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Abstract

K. Raith and G. Hochhaus

Department of Pharmaceutics, School of Pharmacy, University of Florida, JHMHSC, Gainesville, FL, USA
Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, a2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.

Abstract

C. Labriola, M. Siro-Brigiani, F. Carrata, E. Santangelo and B. Amantea

¹Department of Cardiac Anesthesia and Postoperative Intensive Care,
²Department of Cardiology, Casa di Cura Santa Maria, Bari, and
³Institute of Anesthesiology and Intensive Care, University School of Medicine, Policlinico Mater Domini, Catanzaro, Italy
Following cardiac surgery, low-output syndrome is relatively common. Since this condition can lead to serious consequences, this postsurgical, low-output state should be reversed whenever possible. Patients with low-output syndrome need drug and fluid management aimed at enhancing cardiac contractility and at facilitating optimal myocardial loading. The objective of this pilot study was to evaluate whether benefits of levosimendan, a new calcium-sensitizing agent approved for treatment of patients with acute exacerbation of chronic heart failure, could be extended to patients with low-output syndrome following cardiac surgery. For this study, each patient was given levosimendan as a loading dose of 12 mg/kg over 10 minutes, followed by a continuous infusion of 0.1 mg/kg/min for 12 hours. Of 11 postsurgical patients with severely impaired cardiac output and hemodynamic compromise, 8 patients (73%) showed evidence of combined hemodynamic improvement (> 30% increase in cardiac index and PCWP corrected to < 18 mmHg) within 3 h after the start of levosimendan infusion. Specifically, cardiac index and stroke volume were significantly increased, while mean arterial pressure, indexed systemic vascular resistance, mean pulmonary pressure, right arterial pressure, and pulmonary capillary wedge pressure were all significantly lowered. Taken together, such changes showed enhanced cardiac output along with significantly decreased preload and afterload – conditions associated with recovery of cardiac function. Levosimendan is thus highly favorable for short-term treatment of patients with low cardiac output following cardiac surgery.

Abstract

J. Wysocki, D. Belowski, M. Kalina, L. Kochanski, B. Okopien and Z. Kalina

¹Department of Internal Diseases and Clinical Pharmacology, ²Department of Clinical Pharmacology, and ³Department of Pediatric Endocrinology and Diabetes, Medical University of Silesia, Katowice, Poland
Background and objective: Metabolic syndrome is characterized by insulin resistance (IR) as well as dyslipidemia, ventral overweight, hypertension and elevated fasting plasma glucose. Since diabetic and prediabetic states are commonly associated with hypertriglyceridemia, fenofibrates have been used in such patients. The aim of this pilot open trial was to study the influence of micronized fenofibrate on insulin resistance and plasma insulin levels in prediabetic and diabetic patients. Subjects: From 114 dyslipidemic patients, 31 with dyslipidemia and insulin resistance were selected to take part in the study. Of the 31 patients, 20 were nondiabetic and only 11 had noninsulin-dependent diabetes mellitus. Eighteen dyslipidemic patients acted as controls. Methods: Insulin resistance was assessed in a short-term insulin tolerance test. Plasma insulin, antiinsulin antibodies, lipid parameters and the insulin sensitivity index (ISI) were measured at entry and after a 3-month therapy with 200 mg micronized fenofibrate daily. Results: Three-month therapy with micronized fenofibrate resulted in significant ISI increase and was accompanied by a decrease in plasma insulin levels in dyslipidemic patients with metabolic syndrome. ISI also improved in patients with type 2 diabetes mellitus and there was an unexpected increase in plasma insulin levels. Antiinsulin antibodies were unchanged throughout the trial. Reductions in plasma triglycerides and total cholesterol exceeding 50% and 20%, respectively, were observed in patients with metabolic syndrome. These changes were accompanied by an increase in mean levels of plasma high-density lipoprotein (HDL) cholesterol (above 35%). Conclusions: Micronized fenofibrate is an effective drug in normalizing lipid-lipoprotein levels in patients with metabolic syndrome. After a 3-month fenofibrate therapy, insulin resistance was reduced in a group of patients with dyslipidemia and metabolic syndrome.

Abstract

D. Philipova, B. Tzenova, A. Iwanowitsch and I. Bognar-Steinberg

¹Institute of Physiology, Laboratory of Motor Control, Bulgarian Academy of Sciences, ²National Center for Hygiene, Sofia, Bulgaria, and ³Department of Clinical Research, Hennig Arzneimittel, Flörsheim am Main, Germany
In the present comparative, double-blind, 3-way crossover study, possible effects of an antivertiginous combination preparation on event-related potentials (ERPs) and performance were investigated. Twenty-one healthy volunteers received 4 doses (within 24 h) of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevert, ARL), dimenhydrinate 50 mg, or a placebo, in randomized order at 1-week intervals. Auditory event-related potentials (ERPs), reaction time (RT) and psychometric tests were assessed before as well as 60 and 150 minutes after the intake of the 1st (Day 1) and the 4th (Day 2) dose of study medication. The evaluation was primarily based on the difference in the outcomes measured 150 min after the 4th dose (t5) and those before the start of medication intake (t0). None of the medications affected the latency and amplitude of the sensory ERP component N100, neither under passive listening nor under discrimination task conditions. The latency of P300 in response to the rare target tones (oddball paradigm and binary series), showed significant (p < 0.05) delays after 4 doses of dimenhydrinate (18 – 24 ms), and no significant differences between ARL (3 – 17 ms) and either dimenhydrinate or placebo (4 – 13 ms). Responses to nontarget tones remained almost unaffected after medication intake. The secondary analysis of the P300 amplitude showed the greatest decreases under DH in both active series, with no significant differences between ARL and either DH or placebo. The 3 medications did not significantly prolong RT nor did they impair the performance of psychometric tests, or cause significant shifts of current mood. The combination preparation ARL showed the lowest rate of adverse events (n = 1), followed by dimenhydrinate (n = 3) and placebo (n = 6). Two subjects withdrew because of adverse events, both after the intake of placebo. In conclusion, the results gave no evidence for an impairment of central information processing and psychomotor performance after multiple dosing with the fixed combination ARL in healthy volunteers, which might, when present, represent an adverse reaction limiting its use in antivertiginous therapy. No significant differences were found between ARL and placebo.

