bluuebunny/crossref_metadata_2025 huggingface dataset:
Commentary; Present status of clinical psychopharmacology
Authors: Berger Frank M.
Published: January 2016

During the first half of the twentieth century American psychotherapy was dominated by the psychoanalytic and behavioristic concepts of mental disease. The view that at least some mental disturbances may have a physical or biological basis, although held and argued by many physicians since antiquity, did not gain wide acceptance until the discovery of the psychotherapeutic drugs in the 1950s.1 The widespread use of these drugs since that time has not only greatly changed the treatment of mental disorders but has also substantially improved our understanding of mental disease. Enough time has now passed to temper the initial enthusiasm that followed the introduction of these drugs and to accumulate enough experience in their use to make this an appropriate time to evaluate their effectiveness and value in the treatment of mental diseases.
Guanabenz effects on blood pressure and noninvasive parameters of cardiac performance in patients with hypertension
Authors: Shah Rajnikant S. , Walker Barry R. , Vanov Svetislav K. , Helfant Richard H.
Published: January 2016

Guanabenz (2,6 dichlorobenzylidene amino guanidine acetate) is a new antihypertensive whose mechanism of action appears to involve both central alpha adrenergic stimulation leading to suppression of sympathetic nervous system activity from bulbar vasoconstriction centers as welt as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statisticalty and clinically significant decrease in blood pressure during a 4‐wk placebo‐controlted double‐blind study. For three additional months continued efficacy and safety were shown under open conditions in 17 hypertensive patients. Mild sedation occurred, but there were no postural hypotension, tachycardia, evidence of sodium retention, gastrointestinal disturbances, or electrocardiographic (ECG) abnormalities. Noninvasive parameters of cardiac performance in JO patients after single doses of guanabenz showed no significant changes. Although the numbers of patients were relatively small, the data suggest that this new drug may be a useful antihypertensive agent that warrants further investigation.”Guanabenz (2,6 dichlorobenzylidene amino guanidine acetate) is a new antihypertensive whose mechanism of action appears to involve both central alpha adrenergic stimulation leading to suppression of sympathetic nervous system activity from bulbar vasoconstriction centers as welt as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statisticalty and clinically significant decrease in blood pressure during a 4‐wk placebo‐controlted double‐blind study. For three additional months continued efficacy and safety were shown under open conditions in 17 hypertensive patients. Mild sedation occurred, but there were no postural hypotension, tachycardia, evidence of sodium retention, gastrointestinal disturbances, or electrocardiographic (ECG) abnormalities. Noninvasive parameters of cardiac performance in JO patients after single doses of guanabenz showed no significant changes. Although the numbers of patients were relatively small, the data suggest that this new drug may be a useful antihypertensive agent that warrants further investigation.
Kinetics of high‐dose intravenous morphine in cardiac surgery patients
Authors: Stanski Donald R. , Greenblatt David J. , Lappas Demetrios G. , Weser Jan Koch , Lowenstein Edward
Published: January 2016

Ten patients received 1.0 mg/kg of morphine sulfate by constant‐rate intravenous infusion at 5 mg/min over 9 to 27 min. Multiple arterial blood samples were drawn during the first 30 to 151 min after termination of the infusion, prior to institution of cardiopulmonary bypass. Postinfusion plasma concentrations were fitted by computer to biexponential functions consistent with a 2‐compartment open pharmacokinetic model. Mean (±SE) pharmacokinetic parameters were: volume ofcentral compartment, 0.09 ± 0.03 L/kg; total apparent volume of distribution, 1.02 ± 0.09 L/kg; distribution T½, 0.90 ± 0.09 min; apparent elimination T½, 137 ± 14 min; total clearance, 378 ± 63 ml/min. Thus distribution of morphine is very rapid, but the apparent volume of distribution is only slightly larger than body weight, suggesting limited tissue uptake. Since apparent elimination T½ are similar to those reported after smaller doses, evidence of saturable or capacity‐limited elimination is lacking. Total clearances, representing mainly hepatic clearance, averaged about 25% of hepatic blood flow, suggesting clinically important first‐pass metabolism of oral morphine.
Reactions to cigarettes as a function of nicotine and “tar”
Authors: Goldfarb Toni , Gritz Ellen R. , Jarvik Murray E. , Stolerman Ian P.
Published: January 2016

Experiments were carried out to examine the effects of nicotine and “tar” on the extent of and subjective reactions to cigarette smoking. It was confirmed that smokers rate commercial, low‐nicotine cigarettes as less “strong” and less “satisfying” than their usual brands. Since such cigarettes deliver reduced amounts of tar as weil as of nicotine, an experiment to distinguish between the two was carried out with special cigarettes. Ratings of “strength” were directly related to nicotine but were not affected by tar. The numbers of cigarettes smoked fell slightly as their estimated delivery of nicotine increased, but tar had no effect on this index. The urinary excretion of nicotine was correlated with the rated yields of nicotine for the different cigarettes, but there was also evidence that subjects tended to adjust their manner of smoking so as to titrate their doses of nicotine. The results are interpreted as indicating a role for nicotine, but not for tar, in the maintenance of cigarette smoking behavior, and as support for the view that less harmful cigarettes should have a high yield of nicotine relative to tar.
Naltrexone: Physiological and psychological effects of single doses
Authors: Gritz Ellen R. , Shiffman Saul M. , Jarvik Murray E. , Schlesinger Joseph , Charuvastra V. C.
Published: January 2016

