bluuebunny/crossref_metadata_2025 huggingface dataset:
Preserved Renal Perfusion During Treatment of Essential Hypertension with the Beta Blocker Nadolol
Authors: O'CONNOR DANIEL T. , BARG ANNA P. , DUCHIN KENNETH L.
Published: March 2013

Abstract: Several beta‐adrenergic antagonists impair renal perfusion during treatment of hypertension in man. The acute and chronic effects of a new noncardioselective beta blocker, nadolol, on renal hemodynamics, intravascular volume, and renal electrolyte excretion were studied in 10 men with essential hypertension. Oral nadolol normalized systemic blood pressure without impairment of glomerular filtration rate or renal blood flow, indicating preserved renal blood flow and glomerular filtration rate autoregulation. Intravascular volume and renal excretion of electrolytes were similarly unaltered. Once‐daily nadolol lowers blood pressure without renal hemodynamic or functional embarrassment.
Acute Pharmacodynamics and Pharmacokinetics of Oral Amrinone
Authors: BENOTTI JOSEPH R. , LESKO LAWRENCE J. , McCUE JANE E.
Published: March 2013

Abstract: Amrinone was administered orally as a single 100‐mg dose to six male patients with moderate‐severe congestive heart failure to determine the acute pharmacodynamic effects and pharmacokinetics of the drug. Following right heart catherization and amrinone administration, measurements of hemodynamic parameters including cardiac index (CI), right atrial pressure (RA), pulmonary capillary wedge pressure (PCW), and serum amrinone concentrations (SAC) were made at hourly intervals for up to 8 hours. CI increased (29.0 per cent) significantly (P < 0.05) at 3 hours after dose. PCW declined quickly after dose and was significantly (P < 0.05) lower (–31.3 per cent) than control at 3 hours. RA declined gradually, and a significant (P < 0.05) reduction (–25.2 per cent) was achieved 5 hours after the dose. Amrinone was absorbed quickly (tmax = 1.4 hour), and the disappearance of amrinone from serum was log‐linear (t½ = 5.1 hours). The time courses of per cent change in CI and SAC were similar, and the correlation between the average per cent change in CI and average SAC was linear and significant (r = 0.80; P < 0.05).
Clinical Experience with Amrinone in Patients with Advanced Congestive Heart Failure
Authors: KINNEY EVLIN L. , CARLIN BRIAN , BALLARD JAMES O. , BURKS JOHN M. , HALLAHAN WILLIAM F. , ZELIS ROBERT
Published: March 2013

Abstract: To examine the efficacy of chronic amrinone therapy, the drug was administered to 12 patients with advanced congestive heart failure on average for 27.9 days. The majority of patients had a persistent increase in cardiac index and a persistent decrease in systemic vascular resistance. A decrease in pulmonary arterial diastolic pressure was observed after oral amrinone administration in three patients. However, changes in pulmonary arterial pressure were not consistent in response to intravenous administration of the drug. Thrombocytopenia occurred in four patients, hypogeusia was noted by three patients, and dysosmia developed in two patients. The cumulative survival of the amrinone patients was significantly poorer than that of a second group of patients with congestive heart failure having similar symptoms. These findings indicate that there is a subset of patients with congestive heart failure who do not benefit from chronic amrinone administration and that in such patients its use (especially when given concomitantly with potentially toxic and hypotentsive drugs) should be extremely guarded.
Pharmacokinetics of Nalidixic Acid in Old and Young Volunteers
Authors: BARBEAU GILLES , BELANGER PIERRE‐M.
Published: March 2013

Abstract: Plasma levels of active naphthyridine were measured in healthy old (mean age 77.3 years) and young (mean age 25.4 years) subjects following oral administration of 1 Gm nalidixic acid. The plasma levels of active naphthyridine, i.e., nalidixic acid and its metabolite 7‐hydroxynalidixic acid, were generally higher in the old group, particularly in the elimination phase. Significant variations in the pharmacokinetic parameters were obtained between the two groups of volunteers. The plasma half‐life of active naphthyridine averaged 11.5 hours in old subjects and 2.7 hours in the younger group. Diminished renal function in the geriatric group may explain the slower elimination of the drug in the old subjects. The mean values of the other parameters calculated were: apparent volume of distribution, 0.55 (old) and 0.47 (young) liter/kg body weight; area under the curve, 327.7 (old) and 156.3 (young) μg/ml · hr; total body clearance 2.9 (old) and 8.3 (young) liters/hr; absorption rate constant, 0.29 (old) and 0.52 (young) hr.−1
Evaluation of Various Methods of Digoxin Dosing
Authors: JONES WILLIAM N. , PERRIER DONALD , TRINCA CARL E. , HAGER W. DAVID , CONRAD KENNETH
Published: March 2013

