EP1037618A1 - Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents - Google Patents

Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents

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Publication number
EP1037618A1
EP1037618A1 EP99969331A EP99969331A EP1037618A1 EP 1037618 A1 EP1037618 A1 EP 1037618A1 EP 99969331 A EP99969331 A EP 99969331A EP 99969331 A EP99969331 A EP 99969331A EP 1037618 A1 EP1037618 A1 EP 1037618A1
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EP
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Prior art keywords
derivatives
methyluracil
side effects
nucleobases
nucleosides
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99969331A
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German (de)
French (fr)
Inventor
Iduna Fichtner
Peter Langen
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Publication of EP1037618A1 publication Critical patent/EP1037618A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

Definitions

  • nucleosides Use of nucleosides, nucleobases and their derivatives to reduce thrombocytopenic side effects of cytostatics
  • the invention relates to the use of nucleosides, nucleobases and their derivatives, in particular 6-methyluracil, for reducing thrombocytopenic side effects of cytostatics and combination preparations of nucleosides, nucleobases and their derivatives and cytostatics, in particular a combination preparation which contains at least one cytostatic and 6-methyluracil .
  • the cytostatics used for the treatment of tumor diseases in addition to their desired anti-tumor activity, generally have toxic side effects which limit the dose. Since the dose-effect curve for cytostatics is particularly steep, it would be advisable to choose the highest possible dose, but this cannot generally be applied because of the serious side effects that then occur.
  • hemopoietic growth factors eg for the stem cells of granulocytes and macrophages
  • the duration of the leukopenia period and thus the risk of infection could be reduced and the therapy optimized by increasing the dose of the cytostatics (F. Hansen : Hemopoietic growth and inhibitory factors in treatment of malignancies. A review. Acta Oncol. 34, 453-68 (1995)).
  • ERSA72B TT (RULE 26) The situation is different with thrombocytopenia. This is e.g. B. especially with new cytostatics, such as the platinum derivatives, for. B. Carboplatin, a particularly serious side effect (eg JF Delaloy, L. Tran, S. Leyvraz, J. Bauer, P. De-Grandl: Intraperitoneal carboplatin in advanced ovarian carcinoma. Gynecol-Obstetrics-Rundschau 33, 25-30 (1993 ); K. Bertelsen, L. Basthold: High-dose platinium chemotherapy in advanced ovarian cancer. Gynecol-Oncol. 44, 79-82 (1992)).
  • new cytostatics such as the platinum derivatives
  • B. Carboplatin a particularly serious side effect (eg JF Delaloy, L. Tran, S. Leyvraz, J. Bauer, P. De-Grandl: Intraperitoneal carboplatin in advanced ova
  • thrombocytopenia Attempts to limit the time and severity of thrombocytopenia through adjuvant drug administration are e.g. Currently still in the experimental stage. In analogy to the procedure for leukocytes, the growth factor for thrombocyte stem cells, thrombopoietin, is being experimentally tested. IL 2 is used in the same way (R. Hoffman, MW Long: Control of thrombocytoiesis. Cancer-Treat-Res. 80, 25-48 (1995); TP. McDonald: Thrombopoietin. Its biology, clinical aspects and possibilities. Am -J- Pediatr-Hematol-Oncol. 14, 8-21 (1992).
  • nucleobases, nucleosides and their derivatives had been shown to stimulate the proliferation of stem cells from granulocytes and macrophages and their regeneration after cytostatica treatment (Endoxan) (P. Langen, H. Schunk, B. Hunger, M. Schutt , OD Laerum: Adherent-cell-dependent stimulation of CFU-GM by nucleobases, nucleosides, their analogues and the hemoregulatory peptide dimer. Exp. Hematol. 20, 196-200 (1993). This was associated with a drastic reduction in the lethal effect highly toxic cans.
  • 6-methyluracil A particularly suitable representative of the substance group mentioned is 6-methyluracil. It has surprisingly been found that 6-methyluracil and other representatives of compounds of the formula I also reduce the thrombopenia caused by cytostatics. Such an effect could not be expected based on our own or literature findings.