An ascending series of single doses of the narcotic antagonist naltrexone, ranging from 20 to 160 mg, was administered to 8 abstinent former addicts in order to assess agonistic activity and any toxic side effects. There was tittle alteration of normal body function. Signijicant, but small, changes in sublingual temperature (0.4° F decrease), and diastolic blood pressure (1.7 mm Hg increase) were induced. Among the battery of tests assessing behavioral or mood‐feeling variables, only 2 showed significant between‐condition effects: facilitated performance on the Cross‐out Test (attention and perception), and a dose‐related decrease in Morphine‐Benzedrine Group (MBG) scores of the Addiction Research Center 1nventory (ARCI) (mild euphoria). On the whole, subjects had few subjective reactions or unpleasant side effects. Naltrexone appears to be a safe, nontoxic medication in the dosage range examined.
The interaction between halofenate and propranolol
Authors: Huffman David H. , Azarnoff Daniel L. , Shoeman Don W. , Dujovne Carlos A.
Published: January 2016

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double‐blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.
Plasma concentration of edrophonium in man
Authors: Calvey T. N. , Williams N. E. , Muir K. T. , Barber H. E.
Published: January 2016

The plasma concentration of edrophonium was measured in man after intravenous administration. In 5 patients, the clearance of edrophonium from the circulation during the 1‐hr period of sampling was invariably resolved into 2 exponential components. An initial rapid phase of elimination from plasma (T/2 = 0.54 to 1.92 min) was followed by a much slower decline (T/2 = 24.23 to 45.00 min), corresponding to the fall in concentration between 10 and 60 min. In parallel experiments in the rat, the clearance of 14C‐edrophonium was resolved into 3 exponential components, although the final component could not be reliably defined until 1 to 3 hr after intravenous injection. It is suggested that the rapid fall in the plasma concentration of edrophonium in both species is not dependent on metabolism or excretion, but is due to the rapid uptake of the drug by the liver and kidneys.
Clinical comparison of adriamycin and a combination of methyl‐CCNU and imidazole carboxamide in disseminated malignant melanoma
Authors: Ahmann David L. , Bisei Harry F. , Edmonson John H. , Hahn Richard G. , Eagan Robert T. , O'Connell Michael J. , Frytak Stephen
Published: January 2016

The effects of adriamycin were compared to a combination program of methyl‐CCNU and imidozole carboxamide (DTIC) in 44 patients with disseminated malignant melanoma. There were objective clinical responses in 6 of 21 patients with the combination of DTIC and methyl‐CCNU who received this program as primary treatment and none in 23 patients receiving adriamycin as primary treatment. Secondary responses were not observed with either treatment regimen. Toxicity with the combination program included leukocyte depression (<3,000/cu mm) in 25% and platelet depression (<100,000/cu mm) in 40% compared to 52% leukocyte depression and 16% platelet depression after adriamycin. There were no responses after the combination treatment program in the absence of myelosuppression. There was nausea and vomiting in virtually all patients, which was moderately severe in one third of the patients receiving the combination and in only 10% of those receiving adriamycin. Alopecia developed in all who received adriamycin but in only 15% of the combination treatment group. The combination treatment response of 28% was of the same order as most response rates previously reported in this disease. This randomized controlled clinical trait found adriamycin without clinical benefit and not worthy of further trial in patients with disseminated malignant melanoma.
Anorectal pruritus after intravenous hydrocortisone sodium succinate and sodium phosphate
Authors: Novak E. , Gilbertson T. J. , Seckman C. E. , Stewart R. D. , DiSanto A. R. , Stubbs S. S.
Published: January 2016

A double‐blind study demonstrated that single intravenous doses of 100, 200, or 400 mg of hydrocortisone sodium succinate and hydrocortisone sodium phosphate were similar in eosinophil suppression, elevation of glucose, white blood count differential shifts (polymorphonuclear celis, lymphocytes, and monocytes), and urinary excretion of sodium and potassium but not in incidence of side effects. More subjects receiving hydrocortisone sodium phosphate experienced systemic or localized adverse effects than those receiving hydrocortisone sodium succinate. The most common side effect was burning or itching in the anorectal area, which occurred in 16 of 18 subjects medicated with hydrocortisone sodium phosphate, in 1 subject of 6 treated with placebo (saline), and in none who received the sodium succinate. The effect is attributed to the phosphate steroid and appears to last as long as it takes to convert to cortisol.
Bailar's laws of data analysis
Authors: Bailar John C.
Published: January 2016

