bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of Midazolam Following Intravenous and Oral Administration in Patients with Chronic Liver Disease and in Healthy Subjects
Authors: Pentikäinen P. J. , Välisalmi L. , Himberg J.‐J. , Crevoisier C.
Published: March 2013

To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2α, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h−1), and longer elimination half‐life (7.36 vs 3.80 h). The bioavailability of oral midazolam was significantly (P < 0.05) higher in patients than controls (76% vs. 38%). The antipyrine‐half‐life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P < 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half‐lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.
Pharmacokinetics of Mexiletine in the Elderly
Authors: Grech‐Bélanger Odette , Barbeau Gilles , Kishka Paul , Fiset Céline , LeBoeuf E. , Blouin M.
Published: March 2013

The effect of advancing age on the kinetics of the antiarrhythmic agent mexiletine was studied by comparing various kinetic parameters calculated after administration of a single oral dose of mexiletine hydrochloride to seven elderly and eight young healthy volunteers. The rate of absorption of the drug from the gastrointestinal tract was significantly slower in the elderly (1.37 ± 0.51 hr−1) than in the young group (2.25 ± 0.79 hr−1). The mean values for elimination half‐life and oral clearance were 12.3 ± 3.7 hr and 10.3 ± 5.4 mL/min/kg respectively in the young group and 14.4 ± 4.5 hr and 8.5 ± 2.9 mL/min/kg respectively in the elderly group. Neither of these parameters was significantly different between the two groups. The amount of mexiletine eliminated in urine up to 48 hours postdose was identical in both groups and represented less than 5% of the administered dose. It is concluded that the age‐related modifications in the kinetics of mexiletine are not clinically important during chronic administration of the drug.
Effects of Traxanox Sodium on Blood Pressure and Serum Uric Acid in Hypertensive Patients: A Preliminary Study
Authors: Fujimura Akio , Ebihara Akio , Hino Naoko , Koike Yuichi
Published: March 2013

The effects of chronic administration of traxanox sodium (traxanox) on blood pressure and serum uric acid level were investigated in 15 patients who had mild to moderate hypertension. Traxanox or its placebo was orally administered in a single‐blind protocol. Blood pressure was significantly reduced from baseline after treatment with traxanox. The serum uric acid level after drug administration was significantly lower than with placebo whereas urinary uric acid excretion was significantly greater and uric acid clearance tended to be greater. These results indicate that chronic administration of traxanox reduces serum uric acid level as well as blood pressure in patients with mild to moderate hypertension. This reduction in serum uric acid is due in part to a traxanox‐induced elevation of urinary uric acid excretion.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

New Perspectives in Anti‐Inflammatory Therapies (Advances in Inflammation Research, Volume 12) Edited by Alan Lewis, Neil Ackerman, and Ivan Otterness

Intravenous Anesthesia and Analgesia Edited by Guenter Corssen, MD, J. G. Reves, MD, Theodore H. Stanley, MD
Classification of Antiarrhythmic Drugs
Authors: Frumin Howard , Kerin Nicholas Z. , Rubenfire Melvyn
Published: March 2013

Although many classification schemes for antiarrhythmic drugs have been proposed, the system introduced by Vaughan Williams and later modified by Harrison has been widely accepted. This classification system is comprised of four categories. Class I agents block sodium channels. Class II agents are Beta blockers. Class III agents prolong the cardiac action potential. Class IV agents are calcium channel blockers. This classification scheme, based largely on clinical observation continues to be useful almost two decades after its introduction. The electrophysiologic bases, strengths and weaknesses of this system are discussed.
Cardiac Excitability and Antiarrhythmic Drugs: A Different Perspective
Authors: Arnsdorf Morton F.
Published: March 2013

