bluuebunny/crossref_metadata_2025 huggingface dataset:
Loratadine: Multiple‐Dose Pharmacokinetics
Authors: Radwanski Elaine , Hilbert James , Symchowicz Samson , Zampaglione Nicola
Published: March 2013

The steady‐state pharmacokinetics of loratadine (L), a new long‐acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40‐mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high‐performance liquid chromatography (HPLC). The plasma L and DCL concentration‐time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady‐state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady‐state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUCτ, was 80 to 96 and 349 to 421 h × ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUCτ ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once‐a‐day) dosage regimen. The t1/2β at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single‐dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Drug Evaluations, Sixth Edition American Medical Association, Department of Drugs, Division of Drugs and Technology in Cooperation with the American Society for Clinical Pharmacology and Therapeutics.

Drugs for the Heart (Second Expanded Edition) Edited by Lionel H. Opie

Drugs for the Respiratory System Edited by Reuben M. Cherniack

Guide to Clinical Interpretation of Data By Bert Spilker
Trends in Drug Development: The 1985‐86 New Drug Approvals
Authors: Kaitin Kenneth I. , Richard Barbara W. , Lasagna Louis
Published: March 2013

New drug approvals in 1985 and 1986 were analyzed to determine whether any new trends have emerged in the US drug development process. Fifty‐three new drugs (including three biologic products) were approved during this period; 46 met the Center for the Study of Drug Development's definition of a new chemical entity (NCE). More than 70% of the 46 approvals were granted in the fourth quarter, 50% in December alone. Four were FDA classified as 1A (important therapeutic gain), 24 as 1B (modest gain), and 16 as 1C (little or no gain); two biologics were not classified. Nine drugs were given orphan status. For the 37 non‐orphan drugs, the duration of the “development phase” (IND filing to NDA submission) was 5.6 years; the “review phase” (NDA submission to approval) was 2.6 years; and the “total time” (IND filing to NDA approval) was 8.2 years. Review phase for the four 1A drugs was 2.4 years; for the 24 1B drugs, 2.6 years; for the 16 1C drugs, 2.8 years; and for the nine orphan drugs, 2.7 years. Of the 46 drugs, 33 (71.7%) were available in foreign markets prior to US approval with a mean of 5.5 years of prior marketing. Although the total of 46 NCE approvals in 1985 and 1986 represents a two‐year high, there has been a dramatic shift towards fourth quarter approvals. Lengths of the development and FDA review phases are in keeping with those values for previous years.
Bromocriptine‐Desipramine Protocol in Treatment of Cocaine Addiction
Authors: Giannini A. James , Billett William
Published: March 2013

Thirty‐six male cocaine abusers, in withdrawal, were studied for 99 days in a double‐blind design. Treatment with bromocriptine was significantly more effective than placebo in alleviating withdrawal symptoms. Adding desipramine to the bromocriptine regimen was significantly more effective than either placebo or bromocriptine alone. The authors hypothesize that these results support a model of dopamine depletion and receptor supersensitivity in cocaine withdrawal.
Nighttime Dosing of Triazolam in Patients with Liver Disease and Normal Subjects: Kinetics and Daytime Effects
Authors: Kroboth Patricia D. , Smith Randall B. , VAN Thiel David H. , Juhl Randy P.
Published: March 2013

This study was designed to determine whether the severity of liver dysfunction in cirrhosis affects the kinetics and next‐day effects of triazolam after bedtime administration of a single oral dose. Eight patients with biopsy‐proven cirrhosis and seven normal subjects matched for age, weight, and sex participated as paid volunteers. The first night was the control night, when no nighttime sedative was administered. The next day, psychomotor testing was performed at 8:30 am, 2 pm, and 5 pm. Triazolam 0.25 mg was administered at 10:30 pm that evening. Psychomotor testing was repeated on the posttriazolam day in the same manner as on the control day. Blood samples were obtained from a venous catheter at 11 predetermined times in the 14 hours after triazolam administration. Memory testing was also performed. Apparent oral clearance of triazolam was directly related to albumin concentration and indocyanine‐green elimination rate constant, and inversely related to partial thromboplastin time expressed as seconds over control. Clearance was 6.69 ± 2.52 mL/min/kg in the normal subjects and 4.99 ± 3.14 in the subjects with cirrhosis. There were no significant differences in Cmax between normal subjects (1.43 ± 0.44 ng/mL) and subjects with cirrhosis (1.62 ± 0.31 ng/mL) or in tmax (2.0 ± 1.0 vs 2.5 ± 1.9 hr) between normal and cirrhosis subjects, respectively. Posttriazolam, cirrhotic subjects took significantly longer to sort cards at 8:30 am than on the control day. There was a significant correlation between extent of impairment on 8:30 am card sorting by suit and AUC0–8 (r = 0.687; P = 0.0046). For all tests other than card sorting, there was less than a 15% change from control day performance. Both normal and cirrhosis subjects recalled significantly fewer items from the two‐hour posttriazolam presentation of items than they did on the control night. Thus, the presence of cirrhosis decreases the clearance of triazolam, with the extent of the reduction depending on the severity of the liver dysfunction. Most subjects had minimal daytime psychomotor impairment after receiving triazolam 0.25 mg at bedtime. However, compared with controls and subjects with minimal liver dysfunction, subjects with severe liver disease have greater psychomotor impairment at 8:30 am, which is explained by higher concentrations of triazolam during the night. Whether cirrhotic patients are additionally more sensitive than control subjects cannot be determined from this study. If nighttime sedation with triazolam is deemed appropriate, patients with severe liver dysfunction should receive 0.125 mg as the starting dose.
Esmolol‐Digoxin Drug Interaction
Authors: Lowenthal David T. , Porter R. Stephen , Achari Ramanuj , Turlapaty Prasad , Laddu Atul R. , Matier William L.
Published: March 2013