If Newton's apple had fallen up, we might have some odd ideas about the laws of gravity.
Kinetics and dose calculations of amikacin in the newborn
Authors: Sardemann Henrik , Colding Hanne , Hendel Jøsrn , Kampmann Jens P. , Hvidberg Eigill F. , Vejlsgaard René
Published: January 2016

The pharmacokinetics of a new aminoglycoside, amikacin, was evaluated in 37 infants between 1 and 34 days old. Fifteen were below 2,500 gm in weight. initial studies, including intravenous infusion in some of the infants, indicated that the disposition of amikacin was best described by a 2 compartment model. The absorption was evaluated in 8 of the infants after intramuscular injection of 7.5 mg amikacin per kilogram of body weight. The absorption rate, estimated by the tmax, was significantly faster than reported in adults. The total body clearance and apparent volume of distribution were studied in 22 infants after the same dose of amikacin intramuscularly. The body clearance expressed in relation to body surface or body weight was significantly less than in adults and correlated with the postnatal age. No correlation could be demonstrated between clearance and gestational age or birth weight. The volume of distribution per kilogram was significantly greater than in adults. On the basis of the derived kinetic parameters, a dose schedule is presented. In 5 children there was a reasonable agreement between the measured and predicted serum levels.
Pentobarbital elimination in patients with poor renal function
Authors: Reidenberg Marcus M. , Lowenthal David T. , Briggs William , Gasparo Maryanne
Published: January 2016

Drug oxidation is slowed in experimental uremia in animals but has been reported to be normal or accelerated in uremic patients. Eleven normal subjects and 9 uremic patients were each given 100 mg pentobarbital orally. Several blood samples were drawn over a 36‐hr period starting on the morning after the dose. Plasma pentobarbital concentration was measured by GLC. The log concentration values were graphed against time elapsed after dose for each patient, and the plasma T/2 and extrapolated value of concentration at the time of drug administration (Co) were determined. The T/2 values in normals ranged from 18 to 48 hr; mean, 26.5 ± 9.2 (SD). In uremic patients, T/2 values are 10 to 38 hr, mean, 21.3 ± 8.7. Four of the uremic patients had T/2 values below 18 hr (which was the lowest in the normals). The apparent volumes of distribution of pentobarbital (aVD = dose 7 Co) were 62 ± 25 L in the normal subjects and 58 ± 24 L in the uremic patients. The four uremic patients with the short T /2 values tended to have small apparent volumes of distribution so that the metabolic clearance rates (aVd x 0.693 ÷ half‐life) were normal in 3 of them. We conclude that pentobarbital elimination is normal in renal failure. Some uremic patients have short plasma T/2 values for pentobarbital, and these more likely result from low apparent volumes of distribution with normal metabolic clearance rates than from accelerated metabolism of pentobarbital.
Elimination of antipyrine and benzo[a]pyrene metabolism in cultured human lymphocytes
Authors: Kellermann Gottfried , Luyten‐Kellermann Mieke , Horning Marjorie G. , Stafford Michele
Published: January 2016

A strong correlation was found in a carefully selected homogenous population (n = 57) between antipyrine plasma half‐life and the percent induction of aryl hydrocarbon hydroxylase by 3‐methylcholanthrene in mitogen‐stimulated lymphocytes from the same individual. The correlation coefficient of r = −0.923 indicates that antipyrine and benzo[a]pyrene share one or several common determinants that are responsible for the observed interindividual variation in the oxidation rates of the two compounds. When a heterogenous population (n = 80) was studied. the above correlation was not found (r = −0.425).
The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic liver disease
Authors: Branch Robert A. , James John A. , Read Alan E.
Published: January 2016

The pharmacokinetics after oral administration of 1,200 mg antipyrine and intravenous administration of 0.5 mg/kg indocyanine green have been investigated in 6 normal subjects and in 20 patients with chronic liver disease of varying etiology. Severe impairment of liver junction associated with a decrease in serum albumin, elevation in serum bilirubin, or prolongation in prothrombin time correlated with a fall in the clearance of both drugs. The clearances of the two drugs correlated well in normal subjects and in patients with chronic liver disease. The presence of a surgical portacaval anastomosis was associated with a lower indocyanine green clearance for comparable clearance of antipyrine. The concept of functioning hepatic parenchymal mass is proposed as a common rate‐limiting parameter for the elimination of the two drugs.
Spironolactone and potassium canrenoate in normal man
Authors: Ramsay Lawrence , Shelton John , Harrison Ian , Tidd Michael , Asbury Michael
Published: January 2016

The pharmacological activity of single doses of the two aldosterone antagonists, potassium canrenoate and spironolactone, was examined in two studies in healthy volunteers. Both drugs were active in reversing urinary electrolyte changes induced by fludrocortisone in periods 2 to 16 hr after treatment. Potassium canrenoate was significantly less potent than spironolactone on a weight or molar basis, with best estimates of the relative potency potassium canrenoate: spironolactone of approximately 0.3 : 1. On a weight basis the two drugs yielded plasma levels of the metabolite canrenone which were approximately equivalent. The results indicate that canrenone is not the principal pharmacologically active metabolite of spironolactone. Our study suggests that a major part of the renal anti mineralocorticoid activity of spironolactone may be attributable to minor sulfur‐containing metabolites or their precursors having a high renal clearance that affords access to their site of activity via the renal tubular fluid.
Effect of diazepam on ventilatory responses
Authors: Lakshminarayan S. , Sahn Steven A. , Hudson Leonard D. , Weil John V.
Published: January 2016

