bluuebunny/crossref_metadata_2025 huggingface dataset:
The Oral Analgesic Efficacy of Bicifadine Hydrochloride in Postoperative Pain
Authors: WANG RICHARD I. H. , JOHNSON ROGER P. , LEE JOHN C. M. , WAITE ELIZABETH M.
Published: March 2013

Abstract: The analgesic efficacy of 75 and 150 mg bicifadine hydrochloride was compared to 650 mg aspirin and placebo in a double‐blind, single‐dose study. Oral doses were administered to 100 patients suffering from moderate to severe postoperative pain. Significant analgesic activity was demonstrated with 650 mg aspirin and 150 mg bicifadine as compared to 75 mg bicifadine or placebo. No significant treatment difference was found between 75 mg bicifadine and placebo. Side effects were minor and did not interfere with the course of therapy.
Gastrointestinal Blood Loss of Oxaprozin and Aspirin with Placebo Control
Authors: LUSSIER ANDRÉ , LeBEL ÉTIENNE , TÉTREAULT LÉON
Published: March 2013

Abstract: The objective of this study was to compare the effects of oxaprozin (4,5‐diphenyl‐2‐oxazolepropionic acid), a nonsteroidal, antiinflammatory compound, and aspirin in a double‐blind, placebo‐controlled study to estimate gastrointestinal bleeding. The determination of fecal blood loss was made quantitatively by the use of the radioactive (51Cr) technique. During the first week, subjects were controlled with and without placebo. At the end of the second week, the subjects were divided and randomly assigned to one of three groups; 10 received 1200 mg oxaprozin (600 mg twice daily), 11 received 3900 mg aspirin (975 mg four times a day), and the remaining 8 subjects received placebo for two weeks. During the last two weeks, all received placebo again. A statistical analysis of variance showed that there were no statistical differences between the groups during the first and last two weeks of placebo therapy. During the active treatment period, weeks 3 and 4, there were statistically significant differences among the three groups. The mean blood loss during week 3 was significantly greater for the aspirin group, 8.8 ml/day, than the oxaprozin group, 3.3 ml/day (P < 0.05), and the placebo group, 1.4 ml/day (P < 0.001). The smaller difference between oxaprozin and placebo was also significant (P < 0.05). During the fourth week, the mean daily blood loss among oxaprozin patients had decreased to 2.3 ml/day, and no statistically significant difference from placebo (1.1 ml/day) was found.
Increased Erythrocyte Calcium in Alcoholism
Authors: MELTZER HERBERT L. , ALEXOPOULOS GEORGE
Published: March 2013

Abstract: The intraerythrocyte calcium concentration in blood samples of 42 hospitalized alcoholic subjects was initially elevated but declined over a period of several weeks toward normal values. The abnormally high values, which appear to be a direct consequence of prior alcohol ingestion, may explain previous reports of lowered erythrocyte potassium in chronic alcoholics, since there is a specific calcium‐gated potassium channel in erythrocyte membranes.
Plasma Pharmacokinetics of Intravenously Administered Atropine in Normal Human Subjects
Authors: ADAMS RICHARD G. , VERMA PRITAM , JACKSON ANDRE J. , MILLER RUSSELL L.
Published: March 2013

Abstract: The pharmacokinetics of atropine (dl‐hyoscyamine) was studied in six normal volunteers following a single 1‐mg intravenous dose of atropine. Atropine plasma levels were collected for 24 hours and analyzed by radioimmunoassay. Pulse rates were monitored and compared with predose values in each subject. Atropine plasma concentrations were fitted by least‐squares regression analysis. The observed maximal increase in pulse rate, at 12 to 16 minutes after the dose, correlated with the maximum predicted tissue levels of atropine based on the computer fit of the plasma atropine concentration‐time data. No correlation between the time of maximum response and atropine plasma concentrations was observed. The average half‐life of atropine was 4.125 hours. This data may be used to design a multiple‐dosing regimen for intravenous atropine in patients.
The Effect of Probenecid on Nafcillin Disposition
Authors: WALLER ELAINE S. , SHARANEVYCH MOTRIA A. , YAKATAN GERALD J.
Published: March 2013

Abstract: Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup‐plate technique with M. Iuteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration‐time curve (AUC) two‐fold and decreased the total body clearance significantly with decreases in both renal and non‐renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non‐renal clearances of nafcillin.
Comparison of the Analgesic Efficacy and Safety of Oral Ciramadol, Codeine, and Placebo in Patients With Chronic Cancer Pain
Authors: Stambaugh John E. , McAdams Janet
Published: March 2013

