CA1117015A - Process for producing detoxified pharmaceutical products containing a cytostatically active alkylating agent - Google Patents
Process for producing detoxified pharmaceutical products containing a cytostatically active alkylating agentInfo
- Publication number
- CA1117015A CA1117015A CA000317744A CA317744A CA1117015A CA 1117015 A CA1117015 A CA 1117015A CA 000317744 A CA000317744 A CA 000317744A CA 317744 A CA317744 A CA 317744A CA 1117015 A CA1117015 A CA 1117015A
- Authority
- CA
- Canada
- Prior art keywords
- mercapto
- sulfonic acid
- chloroethyl
- alkylating agent
- salt
- 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.)
- Expired
Links
- 229940100198 alkylating agent Drugs 0.000 title claims abstract description 30
- 239000002168 alkylating agent Substances 0.000 title claims abstract description 30
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 11
- 229940127557 pharmaceutical product Drugs 0.000 title claims description 9
- 238000000034 method Methods 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 15
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 229910006069 SO3H Inorganic materials 0.000 claims abstract 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 11
- -1 alkali metal salt Chemical class 0.000 claims description 10
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 claims description 10
- 229960001101 ifosfamide Drugs 0.000 claims description 10
- 229940006193 2-mercaptoethanesulfonic acid Drugs 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 claims description 7
- 229960000875 trofosfamide Drugs 0.000 claims description 6
- ZSZKJARKHWCBJK-UHFFFAOYSA-N 2-[[3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-yl]amino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCNP1(=O)OCCCN1CCCl ZSZKJARKHWCBJK-UHFFFAOYSA-N 0.000 claims description 4
- 229950008275 sufosfamide Drugs 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims 1
- 230000001085 cytostatic effect Effects 0.000 description 24
- 230000000694 effects Effects 0.000 description 23
- 239000000824 cytostatic agent Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 14
- 210000003932 urinary bladder Anatomy 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 10
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 6
- 229960004397 cyclophosphamide Drugs 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 210000001635 urinary tract Anatomy 0.000 description 6
- 238000001784 detoxification Methods 0.000 description 5
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- OGNVQLDIPUXYDH-ZPKKHLQPSA-N (2R,3R,4S)-3-(2-methylpropanoylamino)-4-(4-phenyltriazol-1-yl)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid Chemical compound CC(C)C(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(O)=O)=C[C@@H]1N1N=NC(C=2C=CC=CC=2)=C1 OGNVQLDIPUXYDH-ZPKKHLQPSA-N 0.000 description 1
- OKVLRTXOHOBONS-UHFFFAOYSA-N 2-methyl-3-sulfanylpropane-1-sulfonic acid Chemical compound SCC(C)CS(O)(=O)=O OKVLRTXOHOBONS-UHFFFAOYSA-N 0.000 description 1
- OBDVFOBWBHMJDG-UHFFFAOYSA-N 3-mercapto-1-propanesulfonic acid Chemical compound OS(=O)(=O)CCCS OBDVFOBWBHMJDG-UHFFFAOYSA-N 0.000 description 1
- HMEJBVOVTCTWRG-UHFFFAOYSA-N 6-sulfanylhexane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCCCS HMEJBVOVTCTWRG-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MRIMWDXKBILRPB-UHFFFAOYSA-N O=P1NCCCO1 Chemical class O=P1NCCCO1 MRIMWDXKBILRPB-UHFFFAOYSA-N 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- COSZWAUYIUYQBS-UHFFFAOYSA-B hexapotassium hexasodium 3-carboxy-3-hydroxypentanedioate 2-hydroxypropane-1,2,3-tricarboxylate hydrate Chemical compound O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[K+].[K+].[K+].[K+].[K+].[K+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O COSZWAUYIUYQBS-UHFFFAOYSA-B 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
Abstract
ABSTRACT OF DISCLOSURE
The present invention is related to a process for producing a pharmaceutical preparation containing a cytostatically active alkylating agent which has been detoxified by adding thereto a a pharmacologically acceptable salt of a mercapto alkane sulfonic acid of the general formula HS-alk-SO3H
wherein alk is an alkylene group having from 2 to 6 carbon atoms, in an amount of at least 20 % of the weight of the alkylating agent thereby substantially improving the properties thereof.
