bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of Cibenzoline in Patients With Renal Impairment
Authors: Canal Muriel , Flouvat Bernard , Aubert Philippe , Guedon Jacques , Prinseau Jacques , Baglin Alain
Published: March 2013

Pharmacokinetic values of cibenzoline, a new, investigational, antiarrhythmic drug, were determined in 13 patients with varying degree of renal impairment, creatinine clearance range between 5 and 53 mL/min. Cibenzoline plasma levels were measured after direct intravenous injection of one single 1 mg/kg dose. The apparent volume of distribution of the drug (276 1) was similar to that reported in healthy subjects. Total body clearance decreased with creatinine clearance, and there was a close correlation between cibenzoline renal clearance and creatinine clearance (r = 0.956; P < 0.001). Plasma elimination half‐life was prolonged, with values ranging from 7.4 to 23.6 hours. This study showed that cibenzoline total body clearance correlated with the degree of renal impairment, and it is suggested that in patients with chronic renal failure dosage should be adjusted according to creatinine clearance values.
Diltiazem, Verapamil, and Quinidine in Patients With Chronic Atrial Fibrillation
Authors: Ochs H.R. , Anda L. , Eichelbaum M. , Greenblatt DJ.
Published: March 2013

The comparative effects of diltiazem and verapamil in 30 patients with long‐standing atrial fibrillation were evaluated in a prospective clinical trial. After a one‐ to two‐day washout period during which drugs other than digoxin were withdrawn, patients were randomly assigned to diltiazem or verapamil treatment groups. All therapy was double blind. Both drugs were given in ascending doses as follows: days 1–6 (part I): diltiazem, 180 mg/d, or verapamil, 240 mg/d; days 7–12 (part II): diltiazem, 360 mg/d, or verapamil, 480 mg/d. Patients failing to convert to sinus rhythm after 12 days had dosage reduced to 180 mg/d of diltiazem or 240 mg/d of verapamil, and quinidine, 750 mg/d, was coadministered for another six days (part III). Medication compliance was verified by frequent measurement of serum drug concentrations. Three verapamil patients dropped out during part I due to adverse reactions (dyspnea, pulmonary congestion, skin rash, or hepatotoxicity). The higher dosage of either verapamil or diltiazem in part II was not well tolerated, and in eight patients part III had to be initiated early due to symptomatic bradycardia. Only one patient in the diltiazem group converted to sinus rhythm, whereas five converted with verapamil (two with verapamil alone, three when combined with quinidine). Thus, diltiazem and verapamil alone are unlikely to convert atrial fibrillation to sinus rhythm. The combination of verapamil and quinidine, however, is a potentially useful pharmacologic approach, having converted atrial fibrillation to sinus rhythm in nearly 50% of patients.
Measuring Drug‐Induced Eye Irritation: A Simple New Clinical Assay
Authors: Scoville Barrett , Krieglstein G.K. , Then Elke , Yokoyama Sumiko , Yokoyama Takashi
Published: March 2013

Thirty‐six normal subjects received a drop in either eye of two of four ophthalmic solutions, balanced saline (S), carteolol, 1% (C1), carteolol, 2% (C2), or timolol, 0.5% (T), in a double‐blind, randomized trial in a balanced incomplete block design. Subjects reported immediately, at three, and again at ten minutes after administration whether one eye felt more irritated and marked an analog scale of irritation. An observer also made ratings at three minutes based on responses to stereotyped questions. Significant differences in irritation between timolol and each of the other drugs and placebo were shown by analog scale scores immediately after instillation of the solutions. Maximum likelihood estimates were calculated based on statements of subject preference, and a significant preference was demonstrated. Observer ratings also demonstrated a treatment effect. This simple clinical assay system provides a new, valid method for estimating irritation induced by ophthalmic solutions.
Treatment of Ulcerative Colitis With Clonidine
Authors: Lechin Fuad , van der Dijs Bertha , Insausti Carmen L. , Gómez Francisco , Villa Simón , Lechin Alex E. , Arocha Luis , Oramas Omar
Published: March 2013

In the present 30‐week, double‐blind study of 45 ulcerative colitis (UC) patients treated with prednisone, sulfasalazine, clonidine, or placebo, we found that clonidine (an alpha2 agonist) and prednisone were effective in treating idiopathic UC. Both drugs were more effective than sulfasalazine. Furthermore, clonidine potentiated prednisone and sulfasalazine effects. Clonidine was chosen because its effect on distal colon motility is similar to thioproperazine, an antipsychotic drug that despite many adverse effects, possesses powerful anti‐UC properties. Rating scales were outlined in order to evaluate clinical, endoscopic, histologic, and radiologic changes. Plasma cortisol levels, sedimentation rate, serum glutamic‐oxaloacetic transaminase, serum glutamic‐pyruvic transaminase, and other biochemical parameters were determined to assess the efficacy of each drug. Distal colon motility changes were also assessed. All our UC patients showed raised cortisol plasma levels and low sigmoidal tone during relapse periods. These parameters were reversed during remission periods. Peripheral and central mechanisms are discussed.
Cimetidine—Acetaminophen Interaction in Humans
Authors: Chen MM. , Lee C.S.
Published: March 2013

