bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of 4‐hydroxy‐alprenolol to adrenergic beta receptor blockade of alprenolol
Authors: Collste Per , Borg Karl-Olof , Åström Hans , von Bahr Christer
Published: January 2016

Alprenolol, like propranolol, is metabolized to a 4‐hydroxy derivative. This study was performed in 6 human volunteers to determine the potency of the metabolite in relation to that of alprenolol with respect to reduction of exercise‐induced tachycardia. The metabolite reached higher plasma levels than alprenolol during the first hours after both single and repetitive oral doses of alprenolol but was not detected in plasma after an intravenous dose. The plasma elimination half‐life for 4‐hydroxy‐alprenolol was one‐third that for alprenolol (0.8 hr and 2.5 hr, p < 0.01). Percentage reduction of exercise heart rate and total plasma levels of alprenolol after a 10‐mg intravenous dose correlated (r = 0.56, p < 0.01). This was generally higher within individuals, since the responsiveness to unchanged alprenolol differs among subjects. The effect‐concentration relationship was slightly higher (r = 0.67) when non‐protein‐bound alprenolol was substituted for total alprenolol. 4‐Hydroxy‐alprenolol contributed to the effect after oral administration of alprenolol; total plasma levels were equipotent with alprenolol. It is concluded that the contribution of the metabolite to effect varied among individuals and was dependent on mode of administration (intravenous or oral), dose, and time after dosage. We also introduce an approach to the evaluation of the activity of drug metabolites in the presence of the parent compound.
Renal sites of action of azosemide
Authors: Brater D. Craig
Published: January 2016

Azosemide is a new monosulfamyl diuretic with potency and spectrum of effects similar to those of furosemide. Eight normal subjects were studied with clearance techniques during water loading and during hydropenia to assess azosemide's site of action. Solute free water reabsorption decreased from 3.1 ± 0.3 to 0.5 ± 0.9 ml/min after azosemide (p < 0.05), indicating an effect of azosemide at the ascending limb of the loop of Henle. During water loading, despite significant 3.5‐fold increases in fractional excretion of sodium and chloride, the per cent increase in free water formation, CH20/CIN × 100 was not significantly changed by azosemide (10.4 ± 1.4 control and 14.8 ± 3.1 after azosemide). This unchanged CH20/CIN × 100 occurred despite increased osmolal clearance after azosemide, from 2.6 ± 0.4 to 3.8 ± 0.4 ml/min (p < 0.02), indicating that azosemide increased delivery of solute to the diluting segment. Evidence is discussed which implies that azosemide inhibits solute transport of the thick ascending limb of the loop of Henle, but may also affect more proximal sites.
Azosemide, a “loop” diuretic, and furosemide
Authors: Brater D. Craig , Anderson Shirley A. , Strowig Suzanne
Published: January 2016

Azosemide is a new monosulfamyl diuretic which inhibits solute transport throughout the thick ascending limb of the loop of Henle. This study compared equal amounts of azosemide and furosemide (20, 40, and 80 mg) in normal subjects. No differences occurred at any dose in volume, sodium, or chloride excretion when analyzed as cumulative excretion at 4, 8, or 12 hr. Azosemide 40 mg caused less potassium excretion than 40 mg of furosemide but there was no significant difference in the sodium/potassium excretion ratio. Analysis of the time course of effect showed that compared to furosemide azosemide tended to have a slower onset of effect. Differences in site of action studies between azosemide and furosemide did not manifest as differences in urinary or electrolyte excretion in our normal subjects.
Caffeine metabolism in the newborn
Authors: Aldridge A. , Aranda J. V. , Neims A. H.
Published: January 2016

The concentrations of caffeine and metabolites in urine have been examined as a function of age to explore the remarkably slow elimination of caffeine by human infants. Urine samples were obtained from 3 adults and 10 infants aged 8 days to 8 months during therapeutic treatment with caffeine. A high‐performance liquid chromatographic (HPLC) procedure involving reversed‐phase partition chromatography was developed to separate caffeine and 13 of its metabolites. During the first month of life, caffeine accounted for more than 85% of the identifiable products in urine. Caffeine remained the predominant component for the first 3 months, but its precentage decreased gradually to the adult value of less than 2% by the age of 7 to 9 months. This change reflected increasing metabolite production, not decreasing urinary caffeine concentration. The adult metabolite pattern of partially demethylated xanthines and urates was attained by 7 to 9 months. The data indicate that the 4‐day plasma t½ of caffeine characteristic of the newborn depends in large part on slow urinary excretion of unchanged drug since there is little or no metabolism. Subsequent decrease in the t½ to about 4 hr by the age of 8 months correlates closely with the rise in metabolite production.
Cocaine metabolism: Cocaine and norcocaine hydrolysis by liver and serum esterases
Authors: Stewart D. J. , Inaba T. , Lucassen M. , Kalow W.
Published: January 2016