The present invention is related to a process for producing a pharmaceutical preparation containing a cytostatically active alkylating agent which has been detoxified by adding thereto a a pharmacologically acceptable salt of a mercapto alkane sulfonic acid of the general formula HS-alk-SO3H
wherein alk is an alkylene group having from 2 to 6 carbon atoms, in an amount of at least 20 % of the weight of the alkylating agent thereby substantially improving the properties thereof.
Description
1~.17015 The present invention is directed to new pharmaceutical products containing cytostatically active alkylating agents which are detoxified. More in particular, the present-inven-tion is related to such pharmaceutical preparations o~ cyto-statically active alkylating agents which are detoxified bycombining these active agent with a pharmacologically accep-table salt of a mercapto alkane sulfonic acid in order to overcome the undesired urotoxic side effects caused by such alkylating agents in the kidneys, urinary tracts and urinary bladder. The invention is further directed to a process for producing such pharmaceutical products.
Cytostatically active alkylating agents such as melphalane, cyclophosphamide, trofosfamide, ifosfamide, sufosfamide, chlorambucil, busulfane, triethylene thiophosphamide or triaziquone and in particular the 2-oxo-1,3,2-oxazaphospho-rinanes cyclophosphamide, trofosfamide, ifosfamide and sufos-famide produce undesired side effects such as serious irrita-tions of the kidneys, the urinary tracts and/or the urinary bladder of the patient treated therewith. ~s is well known, such undesired side effects occur readily in particular after such organs have been damaged for the first time. The undesired side effects are sometimes produced to such a degree that the cytostatic therapy of the patient suffering from cancer has to be interrupted temporarily or is rendered even impossible at all. In view of the fact that malign tumors readily produce resistency against a particular cytostatic, such cytostatics are successful in the so-called li l7~)~ 5 highdosage therapy. In such a treatment, the cytostatic is administered at first in a dosage which is very high in comparison to the toxicity of the cytostatic in order to produce an initial dosage as high as possible of the cytosta-tic at the tumor tissue. Thereafter, the cytostatics areadministered in several lower dosages over a prolonged period of time. It is known that such undesired side effects are caused by metabolites of the cytostatics produced in the body of the patient treated therewith. These undesired side effects quite often occur also with alkylating agents such as 2-~N,N-bis-(2-chloroethyl)-amino~-2-oxo-1,3,2-oxazaphosphorinane (R) known under the well-known trade names Endoxan or Cytoxan or un~er the generic name cyclophosphamide, and 2-CN,N-bis-(2-chloroethyl)-amino~-3-(2-chloroethyl)-2-oxo-1 3,2-oxaza-phosphorinane known under the trade name Ixoten ~R) or thegeneric name trofosfamide. Of even more importance are these undesired side effects when using alkylating agents having a high cytostatic activity at a lower toxicity such as 2-(N-2-chloroethyl-amino)-3-(2-chloroethyl) 2-o~o~1,3,2-oxazaphGspho-rinane known under the generic name ifos~amide. The thera-peutic usefulness of such valuable alkylating agents which is particularly based upon the low toxicity, is again sub-stantially limited by these undesired side effects. It has been observed recently that such irritations of the urinary bladder may even cause the formation of malign tumors there.
Many experiments have been made in order to avoid or at least alleviate these detrimetal and undesired side effects of the cytostatically active alkylating agents since they can no more be replaced in the treatment of malign tumors, and a premature 30 rupture of the therapy would produce severe damage or prema-ture death of the patient. One of the attempts consists in the administration of increased amounts of liquid, possibly in combination with the administration of agents increasing the formation of urine in order to obtain a passage of urine containing metabolites of cytostatics as quick as possible through the kidneys, the urinary tracts and the urinary bladder ~ 1~7~ ~ ~
and to avoid the formation of high concentrations of meta-bolites in particular in thc urlnary bladder. This so-called hydratation in general is combined with an alkalinazation of the urine for instance by means of the hexapotassium hexa-sodium pentacitrate hydrate complex known under the registeredtrade name Uralyt-U and in particular by introducing solutions of mercapto group containing compounds into the urinary bladder by means of a catheter. With such mercapto group containing compounds it was supposed that the mercapto group undergoes reaction with the alkylating agent, thus inactivating the same.
N-Acetyl cysteine and cysteine i.n particular have been used as such mercapto group containing compounds. However, the results only where very limited, in particular in cases where the cytostatics had to be administered in very high dosages.
Furthermore, the washing of the urinary bladder or vesicoc-lysis is a procedure very burdensome to the patient, and can only very hardly be practiced in the treatment with cytostatics over prolonged periods of time. Furthermore, more upward areas in the urinary tract cannot be reached by vesicoclysis.
