UTILISATION D'INHIBITEURS DE THROMBINE POUR L'INHIBITION DE LA FIBRINE OCULAIRE

USE OF THROMBIN INHIBITORS FOR THE INHIBITION OF OCULAR FIBRIN FORMATION

Abrégé anglais

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Abstract of the disclosure
The use of thrombin inhibitors for the inhibition
of ocular fibrin formation
The use of substances which are able to inhibit the
activity of soluble and fibrin- and cell-bound thrombin,
in particular hirudin, its derivatives, peptides derived
therefrom and low molecular weight thrombin inhibitors in
a process for the preparation of a pharmaceutical for the
inhibition of ocular fibrin formation and deposition is
described.

Revendications

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The use of substances which are able to inhibit the
activity of soluble and fibrin- and cell-bound
thrombin in a process for the preparation of a
pharmaceutical for the inhibition of ocular fibrin
formation and disposition.
2. The use as claimed in claim 1, wherein the thrombin
inhibitor is hirudin, one of its derivatives or a
peptide derived therefrom, which contain sequences
from the amino-acid sequence of hirudin, or is an
analog or generally a functional equivalent of
hirudin.
3. The use as claimed in claim 1, wherein the thrombin
inhibitor is a low molecular weight thrombin
inhibitor.
4. The use as claimed in claim 1, wherein the thrombin
inhibitor is used in a concentration of 0.01 to
20 mg/kg of body weight (oral or i.v. administra-
tion), or of 0.01 to 100 µg/kg of body weight
(intraocular, topical).
5. The use as claimed in claim 1, wherein the thrombin
inhibitor is used in a concentration of 0.05 to
5 mg/kg of body weight (oral or i.v. administration)
and of 0.1 to 10 µg/kg of body weight intraocular,
topical).
6. The use as claimed in claim 1, wherein a pharma-
ceutical or a pack unit which additionally contains
a plasmin inhibitor or a plasminogen activator
inhibitor is prepared.
7. The use as claimed in claim 1, wherein a pharmaceutical or a
pack unit which additionally contains 0.001 to 50 mg/kg
body weight (oral/i.v.) or 0.001 to 100 µg/kg body weight
(intraocular, topical) of a plasmin inhibitor or a plas-
minogen activator inhibitor is prepared.