Abstract: The ability to precisely predict serum digoxin concentrations using 12 published methods in a group of 85 patients was undertaken. Two methods of estimating creatinine clearance and two estimates of ideal body weight were employed as input variables using the 12 dosing methods. This resulted in 40 relationships from which correlation coefficients and linear regression constants were derived for predicted versus measured serum digoxin concentrations. The correlation coefficients between predicted and measured serum digoxin ranged from −0.393 to 0.389. Possible explanations for the low correlation coefficients are interpatient variability in the kinetics of digoxin, the small number of subjects used to generate some of the digoxin dosing methods, undetected patient noncompliance in the present study, the use of empirically derived dosing methods, and/or the use of rather homogeneous patient populations to develop a given method while this study is comprised of a heterogeneous group of patients. The methods studied tend to overpredict serum digoxin concentrations and therefore generally allow safe, first approximations for digoxin dosing.
Effect of Food on Acetaminophen Absorption in Young and Elderly Subjects
Authors: DIVOLL MARCIA , GREENBLATT DAVID J. , AMEER BARBARA , ABERNETHY DARRELL R.
Published: March 2013

Abstract: Twenty‐four healthy volunteers aged 22 to 78 years received 650‐mg doses of acetaminophen (AAP) on five separate occasions. The modes of administration were: intravenous AAP by 5‐minute infusion; oral AAP as two 325‐mg tablets in the fasting state; oral AAP 650 mg as an elixir preparation in the fasting state; tablets with food; and elixir with food. Plasma concentrations of AAP were determined by high‐pressure liquid chromatography for up to 12 hours after the dose. In both the young and the elderly groups, the four oral modes of administration were significantly different with respect to peak plasma concentration (P < 0.001), time to peak plasma concentration (P < 0.001), and systemic availability (P < 0.01). Although food slowed the rate of absorption of both oral preparations, no significant difference in peak acetaminophen plasma concentration or time of peak concentration was observed as a function of age. Absolute systemic availability of elixir and tablets in the fasting state tended to be lower in the elderly subjects (P < 0.05). However, when either preparation was coadministered with food, there were no differences between the two age groups. Thus, age as such does not appear to be a critical determinant in the design of oral acetaminophen dosage schedules.
A Comparative Pilot Study of Enalapril, A New Converting Enzyme Inhibitor, and Hydrochlorothiazide in Essential Hypertension
Authors: FERGUSON ROGER K. , VLASSES PETER H. , IRVIN JOHN D. , SWANSON BRIAN N. , LEE ROBYN B.
Published: March 2013

Abstract: Eight patients with essential hypertension completed a double‐blind, randomly allocated crossover comparison of either 5 or 10 mg enalapril maleate, 50 mg hydrochlorothiazide, or their combination administered once daily during sequential two‐week periods. Blood pressure, pulse rate, plasma renin activity, angiotensin‐converting enzyme activity, plasma aldosterone concentration, and urinary electrolytes were monitored for 24 hours after placebo and on days 1 and 14 of each treatment period. After two weeks of each treatment, only the combination of enalapril and hydrochlorothiazide significantly lowered the mean seated diastolic blood pressure (SDBP). Likewise, SDBP control (≤ 90 mm Hg) was achieved only after combination therapy; six of the eight patients were controlled by the combination for up to 24 hours. The initial SDBP response to combination therapy differed with the sequence of drug addition; however, by day 14 the responses were comparable, regardless of whether hydrochlorothiazide or enalapril was first given. Mean converting enzyme activity was suppressed by enalapril in all patients, though it did not always correlate with changes in SDBP or plasma aldosterone. Mean plasma renin activity increased, but the increase was significant only on the combination. There were no serious adverse effects.
The Pharmacokinetics and Pharmacodynamics of Minaxolone
Authors: DUNN G.L. , MORISON D. H. , McCHESNEY J. , KUMANA C. R. , GUPTA R. N.
Published: March 2013

Abstract: Plasma concentrations of minaxolone were measured in 15 female patients during and for up to 3 hours after a minaxolone and nitrous oxide anesthetic. Nine patients received a single dose and six patients two or three doses of minaxolone. Plasma minaxolone decay can be described by two‐compartment kinetics. Distribution is rapid, with a mean half‐life of 2.1 minutes, and the elimination half‐life is short (47 minutes). Plasma clearance is high (1.55 l./min). Plasma levels of minaxolone at recovery were similar in patients receiving both single and multiple doses, suggesting a valid relationship between plasma level and effect. It is suggested that minaxolone may be a suitable agent for administration by continuous infusion.
Unstructured Two‐Point Estimation of One‐Compartment Linear Pharmacokinetic Parameters
Authors: BALL WILLIAM D.
Published: March 2013

Abstract: A method is described which estimates one‐compartment linear pharmacokinetic parameters from two serum drug concentrations obtained at any known times during a drug regimen. During multidose regimens, these two samples need not have a specific temporal relationship to a particular dose. Also, the method will predict eventual steady‐state drug concentrations early in the course of a continuous infusion. Modifications of the basic method will accommodate variations in the dosage regimen and permit the analysis of data in patients who have measurable serum drug concentrations prior to the start of the regimen.
Pharmacokinetic Implications of Lorcainide Therapy in Patients With Normal and Depressed Cardiac Function
Authors: Somani Pitambar , Fraker Theodore D. , Temesy‐Armos Peter N.
Published: March 2013