The hydrolysis of cocaine and its N‐demethylated product, norcocaine, by esterases was examined in liver and serum. Both liver and serum enzymatically formed ecgonine methyl ester from cocaine. The liver enzyme had a much lower affinity for cocaine than that of serum, indicating that a different form of esterase was present in liver. The liver enzyme had a similar affinity for both norcocaine and cocaine. Likewise, the serum enzyme showed similar affinities for both substrates. The Vmax estimates, however, were consistently higher for norcocaine than cocaine in both liver and serum. Benzoyl ecgonine, a major metabolite of cocaine formed by hydrolysis, was not produced enzymatically in either serum or liver; the rate of spontaneous formation at physiological pH suggests that this metabolite may arise nonenzymatically in the body.
Effect of disulfiram on adrenergic function
Authors: Rogers Walter K. , Benowitz Neal L. , Wilson K. Margaret , Abbott Joseph A.
Published: January 2016

Disulfiram inhibits dopamine β‐hydroxylase activity, and in animals dopamine (3‐hydroxylase activity becomes rate‐limiting in norepinephrine synthesis. It has been suggested that altered synthesis disturbs adrenergic function and plays a role in the hypotensive aspect of the ethanol‐disulfiram reaction in man. We evaluated adrenergic function in 7 normal subjects before and during disulfiram administration, 500 mg/day orally, for 2 wk. Urinary excretion of vanilmandelic acid (VMA) (5.8 ± 0.45 to 2.8 ± 0.31 mgl24 hr, p < 0.01) and norepinephrine (37.8 ± 6.5 to 16.3 ± 2.9 µg/24 hr, p < 0.02) decreased, whereas homovanillic acid (HVA) (4.0 ± 0.4 to 13.9 ± 3.2 mg/24 hr, p < 0.05) increased during disulfiram. During disulfiram use, blood pressure rose in the supine position (from 125/71 to 136/83 mm Hg, p < 0.01) and after 2 min of standing (from 120/87 to 138/97, p < 0.01) in all subjects. In response to nitroglycerin and upright posture, systolic hypotension was greater during disulfiram use (19.1 ± 2.2 vs 29.3 ± 1.8 mm Hg, p < 0.01); hypotension‐associated heart rate responses (change in heart rate/change in systolic blood pressure) were diminished (from 2.8 ± 0.5 to 1.9 ± 0.2 beats/min/mm Hg, p < 0.02). Disulfiram had no effect on pressor responses to tryamine and norepinephrine. Urinary excretion data were consistent with reduced norepinephrine synthesis during disulfiram administration. The cardiovascular responses to usual activities were unchanged by disulfiram, although with extreme hypotensive stress there was evidence of impaired response.
Single and divided doses of penbutolol
Authors: Müller F. O. , Hundt H. K. L. , Bromley P. A. , Torres J. , Vanderbeke O.
Published: January 2016

Penbutolol, a nonselective β‐adrenoceptor antagonist, induced reduction of exercise‐induced heartbeats for at least 24 hr after a single 40‐mg oral dose, and was equipotent with respect to a 2 × 20‐mg regimen over the same period. Ingestion for 7 days did not influence the pharmacodynamics or pharmacokinetics of penbutolol, and there was no cumulation of drug in serum. A relationship was found between the logarithms of measurable serum concentrations of penbutolol and the percentage reduction of total heartbeats. Absorption of oral penbutolol appeared to be reduced when administered in the evening. Since β‐adrenoceptor activity was relatively unchanged between 13 and 24 hr after a single 40‐mg dose of penbutolol, there is a possibility that an active metabolite or metabolites may contribute to prolonged duration of action.
Cotinine excretion and daily cigarette smoking in habituated smokers
Authors: Matsukura Shigeru , Sakamoto Noboru , Seino Yutaka , Tamada Taeko , Matsuyama Hitoshi , Muranaka Hideo
Published: January 2016

A sensitive and specific radioimmunoassay of cotinine, a major metabolite of nicotine, was developed using an antiserum raised against ∓‐1‐(β‐aminoethyl)‐cotinine coupled to bovine serum albumin (BSA) and l25I‐cotinine derivative. Inhibition studies with related compounds of cotinine revealed that the antiserum was not only specific for both the pyrrolidine and the pyridine ring but also highly reactive to the side chain attached to the latter ring for preparing the antigen and the labeled derivative of cotinine. The minimum detectable amount of cotinine was 1 ng. Urinary cotinine was extracted with chloroform and the mean recovery of cotinine added to nonsmoker's urine was 81 ± 10 (SEM) percent. The intra‐assay and the inter‐assay coefficients of variation were 17% and 28%. Urinary excretion of cotinine was high in habituated smokers before smoking and increased slightly after smoking three cigarettes. There was no correlation between urinary cotinine excretion and pH or urine flow after smoking. Daily urinary excretion of cotinine in smokers tended to relate roughly to daily cigarette consumption although excretion varied even among the smokers who consumed approximately equal numbers of cigarettes. There was no urinary excretion of cotinine in nonsmokers. Successive determinations of the daily cotinine excretion in 7 smokers revealed that the excretion correlated well with cigarette consumption on the corresponding days. We suggest that the measurement of urinary cotinine excretion provides a good index of cigarette smoking.
Excretion of chlordecone by the gastrointestinal tract: Evidence for a nonbiliary mechanism
Authors: Boylan J. J. , Cohn W. J. , Egle J. L. , Blanke R. V. , Guzelian P. S.
Published: January 2016

