bluuebunny/crossref_metadata_2025 huggingface dataset:
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After a 2‐week placebo wash‐out when any antihypertensive treatment was withdrawn, patients were kept on a well balanced normocaloric diet without salt intake restriction.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.
Pharmacodynamic Dependent Disposition of the Angiotensin Converting Enzyme Inhibitor, Libenzapril
Authors: Kochak Gregory M. , Choi R. Leslie , deSilva Jacqueline K. , Reydel‐Bax P.
Published: March 2013

Libenzapril, an angiotensin converting enzyme inhibitor, was administered to healthy male volunteers in a randomized, two‐phase pharmacokinetic study. One phase compared the pharmacokinetics of a 4 mg intravenous infusion and 20 mg oral solution, and the other phase provided two additional intravenous infusions of 1.7 and 12 mg for comparison. The intravenous model‐independent pharmacokinetic parameters MRTiv, Vss, CL, and CLr all exhibited dose dependence. The concentration dependent renal clearance was maximal at 83 mL/min and minimal at 32 mL/min following intravenous administration. The mechanism of libenzapril's self‐inducible clearance appears to have a pharmacodynamic basis. The absolute bioavailability was estimated at less than 10% and the renal clearance following oral administration exhibited additional route dependency.
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.
Lack of Effect of the Vasodilator Pinacidil on Insulin Secretion in Healthy Humans
Authors: Nielsen‐Kudsk Jens Erik , Mellemkjœr Søren , Nielsen Claus Brøckner , Siggaard Charlotte
Published: March 2013

Pinacidil is a new antihypertensive vasodilator drug which is supposed to act by opening of ATP‐sensitive and glibenclamide‐sensitive K+ channels in vascular smooth muscle cell membranes. Similar K+ channels play an important role in insulin secretion from pancreatic islets cells. Inhibition of insulin secretion has been demonstrated with high concentrations of pinacidil in vitro. In the present study the insulin response to oral glucose were studied in six healthy subjects before and on the last day of 2 weeks treatment with pinacidil. The drug was given by the oral route 12.5 mg bid in the first week and 25 mg bid in the second. There were no significant changes in fasting blood levels of insulin or glucose, glucose‐stimulated insulin secretion, or oral glucose tolerance during pinacidil administration. These results may suggest that pinacidil at therapeutic concentrations does not activate insulin regulating K+ channels in pancreatic islet cells.
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.
Is Metoprolol CR/ZOK More Selective Than Conventional Metoprolol and Atenolol?
Authors: Kendall Martin , Akhlaghi Shirin , Hughes Beverly , Lewis Helen
Published: March 2013

An alternative, simple method to assess beta1‐selectivity is to establish the impact of the beta blocker on beta2‐stimulated increases in plasma glucose and decreases in plasma potassium during an intravenous infusion of terbutaline. In the present study the effects of metoprolol CR/ZOK 100 mg, conventional metoprolol 100 mg, atenolol 100 mg, and placebo on these biochemical changes have been compared.

In 12 healthy volunteers, terbutaline infusion of 6 μg/kg was administered intravenously over 1 hour. Three and a half hours before the infusion they were given a single dose of each of the four treatments in random order, single‐blind. The maximum increase in plasma above baseline occurred at the end of a 60‐minute terbutaline infusion. All three beta blockers decreased the peak plasma glucose level achieved compared with placebo (P < .01) but this reduction was significantly less with metoprolol CR/ZOK pretreatment than with atenolol (P < .05). Similar results were seen for the AUC values for the curves obtained from the increments over the 60 minutes of the infusion and the subsequent 120 minutes after the infusion. In addition, both the AUC values and the maximum fall in potassium were significantly reduced by all treatments (P < .05). The metoprolol CR/ZOK preparation produced significantly less effect than atenolol with respect to both AUC (P < .05) and maximum fall (P < .01) and significantly less effect than conventional metoprolol tablets in maximum fall (P < .01). In conclusion, the metoprolol CR/ZOK formulation produces lower plasma concentrations and results in less effect on potassium and glucose compared to conventional metoprolol and atenolol. This can be interpreted as an indication that it behaves as a more beta1‐selective agent.
Beta‐Adrenoceptor Blockade and CNS‐Related Subjective Symptoms: A Randomized, Double‐Blind, Placebo‐Controlled Comparison of Metoprolol CR/ZOK, Atenolol and Propranolol LA in Healthy Subjects
Authors: Dimenäs Elof , Kerr David , Macdonald Ian
Published: March 2013