Ciramadol is a new opioid agonist‐antagonist analgesic with low potential for dependency. Forty‐three patients with moderate to severe chronic pain from primary or metastatic malignancy of the bone or major organs were enrolled in a randomized double‐blind study that compared orally administered ciramadol (30 mg or 90 mg) to codeine (60 mg) and placebo. A single‐dose, four‐way crossover design, with a randomized Latin‐square treatment sequence, was used. Data for 40 patients who received the above four study medications were included in the final statistical analysis of efficacy. Analgesic efficacy was measured at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, and 6.0 hours, using standard visual and verbal pain relief and pain intensity scales. All active therapies provided greater pain relief than placebo (P < .05). Ciramadol 30 mg and codeine 60 mg demonstrated equal analgesic activity, whereas ciramadol 90 mg was superior to both therapies. The predominant adverse experiences associated with ciramadol were nausea and drowsiness, which were apparently not dose related. Ciramadol appears to be an effective analgesic at the doses tested, with tolerable gastrointestinal central nervous system side effects at both the 30‐ and 90‐mg dose levels.
Effect of Congestive Heart Failure on the Pharmacokinetics of Cibenzoline
Authors: Massarella Joseph W. , Silvestri Tina , DeGrazia Francis , Miwa Barbara , Keefe Deborah
Published: March 2013

Six patients with chronic congestive heart failure (CHF) (New York Heart Association functional class II or III) and five healthy subjects completed this study designed to determine if CHF alters the pharmacokinetics and absolute bioavailability of cibenzoline when compared with healthy subjects. Each subject or patient was administered a one‐hour intravenous infusion of 80 mg of 15N2‐cibenzoline and simultaneously received an 80‐mg oral dose of cibenzoline that allowed for analytic separation of each route of administration. Resulting plasma concentration‐time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for cibenzoline. There were no statistically significant differences in any pharmacokinetic parameter between patients with CHF and healthy subjects. The absolute bioavailability ranged from 74% to 97% in those with CHF. The volume of distribution following the intravenous dose ranged from 3.4 to 6.1 L/kg, and plasma clearance ranged from 245 to 642 mL/min, with an apparent elimination half‐life of approximately ten hours. Approximately 60% of the dose was recovered in the urine. Overall, the pharmacokinetics of cibenzoline in patients with chronic CHF do not differ from those observed in healthy subjects.
The Relationship of Serum Albumin Level to Phenytoin Toxicity
Authors: Black Jimmy , Hannaman Tony , Malone Christine
Published: March 2013

Phenytoin (DPH) is a commonly used anticonvulsant that can be associated with potentially serious toxicity when serum concentrations exceed 20 μg/mL. Phenytoin is also highly protein‐bound and exhibits dose‐dependent absorption characteristics. The therapeutic effect and the degree of toxicity are dependent on free phenytoin concentrations (free fraction), which in turn depend on the degree or percentage of binding to serum albumin. We report a case in which the effects of profound DPH toxicity were attenuated after the intravenous administration of albumin. We comment on the importance of gastric lavage in the decontamination of patients with acute drug overdose.
Bromocriptine Therapy in Cocaine Withdrawal
Authors: Giannini A. James , Baumgartel Peter , DiMarzio Lynn R.
Published: March 2013

Twenty‐four cocaine addicts who experienced withdrawal symptoms were studied for six weeks in a double‐blind design. Half of the group received daily treatment with bromocriptine and the other half with placebo. Significant relief with bromocriptine was seen almost immediately and continued throughout the detoxification period. The authors speculate that the results are consistent with the “dopamine‐depletion model” of cocaine withdrawal.
Lorcainide for the Treatment of Refractory Ventricular Tachycardia: Clinical and Electrophysiologic Results
Authors: Hanyok James J. , Kluger Jeffrey , Chow Moses S. S. , Fieldman Arnold
Published: March 2013

The electrophysiologic effects and antiarrhythmic efficacy of lorcainide were evaluated using programmed electrical stimulation (PES) in 14 patients with ventricular tachycardia (VT) refractory to conventional drug therapy. Lorcainide was administered orally (200–400 mg/d, eight patients), intravenously (150 mg/d, one patient), or by both routes (250–380 mg/d, five patients) prior to PES. In 13 patients undergoing both control and lorcainide PES, lorcainide increased the QRS duration (102 ± 28 to 125 ± 28 ms, P < .001) and the QTc interval (430 ± 39 to 471 ± 32 ms, P < .01) but had no effect on the RR interval (786 ± 156 to 780 ± 172 ms, P > .2). The right ventricular effective refractory period increased from 258 ± 8 to 285 ± 22 ms (P < .001). Lorcainide prevented VT induction or resulted in induction of only well‐tolerated, nonsustained VT in six of 14 patients (43%). The cycle length of induced VT increased from 264 ± 32 to 306 ± 34 ms (P < .01). Of six patients started on chronic therapy, four still receive lorcainide after 18 ±7 months. Adverse effects have consisted mainly of sleep disturbances. Thus, it can be stated that lorcainide is effective in certain patients with VT refractory to conventional therapy.
Disposition of Aspirin and Its Metabolites in the Semen of Man
Authors: Kershaw Richard A. , Mays Dennis C. , Bianchine Joseph R. , Gerber Nicholas
Published: March 2013