Workers exposed to chlordecone (Kepone), a toxic organochlorine pesticide, excreted larger amounts of chlordecone in bile than in stool, suggesting that it may undergo enterohepatic recirculation. We found in a single subject that equal amounts of chlordecone and of its reduced metabolite, chlordecone alcohol, were excreted in bile at a rate four times as great as in stool. When biliary contents were diverted from the intestine through a T tube, fecal excretion of chlordecone alcohol was abolished, presumably due to interruption of its passage via bile to intestine. This change was not accompanied by disappearance of chlordecone from the stool. The amount of chlordecone in stool when bile was diverted was increased six‐ to tenfold over that when diverted bile was continuously infused into the duodenum. Analogous experiments with [14C]‐chlordecone‐treated rats in which bile flow was exteriorized through a plastic cannula showed that the excretion of radioactivity in feces was in the same range when bile was reinfused in the duodenum or was totally diverted. Moreover, in rats with bile diverted, cholestyramine, an anion‐exchange resin which binds chlordecone in vitro, doubled the excretion of radioactivity in stool. A similar effect was observed in intact animals. We conclude that chlordecone enters the intestinal lumen from a nonbiliary source, probably the gut, and that net excretion of chlordecone from this source can be augmented by cholestyramine.
Effect of enzyme induction on plasma lipids using antipyrine, phenobarbital, and rifampicin
Authors: Ohnhaus E. E. , Kirchhof B. , Peheim E.
Published: January 2016

The liver microsomal enzyme system was induced by antipyrine, phenobarbital, or rifampicin in 19 healthy subjects and the effect on plasma lipids was followed. Before and after each study antipyrine elimination, γ‐glutamyl‐transpeptidase, D‐glucaric acid, and 6‐β‐hydroxycortisol were measured, and plasma lipids including lipoprotein electrophoresis were estimated. The subjects were given 1,200 mg antipyrine, 100 mg phenobarbital, 600 mg rifampicin, or 1,200 mg rifampicin daily for 14 days. Following enzyme induction by antipyrine, the antipyrine half‐life fell from 11.8 to 8.7 hr, by phenobarbital, from 13.8 to 8.9 hr, by rifampicin (600 mg), from 11.7 to 7.1 hr, and by rifampicin (1,200 mg), from 11.7 to 5.6 hr; the antipyrine clearance was increased after antipyrine by 30%, after phenobarbital, by 56%, after rifampicin (600 mg), by 59%, and after rifampicin (1,200 mg), by 125%. D‐Glucaric acid excretion in urine showed a tendency to rise to the same extent in each group, while the γ‐glutamyl‐transpeptidase values were affected similarly after antipyrine and phenobarbital but remained unchanged after rifampicin. The 6‐β‐hydroxycortisol urinary excretion corrected by the 17‐hydroxycorticosteroids increased in all groups. There were no changes in plasma cholesterol, triglyceride, and other plasma lipids measured, and lipid electrophoresis was unchanged. Steady‐state plasma concentrations of cholesterol and plasma triglycerides were not elevated after induction of the microsomal enzyme system by the drugs used.
Prediction of steady‐state imipramine and desmethylimipramine plasma concentrations from single‐dose data
Authors: Brunswick David J. , Amsterdam Jay D. , Mendels Joseph , Stern Stephen L.
Published: January 2016

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dose of desmethylimipramine (DM1) or imipramine (IMl) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady‐state plasma levels. In patients receiving DM1 there was a correlation (r = 0.97, n = 10) between 24‐hr and steady‐state DM1 levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24‐hr and steady‐state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a “therapeutic” dosage regimen without delay.
Opening remarks
Authors: Gordon Robert S.
Published: January 2016

The meeting on Clinical Trials Methodology will be opened by Dr. Donald S. Fredrickson, Director of the National Institutes of Health (NIH). If he had never become Director, indeed, if he had never done anything else in biomedical research, Dr. Fredrickson might still be known to many of you as the author of the oft‐quoted article (Bull. N. Y. Acad. Med. 44 Series 2: 985–993, 1968) that first attached the epithet “indispensable ordeal” to clinical trials. I should like to read another passage from that article, to let you know why we at NIH feel that this conference is important.
Responses
Authors: Meier Paul , Klimt Christian R.
Published: January 2016

Dr. Meier: I am glad that I got a rise out of Canon Hamilton with my criticism of Calabresi's proposal. I do want to say that I am not at all opposed to making good to patients who have been damaged in a trial for their suffering. What I do say (and I will argue with hirn later) is that the occasions on which that opportunity is before us are, I believe, very few. I don't think it provides a very powerful or widely applicable tool to meet our obligations.
Who will be effective as a clinical trials investigator and what are adequate incentives?
Authors: Gordon Robert S.
Published: January 2016

We have often heard that clinical trials are very expensive and that they require large investments of resources to obtain relatively few, though important, answers. One of the critical resources is the supply of clinical investigators, physicians who are interested, willing, and able to treat selected patients according to an agreed protocol and who are sufficiently motivated to carry out the meticulous recording of data that a good trial requires. Such collaborators are difficult to identify and recruit; yet, without their devoted and continuous cooperation, no trial will succeed.
Recruitment for the Coronary Primary Prevention Trial
Authors: Agras W. Stewart , Marshall Gary
Published: January 2016