Abstract

S. de la Motte and A. Gianella-Borradori

¹Harrison Clinical Research GmbH, Munich, Germany, and ²Cyclacel Ltd., Dundee, UK
Objective: To characterize the pharmacokinetics of R-roscovitine, a novel cyclin-dependent kinase inhibitor, and its carboxylate metabolite in man. Method: Twelve healthy male subjects received single oral doses of 50, 100, 200, 400 or 800 mg in a hierarchical 3-period, 6-sequence crossover design. One dose was given after breakfast, the others under fasting conditions. R-roscovitine and the carboxylate metabolite were measured in plasma and urine. A 2-compartment model for R-roscovitine with 1 compartment for the metabolite and a component for first-pass extraction was adequate. Protein binding was calculated from plasma and urine data. Results: R-roscovitine undergoes nonsaturatable first-pass extraction, rapid metabolism, exhibits high nonsaturated protein binding, is slowly absorbed from the GI tract and is rapidly and extensively distributed into tissues. The slow release of the molecule from tissue determines the apparent terminal half-life. Food delays the absorption and slows down the absorption rate but does not influence bioavailability. The formation rate of the carboxylate is a determinant of the plasma concentrations of this metabolite. It has low protein binding, limited tissue distribution and a renal clearance reflecting with good water solubility. Conclusion: The compartmental analysis clarified important pharmacokinetic aspects relevant for the clinical development of the compound.

Abstract

I. Mahmood and V. Tammara

¹Division of Pharmaceutical Evaluation I, Office of Clinical Pharmacology and Biopharmaceutics (HFD-⁸⁶⁰), Food and Drug Administration, Woodmont Office Center II, Rockville, Pike, MD and ²Wyeth Pharmaceuticals, Collegeville, PA, USA
Background and objective: The objectives of this study were to assess pharmacokinetic parameters (clearance, volume and half-life) in children using sparse sampling population as well as Bayesian (post hoc) approach. Methods: Three drugs were selected for this study. Two sparse sampling methods (variable or fixed) using population and Bayesian approaches were used to assess pharmacokinetic parameters in children following a single oral dose. The initial estimates of the model parameters and inter- and intrasubject variability were obtained from the pharmacokinetic studies conducted in adults. The estimated pharmacokinetic parameters using sparse sampling (3 blood samples) were compared with the pharmacokinetic parameters obtained by extensive sampling (³ 7 blood samples). Results and conclusions: The results indicated that both variable and fixed sampling approaches could be used to estimate mean population as well as individual pharmacokinetic parameters in children with fair degree of accuracy. The methods described here can be used to assess either population or individual pharmacokinetic parameters in children, provided there is a prior knowledge of the pharmacokinetics of a drug in adult population.

Abstract

R. Kitzes-Cohen, D. Koos and M. Levy

¹Clinical Pharmacology and Infectious Diseases Unit, Carmel Medical Center, Haifa, and ²Department of Clinical Pharmacology, Hadassah University Hospital, Jerusalem, Israel
Objectives: To investigate the pattern of antibiotic use in the hospital over a 3-year period according to individual drugs and hospital departments. Setting: 335 adult beds of a tertiary hospital in Northern Israel during the years 1998 – 2000. An antibiotic control policy restricts the use of the most expensive antibiotics and those with broad spectrum of activity and a major impact on bacterial resistance. Methods: The ATC/DDD and DU 90% methodologies were used. The use of antibiotics was expressed as the number of defined daily doses (DDD) per 100 bed-days. Results: The total antibiotic use varied during the study period from 93.7 – 101.0 DDD/100 bed-days (p < 0.1). Thirteen drugs accounted for 90% of the total volume. The use of broad spectrum penicillins was the highest of all drugs followed by cephalosporins and oral quinolones. The highest rates of antibiotic use were found in the departments of ENT, urology, gynecology and orthopedics and in the intensive care unit (ICU). The total restricted antibiotics use was 7.2 DDD/100 bed-days and was the highest in the ICU. Conclusions: The ATC/DDD methodology provided delineation and interpretation of antibiotic usage patterns in the hospital. Although the overall use is higher then that found in several reports from European hospitals, stratification by individual drugs and by hospital department yielded similar trends.

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Volume 42, No. 4/2004(April)