The effect of single‐dose and multiple‐dose cimetidine administration on acetaminophen pharmacokinetics was investigated in a three‐phase, randomized, crossover study using four normal subjects. In each phase of the study, subjects ingested 750 mg of acetaminophen as a single dose alone (A), or in combination with 200 mg of cimetidine (A + C), or following a one‐week pretreatment with daily cimetidine, 200 mg every six hours and 400 mg before retiring (A + C*). Statistical analysis using two‐way analysis of variance indicated no significant difference in peak concentration and peak time of acetaminophen between treatments. Cimetidine did not significantly affect acetaminophen half‐life, 2.38 hours (A), 2.65 hours (A + C), and 2.50 hours (A + C*). Acetaminophen clearance was minimally affected by cimetidine; the mean clearance of acetaminophen ranged from 4.16 (A + C*) to 5.57 mL/min/kg (A). Area under the acetaminophen plasma concentration‐time curve was slightly increased by cimetidine, 35.4 (A), 41.6 (A + C), and 47.6 μg/mL/h (A + C*). Since cimetidine did not affect acetaminophen pharmacokinetics to any significant extent, clinical combination of both medications at therapeutic dosage presumably would not produce adverse interactions.
The Pharmacokinetization of Psychiatry
Authors: Greenblatt David J.
Published: March 2013

The titration and monitoring of drug therapy using pharmacokinetic principles along with measurements of serum or plasma drug concentrations have become essential components of pharmacotherapy in many areas of clinical medicine, including the treatment of asthma, seizure disorders, certain infectious diseases, and cardiac arrhythmias. The value of pharmacokinetic principles in these therapeutic areas follows from several mathematical and biologic requisites. The first is that the drug's steady‐state serum or plasma concentration (Css) during multiple dosage bears a reasonably predictable relationship to clinical outcome. When Css falls in some “therapeutic range,” the likelihood of clinically effective drug therapy is maximized. If Css exceeds this range, toxicity becomes increasingly likely, while values of Css below the therapeutic range may be therapeutically ineffective. Second, Css can be expressed as the quotient of two independent factors: dosing rate divided by total clearance. The health care professional has control over dosing rate, and therefore controls one major determinant of Css. All else being equal, Css will rise or fall correspondingly as dosing rate is changed. However, the health care practitioner has no control over total clearance, the other major determinant of Css. Clearance best describes the capacity of a given patient to remove a given drug, and is a unique property of each drug in each individual. Because clinicians seldom know the clearance of a particular drug in a particular patient, clearance usually must be estimated, based on findings from prior pharmacokinetic studies along with consideration of physiologic factors, disease states, or drug interactions that may alter clearance.
Second Generation Antidepressants: A Comparative Review
Authors: Coccaro Emil F. , Siever Larry J.
Published: March 2013

The authors review four “second generation” antidepressants (maprotiline, amoxapine, trazodone, and nomifensine) in terms of action on biogenic amines and receptors, antidepressive efficacy, and adverse effects. Doxepin is used as a comparative agent and is similar to the prototypical tricyclic agents in all the above categories. Maprotiline is a selective noradrenergic agent, but shares a similar adverse effect profile with doxepin and may be associated with a high frequency of seizures in overdose. Amoxapine is a mixed action antidepressant with significant neuroleptic activity in vivo. Its adverse effect profile is highlighted by symptoms related to its neuroleptic activity, and seizures and acute renal failure in overdose. Trazodone is a selective serotonergic agent with low anticholinergic activity, and minimal morbidity/mortality in overdose. Reports of priapism, leading to impotence in some men, however, is of concern. Nomifensine is a potent noradrenergic and dopaminergic agent with low anticholinergic activity, and minimum cardiotoxicity and low morbidity/mortality in overdose. Its most important adverse effects include overstimulation and infrequent, usually reversible, immunologic hypersensitivity reactions. Trazodone and nomifensine have favorable profiles for use in the elderly. Trazodone may be more favorable in the anxious/agitated patient due to its sedative effects, whereas nomifensine may be more beneficial in the retarded, apathetic patient.
A Multivariable Analysis of Factors Governing the Steady‐State Pharmacokinetics of Valproic Acid in 52 Young Epileptics
Authors: Hall K. , Otten N. , Johnston B. , Irvine‐Meek J. , Leroux M. , Seshia S.
Published: March 2013

A number of factors have been implicated in the interpatient variability of valproic acid (VPA) pharmacokinetics. These include patient age, concurrent anticonvulsant therapy, and dosage of VPA. In the clinical setting, it is important to determine which of these variables exert a major effect on the observed differences in VPA disposition. Accordingly, we analyzed the data from 52 young epileptic patients using multivariate statistical methods. Concurrent anticonvulsant therapy was the major determinant of VPA clearance in this patient population. The half‐life of VPA was significantly related to age, but volume of distribution and clearance were not. The dosage of VPA affected the volume of distribution of VPA but not the half‐life or clearance of this drug. These results provide a more rational understanding of VPA pharmacokinetics in the clinical setting and have implications for the monitoring and manipulation of VPA therapy in the epileptic population.
Objectively Measured Hyperactivity—I. Comparison With Normal Controls
Authors: Schechter Martin D. , Timmons G. Dean
Published: March 2013

Seventy‐five normal (control) children were compared to 15 hyperactive children on a Continuous Performance Test over an eight‐week period. The control children were observed to have a relatively constant number of correct responses, chair movements, and reaction times throughout the testing period. However, when the hyperactive children were differentiated according to their scores on the Conner's Abbreviated Parent Questionnaire, those children scoring one standard deviation above the normative mean were later revealed to have more errors of commission and omission, chair movements, and a longer reaction time than did the normal control children.
Objectively Measured Hyperactivity—II. Caffeine and Amphetamine Effects
Authors: Schechter Martin D. , Timmons G. Dean
Published: March 2013

