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WO1991007983A1 - Protection de structures intra-oculaires - Google Patents

Protection de structures intra-oculaires Download PDF

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Publication number
WO1991007983A1
WO1991007983A1 PCT/FI1990/000286 FI9000286W WO9107983A1 WO 1991007983 A1 WO1991007983 A1 WO 1991007983A1 FI 9000286 W FI9000286 W FI 9000286W WO 9107983 A1 WO9107983 A1 WO 9107983A1
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WO
WIPO (PCT)
Prior art keywords
intraocular
plasmin
eye
protection
proteinase inhibitor
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.)
Ceased
Application number
PCT/FI1990/000286
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English (en)
Inventor
Timo Tervo
Gysbert-Bostho Van Setten
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huhtamaki Oyj
Original Assignee
Huhtamaki Oyj
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 Huhtamaki Oyj filed Critical Huhtamaki Oyj
Priority to FI922393A priority Critical patent/FI922393A0/fi
Publication of WO1991007983A1 publication Critical patent/WO1991007983A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans

Definitions

  • This invention relates to protection of intraocular structures against disintegration caused by irritative stimuli, e.g. mechanical or chemical irritation. Especially the invention relates to the protection of the integrity of the endothelial cells of the cornea. The invention can be used especially in connection with intraocular surgical operations.
  • ocular irritation such as miosis, breakdown of the blood aqueous barrier with increased protein in the aqueous humour, uveal and pericorneal vasodilatation, and elevation of the intraocular pressure are often seen in response to various irritative stimuli, e.g. mechanical irritation (surgery) or chemically induced trauma of the eye.
  • ocular irritative response comprises all these symptoms.
  • Intraocular surgery of the anterior segment of the eye is known to be accompanied by loss of endothelial cells. This may in part be due to surgical manipulations, use of irrigation solutions or direct toxic effects drugs.
  • Endothelial cells show in contrast to other species only a very limited regenerative capacity.
  • endothelial wound healing is achieved mainly not by cell division but by enlargement of neighbouring endothelial cells covering the defect by migration and expansion of their surface resulting in a permanent decrease of endothelial cell density and by this in an impairment of functional capacity.
  • any endothelial cell loss is a serious complication since the endothelial cell
  • S UBSTITUTESHEET layer plays a key role in the maintance of corneal stromal dehydration and transparency.
  • the endothelial cell damage can be partially reduced by the use of gentle operation techniques, often in combination with viscoelastic substances such as sodium hyaluronate.
  • the preoperative use of inhibitors of prostaglandin -synthetase has been suggested.
  • it seems that endothelial cell loss as side effect of anterior segment surgery cannot be avoided with current surgical techniques Draeger, J. , Winter R. : Developments in intracapsular cataract extraction. In: Cataract surgery (Steele, A.D. , Drews, R.C., Eds.) Butterworth International Mediacal Reviews, Ophthalmology 2, Butterworth & Co (Publishers), London, UK, 1984, pp 72-85) .
  • the general idea of the invention resides a method for inhibition of proteolytic"activity in intraocular fluids by applying a therapeutically effective amount of proteinase inhibitor, e.g. plasmin inhibitor such as aprotinin, in the form of a physiologically acceptable preparation.
  • proteinase inhibitor e.g. plasmin inhibitor such as aprotinin
  • SUBSTITUTE SHEET present, and in this way also the disintegration of cells is prevented.
  • the application might be pre-, per-, or postoperative depending on the intention to prevent or to therapy occurence of proteolytic activity in intraocular fluids.
  • the way of drug application may be topical into the conjuctival sac as drop; intracameral, intravitreal or subretinal injections or intravenous infusions.
  • proteolytic activity in ocular fluids after either surgical trauma (mechanical irritation of intraocular structure of the anterior segment of the eye) or chemical induction of sensory axon reflex with capsaicin (neurogenic inflammation) and the inhibition of the proteolytic activity by the use of proteinase inhibitor aprotinin is described hereinafter.
  • SUBSTITUTESHEET capsaicin (8-methyl-N-vanillyl-6-nomenamide) (Sigma, St. Louis, USA) (250 mg) was solved in 2,5 ml ethanol, 2,5 ml tween-80 and diluted in 0,9 % NaCl to a final concentration of 1 %.
  • OIR was provoked mechanically by rubbing with the aspiration needle on the surface of the iris of the right eye of five rabbits.
  • Anterior chamber fluid (ACF) specimens were collected from these eyes before, 15 minutes after and 1 hour after irritation during paracenthesis with a sharp needle attached to a 1 ml syringe.
  • 0,5-1,0 ml 1 % capsaicin solution was injected subconjunctivally to the right eye of four rabbits.
  • the left eye received 0,5-1,0 ml of a control solution (2,5 ml ethanol, 2,5 ml tween-80 and 120 ml 0,9 % NaCl) which was administered subconjunctivally.
  • ACF was collected from both eyes by the use of 1 ml syringes and a sharp needle. 60 minutes after application ACF was collected again from both eyes.
  • ACF was collected before and 30 minutes after injection of 50-150 microl capsaicin (1 %) into the anterior chamber of five rabbits using a sharp needle. To the control eyes only paracenthesis and aspiration of ACF was performed in the same time intervals without injection of any substance. All specimens collected were transferred into Eppendorf-tubes, immediately frozen on dry ice and stored at -70 °C.
  • plasminogen for the assay of PA, purified plasminogen (Plasminogen, Kabi Diagnostica, Sweden, > 20 CU/mg protein) was added to the agarose at 50-56 °C. The final concentration of plasminogen in the agarose was 4 microg/ml.
