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L Dedík

Publications and source records attributed to L Dedík.

At least 19 recordsLinked to original sources
PubMed2002

System approach to modeling metabolite formation from parent drug: a working example with methotrexate.

The aim of this methodological study was to present and exemplify a system-approach-based technology in modeling the formation of the metabolite from the parent drug. To represent this process, the parent-metabolite dynamic system was defined in such a way that the concentration-time profile of the parent drug was considered the input, while the concentration-time profile of the metabolite the output, of this system. The system-approach-based modeling technology was used to determine the model of the parent-metabolite dynamic system and to obtain the model-based estimates of the rate of metabolite formation, the rate of metabolic ratio and the mean time of metabolite formation. The technology was applied to concentration data for methotrexate and 7-hydroxymethotrexate in patients with psoriasis after a single oral methotrexate dose. Third-order linear models were selected as optimal to approximate the parent-metabolite dynamic systems representing the formation of 7-hydroxymethotrexate from methotrexate of these patients. The model-based estimates of the metabolic ratios ranged from 0.53 to 0.95. The model-based estimates of the mean times of formation of 7-hydroxymethotrexate from methotrexate ranged from 9.13 to 25.13 h. The model-based estimates of the rates of formation of 7-hydroxymethotrexate from methotrexate reached peak values (ranging from 0.03 to 0.11 h-1) in the time interval 1.5-4.5 h after administration of methotraxate. This study does not only introduce the method that may be useful in gaining insight into metabolite formation, but also presents a new example of the methodological, conceptual and computational uniformity of the system-approach-based technology in modeling various biomedical systems.

Administration, Oral↗
PubMed2001

Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

PURPOSE: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III. METHODS: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model. RESULTS: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms). CONCLUSION: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

Administration, Oral↗
PubMed2001

Modeling drug absorption from enteric-coated granules.

A system-approach-based method is proposed for modeling drug absorption from enteric-coated granules. This method was exemplified using enteric-coated granules of aspirin given to healthy subjects. Based on the results obtained, it can be concluded that absorption of salicylate from the granules can be sufficiently described using a first-order linear model with an absorption rate constant of salicylate similar to that reported for an aqueous solution of aspirin administered orally to healthy subjects. The method proposed in this study may contribute to the working library of modeling techniques in pharmacokinetics since it allows direct modeling of the drug absorption process and estimates the absorption rate constant of a drug when its behavior in the body is significantly influenced by a gastric emptying process. i.e., when the absorption rate constant of the drug cannot be estimated on the basis of its cumulative absorption-time profile.

Aspirin↗
PubMed2000

Weighting function used for adjustment of multiple-bolus drug dosing.

This paper presents a new method for the adjustment of the multiple-bolus dosing of a drug. The method is based on the weighting function of the system describing the behavior (absorption, distribution and elimination) of the drug in the patient, identified employing a test dose administration of the drug to a patient. This method can be employed for the adjustment of the multiple-bolus dosing of the drugs whose behavior in the patient can be sufficiently described by linear time invariant models. The method allows to estimate loading and maintenance bolus doses of the drug, necessary to reach and maintain prescribed trough levels of the drug in a patient at desired time-points, both (the levels and time-points) specified by treatment requirements. The method is particularly suitable for the adjustment of multiple-bolus dosing of drugs with narrow therapeutical windows or of very expensive products such as the clotting factors. The method is exemplified by the adjustment of the multiple-bolus dosing of factor VIII in postoperative treatment of hemophilia A.

Dosage Forms↗
PubMed1999

Model of lymphocyte migration in Merino ewes under physiological conditions.

The paper presents an example of a new type of a structured model containing time delays in parallel branches. This model was selected as optimal to describe mathematically the lymphocyte migration between the venous blood and prescapular lymph in Merino ewes under physiological conditions. The model allowed to identify and quantify several lymphocyte fractions exhibiting different migration dynamics.

Animals↗
PubMed1998

[Osteoporosis in multiple myeloma].