The study was undertaken to determine the distribution of aspirin and its metabolites in the semen of humans after an oral dose of aspirin. Each of seven healthy male volunteers was given a single oral dose of 975 mg of aspirin on an empty stomach together with 200 mL of water. Timed samples of blood and semen were obtained from each subject, and the concentrations of aspirin, salicylic acid, and salicyluric acid determined by a specific high‐performance liquid chromatographic assay. The mean peak concentration of aspirin was 6.5 μg/mL in plasma (range, 4.9‐8.9 μg/mL), reached in 26 minutes (range, 13–33 minutes). The half‐life of aspirin was 31 minutes. The concentration ratio of aspirin (semen/plasma) was 0.12 (except for one subject in whom it was 0.025). The mean peak concentration of salicylate in plasma was 49 μg/mL (range, 42–62 μg/mL), reached in 2.5 hours (range, 2.0–2.8 hours). Salicylate distributed rapidly into semen and maintained a concentration ratio (semen/plasma) of 0.15. Salicyluric acid (the glycine conjugate of salicylic acid) was found in the semen. Its high concentration in some subjects' semen (four times the concurrent plasma concentration) was attributed to contamination of semen sample with residual urine, containing salicylurate, in the urethra of those who urinated after the dose of aspirin. Possible side effects of aspirin and salicylate in semen include adverse effects on fertility, male‐mediated teratogenesis, dominant lethal mutations, and hypersensitivity reactions in the recipients.
Estimation of the Elimination Half‐Life of a Drug at Any Serum Concentration When the Km and Vmax of the Drug Are Known: Calculations and Validation With Phenytoin
Authors: Browne Thomas R. , Greenblatt David J. , Evans James E. , Szabo George K. , Evans Barbara A. , Schumacher Gerald E.
Published: March 2013

A method of estimating the elimination half‐life of a drug at any selected serum concentration when the Km and Vmax of that drug are known is described. The method was validated in six patients by determining their Km and Vmax values for phenytoin, using data obtained at two serum concentrations and then using the Km and Vmax values to predict the elimination half‐life of phenytoin at a third serum concentration. The predicted elimination half‐lives at the third serum concentration did not differ significantly (t = 1.16, P = .30) from observed elimination half‐lives determined with stable isotope tracer techniques.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

The Heart (Arteries and Veins) (Sixth Edition) Edited by J. Willis Hurst, MD

Pharmacology of Eating Disorders: Theoretical and Clinical Developments Edited by Michele O. Carruba and John E. Blundell

Reviews of Physiology, Biochemistry, and Pharmacology (Volume 102) Edited by R.H. Adrian, et al
Antiarrhythmic Effect of Lorcainide in Patients Taking Digoxin
Authors: Giardina Elsa‐Grace V. , Raby Khether , Saroff Alan L. , Louie‐Chu May
Published: March 2013

To assess the antiarrhythmic effect of lorcainide and determine whether there is a pharmacokinetic interaction between lorcainide and digoxin, 12 patients with frequent premature ventricular depolarizations (PVDs) who were taking digoxin were treated with lorcainide. During a placebo period, serum digoxin concentration was measured for three days; plasma lorcainide concentration, a 12‐lead electrocardiogram (ECG), and a 24‐hour continuous ECG were measured on the day before the patients began lorcainide and repeated on days 3, 7, and 14 of treatment Lorcainide was given 100 mg bid or 100 mg tid. Lorcainide did not suppress group mean PVDs per hour, pairs, or ventricular tachycardia. Only four patients (33%) responded with ≥ 80% suppression of PVDs. Mean ejection fraction for responders was 46 ± 6%, and for nonresponders it was 28 ± 9% (P < .01). There was no significant pharmacokinetic interaction between lorcainide and digoxin. Mean digoxin concentration did not change after lorcainide administration; two patients had ≥ 50% increase in serum digoxin concentration. Patients with heart failure or reduced ejection fraction define a subset who have unpredictable effects from lorcainide, including a reduced antiarrhythmic effect.
Phase I Study of Cefixime, a New Oral Cephalosporin
Authors: Nakashima Mitsuyoshi , Uematsu Toshihiko , Takiguchi Yoshiharu , Kanamaru Mitsutaka
Published: March 2013

The tolerance to and pharmacokinetics of cefixime, a new oral cephalosporin, were evaluated in healthy volunteers given the drug in single doses of 50, 100, and 200 mg and repeated doses of 200 mg bid for 14 days. In the repeated‐dose study, there were mild and transient subjective symptoms such as soft stools, diarrhea, and anorexia, which disappeared without additional treatment during the dosing period. Slight increases in eosinophil and serum amylase levels were also observed. The serum concentrations of cefixime peaked at 0.71, 1.17, and 2.08 μg/mL on average, four to five hours after dosing with 50, 100, and 200 mg, respectively, and the half‐lives were 2.54, 2.38, and 2.29 hours. Serum concentrations and urinary recoveries after dosing with 100 mg were little affected by food ingestion. There was no evidence of cefixime accumulation in the body by repeated dosing since mean serum concentrations and urinary recoveries were almost the same on the first, third, seventh, and 14th days of dosing.
Pharmacokinetics of Interferon α‐2b in Healthy Volunteers
Authors: Radwanski Elaine , Perentesis George , Jacobs Sheila , Oden Edwin , Affrime Melton , Symchowicz Samson , Zampaglione Nicola
Published: March 2013

