[Pharmacokinetic study of dibromodulcitol in children with brain tumors]. / A dibrómdulcit farmakokinetikai vizsgálata agytumoros gyermekekben.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic studies on Elobromol in children with brain tumors.

Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70-6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The biological activity of cisplatin and dibromodulcitol in combination therapy.

The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.

Treatment of malignant scala posterior brain tumors in children: the chemotherapy of relapsed medulloblastoma with a dibromdulcitol containing drug regime and pharmacokinetic studies of dibromdulcitol in children.

Dibromdulcitol (Elobromol) has favorable pharmacokinetic parameters for the treatment of brain tumors: high spinal fluid/plasma ratio and long half-life in spinal fluid. Oral application makes its administration easy. The drug combination vincristine, procarbazine, and dibromdulcitol proved to be effective in a pilot trial on relapsed medulloblastomas: 8 complete and 4 partial remissions were achieved from 16 cases. The main side effect was granulocytopenia, which was in some cases severe. However, in the dose-schedule we used it did not delay the treatment longer than 1 week.