The problem of osteoporosis is world-wide in people above 50 years of age. As this period is also a risk period for the development of multiple myeloma or other malignant processes, comprehensive differential diagnosis of malignant and benign osteoporosis is essential. By retrospective analysis of a 12-year group of 270 patients treated by chemotherapy on account of multiple myeloma the authors selected a group of 151 patients treated in addition to chemotherapy and immunomodulating drugs (mixture of proteolytic enzymes-Wobe Mugos) for 2-3 years, also with biphosphonates. At the time ofdiagnosis osteoporosis was in 24.5% patients the only finding on bones. When biphosphonates (Bonefos, Ibandronate) and chemotherapy were administered during a three-year observation period the bone process was stable in 61.59%, osseous changes disappeared in 11.26% and progression of osteolysis was recorded in 27.15%. The objective of the work was to emphasize the importance of a correct diagnosis of osseous changes which can progress even in clinically asymptomatic myelomas.

Diagnosis, Differential↗
PubMed1998

Pharmacokinetics of factor VIII in hemophilia A patients assessed by frequency response method.

The frequency response method, having its mathematical underpinnings in the theory of linear dynamic systems, was utilized to model pharmacokinetic systems describing the fate of factor VIII (F VIII) administered to hemophilia A patients before surgery. The pharmacokinetic system was defined on the basis of the patient's data in such a way that the injection of F VIII during 5-15 min was considered the input, and the corresponding plasma F VIII concentration profile consisting of both the injection and post-injection part the output of this system. The approach is an alternative to routine procedures based only on evaluation of the post-injection part of the F VIII concentration profile. With respect to the common sampling schedule of F VIII, simple second-order models were found acceptable for all the patients involved in the study. However, in the patients whose plasma F VIII concentration profiles did not decrease monotonously after the injection, these models failed to approximate secondary peaks indicating the presence of time delays in F VIII kinetics. The results obtained were discussed with respect to applications of pharmacokinetic models for the adjusted dose continuous infusion of F VIII in hemophilia A patients during and after surgical interventions.

Adolescent↗
PubMed1997

Modeling in frequency domain used for assessment of in vivo dissolution profile.

PURPOSE: To present a model-dependent approach for the assessment of the in vivo drug dissolution profile based on in vitro data for the multiple unit dosage form, as an alternative to the numerical method proposed in the study by Hayashi et al., Pharm Res. 12:1333-1337 (1995). METHODS: The data for aspirin granules administered to healthy subjects obtained in the above mentioned study were re-evaluated. The subject dissolution system was considered to consist of two subsystems connected in series, i.e. the subsystem describing the gastric-emptying process and the subsystem describing the intestinal dissolution process. The frequency response method was used to model the subject dissolution system. RESULTS: The model in vivo dissolution profile of aspirin, assessed as the integral of the model weighting function of the subject dissolution system, was in agreement with the in vivo cumulative absorption profile calculated by the Wagner-Nelson method. CONCLUSIONS: Comparison of dynamic properties of the subject dissolution system with the subsystem describing the gastric-emptying process yielded quantitative confirmation of the decisive role of the gastric-emptying process in the in vivo drug dissolution after administration in the multi unit dosage form.

Models, Chemical↗
PubMed1996

CXT-MAIN: a software package for determination of the analytical form of the pharmacokinetic system weighting function.

A new procedure specific for the determination of the analytical form of the model weighting function of a complex multicomponent pharmacokinetic system with or without a shunt and time delays is described. The procedure is based on the theory of linear dynamic systems and on a circulatory pharmacokinetic model of the living body. The model transfer function of the system under study was obtained by the frequency response method in the form of the ratio of two frequency dependent polynomials. Subsequently, the technique of the partial fraction inversion was employed to determine the analytical form of the model weighting function. Two examples from bioavailability studies in pharmacokinetics are given. The first example presents two estimates of the model weighting function of a pharmacokinetic system obtained by the new procedure and by a polyexponential deconvolution method. To compare these results, two models of the measured system output were determined using the two estimates of the model weighting function, the actual system input and a convolution method. The model weighting function obtained by the new procedure yielded a better model approximation of the output data than that obtained by the polyexponential deconvolution method. The second example, using the new procedure, presents the determination of the model weighting function of such a system that the deconvolution methods, commonly used in pharmacokinetics, cannot be applied to.

