bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia
Authors: Rane A. , Villeneuve J. P. , Stone W. J. , Nies A. S. , Wilkinson G. R. , Branch R. A.
Published: January 2016

The pharmacokinetic disposition of furosemide has been investigated in six normal subjects, 7 patients with the nephrotic syndrome and 6 patients with uremia. Furosemide levels were measured using a specific HPLC analytical procedure and protein binding was measured by equilibrium dialysis using 3H‐furosemide. The high binding offurosemide in normal subjects (95.9 ± 0.1%) was reduced in both uremia (94.4 ± 0.4%) and the nephrotic syndrome (93.2 ± 0.5%). When alt three study groups were combined, furosemide binding correlated with the serum albumin concentration measured in each subject at the time of the study (r = −0.83, p < 0.001). Approximately 50% of the systemic clearance of total drug in controls (158 ± 11 ml/min) was due to renal clearance. The renal clearance of total furosemide in the nephrotic syndrome was not altered, but renal clearance of unbound drug decreased in proportion to the creatinine clearance. Extrarenal clearance was unaffected in the nephrotic syndrome. In contrast, in uremia, both renal and extrarenal clearances were significantly reduced. The fall in renal clearance was consistent with a reduction in functioning nephrons and the presence of competitive inhibitors for tubular secretion. The volume of distribution offurosemide at steady‐state correlated with both serum albumin (r= +0.73, p < 0.001) and drug binding (r = +0.63, p < 0.005) and was increased in the nephrotic syndrome. Furosemide half‐life was unchanged in nephrotic syndrome but prolonged by threefold in uremia. Chronic hemodialysis for two to four months in 4 of the uremic subjects produced no significant change in any pharmacokinetic parameter. This study indicates that the disposition of furosemide is not only dependent on renal function but also on the serum albumin concentration.
Phenytoin therapy
Authors: Golby Robert L.
Published: January 2016

I wish to point out a significant error in the article by Peter W. Mullen, “Optimal phenytoin therapy: A new technique for individualizing dosage,” which appeared on page 228 of the February, 1978, issue of the Journal. In Table I, the serum phenytoin concentrations he predicted by using the method described by Ludden and colleagues (Clin. Pharmacol. Ther. 21:287–293, 1977) for Patient C are given as 9.7 and 24.3 mg/L for the 200 and 300 mg/day doses, respectively. I obtain 7.6 and 31.5 mg/L, respectively, using Ludden and co‐workers' method.
Time‐course of interaction between carbamazepine and clonazepam in normal man
Authors: Lai Allen A. , Levy Rene H. , Cutler Ralph E.
Published: January 2016

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested by chronic dosing situation using carbamazepine (Tegretol) as the inducer and clonazepam (Clonopin) as the drug affected. Seven healthy subjects received one 1.0 mg clonazepam tablet once a day for 29 days and one 200 mg carbamazepine tablet once a day from days 8 to 29. Plasma levels of clonazepam were measured by electron‐capture gas‐liquid chromatography and those of carbamazepine and its epoxide metabolite by gas chromatographic‐chemical ionization‐mass spectrometry. Clonazepam plasma levels reached an initial steady‐state by day 7 and declined to a lower steady‐state over 5 to 15 days after additions of carbamazepine. The decrease in clonazepam levels ranged between 19% and 37%. Autoinduction of carbamazepine metabolism was also evident. Urinary excretion of d‐glucaric acid increased 2‐ to 4‐fold following carbamazepine administration (p < 0.005). This increase provided additional evidence that the present interaction was due to enzyme induction. Experimental clonazepam levels were fitted to an induction pharmacokinetic model for multiple dosing with an exponentially increasing clearance. Induced half‐lives of clonazepam (mean = 22.5 ± 11.5 hr)wereshorter(p < 0.005) than controlvalues (32.1 ± 16.6hr). Apparent enzyme(s) turnover half‐lives ranged between land 6 days.
The thorny path of clinical pharmacology
Authors: Gross Franz
Published: January 2016

Clinical pharmacology has not yet been generally acknowledged as a medical specialty, is not represented in the curricula of many medical schools in the United States, and is unknown to the major part of the medical profession. Outside this country, the situation is even worse, and with the exception of a few countries, such as Great Britain and Sweden, clinical pharmacology has nowhere achieved the place it should have, nor is it recognized in the way it deserves. Not infrequently, clinical pharmacology finds itself in the unhappy position of a discipline which is tolerated but not much liked and not at all supported.14 Many reasons are given to explain this status, the most often quoted but least convincing being the lack of funds, which, even if not made available in amounts comparable to those in the United States, should be and could be found, if clinical pharmacology were generally accepted as a discipline.
Kinetics of norethindrone in women; I. Radioimmunoassay and concentrations during multiple dosing
Authors: Back D. J. , Breckenridge A. M. , Crawford Francesca E. , McIver M. , Orme M. L'E. , Park B. K. , Rowe P. H. , Smith Eileen
Published: January 2016