To investigate the effects of diazepam on ventilatory control, hypoxic and hypercapnic ventilatory responses were studied in 8 normal subjects before and after 10 mg of intramuscular diazepam. There was no significant change in either resting minute ventilation or resting end‐tidal CO2 tension, but depression of hypoxic ventilatory response was observed 15 (60% of control) and 30 min (53% of control) after diazepam (p < 0.05). No significant depression of hypercapnic ventilatory response was noted 70 to 130 min alter diazepam. In view of the depression of hypoxic ventilatory response by diazepam in normal subjects, adverse responses along these lines should be considered in patients with impaired ventilatory function, such as chronic airways obstruction, and in those encountering acute hypoxemia.
Lithium treatment during alcoholic withdrawal
Authors: Sellers E. M. , Cooper S. D. , Zilm D. H. , Shanks C.
Published: January 2016

The efficacy of lithium carbonate was studied in 18 chronic alcoholic male patients in withdrawal. In mild alcoholic withdrawal, oral lithium carbonate, 0.3 gm every 8 hr, diminishes subjective symptoms of withdrawal and normalizes performance on a motor tracking task. Patients who start lithium while drinking ethanol improve most probably because it takes longer than 3 days for lithium concentrations in the blood to plateau. Lithium does not importantly alter patterns of catecholamine excretion, blood pressures, heart rate, serum cyclic‐adenosine monophosphate (AMP), serum dopamine ß‐hydroxylase (DBH), sleep pattern, or tremor amplitude during withdrawal.
Metabolism of ethosuximide
Authors: Goulet J. R. , Kinkel A. W. , Smith T. C.
Published: January 2016

Twenty subjects, in a double‐blind, controlled, rising dose study, were given ethosuximide either once daily or 3 times daily. Steady‐state plasma levels and urinary throughput were proportional to dose and were equivalent whether the daily dose was given as a single or a divided dose. This finding adds validity to consideration of the single daily dose regimen as a therapeutic possibility. The metabolic principles should be considered both in patient management and in the treatment of overdosage.
Enzyme induction by oral testosterone
Authors: Johnsen Svend G. , Kampmann Jens P. , Bennett Edgar P. , Jørgensen F. Schønau
Published: January 2016

Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half‐life had decreased significantly from 8.0 ± 2.7 to 5.7 ± 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty‐first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine‐amino‐transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug‐metabolizing system including that of testosterone.
Intestinal blood loss after a new anti‐inflammatory drug, sulindac
Authors: Cohen Albert
Published: January 2016

Sulindac was tested for fecal blood loss in 40 healthy male subjects whose red cells had been labeled with Na251CrO4. Two daily dose levels of 240 mg and 400 mg were compared with 4.8 gm of aspirin and placebofor 2 wk. At day 15, aspirin‐induced blood loss was greater than that of both dose levels of sulindac and of placebo (p < 0.05). There were no significant differences between the two sulindac groups and the placebo group. Aspirin caused more adverse reactions than sulindac, 240 mg (p < 0.05), 400 mg (p < 0.05), and placebo (p < 0.05).
Transient cardiac arrhythmias after single daily maintenance doses of digoxin
Authors: Manninen V. , Reissell P. , Paukkala E.
Published: January 2016

Ten digitalized patients were monitored for detection of cardiac arrhythmias 0 to 8 hr after daily maintenance dose of digoxin in the fasting state. Transient cardiac arrhythmias attributable to digoxin were seen at 2 to 5 hr in 5 subjects. Initial serum concentrations of digoxin were within standard clinical limits in all subjects, but, higher steady‐state levels were present in patients with arrhythmias (1.2 to 1.7 nglml) than in the others (0.7 to 1.2 nglml). The postadministrative serum peak concentrations were also higher in the patients with arrhythmias.
Pharmacokinetics of naproxen overdoses
Authors: Runkel Richard , Chaplin Melvin D. , Sevelius Hilli , Ortega Eduardo , Segre Eugene
Published: January 2016

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subjects without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of J, 2, 3, or 4 gm (up to eight times the clinically e.ffective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.
Influence of viral hepatitis on the disposition of two compounds with high hepatic clearance: Lidocaine and indocyanine green
Authors: Williams Roger L. , Blaschke Terrence F. , Meffin Peter J. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