A matrix of active and passive cellular properties determines net cardiac excitability. The hypothesis of altered excitability suggests that for cardiac arrhythmias to arise, the normal matrix must be perturbed by arrhythmogenic influences to produce a proarrhythmic metrical configuration to permit rhythm disturbances caused by abnormalities of propagation, abnormal automaticity, or altered excitability. Antiarrhythmic drugs may act with one or more components of the normal or proarrhythmic matrix to normalize or to create new antiarrhythmic or, perhaps, proarrhythmic matrices. Traditionally, antiarrhythmic drug classifications have been based on predominant drug actions. These classifications have clinical and some experimental utility but fail to consider the complicated effects that pathophysiologic influences and pharmacologic actions may have on active and passive cellular properties. Cluster analysis may allow the development of new classifications of arrhythmogenesis and antiarrhythmic drugs. The matrical concept has important clinical implications and suggest strategies for treating patients with cardiac rhythm disturbances.
Potentially Lethal Ventricular Arrhythmias: From Mundane to Esoteric
Authors: Kerin N. Z. , Aragon E. , Frumin H. , Liu H. , Rubenfire M.
Published: March 2013

Patients with potentially lethal ventricular arrhythmias (VAs) represent a heterogenous group with frequent and high grade ventricular arrhythmias (including couplets and runs of nonsustained ventricular tachycardia), structural heart disease and decreased left ventricular function. This is a group at intermediate risk of sudden death, with risks varying from 10% to 38%. The electrical and mechanical risks of patients with potentially lethal VA is discussed in relation to their ability of promoting sudden death. The studies reviewing the impact of antiarrhythmic treatment on survival of patients with potentially lethal VA is discussed.
The Effect of Smoking on Theophylline Kinetics in Healthy and Asthmatic Elderly Males
Authors: Samaan S. , Fox R.
Published: March 2013

The effect of smoking on theophylline kinetics was investigated in four groups of males over the age of 65 yr. The first group consisted of 14 healthy non‐smoking males, the second group consisted of 8 healthy smoking males. The first and the second groups were administered a single oral dose of 300 mg tablet of sustained‐release anhydrous theophylline product and serial blood samples were collected over 24 hr. The third group consisted of 22 clinically stable asthmatic non‐smoking males, the fourth group consisted of 9 clinically stable asthmatic smoking males. The third and the fourth groups, were administered multiple oral doses equivalent to 300 mg of anhydrous theophylline from sustained‐release Oxtriphylline every 12 hr for 72 hr; and blood samples were collected every two hours between 72–82 hrs. Serum theophylline concentrations were determined by HPLC. There were no significant differences between the smokers and non‐smokers in observed maximum concentration (Cmax), its time (tmax), the area under the time‐concentration curve (AUCo‐t), and total body clearance rate (Cl). Aging appears to offset the known smoking inducing effect on the hepatic microsomal enzymes.
The Effect of Route of Administration on the Cimetidine‐Theophylline Drug Interaction
Authors: Cremer Karl F. , Secor John , Speeg K. V.
Published: March 2013

The effect of route of cimetidine administration on cimetidine‐mediated inhibition of theophylline oxidation was examined in healthy individuals. Based on the evidence that cimetidine‐mediated inhibition of drug oxidation is competitive and, therefore, dependent on cimetidine concentration in the liver, oral cimetidine was tested to determine whether it would cause greater inhibition of drug oxidation than intravenous (IV) cimetidine. Both oral and IV cimetidine decreased theophylline clearance to the same extent. However, when clearance was corrected for cimetidine AUC, oral cimetidine resulted in a greater inhibition than IV cimetidine. Thus, the potential for increased inhibitory effect of oral cimetidine was balanced by decreased absorption after oral administration. Degree of inhibition (absolute change in theophylline clearance) and percent of inhibition after cimetidine correlated with the basal theophylline clearance. Individuals with higher basal theophylline clearances had greater degree and percent of inhibition than individuals with lower basal theophylline clearances.
Pharmacokinetics of Chloroquine and Some of Its Metabolites in Healthy Volunteers: A Single Dose Study
Authors: Ette Ene I. , Essien Ettiene E. , Thomas Wilkinson O. A. , Brown‐Awala Esther A.
Published: March 2013

