DE19720111C2 - Use of a benzylamine series secretolytic in preservation solutions for organs removed for transplantation - Google Patents
Use of a benzylamine series secretolytic in preservation solutions for organs removed for transplantationInfo
- Publication number
- DE19720111C2 DE19720111C2 DE19720111A DE19720111A DE19720111C2 DE 19720111 C2 DE19720111 C2 DE 19720111C2 DE 19720111 A DE19720111 A DE 19720111A DE 19720111 A DE19720111 A DE 19720111A DE 19720111 C2 DE19720111 C2 DE 19720111C2
- Authority
- DE
- Germany
- Prior art keywords
- hydroxy
- benzyl
- dibromo
- cyclohexylamine
- trans
- 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 - Lifetime
Links
- 150000003939 benzylamines Chemical class 0.000 title claims description 8
- 210000000056 organ Anatomy 0.000 title claims description 8
- 238000002054 transplantation Methods 0.000 title claims description 7
- 239000003761 preservation solution Substances 0.000 title claims description 6
- -1 hydroxycyclohexyl group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims description 9
- 150000007522 mineralic acids Chemical class 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 235000005985 organic acids Nutrition 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 229960005174 ambroxol Drugs 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 claims description 2
- GEDPQKGMHLHFOZ-XYPYZODXSA-N chembl2106163 Chemical compound C1C[C@@H](O)CC[C@@H]1NCC1=CC(Br)=CC(Br)=C1O GEDPQKGMHLHFOZ-XYPYZODXSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 6
- 239000000243 solution Substances 0.000 description 10
- 238000007792 addition Methods 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Natural products OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 2
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- RKTQEVMZBCBOSB-UHFFFAOYSA-N 4-aminocyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1CCC(O)CC1 RKTQEVMZBCBOSB-UHFFFAOYSA-N 0.000 description 1
- HAAZMOAXEMIBAJ-UHFFFAOYSA-N 4-chloro-2-methylquinazoline Chemical compound C1=CC=CC2=NC(C)=NC(Cl)=C21 HAAZMOAXEMIBAJ-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- YCAGGFXSFQFVQL-UHFFFAOYSA-N Endothion Chemical compound COC1=COC(CSP(=O)(OC)OC)=CC1=O YCAGGFXSFQFVQL-UHFFFAOYSA-N 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- RWSXRVCMGQZWBV-PHDIDXHHSA-N L-Glutathione Natural products OC(=O)[C@H](N)CCC(=O)N[C@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-PHDIDXHHSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 108700042768 University of Wisconsin-lactobionate solution Proteins 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002335 bromhexine hydrochloride Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/10—Preservation of living parts
- A01N1/12—Chemical aspects of preservation
- A01N1/122—Preservation or perfusion media
- A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/10—Preservation of living parts
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Die Erfindung betrifft die Verwendung eines Sekretolyticums aus der Benzylaminreihe in Konservierungslösungen für zur Trans plantation entnommenen Organen, insbesondere der humanen Leber.The invention relates to the use of a secretolytic the benzylamine series in preservation solutions for trans organs taken from the plantation, especially the human liver.
Die erste Lebertransplantation beim Menschen wurde 1963 von Dr. Thomas Starzl durchgeführt (Starz et al., Surg. Gynecol. Ob stet, 17: 659-676, 1963). Danach nahm durch die Zunahme der technischen und medizinischen Behandlungsmöglichkeiten die Le bertransplantationsmedizin an Umfang weltweit gesehen sprung haft zu. Einen limitierenden Engpaß stellt die Verfügbarkeit von vitalen transplantablen Organen dar, die noch erhebliche Defizite aufweist.The first human liver transplant was performed in 1963 by Dr. Thomas Starzl (Starz et al., Surg. Gynecol. Ob stet, 17: 659-676, 1963). After that, increased by the increase technical and medical treatment options the Le Over transplantation medicine jump in scope seen worldwide imprisoned. Availability is a limiting bottleneck of vital transplantable organs that are still substantial Shows deficits.
