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Biomedical subjects

L Lesko

Publications and source records attributed to L Lesko.

At least 19 recordsLinked to original sources
PubMed2005

The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers.

BIBN4096BS is a CGRP-antagonist effective in the treatment of migraine. Blocking the receptor of a strong vasodilator involves a theoretical risk of causing cerebral vasoconstriction, a probability not previously investigated with BIBN4096BS. Seven healthy volunteers completed this double-blinded placebo-controlled crossover study. The volunteers received randomly 10 min infusions of either placebo, 2.5 mg or 10 mg of BIBN4096BS on 3 separate days. Transcranial Doppler was used to measure the middle cerebral artery blood flow velocity (V(MCA)); global and regional cerebral blood flow (rCBF(MCA)) was measured by 133-Xenon inhalation SPECT. The diameter of the temporal and radial artery was measured by high-resolution ultrasound. Systemic haemodynamics and partial pressure of CO(2) (P(et)CO(2)), and adverse events were monitored regularly. BIBN4096BS had no influence on global or regional cerebral blood flow, or on the blood flow velocity in the middle cerebral artery. There was no effect on systemic haemodynamics and adverse events were minor. We conclude that there is no effect of CGRP-receptor blockade on the cerebral or systemic circulation in humans. Circulating CGRP is therefore not likely to exert a vasodilatory activity in the resting state and the use of BIBN4096BS for acute migraine seems to be without risk of cerebral vasoactivity. These data suggest that BIBN4096BS is the first specific antimigraine drug without vasoactive effect.

Adult↗
PubMed2002

The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique.

The purpose of this human intestinal perfusion study (in vivo) was twofold. Firstly, we aimed to determine the effective in vivo jejunal permeability (P(eff)) of amoxicillin and to classify it according to the Biopharmaceutics Classification System (BCS). Secondly, we investigated the acute effect of amiloride on the jejunal P(eff) of amoxicillin. Amoxicillin, a beta-lactam antibiotic, has been reported to be absorbed across the intestinal mucosa by both passive diffusion and active transport. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut perfusion tube in 14 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The concentration of amoxicillin entering the jejunal segment was 300 mg/l in both periods, and amiloride, an inhibitor of the Na+/H+ exchanger, was added at 25 mg/l in period 2. The concentrations of amoxicillin and amiloride in the outlet jejunal perfusate were measured with two different HPLC-methods. Antipyrine and [14C]PEG 4000 were added as internal standards to the perfusion solution. Amiloride had no significant effect on the jejunal P(eff) of amoxicillin. The human in vivo jejunal P(eff) for amoxicillin was 0.34+/-0.11 x 10(-4) and 0.46+/-0.12 x 10(-4) cm/s in periods 1 and 2, respectively. The high jejunal P(eff) for amiloride was 1.63+/-0.51 x 10(-4) cm/s which predicts an intestinal absorption of more than 90%. Following the BCS amoxicillin was classified as a low P(eff) drug, and amiloride had no acute effect on the in vivo jejunal P(eff) of amoxicillin.

Adult↗
PubMed2001

Human jejunal permeability of two polar drugs: cimetidine and ranitidine.

PURPOSE: To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs. METHODS: A sterile multi-channel perfusion tube, Loc-I-Gut, was inserted orally and positioned in the proximal region of the jejunum. A solution containing cimetidine or ranitidine and phenylalanine, propranolol, PEG 400, and PEG 4000 was perfused through a 10 cm jejunal segment in 6 and 8 subjects, respectively. RESULTS: The mean Peff (+/- se) of cimetidine and ranitidine averaged over both phases were 0.30 (0.045) and 0.27 (0.062) x 10(-4) cm/s, respectively, and the differences between the two were found to be statistically insignificant. The mean permeabilities for propranolol, phenylalanine, and PEG 400 averaged over both phases and studies were 3.88 (0.72), 3.36 (0.50), and 0.56 (0.08) x 10(-4) cm/s, respectively. The differences in permeability for a given marker were not significant between phases or between the two studies. CONCLUSIONS: The 10-fold lower permeabilities found for cimetidine and ranitidine in this study, compared to propranolol and phenylalanine, appear to be consistent with their less than complete absorption in humans.

Adolescent↗
PubMed2001

Bioavailability and bioequivalence: an FDA regulatory overview.

Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDA's recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.

Biological Availability↗
PubMed2001

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.

Acetylcholinesterase↗
PubMed2001

Measures of exposure versus measures of rate and extent of absorption.