  • R x OH or NH 2
  • R 2 H or alkyl
  • R 3 H, alkyl or COOH
  • R 4 H or optionally substituted deoxyribosyl
  • -ribosyl or -arabinosyl mean.
  • 6-Methyluracil can be used orally, cheaply and side effects have so far neither been observed by own experiments nor described in the literature. According to the results available to date, its use in combination with cytostatics is an important contribution to optimizing cancer chemotherapy.
  • the preferred doses for 6-methyluracil are 150 to 600 mg / kg • day, it being shown that a dose of 300 mg / kg • day works significantly better than half, while a further doubling 600 mg / kg • Day does not lead to any clear improvements. A dose of 300 mg / kg is therefore particularly preferred. Day 6-
  • REPLACEMENT BILL (RULE 26) Methyluracil applied. 6-Methyluracil is preferably used orally, although it can also be added to a drink.
  • the invention also relates to a combination preparation which contains at least one cytostatic and one nucleoside, a nucleobase or derivatives thereof of the general formula I.
  • R x OH or NH 2
  • R 2 H or alkyl
  • R 3 H, alkyl or COOH
  • R ⁇ H or optionally substituted deoxyribosyl -ribosyl or -arabinosyl,
  • the combination preparation contains carboplatin with auxiliaries, carriers and additives which are customary per se and 6-methyluracil also with auxiliaries, carriers and additives which are customary per se.
  • mice Female B6D2F1 mice (8 / experimental group) were treated with carboplatin ip one day after inoculating Lewis lung carcinoma cells. One test group each received 100, 150 or 175 mg / kg, the highest dose corresponding approximately to an LD 40 . Further carboplatin-treated test groups received an addition of 2.4 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein in the mice 10 days after treatment with carboplatin. The platelet count was determined using a Coulter Counter.
  • mice Female B6D2F1 mice (8 / experimental group) were treated with carboplatin ip one day after inoculating B16 melanoma cells. One test group each received 100 or 150 mg / kg, the highest dose corresponding approximately to an LD 10 . Further carboplatin-treated test groups received an addition of 1.2 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein from the mice 10 days after carboplatin treatment. The platelet count was determined using a Coulter Counter.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the use of nucleosides, nucleobases and their derivatives, especially 6-methyluracil, for reducing the thrombocytopenic side effects of cytostatic agents, and to combination preparations of nucleosides, nucleobases and their derivatives and cytostatic agents, especially carboplatin.

Description

Verwendung von Nucleosiden, Nucleobasen und deren Derivaten zum Herabsetzen thrombocytopenischer Nebenwirkungen von CytostatikaUse of nucleosides, nucleobases and their derivatives to reduce thrombocytopenic side effects of cytostatics
Beschreibungdescription
Die Erfindung betrifft die Verwendung von Nucleosiden, Nucleobasen und deren Derivaten, insbesondere von 6-Methyluracil, zum Herabsetzen thrombocytopenischer Nebenwirkungen von Cytostatika sowie Kombinationspräparate von Nucleosiden, Nucleobasen und deren Derivaten und Cytostatika, insbesondere ein Kombinationspräparat, das mindestens ein Cytostatikum und 6- Methyluracil enthält.The invention relates to the use of nucleosides, nucleobases and their derivatives, in particular 6-methyluracil, for reducing thrombocytopenic side effects of cytostatics and combination preparations of nucleosides, nucleobases and their derivatives and cytostatics, in particular a combination preparation which contains at least one cytostatic and 6-methyluracil .
Bekanntermaßen weisen die zur Behandlung von Tumorerkrankungen eingesetzten Cytostatika neben ihrer gewünschten anti- Tumorwirkung in der Regel toxische, die Dosis limitierende Nebenwirkungen auf. Da die Dosis-Effekt-Kurve bei Cytostatika besonders steil ist, wäre die Wahl einer möglichst hohen Dosis angezeigt, wie sie aber wegen dann gravierenden Nebenwirkungen im allgemeinen nicht appliziert werden kann.As is known, the cytostatics used for the treatment of tumor diseases, in addition to their desired anti-tumor activity, generally have toxic side effects which limit the dose. Since the dose-effect curve for cytostatics is particularly steep, it would be advisable to choose the highest possible dose, but this cannot generally be applied because of the serious side effects that then occur.