Eight healthy volunteers who had not taken chloroquine 2 to 12 months previously participated in a single dose study designed to evaluate the pharmacokinetics of chloroquine and some of its metabolites. Each subject received two tablets of chloroquine sulfate (300 mg base) only. Blood and urine samples were collected just before and periodically after chloroquine administration. These samples were assayed for chloroquine and its N‐dealkylated metabolites (monodesethylchloroquine, didesethylchloroquine, 7‐chloro‐4‐aminoquinoline), chloroquine side chain N‐oxide and chloroquine di‐N‐oxide using a high performance liquid chromatographic method. Residual levels of chloroquine and its N‐oxidation metabolites were found in all subjects. 7‐chloro‐4‐aminoquinoline was eliminated more slowly (t½z = 126.48 ± 20.13 h) than the other metabolites and the unchanged drug (t½z = 106.43 ± 10.13 h). Also, 7‐chloro‐4‐aminoquinoline had a significantly faster (Student's t‐test, P < 0.05) formation clearance when compared with the other metabolites. The plasma concentration of 7‐chloro‐4‐aminoquinoline was about twice that of the unchanged drug while the plasma concentration of monodesethylchloroquine was about 46% that of the unchanged drug. In order to investigate whether the metabolites were produced from the same binding sites or closely related sites on the cytochrome P‐450 system, their formation clearances were correlated. The best correlation (r2 = 0.83) was observed for didesethylchloroquine and monodesethylchloroquine, and a fair correlation (r2 = 0.59) was observed for monodesethylchloroquine and 7‐chloro‐4‐aminoquinoline. Formation clearances of the other metabolites were poorly correlated. The N‐dealkylated metabolites of chloroquine are of pharmacological and toxicological importance. It may, therefore, be necessary to monitor their plasma concentrations in addition to that of chloroquine in patients on long‐term chloroquine therapy.
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.
Clinical Utility of Nifedipine and Diltiazem Plasma Levels in Patients with Angina Pectoris Receiving Monotherapy and Combination Treatment
Authors: Goldberger Jeffrey , Frishman William H.
Published: March 2013

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run‐in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem‐nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high‐pressure liquid chromatography from specimens obtained 2–5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage.
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.
Impaired Bioavailability of Famotidine Given Concurrently with a Potent Antacid
Authors: Barzaghi N. , Gatti G. , Crema F. , Perucca E.
Published: March 2013

The effect of a high potency antacid on the oral bioavailability of a single dose of famotidine (40 mg) was evaluated in normal volunteers according to a randomized cross‐over design. Ingestion of the antacid concurrently with famotidine resulted in a significant reduction of peak plasma famotidine concentration (from 156 ± 22 to 104 ± 7, P < 0.05) and area under the famotidine plasma concentration curve (from 956 ± 125 to 607 ± 56, P < 0.02). No significant interaction was observed when the antacid was ingested 2 hours after famotidine administration.
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.
Absence of Tobramycin Pharmacokinetic and Creatinine Clearance Variation During the Menstrual Cycle: Implied Absence of Variation in Glomerular Filtration Rate
Authors: Nafziger Anne N. , Schwartzman Michael S. , Bertino Joseph S.
Published: March 2013

During the menstrual cycle, a 20% increase in creatinine clearance (CLCR) has previously been reported between the menstrual (phase 1) and late luteal (phase 4) phases. Tobramycin pharmacokinetics and CLCR were studied in eight healthy women with documented, regular, ovulatory menses. During the first and fourth phases of the menstrual cycle (as determined by urinary luteinizing hormone peak and basal body temperature shift), subjects received tobramycin by intravenous bolus. Tobramycin half‐life, total body clearance, and volume of distribution were not significantly different between the two study phases. No significant change in total urinary creatinine excretion or CLCR was seen between phases. Total 24 hour urinary recovery of tobramycin was 98–99.7%. We conclude that no significant changes in renal function, as evaluated by tobramycin pharmacokinetics and CLCR, occur between these hormonally different phases of the menstrual cycle, and that urinary recovery of a single dose of tobramycin is nearly complete within 24 hours in premenopausal women with normal renal function.
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 McGuire

The 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. Reisfeld

Statistics and Experimental Design for Toxicologists Shayne Gad and Carrol Weil

Gerontokinetics: Pharmacokinetics of Drugs in the Elderly. Wolfgang A. Ritschel.