The effect of once daily treatment with atenolol (100 mg), metoprolol CR/ZOK (100 mg) and propranolol LA (160 mg) for one week on CNS‐related subjective symptoms was compared with that of placebo using a randomised, double‐blind cross‐over design in 12 healthy volunteers. The symptoms were recorded using a previously documented self‐administered questionnaire (MSE‐profile), which included three dimensions: Contentment, Vitality and Sleep.

Compared to placebo, all three beta‐adrenoceptor antagonists reduced the exercise heart rate at 24 hours but a somewhat more pronounced effect was found with propranolol LA.

No significant difference in any of the dimensions was detected between placebo and either metoprolol CR/ZOK or atenolol tablets. Following propranolol LA treatment a deterioration in the dimensions Vitality and Sleep was observed compared with both placebo and the beta1‐selective drugs.

Difference in lipophilicity between the beta1‐selective agents metoprolol and atenolol has little bearing on the occurrence of the CNS‐related symptoms, in comparison to the marked effects of the lipophilic and nonselective compound propranolol.
Drug Delivery Systems 4. Implants in Drug Delivery
Authors: Ranade Vasant V.
Published: March 2013

In comparison with many of the other drug delivery systems, implantable pumps and implants for variable rate delivery are at a crude stage of development. Although exceptions exist, the typical implantable pump consists of an electromechanically complex mechanism to regulate drug delivery from a percutaneous refillable reservoir, while power to drive the system comes from a transcutaneous energy transmission system. The potential for electrical or mechanical failure is high, and the systems are not yet sufficiently convenient or easy to use to recommend in a routine therapy. Problems with refilling of an apparently well designed implanted reservoir have been observed while, at the same time, cutaneous energy transmission systems are not well established.

In most instances, the development of an elementary osmotic pump system dosage form follows a well defined path of physical—chemical formulation and clinical testing. The benefits most often provided by the dosage form are expected to be (1) increase in selectivity of drug action achieved by the system's zero‐order release rate, and (2) decrease in frequency of administration.

The success in achieving these values is quantifiable from the pharmacology of the drug substance and its pharmacokinetics. Osmotic and other technical approaches to producing economical, rate‐controlled dosage forms will make it possible for all new parmaeceutical products to carry kinetic specification of rate as well as static specification of content. This review considers the characteristics of the ideal implantable pump, the clinical situations which require pumps, the limitations of portable pumps, and the detailed characteristics of existing implantable pumps and implants. Most of the review, however, focuses on insulin delivery because of the importance of this subject.
Pharmacokinetics of Cephradine Administered Intravenously and Orally to Young and Elderly Subjects
Authors: Schwinghammer Terry L. , Norden Carl W. , Gill Elizabeth
Published: March 2013

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5‐minute intravenous (IV) infusion followed the next day by a 1‐gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 ± 0.41 mcg/mL) and 8 hours (0.73 ± 0.22 mcg/mL) than in the young group at 6 hours (0.43 ±0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 ± 0.34 vs. 4.81 ± 0.59 ml/min/kg) and the elimination half‐life was significantly longer (1.71 ± 0.20 vs 1.12 ± 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age‐related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.
Safety, Tolerance, and Pharmacokinetics of Cefepime Administered Intramuscularly to Healthy Subjects
Authors: Barbhaiya Rashmi H. , Knupp Catherine A. , Tenney James , Martin R. Russell , Weidler Donald J. , Pittman Kenneth A.
Published: March 2013

Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0–1.6 hours. Pharmacokinetics were linear over the 250‐mg to 2000‐mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose‐proportional manner. The apparent elimination half‐life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple‐dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.
Estimation of Hepatic Blood Flow in Branches of Hepatic Vessels Utilizing a Noninvasive, Duplex Doppler Method
Authors: Horn John R. , Zierler Brenda , Bauer Larry A. , Reiss William , Strandness D. E.
Published: March 2013

The measurement of hepatic blood flow by indirect methods such as indocyanine green clearance has several limitations. The duplex Doppler offers the potential for noninvasive, real‐time measurement of blood flow and has been employed in the evaluation of arterial disease in a variety of vascular beds. We evaluated Doppler ultrasound estimation of blood flow in branches of the hepatic artery, hepatic vein, and portal vein in 12 healthy subjects on two separate days. In vitro accuracy of the scanner was assessed using phantom targets of known diameter and velocity. Blood velocity and vessel diameter measurements were obtained five times over a period of 2 hours. No significant differences were seen in velocity or blood flow measurements within or between days. The interday coefficients of variation, which include intrasubject variability, were 10–15% and 14–20% for velocity and blood flow measurements, respectively. This study demonstrates the potential utility of Doppler ultrasound to detect intrinsic, drug, or disease‐induced changes in hepatic blood flow.
Pharmacokinetics of Quinapril and Its Active Metabolite, Quinaprilat, in Patients on Chronic Hemodialysis
Authors: Blum Robert A. , Olson Stephen C. , Kohli Romesh K. , Horvath Ann Marie , Sedman Allen J. , Posvar Edward L.
Published: March 2013

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end‐stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20‐mg oral dose of quinapril 4 hours before a 4‐hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half‐life of 1.7 hours. Quinapril was extensively de‐esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half‐life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr < 29 mL/min) not yet requiring hemodialysis (RDND).
Placebo‐Controlled Trial of Once‐A‐Day Isradipine Monotherapy in Mild to Moderately Severe Hypertension
Authors: Winer Nathaniel , Kirkendall Walter M. , Canosa Frank L. , Lewin Andrew J. , McMahon F. Gilbert , Carr Albert A. , Cohen Michael
Published: March 2013

The efficacy and safety of once‐daily dosing of isradipine, a new calcium antagonist vasodilator, was evaluated in a multicenter, placebo‐controlled trial in hypertensive patients who had supine diastolic blood pressure (SDBP) 100–119 mm Hg. After a 3‐week single‐blind placebo washout patients randomly received either isradipine, 5 mg once daily, or a matching placebo; if SDBP remained ≥95 mm Hg or ≤10 mm Hg below baseline at four weekly clinic visits, isradipine was increased at weekly intervals by 5 mg once daily up to 20 mg and maintained during weeks 5 and 6. At week 6 mean supine blood pressure 24 hours after dosing had declined from 163 ± 20/105 ± 5 (N = 78) to 146 ± 17/92 ± 7 mm Hg (N = 60) on isradipine, 14.5 mg once daily, and from 163 ± 20/105 ± 6 (N = 85) to 157 ± 18/99 ± 10 mm Hg (N = 64) on placebo (P < .001 between groups). Standing blood pressure decreased from 159 ± 20/104 ± 8 to 144 ± 18/93 ± 11 mm Hg with isradipine and from 160 ± 22/105 ± 9 to 154 ± 19/101 ± 11 mm Hg with placebo (P < .001 between groups) without signs or symptoms of postural hypotension. A SDBP ≤ 90 mm Hg or a ≥ 10 mm Hg fall below baseline was achieved in 41 of 78 isradipine‐treated (53%) and 18 of 85 placebo‐treated subjects (21%). Four isradipine‐treated and 11 placebo‐treated patients were discontinued because of inadequate blood pressure control. Adverse effects in patients receiving isradipine and placebo included headaches (34.5% vs. 17.4%), weakness (7.1% vs. 0%), and palpitations (8.3% vs. 1.2%). Thus, isradipine, 5–20 mg once daily is safe and effective in lowering blood pressure over 24 hours in about one‐half of patients with mild to moderately severe hypertension.
Binding of Diltiazem to Albumin, α1‐Acid Glycoprotein and to Serum in Man
Authors: Belpaire F. M. , Bogaert M. G.
Published: March 2013

