WO1996030024A1 - The pharmaceutical composition containing the 1,3,2-oxazaphosphorinane and mesna for the cancer treatment - Google Patents
The pharmaceutical composition containing the 1,3,2-oxazaphosphorinane and mesna for the cancer treatment Download PDFInfo
- Publication number
- WO1996030024A1 WO1996030024A1 PCT/PL1996/000005 PL9600005W WO9630024A1 WO 1996030024 A1 WO1996030024 A1 WO 1996030024A1 PL 9600005 W PL9600005 W PL 9600005W WO 9630024 A1 WO9630024 A1 WO 9630024A1
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- Prior art keywords
- oxazaphosphorinane
- mesna
- derivative
- pharmaceutical composition
- sodium
- Prior art date
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Classifications
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
Definitions
- This invention relates to the pharmaceutical composition with anti-cancer activity, the use of the 1,3,2-oxaza- phosphorinane derivatives and the etod of cancer treatment.
- 1,3,2-oxazaphosphorinane derivatives described in EP 0295576B1 have urotoxic activity, manifested by toxic swelling of urinary bladders in mice as indicated by increased bladder weight and organ wall oedema. Although intensity of these changes varied depending on the dosage and route of administration, this effect can restrict the effective dose and clinical effective- ness of the medicament.
- 1,3,2-oxazaphosphorinane derivatives together with sodium 2-mercaptoethanosulfonate also known under the name mesna.
- administration of 1,3,2-oxazaphosphorinane derivatives together with mesna has additional beneficial effect, namely it potentiates therapeutic activity of these 1,3,2-oxazapho- sphorinane derivatives and therefore may allow to lower their dosage.
- Fig. 1 shows urotoxic activity of racemic (CBM-4A) and S-(-) (CBM-11) forms of chlorobromofosfamide in comparison with ifosfamide after administration of single therapeutic doses.
- Fig. 2 is a bar diagram showing changes of the urinary bladders weight in mice after intraperitoneal (IP) or oral (PO) administration of racemic and S-(-) forms of chlorobro- mofosfamide in maximal tolerated dose when administered with mesna or without mesna in comparison with ifosfamide.
- Fig 3 is a bar diagram showing swelling of urinary bladders wall in mice after intraperitoneal (I) or oral (PO) administration of racemic and S-(-) forms of chlorobromofos- famide in maximal tolerated dose in comparison with ifosfamide.
- Fig. 4 shows diagram comparing increase in life span versus chlorobromofosfamide dose in mice with leukemia L1210 treated with racemic ⁇ chlorobromofosfamide with or without mesna.
- Present invention relates to the use of 1, 3, 2-oxazaphos- phorinane derivatives of the general formula 1
- X- ⁇ and X 2 are the same or different and are chlorine or bromine atom, provided that X-*_ and X 2 are not at the same time chlorine atom, for the manufacture of the medicament for the administration together with sodium 2-mercaptoethanosul- fonate (mesna) .
- the use relates to the l, 3, 2-oxazaphosphori- nane derivatives in the form of S-(-) isomer.
- 2-oxazaphosphorinane derivative is S- (-) -2- (2-chloro- ethylamino) -2-oxo-3- ⁇ 2-bromoethyl) -1, 3 , 2-oxazaphosphorinane
- Sodium 2-mercaptoethanosulfonate can be administered together with 1, 3, 2-oxazaphosphorinane derivatives in the same preparation, containing both substances, or both substances can be administered in the form of single preparations. Form of the preparation is selected depending on the way of the administration.
- 1, 3, 2-oxazaphosphorinane derivatives is in the form suitable for oral administration. If both substances are administered in the form of different single preparations, they can be administered at the same time or separately, one after another. Typically, sodium 2-mercaptoethanosulfonate would be administered in one or several divided doses before and/or after 1,3,2-oxaza- phosphorinane derivative administration.
- the invention provides a new method of cancer treatment.
- 3, 2-oxazaphosphorinane derivative of the general formula 1 2-oxazaphosphorinane derivative of the general formula 1
- X-*_ and X 2 are the same or different and are chlorine or bromine atom, provided that X- and X 2 are not at the same
- RECTIFIED SHEET time chlorine atom, is administered to a patient in a therapeutically effective amount together with sodium 2-mercaptoethanosulfonate (mesna) .