A preliminary account of some aspects of recruitment for the Coronary Primary Prevention Trial is provided. Extension of recruitment sources to include various forms of community screening resulted in more rapid acquisition of potential participants than was possible when recruitment was restricted to the more traditional sources of physician and laboratory referral. Extended recruitment was supported by augmented data feedback and by the development of the job of recruitment coordinator at each participating c1inic. The identification of delays in reaching the maximal recruitment rate from particular sources points to the need for detailed planning of a recruitment campaign before large‐scale clinical trials are begun.
Other examples of recruitment problems and solutions
Authors: Prout Thaddeus E.
Published: January 2016

Plans to recruit patients for a clinical trial must begin early and must utilize a variety of workable techniques if patients are to be acquired at an acceptable rate. Publicity campaigns must be directed toward winning the confidence and good will of the public and of interested physicians.
A framework for the quality assurance of clinical data
Authors: Williams O. Dale
Published: January 2016

The process of obtaining scientific results from clinical trials is described as a system. The different steps in the system are discussed in terms of a quality enhancement program. Discussions and recommendations are provided for the major steps.
Diagnostic standardization
Authors: Kahn Harold A.
Published: January 2016

Diagnostic standardization requires substantial effort, including detailed specification of procedures in a written protocol and training of examiners in such procedures. Success is neither automatic nor assured. It is essential to monitor performance through replicate examinations and/or computation of examiner variance. When examiner variance exceeds permissible limits, consideration should be given to discarding the data.
Invited remarks
Authors: Lachenbruch P. A.
Published: January 2016

One goal of the Study on the Effectiveness of Nosocomial Infection Control (SENIC) is to determine which components of infection surveillance and control programs are effective in reducing nosocomial infections. In designing SENIC, it was found impossible to conduct a prospective study for several reasons. First, the ethical question of withholding a beneficial procedure arose. Second, since surveillance procedures are part of infection control programs, the act of observing procedures constituted part of an infection control program. Therefore, it was decided instead to survey medical records from a sampie of United States hospitals.
Invited remarks
Authors: Silvers Abraham
Published: January 2016

The previous speakers addressed the problem of the standardization of procedures and definitions and that of variable medical support arising from the fact that many physicians may treat the same patient during the course of a clinical trial. As a consequence of these issues, the internal monitoring of physician and patient adherence to protocol is necessary if protocol results are to be interpreted. At the Mayo Clinic, we have developed procedures to address these problems which are especially important since we simultaneously monitor some 150 protocols.
Invited remarks
Authors: Fletcher John C. , Branson Roy , Freireich Emil J.
Published: January 2016

Dr. Fleteher: I agree wih the “nonlegalistic ,” “nonabsolutist,” or “nonregulatory” approach to decision making about the ethical matters that relate to randomized clinical trials (RCTs) that was presented by Drs. Levine and Lebacqz. It is necessary, however, to explore the implications of such an approach in terms of decision making. Principled arguments do not preclude emotional confiicts. The question must be asked whether it is acceptable that ethical tolerance prevail at the top levels of decision making when, at different times, there is a competition between ethical principles, such as respect for persans and beneficence. If so, how does this ethical tolerance affect the outcomes of the decision‐rnaking process?
Methodology: The case for improved communications
Authors: Meinert Curtis L. , Hawkins Barbara S.
Published: January 2016

Despite their long history, the number that are in operation now, and the current level of expenditures on them, clinical trials have not been the focus of sufficient methodologic research. The paucity of methodologic explorations is further aggravated by the constraints on communications regarding methodology. Those individuals working in the area of clinical trials need to establish some professional identity with the field. Methodology in the areas of design and management of clinical trials needs to be stimulated, perhaps through special requests for applications (RFAs) and requestsfor proposals (RFPs). Communications could be improved by the establishment of a professional society, the development of an appropriate journal, and establishment of national training and information centers for clinical trials.
Concluding remarks
Authors: Roth Harold P.
Published: January 2016

Those of us who originally proposed this meeting questioned whether there were enough people interested in clinical trials methodology and enough translatable technology to justify it. The questions about interest and translatable technology have been answered. But we have been told that the systems for communication are inadequate; and we have been given a number of suggestions on how communications might be improved. A reviewer might ask for more information on methodology in a paper that he reviews. An author might present more information on methodology and might emphasize the new techniques that he has tried and the problems that he has overcome. Further, he might make the information he provides retrievable, by putting in his abstract key words that the National Library of Medicine can use. An editor could insist on more information on methodology and publish material on methodology to the extent that space allows. Widely proposed was the establishment of an organization of those interested in clinical trials methodology; that organization could perform many useful services, including organizing conferences and sponsoring a journal.
Drug‐related transient dyskinesias
Authors: Osifo Nosakhare G.
Published: January 2016

The ability of some antimalarials, especially chloroquine and amodiaquine, to provoke alarming but transient extrapyramidal movement disorders has been reported. The basis of the reported extrapyramidal symptoms has been the cause of some speculation. This paper reviews case reports and presents some data of the regional uptake of chloroquine in mammalian brain as a factor to consider, along with other factors that could influence the action of chloroquine on the extrapyramidal system. A neuropharmacologic mechanism for the transient extrapyramidal disturbances has been formulated.
Digoxin in the elderly: Pharmacokinetic consequences of old age
Authors: Cusack Barry , Kelly John , O'Malley Kevin , Noel Jacques , Lavan John , Horgan John
Published: January 2016

