bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of Y‐20811, a New Long‐Acting Thromboxane Synthetase Inhibitor by Intravenous Administration
Authors: Kanamaru Mitsutaka , Nakashima Mitsuyoshi 
Published: March 2013

The safety, pharmacological action and pharmacokinetics of Y‐20811, a thromboxane (TX) synthetase inhibitor, were investigated by single intravenous administration of 5, 10, and 25 mg each to six healthy adult male volunteers.Throughout the entire test period, no abnormality attributable to the test drug was found in subjective and objective symptoms, routine laboratory tests, physical tests, or bleeding time; and the drug was well tolerated by subjects.Inhibition of serum TXB2 production and an increase in 6‐keto‐prostaglandin (PG) F1α production during whole‐blood coagulation exhibited a dose‐dependent change from 0.5 hours after administration. In addition, arachidonic acid (AA)‐induced platelet aggregation was inhibited, and adenosine diphosphate (ADP)‐induced secondary aggregation was also inhibited. The duration of these actions was long: inhibition of serum TXB2 production and the increase in 6‐keto‐PGF1α production lasted for 168 hours after administration, and inhibition of platelet aggregation lasted for more than 48 h after administration.The initial phase half‐life (t1/2α) and final phase half‐life (t1/2β) of Y‐20811, calculated from the change in plasma concentration, were 0.1–0.3 hours and 1.9–3.1 hours, respectively. The area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the values of volume of distribution (Vss) and total clearance (CLt) were almost constant in any dose group. At each of the three doses, 60–64% of the dose was excreted in unchanged form, and 8–10% in conjugated form in the urine, within 48 hours after administration.We concluded that the intravenous administration of Y‐20811 was very safe and inhibited TXB2 production and platelet aggregation.
Augmentation of Acetaminophen Analgesia by the Antihistamine Phenyltoloxamine
Authors: Sunshine Abraham , Zighelboim Itic , de Castro Ana , Sorrentino James V. , Smith Douglas S. , Bartizek Robert D. , Olson Nancy Z. 
Published: March 2013

A double‐blind, placebo‐controlled, parallel‐group study was performed to compare the analgesic activity of the combination of 650 mg acetaminophen plus 60 mg phenyltoloxamine citrate with that of 650 mg acetaminophen alone. Two hundred female inpatients who had severe pain associated with a recent episiotomy procedure were randomly assigned to receive a single dose of one of the two active treatments or a placebo. Analgesia was assessed over a 6‐hour period. Treatments were compared on the basis of standard subjective scales for pain intensity and relief, a number of derived variables based on these data and two global measures.For essentially all measures, the two active treatments were significantly superior to the placebo control. The combination was significantly superior to acetaminophen alone for all analgesic measures including SPID, TOTAL, and global ratings. The results of this study demonstrate that 60 mg phenyltoloxamine produces significant augmentation of the analgesic activity of 650 mg acetaminophen in postepisiotomy pain.
Drug Delivery Systems. 1. Site‐Specific Drug Delivery Using Liposomes as Carriers
Authors: Ranade Vasant V. 
Published: March 2013