The use of mercapto group containing compounds f~r the general - detoxification in the therapy with alkylating agents has been first published by T.A. Connors, Eur~p. J. Cancer 2, 393 to 395 (1966). However, these experiments showed no result because the mercapto group containing compounds there used at the same time decreased the cytostatic activity of the alkylating agents (see in particular loc. cit. p. 300 and 303, last but one sentence).
After introduction of t~e2-oxo-1,3,2-oxazaphosphorinanes as alkylating agents and after observation of urotoxic side effects (hemorrhaginal cysto-pyelonephritis), the first attempts to avoid such undesired side effects where made by topically applying mercapto group containing compounds in the urinary bladder itself. This instillation of N-acetylcysteine up to now represented a standard prophylaxis against urotoxic side effects when administering cyclophosphamide and ifosfamide 11~ 7~ 15 at very high dosages (see for instance Hoe~er-Janker et al., Med. Welt 26, 972 (1975); Drings et al., Verh. Dtsch. Ges.
inn. Med. 78, 166 (1972); Cohen et al., Cancer Chemother.
rep., Part 1, 59, 751 (1975); Creaven et al., Cancer Treatm.
Rep. 60, 445 (1976); and Primack, J. Nat. Cancer Inst. 47, 223 (1971)).
However, the instillation of HS-group containing compounds into the urinary bladder did not solve the problem of a general detoxification. The bene~icial effects of the applied mercapto group containing compound were limited to the urinary bladder. Furthermore, the application by means of a catheter was not regarded as most favourable. Finally, the clinical effectiveness of this burdensome prophylaxis by no means was sati~factory (see for instance Falkson, Suid-Afrikaanse Kankerbulletin 15, 97, 1971).
It surprisingly now has been found that the above described undesired urotoxic side effect produced by cytostatically active alkylating agents in the kidney, the urinary tract and the urinary bladder of patient treated therewith may be overcome in a simple manner and to a substantially complete degree, and pharmaceutical products of cytostatically active alkylating agents may be detoxified, by admixing to such pharmaceutical products a known pharmacologically acceptable salt of a mercapto alkane sulfonic acid having the general formula HS-EIlk-$03H
wherein alk is a straight or branched alkylene group having from 2 to 6, in particular from 2 to 4 carbon atoms in an amount of at least 20 % of the weight of the cytostatically active alkylating agent contained therein up to the highest dose which is tolerated by the patient. The present invention therefor is directed to such d~toxified pharmaceutical pro-ducts containing cytostatically active alkylating agents by 1117~15 combining them and adding thereto a pharmacologically accep-table salt of a mercapto alkane sulfonic acid having the general formula HS-alk-S03H
wherein alk is a straight or branched alkylene group having from 2 to 6 carbon atoms, and process for producing such detoxified pharmaceutical products.
Particularely good detoxification results have been obtained with such salts o~` 2-mercapto ethane sul~onic acid. Thus, the pharmacologically acceptable salts of 2-mercapto ethane sulfonic ac~d are preferred according to the present invention.
Particularly preferred among these salts are the alkali metal salts of 2-mercapto ethane sulfonic acid, in particularly its sodium salt. This is the most preferably used salt.
In order to obtain an effective protection of the patient to be treated with cytostatically active alkylating agen~sagainst the urotoxic side effects upon the kldney, the urinary tracts and the urinary bladder it is sufficient to admix to the pharmaceutical product so small amounts as 20 % of the amount of cytostatic contained therein. This is particularly true at low doses of the cytostatic. If the alkylating agent is to be administered in higher doses, the urotoxic side effect may be avoided with ~0 % of the amo~mt of the alkylating agent. Since the uroto~ic side effects in particular occur upon administra-tion of the cytostatic at high doses, the lower limit of 30 %of the amount of cytostatic is the preferred lower limit for the amount of the salt of the mercapto alkane sulfonic acid admixed ~or detoxification of the cytostatics. In view of the known very low toxicity of the pharmacologically acceptable salts of the mercapto alkane sulfonic acids, the upper limi~
of the amount of salts of mercapto alkane sulfonic a~ids is of minor importance. It is surprising and important that the cytostatic activit~ of the alkylating agents is not at all al~
decreased or otherwise affected by the use of the salts of mercapto alkane sulfonic acids in accordance with the present invention. Even when administering the sodium salt of 2-mer-capto ethane sulfonic acid in a dose amounting to 100 times the dose of ifosfamide there was observed no decrease in the cytostatic activity in test animals. Since the undesired uro-toxic side effects even at high doses of the cytostatic may be substantially completely removed with equal arnounts of the salts of the mercapto alkane sulfon~cs acids, it is preferred to use the salt of the mercapto alkane sulfonic acids in amounts corresponding to 30 to 100 % of the amount of cyto-static.
