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Biomedical subjects

I Bartosek

Publications and source records attributed to I Bartosek.

At least 19 recordsLinked to original sources
PubMed1991

Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma.

The plasma and tissue pharmacokinetics of fotemustine (diethyl-1-[3-(2-chlorethyl)-3-nitrosoureido]-ethylphosphonate+ ++) and BCNU (1,3-bis-[2-chlorethyl]-1-nitrosourea) were investigated in healthy control rats and in animals bearing either the nitrosourea-sensitive line A (W256/A) or the nitrosourea-resistant line B (W256/B) of Walker 256 carcinoma. The antitumor activities of these nitrosoureas were similar following i.v. doses ranging from 10 to 40 mg/kg. For both drugs, the survival of tumor-bearing rats was lower in the W256/B than in the sensitive W256/A line. Some sex differences were observed, female rats being more responsive than males to both drugs. Nitrosourea concentrations were assayed in plasma and tissues by differential pulse polarography so as to assess whether the pharmacokinetics could explain the differences in antitumor activity. The antineoplastic effects of fotemustine seemed to be influenced by its pharmacokinetics. The plasma AUC of the intact nitrosourea was higher in females than in males. Fotemustine was cleared 2-5 times more slowly than BCNU from tumor tissue, and its clearance was higher in W256/B- than in W256/A-bearing rats. This suggests that the antitumor activity in the responsive line might partly be due to longer exposure of the growing tumor to the drug. The distribution volume of both nitrosoureas in plasma was higher in tumor-bearing animals than in healthy controls, indicating that the tumor tissue probably constitutes an additional distribution space.

Animals↗
PubMed1991

Glutathione restores normal cell activation and cell cycle progression in cis-platinum treated human lymphocytes.

Cis-platinum (CDDP) induces severe inhibition of cell activation and cell cycle progression in PHA-stimulated human PBL's. Applying the novel BrdU/Hoechst flow cytometric technique for high resolution cell cycle analysis we show that CDDP induced multiple cell kinetic disturbances occur simultaneously comprising G0/G1-arrest, and slow down and arrest of cells in S and G2/M-phase. We investigated whether the administration of reduced glutathione (GSH) might rescue cells from proliferative disturbances induced by CDDP. GSH at 0.15 mg ml-1 only partially restored normal cell activation and cell cycle progression. However, at 1.5 mg ml-1 a complete normal proliferation pattern was obtained. At the highest GSH dose rescue from inhibition of cell activation (G0/G1-phase arrest) as well as of cell cycle progression (S- and G2/M-phase arrest) was also present after delayed addition of GSH (1, 4 and 20 h) to CDDP treated PBL's. In addition cell viability of CDDP exposed PBL's is restored after GSH treatment. Our in vitro experiments give evidence that an increase of WBC found in CDDP/GSH treated patients has a real underlying cellular physiological mechanism protecting human peripheral lymphocytes from CDDP toxicity.

Bromodeoxyuridine↗
PubMed1991

Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection.

1. A differential pulse polarographic (DDP) assay of diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido] ethylphosphonate (fotemustine) was developed to determine the kinetics of this nitrosourea in plasma, brain, liver, lung and kidney. The optimized polarographic determination, previously applied to BCNU and CCNU, attained a limit of detection of 0.3 micrograms fotemustine/ml plasma and 1 microgram/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0.5 and 100 micrograms/ml. 2. The choice of electrolyte, the effects of pH, temperature, light, and the stability of fotemustine in samples were investigated. Recovery of fotemustine was 76-90% from lung greater than kidney greater than plasma greater than brain greater than liver; the variability coefficients were low (4.0-7.3%). Tissue samples could be stored for 20 days at -20 degrees C without loss of the compound. 3. Plasma kinetics of fotemustine and BCNU given to male rats at therapeutic doses (20 mg/kg i.v.) fitted a bi-exponential equation. Two minutes after injection plasma, levels of unchanged nitrosoureas were 15 and 11 micrograms/ml respectively. Fotemustine could be measured (0.92 microgram/ml) for 3 h, while BCNU could not be detected after 60 min. Unchanged fotemustine was cleared from the blood stream 3-5 times more slowly than BCNU.

