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WO1997006815A2 - Solution rinçante aqueuse pour operations endoscopiques - Google Patents

Solution rinçante aqueuse pour operations endoscopiques Download PDF

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Publication number
WO1997006815A2
WO1997006815A2 PCT/EP1996/003579 EP9603579W WO9706815A2 WO 1997006815 A2 WO1997006815 A2 WO 1997006815A2 EP 9603579 W EP9603579 W EP 9603579W WO 9706815 A2 WO9706815 A2 WO 9706815A2
Authority
WO
WIPO (PCT)
Prior art keywords
rinsing solution
oligopeptide
solution according
sequence
oligopeptides
Prior art date
Application number
PCT/EP1996/003579
Other languages
German (de)
English (en)
Other versions
WO1997006815A3 (fr
Inventor
Andreas BÖHLE
Original Assignee
Fresenius Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fresenius Ag filed Critical Fresenius Ag
Publication of WO1997006815A2 publication Critical patent/WO1997006815A2/fr
Publication of WO1997006815A3 publication Critical patent/WO1997006815A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides

Definitions

  • the invention relates to an aqueous rinsing solution for use during and after endoscopic operations and the use of certain oligopeptides or oligopeptide mixtures in such rinsing solutions.
  • endoscopic, transurethral electrosurgery is considered a patient-friendly therapy method, thus the method of choice, e.g. in the treatment of obstructive prostate enlargement, in bladder tumors and for the destruction of bladder stones.
  • the bladder trauma is relatively severe, so that urothelial abrasion and blood clot deposits occur not only at the site of the resection, but also elsewhere.
  • the superficial tumors After such an organ-preserving treatment, however, about 70% of the superficial tumors recur, partly depending on the tumor stage and degree of differentiation, but also depending on other prognostic factors such as tumor size, multifocal growth and accompanying urothelial dysplasia.
  • About 25% of relapsed tumors show a progression, ie a deterioration of the tumor stage or tumor differentiation in relapse compared to the first tumor.
  • a recognized therapeutic measure to prevent such tumor recurrences in the bladder is postoperative intravesical relapse prevention with chemotherapeutic agents (doxorubicin, mitomycin) or immunotherapeutic agents (Bacillus Calmette-Guerin (BCG)), whereby immunotherapy with BCG is the most effective measure of topical treatment.
  • chemotherapeutic agents doxorubicin, mitomycin
  • BCG Bacillus Calmette-Guerin
  • the extent of the tumor cell implantation also varies depending on the resection method used: It could be shown that 620% more cells were released after electrocoagulation than after laser irradiation of tumors of the same size (J. Ural., 137, 1987, 1266-1269).
  • the tumor implantation theory can therefore be regarded as a relevant factor in the frequency of recurrence of superficial bladder cancer (Cancer Res., 50, 1990, 2499-2504).
  • This problem also applies analogously to other conventional endoscopic surgical techniques for removing tumors and for endoscopic operations for the same purpose in other cavities and hollow organs, such as the uterus, pleura, peritoneum, joints, mediastinum and the like.
  • EP 0 380 370 proposes a method for inhibiting tumor recurrence in a local area in connection with tissue resection in this area, an agent being used in this area, which contains an agent for inhibiting the attachment of a tumor cell in the region of the tissue, and the agent contains a synthetic fibronectin peptide which contains the RGD sequence or a YIGSR sequence or the cyclic peptide Gly-Pen-Gly-Arg-Gly-Asp -Ser-Pro-Cys-Ala can be.
  • this driving did not lead to the desired success.
  • the object of the present invention is therefore to provide an agent which does not have the disadvantages of the known agents and is able to effectively prevent or reduce these tumor recurrences, i.e. that enables effective relapse prevention.
  • an aqueous rinsing solution to be used during and after endoscopic operations which is characterized in that it contains one or more oligopeptides, the property of which is to bind to cell adhesion molecules however, an oligopeptide containing only an RGD sequence or a YIGSR sequence as the sole oligopeptide.
  • cell adhesion molecules are understood to mean molecules or groups of molecules which serve to establish contact between cells with one another or between cells and various matrix structures (such as fibronectin, fibrinogen, collagen, vitronectin, laminin).
  • Cell adhesion molecules include e.g. also so-called adhesins or integrins. Oligopeptides of this type are already known (see, for example, US Pat. No. 4,578,079, US Pat. No. 4,614,517, US Pat. No. 4,792,525).
  • the rinsing solution according to the invention preferably contains one or more oligopeptides which contain at least one of the following amino acid sequences: RGD
  • oligopeptide containing only an RGD sequence or a YIGSR sequence as the sole oligopeptide.
  • the cell adhesion molecules such as, for example, integrin receptors located on the tumor cells and thus an adhesion of the tumor cells by means of the cell adhesion molecules (such as, for example, integrin receptors) on them to prevent extracellular matrix (such as fibronectin, fibrinogen, collagen, vitronectin, von Willebrand factor (vWF) or laminin) or to other cells.
  • extracellular matrix such as fibronectin, fibrinogen, collagen, vitronectin, von Willebrand factor (vWF) or laminin