A radioimmunoassay for norethindrone has been developed with the use of an antiserum raised in rabbits after the injection of norethindrone‐3‐carboxymethyloxime linked to bovine serum albumin. The immunoassay is sensitive to 30 pg/ml norethindrone. With this assay plasma concentrations of norethindrone in 40 women receiving 1 mg norethindrone acetate with 50 µg ethinylestradiol were between 1.6 and 15.2 ng/ml 12 hr after dosing during multiple dosing. After a single dose of 1 mg of norethindrone acetate with 50 mg ethinylestradiol, the plasma half life (t½) of the terminal apparently monoexponential phase of norethindrone decay was between 6.1 and 12.3 hr in 6 patients. During long‐term therapy with contraceptive steroids the plasma t½ of norethindrone did not differ from the t½ after a single dose. In 4 women receiving contraceptive steroids for the first time. plasma concentrations of norethindrone rose progressively during the first cycle to concentrations higher than predicted from simple accumulation pharmacokinetics. The sex hormone‐binding globulin capacity also increased and there was a good correlation between the plasma concentration of norethindrone and the sex hormone‐binding capacity (r between 0.695 and 0.910 in 4 patients). In 3 women starting the contraceptive steroid 4 wk postpartum there was a reduction of plasma norethindrone concentration with time (r = 0.528 p < 0.01) and this correlated with a fall in the sex hormone‐binding capacity (p < 0.05). In women taking a preparation containing 3 mg norethindrone acetate. the mean plasma norethindrone concentration was only 1.4 times as high as that in women taking 1 mg norethindrone acetate.
Kinetics of norethindrone in women; II. Single‐dose kinetics
Authors: Back D. J. , Breckenridge A. M. , Crawford Francesca E. , McIver M. , Orme M. L'E. , Rowe P. H. , Smith Eileen
Published: January 2016

In order to study the kinetics of norethindrone in women, we have administered single doses of 4 preparations of norethindrone (N) to 6 women (aged 21 to 23) in random order. The preparations were 1 mg N acetate and 50 µg ethinylestradiol EE2) (Minovlar), a dose of 1.05 mg N (Noriday), 3 mg N acetate and 50 µg EE2 (Gynovlar), and an intravenous preparation of 1 mg N with 50 µg EE2. Blood samples were taken at intervals up to 24 hr after dosing and plasma norethindrone concentrations were measured by radioimmunoassay. The plasma concentration decay slope fitted a two‐component open model with an initial rapid decay (half life 0.41 to 2.6 hr) followed by a slower beta phase with a half‐life of between 4.8 and 12.8 hr. The kinetics of norethindrone were not affected by the concomitant administration of EE2. The bioavailability of norethindrone after an oral dose of 1 mg was between 47% and 73% compared with an equivalent intravenous dose. The plasma clearance of norethindrone after 1 mg N acetate and 50 µg EE2 was 404.7 ± 31.7 ml/kg/hr and the apparent volume of distribution was 4.28 ± 0.56 L/kg. These values were not significantly different from the figures obtained after administration of 1.05 mg N. After an oral dose of 3 mg N acetate and 50 µg EE2, the bioavailability of norethindrone was significantly less (between 32% and 70%) than that after 1 mg N acetate and 50 µg EE2 explaining, at least in part, the lower than expected plasma concentrations of norethindrone in women on long‐term treatment with 3 mg N acetate and 50 µg EE2.
A “bodi of pharmacologifts”
Authors: Thompson Jeremy H.
Published: January 2016

Some time ago, while attending an international gathering of pharmacologists, my mind, such as it is, slipped gear during a rather vociferous but tedious question and answer period and registered yet again the diverse nature of my fellow scientists. They ran the gamut from beardless (almost) striplings to the gray‐haired sage, the natty dresser to the wearer of the stained frock coat, and the “sweet young thing” to those of more mature vintage. I posed (silently, of course, because the chairman was speaking) the rhetorical questions: “Could all these people really be of similar ilk?” “Could they all really be pharmacologists?”
Role of aldosterone in the antihypertensive effect of spironolactone in essential hypertension
Authors: Benraad H. , Drayer J. , Hoefnagels W. , Kloppenborg P. , Benraad Th.
Published: January 2016

In order to evaluate the relationship between aldosterone status and the blood pressure‐lowering effect of spironolactone, 38 patients with essential hypertension were treated with spironolactone (400 mg/day) during one week in hospital on a rigidly sodium‐restricted diet. The degree of hyperaldosteronism was assessed by the aldosterone secretory rate after 5 days of salt loading (315 mmol Na+/day). The mean arterial pressure decreased 5.6% (range, −21 to +8%). When the patients were divided into subgroups with low and normal renin activity, there was no difference in the change in mean arterial pressure (−5.0% and −6.1%). When the patients were divided into three groups with low, normal, and supranormal aldosterone secretory rates, the last group had a significantly greater fall in blood pressure after the spironolactone than the other groups (−1.0, −7.1, −11.1%). Thus there was a correlation between the aldosterone secretory rate after sodium loading and the blood pressure‐lowering effect of spironolactone (r = −0.53, p < 0.01). The blood pressure‐lowering effect was not related to changes in body weight, kidney function, or plasma electrolytes. Our findings do not provide solid arguments for the view that the blood pressure‐lowering effect of high dose spironolactone is due to its antimineralocorticoid activity, but the correlation between the degree of hyperaldosteronism and the blood pressure‐lowering effect strongly suggests that aldosterone does play a role in the genesis or maintenance of the hypertension in these patients.
Effects of oxprenolol and propranolol on systolic time intervals
Authors: van Herick Robert , Aronow Wilbert S.
Published: January 2016