Binding of drugs can vary considerably. Therefore, binding of the calcium antagonist diltiazem was studied in protein solutions and in serum of healthy persons, patients with renal failure, patients with cirrhosis, patients with rheumatoid arthritis, patients with myocardial infarction, and intensive care patients. The effect of in vitro addition of some cardiovascular drugs (lidocaine, disopyramide, quinidine, and bupivacaine) on the binding of diltiazem in serum of healthy volunteers was also investigated. Diltiazem is bound as well to α1‐acid glycoprotein (AAG) as to albumin. In patients with renal failure, myocardial infarction, and rheumatoid arthritis and in intensive care patients, AAG concentrations are increased, and in the patients with myocardial infarction an increased binding of diltiazem is found. In patients with cirrhosis, AAG concentrations and diltiazem binding are decreased. In vitro addition of lidocaine, disopyramide, bupivacaine, or quinidine in concentrations between 5 and 100 μg/mL, before dialysis, decreases the binding of diltiazem; the displacing effect is most pronounced with bupivacaine.
Intravenous Lidocaine and Cerebral Blood Flow: Impaired Microvascular Reactivity in Diabetic Patients
Authors: Kastrup Jens , Petersen Palle , MD Anders Dejgård
Published: March 2013

Lidocaine infusions are used for treatment of ventricular arrhythmias and painful diabetic neuropathy. In animals high doses of lidocaine reduces cerebral blood flow (CBF). The effect of lidocaine on CBF in humans is unknown. Cerebrovascular reactivity may he impaired in long‐term diabetic patients. The effect of intravenous lidocaine (5 mg/kg body weight) on CBF was investigated in eight healthy subjects and eight long‐term diabetic patients with painful neuropathy. Cerebral blood flow was measured with the intravenous 133‐Xenon method immediately before and after lidocaine infusion and 60 minutes later. In healthy subjects, CBF decreased 12% (P <.02) during lidocaine infusion and normalized within 60 minutes. Diabetic patients had identical CBF level before and after lidocaine suggesting decreased cerebrovascular reactivity.
Safety and Tolerability of Single Intravenous Doses of T Cell Modulatory Peptide (TCMP‐80) in Healthy Volunteers
Authors: Eldon Michael A. , Smith Richard A. , Leese Philip T. , Daigle Anne E. , Katz Darlene V. , Richieri Steven P.
Published: March 2013

T Cell Modulatory Peptide (TCMP‐80), L‐lysine‐L‐serine, is a synthetic dipeptide structurally related to a selected amino acid sequence in human immunoglobulin G. Based on in vitro and preclinical in vivo testing, TCMP‐80 has immunomodulatory properties. This report describes the first administration of TCMP‐80 to man in a randomized, double‐blind, placebo‐controlled, single rising‐dose tolerability trial. Healthy male volunteers received TCMP‐80 or placebo as a 10‐minute intravenous infusion. At weekly intervals, two of four subjects were given TCMP‐80; the remaining two received placebo. Each subject could receive only one dose during the study. Dosing started at 0.01 mg/kg and was increased to 0.03, 0.1, 0.3, 1, 3, 6.5, and 10 mg/kg. CBCs, blood chemistries, urinalyses, and lymphocyte subset populations were monitored predose and postdose on Days 1, 5, and 14. Three placebo and three TCMP‐80 subjects reported adverse events. Adverse events reported after TCMP‐80 administration were mild in nature (headache, dizziness, hematoma at injection site), appeared to be independent of dose, and resolved without medical intervention. No clinically significant alterations in vital signs, physical examination parameters, or clinical laboratory values were observed. Based on the results of this study, TCMP‐80 is safe and well‐tolerated within the dose range studied when administered as single intravenous infusions. Additionally, this study design represents an approach to assess the safety of an investigational immunomodulatory drug.
New Pharmacokinetic Methods: L Estimation of Mean Serum Concentration From Trough Serum Concentration
Authors: Browne Thomas R. , Greenblatt David J. , Szabo George K. , Evans James E. , Evans Barbara A.
Published: March 2013