Drug delivery systems, offering controlled delivery of biologically active agents, are rapidly gaining importance in pharmaceutical research and development. To achieve controlled drug delivery, i.e., the administration of drugs so that optimal amount reaches the target site to cure or control the disease state, increasingly sophisticated systems containing different carriers have been developed. Macromolecules represent one of the carriers involved, and they have taken on a significantly prominent role in various modes of administration of therapeutic agents. Among macromolecules, for example, synthetic copolymers, polysaccharides, liposomes, polyanions and antibodies, as drug carriers, liposomes have proved most effective for diseases affecting the reticuloendothelial system and blood cells in particular.Liposomes, which are vesicles consisting of one or more concentrically ordered assemblies of phospholipids bilayers, range in size from a nanometer to several micrometers. Phospholipids such as egg phosphatidylcholine, phosphatidylserine, synthetic dipalmitoyl‐DL‐α‐phosphatidylcholine or phosphatidylinositol, have been used in conjunction with cholesterol and positively or negatively charged amphiphiles such as stearylamine or phosphatide acid. Alteration of surface charge has been shown to enhance drug incorporation and also influence drug release. Because of the multifold characteristics as drug carriers, liposomes have been investigated extensively as carriers of anticancer agents for the past several years. Liposomal entrapments include a variety of pharmacologically active compounds such as antimalarial, antiviral, anti‐inflammatory and antifungal agents as well as antibiotics, prostaglandins, steroids and bronchodilators to name a few. The liposomal entrapment has been shown to have considerable effect on the pharmacokinetics and tissue distribution of administered drugs.Despite the potential value of liposomes as unique carriers, the major obstacles are the first order targeting of a systemically given liposomes, physical stability and manufacture of the liposomal products and these problems still remain to be overcome. Drug delivery systems evolving in the 1980s have become increasingly dependent on fundamental cell‐biology and receptor‐mediated endocytotic mechanisms. Drug delivery systems during the 1990s may take advantage of the specificity of receptor‐mediated uptake mechanisms as well as polymer chemistry and cell‐biology in order to introduce more precise and efficient target‐specific delivery systems that are based especially on the liposome technology.
BOOK REVIEWS
Authors: Maggio Beth 
Published: March 2013

Book reviewed in this article:The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy: Advances in Experimental Medicine and Biology, Volume 244 (Proceedings of an International Symposium, April, 1988, Buffalo, NY). Edited by Youcef Rustum and John McGuireThe Implications of the Blood‐Brain Barrier and Its Manipulation. Volume 1: Basic Science Aspects; Volume 2: Clinical Aspects. Edited by Edwin Neuwelt, M.D.Molecular Probes: Technology and Medical Applications. (Lorenzini Foundation Symposia Series). Editors: Alberto Albertini, Rodolfo Paoletti, and Ralph A. ReisfeldStatistics and Experimental Design for Toxicologists Shayne Gad and Carrol WeilGerontokinetics: Pharmacokinetics of Drugs in the Elderly. Wolfgang A. Ritschel.Clinical Pharmacokinetics: The MCQ Approach. Stephen H. CurrySlow Wave Sleep: Physiological, Pathophysiological and Functional Aspects. Editors: A. Wauquier, C. Dugovic, M. Radulovacki.Pharmacotherapy: A Pathophysiological Approach. Editors: Joseph DiPiro, Robert Talbert, Peggy Hayes, Gary Yee, and L. Michael Posey.
Chronopharmacokinetic Studies of Pranoprofen and Procainamide
Authors: Fujimura Akio , Kajiyama Hiroyuki , Kumagai Yuji , Nakashima Hajime , Sugimoto Kouichi , Ebihara Akio 
Published: March 2013

There is increasing evidence demonstrating that plasma drug concentrations are affected by their time of administration. In the current study, the chronopharmacokinetic profiles of an antipyretic agent, pranoprofen, and an antiarrhythmic agent, procainamide, were examined. In the first study, 75 mg of pranoprofen was given orally in seven healthy subjects at 10:00 (morning trial) or 22:00 (evening trial). In the second study, 500 mg of procainamide was given orally in eight subjects with premature ventricular contractions at 10:00 or 22:00. Blood samples for plasma drug concentrations were taken for a 10‐hour (pranoprofen study) or a 24‐hour (procainamide study) post‐drug period.In the first (pranoprofen) study, the mean time to maximum concentration was significantly shorter, and the mean maximum plasma concentration as well as absorption rate constant had a tendency to be greater after the morning than after the evening trial. The mean area under the plasma concentration‐time curve, elimination half‐life or oral clearance of the morning and evening dosages did not differ. In the second (procainamide) study, no significant difference was observed in any pharmacokinetic parameter concerning procainamide or its active metabolite, N‐acetyl‐procainamide (NAPA) between the morning and evening trials.These data indicate that plasma levels of pranoprofen are affected by its administration time while plasma concentrations of procainamide and NAPA do not vary with the time of dosage.
Gastrointestinal Behavior of Orally Administered Radiolabeled Erythromycin Pellets in Man as Determined by Gamma Scintigraphy
Authors: Digenis G. A. , Sandefer E. P. , Parr A. F. , Beihn R. , McClain C. , Scheinthal B. M. , Ghebre‐Sellassie I. , Iyer U. , Nesbitt R. U. , Randinitis E. 
Published: March 2013