Twenty patients with coronary heart disease participated in a double‐blind, randomized, crossover study on three study mornings to evaluate the effect of oral oxprenolol 80 mg, oral propranolol 80 mg, and placebo on left ventricular contractility. Systolic time intervals were performed in the control period and at 60, 90, 120, 150, 180, 240, 300, and 360 min after medication. None of 20 patients developed adverse effects. The 80‐mg doses of oxprenolol and propranolol had a negative chronotropic effect, with the resting heart rate slightly but consistently decreased more after propranolol, attaining statistical significance at 90, 150, and 300 min. That the 80‐mg doses of oral oxprenolol and propranolol also induced a negative inotropic effect was indicated by a similar prolongation of the external isovolumic contraction time and pre‐ejection period intervals. This equipotent dose of oxprenolol in producing a negative inotropic effect induces less resting bradycardia than propranolol.
Diurnal rhythms of aminopyrine metabolism: Failure of sleep deprivation to affect them
Authors: Poley Gerald E. , Shively Carol A. , Vesell Elliot S.
Published: January 2016

After a single oral dose of aminopyrine (9 mg/kg), mean salivary aminopyrine half‐lives (t½s) and metabolic clearance rates in 12 normal male volunteers exhibited diurnal variations. Salivary aminopyrine t½s were approximately 50% longer at 8 p.m. (2.1 ± 0.7 hr) than at 8 a.m. (1.4 ± 0.3 hr). Mean aminopyrine metabolic clearance rates decreased 20% from 8 a.m. (418.2 ± 152.0 ml/min) to 8 p.m. (335.3 ± 107.6 ml/min). There were large interindividual variations in the magnitude of these diurnal changes in aminopyrine t½ and metabolic clearance rates. There were nonsignificant changes in mean aminopyrine apparent volumes of distribution (aVd) which increased only slightly from 53.1 ± 20.6 L at 8 a.m. to 59.7 ± 26.5 L at 8 p.m. There were diurnal variations in plasma 11‐hydroxycorticosteroids (11‐0HCS), mean values of which decreased 60% from 16.2 ± 4.2 µg/100 ml at 8 a.m. to 6.5 ± 1.9 µg/100 ml at 8 p.m. Sleeplessness for 24 or 48 hr under the conditions of this experiment failed to affect diurnal rhythms in aminopyrine metabolism or plasma 11‐OHCS concentrations.
Isosorbide dinitrate in acute and chronic heart failure
Authors: Venkataraman Kalyansundaram , Durairaj Sadayappa K. , de Guzman Maria , Haywood L. Julian
Published: January 2016

The hemodynamic effects of sublingual isosorbide dinitrate (ISD) were studied in 12 patients with congestive heart failure (CHF) of many causes. The duration of CHF in the chronic group varied from 3 to 62 months (mean, 29.5). Hemodynamic parameters were obtained serially before and 10, 20, 30, 45, 60, and 120 min after a 5 to 15 mg dose of ISD sublingually. The hemodynamic effects were pronounced at 45 min and returned to control levels in 120 min. Heart rate did not change. Hemodynamic parameters that changed after ISD were mean arterial pressure (−7%, p < 0.05), mean pulmonary artery pressure (−17%, p < 0.05), and mean pulmonary capillary wedge pressure (−29%, p < 0.005). Mean cardiac index (+3%, p = NS) and mean stroke work index rose (+9.4%, p × NS); mean total systemic resistance fell (−10%, p = NS). Thus the duration of hemodynamic effects of ISD is less than 2 hr and sublingual ISD induces beneficial reduction of pulmonary capillary wedge pressure in patients with acute and chronic CHF without increasing cardiac index and stroke work index.
Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose of warfarin
Authors: Slattery John T. , Levy Gerhard , Jain Adesh , McMahon F. Gilbert
Published: January 2016

The purpose of this investigation was to determine the effect of the nonsteroidal anti‐inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half‐life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of naproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.
The unrealized potential of the medication monitor
Authors: Moulding Thomas S.
Published: January 2016