Clinical Pharmacokinetics: The MCQ Approach. Stephen H. Curry

Slow 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.
Disposition of Minoxidil in Patients with Various Degrees of Renal Function
Authors: Halstenson Charles E. , Opsahl John A. , Wright C. Eugene , Fleishaker Joseph C. , Andreadis N. A. , Sobieraj Jadwiga , Matzke Gary R.
Published: March 2013

The disposition of minoxidil was evaluated after a 5 mg oral dose in 24 subjects with various degrees of renal function. Patients were divided into four groups based on a 24‐hour ambulatory creatinine clearance (Clcr): Group I (n = 6) Clcr >90 mL/min, Group II (n = 6) Clcr 50–80 mL/min, Group III (n = 5) Clcr of 30–49 mL/min, and Group IV (n = 7) Clcr <30 mL/min. Blood and urine samples obtained over 36 hours were analyzed for minoxidil by a high pressure liquid chromatography technique. Maximum plasma concentration (Cmax) and time to reach Cmax did not differ among the four groups. The terminal elimination half‐life was prolonged in Group IV subjects (8.87 ± 6.12 hours) (mean ± SD) compared to those in Groups I, II and III (1.38 ± 0.16, 1.99 ± 0.45 and 2.42 ± 0.53 hours, respectively). Apparent total body clearance (Clp/F) decreased as renal function declined; Clp/F = 0.82(Clcr) + 21.8, r = 0.739, P = 0.0001. Renal clearance and apparent nonrenal clearance also were significantly correlated with Clcr. The apparent volume of distribution significantly increased as renal function declined. Thus, the disposition of minoxidil is significantly delayed and dosage adjustment may be necessary in patients with renal insufficiency.
The Pharmacokinetics and Pharmacodynamics of Hydroxyzine in Patients with Primary Biliary Cirrhosis
Authors: Simons F. Estelle R. , Watson Wade T. A. , Chen X. Y. , Minuk Gerald Y. , Simons Keith J.
Published: March 2013

Hydroxyzine, a potent H1‐receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 ± SD11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 ± 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6–12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 ± 60.6 ng/mL occurred at 2.3 ± 0.7 hours and mean peak cetirizine levels of 500.4 ± 302.0 ng/mL occurred at 4.8 ± 2.8 hours. The mean serum elimination half‐life of hydroxyzine was 36.6 ± 13.1 hours, and the mean serum elimination half‐life of cetirizine was 25.0 ± 8.2 hours. The mean hydroxyzine clearance rate was 8.65 ± 7.46 mL/min/kg, and the mean volume of distribution was 22.7 ± 13.3 L/kg. The mean wheal area was suppressed (P < 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P < 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis. If hydroxyzine is prescribed for pruritus relief in these patients, the dosage regimen may need to be modified.
Pharmacokinetics of Nifedipine Slow Release Tablet in Mexican Subjects: Further Evidence for an Oxidation Polymorphism
Authors: Hoyo‐Vadillo C. , Castañeda‐Hernández G. , Herrera J. E. , Vidal‐Gárate J. , Moreno‐Ramos A. , Chávez F. , Hong E.
Published: March 2013

Nifedipine kinetics after ingestion of 20 mg slow release tablets were studied in 12 young, healthy, Mexican subjects. Plasma levels were determined by a nifedipine‐specific HPLC assay. Levels rose after drug administration reaching a maximum concentration of 48.7 ± 7.3 ng/ml in 2.1 ± 0.7 h (mean ± SEM). Concentrations then decayed with a terminal half‐life of 16.9 ± 3.1 hours. AUC was 526 ± 62 ng h/ml. Five individuals were fast and seven were slow nifedipine metabolizers, according to the AUC criterion proposed by Kleinbioesem and coworkers. Individual AUC/Dose values from this and from other two studies on oral nifedipine kinetics in Mexicans were cumulated and the frequency histogram and probit analyses were performed (N = 30). A bimodal distribution was clearly observed. Fast and slow metabolizers were distinguished as those subjects with AUC/Dose values either lower or higher than 22.5 ng h/ml mg. Unlike European populations, it appears that slow metabolization is more frequent in Mexicans. Data strongly support the hypothesis of the existence of a polymorphism concerning nifedipine disposition kinetics due to genetic basis.
Stevens‐Johnson Syndrome, Respiratory Distress and Acute Renal Failure Due to Synergic Bleomycin‐Cisplatin Toxicity
Authors: Brodsky Andrés , Aparici Inés , Argeri Cecilia , Goldenberg Daniel
Published: March 2013