Administration, Oral↗
PubMed1995

Building a structured model of a complex pharmacokinetic system with time delays.

This paper presents a description of the procedure for building a structured model of a complex pharmacokinetic system on using its transfer function. The example employed is that of the pharmacokinetic system based on gentamicin plasma concentrations after intravenous and intratracheal administration to guinea pigs, describing the pathway of the drug into the systemic circulation after the extravascular injection mentioned. The structured model selected consisted of a submodel of a proportional linear subsystem, two submodels of simple linear dynamic subsystems with time constants of 0.135 +/- 0.065 hr (95% I.C.) and 0.052 +/- 0.049 hr, and two submodels of parallel subsystems with time delays of 0.25 +/- 0.046 hr and 1.135 +/- 0.288 hr, connected in serial. Two estimates of the mean residence time of the total amount of gentamicin in the system, i.e., 0.347 and 0.335 hr, were obtained, based on the system frequency and structured model, respectively. From the methodological point of view, our paper demonstrates the efficiency of combination of modelling in the frequency and in the time domain, designed to facilitate studies of pharmacokinetic systems.

Administration, Oral↗
PubMed1995

CXT: a programme for analysis of linear dynamic systems in the frequency domain.

In this paper, the computer programme CXT (CompleX Tools for Linear Dynamic System Analysis), using the frequency response method, is described and exemplified. The method is based on the approximation of the frequency response of the linear or linearised dynamic system, measured or calculated from input-output measurements, by the frequency model of the system transfer function in the form of the ratio of two frequency-dependent polynomials. The form of the programme is sufficiently general to permit application in many areas, e.g., in modelling linear or linearised dynamic biological systems consisting of several subsystems arranged in serial and/or parallel fashion, with or without time delays. The programme is a menu-driven software taking data from a keyboard or disk file to produce outputs on a screen, printer, or disk file in tables and plots. The programme can run interactively or in an automatic tutorial mode, under DOS and/or WINDOWS. Numerical examples are taken from pharmacokinetics and indocyanine green liver function tests.

Humans↗
PubMed1995

[Transplacental transfer of stobadine in rabbits in various stages of pregnancy--an approximation using a pharmacokinetic model].

Stobadine (STB), a cardioprotective drug, was investigated for its placental transfer in rabbits on the 20th and 27th day of gestation. The concentration of 3H-STB and its metabolites was determined in maternal and foetal plasma and organs at 0.5; 1; 2; and 6 h after the oral administration of 5 mg/kg STB. The third and fifth order linear models were selected as the optimal models of the fate of STB in the maternal plasma at the 20th and 27th day of gestation, respectively. The high order of the latter model indicated recirculation of STB in the maternal body at the last stage of gestation. The concentrations of STB and its metabolites in the uterus were found to be higher at mid- than late-pregnancy. At the 27th day of pregnancy the concentration of STB and its metabolites were higher in all foetal organs than on the concentrations at the 20th day of pregnancy, indicating active placental barrier function in mid-pregnancy.

Animals↗
PubMed1994

Frequency response method in pharmacokinetics.