The medication monitor is a dispenser with a time recording system for determining when patients remove medication. ft has demonstrated that nurses and physicians can estimate patient compliance with considerable accuracy. It could be used: (1) to assure that only patients actually ingesting medication are used to evaluate new drugs, (2) to study the factors that influence compliance and strategies to improve compliance, (3) to prevent escalation to more toxic drugs or expensive diagnostic procedures when failure to respond is due to poor compliance, (4) to supervise compliance when society has an overriding interest in therapeutic success, and (5) to monitor the effects of air pollution. Specially designed medication monitors could be used to provide the proper amount of compensatory medication when a patient forgets and to reduce the chance that a suicidal patient will impulsively take an overdose.
Mechanisms of nonlinear disposition kinetics of sulfamethazine
Authors: du Souich Patrick , Lalka David , Slaughter Richard , Elvin Alfred T. , McLean Allan J.
Published: January 2016

Five healthy male subjects received oral doses of 10 and 40 mg/kg of sulfamethazine (SMZ) approximately 14 days apart in a nonrandomized crossover study. Blood and urine samples were collected for at least 24 and 72 hr, respectively. All samples were assayed by the Bratton‐Marshall procedure for SMZ and apparent N‐acetylsulfamethazine (NSMZ). Recovery of total drug (SMZ + NSMZ) in urine was 88.9% following the low and 79.5% following the high dose. The low and high dose plasma concentration time curves were not readily superimposable (i.e., nonlinear kinetic behavior was observed). The data suggest that several mechanisms contribute to the nonlinearity. Specifically, a dose‐dependent decrease in absorption rate displaced the plasma concentration‐time curve to the right in some subjects, whereas apparent metabolic clearance (Clm) decreased with increasing dose (estimated assuming dose = amount of SMZ + NSMZ in urine to 72 hr) in all subjects (0.35 ml/min/kg for the low and 0.23 for the high dose). Still greater dose‐dependent effects were found when apparent Clm of unbound drug was determined, since free fraction rose from 0.11 to 0.30 over the observed plasma concentration range. Renal clearance (ClR) of SMZ appeared to be a complex function of time. In the low dose study it ranged from an average of 0.071 ml/min/kg at 2 hr to 0.146 mllminlkg at 6 hr after drug. After the high dose comparable values were 0.083 and 0.128. Interindividual variability and pronounced nonlinear kinetics of SMZ after 40 mg/kg suggest that this dose is probably a poor choice for the determination of acetylator phenotype.
Guanfacine kinetics in patients with hypertension
Authors: Weiss Yves A. , Lavene Daniele L. , Safar Michel E. , Simon Alain Ch. , Loria Yolande , Georges Daniel R. , Milliez Paul L.
Published: January 2016

Guanfacine kinetics were studied in 19 patients with hypertension after single and repeated oral doses. The single‐dose study was performed in two homogeneous groups who received 2 mg (n = 9) and 4 mg (n = 10). The plasma concentrations were fitted in a two‐compartment open model with first‐order absorption. After a lag time of 0.8 hr, the absorption occurred rapidly (t½ ≅ 0.53 hr). The fast and slow elimination phases occurred with t½s of 2 and 19 hr. At therapeutic levels the percent of drug in red blood cells (55%) was independent of total drug concentration. Peak plasma levels had small interindividual variations. Comparison of kinetic parameters and AUC at the two doses studied demonstrated that their bioavailability was equal and the kinetics were linear. In a multiple‐dosing study, performed in the same subjects, the plasma levels at steady state were in good agreement with the predicted values (p < 0.001) and proportional to daily dosage. A single method based on four blood samples collected after 24, 28, 32, and 36 hr allows a reasonable prediction of the effective steady‐state plasma levels during chronic dosing with guanfacine.
Acute effects of piretanide in normal subjects
Authors: Teredesai Pradip , Puschett Jules B.
Published: January 2016

Acute clearance studies were performed in normal subjects to assess the actions of the new diuretic, piretanide, on renal function. The drug increased both glomerular filtration rate and effective renal plasma flow in roughly proportionate amounts, so that filtration fraction did not change. In a dosage of 2 to 3 mg, it induced an increase in sodium excretion of almost 13% of filtered load, and there was an associated 2‐ to 3‐fold increase in potassium excretion. The abstraction of solute‐free water from the collecting duct was markedly reduced, but the drug induced no significant decline in the generation of free water. The rate of bicarbonate excretion, as well as that of titratable acid and ammonium, was increased approximately proportionately so that there was no increase in urinary pH or net hydrogen ion excretion. There was no phosphaturia, a unique finding, since all other drugs and maneuvers that cause a bicarbonate diuresis are also phosphaturic. Piretanide increased calcium excretion by approximately 19% of filtered load. The data suggest that the drug acts largely in the ascending limb of the loop of Henle and that it also affects the proximal tubule. Despite its sulfonamide structure, none of the drug's effects appear to be related to inhibition of carbonic anhydrase.
Influence of pentobarbital on effect and plasma levels of alprenolol and 4‐hydroxy‐alprenolol
Authors: Collste Per , Seideman Peter , Borg Karl-Olof , Haglund Kjell , von Bahr Christer
Published: January 2016