A study of single‐dose digoxin kinetics was performed in 6 young and 7 elderly patients. The rate of absorption, determined by the time to peak concentration after an oral dose, was more rapid in the younger group. The extent of absorption, as measured by comparison of the area under the plasma concentration/time curve after oral and intravenous administration, was similar in both groups. Mean plasma half‐life was longer and individual values were more variable in the elderly patients. The absolute apparent volume of distribution was reduced in the older patients and correlated inversely with age. When corrected for weight, however, the difference in the apparent volume of distribution did not approach significance. Both absolute and weight‐corrected values for plasma clearance of digoxin were reduced in the elderly subjects.
Creatinine VIII: Saliva levels of endogenous “true” creatinine in normal subjects
Authors: Chiou Win L. , Pu Frances S.
Published: January 2016

Concentrations of endogenous “true” creatinine in saliva and serum were measured in 6 normal subjects using a specific and sensitive high‐performance liquid chromatographic method. There were marked intra‐ and intersubject variations in saliva levels during an 11‐wk study. There were also large variations in the ratios of the saliva/serum creatinine level during the one‐day study for all the subjects, the average highest intrasubject variation being 481% and the range being 128% to 816%. The average ratio of saliva/serum level was 0.0999 ± 0.097 (CV = 97%); the highest saliva level was 1.5 mg%. Lower salivary levels were probably due to the extremely low lipid solubility of creatinine resulting in a relatively slower diffusion rate than of the transport of water into the saliva. Salivary monitoring of creatinine is concluded to be of little use in indicating its concentration in plasma or serum because, unlike many other substances it does not follow the pH‐partition principle for saliva/plasma distribution.
Development of antinuclear antibodies during acebutolol therapy
Authors: Cody Robert J. , Calabrese Leonard H. , Clough John D. , Tarazi Robert C. , Bravo Emmanuel L.
Published: January 2016

Eleven patients were studied while taking the beta blocker acebutolol for a period ranging from 12 to more than 24 wk. Control titers for fluorescent antinuclear antibody (ANA) were obtained in all. Serial testing was performed over the duration of the therapy and following its discontinuation. Additional immunologic testing was performed in most patients. The patients were observed closely for the development of clinical autoimmune disease. Using a sensitive assay, fluorescent ANA developed in 8 of 9 patients with negative values in the control period. In no patient has evidence of clinical autoimmune disease developed. In general, the titers of ANA tended to rise with increasing duration of therapy and decline after its discontinuation. Positive lupus erythematosus cell preparations were also observed in several patients. These data suggest that autoantibodies are frequently induced by acebutolol and, although no evidence of clinical autoimmune disease has been reported, immunologic surveillance is warranted.
Dose‐dependent urinary excretion of chlorthalidone
Authors: Fleuren Harry L. J. , Wissen Corrien Verwey-van , van Rossum Jacques M.
Published: January 2016

Renal excretion, plasma concentration, and erythrocyte concentration profiles of chlorthalidone were studied in 17 healthy human subjects for 100 to 200 hr after oral administration of single doses of 50, 100, or 200 mg. Three subjects received all three doses in a crossover design. The other 14 were involved in the study at one dosage level. The 50‐mg dose was taken altogether by 6 subjects, the 100‐mg dose by 11, and the 200‐mg dose by 6. Total urinary recovery of chlorthalidone extrapolated to infinity was 44.4% of the 50‐mg dose (22.2 ± 3.4 mg), 43.1% of the 100‐mg dose (43.1 ± 4.7 mg), but only 29.0% of the 200‐mg dose (58.0 ± 9.7 mg; mean values ± SD). There was a large interindividual variation in the renal plasma clearance of chlorthalidone (52 to 125 ml/min after 50 mg, 43 to 107 ml/min after 100 mg, and 47 to 77 mllmin after 200 mg). This variation correlated more with differences between subjects in the area under the plasma concentration curve than with those in total urinary recovery of the drug. The subjects available for between‐dose comparison showed an average decrease of 27% in renal clearance in going from the single 50‐mg to the 200‐mg dose, suggesting a causal relationship with the limited urinary recovery of the drug at the higher dose. These pharmacokinetic results indicate that the known antihypertensive dose‐response curve of chlorthalidone in man may well be related to the extent of its urinary recovery.
Diazepam kinetics in acute alcohol withdrawal
Authors: Pond Susan M. , Phillips Michael , Benowitz Neal L. , Galinsky Raymond E. , Tong Theodore G. , Becker Charles E.
Published: January 2016

We performed a within‐subject comparison of the kinetics of diazepam given to 7 alcoholic subjects during acute alcohol withdrawal and again after detoxification. The initial rapid exponential decline of plasma diazepam concentrations (t½α) was more rapid during (0.21 ± 0.03 hr) than after withdrawal (0.44 ± 0.14 hr, p < 0.05). Terminal t½, clearance, and volumes of distribution changed in individual patients, but mean values did not change. Protein binding was less in patients (93.4 ± 2.4%) than in healthy controls (97.0 ± 1.0, p < 0.05). The effects of alcohol withdrawal on diazepam disposition do not explain the high doses of diazepam commonly required to treat the withdrawal.
Renal excretion of cephapirin and cephaloridine: Evidence for saturable tubular reabsorption
Authors: Arvidsson Annie , Borgå Olof , Alvan Gunnár
Published: January 2016

Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high‐pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis‐Menten constant Km and its maximum transport capacity Tm.
Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination
Authors: Wood A. J. J. , Vestal R. E. , Wilkinson G. R. , Branch R. A. , Shand D. G.
Published: January 2016