The disposition of lidocaine and indocyanine green was studied in 6 individuals during and after recovery from an episode of acute viral hepatitis. Both compounds are highly cleared from the blood by the liver so that clearance of both should be sensitive to changes in hepatic blood flow. During the acute phase of illness, clearance of indocyanine green decreased without apparent change in volume of distribution, whereas clearance of lidocaine, decreased in 4, did not change in I, and increased in 1 during the acute phase of hepatitis. Volume changes for lidocaine were also variable. We observed no significant correlation between any parameters of lidocaine disposition and any of several tests of liver function or any parameters of indocyanine green disposition. The absence of correlation between pharmacokinetic parameters of the disposition of lidocaine and indocyanine green indicates that the influence of hepatic disease on the hepatic processes that lead to the elimination of each compound is not predictable. No useful clinical correlates are now available by means of which to predict lidocaine disposition in patients with altered hepatic function.
Naltrexone: Disposition, metabolism, and effects after acute and chronic dosing
Authors: Verebey Karl , Volavka Jan , Mule Salvatore J. , Resnick R. B.
Published: January 2016

The disposition of naltrexone during acute and chronic administration of 100‐mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 ± 29.9 ng/ml at 1 hr and for the major biotransformation product, β‐naltrexol, was 87.2 ± 25.0 ng/ml at 2 hr. Twenty‐four hours after the dose the X levels of naltrexone and f3‐naltrexol declined to 2.1 ± 0.47 and 17.6 ± 5.0 ng/ml, respectively. Following chronic administration the X peak plasma levels of naltrexone and β‐naltrexol rose to 46.4 ± 18.5 and 158.4 ± 89.9 ng /ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and f3‐naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady‐state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and β‐naltrexol in the first 24 hr. The half‐life of naltrexone and β‐naltrexol decreased slightly from the acute to the chronic study from 10.3 ± 3.3 to 9.7 ± 1.1 hr and from 12.7 ± 2.6 to 11.4 ± 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half‐life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6%, while urinary excretion was 38% and 70% of the dose in a 24‐hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half‐life of naltrexone and opiate antagonism it was 0.99.
Clinical pharmacokinetics of lorazepam
Authors: Greenblatt David J. , Schillings Roger T. , Kyriakopoulos Adrian A. , Shader Richard I. , Sisenwine Samuel F. , Knowles John A. , Ruelius Hans W.
Published: January 2016

Eight healthy male subjects received single 2‐mg oral doses of lorazepam containing 24 uLCi Img of 2‐14C‐lorazepam. Multiple venous blood samples were drawn during the .first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first‐order half‐life of 15 min. The peak plasma concentration was 16.9 ng Iml, measured in the pooled sample drawn 2 hr after the dose. This corresponded to the time at which clinical eflects appeared to be maximal. The apparent elimination half‐life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.
Amobarbital—a probe of hepatic drug oxidation in man
Authors: Inaba T. , Tang B. K. , Endrenyi L. , Kalow W.
Published: January 2016

Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of' orally available over intravenously injected amobarbital was established as 0.99 ± 0.11 (SD), by comparing integrated concentration‐time curves, indicating complete absorption and absence of a first‐pass eff'ect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first‐order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 ± 1.8 [SD] ml/min) exhibited remarkable constancy, while biologic half/lives (26.5 ± 3.1 hr) and distribution volumes (73.6 ± 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half‐lives (23.8 ± 6.7 hr) appeared to be normally distributed, while the clearances (36.7 ± 10.0 ml/min) might not follow a normal distribution.
Side effects of levomethadone and racemic methadone in a maintenance program
Authors: Judson Barbara A. , Horns William H. , Goldstein Avram
Published: January 2016

use, clinic attendance, and dose changes on levomethadone and d,l (racemic) methadone. The hypothesis under examination was that dextromethadone, while adding no narcotic actions to the racemate, was contributing to side effects. An earlier single‐blind pilot study showed that 9 out of 11 side effects improved while patients were receiving levomethadone, but this larger study did not duplicate those results. Analysis of 25 variables showed no significant differences between levo‐ and racemic methadone. There appears to be no advantage in levomethadone over racemic methadone in the treatment of patients in maintenance programs.
Nortriptyline plasma levels and therapeutic response
Authors: Ziegler Vincent E. , Clayton Paula J. , Taylor John R. , Co Bun Tee , Biggs John T.
Published: January 2016

Eighteen depressed outpatients were treatedfor 6 wk with a mean daily dose of 121 mg of nortriptyline. The mean plasma level was 138 ng/ml during treatment. Therapeutic response was monitored by the Zung Self‐Rating Depression Scale and the Hamilton Depression Scale administrered by two psychiatrists blind to the tricyclic used, dose, and plasma levels. Eight patients recovered (Hamilton ≧ 6) by the fourth week and 12 by the sixth week. During the steady‐state (wk 4 to 6) there was a positive correlation between the weekly Hamilton scores and the weekly nortriptyline levels (p < 0.01). The 9 patients with mean plasma levels between 50 and 139 ng/ml had a better therapeutic response after 6 wk measured by percent recovered (p < 0.005), Zung score (p < 0.05), and Hamilton score (p < 0.025) than the 9 patients with mean plasma levels between 140 and 260 nglml.
Antipyrine clearance in homozygous β‐thalassemia
Authors: Rifkind Arleen B. , Canale Virginia , New Maria I.
Published: January 2016