Regulatory assessment of bioavailability and bioequivalence in the US frequently relies on measures of rate and extent of absorption. Rate of absorption is not only difficult to measure but also bears little clinical relevance. This paper proposes that measures of bioavailability and bioequivalence for drugs that achieve their therapeutic effects after entry into the systemic circulation are best expressed in terms of early [partial area under the concentration-time curve (AUC)], peak plasma or serum drug concentration and total AUC exposure for a plasma or serum concentration-time profile. With suitable documentation, these systemic exposure measures can be related to efficacy and tolerability outcomes. The early measure is recommended for an immediate release drug product where a better control of drug absorption is needed, for example to ensure rapid onset of a therapeutic effect or to avoid an adverse reaction from a fast input rate. The 3 systemic exposure measures for bioavailability and bioequivalence studies can provide critical links between product quality and clinical outcome and thereby reduce the current emphasis on rate of absorption.

Absorption↗
PubMed2000

Stress and burnout in oncology.

This article identifies the professional stressors experienced by nurses, house staff, and medical oncologists and examines the effect of stress and personality attributes on burnout scores. A survey was conducted of 261 house staff, nurses, and medical oncologists in a cancer research hospital, and oncologists in outside clinical practices. It measured burnout, psychological distress, and physical symptoms. Each participant completed a questionnaire that quantified life stressors, personality attributes, burnout, psychological distress, physical symptoms, coping strategies, and social support. The results showed that house staff experienced the greatest burnout. They also reported greater emotional exhaustion, a feeling of emotional distance from patients, and a poorer sense of personal accomplishment. Negative work events contributed significantly to level of burnout; however, having a "hardy" personality helped to alleviate burnout. Nurses reported more physical symptoms than house staff and oncologists. However, they were less emotionally distant from patients. Women reported a lower sense of accomplishment and greater distress. The four most frequent methods of relaxing were talking to friends, using humor, drinking coffee or eating, and watching television. One unexpected finding was that the greater the perception of oneself as religious, the lower the level of burnout. Thus, while the rewards of working in oncology are usually sufficient to keep nurses and doctors in the field, they also experience burnout symptoms that vary by gender and personal attributes. House staff are most stressed and report the greatest and most severe symptoms of stress. Interventions are needed that address the specific problems of each group.

Adult↗
PubMed1999

Evaluation of truncated areas in the assessment of bioequivalence of immediate release formulations of drugs with long half-lives and of Cmax with different dissolution rates.

PURPOSE: To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for drugs with long half-lives and to study the relationship between Cmax and in vitro dissolution rates. METHODS: Monte-Carlo simulations were conducted using actual mean plasma concentrations of five long half-life drug products. The simulations were based on a catenary pharmacokinetic system in which the drug disposition in the body was represented by a one-or two-compartment model, characterizing the observed mean profiles. The influence of dramatic changes in the in vitro dissolution rate constant 'kd', was simulated in scenarios consisting of 20 crossover trials with 24 subjects per trial, comparing a fast dissolving reference and a hypothetical, slow dissolving test formulation. RESULTS: The AUC's truncated after the completion of distribution phase were found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the Cmax measure was insensitive to the changes in the in vitro dissolution rate. The Cmax measure was found to be useful in the bioequivalence assessment since it reflected both the rate and extent of absorption. (Cmax/AUCt) measure was specific to absorption rate. CONCLUSIONS: For the bioequivalence determination of long half-life drug products, (1) the use of truncated AUC's after completion of the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may be insensitive to input rate changes, if the absorption rate is not constrained by the input rate in relation to the distribution or elimination rate. (3) (Cmax/AUCt) may be more specific to 'ka' differences, but Cmax reflects differences in both rate and extent of absorption.

Area Under Curve↗
PubMed1999

Population pharmacokinetics. A regulatory perspective.

The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).

Data Interpretation, Statistical↗
PubMed1998

Evaluation of bioequivalence of highly variable drugs using clinical trial simulations. II: Comparison of single and multiple-dose trials using AUC and Cmax.

PURPOSE: Evaluating of the effects of high intrasubject variability in clearance (CL) and volume of distribution (V), on 90% confidence intervals (CIs) for AUC (Area Under the concentration Curve) in single and multiple-dose bioequivalence studies. The main methodology was Monte Carlo simulation, and we also used deterministic simulation, and examination of clinical trials. The results are compared with those previously observed for Cmax (maximum concentration.) METHODS: The time course of drug concentration in plasma was simulated using a one-compartment model with log-normal statistical distributions of intersubject and intrasubject variabilities in the pharmacokinetic parameters. Both immediate-release and prolonged-release products were simulated using several levels of intrasubject variability in single-dose and multiple-dose studies. Simulations of 2000 clinical bioequivalence trials per condition (138 conditions) with 30 subjects in each crossover trial were carried out. Simulated data were compared with data from actual bioequivalence trials. RESULTS: The current simulations for AUC show similar probabilities of failure for single-dose and multiple-dose bioequivalence studies, even with differences in the rate of absorption or fraction absorbed. AUC values from prolonged-release scenario studies are more sensitive to changes in the first order absorption rate constant ka, and to variability in CL and V than AUC from studies of immediate-release studies. CONCLUSIONS: We showed that multiple-dose designs for highly variable drugs do not always reduce intrasubject variability in either AUC or Cmax, although the behavior of AUC differs from Cmax. Single dose AUC to the last quantifiable concentration was more reliable than either single dose AUC extrapolated to infinity, or multiple dose AUC during a steady-state interval. Multiple-dose designs may not be the best solution for assessing bioequivalence of highly variable drugs.