An equation is derived to estimate mean steady state serum concentration (C̄ss) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated C̄ss did not differ significantly from measured C̄ss, while Cmin differed significantly (P < .0001) from measured C̄ss and estimated C̄ss. Clearance (CL) and elimination half‐life (t1/2) values determined by stable isotope tracer methods or by standard equations and measured C̄ss or estimated C̄ss did not differ significantly, while CL and t1/2 values calculated with standard equations and Cmin differed significantly (P < .02) from values obtained by any of the other three methods. We conclude: 1) Cmin values and CL and t1/2 values calculated with Cmin values may differ significantly from C̄ss values and CL and t1/2 values calculated with C̄ss; 2) accurate estimates of C̄ss and of CL and t1/2 can be obtained using our procedure to correct a Cmin value to an estimated C̄ss value.
Clinical Safety, Tolerance, and Plasma Levels of the Oral Anticholinesterase 1,2,3,4‐Tetrahydro‐9‐aminoacridin‐1‐oL‐maleate (HP 029) in Alzheimer's Disease: Preliminary Findings
Authors: Cutler Neal R. , Murphy Michael F. , Nash Ralph J. , Prior Pat L. , De Luna Diane M.
Published: March 2013

HP 029 (1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐oL‐maleate), an oral anticholinesterase, enhances memory in rodents and may be useful in treating Alzheimer's disease (AD). To assess adverse events in relation to dosage and plasma drug levels, 24 hospitalized AD subjects were randomly assigned to receive placebo or HP 029 for 10 days in a double‐blind, sequential escalation study. Maximum daily dosages were 450 mg (group 1), 300 mg (group 2), and 225 mg (group 3), divided into three doses per day. The group 1 trial was discontinued on day 5 because one subject, 6 hours following the second of three scheduled 150‐mg doses, had a tonic seizure after protracted vomiting and hyperventilation; adverse events in other patients included nausea, vomiting, abdominal cramps, diarrhea, dizziness, and syncope. Adverse events were generally less severe in group 2, but only two of six HP 029 subjects could complete the trial at 300 mg/day. All group 3 subjects completed the trial at 225 mg/day with drug related, mild adverse events (nausea, vomiting, lacrimation, rhinorrhea) in only two subjects. Although mean plasma drug levels were related to adverse events across dosage groups, they did not adequately predict the occurrence or severity of adverse events in individual subjects. The 225 mg/day dose appears to be safe for use in multicenter outpatient trials of HP 029 efficacy in AD. Further patient studies are ongoing to determine the relation of specific subject characteristics to the metabolic profile of HP 029 and biological response.
Pharmacokinetics of Oral and Transdermal Triprolidine
Authors: Miles Michael V. , Balasubramanian Ramadas , Pittman A. Wayne , Grossman Steven H. , Pappa Keith A. , Smith Mary Faye , Wargin Willam A. , Findlay John W. A. , Poust Rolland I. , Frosolono Michael F.
Published: March 2013