  • SUBSTITUTESHEET ACF of only one eye contained plasmin activity.
  • the plasmin activity was lower than in the treated eyes and associated with a bleeding into the anterior chamber due to accidental contact of the aspiration needle with the iris during the first aspiration.
  • Proteolytic activity of ACF specimens was shown to be due to plasmin and to be successfully inhibited in vitro by the use of aprotinin.
  • proteolytic activity occursed in the anterior chamber fluid after mechanical stimulation and chemical induction of OIR. This proteolytic activity was shown to be at least in part due to enzymes of the fibrinolytic system, e.g. plasmin, and could be inhibited by proteinase inhibitor, such as aprotinin.
  • Fagerholm P. : Endothelial healing in rabbit corneal alkali wounds, Acta Ophthalmol (Copenh) 65, 1987, 648-656) .
  • the damage of intraocular structures caused by the penetration of alkaline substances into the anterior segment can neither be predicted nor clearly quantified.
  • primary ACF did not contain plasmin activity. This is in accordance to earlier results (Pandolfi, M. , Kwaan, H.C.: Fibrinolysis in the anterior segment of the eye, Arch ophthalmol 77, 1967, 99-104) .
  • OIR produced either by mechanical irritation of the iris (similar to surgical manipulations) or by chemical stimulation of axon reflexes in the anterior segment of the eye was followed by the occurrence of free plasmin in the ACF. Notably the stimulation methods used did not cause any permanent tissue damage.
  • Occurence of plasmin activity in ACF as part of OIR speaks for the development of a acute failure of the inhibitory regulation of the plasmin-plasminogen activator system in the aqueous humor leading to a tilt of the equilibrance towards fibrinolysis. This, in turn, might be due to the initial increase of PA from damaged or affected intraocular tissues such as the iris which is known to contain t-PA activity (Pandolfi and Kwaan, ibid) . In the present study not only the induction of OIR by mechanical manipulation of the iris, but even
  • SUBSTITUTESHEET minor trauma caused by slight contact of the aspiration needle with the iris and associated with consecutive bleeding (one eye) led the occurrence of plasmin in the ACF. Basically the same mechanism is expected to lead to even higher elevation of plasmin activity after the traumatising procedure used in intraocular surgery.
  • the present study shows that the activation of the fibrinolytic system is also essential part of the normal response of the eye to surgical manipulations or induction of OIR. It is even possible that there is a link between the intraocular fibrinolytic system and the intraocular (patho-)physiology of neuropeptides and prostaglandins.
  • intraocular proteinase inhibitors such as aprotinin
  • aprotinin similar to the preoperative application of corticosteroids or inhibitors of prostaglandin-synthesis used in today's practice, might be beneticial in reducing the occurrence and the effects of OIR. It might furthermore enhance the wound healing of structures localized in the anterior segment of the eye after acute trauma (operations) , corrosion injuries, or acute inflammation such as serious intraocular infections (endophthalmitis) .
  • Peroperative administration of proteinase inhibitor may even have protective effects on the adherence of the corneal endothelium to the underlying stroma.
  • fibrin as a temporary sealant to plug retinal holes (Nasaduke, I., Peyman, G.A.
  • thrombin has been shown to catalyse the conversation of fibrinogen to fibrin and appears to be nontoxic to the corneal endothelium (Mannis, M.J. , Sweet, E. , Landers, M.B., 3rd; Lewis, R.A. : Uses of thrombin in ocular surgery. Effect on the corneal endothelium, Arch Ophthalmol 106, 1988, 251-253). Intraocular inhibition of plasmin would also diminish the cleavage of fibronectin molecules inthe anterior segment.
  • Activated leucocytes in turn, especially polymorphonuclear leucocytes (PMNLs) display proteolytic enzymes such as collagenase and plasmin (Prause, J.U. : Cellular and biochemical mechanisms involved in the degradation and healing of the cornea, Acta Ophthalmol (Copenh) Suppl. 168, 1984, 9-10, Kao, W.W.-Y., Ebert, J. , Kao, C.W.-C, Covington, H.
  • proteolytic enzymes such as collagenase and plasmin
  • Cintron, C Development of monoclonal antibodies recognizing collagenase from rabbit PMN; the presence of this enzyme in ulcerating corneas Curr Eye Res 5, 1986, 801-815) .
  • topical aprotinin application has been shown (Salonen, E.-M., Tervo, T. , Torma, E. , Tarkkanen, A., Vaheri, A.: Plasmin in tear fluid of patients with corneal disease: basis for new therapy, Acta Ophthalmol (Copenh) 64, 1987, 3-12, Tervo, T.
  • proteinase inhibitor gives new perspectives for the therapy of acute and possibly also chronic changes of the fibrinolytic system in intraocular fluids of the eye.
  • the initation of the therapy with proteinase inhibitor might be as well pre-, per- or post-operative, the way of administration topical to the external surface of the eye, directly into the anterior or posterior part of the eye or intravenously.
  • Temporary intravenous application of proteinase inhibitor might be as efficient in intraocular inhibition of proteolysis as it has already been shown for the therapy of acute pancreatitis.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (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)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Protection de structures intra-oculaires contre la désintégration provoquée par des stimuli irritatifs. La protection est mise en ÷uvre par application d'un inhibiteur de protéinase dans l'÷il.
PCT/FI1990/000286 1989-11-27 1990-11-26 Protection de structures intra-oculaires Ceased WO1991007983A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI922393A FI922393A0 (fi) 1989-11-27 1990-11-26 Skyddande av intraokulaera strukturer.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI895671 1989-11-27
FI895671A FI895671A7 (fi) 1989-11-27 1989-11-27 Skyddande av intraokulaera strukturer.