In a three‐way crossover design, 12 healthy male volunteers received 5 × 106 IU/m2 body surface area interferon α‐2b(IFN α‐2b) by intravenous (IV) infusion over 30 minutes, intramuscular (IM) injections, and subcutaneous (SC) injections. Blood and urine samples were collected at specified times, and analysis of IFN α‐2b concentrations was performed by immunoradiometric assay. “Flulike” symptoms were the most frequently reported adverse experiences and were independent of the route of administration. After a 30‐minute IV infusion, IFN α‐2b disappeared rapidly from serum, with distribution and elimination phase half‐lives of 0.1 hour and 1.7 hours, respectively. Interferon α‐2b was absorbed slowly after IM and SC administration, with similar absorption half‐lives of 5.8 and 5.5 hours, respectively. The observed maximal concentrations after IM and SC administration were 42.1 IU/mL at six hours and 45.8 IU/mL at eight hours, respectively. Interferon α‐2b was eliminated with half‐lives of 2.2 hours after IM administration and 2.9 hours after SC administration. The areas under the serum concentration‐time curves for the SC and IM doses were higher than those obtained for the IV infusion. Measurable amounts of IFN α‐2b were not found in urine regardless of the route of administration.
The Clinical Pharmacology Consultation Service: Results of a Physician Survey Before and After Implementation
Authors: Casner Paul R. , Dillon Kevin R.
Published: March 2013

A total of 175 physicians were surveyed by questionnaire before a Clinical Pharmacology Consult Service was started. Of those that responded, 72% thought the service would be helpful although 40% said they would use the service no more than once a month. Most physicians (75%) preferred self‐initiated consultations to automatic surveillance. Ninety‐two percent believed a physician should be involved in making drug recommendations. A second questionnaire was circulated 30 months later. Actual use of the service closely paralleled the results of the first survey. There was an increased preference for automatic surveillance (5% vs 32%) and many physicians (48%) indicated they felt comfortable accepting drug consultations from a pharmacist or clinical pharmacist. Despite a general attitude of acceptance, the majority of respondents ranked the Clinical Pharmacology Consult Service last as a source of drug information.
Naltrexone: Lack of Effect on Hepatic Enzymes
Authors: Brahen Leonard S. , Capone Thomas J. , Capone Daniel M.
Published: March 2013

A number of studies have established the clinical efficacy of naltrexone in the treatment of opiate addiction. However, questions have been raised regarding its hepatotoxic potential and warnings have been given prominence in the package insert regarding its use for those with even less severe liver disease. The current study monitored 53 male patients receiving naltrexone 350 mg weekly for 12 weeks. The lactic acid dehydrogenase (LDH) and serum glutamic oxalacetic transaminase (SGOT) Jevels were determined at pretreatment and at monthly intervals thereafter for three months. LDH and SGOT were found to drop significantly from baseline over this three‐month period. This decrease appeared most notable for those with pretreatment hepatic enzyme levels exceeding the normal range. Moreover, changes in hepatic enzyme levels were not consistently correlated with the patients use of illicit drugs such as opioids, benzodiazepines, cocaine, barbiturates, and amphetamines. Based on these data, we have concluded that contrary to cautions implied in the naltrexone package insert, the benefit of admitting patients with the sole problem of elevated hepatic enzymes generally exceeds the risk.
Mechanism of Cephalosporin‐induced Hypoprothrombinemia: Relation to Cephalosporin Side Chain, Vitamin K Metabolism, and Vitamin K Status
Authors: Shearer M. J. , Bechtold H. , Andrassy K. , Koderisch J. , McCarthy P. T. , Trenk D. , Jähnchen E. , Ritz E.
Published: March 2013

The mechanism of cephalosporin‐induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N‐methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl‐thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3‐epoxide in response to a 10‐mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3‐epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA‐II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef‐associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub‐normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT‐cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional‐vitamin K status predisposes to hypoprothrombinemia.
Safety, Tolerance and Pharmacokinetics of Intravenous Doses of the Phosphate Ester of 3‐Hydroxymethyl‐5,5‐Diphenylhydantoin: A New Prodrug of Phenytoin
Authors: Gerber N. , Mays D. C. , Donn K. H. , Laddu A. , Guthrie R. M. , Turlapaty P. , Quon C. Y. , Rivenburg W. K.
Published: March 2013