The behavior of single 250‐mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron‐activated samarium‐153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points.Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 μg/mL versus 0.94 μg/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0‐∞) of the plasma erythromycin concentration versus time curve, was 7.6 hr/μg/mL in the fasted state, versus 3.5 hr/μg/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges.Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric‐coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial‐to‐distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 μg/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 μg/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle‐in‐tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially‐produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.
A Single‐Dose Study of the Efficacy and Safety of FS 205–397 (250 mg or 500 mg) Versus Aspirin and Placebo in the Treatment of Postsurgery Dental Pain
Authors: Mehlisch Donald R. , Sterling William R. , Mazza Frank A. , Singer Jack M. 
Published: March 2013

The efficacy and safety of two dose levels of FS 205–397 (either 250 or 500 mg) were compared with the efficacy and safety of aspirin 650 mg and placebo in a 6‐hour, single‐dose, double‐blind study in 161 patients who had undergone extraction of third molars.Each of the doses of FS 205–397, as well as aspirin, produced analgesia. However, the analgesic effects of both the 500 mg dose of FS 205–397 and aspirin were at times significantly better and more prolonged than those produced by the lower dose of FS 205–397. On the other hand, both doses of FS 205–397 had a significantly faster onset of action than aspirin.Side effects, reported by 17% of the 161 patients, did not differ significantly among the four treatment groups with respect to frequency, type, or severity. The most commonly reported side effects were nausea (7%) and drowsiness (6%).The results indicated that FS 205–397, administered in single doses of either 500 or 250 mg, is a safe and effective analgesic for the relief of pain following dental surgery, and may offer particular advantages in terms of onset of effects.
The Effects of Nicardipine on Sodium and Calcium Metabolism in Hypertensive Patients: A Chronic Study
Authors: Soro Stefano , Cocca Angelo , Pasanisi Fabrizio , Tommaselli Antonio , de Simone Giovanni , Costantino Guido , Ferrara L. Aldo 
Published: March 2013

There is evidence in the literature that calcium entry blockers are able to affect calcium‐dependent hormone secretion and therefore can influence sodium and calcium metabolism.We have studied in 18 mild to moderate hypertensives (27–65 yrs) the effects of chronic treatment with nicardipine, a dihydropyridine derivative, vs placebo on: 1) renin‐angiotensin‐aldosterone axis; 2) parathyroide hormone and calcium metabolism; 3) daily sodium and calcium urinary excretion.After a 2‐week placebo wash‐out when any antihypertensive treatment was withdrawn, patients were kept on a well balanced normocaloric diet without salt intake restriction. Blood pressure, plasma renin and serum aldosterone after a 1‐hour standardized walk, serum PTH, serum and 24‐hour urinary Na, K, Ca, P, Mg were measured. Thereafter patients were randomly and blindly given nicardipine 20 mg tid or placebo tablet tid for 2 months. At the end of this period the same measurements were repeated. Blood pressure significantly dropped during nicardipine (from 165/96 ± 19/9 vs 150/88 ± 16/9 mm Hg P < .05) without change in heart rate. No change was observed on placebo. Plasma renin, serum aldosterone, serum parathyroid hormone and serum and urinary electrolytes did not change during active and placebo treatment. The results of this study suggest that chronic nicardipine does not affect hormone secretion.
Antiarrhythmic Drug Therapy for Suppression of Ventricular Arrhythmia: Experience with 122 Patients Treated for Two Years
Authors: Salerno David M. , Fifield Jeanne , Hodges Morrison 
Published: March 2013

