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Biomedical subjects

H Ehrsson

Publications and source records attributed to H Ehrsson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Pharmacokinetics of peptichemio in myeloma patients: release of m-L-sarcolysin in vivo and in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each of which contains the alkylating residue m-[di(2-chloroethyl)amino]-L-phenylalanine (L-mSL). The fate of PTC was investigated in eight patients with multiple myeloma after intravenous infusion of the drug. The quantitative analysis of the plasma samples was performed by liquid chromatography with fluorometric detection. L-mSL was rapidly released from the peptides and reached its maximal plasma concentration at the end of the infusion. Its median elimination half-life was 1.73 (range, 0.72-2.41) h. It was possible to follow the concentration of only one of the peptides, L-mSL-L-Arg(NO2)-L-Nval.OEt, during and shortly after the infusion of PTC. The stability of L-mSL and the peptides was studied in buffer solution (pH 7.3), plasma, and blood. The stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min. We conclude that L-mSL plays an important role in the mechanism of action of PTC.

Aged↗
PubMed1992

In vivo distribution of [11C]-busulfan in cynomolgus monkey and in the brain of a human patient.

The in vivo distribution of the antileukemic agent busulfan labeled with the positron-emitting radionuclide carbon 11 was investigated in cynomolgus monkeys and in a human patient using positron emission tomography. After i.v. injection of the radiotracer, its regional uptake was monitored for about 1 h in the monkey's body and, in a separate experiment, in the monkey's brain. The concentration of radioactivity in the liver, which showed the highest levels of all the organs scanned, increased throughout the experiment and was 9-fold that in the brain at the end of the experiment. [11C]-Busulfan rapidly crossed the blood-brain barrier. The radioactivity peaked in both the cortex and the white matter showing a ratio of 1.25, at 3 min but declined quickly to yield a ratio of approximately 1 after 30 min. In the human brain, radioactivity in the cerebellum, cortex, and white matter reached a maximum within 5 min showing a cortex:white matter ratio of 1.6. The activity in the cortex declined to yield a ratio of 1 within 30 min. Of the delivered dose, 20% penetrated into the brain.

Adult↗
PubMed1991

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology.

Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg x 4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged less than 5 years (237 ng ml-1) was lower than that observed in adults or older children (607 and 573 ng ml-1, respectively). The AUC for the last dose was significantly lower in young children (2.315 h ng ml-1) than in adults or older children (6,134 and 5,937 h ng ml-1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min-1 kg-1) as compared with both older children and adults (3.02 and 2.7 ml min-1 kg-1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.

Adolescent↗
PubMed1991

Efficacy of peptide bound m-L-sarcolysin (peptichemio) on melphalan resistant human myeloma cells in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each containing the alkylating agent m-di(2-chloroethyl)amino-phenylalanine. Freshly obtained myeloma cell infiltrated human bone marrow specimens were in parallel exposed to melphalan and PTC. The cytotoxic effect of the drugs on the myeloma cells of each specimen was measured by the differential staining culture method (DISC). PTC displayed higher cytotoxicity to the myeloma cells as compared to melphalan in all 12 cases analysed. The increase of the cytotoxic effect of PTC compared to melphalan varied between different cases. In melphalan resistant cases the cytotoxic effect of PTC as compared to melphalan was clearly significant (P = 0.001).

Aged↗
PubMed1990

Oral melphalan pharmacokinetics: influence of interferon-induced fever.

The influence of interferon-induced fever on oral melphalan pharmacokinetics has been studied in 10 myeloma patients in a randomized crossover design. The melphalan dose (0.25 mg/kg) was given alone and 5 hours after the administration of human interferon alpha (7 x 10(6) IU/m2), respectively. The plasma concentration of melphalan was determined by liquid chromatography with fluorometric detection after derivatization of melphalan with N-acetylcysteine. The area under the plasma concentration-time curve (AUC) was significantly lower (p = 0.02) when melphalan was given with interferon. There was a significant negative correlation (p = 0.008) between body temperature and dose normalized AUC, whereas no effect was noticed on the maximum plasma concentration (Cmax) and on the time to obtain Cmax. The rate of elimination showed a tendency (p = 0.06) to increase with increasing body temperature. It is suggested that the cytotoxicity of the drug is most probably enhanced because of the higher alkylating activity of the compound at elevated body temperatures.

Aged↗
PubMed1989

Pharmacokinetic and metabolic studies of high-dose busulphan in adults.

The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg.kg-1 every 6 h for 4 days. The mean steady-state plasma concentration was 1080 ng/ml-1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment. The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine. For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.

Adult↗
PubMed1989

Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma.

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.

Administration, Oral↗
PubMed1989

Pharmacokinetics of oral melphalan in relation to renal function in multiple myeloma patients.

The impact of renal function on oral melphalan pharmacokinetics was studied in 15 patients with multiple myeloma. A two-fold interindividual variation in the plasma concentration-time curve (AUC) was found. An increase in AUC and melphalan mean residence time (MRT) was noted in patients with renal dysfunction. No correlation was found between GFR and the terminal plasma half-life time. We conclude from these results that renal dysfunction is associated with an increase in AUC and MRT of oral melphalan. A careful follow-up of hematological toxicity and possibly a dose reduction of melphalan are proposed for myeloma patients with renal impairment.

Aged↗
PubMed1989

Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy.