A new prodrug of phenytoin, the disodium phosphate ester of 3‐hydroxymethyl‐5,5‐diphenylhydantoin (ACC‐9653), was administered intravenously over 30 minutes to four different groups of volunteers at doses of 150, 300, 600, and 1200 mg. The prodrug and phenytoin were measured in plasma samples, collected at specified times, by specific high performance liquid chromatography (HPLC) assays. The prodrug, after achieving a maximum concentration at the end of the 30‐minute infusion (Cmax 20, 36, 75, 129 μg/mL) declined rapidly with a half‐life (t1/2) of about 8 minutes. The area under the plasma concentration‐time curve (10, 19, 43, 77 mg ṁ hr/L) was proportional to dose whereas the total clearance, 14 L/hr, was independent of dose. The volume of distribution of the prodrug, a polar, water‐soluble molecule was about 2.6 L, indicating that most of the dose remained in the plasma. The concentration of phenytoin reached 90% of its maximum about 12 minutes after the end of the infusion of ACC‐9653. At the dose of 1200 mg of prodrug, the average peak concentration of phenytoin was about 17 μg/mL, near the upper limit of the therapeutic range. Adverse reactions (lightheadedness, nystagmus, incoordination) were minor and attributed to phenytoin. No significant abnormalities in ECG, Holter monitoring, or EEG were noted after the infusion of ACC‐9653.
Bioavailability of Potassium From Three Dosage Forms: Suspension, Capsule, and Solution
Authors: Melikian Armen P. , Cheng Lawrence K. , Wright George J. , Cohen Albert , Bruce Ruth E.
Published: March 2013

A crossover study was performed in 28, healthy, male volunteers to determine the bioavailability of potassium from a suspension containing microencapsulated potassium chloride compared with that from a marketed microencapsulated potassium chloride capsule and a marketed potassium chloride solution. The 20‐day study consisted of four, five‐day periods. In three of the periods, a single, 40‐mEq dose of one of the potassium formulations was administered; no drug treatment was given in the remaining period so that the amount of potassium contributed by dietary sources could be determined. Meals were served that provided controlled amounts of potassium and sodium.

Bioavailability was represented by cumulative amount of K+ excreted in urine 24 and 48 hours after drug administration. The rate of absorption was calculated from excretion rates during each of the intervals of urine collection on Days 4. The pattern of excretion exhibited by the solution indicated rapid absorption and elimination. The potassium from the suspension and the capsules was excreted more slowly and over a longer period, indicating that the potassium content from these formulations was not being dumped. No statistically significant differences between the suspension and the capsules were found. The extent of absorption of K+ was similar from all three products, and the potassium from the suspension was found to be fully bioavailable when compared with the liquid and the capsule.
Excretion of Loratadine in Human Breast Milk
Authors: Hilbert James , Radwanski Elaine , Affrime Melton B. , Perentesis George , Symchowicz Samson , Zampaglione Nicola
Published: March 2013

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40‐mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration‐time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration‐time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk‐plasma AUC ratio was 1.2 and 4.2 μg of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8‐hour collection interval. Through 48 hours, the mean milk‐plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 μg of descarboethoxyloratadine (7.5 μg loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 μg loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4‐kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis. An estimated “worst‐case” dose (i.e., the maximum dose that could be expected under any circumstances) of loratadine and descarboethoxyloratadine to an infant was calculated to be only 1.1% of the adult loratadine dose on a mg/kg basis. The adult dose has been reported to be safe and well tolerated, so it is unlikely that this dose presents a hazard to infants.
Phase I Clinical Studies of 7432‐S, a New Oral Cephalosporin: Safety and Pharmacokinetics
Authors: Nakashima M. , Uematsu T. , Takiguchi Y. , Mizuno A. , Yoshida T. , Yamamoto S. , Kitagawa K. , Oguma T. , Ishii H. , Yamada H.
Published: March 2013

Phase I clinical studies of 7432‐S, a new oral cephalosporin, including a randomized placebo‐controlled trial were conducted with 40 healthy volunteers, in single‐dose studies, 7432‐S was orally administered at doses of 25, 50, 100, and 200 mg. The mean plasma levels peaked at 2.1 to 3.0 hours and reached 1.9, 3.6, 5.6, and 11.6 μg/ml, respectively. Linear correlation was observed between plasma AUC values and doses given. The half‐lives of the plasma levels were 0.88 to 2.26 hours with a mean of 1.53 ± 0.33 hours. The mean urinary recoveries were 67.5 to 75.2% of the dose within 24 hours. 7432‐S was partially metabolized to 7432‐S‐trans which was excreted in urine at 7.2 to 9.2% of the doses. Study of the meal effect showed that AUC values and peak levels were not altered although the time to the peak levels was slightly prolonged, In multiple‐dose studies, 100 mg of 7432‐S twice daily for 2 weeks and 200 mg twice daily for 1 week were administered and there was no abnormal accumulation of 7432‐S in plasma throughout the study. No significant differences were observed in plasma levels and urinary recoveries between single‐ and multiple‐dose regimens. Clinical symptoms, physical tests, laboratory parameters, and fecal levels of vitamins K1 and K2 were in normal ranges. 7432‐S was concluded to be safe and well tolerated.
Clinical and Electrophysiologic Effects of Flecainide in Patients with Refractory Ventricular Tachycardia
Authors: Capparelli Edmund V. , Kluger Jeffrey , Regnier Jane C. , Chow Moses S. S.
Published: March 2013