Six healthy subjects were given placebo and a single oral 0.2‐gm dose of alprenolol (Aptin) before and after 0.1 gin pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4‐hydroxy‐alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4‐hydroxy‐alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half‐lives were unchanged. The inhibition of exercise tachycardia during a 7‐hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.
The calcium carbimide‐ethanol interaction: Effects of ethanol dose
Authors: Brien J. F. , Peachey J. E. , Loomis C. W. , Rogers B. J.
Published: January 2016

In a double‐blind, placebo‐controlled study involving five male alcoholic volunteers, oral administration of 0.7 mglkg of calcium carbimide (CC) 12 hr before ingestion of ethanol (0.125, 0.25, and 0.5 gm/kg) produced an interaction consisting of increased blood acetaldehyde level, tachycardia, and decreased diastolic blood pressure. The order of intensity of the interaction with regard to ethanol dose was 0.5 > 0.25 > 0.125 gm/kg. The subjects were aware of a CC‐ethanol interaction only for 0.25 and 0.5 gm/kg of ethanol, for which heart rate was elevated above 100 bpm. With the criterion of heart rate above 100 as indicative of the CC‐ethanol interaction, the onset was 0.25 and 0.38 hr for the 0.5 and 0.25 gm/kg ethanol doses and the duration of the interaction was 1.0 and 0.38 hr, respectively. There were positive, linear correlations between blood acetaldehyde level and both heart rate and pulse pressure. There was appreciable individual variability in the intensity and duration of the interaction. Pretreatment with CC reduced the rate of ethanol metabolism at the 0.5 gm/kg ethanol dose.
Serum concentration and phototoxic effect of methoxsalen in patients with psoriasis
Authors: Swanbeck Gunnar , Ehrsson Hans , Ehrnebo Mats , Wallin Inger , Jonsson Lennart
Published: January 2016

The correlation between serum concentration of methoxsalen (8‐methoxypsoralen; 8‐MOP) and phototoxic effect using long‐wave ultraviolet light has been studied in 5 psoriatic patients. The maximum serum concentration occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg of methoxsalen. The lowest value for the minimum phototoxic dose (MPD), i.e., highest photosensitivity, was obtained between 1 and 2 hr. There was a significant negative correlation between the logarithm of the serum concentration and minimum phototoxic dose (MPD) (r = 0.780). Hence, the degree of photosensitivity appears to be related to the serum level of methoxsalen.
XLVII. Scientific standards vs. statistical associations and biologic logic in the analysis of causation
Authors: Feinstein Alvan R.
Published: January 2016

The word causation (or causality) refers to decisions about whether a particular cause has produced a particular effect. In clinical medicine, such decisions occur when causal efficacy is determined for the roles of étiologie agents in provoking a disease, or for therapeutic agents in either remedying a disease or preventing its adverse progress.
Effect of pH and urine flow on urinary nicotine excretion after smoking cigarettes
Authors: Matsukura Shigeru , Sakamoto Noboru , Takahashi Keiichi , Matsuyama Hitoshi , Muranaka Hideo
Published: January 2016

Effects of pH and urine flow on urinary excretion of nicotine were examined in 11 smokers after they had smoked 3 cigarettes during water diuresis. Plasma nicotine showed a slight but nonsignificant rise after smoking. Urinary excretion of nicotine increased significantly from the pre‐smoking levels of 258 ± 76 and 252 ± 147 (mean ± SEM) ng/15 min to the peaks of 2,587 ± 1,224 and 2,561 ± 584 ng/15 min 30 and 45 min after the start of smoking. Thereafter, urinary nicotine tended to decrease and rise with changes in urinary flow. There was a correlation between urinary nicotine and urinary flow after smoking (r = 0.26, p < 0.05). Eleven subjects were grouped based on the mean urinary pH throughout the experiment. No significant amount of nicotine was excreted in the group with pH above 7.5 while groups with pH below 7.4 excreted substantial nicotine after smoking. There was a negative correlation between urinary pH and nicotine excretion (r = −0.58, p < 0.001). Urinary excretion of nicotine cannot be used as an index of smoking unless pH and urine flow are controlled.
Dichloroallyl lawsone
Authors: McKelvey Eugene M. , Lomedico Marcia , Lu Katherine , Chadwick Marjory , Loo Ti Li
Published: January 2016

Dichloroallyl lawsone (DCL, NSC‐126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase 1 clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1‐ or 4‐14C] DCL, 250 µCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 ± 0.3 mg/L. The drug had a mean initial plasma half‐life of 48.9 ± 19 min and a terminal half‐life of 20.3 ± 1.8 hr, with a C × t of 50.1 ± 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.
Invited remarks
Authors: Chalmers Thomas C.
Published: January 2016