In this open, nonrandomized, three‐way crossover study, six healthy male volunteers received single doses of triprolidine (TPL) hydrochloride syrup orally (2.5 mg) and wore transdermal TPL patches (5 mg and 10 mg doses) to compare the pharmacokinetic profiles and dose tolerance of the two formulations. A washout period of at least 1 week was scheduled between the three dosing periods. Blood samples were collected at defined times, and plasma concentrations were determined using a radioimmunoassay. Maximum plasma drug concentration (Cmax) decreased from 5.6 ± 2.9 ng/mL (mean ± SD) with oral dosing to 2.0 ± 1.0 ng/mL and 4.2 ± 2.0 ng/mL following 5 mg and 10 mg transdermal doses, respectively. Time to reach peak concentration (tmax) increased from 2.0 ± 1.2 hours with oral dosing to 12.0 ± 5.9 and 14.3 ± 9.9 hours following 5 mg and 10 mg transdermal doses, respectively. The differences between AUC0‐α values with the oral syrup and the 5 mg and 10 mg transdermal doses were not significant when normalized to 2.09 mg (TPL base). The bioavailabilities of the 5 mg and 10 mg transdermal doses relative to the oral 2.09 mg doses were 0.89 ± 0.32 and 1.04 ± 0.33, respectively.

Mild erythema and pruritus were the most common adverse effects secondary to TPL transdermal application. Drowsiness observed following oral TPL, was not evident following either transdermal dose.

The results of this study, therefore, indicate that TPL can be absorbed transdermally, providing consistent plasma concentrations.
Dietary Fiber for Reducing Blood Cholesterol
Authors: Lipsky Harold , Gloger Mark , Frishman William H.
Published: March 2013

Soluble dietary fiber, including psyllium, has been shown to have mild to modest cholesterol lowering properties. Psyllium hydrophilic mucilloid (Metamucil®, Procter and Gamble, Cincinnati, OH), a bulk laxative, when used as a dietary supplement in combination with a low fat diet, can lower total serum cholesterol and low‐density lipoprotein (LDL) cholesterol, and raise high‐density lipoprotein (HDL) cholesterol in hypercholesterolemic patients. The cholesterol lowering effects of psyllium are much less evident than those observed with cholestyramine and the HMG‐CoA reductase inhibitors. The mechanism for the cholesterol lowering effect of psyllium is not known. The substance is well tolerated with long‐term use.
Bioavailability and Kinetics of Cibenzoline in Patients with Normal and Impaired Renal Function
Authors: Aronoff George , Brier Michael , Mayer Mary Lou , Barbalas Michael , Aogaichi Keiko , Sloan Rebecca , Brazzell Romulus , Massarella Joseph
Published: March 2013

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80‐mg intravenous infusion of 15N‐2‐cibenzoline and a single 80‐mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic—mass spectrometric assay. A compartment‐independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half‐life of 7.3 hours after the intravenous dose in healthy volunteers. In renal‐failure patients, cibenzoline clearance decreased to 224 mL/min and half‐life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal‐failure patients, respectively. Hemodialysis accounted for only 13% of drug clearance.
Chronotherapy of Trichlormethiazide in Hypertensive Patients
Authors: Fujimura Akio , Ohashi Kyo‐ichi , Ebihara Akio
Published: March 2013

Circadian influence of trichlormethiazide on serum electrolyte levels, lipid levels, and glucose levels were evaluated in 12 hypertensive patients. One tablet of trichlormethiazide (2 mg) was given once a day at 7:00 am or 7:00 pm for 8 weeks. The study was done by a crossover design. Twenty—four‐hour urine was collected, and fasting blood samples were obtained during the control period and at the end of each treatment period. The 24‐hour urine level increased slightly after treatment with trichlormethiazide in the morning and evening trials. Urinary excretion of sodium also increased slightly in the morning trial and increased significantly in the evening trial. Serum concentrations of potassium and chloride decreased, and serum uric acid level increased after trichlormethiazide treatment. No significant difference was observed in these parameters between morning and evening trials. Fasting blood glucose levels increased after trichlormethiazide treatment. The increment in blood glucose levels was greater in the evening trial than in the morning trial. These data indicate that the influence of trichlormethiazide on glucose tolerance might vary with its administration time.
The Immunosuppressive Activity of the Aldehydic Transformation of Cyclosporine on Alloreactive T‐Cells
Authors: Eiras Gabriella , Hashem Hanaa , Zeevi Adriana , Wong Lan , Duquesnoy Rene J. , Burckart Gilbert J.
Published: March 2013