The electrophysiologic effects and antiarrhythmic efficacy of flecainide were evaluated by electrophysiologic study (EPS) in 20 patients with ventricular tachycardia (VT) refractory to an average 2.9 drugs, In 19 patients EPSs were performed with patients not receiving antiarrhythmic medications and receiving oral flecainide therapy at steady state (mean dose, 235 ± 67 mg/day). Flecainide significantly increased the QRS complex duration (27%, P < .001), PR interval (17%, P < .001), and right ventricular effective refractory periods 8.5% and 21.1% (P < .01) for the first and second extrastimuli, respectively. During baseline EPS, 17 patients were induced into VT and two were noninducible. Flecainide prevented EPS‐induced VT in five patients and the induced VT became slow and hemodynamically stable in three. Two patients who failed flecainide monotherapy were induced into slow hemodynamically stable VT with flecainide in combination with amiodarone. The two noninducible patients, during baseline EPS, had suppression of spontaneous VT with flecainide. Overall, 13 of 20 patients received flecainide either alone or in combination with amiodarone for chronic therapy. Side effects encountered during the study consisted of blurred vision, dizziness, weakness, lethargy, nausea, worsened heart failure and bradyarrhythmias. After a mean 9‐month follow‐up (3 to 16 months), nine patients remain on flecainide therapy. There were three recurrences of slow, hemodynamically stable VT and no episodes of sudden death. Low‐dose flecainide, either alone or in combination with other agents, is effective therapy for certain patients with refractory VT but heart failure remains a significant concern in patients with depressed left ventricular function.
Amrinone Pharmacokinetics in Neonates and Infants
Authors: Lawless Stephen , Burckart Gilbert , Diven Warren , Thompson Ann , Siewers Ralph
Published: March 2013

Amrinone is a bipyridine derivative that exerts systemic pulmonary vasodilatory effects while also being a positive inotrope. Amrinone is used frequently to treat pulmonary hypertension, congestive heart failure, and postoperative heart failure. Because there is a direct relationship between plasma amrinone levels and cardiac index,1 knowledge of the pharmacokinetics of amrinone would be beneficial in patient management. Despite its widespread use in critically ill adults and increasing use in critically ill pediatric patients, little information is available about the dosing and pharmacokinetics of amrinone in pediatric patients.2 Our objective was to determine the pharmacokinetics of amrinone in the critically ill pediatric patient as a guide to drug dosage requirements.
Pharmacokinetic and Pharmacodynamic Interactions of Propafenone and Cimetidine
Authors: Pritchett Edward L. C. , Smith William M. , Kirsten Edward B.
Published: March 2013

The pharmacokinetics and pharmacodynamics of the extensively metabolized antiarrhythmic agent propafenone were assessed alone and during concomitant administration of cimetidine. Twelve healthy subjects were given successively the following treatments: propafenone 225 mg q8h plus cimetidine placebo; cimetidine 400 mg q8h plus propafenone placebo; and propafenone 225 mg plus cimetidine 400 mg q8h. After a minimum of 5 days on each regimen, plasma drug concentrations and electrocardiogram conduction intervals were measured during a drug washout period. The maximum concentration of propafenone in plasma was 993 ± 532 ng/mL when propafenone was given alone compared with 1230 ± 591 ng/mL when propafenone was given with cimetidine (P = .0622). Differences in tmax, t1/2, and Cp ss did not approach statistical significance when propafenone alone was compared with propafenone plus cimetidine. When compared with cimetidine, propafenone significantly increased the PR interval from 161 ± 5 msec to 192 ± 6 msec (P < .01) and the QRS duration from 89 ±3 msec to 98 ±4 msec (P < .01). Combination therapy caused a modest additional increase in QRS duration to 103 ±3 msec (P < .01). In conclusion, cimetidine caused small changes in propafenone pharmacokinetics and pharmacodynamics; but these changes are unlikely to be clinically important.
An Acute Dose‐Response Pharmacodynamic Evaluation of Orally Administered Isradipine (PN‐200‐110) in Hypertensive Patients
Authors: McMahon F. Gilbert , Vargas Ramon , Ryan Jerome R. , Miller Howard , Faraday Susan
Published: March 2013

This study was conducted to assess acute oral dose‐responses of four dose levels (2.5,5,10, 20 mg) of isradipine, a new calcium channel blocking agent of the 1,4‐dihydropyridine group. Sixteen patients with mild essential hypertension were investigated using a randomized, four‐way cross‐over, double‐blind, placebo‐controlled design. After a 2‐week washout period, all patients were admitted to a research unit where they entered a 3‐day placebo equilibration, followed by 9 days of double‐blind single doses of isradipine. Drug administration was randomized, and baseline blood pressure values obtained preceding active medication doses were fairly constant. Dose‐related reductions in supine and in standing blood pressures were obtained. The mean peak supine blood pressure decrements to doses of 2.5, 5, 10, and 20 mg were 17/16, 25/19, 35/22, and 37/25 mm Hg, respectively. Pulse rates increased slightly. Similar responses were obtained with patients in the erect position. Peak hypotensive responses occurred within 3 hours after dosing. The duration of effect persisted as long as 21 hours, particularly after the 10‐ and 20‐mg doses (15/9 and 17/12 mm Hg mean supine blood pressure decrements, respectively).
Dose‐Response Effect of Sublingual Captopril in Hypertensive Crises
Authors: del Castillo Antonio Castro , Rodriguez Melchor , Gonzalez Eduardo , Rodriguez Francisco , Estruch Jorge
Published: March 2013