The influence of cardiac function as measured by the left ventricular ejection fraction on the pharmacokinetic variables of a new antiarrhythmic drug, lorcainide, was investigated in 20 cardiac patients. Patients were divided into two groups: those with normal (ejection fraction >.40) or depressed (ejection fraction >.40) left ventricular function. The elimination half‐life, plasma clearance rates, or volume of distribution of lorcainide were not significantly different in patients with either normal or depressed cardiac function. A decrease in arrhythmia frequency could be correlated to plasma lorcainide concentration in the majority of patients, and it was noted that at least 0.1 mg/L of lorcainide was required for the presence of an antiarrhythmic effect. Three unusual cases are presented to illustrate the importance of measuring plasma drug concentrations and calculating the drug pharmacokinetics and to correlate these to the antiarrhythmic response in order to minimize the risk of plasma drug accumulation and side effects. A review of published data shows a three‐ to sixfold interpatient variation in the elimination half‐life of lorcainide with practical implications in its use as an antiarrhythmic drug.
The Polymorphic Metabolism of Dextromethorphan
Authors: Woodworth J. R. , Dennis S. R. K. , Moore L. , Rotenberg K. S.
Published: March 2013

The ability of healthy male volunteers to metabolize a 30‐mg oral dose of dextromethorphan (DM) was studied in 252 Americans. Two blood samples were collected at four and 24 hours after administration of the dose. The resulting plasma was analyzed for unchanged DM. The volunteers were classified as slow, intermediate, or fast metabolizers on the basis of plasma concentrations of DM. Further differentiation of slow and intermediate metabolizers was achieved by comparing the two‐point estimates of elimination‐rate constants. In the population studied, 84.3% were fast DM metabolizers, 6.8% were intermediate metabolizers, and 8.8% were slow metabolizers. Previous reports have related the slow DM metabolizers to slow debrisoquin metabolizers, but no such correlations have been achieved with intermediate DM metabolizers. These intermediate DM metabolizers may suggest a new polymorphism not related to debrisoquin or may suggest that “debrisoquin gene” regulation is more complex than originally suggested.
The Bioavailability and Pharmacokinetics of Oral and Depot Intramuscular Haloperidol in Schizophrenic Patients
Authors: Nayak Ramchandra K. , Doose Dennis R. , Nair N. P. Vasavan
Published: March 2013

In a four‐segment long‐term (≥ 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration‐time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration‐time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5–35 mg/d for oral haloperidol (mean, 17 mg/d), and 75–500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long‐acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady‐state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose‐normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days. The calculated median IM dose was greater than the actual doses of haloperidol decanoate that had been used. However, clinical results, and not drug plasma concentrations, are the primary determinant of dose level, especially since haloperidol decanoate is given q28d. Thus, the appropriate method for determining the proper dose is to start low and to increase gradually as required by the patient's symptoms.
Nocturnal Doses of Ranitidine and Nizatidine Do not Affect the Disposition of Diazepam
Authors: Klotz U. , Gottlieb W. , Keohane P. P. , Dammann H. G.
Published: March 2013

The disposition of diazepam (D) after a single oral dose of 10 mg was evaluated in nine healthy male volunteers under the following conditions (randomized, double‐blind, crossover design): D + comedication of placebo and D + nocturnal dosing with 300 mg ranitidine or 300 mg nizatidine. Plasma concentrations of D and its major active metabolite, desmethyldiazepam (DD), were monitored by a gas‐liquid chromatography‐electron‐capture detection assay for 84 hours. Neither ranitidine nor nizatidine had any significant effect on the hepatic elimination of D as characterized by its terminal half‐life (mean ± SD) of 35.3 ± 24.2 hours (+ ranitidine: 30.1 ± 9.9 hr; + nizatidine: 37.3 ± 18.3 hr) or total plasma clearance of 28.2 ± 12.0 mh/min (+ ranitidine: 26.5 ± 7.9 mL/min; + nizatidine: 26.7 ± 10.4 mL/min). Likewise, the formation of DD as measured by its AUC was not affected by ranitidine or nizatidine. Thus, it can be concluded that concomitant once‐daily dosing (300 mg nocturnally) with ranitidine or nizatidine does not impair hepatic drug metabolism.
Lack of Effect of Withdrawal from Cigarette Smoking on Theophylline Pharmacokinetics
Authors: Eldon M. A. , Luecker P. W. , MacGee J. , Ritschel W. A.
Published: March 2013