There are many reasons why I wish Jerry Cornfield were here—not the least of which is that he would then have had to follow a preacher to the podium. Actually, Canon Hamilton, I think, has added more than anybody I can think of to the whole problem of the ethics of c1inical trials, and I have had the pleasure of serving with him on policy advisory boards for a number of years. I rnight be able to take Jerry Cornfield's place on the program, but I could never fill his shoes, at least not in this generation. I hope you recognize that both speakers are biostatisticians and none of the three discussants are.
Publications and promotions for the clinical investigator
Authors: Relman Arnold S.
Published: January 2016

Major clinical trials are usually large projects involving many institutions and large numbers of individuals. They are often administered as contracts rather than as research grants, with all the attendant centralization of control that this arrangement implies. Whether supported by contract or grant, however, the typical large trial in this country tends to be an elaborately organized enterprise replete with prearranged guidelines, staff assistants, expert consultants, and a panoply of committees, each concerned with a particular aspect of the project. Personal identification with such projects therefore tends at best to be limited to a few leading spirits, whereas the association of most of the other participants is so tenuous as to be virtually invisible. Furthermore, the role of the rank‐and‐file collaborator is often quite different from that of the few at the top of the administrative hierarchy. As Cochrane1 observed some years ago, “a randomized c1inical trial is great fun for the coordinator but can be very boring for the physicians filling in the forms.”
Internal monitoring: Patient and study management at the clinic
Authors: Evans James T.
Published: January 2016

Adequate methods to assure the quality of data collected at the clinic need to be developed. A full understanding of the limitations of physicians as information processors and reasonable performance expectations for physicians during peak information periods will result in concentrated planning for patient visits and will limit the data that must be collected at the clinic. It is mandatory for each clinical research project that protocol treatment take into account the question of variable provider follow‐up versus constant provider follow‐up. It is also imperative that all clinical research providers receive special training, testing, and follow‐up evaluation. The prime responsibility for the overall conduct of clinical research rests with the principal investigator. A monitoring tool that should be more fully used is the informed patient.
Problems of omission in communications
Authors: Mosteller Frederick
Published: January 2016

The paper describes six difficulties that arise from omissions in reporting on data or their analysis, For each a remedy is suggested: (1) Randomization. Care in reporting the method and execution of randomiration would remedy this omission. (2) Informed consent. Reporting how informed consent was obtained would remind us that it was obtained, and the cumulative experience might also improve our ability to handle the matter both to our own satisfaction and that of many critics. (3) Analytie techniques. Reporting what analytic technique was used gives the reader a chance to consider whether the appropriate method was used or whether some other approach would have been preferable. (4) Descriptive statistics. If the reader is to understand the data analysis, some descriptive statistics are required. These data may be of much more value to the future of medicine than the significance test performed, because later use of the data cannot be anticipated. It is time to consider ways to make data available for those who request it and to examine the conditions for such transactions. (5) Power. Reporting the power of a test will tell us something about the strength of the investigation. It should be encouraged by editors. At present, it is possible to report the power of only the simpler tests. (6) Selectivity and multiplicity. The variety of methods used and the method of selecting the statistics presented in the final paper need to be presented if the reader is to get an honest appraisal of the uncertainty of the study.
Antihypertensive effects of Clonidine
Authors: Lilja Mauno , Jounela Antti J. , Juustila Heikki , Marvola Martti
Published: January 2016

The antihypertensive effect of clonidine given either two or three times a day with a diuretic was compared in a double‐blind crossover study in 18 hypertensive patients. In II patients given clonidine three times a day there was better control of blood pressure, although the differences in most instances were of the order of only a few millimeters Hg. There were no differences in the frequency or severity of side effects. Clonidine twice daily with a diuretic appears to be adequate for most patients.
Lack of effect of bran on digoxin absorption
Authors: Woods Margo N. , Ingelfinger Joseph A.
Published: January 2016

The effect of dietary fiber on digoxin absorption was investigated in 12 patients taking digoxin. Steady‐state serum digoxin concentrations were determined while subjects were on a regular diet and while they were on a diet supplemented with 22 gm bran daily. During the period of bran supplementation, the serum digoxin concentration did not change (average change, +0.5%; 90% confidence interval, −12% to +14%). Bran does not cause a clinically significant reduction in digoxin absorption.
Identification and quantitation of hydrazine in the urine of patients treated with hydralazine
Authors: Timbrell John A. , Harland Steven J.
Published: January 2016

Hydrazine has been identified by gas chromatography‐mass spectrometry in the 0‐ to 24‐hr urine of patients administered hydralazine. With a specific gas chromatographic assay procedure, the amount of hydrazine in the 0‐ to 24‐hr urine was determined in patients treated with various doses of hydralazine. The amount of hydrazine detected in the urine was greater in the slow acetylator phenotype than in the rapid acetylator phenotype. Studies indicated that hydrazine was not produced by chemical breakdown of hydralazine or its known metabolites in urine and therefore was unlikely to be a urinary artefact formed by chemical decomposition in the urine.
Metabolic responses to plasma concentrations of theophylline
Authors: Cathcart-Rake W. F. , Kyner J. L. , Azarnoff D. L.
Published: January 2016