An open‐label baseline‐controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short‐acting beta blocker esmolol and digoxin when administered concurrently under steady‐state conditions. Steady‐state concentration, elimination half‐life, and the total body clearance of esmolol were not changed significantly (P > .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six‐hour esmolol infusion increased from 2.60 ± 0.59 to 2.88 ± 0.75 ng ṁ hr/mL (P < .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.
Hemodynamic Effects of Esmolol, an Ultrashort‐acting Beta Blocker
Authors: Askenazi Joseph , MacCosbe Paul E. , Hoff Julie , Turlapaty Prasad , Hua Tsushung A. , Laddu Atul
Published: March 2013

The hemodynamic effects of esmolol were evaluated in 12 male patients at rest (mean age, 51 ± 10 years) undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to esmolol), at steady state (during an intravenous infusion of esmolol 300 μg/kg/min), and at 30 minutes after stopping esmolol (postinfusion). Esmolol produced hemodynamic effects similar to the effects of other beta blockers. Significant reductions in rate‐pressure product (mean decrease, 15%), cardiac index (mean decrease, 17%), stroke volume index (mean decrease, 13%), left ventricular stroke work index (mean decrease, 20%), and left ventricular ejection fraction (mean decrease, 18%) were observed. In contrast to other beta blockers, all hemodynamic effects of esmolol had returned to baseline values within 30 minutes after the infusion stopped. One patient exhibited hypotension during the esmolol infusion; this episode resolved without sequelae after discontinuation of esmolol. In summary, the effects of esmolol at rest on hemodynamic parameters and left ventricular function are similar to other beta‐adrenergic blocking agents. Due to its ultrashort half‐life, esmolol can be administered safely in critically ill patients whose disease status makes treatment with currently available beta blockers risky.
Characterization of the Dose—Concentration‐Dependent Hemodynamic Effects of Nifedipine in Heart Failure
Authors: Green Jeffrey A. , Nara Andrew R. , Gengo Fran M.
Published: March 2013

The hemodynamic effects of increasing oral doses of nifedipine (10 to 30 mg) were studied in 12 patients who had low output heart failure. With each set of hemodynamics, serum concentrations of nifedipine were measured to determine the concentration/response relationships. Eleven of twelve patients responded acutely to nifedipine, defined as a reduction in systemic vascular resistance (SVR), and an augmentation in cardiac index (CI) and stroke volume index (SVI). The differential dose effects (X ± SD) for SVR and SVI for baseline (N = 11), 10 mg (N = 10), 20 mg (N = 3) and 30 mg (N = 4) were: 1913 ± 486, 1102 ± 221, 1128 ± 166, 803 ± 176 and 17.9 ± 4.8, 23.8 ± 4.5, 31 ± 0.42, 33 ± 3.5, respectively. All nifedipine doses reduced SVR and increased CI and SVI compared with baseline (P < .001). The increase in CI and SVI was significantly correlated to the mg/kg dose of nifedipine (r = 0.79; P < .001). Nifedipine administration resulted in no significant change in central venous pressure, pulmonary capillary wedge pressure, or pulmonary vascular resistance. No relationship could be demonstrated between serum concentrations of nifedipine and any hemodynamic effect. Conclusions drawn were: [1) the afterload reduction effects of nifedipine are acutely efficacious in a large portion of patients with heart failure and this activity supercedes the negative inotropic effects of the drug at doses between 10 and 30 mg; (2) the magnitude of the hemodynamic effects are dose dependent; (3) large decrements in systemic blood pressure (≥20% reduction in mean arterial pressure) can be produced with single 10‐mg doses of nifedipine in patients with heart failure, indicating that the use of this drug in this population be closely supervised; and (4) the lack of a direct concentration‐effect relationship may indicate that the pharmacodynamics of nifedipine in heart failure differ from those demonstrated for other physiologic states.
The Effect of Beta Blockers on Cardiac Neural Discharge Associated with Coronary Occlusion in the Cat
Authors: Lathers Claire M. , Spivey William H.
Published: March 2013