The intravenous disposition of theophylline was determined in 12 healthy young male smokers during periods of smoking and short‐term withdrawal (24 to 36 hours), using a crossover design. Median half‐life, clearance, volume of distribution, hepatic extraction, and intrinsic clearance of theophylline during withdrawal were within ±5% of the corresponding median control (smoking) parameters and were normal in comparison with values published for smokers. The lack of change in the pharmacokinetic profile of theophylline indicates that adjustment of the dosage regimen should not be necessary immediately after smoking withdrawal.
Blood Protein Binding of Cyclosporine in Transplant Patients
Authors: Zaghloul Iman , Ptachcinski Richard J. , Burckart Gilbert J. , VAN Thiel David , Starzel Thomas E. , Venkataramanan Raman
Published: March 2013

The objective of this study was to compare the binding of cyclosporine to blood proteins between four healthy subjects and five liver and eight renal transplant patients. Fresh heparinized blood was obtained, to which sufficient quantities of tritium‐labelled cyclosporine and unlabelled cyclosporine were added to blood samples or red blood cell (RBC) suspensions. Concentrations of cyclosporine in whole blood, plasma, RBC suspension, and phosphate buffer were estimated by liquid scintigraphy. The blood:plasma ratio of cyclosporine in transplant patients was significantly lower (P < .05) than that in healthy volunteers. The RBC:buffer ratio, a measure of affinity of RBCs for cyclosporine, was highest in those with liver transplants and lowest in those with kidney transplants. The unbound fraction of cyclosporine in plasma was less in transplant patients than in healthy volunteers. The results of this study indicate that there are differences in blood protein binding of cyclosporine between transplant patients that may contribute to the differences in the pharmacokinetics and pharmacodynamics of this drug.
COMMENTARY—OBSERVATIONS ON SULFASALAZINE IN CROHN'S DISEASE AND ULCERATIVE COLITIS
Authors: Korelitz Burton I.
Published: March 2013

I compliment Dr. Peppercorn on his organization of past and current information on the role of sulfasalazine and its analogues in the treatment of IBD. I offer the following comments, based on my own interpretation of the literature, my own clinical research, and my own practical experience in the management of Crohn's disease and ulcerative colitis.
Falsely Elevated Urinary Excretion of Catecholamines and Metanephrines in Patients Receiving Labetalol Therapy
Authors: Feldman Jerome M.
Published: March 2013

Five patients with essential hypertension who were receiving treatment with the beta‐and alpha‐adrenoreceptor‐blocking drug labetalol had elevated urinary excretion of catecholamines. When measured with a radioenzymatic assay, all five subjects had elevated urinary excretion of norepinephrine and normal urinary excretion of epinephrine; when measured with a fluorometric assay, four subjects had elevated urinary excretion of epinephrine with normal urinary excretion of norepinephrine, and one subject had elevated urinary norepinephrine excretion with normal urinary excretion of epinephrine. In three subjects who could be reevaluated three days to two months after labetalol therapy was discontinued, the urinary catecholamine levels had returned toward normal. Our studies indicate that labetalol produced a false elevation of urinary catecholamine levels. Although labetalol also interfered with the measurement of urinary excretion of metanephrine, it did not interfere with the measurement of urinary excretion of vanillylmandelic acid, homovanillic acid, 5‐hydroxyindoleacetic acid, and serotonin, and it probably did not interfere with the measurement of plasma concentrations of dopamine, norepinephrine, and epinephrine. We conclude that labetalol therapy should be discontinued, and another beta‐blocking drug, such as propranolol, that does not interfere with these tests should be temporarily substituted at least three days before a patient collects a 24‐hour urine for measurement of the urinary excretion of catecholamines and metanephrine.
Effect of Two Different Meals on Bioavailability of Nilvadipine in Healthy Volunteers
Authors: Terakawa Masato , Tokuma Yoji , Shishido Akira , Yasuda Kohtaro , Noguchi Hideyo
Published: March 2013

The effect of two different meals on the bioavailability of nilvadipine, a new antihypertensive and antianginal drug, was examined in 16 healthy male volunteers in two separate studies. In each study of eight subjects in a Latin‐square, two‐way crossover design, two groups of four subjects each were given a single 6‐mg oral dose of nilvadipine after overnight fasting or 30 minutes after a 464‐ or 748‐kcal meal. There were no significant differences in the area under the plasma concentration‐time curve or the maximum plasma concentration between the fasting and fed states for either meal. Although the time to reach the maximum plasma concentration was about the same after a 464‐kcal meal and after fasting, it increased slightly but significantly after a 748‐kcal meal, indicating possible delay in drug absorption after meals. These studies showed that the extent of bioavailability of nilvadipine appears to be little affected in the presence of food. Although a possible delay in the onset of absorption would occur, such a delay may not have any therapeutic importance in chronic therapy.
Respiratory Effects of Quazepam and Pentobarbital
Authors: Murray Anne , Bellville J. Weldon , Comer Walter , Danielson Laura
Published: March 2013