  • one or more oligopeptides can be contained in the rinsing solutions according to the invention. It is essential that such an oligopeptide is used which contains at least one of the amino acid sequences mentioned, or several such oligopeptides are used, each of which contains at least one of the amino acid sequences mentioned.
  • the oligopeptides can contain one or more of the amino acid sequences mentioned, preferably they contain several of the amino acid sequences mentioned.
  • the amino acid sequences mentioned are arranged anywhere in the oligopeptides used according to the invention, e.g. terminal, almost terminal and / or in a central region of the peptide molecule. If several of the amino acid sequences mentioned are present simultaneously in the oligopeptides used according to the invention, these amino acid sequences can be the same or different, preferably different.
  • the oligopeptides can each comprise 3 to 15 amino acids, preferably 3 to 12, in particular 3 to 6 amino acids.
  • the oligopeptides comprise 3 to 9 amino acids.
  • the amino acids are usually in L-form in the oligopeptides; however, one or more amino acids in D-form, in the form of homologues and / or in modified form. If there is no special information, it is the L-form of the amino acid. If one of the amino acids is in D form, this is indicated by the expression “(D *)” in front of the single letter code of the amino acid in question.
  • oligopeptides with the amino acid sequence RGD are: RGD, RGDS, RGDC, RGDT, GRGDS, GRGDTP, RGDF, GRGDSP, GRGD (D *) SP, GRGDNP, n-methyl-GRGDSP, GRGDSPC, GRGDSPK, G (D *) RGDSPASSK, RGDSPASSKP, RGDRGD and the like.
  • RGD RGD
  • RGDS RGDC
  • RGDT GRGDS
  • GRGDS GRGDTP
  • RGDF GRGDSP
  • GRGD (D *) SP GRGDNP
  • n-methyl-GRGDSP GRGDSPC
  • GRGDSPK G (D *) RGDSPASSK, RGDSPASSKP, RGDRGD
  • no oligopeptide which contains only one RGD sequence is contained as the only oligopeptide in the flushing solution according to the invention.
  • Suitable oligopeptides with the amino acid sequence LDV are: LDV, LDVPS, EILDV, LDVLDV, EILDVPST, GLDVG and the like.
  • oligopeptides with amino acid sequence IDA are: IDA, IDAPS, IDAIDA and the like.
  • Suitable oligopeptides with the amino acid sequence DGEA are: DGEA, DGEADGEA and the like.
  • Suitable oligopeptides with the amino acid sequence GPRP are: GPRP, GPRPGPRP and the like.
  • Suitable oligopeptides with the amino acid sequence KQAGDV are:
  • KQAGDV KQAGDVKQAGDV and the like .
  • Suitable oligopeptides with the amino acid sequence REDV are: REDV, REDVREDV and the like.
  • suitable oligopeptides with the amino acid sequence VTL are: VTL, PQVTL, VTLPH, PQVTLPH, PQVTLPHPN, VTLVTL and the like.
  • oligopeptides with the amino acid sequences PHSRN, CRRETAWHC or CWDDGWLG are the oligopeptides PHSRN, CRRETAWHC and CWDDGWLG and the like.
  • Suitable oligopeptides with the amino acid sequence YIGSR are: YIGSRYIGSR, SGYIGSR, RGDSGYIGSR, YIGSR and the like. However, no oligopeptide containing only one YIGSR sequence is contained as the only oligopeptide in the rinsing solution according to the invention.
  • the rinsing solution according to the invention can contain one or more oligopeptides with the amino acid sequence RGD or more RGD amino acid sequences.
  • one or more of the oligopeptides RGD, RGDS, RGDC, RGDT, GRGDS, GRGDTP, RGDF, GRGD (D *) SP, RGDRGD, GRGDNP, n-methyl-GRGDSP, GRGDSPC, GRGDSPK, G (D *) RGDSPASSK, RGDSPASSKP and GRGDSP may be included.
  • the rinsing solution preferably contains RGD, GRGDS, GRGDTP, GRGDNP and / or GRGDSP.
  • the rinsing solution preferably contains a mixture of two or more oligopetides with one or more of the amino acid sequences mentioned.
  • the rinsing solutions according to the invention preferably contain a mixture of oligopeptides with all of the above-mentioned amino acid sequences.
  • the rinsing solutions according to the invention contain the oligopeptide or the oligopeptide mixture in an amount from 1 ⁇ g / ml to 100 mg / ml, preferably from 10 ⁇ p / ml to 10 mg / ml, in particular from 1 mg / ml to 10 mg / ml.
  • the rinsing solutions according to the invention can also be in the form of concentrates which are diluted accordingly immediately before use, e.g. with distilled water or suitable known rinsing solutions.
  • the oligopeptide or the oligopeptide mixture is suitably present in an amount of 10 ⁇ g / ml - 1 g / ml, preferably 100 ⁇ g / ml - 100 mg / ml, in particular 10 mg / ml - 100 mg / ml.
  • the irrigation solutions according to the invention are used for irrigation of the cavities and hollow organs during and after endoscopic operations.
  • Suitable rinsing solutions to which the oligopeptides inhibiting the adhesion of malignant cells can be added are all rinsing solutions that are usually used for endoscopic operations.
  • the rinsing solutions can be electrolyte-free or electrolyte-containing.
  • Non-conductive, electrolyte-free irrigation solutions must be used for high-frequency surgery are used, while using mechanical instruments and in the postoperative rinsing phase, electrolyte-containing rinsing solutions can also be used.
  • Suitable electrolyte-free rinsing solutions are distilled water, rinsing solutions containing mannitol and / or sorbitol, rinsing solutions containing glycine and the like.
  • An example of a rinsing solution containing sorbitol / mannitol is one containing 27.0 g of sorbitol and 5.4 g of mannitol per liter.
  • Suitable electrolyte-containing rinsing solutions are physiological saline, Ringer's solution, Ringer's lactate solution and the like.