The effect of timolol on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate, and rhythm changes associated with acute coronary occlusion of the left anterior descending artery was examined and compared with the effects of the beta blockers practolol and metoprolol. Timolol (5 mg/kg, IV) was infused 15 minutes prior to coronary occlusion in cats anesthetized with alpha‐chloralose. Control heart rate fell from 129 ± 10 to 106 ± 2 one minute prior to coronary occlusion and remained at 106 ± 2 beats/minute in the minute prior to arrhythmia. Control blood pressure fell from 126 ± 20 to 91 ± 19 and stabilized at 99 ± 19 mm Hg one minute prior to coronary occlusion. Mean time to arrhythmia and death was 4.7 ± 2.3 and 68.0 ± 51.0 minutes (P > .05 vs no drug), respectively. Three cats died and two were sacrificed six hours after coronary occlusion. Blood pressure fell to 86 ± 20 mm Hg two minutes after coronary occlusion, rose to 95 ± 23 mm Hg at ten minutes, and remained there for ten minutes. Timolol did not alter postganglionic cardiac sympathetic neural discharge prior to coronary occlusion. Two minutes after coronary occlusion, mean postganglionic cardiac sympathetic neural discharge was 128 ± 27 and increased to 139 ± 36 impulses/second (% control) 4 minutes after coronary occlusion. A similar trend was found for the data recorded in 15 nerves (eight cats) in which coronary occlusion was initiated without timolol. The data suggest that a difference exists among beta blockers because prior to coronary occlusion, the cardioselective drugs metoprolol (1, 5, and 10 mg/kg, IV) and practolol (8 mg/kg, IV) depressed postganglionic cardiac sympathetic neural discharge whereas noncardioselective timolol did not. Because all three beta blockers increased the times to arrhythmia and death (although the increase was significant only after metoprolol and practolol), the acute protective mechanism does not appear to be due primarily to a depression of spontaneous sympathetic neural discharge.
Effects of Celiprolol on Systemic and Forearm Circulation in Hypertensive Patients: A Double‐Blind Cross‐Over Study Versus Metoprolol
Authors: Trimarco Bruno , Lembo Giuseppe , de Luca Nicola , Ricciardelli Bruno , Rosiello Giovanni , Volpe Massimo , Orofino Giuseppe , Condorelli Mario
Published: March 2013

The antihypertensive efficacy of a new beta‐receptor blocking agent, celiprolol, was compared with that of a well‐established antihypertensive drug, metoprolol. Their systemic and forearm hemodynamic effects were investigated using echocardiography and two‐dimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive patients completed a double‐blind, cross‐over, randomized study using celiprolol and metoprolol. Two six‐week courses with celiprolol or metoprolol were preceded and followed by a two‐week placebo period; the total duration of the study was 18 weeks. In spite of a comparable efficacy in reducing systolic and diastolic blood pressure (about 10% of the basal value), the two drugs showed quite different systemic and regional hemodynamic effects. Celiprolol induced a significant decrease in forearm vascular resistance (from 157 ± 17 to 113 ± 13 mm Hg/mL/s, P < .01) and total peripheral resistance (from 1596 ± 90 to 1398 ± 91 dyne ṁ s ṁ cm−5, P < .05) whereas cardiac output remained unchanged and forearm blood flow increased. Metoprolol reduced cardiac output (from 6.5 ± 3 to 5.7 ± 3 L/min, P < .05), through a reduction in heart rate, since stroke volume was unchanged. Both drugs did not significantly modify cardiac performance, as evaluated by left ventricle fractional percent shortening and ejection fraction. Thus, the two drugs seem to reduce blood pressure through different hemodynamic mechanisms.
Bioavailability and Disposition of Metoclopramide after Single‐ and Multiple‐Dose Administration in Diabetic Patients with Gastroparesis
Authors: O'Connell Mary E. , Awni Walid M. , Goodman Michael , Cass Oliver , Melikian Armen P. , Wright George J. , Matzke Gary R.
Published: March 2013

The disposition of metoclopramide after acute and chronic administration was determined in four diabetic patients with gastroparesis who had a creatinine clearance of 70.8 ±10.7 mL/min (mean ± SD). Single, 10‐mg oral and intravenous doses were administered on days 1 and 2, respectively, followed by 10 mg orally every six hours for three weeks. A second, 10‐mg intravenous bolus dose was administered on the last morning of chronic therapy. Metoclopramide concentrations were determined by high performance liquid chromatography. The elimination half‐life, steady‐state volume of distribution, and total body clearance after the initial intravenous dose were 3.9 ± 1.2 hr, 2.7 ± 0.3 L/kg, and 0.57 ± 0.14 L/hr/kg, respectively. The initial bioavailability was 67.7 ± 12.6%. After three weeks of chronic therapy, no significant differences in total body clearance (0.72 ± 0.42 L/hr/kg) or bioavailability (77.5 ± 16.8%) were observed. Thus the pharmacokinetics and bioavailability of metoclopramide were not altered during chronic therapy in these diabetic patients.
Nizatidine, an H2‐Receptor Antagonist: Disposition and Safety in the Elderly
Authors: Callaghan John T. , Rubin Alan , Knadler Mary Pat , Bergstrom Richard F.
Published: March 2013