Eine der wichtigsten Voraussetzungen für den Erfolg der Leber transplantation ist, wie bei allen Transplantationen, die ex trakorporale schädigungsfreie Konservierung des Spenderorgans. Bei der herkömmlichen hypothermen Perfusionskonservierung des explantierten Organs treten jedoch bereits nach wenigen Stunden schwerwiegende Gewebeschäden auf.One of the most important requirements for the success of the liver As with all transplants, transplantation is ex Tracorporal damage-free preservation of the donor organ. In the conventional hypothermic perfusion preservation of the explanted organs appear after a few hours serious tissue damage.
In den US 3.336.308 A, 3.536.713 A und 4.113.777 A werden Benzyl aminderivate und deren physiologisch verträgliche Säureaddi tionssalze mit anorganischen oder organischen Säuren beschrie ben, welche neben einer hustenstillenden Wirkung insbesondere sekretolytische Eigenschaften aufweisen. Hierbei haben die bei den Verbindungen Bromhexin-hydrochlorid [N-Methyl-N-(2-amino- 3,5-dibrom-benzyl)-cyclohexylamin-hydrochlorid] und Ambroxol hydrochlorid [N-(2-Amino-3,5-dibrom-benzyl)-trans-4-hydroxy cyclohexylamin-hydrochlorid] Eingang in die Therapie als Sekre tolytica gefunden.In US 3,336,308 A, 3,536,713 A and 4,113,777 A, benzyl amine derivatives and their physiologically acceptable acid addi tion salts with inorganic or organic acids ben, which in addition to an antitussive effect in particular have secretolytic properties. Here they have the compounds bromhexine hydrochloride [N-methyl-N- (2-amino- 3,5-dibromo-benzyl) cyclohexylamine hydrochloride] and ambroxol hydrochloride [N- (2-amino-3,5-dibromo-benzyl) trans-4-hydroxy cyclohexylamine hydrochloride] Entry into therapy as secretion tolytica found.
Desweiteren ist aus der DE 34 32 411 A1 bekannt, daß die obigen Benzylaminderivate die bakterielle Kontamination u. a. der Lun ge, des Mund- und Rachenraumes sowie des Urogenitaltraktes ver hüten und aus Pneumologie 46, 461-504 (1992) die antioxidative Wirkung von Ambroxol.Furthermore, it is known from DE 34 32 411 A1 that the above Benzylamine derivatives bacterial contamination u. a. the lun ver, the mouth and throat and the urogenital tract ver beware and from Pneumologie 46, 461-504 (1992) the antioxidative Effect of ambroxol.
Überraschenderweise wurde nun gefunden, daß Lösungen von Ben
zylaminen der allgemeinen Formel
Surprisingly, it has now been found that solutions of benzylamines of the general formula
in der
R1 in 2- oder 4-Stellung eine Hydroxygruppe oder in 2-Stellung
eine Aminogruppe,
R2 ein Wasserstoffatom oder eine Methylgruppe und
R3 eine Cyclohexyl- oder Hydroxycyclohexylgruppe bedeuten, ins
besondere die Lösungen von deren physiologisch verträglichen
Säureadditionssalzen mit anorganischen oder organischen Säuren,
auch eine konservierende Wirkung auf zur Transplantation geeig
neten Organe aufweisen.in the
R 1 in the 2- or 4-position is a hydroxyl group or in the 2-position is an amino group,
R 2 represents a hydrogen atom or a methyl group and
R 3 represents a cyclohexyl or hydroxycyclohexyl group, in particular the solutions of their physiologically compatible acid addition salts with inorganic or organic acids, also have a preservative effect on organs suitable for transplantation.