While the salts of the mercapto alkane sulfonic acids may be used in combination with all of the cytostatically active alkylating agents to overcome the above described urotoxic and in particular undesired side effects these salts of mercapto alkane sulfonic acids are of particular importance in combination with the 2-oxo-1,3,2--oxazaphosphorinanes cyclophosphamide, ifosfamide, trofosfamide and sufosfamide us~ to a great extent in the treatment of humans suffering from many kinds of cancer diseases.
The pharmacologically acceptable salts of mercapto alkane sulfonic acids used in accordance to the present invention are known compounds (see USP 2 69L~ 732). These or simular compounds up to now have however never been used to remove the described urotoxic side e~fects of cytostatically active alkylating agents. Up to now the medical profession was of the opinion that the alkylating agents or, respectively, metabolites thereof causing these undesired side effects have to be detoxified topically at the place where they produce the injury and damage and that mercapto group con-taining compounds have to be applied in these damaged areas (for instance by instillation into the urinary bladder of the cytostatically treated patient) so that they produce their beneficial detoxifying activity at the place of damage.
Furthermore, the mercapto group containing compounds used up to now showed to be ineffective with this respect when applied orally. Still furthermore, it was -the opinion of the medical profession that the cytostatic activity of the alky-lating agents is produced just by the metabolites blamedfor the urotxic side effects and that, therefor, the mercapto grovp containing compounds have to be administered as late as possible in the passage through the human body in order to avoid a negative influence upon the cytostatic activity of the alkylating agents and their metabolites. However, even with the mercapto group containing compounds used up to now the degree o~ detoxification only was quite limited. The undesired side effects described hereinabove can be overcome only to a very limited degree.
The following examples serve to further illustrate the present invention without howe~er limiting the same thereto.
-One part by weight of ifosfamide 2-~N-(2-chloroethyl)-amino~-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane) and 0.63 parts by weight of the sodium salt of 2-mercapto ethane sulfonic acid, both in pure sterile form, are homogenously mixed under sterile conditions in a sterile mixer and filled into injection ampoules such that each ampoule contains 500 mg.
of ifosfamide and 315 mg. of the sodium salt of 2-mercapto ethane sulfonic acid per 10 ml. of injection solution.
EXAMPL~. 2 Example 1 was repeated using for each part by weight of ifos-famide 0.20, 0.50 or, respectively, 1.00 paPts by weight of the sodium salt of 2-mercapto ethane sulfonic acid.
~ 17`~15 Injec-tion solutions are prepared as described in Example i above, containing for each part by welght of ifosfamide 1.3 parts by weight of the sodium salt of 3-mercapto-1-propane sulfonic acid, 3-mercapto-2-methyl-1-propane sulfonic acid and, respectively, 6-mercapto hexane-1-sulfonic acid.
Injection solutions are prepared as described in Example 1 above, containlng for each part by weight of cyclophosphamide 0.63 parts by weight of the sodium salt of 2-mercapto ethane sulfonic acid.