Publications (1)

Publication Number Publication Date
WO1991007983A1 true WO1991007983A1 (fr) 1991-06-13

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ID=8529428

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI1990/000286 Ceased WO1991007983A1 (fr) 1989-11-27 1990-11-26 Protection de structures intra-oculaires

Country Status (5)

Country Link
EP (1) EP0502878A1 (fr)
JP (1) JPH05504126A (fr)
AU (1) AU645044B2 (fr)
FI (1) FI895671A7 (fr)
WO (1) WO1991007983A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005322A1 (fr) * 1992-09-04 1994-03-17 Summit Technology, Inc. Agent reducteur de l'activite des plasmines pour le traitement d'une plaie resultant de l'ablation superficielle de la cornee et procede de depistage associe
GB2271507A (en) * 1992-09-04 1994-04-20 Summit Technology Ireland Bv Compositions containing plasmin activity inhibitors
US6638909B1 (en) 1996-11-01 2003-10-28 Ethicon, Inc. Wound healing compositions containing alpha-1-antitrypsin

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223254A2 (fr) * 1985-11-22 1987-05-27 Huhtamäki Oy Utilisation de préparations pour le traitement et la prévention de la destruction d'épithélium
EP0353018A1 (fr) * 1988-07-25 1990-01-31 Kiyoshi Kita Anticoagulant intra-oculaire
WO1990004409A1 (fr) * 1988-10-27 1990-05-03 University Of Kentucky Research Foundation Inhibiteurs de l'elastase de leucocytes humains, leurs procedes de production et d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223254A2 (fr) * 1985-11-22 1987-05-27 Huhtamäki Oy Utilisation de préparations pour le traitement et la prévention de la destruction d'épithélium
EP0353018A1 (fr) * 1988-07-25 1990-01-31 Kiyoshi Kita Anticoagulant intra-oculaire
WO1990004409A1 (fr) * 1988-10-27 1990-05-03 University Of Kentucky Research Foundation Inhibiteurs de l'elastase de leucocytes humains, leurs procedes de production et d'utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005322A1 (fr) * 1992-09-04 1994-03-17 Summit Technology, Inc. Agent reducteur de l'activite des plasmines pour le traitement d'une plaie resultant de l'ablation superficielle de la cornee et procede de depistage associe
GB2271507A (en) * 1992-09-04 1994-04-20 Summit Technology Ireland Bv Compositions containing plasmin activity inhibitors
US6638909B1 (en) 1996-11-01 2003-10-28 Ethicon, Inc. Wound healing compositions containing alpha-1-antitrypsin

Also Published As

Publication number Publication date
AU645044B2 (en) 1994-01-06
FI895671A7 (fi) 1991-05-28
EP0502878A1 (fr) 1992-09-16
FI895671A0 (fi) 1989-11-27
JPH05504126A (ja) 1993-07-01
AU6736790A (en) 1991-06-26

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