Animals↗
PubMed1991

First dose and steady state pharmacokinetics of nimesulide and its 4-hydroxy metabolite in healthy volunteers.

The pharmacokinetics of nimesulide (4-nitro-2-phenoxymethane-sulfonanilide, NMS), a non-steroidal antiinflammatory drug, and of its 4-hydroxy metabolite (4-nitro-2-(4'-hydroxy-phenoxy)-methane sulfonanilide, OH-NMS) was studied after a single oral dose (200 mg) and after repeated treatments (100 mg every 12 hours for 7 days) of NMS to two groups of 12 healthy volunteers. Plasma concentrations of NMS and OH-NMS were followed for 48 hours after the single dose and up to the 12th hour on the 1st day and on the 7th day during repeated treatment. After the single dose of 200 mg peak plasma concentrations of the drug (9.85 micrograms/ml) were reached at 3.17 hours and the half-life during the elimination phase was 4.95 hours. The metabolite reached highest plasma levels (3.03 micrograms/ml) at 5.33 hours and its apparent half-life was similar to that of the parent drug (4.78 hours). NMS plasma levels on the 7th day, predicted from the results of the 1st day, were similar to the measured values. The pharmacokinetics of NMS or OH-NMS after single or repeated dose was not time or dose dependent.

Adult↗
PubMed1990

Bone invasion by Walker 256 carcinoma, line A in young and adult rats: effects of etidronate.

Line A of Walker 256 carcinoma implanted in the muscle adjacent to the tibia of young (6 weeks) and adult (9 months) male rats invaded the bone. Osteolysis and reactive growth were greater in the bone of young animals than in adults. Ethane-1-hydroxy-1, 1-bisphosphonate prevented bone lysis and tumor invasion of the cortex both in young and adult animals. This model may be useful for studies of age-related differences in tumor infiltration into the bone and for investigating drug effects on this process.

Age Factors↗
PubMed1989

Doxorubicin toxicity and pharmacokinetics in old and young rats.

Doxorubicin (Dx) toxicity was compared in old (24 months) and young (6 weeks) Crl:CD(SD) BR male rats, and a clear age-related increase was found. The mortality of all animals receiving a single i.v. Dx dose was followed for 270 days. Old rats died after doses of 2.5 mg/kg, while young animals died after doses two times higher, 5 mg/kg. In old rats body weight loss started 10 to 15 days after Dx, compared to 50 to 80 days for young animals. In young and old rats pharmacokinetic and metabolic studies of Dx were conducted in vivo and in the liver perfusion model. Peak levels of Dx and areas under the time/concentration curves (AUC) in serum and in several tissues of old rats were 1.5 to 2 times higher than in young rats. Concentrations of Dx metabolites in serum and tissues (doxorubicinol, Dxol, and doxorubicinone, Dxone) in young and old rats were not noteworthy. However, higher percentages of Dxone than Dxol were found in both groups in vivo and in vitro. Old livers appeared to produce more Dxone as a percentage, particularly in the bile, which was higher. Urinary elimination of Dx markedly slowed with age; only small amounts of the metabolites were eliminated in urine. In vivo and in vitro availability of Dx and its metabolites is discussed in view of their possible role in the greater toxicity observed in 24-month-old rats.

Aging↗
PubMed1988

Toxicity, uptake, and subcellular distribution in rat hepatocytes of roxithromycin, a new semisynthetic macrolide, and erythromycin base.

Rat hepatocytes were used to study the toxicity of a new semisynthetic macrolide, roxithromycin, in comparison with erythromycin base and erythromycin estolate. Roxithromycin caused lactate dehydrogenase leakage close to that of erythromycin estolate and higher than erythromycin base after 21 h of exposure to the drugs. This effect was, at least in part, explained by the higher uptake: roxithromycin was two to three times more concentrated by liver cells than erythromycin base. For both roxithromycin and erythromycin base, the uptake depended on time, temperature, and extracellular antibiotic concentration. The accumulated macrolides egressed rapidly when cells were incubated in antibiotic-free medium. No uptake and no loss of accumulated drugs were observed at 4 degrees C. After accumulation by hepatocytes, roxithromycin and erythromycin base underwent similar subcellular distribution, mostly concentrating in cytosol and lysosomes. The small amount accumulated in the other particulate fractions followed the order mitochondria much greater than nuclei greater than microsomes. Roxithromycin, however, was less concentrated than erythromycin base in the microsomes.