Cytostatically active alkylating agents such as melphalane, cyclophosphamide, trofosfamide, ifosfamide, sufosfamide, chlorambucil, busulfane, triethylene thiophosphamide or triaziquone and in particular the 2-oxo-1,3,2-oxazaphospho-rinanes cyclophosphamide, trofosfamide, ifosfamide and sufos-famide produce undesired side effects such as serious irrita-tions of the kidneys, the urinary tracts and/or the urinary bladder of the patient treated therewith. ~s is well known, such undesired side effects occur readily in particular after such organs have been damaged for the first time. The undesired side effects are sometimes produced to such a degree that the cytostatic therapy of the patient suffering from cancer has to be interrupted temporarily or is rendered even impossible at all. In view of the fact that malign tumors readily produce resistency against a particular cytostatic, such cytostatics are successful in the so-called li l7~)~ 5 highdosage therapy. In such a treatment, the cytostatic is administered at first in a dosage which is very high in comparison to the toxicity of the cytostatic in order to produce an initial dosage as high as possible of the cytosta-tic at the tumor tissue. Thereafter, the cytostatics areadministered in several lower dosages over a prolonged period of time. It is known that such undesired side effects are caused by metabolites of the cytostatics produced in the body of the patient treated therewith. These undesired side effects quite often occur also with alkylating agents such as 2-~N,N-bis-(2-chloroethyl)-amino~-2-oxo-1,3,2-oxazaphosphorinane (R) known under the well-known trade names Endoxan or Cytoxan or un~er the generic name cyclophosphamide, and 2-CN,N-bis-(2-chloroethyl)-amino~-3-(2-chloroethyl)-2-oxo-1 3,2-oxaza-phosphorinane known under the trade name Ixoten ~R) or thegeneric name trofosfamide. Of even more importance are these undesired side effects when using alkylating agents having a high cytostatic activity at a lower toxicity such as 2-(N-2-chloroethyl-amino)-3-(2-chloroethyl) 2-o~o~1,3,2-oxazaphGspho-rinane known under the generic name ifos~amide. The thera-peutic usefulness of such valuable alkylating agents which is particularly based upon the low toxicity, is again sub-stantially limited by these undesired side effects. It has been observed recently that such irritations of the urinary bladder may even cause the formation of malign tumors there.
Many experiments have been made in order to avoid or at least alleviate these detrimetal and undesired side effects of the cytostatically active alkylating agents since they can no more be replaced in the treatment of malign tumors, and a premature 30 rupture of the therapy would produce severe damage or prema-ture death of the patient. One of the attempts consists in the administration of increased amounts of liquid, possibly in combination with the administration of agents increasing the formation of urine in order to obtain a passage of urine containing metabolites of cytostatics as quick as possible through the kidneys, the urinary tracts and the urinary bladder ~ 1~7~ ~ ~
and to avoid the formation of high concentrations of meta-bolites in particular in thc urlnary bladder. This so-called hydratation in general is combined with an alkalinazation of the urine for instance by means of the hexapotassium hexa-sodium pentacitrate hydrate complex known under the registeredtrade name Uralyt-U and in particular by introducing solutions of mercapto group containing compounds into the urinary bladder by means of a catheter. With such mercapto group containing compounds it was supposed that the mercapto group undergoes reaction with the alkylating agent, thus inactivating the same.
N-Acetyl cysteine and cysteine i.n particular have been used as such mercapto group containing compounds. However, the results only where very limited, in particular in cases where the cytostatics had to be administered in very high dosages.
Furthermore, the washing of the urinary bladder or vesicoc-lysis is a procedure very burdensome to the patient, and can only very hardly be practiced in the treatment with cytostatics over prolonged periods of time. Furthermore, more upward areas in the urinary tract cannot be reached by vesicoclysis.
The use of mercapto group containing compounds f~r the general - detoxification in the therapy with alkylating agents has been first published by T.A. Connors, Eur~p. J. Cancer 2, 393 to 395 (1966). However, these experiments showed no result because the mercapto group containing compounds there used at the same time decreased the cytostatic activity of the alkylating agents (see in particular loc. cit. p. 300 and 303, last but one sentence).
After introduction of t~e2-oxo-1,3,2-oxazaphosphorinanes as alkylating agents and after observation of urotoxic side effects (hemorrhaginal cysto-pyelonephritis), the first attempts to avoid such undesired side effects where made by topically applying mercapto group containing compounds in the urinary bladder itself. This instillation of N-acetylcysteine up to now represented a standard prophylaxis against urotoxic side effects when administering cyclophosphamide and ifosfamide 11~ 7~ 15 at very high dosages (see for instance Hoe~er-Janker et al., Med. Welt 26, 972 (1975); Drings et al., Verh. Dtsch. Ges.
inn. Med. 78, 166 (1972); Cohen et al., Cancer Chemother.
rep., Part 1, 59, 751 (1975); Creaven et al., Cancer Treatm.
Rep. 60, 445 (1976); and Primack, J. Nat. Cancer Inst. 47, 223 (1971)).
However, the instillation of HS-group containing compounds into the urinary bladder did not solve the problem of a general detoxification. The bene~icial effects of the applied mercapto group containing compound were limited to the urinary bladder. Furthermore, the application by means of a catheter was not regarded as most favourable. Finally, the clinical effectiveness of this burdensome prophylaxis by no means was sati~factory (see for instance Falkson, Suid-Afrikaanse Kankerbulletin 15, 97, 1971).