Errors of commission and omission, chair movements, and reaction times were assessed in fifteen previously diagnosed hyperactive children on a Continuous Performance Test after four drug regimens: amphetamine at doses of 1.6 and 5.0 mg twice a day, as well as 300 mg caffeine administered alone and with 1.6 mg amphetamine twice a day, produced significant reductions in errors of commission and increased reaction times in those children scoring 24 or more on the Conner's Abbreviated Parent Questionnaire. In addition, subjective symptoms on this questionnaire were significantly reduced by all drug treatments. The high (600 mg) daily dose of caffeine was observed to significantly control hyperactive symptoms, however, it also produced a number of side effects as well.
Prediction of Thiopental Induction Dose Based on Caffeine Volume of Distribution
Authors: Inchiosa Mario A. , Schmahai Theodore J. , Phang Whang , Inchiosa Mario E. , Bizzarri Dante V.
Published: March 2013

Similarities in the physicochemical properties of caffeine and thiopental would suggest that the apparent volume of distribution of caffeine (aVd) may be comparable to the initial volume of distribution of thiopental. It is the initial volume of distribution of thiopental that is critical in the early minutes of anesthetic induction. A comparison of the aVd of caffeine and thiopental induction dose was made in 21 male New Zealand white rabbits. The aVd of caffeine was determined from serial saliva determinations following intravenous injection of caffeine (7.5 mg/kg). The loss of the pupillary light reflex was used as the end point for induction with thiopental. A statistically significant correlation (r = .722, P < .0001) was found between the aVd of caffeine and thiopental induction dose. Also, both thiopental induction dose and caffeine aVd decreased significantly with age in these animals. These findings provide a basis for development of an uninvasive test for predicting thiopental dose in humans.
Mood Alteration Following Oral and Intravenous Haloperidol and Relationship to Drug Concentration in Normal Subjects
Authors: Magliozzi Joseph R. , Gillespie Hampton , Lombrozo Leon , Hollister Leo E.
Published: March 2013

Haloperidol was administered to 12 subjects intravenously (0.125 mg/kg) and to nine subjects orally (0.5 mg/kg). These doses produced sedation in most subjects. A minimal decrease in orthostatic blood pressure was observed. Administration of the Profile of Mood States to these subjects revealed effects on factor 4, vigor‐activity, and factor 6, confusion‐bewilderment, but many subjects could not complete testing due to excessive sedation. Haloperidol concentrations were obtained during testing and correlated moderately with scores of these subscales. Correlation was also noted between haloperidol concentration and chlorpromazine effect as measured by the Addiction Research Center Inventory. Extrapyramidal reactions, mainly acute dystonic reactions and akathisia, were common. Dystonia occurred in four subjects after intravenous, and three subjects, after oral administration. Akathisia occurred in eight subjects after intravenous, and three subjects after oral administration. Extrapyramidal reactions tended to occur relatively early or relatively late, at times when drug concentrations were far less than peak values.
Pharmacokinetics of Oral Pramiracetam in Normal Volunteers
Authors: Chang T. , Young R. Montalbo , Goulet J. R. , Yakatan G. J.
Published: March 2013

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double‐blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (± SD) peak plasma concentrations of the four dose groups (2.71 ± 0.54, 5.40 ± 1.34, 6.13 ± 0.71, 8.98 ± 0.71 μg/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half‐life (4.5–6.5 hours), the mean total body clearance (4.45‐4.85 mL/min/kg), the mean renal clearance (1.83‐3.00 mL/min/kg), and the mean apparent volume of distribution (1.82‐2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.
Single‐Dose and Steady‐State Pharmacokinetics of Tomoxetine in Normal Subjects
Authors: Farid Nagy A. , Bergstrom Richard F. , Ziege Edgar A. , Parli C. John , Lemberger Louis
Published: March 2013

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90‐mg oral dose of tomoxetine to four normal volunteers, the plasma half‐life was 4.3 ± 0.5 hours. Mean plasma clearance was 0.60 ± 0.14 L/Kg/hr, and the mean volume of distribution was 3.7 4pL 0.9 L/kg. Multiple doses of tomoxetine (20 mg bid and 40 mg bid) for seven days were administered to an additional seven subjects. The data appeared to have a bimodal distribution. The mean plasma half‐life determined following the last dose was 4.6 ± 0.5 hours in five subjects. The other two subjects, one at each dose level, demonstrated accumulation of tomoxetine occurring from the first to last dose where tomoxetine disappeared from plasma with a mean half‐life of 19 hours.
Phenytoin Pharmacokinetics in Therapeutic Plasmapheresis
Authors: Nasca Thomas J. , Huff Nancy , Livengood Bruce H.
Published: March 2013

Total and free serum phenytoin concentrations and net phenytoin removal were examined in two stable patients (henceforth referred to as patient D.K. and patient C.L.) receiving therapeutic plasmapheresis for myasthenia gravis at Mercy Hospital. Similar serum determinations were obtained on the days prior to and after plasmapheresis in order to determine if a single patient plasma volume exchange replaced isovolumetrically with a 4.0 g% albumin solution would significantly alter serum concentrations of phenytoin.
Neuroleptic Bioequivalency: Tablet Versus Concentrate
Authors: Fann W.E. , Moreira Alvaro F.
Published: March 2013