Although there are many reports of the short‐term effectiveness of antiarrhythmic drugs for suppression of ventricular ectopic depolarizations, there are less data available on the long‐term use of these drugs. We treated 122 patients for up to 2 years with antiarrhythmic drugs for suppression of frequent ventricular ectopic depolarizations. The percent suppression of ventricular ectopic depolarizations and nonsustained ventricular tachycardia for each drug was determined at 1, 3, 6, 12, 18, and 24 months of therapy. Among 33 patients treated with flecainide, the mean suppression of ventricular ectopic depolarizations (average of all data during 24 months) was 93 ± 17% and of nonsustained ventricular tachycardia was 97 ± 7%. In 27 patients treated with encainide, the mean suppression of ventricular ectopic depolarizations was 88 ± 18% and of ventricular tachycardia was 95 ± 16%. Among 26 patients treated with propafenone, the mean suppression of ventricular ectopic depolarizations was 77 ± 32% and of ventricular tachycardia was 93 ± 15%. For the 20 patients treated with moricizine, the mean suppression of ventricular ectopic depolarizations was 62 ± 35% and of ventricular tachycardia was 90 ± 14%. Among 16 patients treated with amiodarone, the mean suppression of ventricular ectopic depolarizations was 92 ± 14% and of nonsustained ventricular tachycardia was 99 ± 3%.In 54 of the 122 patients (44%), the study drug was stopped during 2 years of therapy because of death (2 sudden, 2 unwitnessed and 6 noncardiac), side effects (21 patients), lack or of loss of efficacy (13 patients), and noncompliance (10 patients).Thus, it is possible to maintain effective suppression of ventricular ectopic depolarizations and nonsustained ventricular tachycardia in patients for up to 2 years, but the rate of withdrawal from therapy is substantial.
Hemodynamic and Humoral Effects of Chronic Antihypertensive Treatment with Fenquizone: Importance of Aldosterone Response
Authors: Costa Francesco V. , Borghi Claudio , Boschi Stefano , Mussi Alessandra , Ambrosioni Ettore 
Published: March 2013

The effects of 1‐year antihypertensive treatment with the diuretic fenquizone were evaluated in 16 patients with mild essential hypertension. During treatment with placebo, after 2, 4, 24, and 52 weeks of treatment we measured blood pressure, heart rate, forearm blood flow (FBF) and vascular resistance (FVR) at rest and after 10 minutes ischemia, and forearm venous extensibility. Subjects whose diastolic blood pressure after fenquizone was reduced at least 10% were classified as responders. On this basis, 56% of patients after 1 month and 68% after 1 year responded to fenquizone. Responders, in comparison to nonresponders, were characterized by a greater increase in FBF and a greater decrease in FVR. The reduction in diastolic blood pressure was significantly related to the fall in FVR whereas no correlation was found between blood pressure and venous compliance changes. Nonresponders had a PRA increase similar to that observed in responders but they showed a much greater increase in aldosterone, whose changes were inversely related to modifications of both FVR and blood pressure.Our results demonstrate that chronic therapy with fenquizone causes a reduction of FVR, and that nonresponders have an exaggerated rise in aldosterone. This observation further reinforces the hypothesis that factors influencing the secretion of aldosterone are important determinants of the antihypertensive mechanism of diuretics.
Clinical Pharmacology of Dilevalol (IV). Influence of Hepatic and Renal Functions on the Disposition of Dilevalol and Atenolol in Hypertensive Subjects
Authors: Kotegawa Tsutomu , Fujimura Akio , Ebihara Akio 
Published: March 2013