It surprisingly now has been found that the above described undesired urotoxic side effect produced by cytostatically active alkylating agents in the kidney, the urinary tract and the urinary bladder of patient treated therewith may be overcome in a simple manner and to a substantially complete degree, and pharmaceutical products of cytostatically active alkylating agents may be detoxified, by admixing to such pharmaceutical products a known pharmacologically acceptable salt of a mercapto alkane sulfonic acid having the general formula HS-EIlk-$03H
wherein alk is a straight or branched alkylene group having from 2 to 6, in particular from 2 to 4 carbon atoms in an amount of at least 20 % of the weight of the cytostatically active alkylating agent contained therein up to the highest dose which is tolerated by the patient. The present invention therefor is directed to such d~toxified pharmaceutical pro-ducts containing cytostatically active alkylating agents by 1117~15 combining them and adding thereto a pharmacologically accep-table salt of a mercapto alkane sulfonic acid having the general formula HS-alk-S03H
wherein alk is a straight or branched alkylene group having from 2 to 6 carbon atoms, and process for producing such detoxified pharmaceutical products.
Particularely good detoxification results have been obtained with such salts o~` 2-mercapto ethane sul~onic acid. Thus, the pharmacologically acceptable salts of 2-mercapto ethane sulfonic ac~d are preferred according to the present invention.
Particularly preferred among these salts are the alkali metal salts of 2-mercapto ethane sulfonic acid, in particularly its sodium salt. This is the most preferably used salt.
In order to obtain an effective protection of the patient to be treated with cytostatically active alkylating agen~sagainst the urotoxic side effects upon the kldney, the urinary tracts and the urinary bladder it is sufficient to admix to the pharmaceutical product so small amounts as 20 % of the amount of cytostatic contained therein. This is particularly true at low doses of the cytostatic. If the alkylating agent is to be administered in higher doses, the urotoxic side effect may be avoided with ~0 % of the amo~mt of the alkylating agent. Since the uroto~ic side effects in particular occur upon administra-tion of the cytostatic at high doses, the lower limit of 30 %of the amount of cytostatic is the preferred lower limit for the amount of the salt of the mercapto alkane sulfonic acid admixed ~or detoxification of the cytostatics. In view of the known very low toxicity of the pharmacologically acceptable salts of the mercapto alkane sulfonic acids, the upper limi~
of the amount of salts of mercapto alkane sulfonic a~ids is of minor importance. It is surprising and important that the cytostatic activit~ of the alkylating agents is not at all al~
decreased or otherwise affected by the use of the salts of mercapto alkane sulfonic acids in accordance with the present invention. Even when administering the sodium salt of 2-mer-capto ethane sulfonic acid in a dose amounting to 100 times the dose of ifosfamide there was observed no decrease in the cytostatic activity in test animals. Since the undesired uro-toxic side effects even at high doses of the cytostatic may be substantially completely removed with equal arnounts of the salts of the mercapto alkane sulfon~cs acids, it is preferred to use the salt of the mercapto alkane sulfonic acids in amounts corresponding to 30 to 100 % of the amount of cyto-static.
While the salts of the mercapto alkane sulfonic acids may be used in combination with all of the cytostatically active alkylating agents to overcome the above described urotoxic and in particular undesired side effects these salts of mercapto alkane sulfonic acids are of particular importance in combination with the 2-oxo-1,3,2--oxazaphosphorinanes cyclophosphamide, ifosfamide, trofosfamide and sufosfamide us~ to a great extent in the treatment of humans suffering from many kinds of cancer diseases.
The pharmacologically acceptable salts of mercapto alkane sulfonic acids used in accordance to the present invention are known compounds (see USP 2 69L~ 732). These or simular compounds up to now have however never been used to remove the described urotoxic side e~fects of cytostatically active alkylating agents. Up to now the medical profession was of the opinion that the alkylating agents or, respectively, metabolites thereof causing these undesired side effects have to be detoxified topically at the place where they produce the injury and damage and that mercapto group con-taining compounds have to be applied in these damaged areas (for instance by instillation into the urinary bladder of the cytostatically treated patient) so that they produce their beneficial detoxifying activity at the place of damage.