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p < 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p < 0.02). In the under 40 yr group, AP clearance was higher in smokers than nonsmokers (p < 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme‐inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p < 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug‐metabolizing enzymes) but also on the effects of environmental factors, such as smoking.
Kinetics of intravenous amoxicillin in patients on long‐term dialysis
Authors: Francke Elliot L. , Appel Gerald B. , Neu Harold C.
Published: January 2016

The kinetics of intravenous amoxicillin was studied in 8 patients with creatinine clearances of less than 7 ml/min who were on long‐term hemodialysis. Kinetic parameters were determined using a 2‐compartment linear model. The serum half‐life (t½) of amoxicillin in these patients ranged from 7.5 to 21 hr. The t½ fell to 2.84 ± 0.45 hr during dialysis. Approximately 30% of the dose was recovered in the dialysate during 4 hr of dialysis and there was a 25% reduction per hour in serum concentration. We present a dosage schedule for intravenous amoxicillin in patients with reduced renal function who are undergoing hemodialysis.
Cephalothin kinetics: Before, during, and after cardiopulmonary bypass surgery
Authors: Miller Kenneth W. , Chan Keith K. H. , McCoy Harry G. , Fischer Ronald P. , Lindsay William G. , Zaske Darwin E.
Published: January 2016

Cephalothin kinetics was studied in 5 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass surgery. The PREOP (114 ml/min) and SURG (94 ml/min) renal clearances were of the same order but both were less than POSTOP renal clearance (248 ml/min). Cephalothin total body clearance during operation was lower (p < 0.01) than PREOP or POSTOP clearance, with decreased metabolic clearance the primary cause. There was reduction in cephalothin elimination throughout the surgical procedure, not only in the period of extracorporeal circulation, indicating that general anesthesia had a significant influence on drug disposition. The metabolite deacetylcephalothin was rapidly formed on all 3 days and its kinetic behavior paralleled that of the parent drug.
Presence of 2,4‐diamino‐N10‐methylpteroic acid after high‐dose methotrexate
Authors: Donehower Ross C. , Hande Kenneth R. , Drake James C. , Chabner Bruce A.
Published: January 2016

Assay of plasma methotrexate has been established as important to its safe use. We have investigated the specificity of 2 assay procedures for methotrexate: the competitive dihydrofolate reductase binding assay (CRBA) and the radioimmunoassay (RIA). The RIA of plasma methotrexate resulted in consistently higher values than the CRRA, with greater differences at later measurement times. A compound that strongly cross‐reacts in the RIA, but not the CRBA, has been identified in plasma and urine of patients on high‐dose methotrexate therapy, and appears to be the carboxypeptidase cleavage product (2,4‐diamino‐N10‐methylpteroic acid) on the basis of chromatographic and ultraviolet spectral properties. Although this compound is present as a minor contaminant in commercial methotrexate preparations, quantitative assessment of urinary excretion suggests that in man a major portion of the compound is derived from methotrexate metabolism.
Effects of age and cigarette smoking on propranolol disposition
Authors: Vestal R. E. , Wood A. J. J. , Branch R. A. , Shand D. G. , Wilkinson G. R.
Published: January 2016

The effects of age and cigarette smoking on the disposition of propranolol have been investigated in 27 normal men, aged 21 to 73 yr. The drug was administered orally (80 mg) every 8 hr and 40 µCi intravenous 3H‐propranolol were administered simultaneously with the seventh dose. Labeled and unlabeled propranolol concentrations were determined in serial blood samples obtained over the next 8 hr. Subgrouping the oral blood concentration/time data according to age (younger or older than 35 yr) showed that the mean levels in the older group were as much as twofold those in the younger group, and that the terminal half‐life (t½β) was prolonged with age (4.19 ± 1.38 vs. 5.05 ± l.36 hr, mean ± SD; p = 0.03). Substratification of cigarette smokers (>10 cigarettes daily) from nonsmokers indicated that the mean levels in the nonsmokers were 200% higher but there was no t½β difference. Despite the considerable interindividual variability, there was a trend for the weight‐normalized, average steady‐state levels to be lower in smokers than in nonsmokers, with the difference becoming smaller with increasing age. Analysis of the data indicated that the intrinsic total clearance of propranolol decreased with age only in the smokers, and toward the constant value of the nonsmokers, while apparent liver blood flow declined equally with age in both groups. Consequently, systemic‐clearance correlated negatively with age in the smokers and in the group as a whole. No age relationships were found in the volume of distribution and, thus, correlations of age and t½β were of the same order as those of systemic clearance. No changes were observed in systemic availability or plasma binding with aging in either group. It, therefore, appears that cigarette smoking habits are important in the altered steady‐state kinetics of propranolol that develops with aging. The results are consistent with a decreased induction of drug‐metabolizing enzyme with aging.
Lorcainide; I. Saturable presystemic elimination
Authors: Jähnchen Eberhard , Bechtold Heinrich , Kasper Wolfgang , Kersting Friedrich , Just Hanjörg , Heykants Jozef , Meinertz Thomas
Published: January 2016