We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mglkg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 µg/ml), caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 ± 3 mg/dl) without changing levels of IRI, IRG, HGH, or cortisol.
Kinetics of intravenous mezlocillin in chronic hemodialysis patients
Authors: Francke Elliot , Mehta Sudhir , Neu Harold C. , Appel Gerald B.
Published: January 2016

The kinetics of intravenous mezlocillin was studied in 8 patients with creatinine clearances under 7 ml/min who were undergoing chronic hemodialysis. Kinetic parameters were determined using a 2‐compartment linear model. The mezlocillin serum half‐life (t½) in these patients ranged from 2.9 to 7.8 hr (mean, 5.4). The t½ decreased to l .57 ± 0.09 hr during dialysis. Approximately 18% of the dose was recovered in the dialysate in 4 hr of dialysis. There was a 30% reduction per hour in serum concentration. The kinetics of mezlocillin, due to removal by nonrenal mechanisms, more closely resemble the kinetics of penicillin G and ampicillin than of carbenicillin and ticarcillin. A dosage schedule for use of intravenous mezlocillin in patients undergoing hemodialysis is presented.
Rectal and oral absorption of methylprednisolone acetate
Authors: Garg Dyal C. , Wagner John G. , Sakmar Ermelinda , Weidler Donald J. , Albert Kenneth S.
Published: January 2016

Rectal absorption of methylprednisolone acetate and oral absorption of methylprednisolone and methylprednisolone acetate were investigated in a single‐dose 3‐way crossover study of 12 normal male volunteers. The median value of bioavailability (relative to oral dose) of methylprednisolone acetate based on unchanged methylprednisolone plasma levels was 14.2% after rectal administration, suggesting that the drug exerts its therapeutic effect topically rather than systemically. In contrast, the median of total radioactivity in urine (as a percentage of rectal dose) was 34.3% (range, 4.52% to 58.8%), suggesting partial bacterial metabolism in the rectum prior to absorption. Mean bioavailability (relative to oral administration of methylprednisolone acetate) of methylprednisolone after oral administration was 89.9%, indicating somewhat better systemic availability of the ester than the alcohol. The average apparent elimination rate constant for methylprednisolone after oral administration of both ester and alcohol was 0.290 hr−1, corresponding to a half‐life of 2.39 hr.
Efficacy of estradiol vaginal cream in postmenopausal women
Authors: Dickerson Janet , Bressler Rubin , Christian C. D. , Hermann Harold W.
Published: January 2016

In a double‐blind parallel study daily intravaginal administration of conjugated estrogen cream and estradiol cream for 14 days relieved vasomotor and vaginal postmenopausal symptoms in 29 postmenopausal women. By day 14, therapy with the estradiol vaginal cream resulted in plasma estrone and estradiol levels closer to those in premenopausal women than therapy with the conjugated estrogen cream. The extent of improvement and final estradiol plasma levels in the estradiol vaginal‐cream group correlated. There was no correlation with severity of symptoms or estradiol plasma level at baseline. The metabolism of the conjugated estrogen cream might account for absence of correlation between improvement and final estradiol plasma levels in the conjugated vaginal‐cream group.
Influence of methylxanthine‐containing foods on theophylline metabolism and kinetics
Authors: Monks Terrence J. , Caldwell John , Smith Robert L.
Published: January 2016

The metabolism and kinetics of 14C‐labeled theophylline have been studied after intravenous doses of 100 mg to healthy subjects, keeping to their usual diets after 7 days of abstention from methylxanthine‐containing foods and beverages and again after such abstention while taking caffeine and theophylline in tablet form. The metabolism of oral 14C‐theophylline has also been investigated. Metabolites were separated and quantitated by ion‐exchange column chromatography, ion‐exchange paper chromatography, and liquid scintillation counting. Three major metabolites were found in urine in addition to theophylline, namely 3‐methylxanthine, 1.3‐dimethyluric acid, and 1‐methyluric acid, and 2 minor metabolites were detected but not identified. The elimination kinetics were studied after intravenous administration; theophylline, 1.3‐dimethyluric acid, and 1‐methyluric acid were eliminated by first‐order processes, while elimination of 3‐methylxanthine was described by Michaelis‐Menten kinetics. Abstention from methylxanthine‐containing foods and beverages led to a significant decrease in the urinary elimination half‐life of 14C from 9.8 to 7.0 hr (p < 0.02) due to increases in the elimination constants for theophylline, 3‐methylxanthine, and 1,3‐ldimethyluric acid. When the methylxanthine content of the methylxanthine‐containing foods and beverages was replaced by caffeine and theophylline in tablet form, kinetics and metabolism of theophylline were the same as in subjects on usual diets.
Effects of metoprolol on blood pressure and plasma renin activity in thiazide‐resistant hypertensive patients
Authors: Velasquez Manuel T. , Wan Suk Han , Maronde Robert F.
Published: January 2016