Furthermore, the mercapto group containing compounds used up to now showed to be ineffective with this respect when applied orally. Still furthermore, it was -the opinion of the medical profession that the cytostatic activity of the alky-lating agents is produced just by the metabolites blamedfor the urotxic side effects and that, therefor, the mercapto grovp containing compounds have to be administered as late as possible in the passage through the human body in order to avoid a negative influence upon the cytostatic activity of the alkylating agents and their metabolites. However, even with the mercapto group containing compounds used up to now the degree o~ detoxification only was quite limited. The undesired side effects described hereinabove can be overcome only to a very limited degree.
The following examples serve to further illustrate the present invention without howe~er limiting the same thereto.
-One part by weight of ifosfamide 2-~N-(2-chloroethyl)-amino~-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane) and 0.63 parts by weight of the sodium salt of 2-mercapto ethane sulfonic acid, both in pure sterile form, are homogenously mixed under sterile conditions in a sterile mixer and filled into injection ampoules such that each ampoule contains 500 mg.
of ifosfamide and 315 mg. of the sodium salt of 2-mercapto ethane sulfonic acid per 10 ml. of injection solution.
EXAMPL~. 2 Example 1 was repeated using for each part by weight of ifos-famide 0.20, 0.50 or, respectively, 1.00 paPts by weight of the sodium salt of 2-mercapto ethane sulfonic acid.
~ 17`~15 Injec-tion solutions are prepared as described in Example i above, containing for each part by welght of ifosfamide 1.3 parts by weight of the sodium salt of 3-mercapto-1-propane sulfonic acid, 3-mercapto-2-methyl-1-propane sulfonic acid and, respectively, 6-mercapto hexane-1-sulfonic acid.
Injection solutions are prepared as described in Example 1 above, containlng for each part by weight of cyclophosphamide 0.63 parts by weight of the sodium salt of 2-mercapto ethane sulfonic acid.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical product comprising as its ingredients a cytostatically active alkylating agent, and at least 20%
of the weight of said alkylating agent of a pharmaceu-tically acceptable salt of a mercapto alkane sulfonic acid having the general formula HS - alk - SO3H
wherein alk is a straight or branched chain alkylene group having from 2 to 6 carbon atoms.
of the weight of said alkylating agent of a pharmaceu-tically acceptable salt of a mercapto alkane sulfonic acid having the general formula HS - alk - SO3H
wherein alk is a straight or branched chain alkylene group having from 2 to 6 carbon atoms.
2. A product as claimed in claim 1 wherein the salt of the mercapto alkane sulfonic acid is the salt of 2-mercapto ethane sulfonic acid.
3. A product as claimed in claim 2 wherein the salt of 2-mercapto ethane sulfonic acid is an alkali metal salt thereof.
4. A product as claimed in any of claims 1, 2 or 3 wherein the salt of the mercapto alkane sulfonic acid is the sodium salt thereof.
5. A product as claimed in any of claims 1 to 3 wherein the alkylating agent is selected from the group consisting of 2-(N,N-bis-(2-chloroethyl)-amino)-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinan (trofosfamide), 2-(N-(2-chloroethyl)-amino)-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane (ifosfamide), and 2-(N,N-bis-(2-chloroethyl)-amino)-mesyloxyethylamino)-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane (sufosfamide).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2756018.5 | 1977-12-14 | ||
| DE2756018A DE2756018C2 (en) | 1977-12-14 | 1977-12-14 | Use of salts of mercaptoalkanesulfonic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1117015A true CA1117015A (en) | 1982-01-26 |
Family
ID=6026256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000317744A Expired CA1117015A (en) | 1977-12-14 | 1978-12-12 | Process for producing detoxified pharmaceutical products containing a cytostatically active alkylating agent |
Country Status (15)
| Country | Link |
|---|---|
| AR (1) | AR216563A1 (en) |
| AT (1) | AT358162B (en) |
| CA (1) | CA1117015A (en) |
| DD (1) | DD140420B5 (en) |
| DE (1) | DE2756018C2 (en) |
| EG (1) | EG14057A (en) |
| GR (1) | GR68356B (en) |
| HU (1) | HU179915B (en) |
| IE (1) | IE47609B1 (en) |