A patient presenting with a cervix uteri epidermoid carcinoma had acute renal failure after treatment with cisplatin and bleomycin. She later developed fatal bleomycin‐induced pneumonitis and Stevens‐Johnson syndrome. This is a very rare association of adverse effects. The risk of causing a drug interaction thus increasing the severity of bleomycin undesired effects must be taken into account when a nephrotoxic drug is added to the former. The authors stress the importance of monitoring renal function under these conditions.
Once‐Daily Lisinopril Compared with Twice‐Daily Captopril in the Treatment of Mild to Moderate Hypertension: Assessment of Office and Ambulatory Blood Pressures
Authors: Whelton Andrew , Miller William E. , Dunne Bernard , Hait Howard I. , Tresznewsky Orysia N.
Published: March 2013

This multicenter, double‐blind, parallel‐group study compared the antihypertensive effects of two angiotensin‐converting enzyme inhibitors, lisinopril and captopril, in 70 patients (35 lisinopril, 35 captopril) with mild‐to‐moderate essential hypertension. Doses of 10, 20, and 40 mg once‐daily lisinopril or 25, 50, and 100 mg bid captopril were increased at biweekly intervals until patients responded to treatment, as defined by a decrease in office diastolic pressure to less than 90 mm Hg or at least a 10 mm Hg decrease from baseline. Patients who responded to a 2‐week titration dose remained at that dose for another 2 weeks. Blood pressure assessments were made using both office and ambulatory blood pressure monitoring. Area under the curve analysis of ambulatory blood pressure reductions showed significant differences between treatment groups for both systolic (P = .023) and diastolic (P = .007) blood pressures, with lisinopril‐treated patients showing the most significant reduction in pressure. Greater reductions (P < .05) were also noted in patients receiving lisinopril at hours 10 to 12, suggesting two blood pressure troughs for those receiving captopril. Both drugs were well tolerated, and no patients withdrew from either treatment group. The authors concluded that after at least 4 weeks of therapy, once‐daily lisinopril administration was more effective than twice‐daily captopril administration in reducing blood pressure, when measured by 24‐hour ambulatory blood pressure monitoring.
Pharmacodynamic Action and Pharmacokinetics of Moxonidine After Single Oral Administration in Hypertensive Patients
Authors: Kirch Wilhelm , Hutt Hans‐Joachim , Plänitz Vera
Published: March 2013

Moxonidine is a new centrally acting alpha2‐adrenoceptor agonist that differs from others by a lower incidence of side effects in hypertensive patients. The effects of moxonidine and placebo on blood pressure, pulse rate, plasma catecholamines, plasma renin activity, sedation, and salivary flow were evaluated in eight hypertensive patients by an intraindividual comparison. Moxonidine induced a significant decrease in blood pressure that corresponded with its plasma concentrations. The maximum antihypertensive effect appears to be delayed when compared with the peak plasma level. Plasma norepinephrine, epinephrine, and plasma renin activity were significantly reduced by moxonidine, and blood pressure reduction corresponded with decrease of plasma norepinephrine. Heart rate, sedation, and salivary flow were not different using moxonidine compared with placebo. Only one patient mentioned dry mouth. No further relevant adverse effects were seen in the patients. This study demonstrates a significant decrease of blood pressure, plasma renin activity, norepinephrine, and epinephrine with a single dose of 0.25 mg moxonidine, but no significant effect on pulse rate, salivation, and sedation.
New Pharmacokinetic Methods II: Determination of the Presence or Absence of Product Inhibition in Drugs with Nonlinear Pharmacokinetics
Authors: Browne Thomas R. , Szabo George K. , Walsh Carol T. , Schumacher Gerald E. , Evans James E. , Evans Barbara A.
Published: March 2013