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind
diejenigen, in denen R2 und R3 zusammen mit dem dazwischen lie
genden Stickstoffatom die N-Methyl-cyclohexylamino-, cis-
3-Hydroxy-cyclohexylamino- oder trans-4-Hydroxy-cyclohexyl
aminogruppe darstellen, insbesondere die Verbindungen
N-Methyl-N-(2-amino-3,5-dibrom-benzyl)-cyclohexylamin,
N-(2-Amino-3,5-dibrom-benzyl)-trans-4-hydroxy-cyclohexylamin,
N-(3,5-Dibrom-4-hydroxy-benzyl)-cis-3-hydroxy-cyclohexylamin
und
N-(3,5-Dibrom-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamin
sowie deren physiologisch verträgliche Säureadditionssalze mit
anorganischen oder organischen Säuren.Preferred compounds of the above general formula I are those in which R 2 and R 3 together with the nitrogen atom lying in between represent the N-methyl-cyclohexylamino, cis- 3-hydroxy-cyclohexylamino or trans-4-hydroxy-cyclohexyl amino group , especially the connections
N-methyl-N- (2-amino-3,5-dibromo-benzyl) cyclohexylamine,
N- (2-amino-3,5-dibromo-benzyl) trans-4-hydroxy-cyclohexylamine,
N- (3,5-dibromo-4-hydroxy-benzyl) cis-3-hydroxy-cyclohexylamine and
N- (3,5-dibromo-2-hydroxy-benzyl) trans-4-hydroxy-cyclohexylamine
as well as their physiologically compatible acid addition salts with inorganic or organic acids.
Besonders bevorzugt ist jedoch die Verbindung
N-(2-Amino-3,5-dibrom-benzyl)-trans-4-hydroxy-cyclohexylamin
(Ambroxol) und deren physiologisch verträgliche Säureadditions
salze mit anorganischen oder organischen Säuren.However, the connection is particularly preferred
N- (2-Amino-3,5-dibromo-benzyl) -trans-4-hydroxy-cyclohexylamine (Ambroxol) and their physiologically compatible acid addition salts with inorganic or organic acids.
Gegenstand der vorliegenden Erfindung ist somit die Verwendung von Benzylaminen der obigen allgemeinen Formel I und von deren physiologisch verträglichen Säureadditionssalzen mit anorgani schen oder organischen Säuren in Konservierungslösungen für zur Transplantation entnommenen Organen.The present invention thus relates to the use of benzylamines of the general formula I above and of their physiologically compatible acid addition salts with inorganic or organic acids in preservation solutions for Organs taken from transplantation.
Geeignete Lösungen weisen beispielsweise eine Konzentration von 10-1 Mol/l bis 10-6 Mol/l auf, vorzugsweise jedoch eine Konzen tration von weniger als 10-2 Mol/l. Besonders bevorzugt ist je doch eine Konzentration von 10-2,1 Mol/l bis 10-6 Mol/l, insbe sondere eine Konzentration von 10-2,5 Mol/l bis 10-3,5 Mol/l.Suitable solutions have, for example, a concentration of 10 -1 mol / l to 10 -6 mol / l, but preferably a concentration of less than 10 -2 mol / l. A concentration of 10 -2.1 mol / l to 10 -6 mol / l is particularly preferred, in particular a concentration of 10 -2.5 mol / l to 10 -3.5 mol / l.
