23.2 and 30.6 ml/min for oxipurinol in 2 patients studied. The metabolic conversion of allopurinol to oxipurinol in man does not appear to be altered by long‐term therapy with allopurinol, which suggests that this conversion takes place by way of an enzymatic reaction not strongly inhibited by either substrate or product. These results suggest the possibility of a nonxanthine oxidase enzymatic pathway for this conversion.