Nizatidine is an orally active H2‐receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vdβ/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.
Calcium Channel Blockade in Experimental Aminoglycoside Nephrotoxicity
Authors: Watson Alan J. , Gimenez Luis F. , Klassen David K. , Stout Robert L. , Whelton Andrew
Published: March 2013

Calcium channel blocker therapy has proved protective in certain models of ischemic‐induced acute renal failure. This effect may be related to the prevention of calcium influx into injured cells or by the vasodilatory effects of verapamil that may result in an improvement in renal blood flow. In the current study, the effect of verapamil treatment on the development of renal insufficiency and renal tissue calcium accumulation following aminoglycoside administration was investigated. The degree of functional damage and cortical tissue calcium accumulation after six or nine days of gentamicin administration (120 mg/kg body weight/day) was not significantly different in rats whose drinking water contained verapamil (10 mg/100 cc) than corresponding values in control animals. The tissue calcium accumulation correlated with the degree of reduction of creatinine clearance and probably reflects the extent of lethal tubular cell injury.
Impairment of β2‐Adrenoceptor‐Stimulated Potassium Uptake in End‐Stage Renal Disease
Authors: Stemmer Craig L. , Perez Guido O. , Oster James R.
Published: March 2013

An abnormality of extrarenal mechanisms is believed to contribute importantly to the impaired potassium homeostasis in chronic renal failure. We evaluated the plasma potassium response to inhalation of albuterol, a β2 agonist, in eight patients who had end‐stage renal disease and who were undergoing chronic hemodialysis and in eight control subjects. The purpose was to assess if an abnormality of the β2 adrenoceptor mechanism is present in uremia. The maximal decrement in plasma potassium concentration in the patients (0.12 ± 0.04 mEq/L) was significantly less than that of the control subjects (0.30 ± 0.05). Furthermore, the final plasma potassium concentration slightly exceeded baseline in the patients but was significantly reduced in controls, leading to the conclusion that an abnormal responsiveness of the β2 adrenoceptor may contribute to the impaired potassium tolerance found in patients who have end‐stage renal disease.
Rules Governing Pharmaceuticals in the European Community
Authors: Sauer F. , Hankin R.
Published: March 2013

In the interest of public health, the European community has progressively established common scientific criteria for the evaluation of human and veterinary medicines and harmonized the national authorization procedures. One major consequence of this has been that neither the tests and trials carried out to obtain authorization nor batch controls need be repeated within the European community. Henceforth the pharmaceutical industry may benefit from two types of procedures intended to facilitate the registration of their medicinal products in the member states. One, reserved for biotechnology/high technology medicinal products, involves community coordination prior to any national decision together with special protection against copies for ten years, irrespective of the position under patent law. The other enables firms to request the recognition by the other member states of an authorization previously granted by one member state. The experience gained from these two procedures will lead to the choice of the most appropriate European registration procedure for the next decade. In the interests of the European consumer, cooperation between the 12 member states and the Commission of the European Communities has progressively increased within the Committee for Proprietary Medicinal Products (adverse effects of medicines/pharmacovigilance) and the Committee for Veterinary Medicinal Products (residues). In association with these committees, several working groups of experts attempt to approximate and codify practices in the evaluation of the quality, safety, and efficacy of medicinal products (guidelines). The Commission has recently transmitted to the Council of Ministers a proposal for a directive concerning transparency in the national systems for controlling the prices of medicinal products and their reimbursement by the social security administrations, which the European Parliament must also discuss. The Commission has also proposed the opening of discussions to enable the Community to adhere to the European Pharmacopoeia Convention. Further proposals will be submitted towards the end of 1987 in the fields of vaccines and veterinary medicines and, over the next few years, to promote the rational use of medicines, in particular, through better information for the patient and the prescriber.
Absolute Bioavailability of Hydromorphone After Peroral and Rectal Administration in Humans: Saliva/Plasma Ratio and Clinical Effects
Authors: Ritschel Wolfgang A. , Parab Prakash V. , Denson Donald D. , Coyle Dennis E. , Gregg Richard V.
Published: March 2013

The absolute bioavailability of hydromorphone was investigated in eight healthy male subjects by a cross‐over design (with washout period of two weeks) after intravenous (2 mgj, peroral (4 mg) and rectal (3 mg) administration of hydromorphone. The use of saliva hydromorphone concentrations as a noninvasive technique in pharmacokinetic evaluation was investigated, and the clinical effects after the three routes of administration were determined. Hydromorphone has an absolute bioavailability of 51.35 ± 29.29% and 36.33 ± 29.60% after peroral and rectal administration, respectively. More side effects were observed after intravenous administration of hydromorphone than after rectal or perorai dosing. The saliva sampling for the hydromorphone concentration was found to be a useful noninvasive technique for the estimation of the elimination half‐life of hydromorphone.
Oral Enoximone Pharmacokinetics in Patients with Congestive Heart Failure
Authors: Lima John J. , Leier Carl V. , Holtz Lee , Sterechele James , Shields Brenda J. , MacKichan Janis J.
Published: March 2013

The pharmacokinetics of enoximone and its sulfoxide metabolite were determined following administration of a single oral dose of 1 or 2 mg/kg in seven patients with congestive heart failure, and in two normal volunteers following a single 75‐mg capsule, and were compared to those published previously. Plasma concentrations of the metabolite were higher than enoximone, and their terminal slopes were parallel. Enoximone and enoximone sulfoxide plasma concentration‐time data were fitted to a simple model that included a lag time. Absorption half‐lives in patients and normal volunteers averaged 17 minutes; the elimination half‐life of enoximone in patients averaged 2.9 hours, and was slightly prolonged as compared with normal volunteers. The elimination half‐life of enoximone sulfoxide averaged 17 minutes in patients and normal volunteers, and was considerably shorter than that reported in other studies. The oral clearance of enoximone in patients averaged 99 L/hr, and was lower than that observed in normal volunteers. The ratio of the area under the plasma concentration time curve of enoximone sulfoxide to enoximone averaged 4.7 in patients, and was similar to that observed in normal subjects. Enoximone oral clearance and the ratio of metabolite to parent were related to liver blood flow (determined by indocyanine green). Enoximone is 65% bound to albumin, which accounts for most of the drug bound to human plasma protein.
Effect of 5‐Hydroxytryptamine Blockade with Ketanserin on Myocardial Uptake of Epinephrine and Norepinephrine in Patients with Congestive Heart Failure
Authors: Majid Pirzada A. , Sole Michael J.
Published: March 2013

Serotonin (5‐hydroxytryptamine) has multiple cardiovascular actions. The presence of serotonin in the heart suggests it may be an endogenous source of inotropic support during physiologic or pathologic stress. Serotonin may increase cardiac contractility by augmenting release of norepinephrine at sympathetic nerve endings. Norepinephrine release is markedly elevated in patients with heart failure. To explore the role of serotonin in enhancing norepinephrine release in patients with heart failure, ketanserin, a specific serotonin antagonist, was used as a physiologic tool to examine the effect on transmyocardial norepinephrine flux. Ketanserin (10 mg bolus, 4 mg/hr infusion for ±40 min) was administered intravenously to nine patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (N = 7), or ischemic heart disease (N = 2). Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured in the aorta (Ao) and the coronary sinus (CS) of patients at rest and during supine leg exercise before and after administration of ketanserin. Baseline norepinephrine levels were markedly elevated at rest and during exercise in all patients. Norepinephrine levels were significantly higher in the CS than in the Ao (rest, CS 1185 ± 235, Ao 878 ± 381 pg/mL, P < .05; exercise, CS 2239 ± 697, Ao 1453 ± 697 pg/mL, P < .05). Baseline epinephrine levels were within normal limits. In contrast to norepinephrine levels, epinephrine levels were consistently higher in the Ao than in the CS, indicating unimpaired extraction or uptake across the heart. The relationship between norepinephrine and epinephrine concentration in the Ao and CS suggested a net overflow of norepinephrine in the CS. Ketanserin did not produce any changes in the absolute levels of catecholamines or the relationship between norepinephrine and epinephrine in CS and the Ao. Serotonin, thus, probably does not have any role to play in increasing norepinephrine release in patients with severe heart failure.
Evaluation of Dosing Interval and Optimum Dose of Cibenzoline
Authors: Zempol Patrica , Aogaichi Keiko , Butler Brenda , Tepper David , Somberg John C.
Published: March 2013

Fifteen patients with ventricular premature complexes (VPCs) were included in this open study designed to assess the relative efficacy of bid (two times daily) and tid (three times daily) dosing regimens for cibenzoline as compared with qid (four times daily) administration. Patients started therapy with qid administration; this was followed in sequence by tid and bid administration at the maximum effective total daily dose determined during the qid administration. Of the nine patients evaluated for efficacy for suppression of VPCs, eight demonstrated a 75% or greater suppression of VPCs with cibenzoline administered qid (total daily dose of 130–325 mg). This effectiveness was maintained in four patients with a bid regimen and in three with a tid regimen. All four patients who had ventricular tachycardia (VT) had a decrease in the number of VT episodes while receiving cibenzoline (only one of these patients had satisfactory supression of VPCs at the same dosage regimen). Twelve patients continued to receive extended therapy with cibenzoline for up to two years, as this was considered to be the optimum antiarrhythmic treatment for these patients. Two patients had to be removed from the study and two had the dosage lowered because of adverse reactions (dry mouth, blurred vision, dizziness, congestive heart failure) although in one instance, the congestive heart failure was subsequently considered to be unrelated to cibenzoline. One patient was able to complete the short‐term phase of the trial, but was not given extended treatment because of persistent dry mouth. Two patients had treatment discontinued during the extended therapy phase because of adverse reactions (fever, nausea, vomiting, asthenia). This pilot study gives pharmacodynamic support to the pharmacokinetic findings of the long half‐life of cibenzoline, enabling a bid dosing regimen to be used in patients and permitting better patient compliance.
A Comparative Trial of Moxalactam Plus Ticarcillin and Clavulanic Acid or Piperacillin as Empiric Antibiotic Therapy for Febrile Cancer Patients
Authors: D'Olimpio James T. , Miller Michael , Sheridan Carol A. , Carlisle Penny , Wollner David I. , McKitrick John C. , Wiernik Peter H.
Published: March 2013

Resistance of bacteria to beta‐lactam antibiotics remains a difficult clinical problem that can be compounded in infected patients with serious underlying illness, especially those who are immunocompromised. In a prospective randomized safety and efficacy trial, febrile cancer patients received either ticarcillin disodium combined with the beta‐lacta‐mase inhibitor clavulante potassium (Timentin, Beecham Laboratories, Bristol, TN) plus moxalactam (T+M), or piperacillin plus moxalactam (P+M) as initial empiric antimicrobial therapy. Sixty‐six febrile episodes in 53 patients were studied. In the T+M group, 14 (78%) of 18 clinically evaluable infections in patients with profound granulocytopenia improved as did all 14 (100%) such infections in the P+M group. In the T+M group 17 of 21 (81%) similarly evaluable infections improved irrespective of granulocyte count, as did 14 (88%) of 16 of such infections in the P+M group. These results are not statistically significantly different. Serious side effects were infrequent and comparable with both regimens. There was one antibiotic related hemorrhage in the P+M group and a serious episode of nephrotoxicity in a patient who died without recovering renal function in the T+M group. These results suggest that the overall safety and efficacy of Timentin plus moxalactam, and piperacillin plus moxalactam are comparable and similar to previous empiric antibiotic trials.
Pharmacokinetic Properties of Mezlocillin in Ambulatory Elderly Subjects
Authors: Meyers Burt R. , Mendelson Meryl H. , Srulevitch‐Chin Elina , Bradbury Keith , McMurdo Lisa , Hirschman Shalom Z.
Published: March 2013

Twelve healthy ambulatory elderly subjects (mean age, 73–78 years) randomly received either a 4‐g or 5‐g dose of mezlocillin intravenously. One week later the regimen was repeated and patients crossed over to the other dose. Peak serum concentrations were 165 mg/L and 281 mg/L for the 4‐g and 5‐g doses, respectively. For both doses, differences in t1/2β (1.32 hr vs 1.13 hr), AUC (275 mg ṁ hr/L vs 403 mg ṁ hr/L), CL (207 mL/min vs 174 mL/min), CLR (59 mL/min vs 45 mL/min), CLNR (152 mL/min vs 130 mL/min) were not statistically significant. The differences in Varea (22.4L vs 168.8L, P ≤ .01) and Cmax (216.6 mg/L vs 317 mg/L, P ≤ .05) were statistically significant. Comparison with pharmacokinetic parameters obtained in younger subjects following the 5‐g dose reveals that in the elderly the AUC, Varea, and CLNR are higher whereas the CL and CLR are lower. The elderly demonstrated an increase in nonrenal clearance compared with young subjects that is not fully compensatory. The increased AUC in the elderly group suggests that clinical studies examining mezlocillin doses and dose intervals in the treatment of serious infections are warranted in infected elderly patients.
Clinical Pharmacology and Therapeutics Education for Senior Medical Students
Authors: Feldman R. D. , Spector R. , Park G. D. , Albanese M. , Roberts R.
Published: March 2013

In many medical schools instruction of students in clinical pharmacology remains informal and may be inadequate. To determine the short‐term efficacy of a mandatory senior medical year course in clinical pharmacology, we compared examination scores of senior students in the College of Medicine, University of Iowa, either prior to or following the Clinical Pharmacology and Therapeutics Lecture Series. A significantly higher (P < .001) mean score was demonstrated by students taking the examination following the course (75 ± 4% correct) versus those taking the examination prior to the course (55 ± 4% correct). To determine student acceptance, postcourse questionnaires were completed. Students surveyed immediately postcourse and alumni surveyed up to four years after graduation highly recommended the course and favored retaining it as a mandatory part of the fourth‐year curriculum. This study confirms the efficacy and acceptance of senior medical courses in therapeutics and suggests an effective role for clinical pharmacologists in their design and execution.
Phenylpropanolamine: Effects on Subjective and Cardiovascular Variables at Recommended Over‐the‐Counter Dose Levels
Authors: Liebson Ira , Bigelow George , Griffiths Roland R. , Funderburk Frank R.
Published: March 2013

Two controlled clinical studies evaluated the effects of phenylpropanolamine HCL (PPA) on measures of blood pressure, pulse, and subjective state (mood). One hundred fifty subjects participated in a parallel groups design that compared a 75‐mg sustained release (SR) preparation with a 25‐mg tid. dosing regimen and placebo. Fifty‐nine of these subjects participated in an additional cross‐over component that compared SR PPA 75 mg with placebo. Measures of blood pressure, pulse, and subjective drug effect were obtained nine times throughout the course of a 12‐hour session. Data analysis revealed no clinically and few statistically significant effects due to drug treatment. As expected, most measures showed circadian changes on both the cardiovascular and mood variables, which were not related to drug treatment. No euphorogenic or “amphetaminelike” effects were noted. Although further work is warranted regarding the effects of chronic or higher‐than‐normal doses of PPA, the current studies suggest that PPA, at currently recommended dose levels, is not associated with adverse effects on either cardiovascular or subjective functioning.
Pharmacokinetics and Dose Proportionality of Loratadine
Authors: Hilbert James , Radwanski Elaine , Weglein Ray , Luc Van , Perentesis George , Symchowicz Samson , Zampaglione Nicola
Published: March 2013

The dose proportionality and pharmacokinetics of loratadine, a new nonsedating antihistamine, were studied in 12 normal volunteers. In a three‐way cross‐over, each volunteer received a single 10‐, 20‐, or 40‐mg loratadine capsule. Blood was collected up to 96 hours after dosing. Plasma loratadine concentrations were determined by radioimmunoassay (RIA), and those of a minor, but active metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Concentrations in the disposition phase were fitted to a biexponential equation for pharmacokinetic analysis. For dose proportionality, AUC‐ and Cmax‐dose relationships were evaluated by linear regression. Also, pharmacokinetic parameters and dose‐adjusted AUCs were compared by analysis of variance. Loratadine was rapidly absorbed, reaching Cmax values (4.7, 10.8, and 26.1 ng/mL) at 1.5, 1.0 and 1.2 hours for the 10‐, 20‐, and 40‐mg doses, respectively. The loratadine t1/2β ranged from 7.8 to 11.0 hours. Descarboethoxyloratadine reached Cmax values (4.0, 9.9, and 16.0 ng/mL) at 3.7, 1.5, and 2.0 hours for the 10‐, 20‐, and 40‐mg doses, respectively. Its t1/2β ranged from 17 to 24 hours. For both compounds, AUC‐ and Cmax‐dose relationships were linear and there were no differences in the t1/2β, CL/F, or dose‐adjusted AUC values among the treatments. Loratadine and descarboethoxyloratadine plasma concentrations and pharmacokinetics were not dose dependent.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Guide to Planning and Managing Multiple Clinical Studies Bert Spilker

Regulation of Hepatic Metabolism Edited by R. G. Thurman et al
Differential Effects of 1,4‐Dihydropyridine Calcium Channel Blockers: Therapeutic Implications
Authors: Katz Arnold M. , Leach Nancy M.
Published: March 2013

Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity, In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long‐term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke, In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects.
Patient‐Initiated Postmarketing Surveillance: A Validation Study
Authors: Fisher Seymour , Bryant Stephen G. , Solovitz Brenda L. , Kluge Ronica M.
Published: March 2013

A new patient‐initiated, pharmacy‐based postmarketing surveillance system is described. At the time a new prescription for a targeted drug was filled, 2705 outpatients (experimentals) randomly assigned to the new system had a printed notice attached to their medication bags: the information requested them to report any “new or unusual symptoms” during the next 2 weeks by a toll‐free telephone number to a trained nonprofessional who conducted a standardized adverse drug reaction (ADR) interview. To help validate the new system, another sample of 1109 patients (controls) did not receive a request for self‐monitoring but were interviewed by telephone 2 weeks later. Target drugs were chosen from two classes for which side effect profiles are well identified: oral antibiotics and tricyclic antidepressants. Results show that within both drug classes, all patient‐initiated reports closely matched those obtained from controls; the experimental and control groups also reported predictably high relative frequencies for the most commonly expected ADRs. Additional analyses suggest that a patient‐initiated monitoring system could prove to be a promising complement to existing physician‐based surveillance systems.
Theophylline Absorption from Sustained‐Release Products: Comparative Steady‐State Bioavailability of Once‐Daily Theo‐Dur, Theo‐24, and Uniphyl
Authors: Hurwitz Aryeh , Karim Aziz , Burns Thomas S.
Published: March 2013