Two forms of the antipsychotic neuroleptic molindone were administered to newly admitted psychotic patients. A coated tablet was administered for ten days, followed by administration of liquid concentrate in equivalent doses for four days. Plasma was analyzed by gas chromatography with electron capture for the parent compound following each dosing phase. Our data suggest that oral doses of the tablet and concentrate forms of this neuroleptic are equivalent in clinical bioavailability.
Comparison of Antimanic Efficacy of Clonidine and Verapamil
Authors: Giannini A. James , Loiselle Robert H. , Price William A. , Giannini Matthew C.
Published: March 2013

The standard treatment for mania has been lithium carbonate, alone or in combination with neuroleptics. Unfortunately, lithium is refractory in some patients and may possess potential thyroid and renal toxicity.1 Neuroleptics also are not without risks and can cause extrapyramidal symptoms as well as tardive dyskinesia.2 As a result, other less potentially troubling agents have been sought to control the symptoms of mania. Two such drugs are the antihypertensive agent, clonidine, and the antianginal drug, verapamil.

Clonidine is an alpha2 agonist. It exerts central pharmacologic effects by stimulating inhibitory auto‐receptors.2 This reduction in noradrenergic activity has proven useful in reducing tension and nervousness associated with opiate withdrawal,3 and panicanxiety disorders.4 Clonidine has also been used successfully as an antimanic drug in two separate trials.5,6 This has been hypothesized to be a result of reduction in the hypernoradrenergic tone associated with mania.6,7

Verapamil, a slow‐channel calcium blocker, has also been shown to be effective in reducing manic symptoms.8,9 In addition to blocking calcium influx in myocardial cells, it inhibits neurosecretory processes including excitation‐secretion coupling at noradrenergic synapses.10 Verapamil's action on calcium metabolism may mimic lithium's; both drugs block adenyl cyclase activity in most organ systems and as well as competing with calcium ions in neuromuscular cells.11 Calcium metabolism is of interest, since the onset of manic episodes are associated with transient increases in serum calcium.12

Since clonidine and verapamil are both cardiovascular drugs as well as putative antimanic agents, the authors thought it appropriate to compare their antimanic effects in the double‐blind, crossover study described below.
Staggered Stable Isotope Administration Technique for Study of Drug Distribution
Authors: Evans James E. , Browne Thomas R. , Kasdon David L. , Szabo George K. , Evans Barbara A. , Greenblatt David J.
Published: March 2013

By infusing intravenously a series of different stable isotope labeled forms of a drug at different times prior to performing a single collection of a body fluid via puncture (or tissue via biopsy), one can obtain the same information about a drug's distribution as would be obtained by infusing a single dose of drug and performing serial collections of fluid (or tissue). Application of this technique of “staggered stable isotope administration” is illustrated with a study of entry of phenobarbital into the cerebrospinal fluid of a dog. Advantages and disadvantages of this technique are discussed.
Book Review
Authors: Cavaliere M. Beth
Published: March 2013

Guide to Clinical Studies and Developing Protocols, by B. Spilker

Experimental and Clinical Toxicokinetics, edited by A. Yacobi and Herbert Barry

New Drugs Annual. Cardiovascular Drugs, vol 2, edited by Alexander Scriabine
Therapeutic Manipulations in Uremic Bleeding
Authors: Watson Alan J. , Whelton Andrew
Published: March 2013

Currently 80,000 patients are maintained by chronic dialysis in the United States, a figure that, however, only represents a small fraction of the overall population who experience acute or chronic impairment in renal function. It is well recognized that such patients with acute or chronic renal failure exhibit an increased tendency to bleed.1 The clinical significance of this complication is that hemorrhagic episodes remain a major contributory factor to the morbidity and mortality associated with uremia.2 Mucosal bleeding, particularly of the gastrointestinal tract, is perhaps the most frequent manifestation of the hemorrhagic diathesis; other manifestations include ecchymoses, epistaxis, hemorrhagic pericarditis, and subdural hematoma. The incidence of gastrointestinal hemorrhage in patients with established acute renal failure is approximately 30% to 40%,3 and in one major study accounted for 30% of the overall mortality.2 In the setting of chronic renal failure, hemorrhagic complications tend to be more frequent than those recorded in acute renal failure with an incidence of 60% in nondialyzed patients and 75% in dialyzed patients.4 In view of the impressive morbidity associated with this complication of acute and chronic renal failure, new approaches to the management of uremic bleeding merit brief commentary.

Definition of the principal hemostatic defect remains elusive despite the fact that several abnormalities of primary hemostasis have been detected. These include defective platelet factor‐Ill generation,5 subnormal platelet aggregation,6 prostacyclin/thromboxane A2 imbalance,7,8 and alterations in the activities of certain coagulation factors.9 Of the various laboratory tests available for assessing hemostasis, the bleeding time, which reflects the combined effects of (1) platelet function; (2) factor VIII: von Willebrand's factor (FVIII:VWF) activity; (3) hematocrit; and (4) vascular contractility, appears to correlate best with the likelihood of actual clinical hemorrhage in the uremic patient.10
Indenolol: A New Antihypertensive Agent: Efficacy, Toxicity, and Hemodynamic Effects in a Crossover Double‐Blind Study With Metoprolol
Authors: Trimarco Bruno , Cuocolo Alberto , Groothold Gisela , Ricciardelli Bruno , de Luca Nicola , Volpe Massimo , Veniero Anna Maria , Condorelli Mario
Published: March 2013