- Sodium 2-mercaptoethanosulfonate can be administered simultaneously with 1,3,2-oxazaphosphorinane derivative in the form of one preparation containing both substances or in the form of separate preparations, or can be administered separately, for example before the administration of 1,3,2-oxazaphosphorinane derivative, or sodium 2-mercapto- ethanosulfonate and 1,3,2-oxazaphosphorinane derivative can be administered successiveively one after another, and typically sodium 2-mercaptoethanosulfonate would be adminis ⁇ tered in one or several doses before and/or the 1,3,2-oxaza- phosphorinane derivative administration.
- Sodium 2-mercaptoethanosulfonate will be preferably administered in a dosage equal at least about 60% by weight of 1,3,2-oxazaphosphorinane derivative dose.
- 1,3,2-Oxazaphosphorinane derivative is used in the form of conventional pharmaceutical preparation, formulated according to the methods known in the art, in association with known and conventional carriers and pharmaceutical auxiliary agents. Specially convenient is the form for oral administration.
- Sodium 2-mercaptoethanosulfonate may be used in the form suitable for injections, especially intramuscular injections, or in the form suitable for oral administration, for example solutions or tablets or capsules.
- Present invention relates also to the pharmaceutical composition with anticancer activity, containing as an active ingredients 1, 3, 2-oxazaphosphorinane derivative of the general formula 1
- X-*_ and 2 are the same or different and are chlorine or bromine atom, provided that X-*_ and X 2 are not at the same time chlorine atom, and sodium 2-mercaptoetha- nosulfonate (mesna) in association with conventional, pharmaceutically acceptable carriers and/or auxilliary agents.
- Such composition preferably is in the form designed for oral administration, that is for example tablets or capsules, formulated according to the conventional pharmaceutical practice.
- the invention can be used in the treatment of cancers such as leukemias, breast cancer, lung cancers, colon cancers, sarcomas, melanomas, etc.
- cancers such as leukemias, breast cancer, lung cancers, colon cancers, sarcomas, melanomas, etc.
- IP per os
- PO per os
- CD50 for ifosfamide 225,0 mg/kg (IP) and 600,0 mg/kg (PO)
- CD50 for chlorobromofosfamide 84,1 mg/kg (IP) and 70,0 mg/kg
- CD90 for S-(-) -chlorobromofosfamide 71 mg/kg (IP) and 70 mg/kg (PO) .
- Preparations were given in the form of the solutions in physiological salt at the concentration depending on the dose. Mice in the control group were given the same volume of physiological salt. After 24 hours from the administration of the preparation mice were sacrificed, urinary bladders were collected and their weight determined (wet) . Average weight of bladders of mice treated were expressed as a percentage of average weight of control mice bladders. Bladders were preserved in 4% neutralised formalin and subjected to histopatological examinations. Cuttings of parafin fixed organs were stained with eosilin and hematoxylin. Two cross-sections from the middle part of the organ were examinated in optical microscope. The oedema of bladder wall was estimated according to the arbitral 5-degree scale. The results shown are calculated according to the formula t/c-l, wherein t is average degree of oedema in treated group and c is the average degree of oedema in control group.
- Racemic chlorobromofosfamide (CBM-4A) was administered PO in single doses on day 2 after IP inoculation of 10 5 L1210 leukemic cells to CD2F1 mice. Second group of mice were given in the same way racemic chlorobromofosfamide and mesna as described in Example II. Mice in control groups were given the same volume of physiological salt or only racemic chlorobromofosfamide. The resulting relationship of the prolongation in the life span versus dose of chlorobromofos ⁇ famide given is shown on Fig. 4.
- ED50 dose that is dose providing 50% increase in life span of treated animals over control
- ED50 dose is 35,1 mg/kg for racemic chlorobromo- fosfamide and for the same preparation co-administered with mesna it is lower and is 31,2 mg/kg.
- ED50 dose is lower when chlorobromofosfamide is administered with mesna, what indicates that mesna not only decreases urotoxicity of cytostatic agent but also improves its therapeutic anticancer activity.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The use of 1,3,2-oxazaphosphorinane derivatives of the general formula (I), wherein X1 and X2 are the same or different and are chlorine or bromine atom, provided that X1 and X2 are not at the same time chlorine atom, for the manufacture of the medicament for the administration together with sodium 2-mercaptoethanosulfonate (mesna), pharmaceutical composition containing 1,3,2-oxazaphosphorinane derivatives of the general formula (I) as defined above and mesna, and the method of cancer treatment.