Serum half‐lives for antipyrine were normal or shorter than normal in 19 subjects between 7 and 23 yr of age with β‐thalassemia major. The mean antipyrine serum half life (±SE) for the group as a whole was 8.5 ± 0.6 hr. The mean antipyrine half‐lives (t½) for the younger subjects were within the range reported for normal children, while the mean t½ for the older males approached the values reported for normal adult males. The mean t½ for the older females was shorter than has been reported for normal adult females. The mean apparent volume of distribution for antipyrine (±SE) in the subjects with thalassemia was 0.69 ± 0.01 L/kg. Thus, total body water appears to be increased in thalassemia. The mean metabolic clearance rate for antipyrine (±SE) in the group as a whole (1.07 ± 0.08 ml/min/kg) is substantially higher than the metabolic clearance rates for antipyrine reported in normal adults. Thus, the relatively short t½s of antipyrine in subjects with thalassemia are attributable to rapid rates of clearance of the drug. The data indicate that antipyrine clearance is unimpaired in patients with thalassemia despite evidence of liver damage and iron overload. Our study supports the proposition that hepatic microsomal hemoprotein synthesis is not adversely affected in homozygous β‐thalassemia.
Aminopyrine demethylation measured by breath analysis in cirrhosis
Authors: Bircher Johannes , Küpfer Adrian , Gikalov Iva , Preisig Rudolf , Preisig Rudolf
Published: January 2016

The method of measuring the rate of aminopyrine demethylation by breath analysis was assessed in 23 normal subjects and 20 patients with cirrhosis. Carbon 14 aminopyrine specifically labeled at the two N‐methyl groups was administered by mouth in a dose of 9 mg/kg, including a total radioactivity of 2 μCi. The decay of the specific activity of 14C02 in breath (kb) was found to correlate (r = 0.91) with the disappearance of aminopyrine from plasma (Kp). In normal volunteers, kb was 22.4%/hr; in patients with alcoholic and nonalcoholic cirrhosis it was depressed to 8.4%/hr (p < 0.001). The degree of functional impairment found with the breath test was similar to the sulfobromophthalein (BSP) disappearance curve and the galactose elimination capacity. Although many questions relating to the aminopyrine breath test remain open, our data confirm and extend previous studies of 14CO2 breath analysis after 14C‐aminopyrine administration. It is concluded that it represents a simple and noninvasive procedure which quantitatively reflects the microsomal function of the cirrhotic liver.
Comparison of the hydroxylation of zoxazolamine and benzo[a]pyrene in human placenta: Effect of cigarette smoking
Authors: Kapitulnik J. , Levin W. , Poppers P. J. , Tomaszewski J. E. , Jerina D. M. , Conney A. H.
Published: January 2016

The in vitro hydroxylation or zoxazolamine was compared with the hydroxylation or benzo[a]pyrene (BP) in full‐term placentas from 11 nonsmokers and from 13 women who smoked cigarettes during pregnancy. Cigarette smoking increased the average zoxazolamine and benzo[a]pyrene hydroxylase activities 13‐ and 39‐fold, respectively. A 59‐fold range in benzo[a]pyrene hydroxylase activity and a 28‐fold range in zoxazolamine hydroxylase activity were found in the placentas of cigarette smokers. A plot of these two enzyme activities showed that zoxazolamine hydroxylase activity was highly correlated, with benzo[a]pyrene hydroxylase activity in the 24 placentas studied (r = 0.98; p < 0.001). A strong correlation between the above enzymatic activities was also found in 8 placentas whieh had been storedfor 2 yr at −20° C (r = 0.95; p < 0.001). The results suggest that benzo[a]pyrene and zoxazolamine are metabolized in the human placenta by the same enzyme system or by different systems that are under the same regulatory control.
Fluoride kinetics after enflurane anesthesia in healthy and anephric patients and in patients with poor renal function
Authors: Carter Roland , Heerdt Mark , Acchiardo Sergio
Published: January 2016

Enflurane, a fluorinated methylethyl ether, is metabolized, in part, to inorganic fluoride, Methoxyflurane has similar metabolism, and cases of fluoride ion‐induced renal failure have been reported after its use. This prospective study was initiated to determine fluoride ion kinetics after enjiurane anesthesia in 16 healthy patients, 18 anephric patients, and 6 patients each having a creatinine clearance of less than 5 ml/min (on dialysis). Serum and urine inorganic fluoride levels were determined. There was no clinical or statistical significance difference among the 3 groups with respect to maximum inorganic fluoride ion concentration or the time to reach it. The fluoride ion values were never above the 50 µM level that has been reported to cause subclinical renal toxicity. The fluoride ion concentration in serum fell rapidly after termination of anesthesia even in the anephric patients. This is presumed to be due to uptake of the ion by bone. Patients with low creatinine clearance also have low fluoride ion clearance. Statistical but not clinical significance was found in the comparison between pre‐enflurane and the 24‐hr fluoride ion va lues in the anephric and low creatinine clearance patients, but this did not persist after one dialysis.
Combination chemotherapy with adriamycin and streptozotocin; I. Clinical results in patients with advanced sarcoma
Authors: Chang Paul , Wiernik Peter H.
Published: January 2016