Im Vordergrund der Nebenwirkungen stehen starke Hemmwirkungen auf die Hämopoese, die zu einer Verminderung der Leukozyten und Thrombozyten führt (Leukopenie, e.g. Granulocytopenie, mit der Folge einer erhöhten Infektionsgefahr; Thrombocytope- nie mit der Folge einer bedrohlichen Verringerung der Blutgerinnung) .In the foreground of the side effects are strong inhibitory effects on hemopoiesis, which leads to a reduction in the number of leukocytes and thrombocytes (leukopenia, e.g. granulocytopenia, with the result of an increased risk of infection; thrombocytope, with the result of a threatening reduction in blood clotting).
Durch den Einsatz von gentechnisch produzierten hämopoeti- schen Wachstumsfaktoren (e.g. für die Stammzellen von Granu- locyten und Macrophagen) konnte die Dauer der Leukopenie- Periode und damit die Gefahr einer Infektion verringert und die Therapie durch Dosiserhöhung bei den Cytostatika optimiert werden (F. Hansen: Hemopoietic growth and inhibitory factors in treatment of malignancies. A review. Acta Oncol. 34, 453-68 (1995)).By using genetically engineered hemopoietic growth factors (eg for the stem cells of granulocytes and macrophages), the duration of the leukopenia period and thus the risk of infection could be reduced and the therapy optimized by increasing the dose of the cytostatics (F. Hansen : Hemopoietic growth and inhibitory factors in treatment of malignancies. A review. Acta Oncol. 34, 453-68 (1995)).
ERSA72B TT(REGEL26) Anders sieht die Situation bei der Thrombocytopenie aus. Diese ist z. B. insbesondere bei neuen Cytostatica, wie den Platin-Derivaten, z. B. Carboplatin, eine besonders gravierende Nebenwirkung (e.g. J.F. Delaloy, L. Tran, S. Leyvraz, J. Bauer, P. De-Grandl: Intraperitoneal carboplatin in advanced ovarian carcinoma. Gynecol-Geburtshilfliche-Rundschau 33, 25- 30 (1993); K. Bertelsen, L. Basthold: High-dose platinium chemotherapy in advanced ovarian cancer. Gynecol-Oncol . 44, 79-82 (1992)).ERSA72B TT (RULE 26) The situation is different with thrombocytopenia. This is e.g. B. especially with new cytostatics, such as the platinum derivatives, for. B. Carboplatin, a particularly serious side effect (eg JF Delaloy, L. Tran, S. Leyvraz, J. Bauer, P. De-Grandl: Intraperitoneal carboplatin in advanced ovarian carcinoma. Gynecol-Obstetrics-Rundschau 33, 25-30 (1993 ); K. Bertelsen, L. Basthold: High-dose platinium chemotherapy in advanced ovarian cancer. Gynecol-Oncol. 44, 79-82 (1992)).
Versuche, Zeit und Schwere der Thrombocytopenie durch adju- vante Arzneimittelgabe zu begrenzen sind z. Zt. noch im experimentellen Stadium. In analoger Weise zu dem Vorgehen bei Leukozyten befindet sich der Wachstumsfaktor für Thrombo- zyten-Stammzellen, das Thrombopoetin, in experimenteller Erprobung. In gleicher Weise wird auch IL 2 eingesetzt (R. Hoffman, M.W. Long: Control of thrombocytoiesis. Cancer- Treat-Res. 80, 25-48 (1995); T-P. McDonald: Thrombopoietin. Its biology, clinical aspects and possibilities. Am-J- Pediatr-Hematol-Oncol . 14, 8-21 (1992).Attempts to limit the time and severity of thrombocytopenia through adjuvant drug administration are e.g. Currently still in the experimental stage. In analogy to the procedure for leukocytes, the growth factor for thrombocyte stem cells, thrombopoietin, is being experimentally tested. IL 2 is used in the same way (R. Hoffman, MW Long: Control of thrombocytoiesis. Cancer-Treat-Res. 80, 25-48 (1995); TP. McDonald: Thrombopoietin. Its biology, clinical aspects and possibilities. Am -J- Pediatr-Hematol-Oncol. 14, 8-21 (1992).