Description
The pharmaceutical composition containing the 1,3,2-oxaza- phosphorinane and mesna for the cancer treatment
This invention relates to the pharmaceutical composition with anti-cancer activity, the use of the 1,3,2-oxaza- phosphorinane derivatives and the etod of cancer treatment.
It is known that 2-(haloethyl)amino-3-(2-haloethyl)- 1,3,2-oxazaphosphorinane derivatives, analogues of known antineoplastic agent ifosfamide, have cytostatic activity (EP 0295576B1) . In studies on mice it was shown that these derivatives are effective for the treatment of cancers, such as leukemias, melanomas, breast cancer, lung cancer and sarcomas (H. Glazman-Kusnierczyk et al., Immunophar . Immunotoxicol. 14(4), 883 (1992). These compounds were also shown to posess significantly higher therapeutic indexes, expressed as a ratio of maximal tolerated dose (MTD) to the curative dose for the 50% of animals treated (CD50) . Especially effective were levorotary isomers S-(-), in particular S-(-)-2-(2-chloroethylamino)-2-oxo-3-(2- bromoethyl)-1,3 ,2-oxazaphosphorinane (chlorobromofosfamide) . It was also observed that oral administration is more efficient than parenteral administration; after oral administration significantly lower toxicity was stated for both racemic as well as for S-(-) isomer compounds with anticancer
activity retained on the same level as for parenteral administration.
It was stated however that 1,3,2-oxazaphosphorinane derivatives described in EP 0295576B1 have urotoxic activity, manifested by toxic swelling of urinary bladders in mice as indicated by increased bladder weight and organ wall oedema. Although intensity of these changes varied depending on the dosage and route of administration, this effect can restrict the effective dose and clinical effective- ness of the medicament.
It was stated that urotoxic effect can be diminished by administering 1,3,2-oxazaphosphorinane derivatives together with sodium 2-mercaptoethanosulfonate, also known under the name mesna. Furthermore it has been found, unexpectedly, that administration of 1,3,2-oxazaphosphorinane derivatives together with mesna has additional beneficial effect, namely it potentiates therapeutic activity of these 1,3,2-oxazapho- sphorinane derivatives and therefore may allow to lower their dosage.
On the drawings:
Fig. 1 shows urotoxic activity of racemic (CBM-4A) and S-(-) (CBM-11) forms of chlorobromofosfamide in comparison with ifosfamide after administration of single therapeutic doses.
Fig. 2 is a bar diagram showing changes of the urinary bladders weight in mice after intraperitoneal (IP) or oral (PO) administration of racemic and S-(-) forms of chlorobro- mofosfamide in maximal tolerated dose when administered with
mesna or without mesna in comparison with ifosfamide.
Fig 3 is a bar diagram showing swelling of urinary bladders wall in mice after intraperitoneal (I) or oral (PO) administration of racemic and S-(-) forms of chlorobromofos- famide in maximal tolerated dose in comparison with ifosfamide. Fig. 4 shows diagram comparing increase in life span versus chlorobromofosfamide dose in mice with leukemia L1210 treated with racemic ^chlorobromofosfamide with or without mesna. Present invention relates to the use of 1, 3, 2-oxazaphos- phorinane derivatives of the general formula 1
X 2
\
H 0— '
wherein X-^ and X2 are the same or different and are chlorine or bromine atom, provided that X-*_ and X2 are not at the same time chlorine atom, for the manufacture of the medicament for the administration together with sodium 2-mercaptoethanosul- fonate (mesna) .
Preferably the use relates to the l, 3, 2-oxazaphosphori- nane derivatives in the form of S-(-) isomer. Especially 1, 3, 2-oxazaphosphorinane derivative is S- (-) -2- (2-chloro- ethylamino) -2-oxo-3- {2-bromoethyl) -1, 3 , 2-oxazaphosphorinane
RECTIFIED SHEET (RULE 91)
[ (S) - (-) -chlorobromofosfamide] .
Sodium 2-mercaptoethanosulfonate can be administered together with 1, 3, 2-oxazaphosphorinane derivatives in the same preparation, containing both substances, or both substances can be administered in the form of single preparations. Form of the preparation is selected depending on the way of the administration.
Preferably 1, 3, 2-oxazaphosphorinane derivatives is in the form suitable for oral administration. If both substances are administered in the form of different single preparations, they can be administered at the same time or separately, one after another. Typically, sodium 2-mercaptoethanosulfonate would be administered in one or several divided doses before and/or after 1,3,2-oxaza- phosphorinane derivative administration.