In a prospectively randomized study, 17 evaluable patients treated with adriamycin alone, 60 mg/m2 intravenously every 3 wk, were compared with 14 patients treated with adriamycin in the same dose and schedule plus streptozotocin, 500 mg/m2/day intravenously for 5 days every 3 wk. All patients had advanced sarcomas, but none had previously received either adriamycin or streptozotocin. Objective responses were seen in 9 patients on the single drug arm (4 with more than 50% tumor shrinkage and 5 with stabilization of disease), and in 8 patients given the combination drug arm (2 with more than 50% tumor shrinkage and 6 with stabilization oldisease). Duration of response and survivalfrom treatmentfor both treatment groups were similar. Transient hepatic dysfunction, renal function abnormalities, and nausea with vomiting were additive in the combination drug arm, the last two limiting therapy most. Leukopenia, thrombocytopenia, and mucositis appeared to be synergistically increased in patients receiving both adriamycin and streptozotocin. Patients with abnormal pretreatment renalfunction were able to tolerate the combination therapy without undue incidence or severity of renal toxicity. Patients who developed transient streptozotocin‐related renal dysfunction were able to toleratefurther doses of streptozotocin alter their renal parameters normalized. Adriamycin in combination with streptozotocin did not offer any therapeutic advantage over adriamycin alone.
Combination chemotherapy with adriamycin and streptozotocin; II. Clinicopharmacologic correlation of augmented adriamycin toxicity caused by streptozotocin
Authors: Chang Paul , Riggs Charles E. , Scheerer Michael T. , Wiernik Peter H. , Bachur Nicholas R.
Published: January 2016

Plasma pharmacokinetics were compared in patients with advanced sarcomas receiving adriamycin, 60 mg/m2 intravenously (iv) on day 1 every 3 wk in combination with streptozotocin, 500 mg/m2/day iv on days 1 to 5 every 3 wk, and patients receiving adriamycin alone in the same dose and schedule. The combination‐treated group had greater adriamycin drug exposure (concentration × time) when serial plasma levels were analyzed by fluorescence assay and by radioimmunoassay (RlA). The plasma t½ of adriamycin equivalents measured by fluorescence assay was also significantly prolonged in the combination‐treated group. These changes correlated welt with an increase in adriamycin‐related toxicity—mucositis and myelosuppression—seen in the patients who received the combination drug therapy. Plasma streptozotocin kinetics and the incidence of streptozotocin‐related side effects—hepatic and renal function abnormalities—were those published for streptozotocin alone. Evidence is presented to support the hypothesis that the increased incidence of adriamycin side effects is due to streptozotocin‐related hepatic dysfunction, affecting both the detoxification and excretion of adriamycin. Combination of other drugs with adriamycin should take into account their potential for inducing hepatic dysfunction which may affect the therapeutic index of adriamycin.
In memoriam—Henry Wood Elliott (1920–1976)
Authors: Gifford Ray W.
Published: January 2016

It is with deep regret and a profound sense of loss that I must report the death of Dr. Henry Wood Elliott on August 1 at his home in Santa Ana, California.
Interaction between antipyrine and aminopyrine
Authors: Vesell Elliot S. , Thomas Passananti G. , Hepner Gershon W.
Published: January 2016

Aminopyrine administered to normal human volunteers in an oral dose of either 9 mg/kg or 4.5 mg/kg prolonged the plasma half‐life and reduced the metabolic clearance rate of antipyrine (18 mg/kg, orally) without changing its apparent volume of distribution. By contrast, this same oral dose of antipyrine given simultaneously with 9 mg/kg aminopyrine failed to alter aminopyrine disposition. Thus, antipyrine and aminopyrine should not be administered simultaneously to measure different steps in hepatic drug oxidation, although in man aminopyrine can be given for this purpose 24 hr after antipyrine. Antipyrine elimination was prolonged to the same extent when aminopyrine was given 5 hr before antipyrine as when the drugs were given simultaneously. Since in man aminopyrine has a biologic half‐life of approximately 2.7 hr, the marked inhibitory effects observed 5 hr after aminopyrine administration may be due to its major metabolite, 4‐aminoantipyrine. To define the mechanism by which aminopyrine affects antipyrine disposition in vivo, hepatic microsomes were prepared from rats, mice, and dogs, and rates of antipyrine hydroxylation were measured in vitro both in the absence and in the presence of aminopyrine. In these species in vitro inhibition of antipyrine hydroxylation by 4‐aminoantipyrine was of a mixed type; antipyrine inhibited competitively aminopyrine N‐demethylation in vitro in rats, mice, and dogs. There were some sex and species differences in the Km, Vmax, and Ki for aminopyrine and antipyrine.
Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content
Authors: Joubert Pieter , Kroening Bruce , Weintraub Michael , Fleckenstein Lawrence
Published: January 2016