Quazepam is a new benzodiazepine that may provide good hypnotic action with negligible effect on motor coordination or respiration. Sleep laboratory studies on human volunteers have shown quazepam 15 mg to be an effective hypnotic dose, with the 30‐mg dose being optimal. At these doses, there was no deterioration of motor performance, and the drug, when given nightly for two weeks, continued to exert hypnotic effects without serious adverse effects. Therefore, this study was designed to compare the respiratory effects of quazepam 15 and 30 mg to those of pentobarbital 50 and 150 mg and to placebo. Five adult male volunteers received each dose at separate times. A double‐blind technique was employed for controlled rebreathing studies, to a ventilation of 40 L/min or a Petco2 of 8%. Respiratory curves were compared with controls. The mean displacement curve at the 20‐liter intercept showed a depressant effect for pentobarbital 150 mg at two hours and a stimulant effect for quazepam 15 mg at two hours but a slight depression effect for quazepam 30 mg at three hours compared with placebo. The slope of the respiratory curve was not affected.
Review of Autonomic Dysfunction, Cardiac Arrhythmias, and Epileptogenic Activity
Authors: Lathers Claire M. , Schraeder Paul L.
Published: March 2013

Similarities in autonomic dysfunction associated with arrhythmias and death in animal models for digitalis toxicity, myocardial infarction, psychotropic toxicity, and epileptogenic activity are reviewed. When intravenous (IV) pentylenetetrazol was given to anesthetized cats, autonomic dysfunction was associated with both interictal and ictal epileptogenic activity. The autonomic dysfunction was manifested by the fact that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure, the development of a marked increase in variability in mean autonomic cardiac nerve discharge, and the appearance of a very large increase in the variability of the discharge rate of parasympathetic nerves first and then secondly in sympathetic discharge. The altered autonomic cardiac nerve discharge was associated with interictal epileptogenic activity and arrhythmia, which may contribute to sudden unexplained death in patients with epilepsy. Since phenobarbital (20 mg/kg, IV 60 min prior to pentylenetetrazol) exhibited anticonvulsant, but not antiarrhythmic and neural depressant activity, phenobarbital does not appear to be the ideal agent to prevent the autonomic dysfunction associated with epileptogenic activity in this animal model.
Phase I and II Agents in Cancer Therapy: Two Cisplatin Analogues and High‐Dose Cisplatin in Hypertonic Saline or With Thiosulfate Protection
Authors: Fuks Joachim Z. , Wadler Scott , Wiernik Peter H.
Published: March 2013

Cisplatin is a chemotherapeutic coordination complex that has been evaluated extensively. It is particularly active against testicular cancer, but carcinomas of the ovary, bladder, cervix, and head and neck are also responsive. To increase efficacy and decrease toxicity, a number of platinum analogues have been developed and tested. One of these, carboplatin, is of particular interest. In clinical trials, it has demonstrated antitumor activity comparable to that of cisplatin, without evidence of significant renal toxicity or neurotoxicity. A second interesting platinum analogue is iproplatin. Preliminary phase I studies suggest reduced adverse renal and neurologic effects similar to those seen with carboplatin, with efficacy comparable to cisplatin. Attempts to overcome the dose‐limiting toxicity of cisplatin by administering high‐dose cisplatin (40 mg/m2/d for five days) in hypertonic saline or with thiosulfate protection are also reviewed. These techniques have eliminated nephrotoxicity as the dose‐limiting toxicity of cisplatin. However, nonrenal toxicity, especially neurotoxicity, remains substantial. The extent to which high‐dose cisplatin‐based chemotherapy should be used in routine clinical practice has not been determined.
The Effect of Intravenous Enalaprilat (MK‐422) Administration in Patients With Mild to Moderate Essential Hypertension
Authors: Evans Robert R. , Henzler Mark A. , Weber Elizabeth M. , DiPette Donald J.
Published: March 2013

The antihypertensive effect of enalaprilat (MK‐422), an intravenous (IV), nonsulfhydryl converting‐enzyme inhibitor, was evaluated in a double‐blind study of 14 patients with mild to moderate hypertension. The seven patients in the treatment group initially received IV enalaprilat 1.25 mg q6h for 24 hours. Thereafter, responding patients (diastolic blood pressure [BP] ≤ 95 mm Hg) continued receiving this dose q6h for an additional 24 hours, whereas nonresponding patients were increased to IV enalaprilat 5 mg q6h for another 24 hours. Baseline BP for enalaprilat was 161 ± 5/107 ± 2 mm Hg (±SEM), and for placebo it was 150 ± 5/103 ± 2 mm Hg. Within the first 60 minutes, a significant reduction in both systolic and diastolic BP was noted in the enalaprilat group (P < .05), without significant changes occurring in the placebo group. Although there was a gradual decline in both systolic and diastolic BP throughout the 48‐hour study period in the placebo group, systolic and diastolic BP reduction was greater in the enalaprilat group, reaching a maximal decrease of 133 ± 3/87 ± 3 mm Hg. Adverse side effects did not occur in any patient.
Effect of Oral Cibenzoline on Steady‐state Digoxin Concentrations in Healthy Volunteers
Authors: Khoo Ko‐Chin , Givens Samuel V. , Parsonnet Mia , Massarella Joseph W.
Published: March 2013