In the another aspect the invention provides a new method of cancer treatment. In the method according to the invention 1, 3, 2-oxazaphosphorinane derivative of the general formula 1
0 N w /
N —P
wherein X-*_ and X2 are the same or different and are chlorine or bromine atom, provided that X- and X2 are not at the same
RECTIFIED SHEET (RULE 91 )
time chlorine atom, is administered to a patient in a therapeutically effective amount together with sodium 2-mercaptoethanosulfonate (mesna) .
Sodium 2-mercaptoethanosulfonate can be administered simultaneously with 1,3,2-oxazaphosphorinane derivative in the form of one preparation containing both substances or in the form of separate preparations, or can be administered separately, for example before the administration of 1,3,2-oxazaphosphorinane derivative, or sodium 2-mercapto- ethanosulfonate and 1,3,2-oxazaphosphorinane derivative can be administered succesively one after another, and typically sodium 2-mercaptoethanosulfonate would be adminis¬ tered in one or several doses before and/or the 1,3,2-oxaza- phosphorinane derivative administration. Sodium 2-mercaptoethanosulfonate will be preferably administered in a dosage equal at least about 60% by weight of 1,3,2-oxazaphosphorinane derivative dose.
1,3,2-Oxazaphosphorinane derivative is used in the form of conventional pharmaceutical preparation, formulated according to the methods known in the art, in association with known and conventional carriers and pharmaceutical auxiliary agents. Specially convenient is the form for oral administration.
Sodium 2-mercaptoethanosulfonate may be used in the form suitable for injections, especially intramuscular injections, or in the form suitable for oral administration, for example solutions or tablets or capsules.
Present invention relates also to the pharmaceutical composition with anticancer activity, containing as an active
ingredients 1, 3, 2-oxazaphosphorinane derivative of the general formula 1
x2
wherein X-*_ and 2 are the same or different and are chlorine or bromine atom, provided that X-*_ and X2 are not at the same time chlorine atom, and sodium 2-mercaptoetha- nosulfonate (mesna) in association with conventional, pharmaceutically acceptable carriers and/or auxilliary agents. Such composition preferably is in the form designed for oral administration, that is for example tablets or capsules, formulated according to the conventional pharmaceutical practice.
The invention can be used in the treatment of cancers such as leukemias, breast cancer, lung cancers, colon cancers, sarcomas, melanomas, etc.
Example I Urotoxicity of 1, 3, 2-oxazaphosphorinane derivatives in comparison with ifosfamide
Healthy female mice CD2F1 were given intraperitoneally
(IP) or per os (PO) one single therapeutic dose CD50 in the case of ifosfamide and racemic chlorobromofosfamide (CBM-4A)
RECTIFIED SHEET(RULE91)
or CD90 in the case of S-(-)-chlorobromofosfamide (CBM-11) (doses curative for 50% or 90% of treated animals, respec¬ tively) . These doses were determined earlier in mice inoculated with leukaemia 1210 after 2 months lasting observation and were as follows:
CD50 for ifosfamide: 225,0 mg/kg (IP) and 600,0 mg/kg (PO)
CD50 for chlorobromofosfamide: 84,1 mg/kg (IP) and 70,0 mg/kg
(PO) ,
CD90 for S-(-) -chlorobromofosfamide: 71 mg/kg (IP) and 70 mg/kg (PO) .
Preparations were given in the form of the solutions in physiological salt at the concentration depending on the dose. Mice in the control group were given the same volume of physiological salt. After 24 hours from the administration of the preparation mice were sacrificed, urinary bladders were collected and their weight determined (wet) . Average weight of bladders of mice treated were expressed as a percentage of average weight of control mice bladders. Bladders were preserved in 4% neutralised formalin and subjected to histopatological examinations. Cuttings of parafin fixed organs were stained with eosilin and hematoxylin. Two cross-sections from the middle part of the organ were examinated in optical microscope. The oedema of bladder wall was estimated according to the arbitral 5-degree scale. The results shown are calculated according to the formula t/c-l, wherein t is average degree of oedema in treated group and c is the average degree of oedema in control group.