  • optical properties of the rinsing solution and the conductivity of the rinsing solution are essentially not impaired by the use of the oligopeptides in the rinsing solutions in the stated concentrations.
  • the flushing solution according to the invention can be used in all endoscopic operations used for tumor resection, both during and after the operation.
  • transurethral electroresections of bladder tumors For example, transurethral electroresections of bladder tumors, laparoscopies with biopsy or resection of malignant tumors, hysteroscopy, pleuroscopy, arthroscopy, mediastinoscopy and the like.
  • the rinsing solutions according to the invention are preferably used in transurethral electroresection of bladder tumors.
  • flushing solutions according to the invention i.e. by using oligopeptides which inhibit or integrate integrally blocking malignant cells in the flushing solutions, such as in urinary bladder flushing solutions, the adhesion of tumor cells released during endoscopic resection to the wall of cavities and hollow organs (e.g. the bladder wall in transurethral electroresections of bladder tumors) effectively prevented and thus the recurrence frequency of the superficial carcinomas of the cavities and hollow organs (eg superficial urothelial carcinoma of the bladder) significantly reduced.
  • the flushing solutions according to the invention i.e. by using oligopeptides which inhibit or integrate integrally blocking malignant cells in the flushing solutions, such as in urinary bladder flushing solutions, the adhesion of tumor cells released during endoscopic resection to the wall of cavities and hollow organs (e.g. the bladder wall in transurethral electroresections of bladder tumors) effectively prevented and thus the recurrence frequency of the superficial carcinomas of the cavities and hollow organs (eg superficial u
  • the flushing solutions according to the invention or the use according to the invention of oligopeptides or oligopeptide mixtures for cavity flushing result in considerable advantages.
  • the principle of action is biological and non-toxic. There is no specific damage to non-malignant cells. Systemic toxicity does not occur if the rinsing solution enters the bloodstream, which may be unavoidable with deep or extensive resection and a large wound area.
  • the flushing solutions according to the invention the burden on the patients is reduced compared to previous treatment methods. The frequency of further treatments is significantly reduced and the aftercare intervals are significantly extended.
  • a bladder irrigation solution was made from the following ingredients:
  • the rinsing solution produced is an electrolyte-free clear solution with an osmolarity of 175 mosmol / 1.
  • This flushing solution can be used in transurethral electroresection of bladder tumors to prevent or reduce tumor recurrences.
  • a concentrate for a bladder irrigation solution was made from the following ingredients:
  • the concentrate thus produced is an electrolyte-free clear solution which has been diluted with distilled water (1 part concentrate and 9 parts water) before use.
  • a further urinary bladder rinsing solution according to the invention was prepared from the components according to Example 1, with the exception that the same amount of the oligopeptide EILDV was used instead of LDV.
  • Example 4
  • a bladder irrigation solution was made from the following ingredients:
  • the rinsing solution produced is an electrolyte-free clear solution with an osmolarity of 270 mosmol / 1.
  • This urinary bladder irrigation solution can be used in transurethral electroresection of hamster tumors to prevent tumor recurrences.
  • a bladder irrigation solution was made from the following ingredients: Sorbitol 27.0 g
  • the rinsing solution produced is an electrolyte-free clear solution with an osmolarity of 300 mosmol / 1.
  • the irrigation solution can be used for transurethral electroresection of hamstring tumors.
  • a bladder irrigation solution was made from the following ingredients:
  • the rinsing solution produced is an electrolyte-containing clear solution with an osmolarity of 285 mosmol / 1. This flushing solution can be used in the postoperative flushing phase to prevent or reduce tumor recurrences.
  • a bladder irrigation solution was made from the following ingredients:
  • the rinsing solution produced is an electrolyte-free clear solution with an osmolarity of 270 mosmol / 1.
  • the urinary bladder irrigation solution can be used in the transurethral electroresection of hamster tumors to prevent tumor recurrences.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des solutions rinçantes aqueuses s'utilisant pendant et après des opérations endoscopiques, qui contiennent un ou plusieurs oligopeptide(s) ayant la propriété de se fixer sur des molécules d'adhésion cellulaire. Les molécules d'adhésion cellulaire sont des molécules ou des groupes moléculaires qui permettent à des cellules ou à des cellules et diverses structures matricielles d'être en contact mutuel. L'utilisation de ces solutions rinçantes permet d'éviter que des cellules tumorales libérées lors de la résection endoscopique n'adhèrent à la paroi de cavités ou d'organes creux, ce qui réduit sensiblement la fréquence de récidives de carcinomes superficiels des cavités et des organes creux concernés.
PCT/EP1996/003579 1995-08-15 1996-08-13 Solution rinçante aqueuse pour operations endoscopiques WO1997006815A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19529909.4 1995-08-15
DE19529909A DE19529909C2 (de) 1995-08-15 1995-08-15 Wässrige Spüllösung