Twenty patients with mild to moderate hypertension whose blood pressures were not adequately controlled by a thiazide diuretic were treated for 4 wk with metoprolol. Normotension (diastolic pressure <90 mm Hg) or reduction in diastolic pressure of at least 10 mm Hg was achieved in 12 of the patients 1 wk after metoprolol (200 mg/day) was added to the hydrochlorothiazide (100 mg/day) regimen. In the other 8 patients, pressure reduction was attained with larger doses (300 to 400 mg/day) of metoprolol. After 1 wk of combined therapy, heart rate decreased by 11% (p < 0.001) and plasma renin activity (PRA) decreased 48% (p < 0.001). The individual changes in mean blood pressure did not correlate with either the premetoprolol PRA level (r = 0.14) or the changes in PRA after metoprolol (r = 0.03) but did correlate with steady‐state metoprolol plasma levels (r = 0.61, p < 0.01). Pressure and heart rate reductions were sustained during the last 3 wk of combined therapy but the PRA decrease did not persist; levels gradually rose to near control by the fourth week. Urinary sodium excretion was not consistently changed on metoprolol therapy.
Metabolic changes in muscle on long‐term alprenolol therapy
Authors: Frisk-Holmberg M. , Jorfeldt L. , Juhlin-Dannfelt A. , Karlsson J.
Published: January 2016

Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual VO2max. before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole · kg−1 · wet weight) of glycogen, glucose, lactate, and high‐energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment, but after 10 min of exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol, indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise, leg muscle metabolism is influenced by long‐term antihypertensive therapy.
Effects of carbamazepine on valproic acid kinetics in normal subjects
Authors: Bowdle T. Andrew , Levy René H. , Cutler Ralph E.
Published: January 2016

Carbamazepine and valproic acid are used together in the treatment of epilepsy. It is therefore, relevant to investigate the possibility of a carbamazepine effect on valproic acid disposition, particularly since carbamazepine is known to induce enzymes. We gave valproic acid orally to 6 normal subjects, 250 mg twice daily for 4 wk. Carbamazepine, 200 mg once daily, was begun after 4 days on valproic acid. Serum drug concentrations were measured during 4 dosing intervals, once before and 3 times after beginning carbamazepine. Minimum steady‐state concentrations of valproic acid declined after carbamazepine from 34.4 ± 5.1 to 27.1 ± 4.4 µg/ml (p < 0.0005). Clearance rose from 6.46 ± 0.80 to 8.48 ± 2.28 ml/hr/kg (p < 0.01). The increase in clearance and decrease in minimum steady‐state levels was apparent only after 2 wk on carbamazepine. The elimination rate constant (KE) during the dosing interval did not rise during carbamazepine administration (0.0623 ± 0.0168 hr−1 before and 0.0573 ± 0.0168 hr−1 after, p > 0.25), raising the possibility of an increase in distribution volume.
Effect of imipramine on norepinephrine and blood pressure in enuretic boys
Authors: Lake C. R. , Mikkelsen E. J. , Rapoport J. L. , Zavadil A. P. , Kopin I. J.
Published: January 2016

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double‐blind, placebo‐controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationship between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug‐induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.
Propranolol glucuronide cumulation during long‐term propranolol therapy: A proposed storage mechanism for propranolol
Authors: Walle Thomas , Conradi Edward C. , Walle U. Kristina , Fagan Timothy C. , Gaffney Thomas E.
Published: January 2016

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady‐state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3‐fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (Ph approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 mi/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.
Effects of sediment flushing from a small Alpine reservoir on downstream aquatic fauna
Authors: Quadroni S. , Brignoli M. L. , Crosa G. , Gentili G. , Salmaso F. , Zaccara S. , Espa P.
Published: January 2016

Sediment flushing is currently performed to recover the storage capacity of small‐sized to medium‐sized reservoirs. However, its environmental impacts are not yet adequately quantified. This work aimed to evaluate the effects of a 3‐day sediment flushing from a small reservoir in the Italian Alps on downstream freshwater fauna. Biomonitoring was carried out in two streams. In the impounded stream, benthic macroinvertebrates were surveyed immediately below the flushed reservoir. In the receiving stream, where diluting flows were released to reduce the sediment concentration and deposition, fish and macroinvertebrates were monitored at two sites, one above and one below the stream junction. Above the stream junction, the only disturbance was the increase in streamflow, while the reach below the stream junction was perturbed by the increase in both streamflow and sediment load. At the site closer to the flushed reservoir, the benthic community was almost completely impaired after the operations, and its recovery was still incomplete after 1 year. In the receiving stream, the average sediment concentration of approximately 6 g l−1 and deposition of 30 kg m−2 were estimated at the site subjected to the sediment increase. A density reduction of 80% and a change in composition affected the macroinvertebrate assemblage, which recovered in approximately 9 months. At the same site, the fish survey showed that brown trout juveniles were affected by the sediment load from the flushing operations. Only minor effects were detected on macroinvertebrates and fish subjected only to the increase in streamflow, i.e. above the stream junction. Copyright © 2016 John Wiley & Sons, Ltd.