Dilevalol (100 mg) or atenolol (50 mg) was given orally in 13 subjects with essential hypertension. Two trials were done by a single‐blind, crossover design with an interval of 6 days. Blood samples for drug concentrations were taken for a period of 24 hours after dosage. A retained percentage of indocyanine green dye at 15 minute (ICG R15) reflecting hepatic function and a creatinine clearance (CLCR) reflecting renal function were determined in each subject during observation period.A significant correlation was observed between the ICG R15 and the area under the plasma concentration—time curve (AUC) of dilevalol, while there was no significant correlation between the CLCR and any pharmacokinetic parameter of the agent. In contrast to dilevalol, significant correlations were observed between the CLCR and AUC or elimination half—life of atenolol. However, there was no significant correlation between the ICG R15 and any pharmacokinetic parameter of atenolol.These data indicate that the disposition of dilevalol is influenced by hepatic rather than by renal function while that of atenolol is altered by renal function.
The Efficacy of Low Dose Metoprolol CR/ZOK in Mild Hypertension and in Elderly Patients with Mild to Moderate Hypertension
Authors: Jäättelä Antti , Baandrup Sören , Houtzagers Johannes , Westergren Gudrun 
Published: March 2013

In two separate but similarly designed placebo‐controlled studies, the efficacy of metoprolol CR/ZOK 50 mg once daily was evaluated in 64 patients (mean age 53 years) with mild hypertension (Study I) and in 34 elderly patients (mean age 68 years) with mild to moderate hypertension (Study II). Both studies were of randomized, double‐blind, parallel‐group design, the entry criteria for diastolic blood pressure being ≥90 <105 mm Hg in Study I and ≥95 < 110 mm Hg in Study II.Study I: The impact of metoprolol CR/ZOK 50 mg once daily for 4 weeks compared with placebo 24 hours post dosing was to produce a significant reduction in supine (P = .0001), and standing (P < .0001) systolic blood pressures and the standing diastolic pressure (P = .035). The supine diastolic pressure was lower after metoprolol CR/ZOK but not significantly so.Study II: Metoprolol CR/ZOK 50 mg daily given to elderly hypertensives when compared with placebo 24 hours post dosing produced a significant fall in supine (P = .022) and standing (P = .022) diastolic pressure. Systolic pressure and heart rate were not significantly reduced.One patient in Study II had a nonfatal myocardial infarct whilst receiving placebo. There were no other serious adverse effects in either study and no patients were withdrawn from the trial because of drug related unwanted events. The studies indicate that 50 mg metoprolol CR/ZOK may be an effective antihypertensive agent which may prove useful in the treatment of mild to moderate hypertension, particularly in the elderly.
Comparison of CNS‐Related Subjective Symptoms in Hypertensive Patients Treated with Either a New Controlled Release (CR/ZOK) Formulation of Metoprolol or Atenolol
Authors: Dimenäs Elof , Östergren Jan , Lindvall Kaj , Dahlöf Carl , Westergren Gudrun , de Faire Ulf 
Published: March 2013

The present study evaluated and compared subjective symptoms in hypertensive patients (N = 83) at therapeutically comparable dosages of a new controlled release (CR/ZOK) formulation of metoprolol (100 mg od) and atenolol (50 mg od). The trial was a 4‐week randomized double‐blind study preceded by a placebo run‐in period. Blood pressure (BP) was recorded 24 hours after intake of last dose. In subpopulations, 24‐hour ambulatory BP was recorded and exercise tests performed. Subjective symptoms were evaluated with a previously documented questionnaire (MSE‐profile) which has been shown to be sensitive in detecting CNS‐related symptoms caused by beta blockers. The MSE‐profile includes three dimensions: Contentment, Vitality and Sleep.The results showed that there were no significant differences between the groups in BP reduction either at 24 hours or over the entire 24‐hour dose interval. Furthermore, the degree of beta1‐blockade (reduction in exercise‐induced tachycardia) 24 hours after last dose did not differ between the groups. There were no significant differences regarding subjective symptoms (Contentment, Vitality, Sleep) between the two treatment groups. An a posteriori power analysis showed that the power to detect a true difference was of an acceptable magnitude. In conclusion, there was no difference in CNS‐related symptoms between metoprolol and atenolol at therapeutically comparable dosages indicating that the degree of lipophilicity may be of minor importance for the occurrence of such symptoms.