As it was shown on the Fig. 1, after the administration of the compounds in therapeutic doses CD50 or CD90 changes were
relatively low and most pronounced for ifosfamide given IP. In the case of chlorobromine preparations changes, as marginal, were detected only by histopatologist and were more pronounced after oral then after intraperitoneal administration. Example II
The effect of Mesna on the weight change and swelling, of urinary bladders in mice after administration of 1,3,2-oxazaphosphorinane derivatives. Healthy female mice CD2F1 were given intraperitoneally (IP) or per os (PO) preparations of racemic chlorobromo- fosfamide (CBM-4A) , S-(-)-chlorobromofosfamide (CBM-11) and Ifosfamide in the form of the solutions in physiological salt in one single maximally tolerated dose (MTD) , that is dose lethal for less than 5% healthy mice, estimated after 2 months of observation. These doses were as follows: racemic chlorobromofosfamide: 220 mg/kg (IP) and 450 mg/kg (PO) , S-(-)-chlorobromofosfamide: 180 mg/kg (IP) and 370 mg/kg (PO) . Ifosfamide: 480 mg/kg (IP) and 600 mg/kg (PO) . Mesna in the form of injections (commercial preparation Antiuron, POLFA) was administered intraperitoneally in 3 divided doses, each in the amount of 20% of cytostatic dose. First injection of Mesna preparation was given 1/2 hour before cytostatic administration and two subsequent injections at 4 hour intervals. Mice in control group were given the same volume of physiological salt. Organs were examined in the same way as described in Example I.
It was found that mesna co-administration prevented completely oedema formation in mice treated intragastri-
cally with 1,3,2-oxazaphosphorinane derivatives and significantly diminished oedema formation after intraperitoneal administration, which was manifested in lower organ weight (Fig. 2) . This effect was also observed in histopatological examination (Fig. 3). Example III
The effect of mesna on the prolongation of the life span of mice treated with 1,3,2-oxazaphosphorinane derivatives
Racemic chlorobromofosfamide (CBM-4A) was administered PO in single doses on day 2 after IP inoculation of 105 L1210 leukemic cells to CD2F1 mice. Second group of mice were given in the same way racemic chlorobromofosfamide and mesna as described in Example II. Mice in control groups were given the same volume of physiological salt or only racemic chlorobromofosfamide. The resulting relationship of the prolongation in the life span versus dose of chlorobromofos¬ famide given is shown on Fig. 4. It was stated that ED50 dose (that is dose providing 50% increase in life span of treated animals over control) is 35,1 mg/kg for racemic chlorobromo- fosfamide and for the same preparation co-administered with mesna it is lower and is 31,2 mg/kg. ED50 dose is lower when chlorobromofosfamide is administered with mesna, what indicates that mesna not only decreases urotoxicity of cytostatic agent but also improves its therapeutic anticancer activity.
Claims
1. The use of l, 3, 2-oxazaphosphorinane derivatives of the general formula 1
x2
O N
X ι\ " \ W N —XP f \
\ /
H
wherein X-_ and X2 are the same or different and are chlorine or bromine atom, provided that X-_ and X2 are not at the same time chlorine atom, for the manufacture of the medicament for the administration together with sodium 2-mercaptoethanosulfonate
(mesna) .
2. The use according to claim 1 wherein 1, 3, 2-oxazaphosphorinane derivative is in the form of S-(-) isomer.
3. The use according to claim 1 or 2 wherein 1,3,2-oxa- zaphosphorinane derivative is S- (-) -2- (2-chloroethylamino) - 2-OXO-3- (2-bromoethyl) -1,3, 2-oxazaphosphorinane
4. The use according to claim l or 2 or 3 wherein
RECTIFIED SHEET (RULE 91) 1, 3, 2-oxazaphosphorinane derivative is in the form for oral administration.
5. Pharmaceutical composition with anticancer activity, characterised in that it contains as an active ingredients l,3,2-oxazaphosphorinane derivative of the general formula 1
X 2
wherein X-]_ and X2 are the same or different and are chlorine or bromine atom, provided that X-*_ and X are not at the same time chlorine atom, and sodium 2-mercaptoethanosul onate (mesna) in association with conventional, pharmaceutically acceptable carriers and/or auxilliary agents.
6. Pharmaceutical composition according to claim 5, characterised in that 1,3, 2-oxazaphosphorinane derivative is in the form of S-(-) isomer.
7. Pharmaceutical composition according to claim 6, characterised in that it contains S- (-) -2- (2-chloro- ethylamino) -2-oxo-3- (2-bromoethyl) -1,3, 2-oxazaphosphorinane.