Es ist festzustellen, daß es heute noch kein anerkanntes bzw. klinisch zugelassenes Mittel zur Begrenzung der Cytostatica- bedingten Thrombocytopenie gibt.It should be noted that there is as yet no recognized or clinically approved agent for limiting cytostatica-related thrombocytopenia.
In unseren früheren Untersuchungen hatten sich Nucleobasen, Nucleoside und deren Derivate davon als Stimulatoren der Vermehrung von Stammzellen von Granulocyten und Macrophagen und deren Reneration nach Cytostatica-Behandlung (Endoxan) erwiesen (P. Langen, H. Schunk, B. Hunger, M. Schutt, O.D. Laerum: Adherent-cell-dependent Stimulation of CFU-GM by nucleobases, nucleosides, their analogues and the hemoregulatory peptide dimer. Exp. Hematol. 20, 196-200 (1993). Das war verbunden mit einer drastischen Verringerung der letalen Wirkung hochtoxischer Dosen.In our previous studies, nucleobases, nucleosides and their derivatives had been shown to stimulate the proliferation of stem cells from granulocytes and macrophages and their regeneration after cytostatica treatment (Endoxan) (P. Langen, H. Schunk, B. Hunger, M. Schutt , OD Laerum: Adherent-cell-dependent stimulation of CFU-GM by nucleobases, nucleosides, their analogues and the hemoregulatory peptide dimer. Exp. Hematol. 20, 196-200 (1993). This was associated with a drastic reduction in the lethal effect highly toxic cans.
Ein besonders geeigneter Vertreter der genannten Substanzgruppe ist das 6-Methyluracil. Es wurde überraschend gefunden, daß 6-Methyluracil und weitere Vertreter von Verbindungen gemäß Formel I auch die durch Cytostatica bedingte Thrombopenie verringern. Eine solche Wirkung konnte weder nach den eigenen, noch nach Literatur- Befunden erwartet werden.A particularly suitable representative of the substance group mentioned is 6-methyluracil. It has surprisingly been found that 6-methyluracil and other representatives of compounds of the formula I also reduce the thrombopenia caused by cytostatics. Such an effect could not be expected based on our own or literature findings.
in derin the
Rx = OH oder NH2,R x = OH or NH 2 ,
R2 = H oder Alkyl,R 2 = H or alkyl,
R3 = H, Alkyl oder COOH undR 3 = H, alkyl or COOH and
R4 = H oder gegebenenfalls substituiertes DesoxyribosylR 4 = H or optionally substituted deoxyribosyl
-ribosyl oder -arabinosyl bedeuten.-ribosyl or -arabinosyl mean.
(6-Methyluracil RA = OH, R2 = H, R3 = Methyl, R4 = H)(6-methyluracil R A = OH, R 2 = H, R 3 = methyl, R 4 = H)
Die der Erfindung zugrunde liegenden Befunde wurden mit Carboplatin erhoben, dessen thrombocytopenische Wirkung besonders negativ für seine Anwendung ist.The findings on which the invention is based were obtained with carboplatin, the thrombocytopenic effect of which is particularly negative for its use.
6-Methyluracil ist oral anwendbar, billig und Nebenwirkungen wurden bisher weder nach eigenen Versuchen beobachtet noch in der Literatur beschrieben. Seine Anwendung in Kombination mit Cytostatica ist nach den bisher vorliegenden Befunden ein wichtiger Beitrag zur Optimierung der Krebs-Chemotherapie.6-Methyluracil can be used orally, cheaply and side effects have so far neither been observed by own experiments nor described in the literature. According to the results available to date, its use in combination with cytostatics is an important contribution to optimizing cancer chemotherapy.