Animals↗
PubMed1988

Effects of roxithromycin, a new semisynthetic macrolide, and two erythromycins on drug metabolizing enzymes in rat liver.

The effects of a new semisynthetic macrolide, roxithromycin, on drug metabolizing enzymes of rat liver were compared with two erythromycins, the base (EB) and the estolate (EE), after 7 days' treatment with high oral doses (400 and 800 mg/kg daily). Dose-related higher concentrations of roxithromycin were reached in serum and liver than after EB or EE. The two reference erythromycins induced the synthesis of microsomal enzymes and formed inactive cytochrome P-450-metabolite complexes. N-Demethylation of erythromycin itself and aminopyrine was increased by the treatment. Liver microsomal enzyme activities were not induced and the inactive cytochrome P-450-metabolite complex was not formed after 400 mg/kg of roxithromycin and only to a very limited extent after 800 mg/kg (10% vs. 50% after EE). At the higher dose microsomal activities were not changed by roxithromycin and only aminopyrine N-demethylation was reduced.

Animals↗
PubMed1986

Non-linear fitting program for biological data.

A simple microcomputer program written in Microsoft Basic estimates pharmacokinetic parameters using the coordinate search technique to minimize the sum of squared errors. The program developed for portable computers combines a plot of data and curve fitting so as to find rapidly the initial parameters with the subsequent optimization of the parameter estimate.

Computers↗
PubMed1986

L-asparaginase effects on inhibition of protein synthesis and lowering of the glutamine content in cultured rat hepatocytes.

Primary cultures of rat hepatocytes were exposed to various concentrations of L-asparaginase derived from Escherichia Coli. Protein synthesis was inhibited by about 33% and cellular glutamine was reduced proportionally to the enzyme concentration. However, protein synthesis was inhibited only by amounts of enzyme able to reduce glutamine to critical levels below 10 nmol/mg cell protein. These data suggest that the glutaminase activity which probably contaminates E. coli asparaginase may be responsible for reduced liver protein synthesis.

Animals↗
PubMed1986

Different sensitivity of two Walker 256 carcinoma lines to cyclophosphamide: correlation with drug distribution, biotransformation and macromolecule binding.

Two closely related lines of the same Walker 256 carcinoma in Crl-CD/COBS rats, described as behaving differently as regards tumor growth and host reaction, show different chemotherapeutic sensitivity to cyclophosphamide (CPA). Line B, which induces early cachexia with marked anorexia, is only moderately sensitive to CPA, while line A, which causes mild anorexia and only terminal cachexia, shows marked responsiveness to CPA, cure being attained in 75% of animals treated with a single dose of 120 mg/kg and in 90-100% of those given 20 mg/kg every other day. Comparative studies in both tumor lines on the distribution of CPA in vivo and on its metabolism by the liver perfusion technique showed no appreciable differences between the two lines in the pharmacokinetics of the compound, but indicate a much greater metabolizing capacity of CPA in the Walker 256/A animals. In vitro metabolic and covalent binding studies confirm that the liver of the Walker 256/A group metabolizes and covalently binds twice as much CPA as the liver of the Walker 256/B group. Conversely to Walker B, microsomal preparations of the Walker tumor line A are able to metabolize CPA to intermediates which irreversibly bind to tissue macromolecules, suggesting an in situ activation of the compound in the sensitive Walker tumor.

Animals↗
PubMed1986

Effects of a new fluorinated macrolide (P-0501A) and other erythromycins on drug metabolizing enzymes in rat liver.

The effects of a new fluorinated macrolide (P-0501A) on drug metabolizing enzymes of rat liver were compared with three erythromycins--the base, the stearate and the estolate--after 7 days of dosing (1.36 mmol/kg po daily). The three erythromycins induced the synthesis of microsomal enzymes, but the products of their metabolism inactivated cytochrome P-450 in the order base less than or equal to stearate less than estolate. N-Demethylation of erythromycin and aminopyrine increased, while O-demethylation of 4-nitroanisole was reduced and hydroxylation of aniline was not changed after in vivo treatment. Pentobarbital sleeping time was prolonged and liver glutathione levels were lower in treated rats than in controls. In contrast to the three erythromycins, P-0501A did not induce the synthesis of microsomal enzymes, did not form an inactive complex with cytochrome P-450 and did not affect mono-oxygenase activities or pentobarbital narcosis.