Forty‐one patients, presenting in the Emergency Service of the Hospital General y Clinico, Tenerife, with symptoms of hypertensive crisis and supine diastolic blood pressure (DBF) > 120 mm Hg, were studied. They received 12.5 mg of sublingual captopril and 30 minutes later, if diastolic blood pressure (DBP) was not 100 mm Hg or less, the same dose was repeated by the same route. Supine systolic blood pressure (SBP), DBP and heart rate (HR) were monitored at 0,5,10,15,30,45,60, and 120 minutes after each administration of captopril. In 27 patients (66%) had a satisfactory response (DBP ≤ 100 mm Hg), after a single dose, less than 30 minutes after administration, which persisted at 120 minutes. In 14, a second administration was necessary after 30 minutes, and a satisfactory response to the second dose, defined again as DBP reaching values of 100 mm Hg or less, was achieved in 12 of them (29% of the total group). In two patients (5% of total) no full response was obtained. The observed pattern of response suggests that a sublingual dose of 25 mg of captopril is the minimum effective dose, but it is also possible that administration of 12.5 mg of sublingual captopril at 10 to 15 minute intervals, perhaps up to a maximum dose of 37.5 mg, might be considered as an alternative treatment in hypertensive crises.
Lack of Unique Ciprofloxacin Pharmacokinetic Characteristics in Patients with Cystic Fibrosis
Authors: Reed Michael D. , Stern Robert C. , Myers Carolyn M. , Yamashita Toyoko S. , PhD Jeffrey L. Blumer
Published: March 2013

The single‐dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight‐matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VssF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty‐two percent of the ciprofloxacin dose was excreted in the urine (0–48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolites were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P <.05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24‐hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.
The Effect of Various Postphlebotomy Storage Conditions on Drug Levels
Authors: Colucci Robert D. , Halpern Neil A. , Levy Ezra , McElhinney A. James , Greenstein Robert J.
Published: March 2013

Monitoring drug levels in patients is standard practice in presentday critical care medicine. Clinical laboratories, however, are often unable to assay drug levels immediately following phlebotomy. This may result in blood samples being kept under a variety of storage conditions for nonuniform periods of time. The current study evaluated the stability of eight frequently monitored medications and one of their metabolites, in whole blood and plasma, at 4°C or 25°C, for up to 72 hours. The drugs included antibiotics, a bronchodilator, antiarrhythmics, and an anticonvulsant. Significant changes in drug levels were not identified at the time points studied. Our data suggests that meticulous postphlebotomy handling of blood samples may not be essential to obtain accurate levels of the drugs studied.
An Evaluation of the Pharmacokinetics, Pharmacodynamics, and Dialyzability of Verapamil in Chronic Hemodialysis Patients
Authors: Hanyok James J. , Chow Moses S.S. , Kluger Jeffrey , Izard Mark W.
Published: March 2013

The pharmacokinetics and pharmacodynamics of verapamil were investigated in six chronic hemodialysis patients. A single oral 120‐mg dose was administered both on a non‐hemodialysis day and a hemodialysis day separated by ≥ 7 days. Blood pressure and PR interval were measured simultaneously with each blood sample. Plasma verapamil and norverapamil concentrations were analyzed by high pressure liquid chromatography. The mean Cmax, tmax, AUC, apparent plasma clearance, and terminal t1/2 were 190 ± 108 ng/mL, 0.6 ± 0.2 hour, 676 ± 443 ng ṁ hr/mL, 3926 ± 1933 mL/min, and 11.4 ± 4.0 hr, respectively, on the nonhemodialysis day. The dialysis clearance of verapamil and norverapamil was negligible. The t1/2 during hemodialysis was 3.6 ± 1.1 hr, compared with 3.4 ± 0.7 hr during the same period of time postdose on the nonhemodialysis day (NS, P > .05). Systolic and diastolic blood pressure decreased for up to 4 hours postdose, whereas the PR interval tended to increase. Conclusions include: (1) the single oral‐dose pharmacokinetics and pharmacodynamics of verapamil in chronic hemodialysis patients are similar to published data in normal subjects and cardiac patients and (2) verapamil and norverapamil are not significantly removed by hemodialysis, so that supplemental doses are not necessary.
Pharmacokinetics of 2‘,3’‐Dideoxycytidine in Patients with AIDS and Related Disorders
Authors: Klecker Raymond W. , Collins Jerry M. , Yarchoan Robert C. , Thomas Rose , McAtee Nanette , Broder Samuel , Myers Charles E.
Published: March 2013