We show that for drugs metabolized by one enzyme the slope of a plot of serum concentration (C) versus 1/clearance (CL) is linear with a value of 1/Vmax in the presence of substrate saturation and may be linear (rarely) or curved (usually) with a slope always greater than 1/Vmax in the presence of substrate saturation and product inhibition (competitive, noncompetitive, or uncompetitive) when the serum concentration of product varies with the serum concentration of substrate. Serum concentration, CL, and Vmax were determined for a group of six subjects receiving phenytoin monotherapy using three approaches. With each approach: 1) a plot C versus 1/CL was linear (r ≥ 0.738, P < .01); 2) the slope of this regression line did not differ significantly (P > .30) from 1/Vmax. We conclude: 1) our method is a simple and useful method for determination of mechanism of a drug's nonlinear pharmacokinetics (substrate saturation versus substrate saturation and product inhibition), 2) phenytoin has nonlinear pharmacokinetics due to substrate saturation only in man.
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.
The Effect of Antacid and Cimetidine on the Oral Absorption of the Antifungal Agent SCH 39304
Authors: Kosoglou Teddy , Perentesis George P. , Affrime Melton B. , Lin Chin‐Chung , Mojaverian Parviz , Radwanski Elaine , Vlasses Peter H.
Published: March 2013

The single‐dose pharmacokinetics of the antifungal agent SCH 39304 (Schering‐Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effect on any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304, as assessed by the area under the plasma concentration‐time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC0‐t for the drug given alone was 80.5 ± 15.8 μg · hr/mL, compared to 81.4 ± 12.7 and 79.7 ± 9.6 μg · hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae0‐t) was 22.7 ± 5.1, 24.2 ± 9.2, and 23.6 ± 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the tmax in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmacokinetic disposition of single‐dose SCH 39304.
Interaction of Etretinate with Methotrexate Pharmacokinetics in Psoriatic Patients
Authors: Larsen Frederik G. , Nielsen‐Kudsk Folmer , Jakobsen Preben , Schrøder Henrik , Kragballe Knud
Published: March 2013

Combined treatment of psoriasis with methotrexate and etretinate may be associated with hepatoxicity. This study investigated the potential effects of steady state etretinate administration on methotrexate pharmacokinetics in six psoriatic patients. When compared with a matched group a significantly higher mean value for the maximum plasma concentration Cmax (992 nmol/L ± 94 SE vs 721 nmol/L ± 35 SE) for methotrexate was found (P < .05) after intramuscular administration of 0.2 mg/kg body weight of the drug. In accordance with this finding mean values of the time (tmax) to reach Cmax, half‐life of the absorption (t1/2ka) and the apparent volume of distribution at steady state Vss were also lower than in the control groups but did not deviate significantly. Total clearance differed very little and insignificantly between the two groups. Absorption and disposition rates of etretinate during combined treatment with methotrexate were not significantly altered compared with previous results in psoriatic patients only receiving etretinate. Overall, these results indicate that the apparently increased risk for developing hepatotoxic reactions during coadministration of methotrexate and etretinate cannot be explained by drug accumulation due to pharmacokinetic interaction. A possible influence on potential hepatotoxicity of an increase of Cmax for methotrexate cannot be excluded.
Effects of Tiaprofenic Acid on the Concentration and Metabolism of Proteoglycans in Normal and Degenerating Canine Articular Cartilage
Authors: Brandt Kenneth D. , Albrecht Marjorie E. , Kalasinski Lorrie A.
Published: March 2013

The effects of tiaprofenic acid (TPA), a nonsteroidal antiinflammatory drug with high potency as a cyclooxygenase inhibitor, on the metabolism of normal and degenerating articular cartilage were examined. When present in the culture medium in clinically relevant concentrations encompassing those achieved in synovial fluid of patients treated with the drug, TPA had no significant effects on net proteoglycan synthesis in organ cultures of normal, osteoarthritic or atrophic canine articular cartilage. When fed to dogs for 8 weeks in a daily dose of 100 mg, TPA had no apparent effect on cartilage water content or uronic acid concentration. The suppression of net cartilage proteoglycan synthesis caused by immobilization was not affected by administration of TPA nor did the drug affect the proportion of newly synthesized glycosaminoglycans recovered from the spent culture medium, suggesting that it did not increase proteoglycan catabolism or affect the integrity of the cartilage matrix.
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.
Probucol: Pharmacology and Clinical Application
Authors: Zimetbaum Peter , Eder Howard , Frishman William
Published: March 2013