Administration, Oral↗
PubMed1986

Effects of in vivo treatment with a new fluorinated macrolide (P-0501A) and other erythromycins on drug clearance and hepatic functions in perfused rat liver.

The hepatic clearance and the effects of a new fluorinated macrolide (P-0501A) on the functions of the isolated, perfused rat liver were compared with two known erythromycins--the base and the estolate--after 7 days of treatment (1.36 mmol/kg po daily). The in vitro metabolism of the antibiotics was induced to different extent but only the base and P-0501A were cleared from the perfusate and the liver faster than in untreated animals. In untreated rats the therapeutically active form of P-0501A was excreted in the bile more than the base and the estolate; after pretreatment, biliary excretion of all erythromycins was nearly double. The content of inactive, complexed cytochrome P-450 was increased only by the base and estolate, with various effects on microsomal activities (some induced, e.g. aminopyrine demethylation, other reduced, e.g. pentobarbital clearance). The clearance and biliary excretion of sulphobromophthalein was not affected by treatment with P-0501A or the base, but was significantly reduced by estolate.

Animals↗
PubMed1985

Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver.

The metabolism of VP16 was studied in isolated perfused rat liver. The rate of elimination into the medium and excretion in bile were determined by h.p.l.c. with u.v. detection. With high VP16 concentrations (180 micrograms/ml medium), the elimination half-life of the compound was prolonged markedly (156 v. 45 min for lower doses), the percentage recovered in bile was more than halved and drug accumulation in the hepatic tissue was three times greater. These findings indicate saturation of metabolism and of biliary elimination during high-dose treatment. The presence of glucuronides in the bile of VP16 perfused livers indicates that VP16 undergoes conjugation with glucuronic acid. Formation of picro isomer of VP16 in the liver also occurs.

Animals↗
PubMed1985

An experimental rat model of local bone cancer invasion and its responsiveness to ethane-1-hydroxy-1,1-bis(phosphonate).

Line A Walker carcinoma differs from line B in that it does not elicit hypercalcemia and hypercalciuria when implanted in rats at various sites (s.c, i.m., intraaortically). However, Walker 256/A, unlike line B, may invade the tibia when implanted i.m. in the adjacent gastrocnemius muscle. This invasion was evaluated by measuring the increased weight of the bone and decreased calcium concentration per unit weight of the tibia, by reduced opacity to X-ray, and by the presence of tumor cells in the compact bone cortex. Ethane-1-hydroxy-1,1-bis(phosphonate), a diphosphonate derivative, at a dose of 10 to 30 mg/kg/day s.c., prevented cancer cell invasion of the tibia as judged by the above criteria. This inhibition was obtained with no apparent effect on the growth of Walker 256/A carcinoma.

Animals↗
PubMed1979

Kinetics of S-adenosyl-L-methionine in isolated perfused rat liver and its effects on microsomal enzyme activity.

S-Adenosyl-L-methionine (SAMe) levels in liver tissue were reduced by 35% after isolation and washing of the organ. The apparent half-life of SAMe (1,75-25 microM) during liver perfusion was between 120 and 460 min; however the uptake of the labelled methyl group by hepatic tissue of fed rats was low (6%). This value increased to 12% in organs isolated from 24-hour fasted animals. Addition of SAMe to the perfusion medium increased tissue levels of ATP. Except for N-demethylation of aminopyrine and cytochrome c reductase, liver microsomal activity was not affected by treatment with SAMe either in vivo or/and in perfused liver.

Adenosine Triphosphate↗
PubMed1978

Differential plus polarographic determination of submicrogram quantities of carmustine and related compounds in biological samples.

A polarographic method was developed to determine the antineoplastic agent carmustine and other nitrosoureas, such as N-methyl-N-nitrosourea and N-cyclohexyl-N-nitrosourea, in biological fluids at levels well below 1 microgram/ml or g. The stability of carmustine in different media was investigated to prevent losses during administration or assay. Examples of nitrosourea determination in biological samples are given.

Animals↗