Die bevorzugten Dosierungen für 6-Methyluracil liegen erfindungsgemäß bei 150 bis 600 mg/kg • Tag, wobei sich gezeigt hat, daß eine Dosis von 300 mg/kg • Tag deutlich besser wirkt als die Hälfte, während eine weitere Verdoppelung 600 mg/kg • Tag zu keinen eindeutigen Verbesserungen führt. Daher wird besonders bevorzugt eine Dosis von 300 mg/kg • Tag 6-According to the invention, the preferred doses for 6-methyluracil are 150 to 600 mg / kg • day, it being shown that a dose of 300 mg / kg • day works significantly better than half, while a further doubling 600 mg / kg • Day does not lead to any clear improvements. A dose of 300 mg / kg is therefore particularly preferred. Day 6-
ERSATCBIATT(REGEL26) Methyluracil appliziert. 6-Methyluracil wird dabei vorzugsweise oral angewendet, wobei es auch einem Getränk beigemischt werden kann.REPLACEMENT BILL (RULE 26) Methyluracil applied. 6-Methyluracil is preferably used orally, although it can also be added to a drink.
Gegenstand der Erfindung ist auch ein Kombinationspräparat, das mindestens ein Cytostatikum und ein Nucleosid, eine Nucleobase oder deren Derivate der allgemeinen Formel IThe invention also relates to a combination preparation which contains at least one cytostatic and one nucleoside, a nucleobase or derivatives thereof of the general formula I.
in der in the
Rx = OH oder NH2, R2 = H oder Alkyl, R3 = H, Alkyl oder COOH undR x = OH or NH 2 , R 2 = H or alkyl, R 3 = H, alkyl or COOH and
RΛ = H oder gegebenenfalls substituiertes Desoxyribosyl -ribosyl oder -arabinosyl bedeuten,R Λ = H or optionally substituted deoxyribosyl -ribosyl or -arabinosyl,
vorzugsweise in getrennten und gegebenenfalls in unterschiedlichen Darreichungsformen, enthält.preferably in separate and optionally in different dosage forms.
In einer bevorzugten Ausführungsvariante enthält das Kombinationspräparat Carboplatin mit gegebenenfalls an sich üblichen Hilfs-, Träger- und Zusatzstoffen und 6-Methyluracil ebenfalls mit gegebenenfalls an sich üblichen Hilfs-, Träger- und Zusatzstoffen.In a preferred embodiment variant, the combination preparation contains carboplatin with auxiliaries, carriers and additives which are customary per se and 6-methyluracil also with auxiliaries, carriers and additives which are customary per se.
Anschließend wird die Erfindung an Hand von Abbildungen näher erläutert. Legende zu Abbildung 1:The invention is then explained in more detail with reference to figures. Legend for Figure 1:
Weibliche B6D2F1 Mäuse ( 8/Versuchsgruppe) wurden einen Tag nach i.m. Inokulation von Lewis lung Carcinom-Zellen mit Carboplatin i.p. behandelt. Je eine Versuchsgruppe erhielt 100, 150 oder 175 mg/kg, wobei die höchste Dosierung etwa einer LD40 entsprach. Weitere Carboplatin-behandelten Versuchsgruppen erhielten in das normalerweise verabreichte Trinkwasser einen Zusatz von 2,4 mg/ml 6-Methyluracil. 10 Tage nach Car- boplatin-Behandlung wurde den Mäusen Blut aus der retroorbi- talen Vene entnommen. Die Bestimmung der Thombozytenzahlen erfolgte mittels Coulter Counter.Female B6D2F1 mice (8 / experimental group) were treated with carboplatin ip one day after inoculating Lewis lung carcinoma cells. One test group each received 100, 150 or 175 mg / kg, the highest dose corresponding approximately to an LD 40 . Further carboplatin-treated test groups received an addition of 2.4 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein in the mice 10 days after treatment with carboplatin. The platelet count was determined using a Coulter Counter.