The disposition of lorcainide after single oral and intravenous doses and during long‐term oral and intravenous dosing was investigated in 17 patients with chronic ventricular premature contractions. Lorcainide is thought to be eliminated mainly by metabolism in the liver. After a single intravenous (IV) dose of 2 mg/kg, the mean systemic clearance was 1.67 1/min, which is equal to the normal liver blood flow rate. When 10 of these patients were treated with 2 different single oral doses, the fraction of the dose reaching the systemic circulation (F) rose from a mean of 0.27 to 0.50 when the dose was increased from 150 to 300 mg. After long‐term oral dosing F increased further and approached unity in some patients. The plasma concentration of the N‐dealkylated metabolite rose and exceeded that of the parent drug when long‐term IV treatment was replaced by long‐term oral treatment. Simultaneous measurements of plasma concentration of lorcainide in the abdominal aorta and hepatic vein in 2 patients showed a high hepatic lorcainide uptake after a single IV dose. When 1 of these 2 patients was treated orally for 3 days (3 × 100 mg/day) concentration differences in afferent and efferent liver blood disappeared. Lung did not extract measurable amounts of lorcainide in 2 patients, in whom the plasma lorcainide concentrations were measured in the pulmonary artery and thoracic aorta over a period of 30 min after a single IV dose of 2 mg/kg. Our results suggest that lorcainide is subject to saturable presystemic elimination, most likely due to a saturation of hepatic extraction.
Ticrynafen and probenecid in hyperuricemic, hypertensive men
Authors: Peitzman Steven J. , Fernandez Pedro C. , Bodison Wilhelmina , Ellis Ida
Published: January 2016

In a double‐blind crossover study of ticrynafen (TCN) and probenecid (PBC), 9 hypertensive, hyperuricemic men completed 12‐wk courses of each drug. With a TCN dose of 125 mg daily, the fall in serum uric acid was prompt, dramatic, and lasting; it was equal to that after PBC, 500 or 1,000 mg daily. There was a small but significant early weight loss (diuresis) after TCN but no antihypertensive effect. Twelve days after resuming TCN for a proposed additional extension study 1 patient suffered acute, reversible bilateral ureteral obstruction, probably caused by sudden urinary uric acid precipitation.
Influence of prazosin on the development of antinuclear antibodies in hypertensive patients
Authors: Wilson J. Douglas , Bullock Jocelyn Y. , Booth Roger J.
Published: January 2016

A recent publication suggested that antinuclear antibodies (ANA) occur in up to one third of patients treated with the hypotensive drug prazosin (Minipress). We have examined a large group of hypertensive patients and found ANA in 9.7% of 145 patients taking prazosin and in 12.2% of hypertensive patients on any treatment regimen. Excluding patients taking methyldopa (a drug associated with a high ANA incidence), the ANA incidence fell to 6.9% in the prazosin‐treated group and to 7.2% of all treated hypertensives. Of over 350 untreated hypertensive patients, 6.0% had ANA. Prazosin did not increase the ANA incidence in patients on or off various drug combinations including beta blockers and diuretics. Analysis of the data by age and sex confirmed our conclusion that prazosin therapy is not accompanied by an increase in ANA.
Maternal, fetal, and neonatal metabolism of lidocaine
Authors: Kuhnert Betty R. , Knapp Daniel R. , Kuhnert Paul M. , Prochaska Anne L.
Published: January 2016

We investigated the metabolism of lidocaine to its active metabolites—monoethylglycinexylidide (MEGX) and glycinexylidide (GX)—in the mother, fetus, and neonate. The study population included normal patients and their infants delivered either vaginally or by cesarean section. A group of infants of mothers in whom pudendal anesthesia was induced was also included. Using gas chromatography and mass spectrometry techniques, the concentrations of lidocaine, MEGX, and GX were determined in maternal plasma during labor, in umbilical cord venous and arterial plasma at delivery, and in maternal and neonatal urine for 3 days post partum. The results indicate the following: In maternal plasma, MEGX rises throughout labor and GX is usually detectable within an hour of medication: in cord blood plasma the levels of lidocaine, MEGX, and GX suggest fetal metabolism of lidocaine; and in neonatal urine, the relative levels of parent compound and metabolites confirm lidocaine metabolism by the neonate.
Alterations in the disposition of differently cleared drugs in patients with cirrhosis
Authors: Klotz U. , Fischer C. , Müller-Seydlitz P. , Schulz J. , Müller W. A.
Published: January 2016

We have compared the disposition of antipyrine orally (15 mg/kg) and the new antiarrhythmic drug lorcainide intravenously (1.5 mg/kg) in 8 patients with alcoholic cirrhosis. Antipyrine (AP) serves as a model drug for drugs which are eliminated independently of liver blood flow and lorcainide (L) elimination as a model for drugs which depend on liver blood flow. Since in healthy subjects elimination half‐life (t½) of L increased with age (r = 0.68, p < 0.01) due to parallel change in the volume of distribution (r = 0.52, p < 0.05), its disposition had to be compared to age‐matched controls. Elimination of both AP and L was impaired in cirrhotic patients, expressed either in terms (mean ± SD) of t½ (AP = 26.8 ± 15.0 hr and 12.3 ± 1.8; L = 12.5 ± 4.5 hr and 7.7 ± 2.2 hr, p = 0.002) or of clearance (Cl) (AP = 21.9 ± 7.9 ml/min and 41.7 ± 5.5 ml/min; L = 814 ± 144 and 1002 ± 304 ml/min, p = 0.06). While the alterations in plasma Cl were great for AP, they were smaller for L. This suggests that elimination of drugs in cirrhotic patients is associated with relatively more impairment of enzyme activity than of hepatic blood flow. The slightly decreased Cl of L in patients with alcoholic cirrhosis would suggest that L should be carefully handled in patients with dysfunction of the liver.
Effects of atenolol and propranolol when added to long‐term antihypertensive diuretic therapy
Authors: van Rooijen G. J. M. , Boer P. , Mees E. J. Dorhout , Geyskes G. G.
Published: January 2016