The antihypertensive efficacy of a new agent, indenolol, was compared with that of the well‐established antihypertensive drug, metoprolol, and its hemodynamic effects were investigated using echocardiography. Eighteen hypertensives completed a double‐blind, crossover, randomized study using indenolol and metoprolol. Two four‐week courses with indenolol or metoprolol were preceded and followed by a two‐week placebo period; the total duration of the study was 14 weeks. Indenolol proved to be significantly more effective than metoprolol in decreasing blood pressure values at rest (P < .05). Furthermore, three patients that failed with metoprolol were successfully treated with indenolol. Both drugs induced a significant decrease in cardiac output that was mediated mainly through a reduction in heart rate, because stroke volume, left ventricle circumferential fiber shortening velocity, and ejection fraction were not significantly reduced by either drug. However, after indenolol, a significant direct relationship was found between the basal values of both cardiac output (r = .809) and total peripheral resistance (r = .800), and the reduction of these parameters. On the contrary, after metoprolol only, the correlation between the basal value of cardiac output and its reduction was significant (r = .790).
Indenolol Pharmacokinetics and Pharmacodynamics After Single and Repeated Daily Doses
Authors: Sega Roberto , Mailland Federico , Colombo Fabrizio , Groothold Gisela , Pantarotto Claudio , Guenzati Giuseppe , Libretti Arnaldo
Published: March 2013

The relationship between indenolol (an investigational agent) plasma levels and the drug's effect on blood pressure and heart rate was investigated after single and repeated once daily administration at two dosage levels (60 mg and 120 mg) in two different groups of patients with first or second stage hypertension, according to the World Health Organization classification. The pharmacokinetic data were indicative of a first order absorption‐elimination curve; time of maximum plasma levels was 1.5 to two hours, and elimination half‐life was four hours. The drug did not accumulate in the central compartment after repeated administrations. A long‐lasting decrease of both resting and isometric exercise systolic pressure values was recorded after acute indenolol administration. Diastolic pressure was affected only by repeated administrations. The lower dose (60 mg daily) of indenolol did not affect heart rate, whereas the higher dose (120 mg daily) decreased this parameter. A steady state of pressure values and heart rate was reached after 14 days of once daily treatment.
A Dose‐Titration Trial of Guanadrel as Step‐Two Therapy in Essential Hypertension
Authors: Oren Arie , Rotmensch Heschi H. , Vlasses Peter H. , Riley Louis J. , Koplin Janice R. , Latini Vincent , Ferguson Roger K.
Published: March 2013

The efficacy and safety of low‐dose guanadrel sulfate were evaluated in 20 patients with essential hypertension based on seated diastolic blood pressures (SDBP) ranging from 95 to 115 mm Hg despite a trial dosage of hydrochlorothiazide 50 mg/d for up to five weeks. These patients had been resistant to, or intolerant of, one or more step‐two antihypertensive drugs in the past (i.e., methyldopa, beta‐adrenergic blocking agents, clonidine, or prazosin). The majority of patients demonstrated a satisfactory response (SDBP 95 mm Hg or reduction in SDBP of 10 mm Hg) to guanadrel. Nine patients responded at a low dosage, 10 to 20 mg/d and remained free from adverse effects throughout the study (up to 12 weeks of treatment). Of the remaining 11 patients titrated to higher dosages of guanadrel (30 to 60 mg/d), three had no discernible response while six developed adverse effects. The results of the study suggest that guanadrel has an acceptable benefit‐to‐risk ratio only when used in low dosages (10 to 30 mg/d) and may be successfully employed as step‐two antihypertensive therapy in patients resistant to, or intolerant of, other step‐two agents.
Plasma Protein Binding of Bepridil
Authors: Pritchard J. Frederick , McKown Linda A. , Dvorchik Barry H. , O'Neill Patrick J.
Published: March 2013

The binding of the calcium‐channel blocking agent, bepridil HCl (Vascor), to plasma proteins was investigated using radiolabeled bepridil and equilibrium dialysis. Greater than 99.7% of added bepridil‐14C was found to freshly collected human plasma. The binding was characterized by a saturable high‐affinity site (KD = 32 ng/mL = 87 nM) on alpha1‐acid glycoprotein (AAG) or on an AAG‐human serum albumin complex and lower affinity binding sites on albumin and other plasma macromolecules. Bepridil that is not bound to plasma proteins is extensively distributed into erythrocytes as evidenced by a red blood cell to free drug distribution coefficient of 71 ± 7. Despite this high value, the blood to plasma ratio of bepridil averaged only 0.67 in humans, indicating that most of the circulating drug is bound to plasma proteins. Bepridil protein binding was not affected by additions of nonesterified fatty acids. Free fractions of bepridil were enhanced by addition of verapamil, nifedipine, diltiazem, disopyramide, and warfarin but only at concentrations above those achieved clinically. Bepridil was also displaced by the plasticizer, tris‐(2‐butoxyethyl)phosphate. Plasma obtained from a small number of angina patients prior to bepridil administration showed no differences in ability to bind bepridil compared with plasma obtained from healthy subjects.
The Bronchosparing Effect of Celiprolol, A New Beta1‐ Alpha2‐Receptor Antagonist on Pulmonary Function of Propranolol‐Sensitive Asthmatics
Authors: Matthys H. , Doshan H. D. , Rühle K. H. , Braig H. , Applin W. J. , Caruso F. S. , Neiss E. S.
Published: March 2013