The effect of oral cibenzoline on steady‐state digoxin concentrations was studied in 12 healthy subjects ranging from 41 to 55 years of age. Each subject received an oral dose of 0.25 mg or 0.375 mg digoxin once daily for 27 days. On days 14 to 21, 160 mg of oral cibenzoline were administered concomitantly every 12 hours for a total of 15 doses. Plasma digoxin concentration‐time profiles obtained before, during, and after cibenzoline coadministration were compared to determine the effect of oral cibenzoline on steady‐state digoxin concentrations. The maximum plasma concentration, time of maximum concentration, area under the curve during a dosing interval and steady‐state trough plasma concentration for digoxin, during and after concomitant doses of cibenzoline were similar to those before administration, indicating that cibenzoline did not affect the pharmacokinetics of digoxin. In addition, plasma cibenzoline concentration‐time profiles after the first and last dose of cibenzoline were similar to those observed in previous studies in which multiple doses of cibenzoline alone were administered. The results of this study indicate that there is no pharmacokinetic interaction between digoxin and cibenzoline when the two drugs are coadministered to healthy subjects in multiple doses.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

A Primer of Human Behavioral Pharmacology Alan Poling

Basic and Clinical Pharmacology B. G. Katzung

Chemically Induced Birth Defects James L. Scharden

Clinical Pharmacology in the Elderly Edited by Cameron G. Swift

Life‐threatening Arrhythmias During Ischemia and Infarction Edited by David J. Hearse et al

Ethics and Regulation of Clinical Research Robert J. Levine
Regulations Which Govern the Availability of Therapeutic Drugs in Australia
Authors: Shaw J.
Published: March 2013

This article looks at the history and development of drug regulation in Australia, concentrating on the changes that have occurred in the last few years. It touches briefly on the system by which many drugs are subsidised and examines the way in which a de facto “restricted” list became less restricted. It deals with clinical trial approval procedures as these have changed markedly and turns to consider advertising and promotion of drugs. In concluding, it discusses the advantages and some of the shortcomings of the system.
Does Chlorpromazine Produce Cardiac Arrhythmia Via the Central Nervous System?
Authors: Lipka Leslie J. , Lathers Claire M. , Roberts Jay
Published: March 2013

The influence of the central nervous system in the production of phenothiazine‐induced arrhythmia and death was examined in this study, In a series of cats, spinal cords were transected at the atlanto‐occipital junction prior to the 1 mg/kg/min, i.v. infusion of chlorpromazine or thioridazine. No protection against drug‐induced arrhythmia or death was afforded by this procedure, In other cats, 60H‐dopamine was administered prior to intravenous injection of atropine and influsion of chlorpromazine, 1 mg/kg/min. in these in situ denervated heart preparations, there was no protection against chlorpromazine‐induced arrhythmia or death, In alpha‐chloralose anesthetized cats, 0.5 mg chlorpromazine administered intracerebroventricularly did not induced arrhythmia or death, although blood pressure decreased initially. Thus, chlorpromazine or thioridazine do not appear to produce arrhythmia or death via a central locus and may instead be acting directly on myocardial conduction to produce arrhythmia and death.
Importance of Oral Dosing Rate on the Hemodynamic and Pharmacokinetic Profile on Nilvadipine
Authors: Cheung Wing K. , Sia Luisa L. , Woodward David L. , Graveline Jane F. , Desjardins Robert E. , Yacobi Avraham , Silber B. Michael
Published: March 2013

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three‐way randomized crossover study at at dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: −33, −13 and +46%; −17, −14 and +38%; and −24, −14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect‐concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration‐time curve (AUC0→∞) between dosing regimens 2 (38.7 ng ṁ hr/mL) and 3 (42.1 ng ṁ hr/mL) (P > 0.05), the mean AUC0→∞ after regimen 1 (76.3 ng ṁ hr/mL) was significantly greater than after dosing regimens 2 or 3 (P < 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively. Overall the results showed that nilvadipine caused changes in blood pressure and HR and that the largest changes were seen with dosing regimen 1, where peak plasma concentrations were greater than about 10 ng/mL.
Serotonergic Blockade Compared with Beta‐Adrenergic Blockade in Systemic Hypertension: A Double‐Blind Comparison of Ketanserin with Propranolol
Authors: Okin Stuart , Huberfeld Seymour I. , Frishman William H. , Soberman Judith , Laifer Larry , Greenberg Steven , Lapsker Jeanne , Charlap Shlomo , Strom Joel A.
Published: March 2013