Area Under Curve↗
PubMed1997

Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG 400 determined by jejunal perfusion.

PURPOSE: To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards. METHODS: Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation. RESULTS: The mean P(eff) (+/-SD) of piroxicam, phenylalanine, propranolol, and PEG 400 were 10.40 +/- 5.93, 6.67 +/- 3.42, 3.59 +/- 1.60, 0.80 0.46 x 10(-4) cm/sec, respectively. The coefficient of variation for the intersubject variability, first and second perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine, 52.8% and 57.8%; propranolol, 62.1% and 44.6%; and PEG 400, 81.7% and 42.3%, indicating a slightly lower CV for the second perfusion period in the same subject. The intrasubject CV's between the two perfusion periods were: 19.4%, 21.3%, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied. CONCLUSIONS: Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.

Adult↗
PubMed1994

Psychotropic medications in oncology and in AIDS patients.

This chapter has reviewed the prevalence of cancer and of psychiatric syndromes in the cancer setting. Guidelines have been given for the evaluation and treatment of specific psychiatric syndromes, as well as several special problems found in the cancer setting. In general, the major principle of using psychiatric medications in the patient with cancer or advanced AIDS is to use them to improve comfort, and not to withhold them when they may be of benefit.

AIDS Dementia Complex↗
PubMed1992

The effects of age on the pharmacokinetics and biotransformation of theophylline in vivo and in vitro in the Mongolian gerbil (Meriones unguiculatus).

The effect of post maturational aging on the in vivo disposition of theophylline was examined in the Mongolian gerbils (Meriones unguiculatus) aged 30-39 (old), 12-18 (middle-aged) and 3 (young) months following a 20 mg/kg i.p. dose. Biotransformation of theophylline was also examined in liver microsomes from non-induced and 3-methylcholanthrene induced gerbils. Analysis of theophylline plasma kinetics showed decreased clearance, increased half-life and increased volume of distribution in old vs. young animals. Clearance to the 1,3-dimethyluric acid metabolite was similar for all age groups, while clearance to the 1-methyluric acid metabolite was significantly lower in the middle-aged group compared to that of young and old gerbils. Urinary recovery of 1-methylurate was increased in old vs. young and middle-aged animals while recovery of theophylline was decreased. 3-Methylcholanthrene induction resulted in decreased recovery of theophylline and increased recovery of 1,3-dimethylurate and 1-methylurate in young and middle-aged gerbils compared to non-induced controls. Decreased microsomal protein content was observed in old vs. young and middle-aged gerbils and an age-related decrease in cytochrome P-450 content (nmol P-450/g liver) was also observed. The rate of dimethylurate formation was decreased 37% in microsomes from old vs. young and middle-aged gerbils. 3-Methylcholanthrene administration resulted in a 2- and 1.5-fold increase in the rate of 1,3-dimethylurate formation in young and middle-aged gerbils, respectively. The results of these experiments indicate that the Mongolian gerbil may be useful for the study of the biochemical mechanisms underlying age-related changes in the biotransformation and kinetics of theophylline.

Aging↗
PubMed1991

Alterations in self-perceptions among adolescent cancer survivors.

Psychosocial adjustment in adolescent cancer survivors has been documented to be quite variable. Factors mediating adjustment need to be identified. The current study is an exploration of the impact that cancer diagnosis and treatment has on adolescent's self-perceptions and the role this has in mediating adjustment in this group. Fifty-eight adolescent survivors of hematologic malignancies were interviewed about alterations in self-perceptions related to their cancer experience and completed a cancer-specific social problem-solving task. Initial findings suggest that cancer universally alters the way adolescent survivors view themselves, but that the alteration can be both positive or negative depending on the meaning ascribed to it.

Adaptation, Psychological↗
PubMed1988

Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. A randomized study.

STUDY OBJECTIVE: To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis. DESIGN: Prospective randomized, double-blind 6-month trial. PATIENTS: Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy. INTERVENTIONS: Patients were randomly assigned to high-dose (10 mg/kg body weight.d) or low-dose (1 mg/kg.d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months. MEASUREMENTS AND MAIN RESULTS: At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0.02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physician's global scores (-1.5; CI, -2.1 to -0.9) and patient's global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97). CONCLUSIONS: Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.

Adult↗