Die neue Verwendung der Benzylamine der obigen allgemeinen For mel I wurde am Beispiel des Ambroxol-hydrochlorids am Hepato zytenmodell wie folgt untersucht:The new use of the benzylamines of the general For mel I was using the example of ambroxol hydrochloride on hepato Cytic model examined as follows:
Nach In-situ-Perfusion mit 200 ml Perfusionsmedium und nachfol gend mit Kollagenasepuffer bei 37°C (Fließgeschwindigkeit: 40 ml/Minute) in einer Atmosphäre von 5% CO2 und 95% O2 wur den Lebern von Wistarratten entnommen, mit einer Pinzette zer kleinert und durch ein Sieb gegeben. Die so gewonnene Suspen sion wurde dreimal hintereinander für 2 Minuten bei 50 × g zen trifugiert und zwischendurch mit einem Waschmedium gewaschen. Anschließend erfolgte die Aufnahme der Zellen in ein Kulturme dium (M 199). Im weiteren wurden die avitalen Zellen durch Zen trifugation mit einer Trennmixtur aus der Suspension entfernt, die nunmehr eine Ausgangsvitalität von 95% besaß (Vitalitäts bestimmung durch Trypanexklusionstest). Nachfolgend wurden die isolierten Hepatozyten in Suspensionen von 1,2 (±0,3) × 106 Zellen/ml in 2,5 ml Lösung unter Stickstoffbegasung in Petri schälchen gefüllt, luftdicht verschlossen und bei 4°C in einem Kühlschrank gelagert.After in-situ perfusion with 200 ml of perfusion medium and subsequently with collagenase buffer at 37 ° C. (flow rate: 40 ml / minute) in an atmosphere of 5% CO 2 and 95% O 2 , the livers of Wistar rats were removed with tweezers crushed and passed through a sieve. The suspension thus obtained was centrifuged three times in succession for 2 minutes at 50 × g and washed in between with a washing medium. The cells were then taken up in a culture medium (M 199). Furthermore, the avital cells were removed from the suspension by centrifugation with a separating mixture, which now had an initial vitality of 95% (vitality determination by trypan exclusion test). Subsequently, the isolated hepatocytes were suspended in petri dishes in suspensions of 1.2 (± 0.3) × 10 6 cells / ml in 2.5 ml of solution under nitrogen gassing, sealed airtight and stored at 4 ° C. in a refrigerator.
Als Kontrollgruppen während der Kühllagerung dienten die beiden Trägerlösungen [UW-(University of Wisconsin; siehe Starzl et al., Current Problems in Surgery, Liver Transplantation: A 31 - Year Perspective, Part 1, Year Book Medical Publishers, Inc., 1990, S. 69) und HTK-(Histidin-Tryptophan-Ketoglurat)-Lösung], für die in einem gesonderten Versuch eine zeitabhängige Vita litätskurve erstellt wurde. Nach Erreichung einer Vitalitäts grenze von 50% (LD 50) wurde die hypotherme Lagerung der Zel len beendet und die Konservierungslösung mit dem Kulturmedium M 199 ausgetauscht. Danach erfolgte die Simulation der Reper fusionsphase durch Inkubation der Hepatozyten in einem Brut schrank bei 37°C unter Begasung mit einem Gemisch aus 17% O2 und 5% CO2 für 2 Stunden.The two carrier solutions [UW- (University of Wisconsin; see Starzl et al., Current Problems in Surgery, Liver Transplantation: A 31 - Year Perspective, Part 1, Year Book Medical Publishers, Inc., 1990, served as control groups during cold storage. P. 69) and HTK (histidine tryptophan ketoglurate) solution], for which a time-dependent vitality curve was created in a separate experiment. After reaching a vitality limit of 50% (LD 50), the hypothermic storage of the cells was ended and the preservation solution was exchanged with the culture medium M 199. The reperfusion phase was then simulated by incubating the hepatocytes in an incubator at 37 ° C. with gassing with a mixture of 17% O 2 and 5% CO 2 for 2 hours.
In gleicher Weise wurden weitere Versuchsreihen mit den Basis lösungen unter Zusatz von Ambroxol durchgeführt.In the same way, further test series with the base were made solutions carried out with the addition of Ambroxol.
Kriterien für die Beurteilung der zytoprotektiven Wirkung der Testsubstanzen waren die Vitalität der Suspensionen nach Anfär bung mit 0,02% Trypanblau sowie das Ausmaß der Transaminasen freisetzung und der Radikalbildung, das durch laborchemische Messungen aus dem Zellüberstand der Konservierungslösung be stimmt wurde. Außerdem erfolgte die Messung von Radikalproduk ten (MDA, SOD).Criteria for assessing the cytoprotective effect of the Test substances were the vitality of the suspensions after fermentation exercise with 0.02% trypan blue and the extent of transaminases release and radical formation by laboratory chemistry Measurements from the cell supernatant of the preservation solution was true. Radical product was also measured ten (MDA, SOD).