A patient with acute myeloblastic leukemia received high-dose busulfan (1 mg/kg by mouth every 6 h for 4 days) as myelo-ablative therapy for autologous bone marrow transplantation. Rapid entry of busulfan into the cerebrospinal fluid (CSF) was observed. Plasma and CSF concentrations of busulfan were comparable during the 4 days of treatment. The elimination half-lives of busulfan in plasma and CSF were 2.6 h and 2.8 h respectively during the first 12 h after the last dose.

Bone Marrow Transplantation↗
PubMed1988

Effect of D,L-buthionine-S,R-sulfoximine on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic drugs in human melanoma cells.

The effects of D,L-buthionine-S,R-sulfoximine (BSO) on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) were investigated. RPMI 8322 cells were exposed to 0.01 mM BSO for 24 h, which resulted in a decrease in cellular glutathione to 14% without any reduction of cell proliferation or plating efficiency. BSO pretreatment significantly enhanced cytotoxicity of melphalan with a dose modification factor (DMF) of 3.4 and nitrogen mustard (HN2) (DMF 3.3). The increased cytotoxicity was paralleled by similar increases in DNA cross-linking (melphalan: DMF 2.2, HN2: DNF 2.5). A small but significant potentiation by BSO of cis-diamminedichloroplatinum(II) toxicity was seen (DMF 1.5), with a corresponding minor but significant increase in DNA cross-linking (DMF 1.1). Similarly, the potentiation of bis-chloroethylnitrosurea toxicity was small but significant (DMF 1.1), with no significant increase in DNA cross-linking (DMF 1.0). No effect of BSO pretreatment on the rate of removal of HN2-induced DNA cross-links was observed. Thus, the observed sensitization of RPMI 8322 cells to melphalan, HN2, cis-diamminedichloroplatinum(II), and bis-chloroethylnitrosourea was correlated to similar changes in drug-induced DNA cross-linking. Despite the increased cytotoxicity and DNA cross-linking BSO did not significantly increase the intracellular concentration of intact melphalan. These findings support the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets.

Antineoplastic Agents↗
PubMed1988

Inter- and intraindividual differences in oral chlorambucil pharmacokinetics.

Inter- and intraindividual variation in the pharmacokinetics of oral chlorambucil was investigated in patients with chronic lymphocytic leukaemia. Five patients were given in randomized order 15, 40, 60 and 70 mg chlorambucil p.o. and plasma was analyzed for chlorambucil and its cytotoxic metabolite phenyl acetic acid mustard. The area under the plasma concentration-time curve of chlorambucil varied two- to fourfold between patients at each dose level. The AUC of the metabolite was higher and showed twofold interindividual variation. The intraindividual dose-corrected AUCcs also varied twofold. No dose dependency of the dose corrected AUC was seen either for chlorambucil or the metabolite. Elimination of both compounds form plasma was rapid, with half-lives of 1.01 and 1.94, respectively.

Administration, Oral↗
PubMed1988

Concentration and time-dependent inter-relationships for cytotoxicities of nitrogen mustard drugs against lymphoblasts in-vitro.

Peripheral lymphoblasts were exposed either to different initial concentrations of the alkylating agents (melphalan, chlorambucil or phenylacetic acid mustard) using a fixed incubation time or a constant [3H]methylthymidine incorporation into the trichloracetic acid-insoluble fraction of the cells. The concentration-time relationships were evaluated by calculating the amount of drug which had chemically reacted in the incubation system. Melphalan showed lower cytotoxicity at short exposure times and high drug concentrations, while chlorambucil exhibited higher cytotoxicity at longer exposure times. In the latter case the effect could be accounted for by the cytotoxic activity of monohydroxy chlorambucil which was formed in the incubation system.

Cell Survival↗
PubMed1988

Concentration of trimethylpsoralen in blood and skin after oral administration.

Trimethylpsoralen (TMP) concentrations were determined in blood and skin of 21 patients given oral TMP therapy and were compared to data obtained from 5 patients treated with TMP baths. The quantitative determination was performed by gas chromatography with selected ion monitoring. Concentrations of up to 5.6 ng/ml were detected in whole blood from orally TMP treated patients, with about the same concentrations in patients given TMP baths. Whole skin biopsies from patients ingesting TMP showed concentrations in 14 patients that ranged from 30 to 1250 ng/g skin, median value 85 ng/g. Large interindividual variations were observed. Stripped skin from 5 patients after TMP baths showed a somewhat higher median value of 160 ng/g and their entire skin had fairly high concentrations, with a median value of 390 ng/g, probably mostly bound to stratum corneum. Different concentrations in different parts of the skin may explain the difference in phototoxic capacity when the drug is given locally.

Administration, Oral↗
PubMed1987

Differential DNA cross-linking and cytotoxicity in PHA-stimulated human lymphocytes exposed to melphalan, m-L-sarcolysin and peptichemio.

DNA interstrand, as well as DNA protein cross-linking, was more efficient in phytohaemagglutinin-stimulated human lymphocytes exposed to m-L-sarcolysin as compared to melphalan at equivalent concentrations of the drug. The cellular uptake of m-L-sarcolysin was more efficient as compared to melphalan. With peptichemio, a mixture of 6 peptides containing m-L-sarcolysin, an intermediate level of DNA cross-linking was found. The differences in DNA cross-linking between the 3 drugs were parallel to differences in cytotoxicity. Peptichemio has been ascribed anti-metabolic properties in addition to the alkylating properties conferred by its m-L-sarcolysin content. In the phytohaemagglutinin-stimulated lymphocytes, however, the effect of peptichemio seems linked to its capacity for DNA cross-linking.

Cell Survival↗