The safety and efficacy of ketanserin, a competitive serotonin blocking agent, and Propranolol were compared in 33 patients with mild to moderate hypertension (sitting diastolic blood pressure {DBP} 95–115 mm Hg) using a placebo run‐in, randomized, double‐blind, parallel study design. All patients received placebo for 4 weeks, then were randomized to receive increasing doses of either ketanerin (20, 40 mg twice daily) or propranolol (40, 80 mg twice daily) to achieve a goal sitting DBP <90 mm Hg. Patients not achieving the goal blood pressure with either drug as monotherapy, received the other drug in combination. At the end of the active monotherapy phase (week 10 of the study), propranolol demonstrated a greater decrease in DBP from baseline, as compared to ketanserin (−7.9 ± 10.9 mm Hg with propranolol, P < 0.05; —1.0 ± 7.2 mm Hg with ketanserin, P = NS). Four out of 16 patients achieved goal response on propranolol, compared to 3/17 for ketanserin. With combination treatment, 9/18 patients reached the goal response; the addition of propranolol to ketanserin in non‐responders resulted in further reduction of sitting DBP of −10.3 ± 6.3 compared to monotherapy (P < 0.001), while the addition of ketanserin to non‐responders produced no significant response in sitting DBP. Propranolol showed a consistent effect in slowing heart rate. Ketanserin displayed less frequent side effects than propranolol. Propranolol used twice daily appears to be more effective than twice daily ketanserin use in patients with mild to moderate hypertension.
Effects of Age, Gender and Oral Contraceptives on Intramuscular Midazolam Pharmacokinetics
Authors: Holazo Alice A. , Winkler Mary Beth , Patel Indravadan H.
Published: March 2013

The effects of age, gender and low‐dose (50 mcg or less) oral contraceptive steroids (OCS) on the pharmacokinetics of midazolam were evaluated following a single 7.5 mg intramuscular dose to five groups (8/group) of healthy volunteers consisting of young males, young females, elderly males, elderly females, and young female users of oral contraceptives. Blood samples were collected at specified times over a 24‐hour period, and plasma concentrations of midazolam and its 1‐hydroxymethyl metabolite were determined by a GC‐EC assay. Midazolam was rapidly absorbed following intramuscular administration to the different groups. Comparison of young men vs elderly men, young women vs elderly women, young men vs young women, elderly men vs elderly women, and young women OCS‐users vs young women non‐OCS users indicated no substantial differences in the pharmacokinetic profile of midazolam between groups except for the comparison between the young and elderly men groups. The rate of elimination of midazolam was significantly slower in the elderly males compared to the young men. The pharmacokinetic profile of 1‐hydroxymethyl midazolam paralleled that of the parent compound. This is to be expected since this metabolite exhibits formation rate‐limited kinetics. Except for one subject who reported hives and itching, considered to be remotely related to test drug, no other adverse experiences or laboratory abnormalities were reported.
Academic‐Industrial Cooperative Graduate Program in Clinical Pharmacology
Authors: Tallarida Ronald J. , Stote R. M. , Smith J. Bryan , Jacob Leonard S.
Published: March 2013

Because a new level of sophistication among clinical investigators is necessary for the testing of new agents in human subjects, a close integration of basic science, clinical medicine, and pharmaceutical medicine is required. Experts from the Departments of Pharmacology and Medicine at Temple University School of Medicine and Smith Kline and French Laboratories have combined to form a joint training program in clinical pharmacology. This structured graduate program for physicians couples didactic courses with a defined program of independent research, leading to a Master of Science degree in pharmacology. The development of new technologies and the transfer of them from the “bench to the bedside” demands that the clinician have special competence in clinical pharamcology. This unique joint academic‐industrial program sets the goals ensuring that this objective is met.
Pentopril‐Cimetidine Interaction Caused by a Reduction in Hepatic Blood Flow
Authors: Kochak Gregory M. , Rakhit Ashok , Thompson Thomas N. , Hurley Margaret E.
Published: March 2013

The interactive effects of the coadministration of steady‐state Cimetidine and single‐dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to be caused by a reduction in liver blood flow probably mediated through H2 receptor blockade. Meanwhile pentopril induced the oral clearance of Cimetidine by 21%, presumably by a reduction in the bioavailable fraction of Cimetidine. The mechanism of this interaction is unknown.
Triazolam Kinetics: Interaction with Cimetidine, Propranolol, and the Combination
Authors: Friedman H. , Greenblatt David J. , Burstein Ethan S. , Scavone Joseph M. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Nineteen healthy volunteers received a single 0.5‐mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with Cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both Cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by Cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL × hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half‐life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL × hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with Cimetidine plus propranolol were similar to those with Cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady‐state plasma Cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 μg/mL), whereas plasma propranolol was significantly higher during Cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P < .001). Thus Cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half‐life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of Cimetidine alone.
Oral Flecainide Pharmacokinetics in Patients with Impaired Renal Function
Authors: Forland Steven C. , Burgess Ellen , Blair Andrew D. , Cutler Ralph E. , Kvam Donald C. , Weeks C. E. , Fox J. M. , Conard Gordon J.
Published: March 2013

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half‐lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half‐lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half‐life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end‐stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half‐life in patients with ESRD needs further study to evaluate possible dose‐dependent kinetics.
Hemodynamic Effects of Flestolol, a Titratable Short‐Acting Intravenous Beta‐Adrenergic Receptor Blocker
Authors: Strom Joel , Josephson Martin , Frishman William H. , Singh Bramah , Heilbrunn Stephen , Osterle Stephen , Turlapaty Prasad , Viray Rico , Coe Jessie , Bell Valerie , Laddu Atul
Published: March 2013