Pro Versuchsreihe wurden drei verschiedene Leberpräparationen mit je 3 Ansätzen pro Konzentration durchgeführt.Three different liver preparations were made per test series carried out with 3 batches per concentration.
Ergebnis:Result:
10-3 Mol/l Ambroxol in HTK zeigten nach 25 Stunden eine signi fikante Verbesserung der Hepatozytenvitalitätsrate um 73% (p < 0,01) gegenüber 49,7% der Kontrolle (HTK-Lösung) bzw. nach 60 Stunden eine Verbesserung der Hepatozytenvitalitätsrate um 56,7% (p < 0,01) gegenüber annähernd 0% der Kontrolle. Gleich zeitig kam es zu einem deutlichen Abfall der Transaminasen, der MDA und der SOD.10 -3 mol / l ambroxol in HTK showed a significant improvement in the hepatocyte vitality rate by 73% (p <0.01) after 25 hours compared to 49.7% of the control (HTK solution) or an improvement in the hepatocyte vitality rate after 60 hours by 56.7% (p <0.01) compared to approximately 0% of the control. At the same time, there was a clear drop in transaminases, MDA and SOD.
Die vorstehend erwähnten HTK- und UW-Lösungen weisen folgende Zusammensetzungen auf:The HTK and UW solutions mentioned above have the following Compositions on:
-
a) HTK-Lösung
15 mMol/l Na-Ionen
10 mMol/l K-Ionen
15 mMol/l CI-Ionen
4 mMol/l Mg-Ionen
2 mMol/l Tryptophan
1 mMol/l α-Ketoglutarat
30 mMol/l Mannitol
180/18 mMol/l Histidin/Histidin-HCl-Puffera) HTK solution
15 mmol / l Na ions
10 mmol / l K ions
15 mmol / l CI ions
4 mmol / l Mg ions
2 mmol / l tryptophan
1 mmol / l α-ketoglutarate
30 mmol / l mannitol
180/18 mmol / l histidine / histidine-HCl buffer -
b) UW-Lösung
25 mMol/l Phosphat
100 mMol/l Lactobionat
30 mMol/l Na-Ionen
120 mMol/l K-Ionen
5 mMol/l Mg-Ionen
50 g/l Hydroxyethylstärke
17,8 g/l Raffinose
1,34 g/l Adenosin
0,922 g/l Glutathion
100 Einheiten Insulin
0,136 g/l Allopurinol
40 mg/l Sulphamethoxazol
8 mg/l Trimethoprin
8 mg/l Dexamethason
320 mOsm/l bei pH 7.4b) UW solution
25 mmol / l phosphate
100 mmol / l lactobionate
30 mmol / l Na ions
120 mmol / l K ions
5 mmol / l Mg ions
50 g / l hydroxyethyl starch
17.8 g / l raffinose
1.34 g / l adenosine
0.922 g / l glutathione
100 units of insulin
0.136 g / l allopurinol
40 mg / l sulphamethoxazole
8 mg / l trimethoprin
8 mg / l dexamethasone
320 mOsm / l at pH 7.4
Claims (6)
in der
R1 in 2- oder 4-Stellung eine Hydroxygruppe oder in 2-Stellung eine Aminogruppe,
R2 ein Wasserstoffatom oder eine Methylgruppe und
R3 eine Cyclohexyl- oder Hydroxycyclohexylgruppe bedeuten, und von deren physiologisch verträglichen Säureadditionssalzen mit anorganischen oder organischen Säuren, in Konservierungslösun gen für zur Transplantation entnommenen Organen.1. Use of benzylamines of the general formula
in the
R 1 in the 2- or 4-position is a hydroxyl group or in the 2-position is an amino group,
R 2 represents a hydrogen atom or a methyl group and
R 3 represents a cyclohexyl or hydroxycyclohexyl group, and of their physiologically compatible acid addition salts with inorganic or organic acids, in preservation solutions for organs removed for transplantation.