Increased levels of cholesterol, LDL‐cholesterol, and VLDL‐cholesterol are known risk factors for the development of atherosclerotic vascular disease. Probucol is an orally active agent that can reduce total cholesterol and LDL‐cholesterol. The drug also reduces HDL‐cholesterol. However, it may modify the lipoprotein in such a way that removal of cholesterol from peripheral tissues is still enhanced. Probucol also has antioxidant activity, which may inhibit the oxidative modification of LDL that contributes to lipid deposition in blood vessel walls. Probucol is a well tolerated agent. However, its ability to prolong life in human subjects still needs to be determined.
Drug Delivery Systems: 3A. Role of Polymers in Drug Delivery
Authors: Ranade Vasant V.
Published: March 2013

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion‐controlled systems; chemically controlled systems; solvent‐activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin‐releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.
Clinical Pharmacology of Predisintegrated Ibuprofen 800 mg Tablets: An Endoscopic and Pharmacokinetic Study
Authors: Friedman H. , Seckman C. , Lanza F. , Royer G. , Perry K. , Francom S.
Published: March 2013

Thirty‐five healthy adults were randomized to receive either: (1) ibuprofen 800 mg tablets; (2) ibuprofen 800 mg aqueous suspension; (3) ibuprofen 800 mg orange juice suspension; or (3) 325 mg aspirin tablets. All treatments were tid for 7 days. Pharmacokinetic sampling was conducted on days 1, 4 and 8. Gastroduodenoscopy was performed on days 1 and 8. Side effects and safety laboratory tests were monitored throughout the study. On day 8 the aspirin group showed significantly more gastric irritation than all of the ibuprofen groups (P < .005). Both ibuprofen suspension groups showed more gastric irritation than the ibuprofen tablet group (P < .1). The duodenal scores did not differ among the treatment groups. The aspirin group experienced a higher rate of tinnitus and abdominal pain. The rate and extent of absorption of the ibuprofen suspensions were significantly less than that of the tablets. These data suggest that the taking of ibuprofen as an extemporaneous suspension is therapeutically inferior to ibuprofen tablets and therefore should be discouraged.
Altered Hemodynamic Response to Isosorbide Dinitrate in Essential Hypertension
Authors: Pannier B. M. , Kando T. , Safarian A. A. , Isnard R. N. , Diebold B. E. , Safar M. E.
Published: March 2013

Relaxation produced by nitrates on venous, arteriolar, and large arterial vessels is well known but has never been studied in human hypertensive aortas studied in vivo. In this investigation, the effects of acute oral administration of 20 mg of isosorbide dinitrate were evaluated in 12 patients with sustained essential hypertension and nine normotensives of the same age. Noninvasive measurements of systolic, diastolic, and mean arterial pressure, carotid‐femoral pulse wave velocity and aortic‐arch diastolic diameter using suprasternal echocardiography were determined before and 3 hours after drug administration. In normal subjects, isosorbid dinitrate significantly decreased systolic blood pressure and pulse pressure but did not affect diastolic and mean arterial pressure. In contrast, in hypertensives, the same dosage of isosorbid dinitrate decreased together systolic, diastolic mean, and pulse pressure. In both populations, pulse wave velocity decreased significantly whereas aortic arch diastolic diameter increased markedly. The increase was observed mainly in normal subjects. The study provided evidence that (1) both in normal subjects and hypertensives, isosorbide dinitrate caused an increase in aortic diameter together with an increase in arterial distensibility; and (2) the changes in mean arterial pressure were significant only in hypertensives, indicating that the altered vasodilator response in essential hypertension is not endothelium‐mediated.