Cyclosporine (CsA) is a potent immunosuppressive compound, and its metabolites have previously been shown to have pharmacologic activity. The aldehydic metabolites have been isolated and are a metabolic intermediate after the conversion of CsA to its most active hydroxylated metabolite. The in vitro sensitivity of alloreactive T‐lymphocytes, which are generated from a mixed lymphocyte reaction and propagated from organ transplant biopsy specimens to the aldehydic metabolites of CsA, was tested. In secondary proliferative assays in the presence of varying concentrations of CsA and the aldehydes, the concentration required to inhibit proliferation by 50% was 50 to 150 ng/mL for CsA and 3150 to 3500 ng/mL for the aldehydes. Pretreatment of alloreactive cells with CsA or the aldehydes did not alter cell viability, as tested with dye exclusion, or cell reactivity on reculturing. These studies concluded that the structural modification formed by metabolism of CsA to the aldehydic structure eliminates its antiproliferative activity on T‐lymphocytes.
Pharmacokinetics of the R(−) and S(+) Enantiomers of Ibuprofen in the Serum and Synovial Fluid of Arthritis Patients
Authors: Cox S. R. , MD E. P. Gall , BA K. K. Forbes , Gresham M. , Goris G.
Published: March 2013

Eight patients with arthritis and knee effusions received 13 doses of a single 800‐mg ibuprofen tablet every 8 hours. Serum and synovial fluid samples were obtained after the first and last doses and assayed for the R(−) and S(+) enantiomers of ibuprofen by a stereospecific assay. Since only S(+)‐ibuprofen inhibits cyclo‐oxygenase, a description of the time course of this isomer in synovial fluid is needed for the development of suitable pharmacodynamic models. The isomers were significantly different with respect to peak concentrations and areas under the concentration—time curves (AUC) in synovial fluid levels. No significant accumulation of either isomer was observed in serum or synovial fluid levels between the first and the last doses. The steady‐state concentration of both isomers fluctuated less in synovial fluid than in plasma, and the synovial fluid concentrations of the S(+) isomer were about twice that of the R(−) isomer. The mean synovial albumin concentration was about 60% of the serum albumin concentration, and the steady‐state isomer AUC values in synovial fluid were significantly correlated with the corresponding serum values after the differences between the two fluids with respect to albumin concentration were corrected. The authors conclude that binding of the isomers to albumin and the serum—synovial fluid albumin ratio controls the steady‐state distribution of the ibuprofen isomers into synovial fluid. The ramifications of these findings in the development of satisfactory concentration—response relationships are discussed.
Effect of a Novel Monoamine‐Oxidase Inhibitor, Moclobemide on the Sensitivity to Intravenous Tyramine and Norepinephrine in Humans
Authors: Cusson Jean R. , Berg Elaine Golden , Larochelle Pierre
Published: March 2013

This study compared the effects of moclobemide (Ro11–1163), a selective and reversible inhibitor of monoamine‐oxidase (MAOI) type A and phenelzine, an irreversible non‐selective MAOI, on the pressor responses to IV tyramine and norepinephrine. Because of the reversibility of this inhibition, the pressor effect of tyramine was expected to be minimal. Twelve healthy men participated in this randomized double‐blind, placebo‐controlled, crossover study. Volunteers began with oral treatment of moclobemide (100 mg TID) or phenelzine (15 mg TID) for 1 week followed by placebo treatment for 2 weeks and then moclobemide or phenelzine treatment for another week. The tyramine and norepinephrine challenge tests were conducted at baseline and then at weekly intervals, for a total of five challenges. The average tyramine dose that was required to increase systolic blood pressure by 25 mm Hg (PD25) was 1.6 ± 0.2 mg after moclobemide treatment, which was lower (P < .01) than the baseline value of 3.6 ± 0.7 mg and that after phenelzine (3.0 ± 0.5 mg) treatment. Moclobemide did not influence norepinephrine sensitivity. In conclusion, moclobemide mildly decreased the sensitivity to IV tyramine as compared with placebo and phenelzine.
The Pharmacokinetics of Acitretin and its 13‐cis‐metabolite in Psoriatic Patients
Authors: Larsen Frederik Grønhøj , Jakobsen Preben , Eriksen Holger , Grønhøj Janne , Kragballe Knud , Nielsen‐Kudsk Folmer
Published: March 2013

The synthetic retinoic acid derivative acitretin has recently been introduced for the treatment of severe psoriasis. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half‐life of up to 120 days for this drug. In the presented study, 12 patients with severe psoriasis were treated with 30 mg acitretin daily for a period of 6 months. The maximum plasma concentration of the drug occurred within about 0.9 to 4.6 hours with an apparent absorption half‐life ranging from 0.2 to 1.7 hours and with half‐lives of the distribution phase within the range of 1.2 to 3.5 hours. After stopping therapy, the terminal elimination half‐life of acitretin varied between 16.5 and 111.1 hours (mean: 47.1 hr ± 29.8 SD), whereas that for the 13‐cis‐metabolite varied between 36.5 and 249.4 hours (mean: 119.4 hr ± 73.4 SD). Suction blister fluid concentrations of both the parent drug and metabolite were lower than plasma concentrations. The mean concentration of serum triglycerides was significantly elevated during the course of therapy, but still remained within the normal range. Saliva concentrations of drug and metabolite at steady‐state were below 1 ng/mL. It is not possible from the observed half‐lives of acitretin and its 13‐cis‐metabolite to draw any definite conclusion with regard to the anticonceptional period after acitretin therapy in psoriatic patients.
Influence of Food on the Oral Absorption and Bioavailability of Moricizine
Authors: Pieniaszek Henry J. , Rakestraw Dariel C. , Schary William L. , Williams Roger L.
Published: March 2013

Moricizine, a unique Class I antiarrhythmic agent, was orally administered with and without a meal to 24 healthy male subjects to determine the effect of food on moricizine absorption and bioavailability. Relative to the fasting state, a standardized breakfast delayed the time to peak plasma moricizine concentration (1.2 vs. 0.9 hr; P <.03) and lowered peak plasma moricizine concentration by 24% (0.55 vs. 0.72 μg/mL; P <.03). Bioavailability, as measured by area under the plasma moricizine concentration versus time curve, was not significantly altered by the meal.
Lack of Effect of Paracetamol on the Pharmacokinetics of Indomethacin and Paracetamol in Humans
Authors: Seideman Peter
Published: March 2013

Paracetamol is an analgetic drug with additive effect if combined with indomethacin. In rat experiments, paracetamol has been shown to be gastro‐protective, and in animal experiments, indomethacin blood levels decreased during combined treatment with paracetamol. The kinetic effect of paracetamol on indomethacin has been investigated in ten healthy volunteers. The mean area under the indomethacin plasma concentration curve AUC 0‐α was 10.4 ± 4.21 ug/mL × hr and did not change during combined paracetamol treatment (11.0 ± 3.24 ug/mL × hr ns). Paracetamol levels were unchanged. In this study, no evidence was found that paracetamol can alter the pharmacokinetics of indomethacin in humans.
Pharmacodynamic Aspects of Spaceflight
Authors: Levy Gerhard
Published: March 2013

Little is known at present about the effects of human exposure to microgravity on the pharmacodynamics of medicinal agents. Considering the known physiologic perturbations associated with spaceflight and the effects of some of these perturbations on the pharmacodynamics of certain medicinals that act on the central nervous system, it is likely that the pharmacodynamics of at least some of these agents will be altered in individuals who are subjected to microgravity and other conditions of spaceflight. It is timely to initiate formal studies, initially in ground‐based animal models and human volunteers during prolonged, head‐down bed rest and eventually in animals and human volunteers exposed to microgravity, of pharmacodynamics and pharmacokinetics during spaceflight.