| IL (1) | IL56097A (en) |
| MC (1) | MC1229A1 (en) |
| PL (1) | PL211758A1 (en) |
| PT (1) | PT68904A (en) |
| YU (1) | YU291978A (en) |
| ZA (1) | ZA786662B (en) |
-
1977
- 1977-12-14 DE DE2756018A patent/DE2756018C2/en not_active Expired
-
1978
- 1978-11-27 ZA ZA00786662A patent/ZA786662B/en unknown
- 1978-11-29 GR GR57769A patent/GR68356B/el unknown
- 1978-11-30 IL IL56097A patent/IL56097A/en unknown
- 1978-12-05 IE IE2404/78A patent/IE47609B1/en unknown
- 1978-12-06 AT AT871078A patent/AT358162B/en not_active IP Right Cessation
- 1978-12-06 AR AR274705A patent/AR216563A1/en active
- 1978-12-12 PT PT68904A patent/PT68904A/en unknown
- 1978-12-12 CA CA000317744A patent/CA1117015A/en not_active Expired
- 1978-12-12 DD DD20969178A patent/DD140420B5/en active IP Right Maintenance
- 1978-12-12 MC MC781346A patent/MC1229A1/en unknown
- 1978-12-13 EG EG702/78A patent/EG14057A/en active
- 1978-12-13 HU HU78AA913A patent/HU179915B/en unknown
- 1978-12-14 PL PL21175878A patent/PL211758A1/xx unknown
- 1978-12-16 YU YU02919/78A patent/YU291978A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU179915B (en) | 1983-01-28 |
| EG14057A (en) | 1982-09-30 |
| DE2756018C2 (en) | 1979-11-22 |
| ZA786662B (en) | 1979-10-31 |
| YU291978A (en) | 1984-02-29 |
| DD140420A5 (en) | 1980-03-05 |
| AR216563A1 (en) | 1979-12-28 |
| IL56097A (en) | 1981-09-13 |
| IE782404L (en) | 1979-06-14 |
| IL56097A0 (en) | 1979-01-31 |
| ATA871078A (en) | 1980-01-15 |
| PT68904A (en) | 1979-01-01 |
| PL211758A1 (en) | 1980-02-11 |
| IE47609B1 (en) | 1984-05-02 |
| DD140420B5 (en) | 1995-06-14 |
| AT358162B (en) | 1980-08-25 |
| MC1229A1 (en) | 1979-10-26 |
| GR68356B (en) | 1981-12-23 |
| DE2756018B1 (en) | 1979-03-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4220660A (en) | Process for the treatment of humans suffering from undesired urotoxic side effects caused by cytostatically active alkylating agents | |
| BR0010257A (en) | Compound, process for the preparation of a compound, pharmaceutical formulation, use of a compound, method for treatment or prophylaxis of conditions associated with the inhibition of carboxypeptidase u, kits of parts, and method of treating a patient suffering from or susceptible to a condition where inhibition of carboxypeptidase and a different antithrombotic mechanism are needed or desired | |
| US5175006A (en) | Method of treating arthritis using gallium compounds | |
| CA2104868C (en) | Method and products for treating the eye | |
| US4107331A (en) | Zinc chelating fungicidal composition | |
| US4218471A (en) | Process for the treatment of humans suffering from undesired urotoxic side effects caused by cytostatically active alkylating agents | |
| CA1117015A (en) | Process for producing detoxified pharmaceutical products containing a cytostatically active alkylating agent | |
| BR0010256A (en) | Compound, process for the preparation of a compound, pharmaceutical formulation, use of a compound, method of treatment or prophylaxis of conditions associated with the inhibition of carboxypeptidase u, kit of parts, and method of treatment of a patient suffering from or susceptible to a condition where inhibition of carboxypeptidase and a different antithrombotic mechanism are required | |
| EP0616803A2 (en) | Method for enhancing T-cell count | |
| BR0311384A (en) | Compound, process for preparing same, pharmaceutical formulation, use of a compound, and method for treating or prophylaxis of conditions wherein inhibition of carboxypeptidase u is beneficial | |
| US5348749A (en) | Method for treating panic disorder | |
| JPS6342603B2 (en) | ||
| US6034126A (en) | Method for treating glycol poisoning | |
| JP2006510714A (en) | How to treat patients exposed to radiation | |
| US4923877A (en) | Composition and method for treating glaucoma | |
| US6172119B1 (en) | Method of treating acute renal failure | |
| US6197831B1 (en) | Method of treating septic shock | |
| JPH01180823A (en) | Brain disorder treating agent | |
| US2497742A (en) | Sclerosing composition | |
| US20060063742A1 (en) | Method of treatment for or protection against lymphedema | |
| DE60233578D1 (en) | Phosphorus containing compounds with antithrombitic activity | |
| US3755567A (en) | Method for treating alcoholism | |
| JPH05201876A (en) | Agent for reducing adverse action of fk565 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |