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Biomedical subjects

A Mrhar

Publications and source records attributed to A Mrhar.

At least 37 records · Page 2Linked to original sources
PubMed1999

Interdependence of histamine and methylhistamine kinetics: modelling and simulation approach.

In the article a model of histamine kinetics is described. A motivation of this project was to investigate the hypothesis that methylhistamine may be a marker of histamine appearance in plasma. A model has been made to support the hypothesis. Since metabolic and transport pathways of histamine and methylhistamine are complex and not very well known, the relationship between histamine and methylhistamine should be elucidated by mathematical modelling. From experimental data and the information in the literature, a nonlinear and time-varying four-compartment model is proposed. Extensive release of histamine from mast cells when methylhistamine is injected, is modelled as histamine to methylhistamine ratio control loop.

Biomarkers↗
PubMed1999

Influence of fever on the pharmacokinetics of ciprofloxacin.

The influence of fever on the pharmacokinetics of ciprofloxacin was investigated in seven patients with acute febrile diseases. Antibiotic serum concentrations were determined using high-performance liquid chromatograpy (HPLC). The analog computer and the Simulink software package were used to identify the pharmacokinetic model and Penoclin software package to obtain the secondary parameters. During fever, higher maximum serum concentrations (Cmax) of ciprofloxacin were observed in six out of seven patients. The result suggests that the influence of fever on the pharmacodynamics of ciprofloxacin is favorable.

Adult↗
PubMed1999

Influence of fever on cefazolin pharmacokinetics.

The influence of fever on the pharmacokinetics of cefazolin was investigated in patients with acute febrile diseases. Nine patients were included in the study. Antibiotic serum concentrations were determined using high performance liquid chromatograpy (HPLC). An analog computer and the SIMULINK software package were used to identify the pharmacokinetic model and PCNONLIN software package to obtain the secondary parameters. In 6 patients a two-compartment pharmacokinetic model of cefazolin was observed during fever and after defervescence. In 2 patients a two-compartment model changed to a one-compartment after defervescence, and a one-compartment model was observed in one patient during both periods. Cefazolin-treated patients with a two-compartment model (6/9) had higher Cmax, mean steady state serum concentrations (Css), and area under the plasma concentration-time curve (AUC(0-->infinity)), smaller central compartment volume (V1), and lower clearance (Cl) during fever. The varying distribution of antibiotics during fever probably reflects different hemodynamic responses to fever.

Adult↗
PubMed1998

The role of pharmacokinetic modelling and computer simulation in drug formulation design.

The purpose of this study is to develop a formulation for a once-a-day peroral application with controlled release of nitrendipine. The second aim of the study is to define by the use of modelling and computer simulation those critical points in the development of the formulation, the knowledge and controlling of which brings a rationalisation in the sense of time and material.

Administration, Oral↗
PubMed1994

Mercury toxicokinetics in Wistar rats exposed to elemental mercury vapour: modeling and computer simulation.

The kinetics of total mercury (Hg) absorption, distribution and elimination in Wistar rats exposed for long periods to elemental mercury vapour (Hg zero) in the Idrija mercury mine were studied. From the experimental data base a compartmental model was built as a framework for experimental data interpretation and prediction of organ mercury levels under different conditions. Using the model the exposures of rats under conditions comparable to those of professionally exposed workers (mercury miners, workers in the chloralkali industry) and individuals with amalgam fillings were simulated.

Animals↗
PubMed1991

Urodynamic modeling of norfloxacin pharmacokinetics by means of computer simulation.

Urodynamic model was developed which, in conjunction with a compartmental pharmacokinetic model, was used for study of factors influencing drug concentrations in urine: urine flow rate, residual bladder urine, maximal bladder urine, stage of renal failure, and elimination kinetics of drugs. Norfloxacin (NOR) was used as a model drug, although the model haw general applicability for all urinary antiseptics. Pharmacokinetic data were obtained from a clinical study in which norfloxacin was administered orally as a single 400mg dose to four subjects with installed urine catheters. Sample of blood, bladder and catheter urine were collected and concentrations of NOR measured by a HPCL method. Modeling was performed on analog--hybrid computer EAI 580. Besides the fitting of model response to obtained in vivo data, simulations of expected clinical situations were performed in which the interplay of above mentioned factors was studied in terms of urine concentrations profiles. NOR treatment with 400mg b.i.d. secured sufficient urine concentrations in most studied cases. This approach should be applied for corresponding study of other urinary antiseptics, especially those with less favourable urinary levels.

Chromatography, High Pressure Liquid↗
PubMed1991

Biopharmaceutic evaluation of some 4-quinolone derivatives.

The relationships between physicochemical properties (ionization, solubility, partition, protein binding) of 4-quinolone derivatives and their pharmacokinetics was studied by means of in vitro methods. This information is needed to clarify the erratic absorption behaviour of quinolone antibacterials following oral administration. The ionization constants of ofloxacin (OF), pefloxacin (PF), norfloxacin (NF) and ciprofloxacin (CF) were determined by solubility, potentiometric, spectrophotometric, and octanol-water partition methods. The quinolones are ampholytes showing small values of partition coefficients (order of magnitude 1) resulting from their hydrophilic nature. Within the series, both partition coefficients and the ionization constants differ only slightly (5.5 less than pK1 less than 6.5, and 7.5 less than pK2 less than 8.5). The intrinsic solubility of nonionized forms of drugs was obtained to be of 1g/l order of magnitude. Linear relationship was observed between the log solubility versus reciprocal temperature. The dissolution of NF is an endothermic reaction with dissolution enthalpy H = 20.4 kJ/mol. In vitro diffusion of OF, PF, NF, and CF was studied by the means of Sartorius in vitro absorption model. The rate of diffusion and the projected in vitro rate of absorption are not functions of structural differences within the series (diffusion rate constant range was 0.5 less than kd less than 5.0 .10-3 cm/min). Binding of NF, CF, PF and OF to bovine serum albumin (BSA) was studied using equilibrium dialysis in the absence and presence of urea. It was found that the quinolones were moderately bound (40-60%) to BSA and that urea in pathologic concentrations diminished their binding for 10-25%.

4-Quinolones↗
PubMed1990

Computer simulation of ciprofloxacin pharmacokinetics in patients on CAPD.

Continuous ambulatory peritoneal dialysis (CAPD) has become an accepted alternative to chronic hemodialysis in the treatment of end-stage renal disease. The method utilizes the diffusion of drugs from the blood through the peritoneal membrane to the peritoneal cavity if administered intravenously (IV) and perorally (PO) and in the opposite direction if applied intraperitoneally (IP). The present work uses an open, two-compartment pharmacokinetic model reversibly linked with the compartment representing the peritoneal cavity and an analog-hybrid computer to simulate drug levels in sampled and unsampled compartments under conditions of various routes of administration (IV, IP and sequential IV, IP and PO) and different clinical status (presence and absence of peritonitis). The drug chosen for simulation was ciprofloxacin (CIP), a new synthetic antibacterial agent of the 4-quinolone group. Eight patients were included in the study, and CIP concentrations in plasma and dialysate were obtained by HPLC analysis to assess the reliability of the model and the efficiency of the sequential dosing scheme. CIP plasma and dialysate levels were adequate for the majority of microbes causing CAPD peritonitis. The proposed regimen was efficient in 85% of cases.

Administration, Oral↗
PubMed1987

Bioavailability of piroxicam: oral and rectal multiple application in humans.

The aim of the work is to evaluate the bioequivalence of piroxicam administered orally and rectally in 20 mg dose every 24 hours. The corresponding "in vivo" study was undertaken and plasma samples were collected during the ninth dosing interval. HPLC method was used for piroxicam plasma concentrations determination. AUC and C were calculated and the obtained data were statistically analyzed. Analog-hybrid simulation was used to confirm additionally the similarity between the discussed formulations. No significant differences were observed using paired t-test and two-way analysis of variance while the methods of Hauck and Westlake, looking strictly, gave nonbioequivalence. Simulated response of one compartment model is suitable for "in vivo" data in both cases. Measured and simulated average steady state concentrations are equal and in complete accordance with those given in literature. Finally it can be concluded that oral and rectal application are bioequivalent in the sense of expected clinical effects.

Administration, Oral↗
PubMed1983

Quantitative high-performance thin-layer chromatographic analysis of ampicillin in human urine.

A quantitative high-performance thin-layer chromatographic (HPTLC) method was developed for the analysis of ampicillin in urine. A dioxane-water-n-butanol-formic acid mobile phase system and HPTLC Silica gel 60 F254 as stationary phase were used. Quantitation was realized on a Zeiss PMQ 2 densitometer connected to a Varian A-25 recorder and an Apple II microcomputer or alternatively with an HP 9830A computer and HP 9862A plotter. A good linear range of detection (0.05-1.00 micrograms) at 480 nm was obtained. Standard statistical methods demonstrated good reproducibility (coefficient of variation is not greater than 3%). The method is appropriate for ampicillin quality control and pharmacokinetic studies.

Ampicillin↗
PubMed1983

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration.

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.

Administration, Oral↗
PubMed1983

Dihydroergosine pharmacokinetic modelling and simulation.

For this study of dihydroergosine pharmacokinetic modelling and simulation, the data from our paper about 3H-DHESN plasma, bile, urine, and faeces concentrations after intravenous and oral administration were used (1). The model obtained with the identified parameters was in agreement with in vivo data. Certain special phenomena, such as the enterohepatic cycle and incomplete absorption, were taken into account. Analog-hybrid simulation and identification represents an effective tool for such studies. In spite of the limited validity of the available in vivo data, the work represents a first step in the introduction of DHESN into human medicine.

Administration, Oral↗
PubMed1979

Clinical pharmacokinetics of nitroxoline.

14C-Nitroxoline was given orally to the rats, and its distribution as well as plasma and bile levels were determined autoradiographically and by the aid of radioactivity measurements, respectively. Nitroxoline was also given to the human volunteers orally and intravenously in three various doses and the corresponding urine concentrations of unconjugated and conjugated nitroxoline were determined spectrophotometrically. A pharmacokinetical model was generated on the basis of the results. The curve fitting procedure between total nitroxoline cumulative quantities in urine and the model response simulated on analog-hybrid computer enabled the evaluation of the validity of the chosen model as well as of the identification of its parameters.

Adult↗
PubMed1979

Appropriate nitroxoline dosage regimen design.

Clinically used dosage regimen of nitroxoline, three times 100 mg daily, was proved to be inappropriate because the successfulness of medical treatment was rarely sufficient. Nitroxoline, used as urinary antiseptic, exhibits its antibacterial activity in concentrations higher than 6 mg/l, as demonstrated in many "in vitro" experiments. This work deals with the most appropriate nitroxoline dosage form as well as with the optimal dosage regimen design. The data were obtained by the aid of the suitable pharmacokinetic model and multiple dosing simulation on analog-hybrid computer EAI 580. From the several studied alternatives two usable dosage forms with the necessary dose and corresponding dosage interval were selected.

Anti-Infective Agents, Urinary↗
PubMedDate not supplied

The bioavailability of oral nifedipine formulations: a statistical and simulation approach.

The bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t-test, Hauck's inverted t-test, and Westlake's method of confidence intervals). Analogue-hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.

Adult↗
PubMedDate not supplied

Formulation of controlled release microspheres containing nicardipine: the role of pharmacokinetic modeling and computer simulation.

Nicardipine is an antihypertensive drug of the dihydropyridine series. It has high solubility in an acidic and low solubility in an alkaline medium. It is rapidly absorbed, extensively presystemically metabolized and excreted in the urine and faeces, mainly as inactive metabolites. Since the duration of its action can be extended by prolonging the absorption interval, the design of controlled release formulation is reasonable. The aim of the present study was to prepare microspheres which would release nicardipine at a decreased rate in gastric and increased rate in intestinal juice during a 12 h interval. Pharmacokinetic modeling based on compartment analysis and supported by analog computer and digital simulation technique showed that the target steady state peak plasma concentrations of 32 microg/l and trough plasma concentration of 7 microg/l would be maintained if nicardipine were incorporated in a formulation releasing the drug as follows: 25% after 1 h, 40% after 2 h, 65% after 4 h, 80% after 6 h, 90% after 8 h and 100% by 12 h. Microspheres have been prepared from hydroxypropylmethylcellulose phthalate polymer using the solvent evaporation method. Drug content, scanning electron micrographs, particle size distribution and dissolution profile were determined. In vitro nicardipine release was described by a biphasic square root of time kinetics and was in accordance with the above values relating to the dissolution. Furthermore, a composed first-pass pharmacokinetic model with derived release function as an input was developed to predict nicardipine plasma concentrations after single- and 12 h multiple-dosage-regimen scheme administration of controlled release microspheres.

Antihypertensive Agents↗
PubMedDate not supplied

Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach.

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.

Acetaminophen↗