The hemodynamic effects of flestolol were evaluated in 30 patients undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to flestolol), at steady state during IV flestolol infusion (1, 5, and 10 μg/kg/min) and at 20 to 30 minutes after discontinuation (postinfusion). Flestolol‐induced hemodynamic changes were similar to those induced by other beta blockers without intrinsic sympathomimetic activity. Significant dose‐dependent reduction in heart rate, rate pressure product, and increase in peripheral vascular resistance were seen. Flestolol produced clinically insignificant decrease in myocardial contractility as shown by slight decrease in LVdp/dt, CI, and LVEF. Hemodynamic data from patients with paced heart rate, further confirms a direct mild cardiac depressant effect of flestolol, a finding common to other beta blockers. Consistent with the short elimination half‐life of flestolol (t1/2 = 6.5 minutes), most of the hemodynamic changes rapidly returned to preinfusion level within 20 to 30 minutes following its discontinuation. Thus flestolol, with its unique pharmacokinetic profile and titrability, may be beneficial in the treatment of critically ill patients.
The Effect of Timolol Given Five Minutes After Coronary Occlusion on Plasma Catecholamines
Authors: Lathers Claire M. , Spivey William H. , Tumer Nihal
Published: March 2013

The reported study determined whether timolol would afford a protective effect by preventing the coronary occlusion‐induced arrhythmias associated with the increase in plasma norepinephrine (NE) and epinephrine (E). Ten anesthetized cats received saline or timolol (5 mg/kg, IV) five minutes after coronary occlusion of the left anterior descending coronary artery 10 to 14 mm below its origin. Coronary occlusion produced arrhythmia in three of the cats that received saline and in four of the cats that received timolol. Three of the saline‐treated cats died in cardiogenic shock; two were sacrificed six hours postocclusion. Four of the timolol‐treated cats died in congestive heart failure postcoronary occlusion. There was a gradual increase in NE (P > .05) and E (P < .05) in both groups after coronary occlusion. Death produced a significant increase in NE and E levels. Timolol did not modify the occurrence of arrhythmias and the associated increase in plasma NE and E that developed after coronary occlusion and at death.
The Effect of Cimetidine Dose Timing on Oral Propranolol Kinetics in Adults
Authors: Asgharnejad Mahnaz , Powell J. Robert , Donn Karl H. , Danis Marion
Published: March 2013

Ten healthy male volunteers completed a study to determine the effect of Cimetidine dose timing on the oral clearance of propranolol. Propranolol HCl 160 mg as tablets, was administered daily at 8 am for 4 consecutive days on three occasions. In addition, Cimetidine HCl 800 mg as tablets, was administered either simultaneously in the morning with propranolol (8 am), at bedtime (10 pm), or not at all (control). Each treatment ivas separated by at least a 3‐day washout. Propranolol and Cimetidine serum samples were measured over the 24‐hour dosing interval after the last propranolol dose. Cimetidine administration at 8 am and 10 pm was associated with significant mean increases in the Propranolol area under the serum concentration‐time curve of 26% and 41%, respectively (P < .002). The mean elimination half‐life of propranolol was 6.3 hours during all three treatments. There was no significant difference in area under Cimetidine serum concentration time curve between 8 am and 10 pm dosing. Dosing Cimetidine at bedtime 10 hours before propranolol does not diminish the magnitude of interaction.
Fluconazole Penetration into Cerebrospinal Fluid in Humans
Authors: Foulds George , Brennan Doreen R. , Wajszczuk Charles , Catanzaro Antonino , Garg Dyal C. , Knopf William , Rinaldi Michael , Weidler Donald J.
Published: March 2013

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.
Effect of After‐Dinner Administration on the Pharmacokinetics of Oral Flunitrazepam and Loprazolam
Authors: Bareggi Silvio R. , Pirola Rodolfo , Truci Giulio , Leva Silvio , Smirne S.
Published: March 2013

The pharmacokinetics of two benzodiazepine hypnotics, flunitrazepam and loprazolam, was determined on two occasions in two groups of eight healthy volunteers. Single 2‐mg oral doses of either drug were given in the fasting state at morning on one occasion and after a standard dinner at night on another. Compared with administration of drugs in the fasting state, administration of the drugs after dinner decreased peak plasma concentrations, delayed the time to reach maximum concentration, and prolonged the absorption half‐life. The extent of absorption was reduced for flunitrazepam but not for loprazolam. The elimination half‐life of both flunitrazepam and loprazolam was not changed in the two conditions. These changes may be of clinical significance because they can delay and reduce the effects of the drugs.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Anesthesia, the Heart and the Vascular System Edited by T. H. Stanley and W. C. Petty

Drug Studies in the Elderly Edited by N. R. Cutler and P. K. Narang

Drugs and Kidney Edited by T. Bertani