Publications (2)

Publication Number Publication Date
WO1997006815A2 true WO1997006815A2 (fr) 1997-02-27
WO1997006815A3 WO1997006815A3 (fr) 1997-03-20

Family

ID=7769478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/003579 WO1997006815A2 (fr) 1995-08-15 1996-08-13 Solution rinçante aqueuse pour operations endoscopiques

Country Status (2)

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DE (1) DE19529909C2 (fr)
WO (1) WO1997006815A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110470A3 (fr) * 2003-06-12 2005-06-02 Univ Bristol Inhibition d'une infection
US7524819B2 (en) 1999-11-18 2009-04-28 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2010113970A (ru) * 2007-09-11 2011-10-20 Мондобайотек Лабораториз Аг (Li) Применение пептида phpfhlfvy (ингибитора ренина) в качестве терапевтического средства
CA2698968A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent therapeutique
RU2010114027A (ru) * 2007-09-11 2011-10-20 Мондобайотек Лабораториз Аг (Li) Большой гастрин i в качестве терапевтического средства

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2625156B2 (ja) * 1988-06-24 1997-07-02 市郎 東 細胞接着活性コア配列の繰り返し構造からなるポリペプチド
CA2008534A1 (fr) * 1989-01-26 1990-07-26 Donald E. Ingber Methode pour empecher la reapparition des tumeurs apres resection chirurgicale
DE69229004D1 (de) * 1991-11-07 1999-05-27 Univ Southern California Zusammensetzungen und verfahren zur verhinderung der adhäsionbildung

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7524819B2 (en) 1999-11-18 2009-04-28 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US8034774B2 (en) 1999-11-18 2011-10-11 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
US8772237B2 (en) 1999-11-18 2014-07-08 Ischemix, Inc. Compositions and methods for counteracting effects of reactive oxygen species and free radicals
WO2004110470A3 (fr) * 2003-06-12 2005-06-02 Univ Bristol Inhibition d'une infection

Also Published As

Publication number Publication date
DE19529909A1 (de) 1997-02-20
WO1997006815A3 (fr) 1997-03-20
DE19529909C2 (de) 1998-04-09

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