The clinical pharmacokinetics of 2′,3′‐dideoxycytidine (DDC) were determined after oral and intravenous administration in ten patients with AIDS or AIDS‐related complex. A high performance liquid chromatography (HPLC) analysis procedure using cation exchange extraction columns was used to measure DDC levels as low as 0.1 μM (21 ng/mL) in plasma and urine. The kinetics of DDC were linear over the dose range of 0.03 to 0.5 mg/kg. Total body clearance was 227 mL/min/m2 and did not change after 6 to 14 days of dosing. The volume of distribution at steady state was 0.54 L/kg. Plasma half‐life was 1.2 hours, and bioavailability was 88%. Most (75%) of the parent drug was found unchanged in the urine. As a result, renal function could play a role in dose adjustment of DDC. Comparison is made between the kinetics of DDC and 3′‐azido‐2′,3′‐dideoxythymidine (AZT). Similarities are noted in half‐life and bioavailability. However, differences are observed for total body clearance, cerebrospinal fluid penetration, volume of distribution, metabolism, and recovery in urine.
The Antihypertensive Response to Lisinopril: The Effect of Age in a Predominantly Black Population
Authors: Cummings Doyle M. , Amadio Peter , Taylor Elmer J. , Balaban Donald J. , Rocci Mario L. , Abrams William B. , Feinberg Jerry , Vlasses Peter H.
Published: March 2013

After a 2–4 week no‐treatment period, 24 patients (12 young, age 29–45 yr.; 12 elderly, age 65–81 yr.; 20 black, 4 white) with an untreated sitting diastolic blood pressure between 91–120 mm Hg received the nonsulfhydryl angiotensin converting enzyme inhibitor, lisinopril for three weeks in a singleblind, parallel group comparison. Patients who did not achieve goal blood pressure with the initial low‐dose (10 mg/day) were treated with a high‐dose regimen (40 mg/day) for three weeks. In those who remained incompletely responsive, hydrochlorothiazide 25 mg/day was added for four weeks in an attempt to normalize blood pressure (≤90 mm Hg). Low‐dose lisinopril monotherapy produced comparable reductions in the mean systolic and diastolic blood pressures (approximately −15/−8 mm Hg in both younger and older patients). Increasing the dose produced a slightly greater fall in mean blood pressures which normalized the blood pressure in five of six elderly patients unresponsive to the lower dose; addition of hydrochlorothiazide normalized three of the five remaining subjects from both groups who were unresponsive to high dose lisinopril. Lisinopril administration resulted in a rise in plasma renin activity and a fall in plasma aldosterone concentrations which were similar in both groups and which returned over time toward the baseline. The drug was well tolerated, producing one episode of symptomatic hypotension following the addition of hydrochlorothiazide to lisinopril monotherapy. Lisinopril alone or in combination with hydrochlorothiazide produces favorable antihypertensive effects in both younger and older predominantly black, low‐renin patients with essential hypertension.
Thromboxane Synthase Activity and Platelet Function After Furegrelate Administration in Man
Authors: Mohrland J. Scott , Lugt J. T. Vander , Gorman R. R. , Lakings D. B.
Published: March 2013

Furegrelate sodium (U‐63,557A), a pyridine‐derivative thromboxane synthase inhibitor, was administered orally in single doses of 200 to 1600 mg to normal male subjects. Furegrelate produced a dose‐related inhibition of thromboxane synthesis for 8–12 hours when measured either ex vivo from platelet‐rich plasma (PRP) or in vivo from urine. In general, the extent of thromboxane synthesis inhibition was greater in PRP than in urine. Furegrelate significantly inhibited platelet aggregation, but the effect was variable and measurements of thromboxane synthase did not predict the impact on platelet aggregation. Bleeding times and coagulation parameters were not altered significantly. Furegrelate was well absorbed orally with Tmax = 1 hr and t½ = 3.5 to 5 hrs. There was no marked metabolism; elimination was primarily by renal excretion of parent compound. Thus, furegrelate is an effective inhibitor of thromboxane synthase in man with a relatively long biologic and circulating half‐life.
Pharmacokinetics of Buspirone in Elderly Subjects
Authors: Gammans R. E. , Westrick M. L. , Shea J. P. , Mayol R. F. , LaBudde J. A.
Published: March 2013

Twenty‐four men and 24 women ages 20–77 years received a single 15 mg oral dose of buspirone followed by 4 days of 15 mg tid administration. Plasma concentrations of buspirone and 1‐pyrimidinylpiperazine following both single and multiple dosing were determined by RIA and GCMS, respectively. There were no significant differences between the young and elderly of either gender with regard to buspirone AUC, Cmax, Tmax and half‐life values. The 1‐PP AUC values were higher for young of either gender compared to the corresponding group of ederly subjects and the 1‐PP Cmax values were higher for women than men. These differences are unlikely to be of clinical significance. The buspirone and 1‐PP AUC values for a dosing interval during multiple dosing are not significantly different than the respective single dose AUC values. Buspirone treatment was well‐tolerated by all subjects even though the 45 mg/day dose was 3 times the recommended starting dose in clinical practice. Overall, the lack of marked or consistent differences in buspirone or 1‐PP pharmacokinetics in elderly subjects compared to younger subjects of the same gender suggest there is no need to alter the initial dose of buspirone based solely on patient age.