N-Methyl-N-(2-amino-3,5-dibrom-benzyl)-cyclohexylamin,
N-(2-Amino-3,5-dibrom-benzyl)-trans-4-hydroxy-cyclohexylamin,
N-(3,5-Dibrom-4-hydroxy-benzyl)-cis-3-hydroxy-cyclohexylamin und
N-(3,5-Dibrom-2-hydroxy-benzyl)-trans-4-hydroxy-cyclohexylamin
oder deren physiologisch verträgliche Säureadditionssalze mit anorganischen oder organischen Säuren.3. Use according to claim 1, containing
N-methyl-N- (2-amino-3,5-dibromo-benzyl) cyclohexylamine,
N- (2-amino-3,5-dibromo-benzyl) trans-4-hydroxy-cyclohexylamine,
N- (3,5-dibromo-4-hydroxy-benzyl) cis-3-hydroxy-cyclohexylamine and
N- (3,5-dibromo-2-hydroxy-benzyl) trans-4-hydroxy-cyclohexylamine
or their physiologically compatible acid addition salts with inorganic or organic acids.
N-(2-Amino-3,5-dibrom-benzyl)-trans-4-hydroxy-cyclohexylamin (Ambroxol) oder dessen physiologisch verträgliche Säureadditi onssalze mit anorganischen oder organischen Säuren.4. Use according to claim 1, containing
N- (2-Amino-3,5-dibromo-benzyl) -trans-4-hydroxy-cyclohexylamine (Ambroxol) or its physiologically tolerable acid addition salts with inorganic or organic acids.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19720111A DE19720111C2 (en) | 1997-05-14 | 1997-05-14 | Use of a benzylamine series secretolytic in preservation solutions for organs removed for transplantation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19720111A DE19720111C2 (en) | 1997-05-14 | 1997-05-14 | Use of a benzylamine series secretolytic in preservation solutions for organs removed for transplantation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE19720111A1 DE19720111A1 (en) | 1998-11-19 |
| DE19720111C2 true DE19720111C2 (en) | 1999-04-22 |
Family
ID=7829389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19720111A Expired - Lifetime DE19720111C2 (en) | 1997-05-14 | 1997-05-14 | Use of a benzylamine series secretolytic in preservation solutions for organs removed for transplantation |
Country Status (1)
| Country | Link |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4113777A (en) * | 1972-10-23 | 1978-09-12 | Boehringer Ingelheim Gmbh | 2- OR 4-Hydroxy-3,5-dihalo-benzylamines and salts thereof |
| DE3432411A1 (en) * | 1983-09-17 | 1985-04-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | ANTIADHAESIVE PROHYLACTICA AND MEDICINAL PRODUCTS CONTAINING A SECRETOLYTICALLY EFFECTIVE BENZYLAMINE DERIVATIVE |
| DE3610997A1 (en) * | 1986-04-02 | 1987-10-15 | Krewel Werke Gmbh | AMBROXOL NOSE SPRAY |
-
1997
- 1997-05-14 DE DE19720111A patent/DE19720111C2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4113777A (en) * | 1972-10-23 | 1978-09-12 | Boehringer Ingelheim Gmbh | 2- OR 4-Hydroxy-3,5-dihalo-benzylamines and salts thereof |
| DE3432411A1 (en) * | 1983-09-17 | 1985-04-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | ANTIADHAESIVE PROHYLACTICA AND MEDICINAL PRODUCTS CONTAINING A SECRETOLYTICALLY EFFECTIVE BENZYLAMINE DERIVATIVE |
| DE3610997A1 (en) * | 1986-04-02 | 1987-10-15 | Krewel Werke Gmbh | AMBROXOL NOSE SPRAY |
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| Publication number | Publication date |
|---|---|
| DE19720111A1 (en) | 1998-11-19 |
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