Twelve normotensive asthmatics who demonstrated bronchoconstriction after a single oral dose of 80 mg of propranolol received (according to a double‐blind, randomized, crossover design) placebo, celiprolol 200 mg, and celiprolol 400 mg at intervals of at least three days. Pulmonary function parameters were measured by whole body plethysmography just before treatment and hourly for three hours. Thereafter, terbutaline (0.5 mg), a beta2 agonist, was administered in aerosol form at 15‐minute intervals for a total of five doses. This design permitted a safety asesessment of the effect of placebo and celiprolol on resting pulmonary function and the evaluation of any interaction between this beta blocker and terbutaline. Propranolol 80 mg produced a statistically significant decrease in a forced one second expiratory volume and forced vital capacity, and a pronounced rise in airways resistance as compared with either dose of celiprolol or with placebo (P < .001). The effect of celiprolol was not statistically distinguishable from placebo. Terbutaline caused further net bronchodilation after administration of celiprolol and placebo but, even at supratherapeutic doses, failed to restore pulmonary function parameters to baseline levels after treatment with propranolol. The bronchosparing effect of celiprolol may be due to its unique pharmacologic profile, which includes cardioselectivity, modest beta2‐agonist activity, and alpha2‐receptor blockade.
A Steady‐State Evaluation of the Effects of Propantheline Bromide and Cholestyramine on the Bioavailability of Digoxin When Administered as Tablets or Capsules
Authors: Brown Donald D. , Schmid Joanne , Long Robert A. , Hull J. Heyward
Published: March 2013

Drug interactions can profoundly alter the absorption of digoxin in tablet form. This study evaluated whether digoxin solution in capsules, a new dosage form with 90% to 100% bioavailability, would reduce such alterations, specifically those caused by cholestyramine and propantheline bromide. The investigation used a six‐treatment, steady‐state, balanced, incomplete block design with 18 healthy adults studied for four continuous two‐week treatment periods. Treatments were either two 0.25 mg digoxin tablets or two 0.20 mg digoxin capsules administered alone, with propantheline, 15 mg qid, or with cholestyramine, 8 g qd. Bioavailability was determined from steady‐state, 24‐hour area under the serum concentration‐time curve (AUC, ng × h/mL) and from 0‐ and 24‐hour trough serum digoxin concentrations (ng/mL). The AUCs for tablets alone, with cholestyramine, and with propantheline were 32.8 ± 13.3 (± SD), 22.4 ± 12.1, and 40.6 ± 13.9, respectively, while corresponding values for capsules were 31.7 ± 9.3, 24.7 ± 7.9, and 35.9 ± 12.8. The trough concentrations for tablets alone, with cholestyramine, and with propantheline were 0.88 ± 0.47, 0.61 ± 0.38, and 1.09 ± 0.35, respectively; trough concentrations for capsules were 0.77 ± 0.28, 0.74 ± 0.28, and 0.96 ± 0.48, respectively. The only significant differences in AUC were seen when comparing tablets alone versus tablets with cholestyramine (P < .0005) and tablets with propantheline (P < .01). A significant finding was also observed when comparing trough concentrations for tablets alone versus tablets with cholestyramine (P < .005). The results confirm (1) bioequivalence of 0.20 mg capsules versus 0.25 mg tablets, (2) significant alterations in tablet bioavailability due to cholestyramine and propantheline, and (3) reduction of these alterations by the capsule dosage form. These findings suggest that digoxin capsules may offer clinical advantages over digoxin tablets in achieving predictable, consistent serum digoxin concentrations in patients receiving cholestyramine, propantheline, and similar drugs.
Excretion of Triamterene and Its Metabolite in Triamterene Stone Patients
Authors: Ettinger Bruce
Published: March 2013

As triamterene users may form kidney stones containing deposits of triamterene and its metabolites, we studied urinary excretion to detect any altered metabolism of triamterene in these patients. We found no significant differences between patients and matched control subjects in total recovery, hourly excretion patterns, and concentrations of triamterene and its sulfate metabolite. Approximately half of all subjects tested revealed urine concentrations of the sulfate metabolite that exceeded the observed solubility limit.
Combined Effect of Bumetanide and Metolazone in Normal Volunteers
Authors: Greenberg Arthur , Wallia Rajni , Puschett Jules B.
Published: March 2013

Bumetanide 1 to 2 mg or metolazone 2.5 mg were administered by mouth separately and then in combination to eight normal men and women in order to determine whether a sequential blockade of sodium reabsorption with diuretic agents that act at different sites within the nephron leads to a supra‐additive diuretic effect. All three treatment regimens resulted in a significant weight loss and increased urine volume and the excretion of sodium, potassium, and chloride. A prolonged diuretic effect lasting up to 48 hours after administration occurred with metolazone alone. Although absolute and fractional chloride and potassium excretion and urine volume were higher after combined therapy (P < .05 or better) than after either drug alone, absolute sodium excretion after combination therapy was higher than excretion after bumetanide [P < .05) but not after metolazone. The percent of fractional sodium excretion after both drugs was greater than after either drug alone (P < .05). However, excretion of chloride, sodium, potassium, and fluid on the combined therapy day was less than the sum of excretion on each single drug therapy day. Thus, the combination of bumetanide and metolazone did not have a supra‐additive effect in normal subjects.
A Comparative Oral Analgesic Study of Indoprofen, Aspirin, and Placebo in Postpartum Pain
Authors: Sunshine Abraham , Zighelboim Itic , Olson Nancy Z. , de Sarrazin Cherokee , Laska Eugene
Published: March 2013

The purpose of this study was to evaluate the analgesic efficacy and adverse effect liability of single oral doses of indoprofen, 50 mg, 100 mg, and 200 mg, compared with aspirin, 300 mg and 600 mg, and placebo in the relief of moderate to severe postpartum pain. Two hundred‐ten patients entered a randomized, double‐blind, parallel group study and were evaluated over a six‐hour period by a single nurse‐observer. There was a significant imbalance in the distribution of pain types across treatments that compromises the interpretation of the results. In addition to analyzing the data from all patients, the subsets with episiotomy/cesarean section pain and uterine cramp pain were examined separately. The latter group had too few patients to permit distinction between drugs. The 100 mg and 200 mg doses of indoprofen were significantly (P .05) more effective than placebo for many variables including the following summary values: sum of pain intensity difference (SPID), sum of hourly relief values (TOTPAR), and % SPID for all patients as well as in the subset of patients with episiotomy/cesarean section pain. Aspirin, 600 mg, was also significantly more effective than placebo for many of the same measures of analgesia in the episiotomy/cesarean section subset. Pairwise differences were also seen between placebo and aspirin, 300 mg, but on fewer variables. Indoprofen, 100 mg, was significantly more effective than aspirin, 600 mg, at hour 6 for pain intensity difference (PID) in the episiotomy/cesarean section subset. The effect of indoprofen appeared to plateau above 100 mg. The relative potency estimates of indoprofen to aspirin ranged from seven to ten for the variables SPID, TOTPAR, and % SPID. There were no observed or reported adverse effects. In summary, indoprofen was found to be an effective oral analgesic similar to aspirin, with the suggestion of a more sustained effect.
Reliability of Theophylline Clearance in Determining Maintenance Intravenous Aminophylline Therapy
Authors: Grambau Geoffrey R. , Johnson Cary E. , Conlon Paul F. , Weg John G.
Published: March 2013

Although theophylline has long been the primary drug used for the management of reversible obstructive airway disease, current recommendations for determining theophylline dosage have not been dependable and, when applied to individual patients, have resulted in a wide range of serum theophylline concentrations (STC) and frequent adverse reactions.1–3

The objective of this study was to evaluate the clinical reliability of using theophylline clearance values to adjust the theophylline infusion rate to achieve a desired STC and to determine the minimum time required for administration of a continuous theophylline infusion in a given population of patients before obtaining a single STC for the clinically reliable calculation of theophylline clearance.
The Effect of Rapid Digitalization on Ventricular Function in Patients With Congestive Heart Failure
Authors: Rotenberg Zvi , Hellman Chaim , Weinberger Itzhak , Fuchs Jacob , Agmon Jacob
Published: March 2013

Cardiac glycosides have been used in the treatment of cardiac failure for more than 200 years. Digitalis and its analogues have been shown to increase myocardial contractility and to decrease left ventricular end‐diastolic pressure and volume, while causing no essential change in aortic pressure and a variable decrease in heart rate.1–2 However, several reports3–8 have questioned the use of digitalis in patients with ventricular dysfunction, particularly in view of the newer modes of therapy.

The aim of this study was to define the effects of rapid digitalization on left and right ventricular function in patients with chronic congestive heart failure, using radionuclide methods.
Biphasic Plasma Aldosterone Responses to Four Single‐Dose ACTH Regimens
Authors: Griffing George T. , Pratt Howard , Melby James C.
Published: March 2013

Adenocorticotropic hormone (ACTH) administration increases cortisol synthesis but produces a biphasic aldosterone response. Some investigators believe that the hypercortisolism from prolonged ACTH administration is responsible for this aldosterone response. The present study evaluated the plasma aldosterone response to four acute single‐dose ACTH regimens that produced only a transient increase in plasma cortisol. Fourteen normal adult men received (1) 1–18 ACTH intravenous bolus (IV), (2) 1–18 ACTH intramuscular (IM), (3) 1–39 ACTH (IM), and (4) 1–24 ACTH (IV). The plasma aldosterone increased within one hour and tended to parallel the cortisol increment with all four ACTH regimens. With all of these ACTH regimens, the plasma aldosterone level decreased below placebo with 1–24 ACTH (IV) (24 hours), 1–39 ACTH (IM) (24 hours), and 1–18 ACTH (IV) and (IM) (48 hours) at a time when the cortisol had returned to normal. These results suggest that the delayed ACTH‐induced aldosterone inhibition production are not directly related to cortisol production and do not require prolonged ACTH administration. These observations are consistent with ACTH induction of a nonaldosterone mineralocorticoid, which is independently suppressing aldosterone production.
Lack of Effects of Diltiazem on Digoxin Pharmacokinetics
Authors: Beltrami Teresa R. , May John J. , Bertino Joseph S.
Published: March 2013

Diltiazem is a member of a class of pharmacologic agents that block the passage of calcium ions across cell membranes, the calcium‐channel blockers. Several investigators have reported a clinically important pharmacokinetic and pharmacologic interaction between digoxin and verapamil.1–4 Despite earlier suggestions of such an interaction with nifedipine, recent works have convincingly shown that no pharmacokinetic changes occur.5–7 Thus, it appears that nifedipine has no clinically significant interaction with digoxin. Similar work has been limited with diltiazem. A recent investigation by Yoshida and associates,8 suggested no increase in digoxin serum concentration and a slight decrease in renal digoxin clearance after diltiazem had been added versus a control period. Rameis and co‐workers9 recently reported a 22.4% increase in serum digoxin concentration when diltiazem was added. The purpose of this study was to further evaluate this potential interaction.
Pharmacokinetics of Atenolol in Patients Treated With Chronic Hemodialysis or Peritoneal Dialysis
Authors: Campese Vito M. , Feinstein Eben L , Gura Victor , Mason William D. , Massry Shaul G.
Published: March 2013

Atenolol is a relatively selective beta1‐adrenoceptor blocking agent devoid of partial agonist or membrane stabilizing properties.1,2 The drug is not significantly bound to plasma proteins and it is excreted in the urine unchanged.3,4 The elimination half‐life in subjects with normal renal function is six to seven hours.3,5 However, since the elimination of the drug is closely related to glomerular filtration rate (GFR), its half‐life is prolonged in subjects with impaired renal function proportionately to the decrease in GFR.6 In dialysis patients, there is very little elimination of the drug during the interdialytic period. The apparent plasma half‐life of atenolol in these patients ranges between 42 and 73 hours.7–10 However, during a standard hemodialysis procedure of four hours, plasma concentration decreases by approximately 50%.10 No data are available on the effects of peritoneal dialysis on the elimination half‐life of this drug. The purpose of this study was to determine the plasma half‐life of this drug in patients treated with chronic peritoneal dialysis or chronic hemodialysis.
Pharmacodynamic Interaction Between Midazolam and a Specific Benzodiazepine Antagonist in Humans
Authors: Klotz U. , Ziegler G. , Ludwig L. , Reimann I.W.
Published: March 2013

The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15–1788 has been investigated in six healthy male volunteers. Hypnotic steady‐state concentrations of midazolam (55 ± 11 ng/mL; mean ± SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two‐hour control period, the antagonist (2.5 mg) or the solvent were injected double‐blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight‐hour trial (Clearance = 670 ± 96 mL/min) concentrations of Ro 15–1788 declined rapidly with an elimination half‐life between 0.7 and 1.8 hours and a total plasma clearance of 702 ± 235 mL/min. Concentrations of Ro 15–1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15–1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15–1788. In conclusion, a small intravenous bolus of 2.5 mg Ro 15–1788 reverses rapidly the hypnotic action of midazolam. The relative short duration of the antagonistic effect is due to the fast hepatic elimination of Ro 15–1788, which might be a suitable antidote of benzodiazepine‐induced oversedation in special clinical situations.
Effect of Transdermal Scopolamine on Salivation
Authors: Gordon C. , Ben‐Aryeh H. , Attias J. , Szargel R. , Gutman D.
Published: March 2013

The effect of transdermal scopolamine on salivary flow and composition was analyzed in 21 healthy volunteers. The flow rate of whole saliva was significantly lowered by transdermal scopolamine. Significant positive correlations were found between the placebo rate of flow and both the quantity and percentage decreases in response to transdermal scopolamine. The magnesium concentration was significantly increased during transdermal scopolamine administration, whereas the sodium, potassium, and calcium concentrations were not consistently altered. Accordingly, the magnesium secretion rate was unaltered, whereas sodium, potassium, and calcium secretion rates were significantly lowered by transdermal scopolamine administration.
Effects of Ketanserin, a 5‐HT2‐Receptor Antagonist, on the Blood Flow Response to Temperature Changes in the Diabetic Foot
Authors: Schneider S. H. , Tendler M. , Apelian A. , Jageneau A. H. M. , Khachadurian A. K.
Published: March 2013

We studied the effect of ketanserin, a relatively specific antagonist for 5‐hydroxytryptamine2‐serotonergic receptors, on the total blood flow to the foot of patients with diabetes using a computerized pulse volume Plethysmograph and a temperature controlled foot chamber. Ketanserin was administered intravenously as a bolus of 10 mg over four minutes followed by a constant infusion at the rate of 5 mg/hr. Saline infusion served as a control in each subject. Sixteen patients with type II diabetes and two patients with type I diabetes were studied. Mean age was 58.5 ± 1.6 years and mean duration of diabetes was 10 ± 2 years. Basal blood flow (mean ± SEM, mL/100 mL/min) at room temperature was 3.77 ± 0.99 with saline and 12.07 ± 1.81 with ketanserin. At 38 to 40°C, the values were 4.84 ± 1.09 and 16.93 ± 1.83. Reactive hyperemia was measured following three minutes of arterial occlusion; at 38 to 40°C the flow rate was 20.67 ± 2.45 with saline and 30.86 ± 3.02 with ketanserin, while at 8 to 10°C the corresponding values were 15.63 ± 2.01 and 27.16 ± 2.03. All differences between saline and ketanserin had a P < .01. Venous distensibility (vol% at 50 mm Hg) at 8 to 10°C was 0.55 ± 0.05 with saline and 0.90 ± 0.15 with ketanserin, P < .05. Our findings are consistent with the hypothesis that serotonin is involved in the limitation of blood flow to the foot in diabetes and that ketanserin may play a potential role in therapy.