Theophylline absorption from three sustained‐release formulations was evaluated in 18 healthy men. First, a 600‐mg oral dose of aminophylline, a rapidly absorbed formulation, was studied to confirm that theophylline clearance was in the expected range (mean ± SD, 0.710 ± 0.096 mL/min/kg), t1/2 = 6.9 ± 1.1 hr. Then each of the three sustained‐release formulations was given at one hour before breakfast for eight days to achieve steady state. Multiple blood samples were drawn on days 7 and 8 over two complete dosing intervals. After a six‐day drug‐free period each subject was crossed over to the next product. At steady state, mean fluctuations of serum theophylline levels were more than 200% with Theo‐Dur (Key Pharmaceuticals, Miami, FL), more than 150% with Uniphyl (Purdue‐Frederick, Norwalk, CT), and about 75% with Theo‐24 (Searle Laboratories, Chicago, IL). Theophylline Cmax levels averaged 16.5 μg/mL after 900 mg Theo‐Dur, with 8% exceeding 20 μg/mL. Despite these high peak levels, nearly half of the Cmin levels were below 5 pg/mL. Uniphyl administration resulted in three‐fourths of trough levels to be at 5 μg/mL or lower. Peak levels from 800‐mg daily doses of Uniphyl were also low, with 42% never reaching 10 pg/mL. With Theo‐24 only 17% of trough levels were below 5 μg/mL, as compared to 47% with Theo‐Dur and 72% with Uniphyl. The three products differed in the areas under the serum concentration‐time curves (AUC), which reflect bioavailability. Theo‐Dur AUC was nearly equivalent to that of rapidly absorbed aminophylline (when adjusted for dosage). AUC from Theo‐24 was 80% relative to Theo‐Dur, and Uniphyl was 67%, when adjusted for dose. These data show the limitations in once‐daily administration of sustained‐release theophylline, even in normal and slow metabolizers. Serum levels fluctuated widely with Theo‐Dur and Uniphyl, whereas the latter had incomplete bioavailability. Of the three products approved in the United States for once‐daily dosing, only Theo‐24 consistently yielded serum theophylline levels within the desired range while providing acceptable bioavailability.
Inhibition of Theophylline Elimination by Diltiazem Therapy
Authors: Nafziger Anne N. , May John J. , Bertino Joseph S.
Published: March 2013

To investigate the effects of diltiazem on theophylline pharmacokinetics, nine healthy male subjects (four smokers and five nonsmokers) received intravenous aminophylline (6 mg/kg) prior to and following 10 days of oral diltiazem therapy. Theophylline half‐life increased significantly whereas total body clearance showed a significant decrease following diltiazem. Volume of distribution was unchanged. The small group of smokers had a significantly greater increase in theophylline half‐life than the nonsmokers. Inhibition of metabolism of theophylline by diltiazem likely explains the significant changes in theophylline pharmacokinetics. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently.
The Disposition and Bioavailability of Intravenous and Oral Nalbuphine in Healthy Volunteers
Authors: Lo Man‐Wai , Schary William L. , Whitney Charles C.
Published: March 2013

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five‐week period, subjects received single doses of each of four different formulations of nalbuphine, with a one‐week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed‐phase high‐performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half‐life of nalbuphine with this route of administration was 2.3 hours, In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half‐lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmax and AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half‐life of nalbuphine associated with oral administration are likely due to extensive first‐pass metabolism and enterohepatic circulation, respectively.
Comparative Pharmacokinetics of Intravenous Propranolol in Obese and Normal Volunteers
Authors: Cheymol Georges , Poirier Jean‐Marie , Barre Jérôme , Pradalier André , Dry Jean
Published: March 2013

Plasma pharmacokinetics of a single IV dl‐propranolol dose (8 mg) were investigated in 12 obese subjects (mean ± SD: 110.3 ± 20.4 kg; 198.7 ± 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 ± 6.8 kg; 94.5 ± 7.8% of ideal body weight). In obese subjects plasma alpha‐1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P < .01) in AUC (161.0 ± 67.0 vs 109.6 ± 23.1 hr · μg/L), and significant decreases (P < .01) in Vss (208.9 ± 71.9 vs 318.6 ± 91.8 L), Vβ (234.3 ± 70.4 vs 340.7 ± 89.1 L), and total clearance (57.5 ± 18.3 vs 75.9 ± 15.4 L/hr). Elimination half‐life was similar for the two populations (3.5 ± 0.9 hr in obese subjects vs 3.1 ± 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.
Pharmacokinetics of Esmolol in Hepatic Disease
Authors: Buchi Kenneth N. , Rollins Douglas E. , Tolman Keith G. , Achari Ramanuj , Drissel Debra , Hulse James D.
Published: March 2013

Esmolol is an intravenous beta blocker with a short duration of action. The pharmacokinetics of esmolol and its acid metabolite, ASL‐8123, were studied in nine patients who had stable, biopsy‐proved Laennec's cirrhosis and in three normal volunteer controls. Kinetics were determined after a four‐hour continuous infusion of esmolol at a rate of 200 μg/kg/min. Blood samples were collected during the infusions and at frequent intervals thereafter. The parameters studied were the steady state concentration, the total body clearance, the elimination half‐life, the area under the curve, and the volume of distribution. No significant differences in any of these parameters were detected between control subjects and those with hepatic disease, for either esmolol or its acid metabolite. It is concluded from this study that Laennec's cirrhosis does not cause any change in the pharmacokinetics of esmolol or its major metabolite. Therefore, adjustments in dosage of esmolol are not required for patients with Laennec's cirrhosis.