The paper presents the demonstration of applicability of the frequency response method in a bioavailability study. The frequency response method, common in system engineering, is based on an approximation of the frequency response of a linear dynamic system, calculated from input-output measurements, by a frequency model of the system transfer function in the frequency domain. In general, the influence of the system structure on the form of the system frequency response is much more distinct than on the form of the system output. This is of great advantage in modeling the system frequency response instead of the system output, commonly used in pharmacokinetics. After a brief theoretical section, the method is demonstrated on the estimation of the rate and extent of gentamicin bioavailability after intratracheal administration to guinea pigs. The optimal frequency model of the system describing the gentamicin pathway into the systemic circulation and point estimates of its parameters were selected by the approximation of the system frequency response in the frequency domain, using a noniterative algorithm. Two similar estimates of the system weighing function were independently obtained: the weighting function of the selected frequency model and the weighting function estimated by the numerical deconvolution procedure. Neither of the estimates of the weighting function does decrease monotonously after the maximum of about 2.2-2.5 unit of dose hr-1 recorded approximately 0.1 hr after drug administration. Both estimates show a marked additional peak approximately at 0.3 hr after administration and possible peaks in the further time period. We hypothesized that the loop found in the frequency response calculated and in the selected optimal frequency model, the high-order of this model, and several peaks identified in the estimates of the system weighting function indicated the complexity of the system and the presence of time delays. Three estimates of the extent of gentamicin intratracheal bioavailability obtained by the three different ways: directly from the calculated frequency response, calculated using the selected frequency model, and by the deconvolution method were 0.950, 0.934, and 0.907 respectively. Thus the conclusion can be made that gentamicin injected intratracheally to guinea pigs is almost completely available.

Animals↗
PubMed1994

Comparative study of human pentacaine pharmacokinetics in time and frequency domain.

Basic principles of the frequency response method are outlined. The method is based on the approximation of the transfer function of the linear dynamic system, measured or calculated from the input-output measurements, by the frequency model in the form of a ratio of polynomials in the frequency domain. The application of the method in pharmacokinetics is demonstrated on the data obtained from the phase I clinical trial of pentacaine, a carbanilate type local anesthetic recently recognized as an antiulcer agent. The results obtained in the conventional compartment analysis of the data were compared with those obtained by the frequency response method. It was demonstrated that better model approximations of the measured concentration data were obtained by the frequency response method than by the compartment method in all subjects participating in the trial.

Anesthetics, Local↗
PubMed1994

[Long-term survival in multiple myeloma].

The authors present the results of 23-year protocol studies of survival with multiple myeloma, focused on problems of perspective long-term survival. Of 535 diagnosed patients between 1970 and 1990 the authors checked regularly and treated 475. In addition to 60 latent forms where treatment was administered only when clinical symptoms developed or after progression of laboratory signs, to all patients treatment was administered according to protocols (monotherapy-cyclophosphamide prednisone in 1970-1975 only to 30 patients, the remainder had combined treatment--COPP, VMCP, MOCCA); in the third stage of the disease MOCCA treatment is better. The median of survival of patients after VMCP treatment (in stage II) MOCCA (in stage III) is more than 90 months, 15% survive for more than 10 years. The authors emphasize the importance of combined intensive treatment of patients for the prognosis of survival. Long-term experience revealed that patients achieve an objective response in 85%, while the risk of leukaemic and cancerogenic complications is low (1.1%). The therapeutic effect and survival period are favourably affected by immunomodulation treatment (Interferon, proteolytic enzymes, thymus factor).

Adult↗
PubMed1993

SURVIVAL--an integrated software package for survival curve estimation and statistical comparison of survival rates of two groups of patients or experimental animals.

SURVIVAL, a new integrated software package for survival curve estimation and statistical comparison of survival rates of two censored or uncensored groups of patients or experimental animals, is described and demonstrated. The software is based on the calculation of the Kaplan-Meier estimates of survival curves and utilizes the Mantel-Haenszel and/or Fisher's test for the statistical comparison of the corresponding survival rates. SURVIVAL can be used for statistical evaluation of survival data obtained either on sequentially created or fixed size groups. The software is menu driven to provide a very user friendly tool for analyzing survival data. It may be of great value mainly in clinical use because it automatically enables evaluation of a large set of survival data, sequentially collected in SURVIVAL's own database during a long survival study, with entry and evaluation possible at any time during the study.

Animals↗