Legende zu Abbildung 2:Legend for Figure 2:
Weibliche B6D2F1 Mäuse (8/Versuchsgruppe) wurden einen Tag nach i.m. Inokulation von B16Melanom-Zellen mit Carboplatin i.p. behandelt. Je eine Versuchsgruppe erhielt 100 oder 150 mg/kg, wobei die höchste Dosierung etwa einer LD10 entsprach. Weitere Carboplatin-behandelten Versuchsgruppen erhielten in das normalerweise verabreichte Trinkwasser einen Zusatz von 1,2 mg/ml 6-Methyluracil. 10 Tage nach Carboplatin-Behandlung wurde den Mäusen Blut aus der retroorbitalen Vene entnommen. Die Bestimmung der Thombozytenzahlen erfolgte mittels Coulter Counter. Female B6D2F1 mice (8 / experimental group) were treated with carboplatin ip one day after inoculating B16 melanoma cells. One test group each received 100 or 150 mg / kg, the highest dose corresponding approximately to an LD 10 . Further carboplatin-treated test groups received an addition of 1.2 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein from the mice 10 days after carboplatin treatment. The platelet count was determined using a Coulter Counter.

Claims

Patentansprücheclaims
1. Verwendung von Nucleosiden, Nucleobasen und deren Derivaten der allgemeinen Formel I1. Use of nucleosides, nucleobases and their derivatives of the general formula I
in. der in the
Rx = OH oder NH2,R x = OH or NH 2 ,
R2 = H oder Alkyl,R 2 = H or alkyl,
R3 = H, Alkyl oder COOH undR 3 = H, alkyl or COOH and
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl ,R 4 = H or optionally substituted deoxyribosyl,
-ribosyl oder -arabinosyl bedeuten, zum Herabsenken thrombocytopenischer Nebenwirkungen von Cytostatika.-ribosyl or -arabinosyl mean to lower thrombocytopenic side effects of cytostatics.
Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß 6-Methyluracil I, Rx = OH, R2 = H, R3 = Methyl, R4 = H eingesetzt wird.Use according to claim 1, characterized in that 6-methyluracil I, R x = OH, R 2 = H, R 3 = methyl, R 4 = H is used.
Verwendung nach Anspruch 2, dadurch gekennzeichnet, daß das 6-Methyluracil oral appliziert wird.Use according to claim 2, characterized in that the 6-methyluracil is administered orally.
4. Verwendung nach einem der Ansprüche 1 bis 3 , dadurch gekennzeichnet, daß 6-Methyluracil in einer Dosis von 150 bis 600 mg/kg • Tag, vorzugsweise 300 mg/kg • Tag appliziert wird. Kombinationspräparat enthaltend mindestens ein Cytostati- kum und ein Nucleosid, eine Nucleobase oder deren Derivate der allgemeinen Formel I4. Use according to one of claims 1 to 3, characterized in that 6-methyluracil is applied in a dose of 150 to 600 mg / kg • day, preferably 300 mg / kg • day. Combination preparation containing at least one cytostatic and a nucleoside, a nucleobase or their derivatives of the general formula I
in der in the
Rα- = OH oder NH2,R α- = OH or NH 2 ,
R2 = H oder Alkyl,R 2 = H or alkyl,
R3 = H, Alkyl oder COOH undR 3 = H, alkyl or COOH and
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl ,R 4 = H or optionally substituted deoxyribosyl,
-ribosyl oder -arabinosyl bedeuten, zum Herabsenken der thrombocytopenisehen Nebenwirkungen der Cytostatika.-ribosyl or -arabinosyl mean to lower the thrombocytopenic side effects of the cytostatics.
Kombinationspräparat nach Anspruch 5, dadurch gekennzeichnet, daß es Carboplatin und 6-Methyluracil enthält.Combination preparation according to claim 5, characterized in that it contains carboplatin and 6-methyluracil.
Kombinationspräparat nach Anspruch 5 oder 6, dadurch gekennzeichnet, daß es Cytostatika und ein Nucleosid, eine Nucleobase oder deren Derivate gemäß Anspruch 5 in getrennten und gegebenenfalls unterschiedlichen Darreichungsformen mit an sich üblichen pharmazeutischen Hilfs-,Träger- und Zusatzstoffen enthält. Combination preparation according to claim 5 or 6, characterized in that it contains cytostatics and a nucleoside, a nucleobase or their derivatives according to claim 5 in separate and optionally different dosage forms with conventional pharmaceutical auxiliaries, carriers and additives.
EP99969331A 1998-09-17 1999-09-16 Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents Withdrawn EP1037618A1 (en)

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PCT/DE1999/002944 WO2000016753A2 (en) 1998-09-17 1999-09-16 Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents

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