The antihypertensive effects of atenolol and propranolol were compared in a double‐blind crossover study of 19 patients with essential hypertension (World Health Organization, I and II) who were receiving long‐term diuretic treatment (chlorthalidone, 50 mg‐daily) during the study. After a 3‐wk placebo period, a β‐adrenergic antagonist was administered once daily (atenolol, 50 mg daily, or propranolol, 80 mg daily) for a week. If the MAP was more than 108 mm Hg at the end of the week, dosage of the β‐blocker was doubled the following week; when necessary, doubling was repeated to a maximum dose of 640 mg propranolol and 400 mg atenolol daily. Fifty milligrams atenolol had a greater effect than 80 mg propranolol and was as effective as 160 mg propranolol. The dose‐response curve flattened off after 160 mg propranolol and 50 mg atenolol daily. The two highest doses of atenolol lowered MAP more than the highest doses of propranolol. Heart rate slowing was the same for both drugs and did not correlate with the fall in blood pressure. PRA was suppressed by all doses of propranolol, whereas atenolol suppressed PRA only at the 2 highest doses, (200 and 400 mg daily). With the lower propranolol doses, the percent MAP change correlated weakly with the percent PRA change (80 mg—r = 0.41, p < 0.1; 160 mg—r = 0.64, p < 0.05). Side effects were minimal, and were noted only with 640 mg propranolol; with this exception, the percentage of patients with no complaints rose when placebo was replaced by β‐blockers.
Phenytoin cumulation kinetics
Authors: Allen John P. , Ludden Thomas M. , Burrow Sandra R. , Clementi William A. , Stavchansky Salomon A.
Published: January 2016

Four male subjects were given phenytoin orally in single or twice‐daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas‐liquid chromatography, ranged from 1 to 18 µg/ml. Serum phenytoin concentration‐time data were fit to a 1‐compartment open model with zero‐order input and Michaelis‐Menten elimination. The resulting computer‐generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/l; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis‐Menten kinetic behavior.
Inhibition of human erythrocyte phenol‐O‐methyltransferase in uremia
Authors: Pazmiño Patricio , Rogoff Frederick , Weinshilboum Richard
Published: January 2016

Phenol‐O‐methyltransferase (PMT) catalyzes the méthylation of a variety of phenols. PMT activity is present in human erythrocyte (RBC) membranes. The enzyme activity is less in RBC membranes from uremic patients on maintenance hemodialysis. 98.1 ±4.4 U/mg membrane protein (mean ± SEM, n = 51), than in blood from randomly selected subjects, 134.5 ± 2.9 (n = 212, p < 0.001). There is no change in RBC PMT activity after hemodialysis. Uremic plasma contains methyl acceptors not present in normal plasma and reversibly inhibits PMT in RBC membranes from nonuremic subjects. There is considerable individual variation in the inhibition of RBC PMT by plasma samples from patients with renal failure, e.g., inhibition varied from 0% to 47% when 20 pd of plasma from each of 21 randomly selected uremic patients was tested. There is a direct correlation between the ability of individual samples of plasma from uremic patients to inhibit PMT activity and their content of endogenous methyl acceptors (r =0.91, n = 21, p < 0.001) but there is no correlation between the level of inhibition and such clinical laboratory values as blood urea nitrogen, serum creatinine, or hematocrit. Kinetic studies with pooled uremic plasma show that the inhibition of PMT is noncompetitive with respect to the phenolic substrate, but is competitive with respect to the methyl donor, S‐adenosyl‐L‐methionine. The approach used in these experiments may serve as one model for future studies of the effect of renal failure on drug metabolism in individual patients.
d‐Propoxyphene kinetics after single oral and intravenous doses in man
Authors: Gram Lars F. , Schou Jens , Way Walter L. , Heltberg Jon , Bodin Nils O.
Published: January 2016

d‐Propoxyphene kinetics was studied in 8 healthy male subjects after single oral doses of d‐propoxyphene at 65, 130, and 190 mg and after slow intravenous infusion of 65 mg. Total urinary excretion (7 days) indicated complete oral absorption but systemic availability was reduced corresponding to first‐pass elimination of 30% to 70%. There was linearity between oral dose and the corresponding area under the plasma concentration/time curve of d‐propoxyphene and the metabolite norpropoxyphene. The kinetic measurements showed 2‐ to 3‐fold interindividual variations: oral clearance, 1.3 to 3.6 Mmin; systemic clearance, 0.6 to 1.2 l/min; apparent volume of distribution, 700 to 1,800 l; d‐propoxyphene half‐life (t½), 8 to 24 hr; and norpropoxyphene t½, 18 to 29 hr. There were pronounced intraindividual dose‐independent variations in oral clearance in some subjects. The intravenous concentration curves indicated a 3‐compartment distribution model.