8. Pharmaceutical composition according to claim 6, characterised in that it is in the form for oral administra-
RECTIFIED SHEET (RULE 91) ISA/EP
9. A method of cancer treatment characterised in that 1,3, 2-oxazaphosphorinane derivative of the general formula 1
X 2
O N X ι\ .--\ W '
\, \ N p
\ H 0
wherein X-^_ and X2 are the same or different and are chlorine or bromine atom, provided that X- and X2 are not at the same time chlorine atom, is administered to a patient in a therapeutically effective amount together with sodium 2-mer¬ captoethanosulfonate (mesna) .
RECTIFIED SHEET (RULE 91) ISA/EP
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PLP.307948 | 1995-03-31 | ||
| PL95307948A PL178713B1 (en) | 1995-03-31 | 1995-03-31 | Pharmaceutic agent anticarcinogenic activity, application of 1,3,2-oxazaapfosphorinane derivatives and method of treating neoplasms |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996030024A1 true WO1996030024A1 (en) | 1996-10-03 |
Family
ID=20064753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL1996/000005 Ceased WO1996030024A1 (en) | 1995-03-31 | 1996-03-28 | The pharmaceutical composition containing the 1,3,2-oxazaphosphorinane and mesna for the cancer treatment |
Country Status (2)
| Country | Link |
|---|---|
| PL (1) | PL178713B1 (en) |
| WO (1) | WO1996030024A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1396268A1 (en) * | 2002-09-05 | 2004-03-10 | Bharat Serums & Vaccines Ltd. | Stable oxazaphosphorine-2-mercaptoethanesulphonate formulations |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0560092A1 (en) * | 1992-03-11 | 1993-09-15 | ASTA Medica Aktiengesellschaft | Tablets, granulates and pellets with a high drug content for highly concentrated solid administration forms |
-
1995
- 1995-03-31 PL PL95307948A patent/PL178713B1/en not_active IP Right Cessation
-
1996
- 1996-03-28 WO PCT/PL1996/000005 patent/WO1996030024A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0560092A1 (en) * | 1992-03-11 | 1993-09-15 | ASTA Medica Aktiengesellschaft | Tablets, granulates and pellets with a high drug content for highly concentrated solid administration forms |
Non-Patent Citations (5)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 94, no. 13, 30 March 1981, Columbus, Ohio, US; abstract no. 096245, BROCK, N.: "The development of mesna for the inhibition of urotoxic side effects of cyclophosphamide, ifosfamide, and other oxazaphosphorine cytostatics" XP000578872 * |
| GLAZMAN-KUSNIERCZYK H ET AL: "ANTITUMOR ACTIVITY EVALUATION OF BROMINE-SUBSTITUTED ANALOGUES OF IFOSFAMIDE", IMMUNOPHARMACOL IMMUNOTOXICOL, 14 (4). 1992. 883-911., XP000578882 * |
| JUSZKIEWICZ M ET AL: "Pharmacological properties of racemic chlorobromofosfamide.", ARCH IMMUNOL THER EXP (WARSZ), 1994, 42 (5-6) P405-13, POLAND, XP000578876 * |
| JUSZKIEWICZ M ET AL: "Pharmacological properties of racemic chlorobromofosfamide.", ARCH IMMUNOL THER EXP (WARSZ), 1994, 42 (5-6) P405-13, POLAND, XP000579139 * |
| RECENT RESULTS CANCER RES., 1980, 270-8 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1396268A1 (en) * | 2002-09-05 | 2004-03-10 | Bharat Serums & Vaccines Ltd. | Stable oxazaphosphorine-2-mercaptoethanesulphonate formulations |
| WO2004022699A3 (en) * | 2002-09-05 | 2005-03-24 | Bharat Serums & Vaccines Ltd | Liquid stable composition of oxazaphosphorine with mesna |
| EA008776B1 (en) * | 2002-09-05 | 2007-08-31 | Бхарат Сирумс Энд Вэксинс Лтд. | Liquid stable composition of oxazaphosphorine with mesna |
| AU2003276689B2 (en) * | 2002-09-05 | 2009-04-09 | Bharat Serums And Vaccines Ltd. | Liquid stable composition of oxazaphosphorine with mesna |
Also Published As
| Publication number | Publication date |
|---|---|
| PL178713B1 (en) | 2000-06-30 |
| PL307948A1 (en) | 1996-10-14 |
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