Serial electrocardiograms and serum digoxin levels were obtained in four healthy volunteers receiving daily doses of digoxin, 0.25 mg for the first two weeks and 0.5 mg for two more weeks. We found a linear relationship between serum digoxin levels and the “PTQ index” (a function of the PR‐interval, corrected QT‐time, and T‐wave depression). In 3 of the 4 subjects the correlation was statistically significant. The degree of linear correlation was improved when PTQ was correlated with the computer‐calculated total body burden of digoxin.
Influence of cannabidiol on secobarbital effects and plasma kinetics
Authors: Dalton William S. , Martz Robert , Rodda Bruce E. , Lemberger Louis , Forney Robert B.
Published: January 2016

To investigate the possible metabolic interaction between cannabidiol (CBD) and secobarbital, 6 male volunteers received 150 mgl70 kg sodium secobarbital orally immediately after smoking a marihuana cigarette prepared to deliver 0, 150, or 500 µg/kg CBD. The study was performed in a double‐blind manner with each of the three treatments being assigned to every subject. Clinical effects and plasma secobarbital concentrations were recorded at periodic intervals. CBD did not alter the summary parameters which describe the secobarbital plasma concentration time curve. Secobarbital half‐life, peak concentration, time of peak concentration, and area under the curve were unchanged by the coadministration of CBD. Clinical effects of secobarbital were also unaltered by CBD pretreatment. Thus at the doses administered, CBD does not appear to inhibit secobarbital metabolism in man.
Antihypertensive efficacy of a single bedtime dose of methyldopa
Authors: Wright J. M. , McLeod P. J. , McCullough W.
Published: January 2016

To compare the antihypertensive efficacy of methyldopa administered once at bedtime with the same total dose given three times daily, a double‐blind crossover study was performed in 14 patients previously well controlled on methyldopa. Each patient received a total daily dose of 0.375 gm, 0.75 gm, or 1.5 gm of methyldopa, depending on the dose of drug that had previously been successful in that individual. The trial design included either 12 wk of methyldopa three times daily (TID) followed by 12 wk of single daily bedtime (HS) doses of methyldopa or administration of drug in the reverse order. Supine and erect blood pressures were recorded 4 times daily (8 A.M., 12 noon, 4 P.M., and 8 P.M.) every 4 wk throughout the study. Blood pressure control was excellent in all patients whether the drug was administered three times daily or at bedtime. Systolic pressures were slightly lower at 8 A.M., when methyldopa was given at bedtime than on doses three times daily, and systolic and diastolic pressures were slightly higher at 8 P.M. that at 8 A.M. on the bedtime regimen.
Normal lymphocyte function in the presence of delta‐9‐tetrahydrocannabinol
Authors: Rachelefsky Gary S. , Opelz Gerhard
Published: January 2016

Delta‐9‐tetrahydrocannabinol (Δ‐9‐THC), the psychoactive component of marijuana, in concentrations of 0.6 × 10−4 M to 10.6 × 10−4 M, has no effect on the deoxyribonucleic acid (DNA) synthesis of resting normal human lymphocytes or on their responses to phytohemagglutinin or to allogeneic lymphocytes.
XXXVIII. Computer malpractice
Authors: Feinstein Alvan R.
Published: January 2016

During the short space of the three decades since World War II, encounters with computers have become commonplace. The intellectual applications of computation, which were once restricted to complex mathematical calculations, now appear in such diverse domains as history, geology, and music. The machines were initially located only in a few, isolated research laboratories; today a housewife can have a computer in her kitchen.
Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes
Authors: Kapitulnik J. , Levin W. , Lu A. Y. H. , Morecki Rachel , Dansette P. M. , Jerina D. M. , Conney A. H.
Published: January 2016

The comparative hydration of styrene 7,8‐oxide, octene 1,2‐oxide, naphthalene 1,2‐oxide, phenanthrene 9,10‐oxide, benzo[a]anthracene 5,6‐oxide, 3‐methylcholanthrene 11,12‐oxide, dibenzo[a,h]anthracene 5,6‐oxide, and benzo[a]pyrene 4,5‐, 7,8‐, 9,10‐, and 11,12‐oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10‐oxide was the best substrate for the human and rat epoxide hydra ses and dibenzo[a,h]anthracene 5,6‐oxide and benzo[a]pyrene 11,12‐oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydra se with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.
Acetaminophen production in man after coadministration of acetanilid and phenacetin; A study with stable isotopes
Authors: Baty John D. , Robinson Philip R.
Published: January 2016

A new method for the investigation of interindividual differenees in drug metabolism is described. We have studied the metabolism of ring‐deuterated acetanilid in man following the coadministration of phenaeetin. The principal metabolite of acetanilid‐d5 is acetaminophen‐d4, and the principal metabolite of phenaeetin is acetaminophen‐d0. Using agas chromatograph‐mass spectrometer (gc‐ms) we are able to monitor both the deuterium‐labeled acetaminophen produeed by hydroxylation of acetanilid‐d5 and the nonlabeled material produecd by oxidative removal of the ethyl group in phenacetin. This system allows us to detect differences in the handling of these drugs by different subjects.