Description

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B~HRI~GW~RRE ARTI~GESE~LSC~AFT HO~ 92/B 029 - Ma 967
Auslandstext
THE USE OF THROMBIN I~IBITORS FOR T~E IN~IBITIO~
OF OCULAR FIBRI~ FORMATIO~
The invention relates to the use of substances which are
able to inhibit the activity of solubie and fibrin- and
cell-bound thrombin, in particular hirudin, its deriva-
tives, peptide~ derived therefrom and low molecular
weight thrombin inhibitors in a process for the prepara-
tion of a pharmaceutical for the inhibition of ocularfibrin formation and deposition.
The activation of fibrinogen to fibrin represents the
central reaction in the production of a primary wound
closure~ This process which is so important after injury
to the vascular system may, if there is uncontrolled
fibrin formation and deposition Ithrombus), considerably
impair physiological functions.
The crucial contribution to fibrinogen activation is
provided by thrombin,the central protease in blood
coagulation. Fibrin formation and deposition occur at
sites of vascular injury and also extend into
extravascular regions when plasma components, including
fibrinogen, leave the vascular system ~for exampls when
endothelial permeability is increased) as, ~or example,
during the course of certain diseases or during or afker
surgical interventions. The endogenous fibrinolytic
system i.s able after some time to dissolve these fibrin
deposits or thrombi. The situation is usually diferent
with certain eye diseases or after operations on the eye
during the course of which or postoperatively there may
be considerable impairments of vision by fibrin tfor
example dimness, opalescence, starburst effect), in somP
cases associated with pain~ However, the intraocular
activit~ of endogenous fibrinolysis is zero or only very
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low, which means that the impairments frequently last a
long time and may lead to blindness.
The fibrin/thrombus breakdown can be therapeutically
initiated or accelerated by administration of substances
with fibrinolytic activity, such as tissue plasminogen
activator (t-PA). However, treatment of this type may
have disadvantageous effects on wound healing processes.
Moreover, it is known that fibrin degradation products
liberated during these breakdown processes have
chemotactic effects on macrophages and granulocytes and
thus considerably increasP the risk of intraocular
inflammation~
It is therefore expedient to take prophylactic measures
against fibrin formation and deposition. The initial
activation of fibrinogen can be substantially suppressed
by inhibiting the activity of soluble thrombin, as
described in EP-A-0 353 018 for the plasma inhibitor
antithrombin III (AT III ) . AT III displays its complete
activity only in combination with its cofactor heparinO
The efficacy of these substances is, however, limited by
the fact that they are able adequately to inhibit only
soluble thrombin. By contrast, thrombin molecules which
are bound to fibrin or cell surfaces are poorly inhibited
by A~ III/heparin. It is known that such surface-bound
thrombin activities represent a considerable problem
because they cause further fibrin deposits. In addition,
they activate other coagulation factors and thus increa~;e
the risk of ocular thrombi in eye diseases and operatiorls
on the eye.
The object therefoxe was to develop an ocular thrombosis
prophylaxis with ~ubstances which are able to inhibit not
only soluble but also fibrin- and cell-bound throm~in.
The invention relates to the use of substances which are
able to inhibit the activity of soluble and fibrin- and
cell bound thrombin in a process for the preparation of
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a pharmaceutical for the inhibition of ocular fibrin
formation and deposition.
Substances of this type which are preferred ar~ hirudin,
its derivatives, peptides derived therefrom or low
S molecular weight thrombin inhibitors.
Hirudin is a speci~ic thrombin inhibitor which is 7 kDa
in size and is derived from the leech Hirudo medicinalis
and can be prepared by genetic manipulation and which
efficiently inhibits both soluble and surface-associated
thrombin independently of cofactors. Likewise suitable
are derivatives of hirudin, for example those which
contain part sequences from the amino-acid sequence of
hirudin or variants of this sequence, an analog or
generally functional equivalents of hirudin or low
molecular weight thrombin inhibitors with the properties
described above, such as ~2R,4R)-4-methyl-1-[N-~3-methyl-
1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-
2-piperidine and substances described in EP-A-0 097 630
or 0 468 231.
Where ocular fibrin deposits already exist, the use of
these substances is likewise worthwhile because the
QppOSing processes of fibrin deposition and endogenous
thrombus disintegration are shifted in favor of fibrino-
lysis. Therapeutic administration of the corresponding
thrombin inhibi-tors with substances with fibrinolytic
activity, for example intraocularly with t-PA, i~ lik~-
wise used for the said reasons.
These inhibitors are used, for axample, during/after
cataract, glaucoma operations, vitrectomies and la~er-
surgical interventions (for example photocoagulation,laser ablation) during the course of which hyphemas
~hemorrhages in chambers of the eye) with subsequent
fibrin deposition/thrombus formation ara a frequen-t
occurrence. This ~avors inter alia the development of
glaucomas ~interference with the outflow of ~luid). The
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described inhibitors are also used after lens implanta-
tions because the resulting fibrin deposits ~caused inter
alia by the artificial surfaces) may cause iridocyclitis,
inflammation of the iris and of the ciliary body. Also
not uncommon ~re retinal arterial or venous thromhoses
(for example during the course of diabetes mellitus,
autoimmune diseases or after operations), which can be
prevented by the inhibitors. These inhibitors can be used
in combination with volume replacers such as, for
example, hyaluronic acid, for example in surgical inter-
ventions. Suitable for the prophylaxis or therapy of
infl~mmatory or infectious irritations or diseases of the
eye are, correspondingly, combinations with steroidal or
non-steroidal antiinflammatory drugs or antibiotics.
It is additionally possible to use together with the
thrombin inhibitor inhibitors of plasmin as well as
plasminogen activator inhibitors (examples: PAI-1 and
PAI-2), especially inhibitors of urokinase (proteins and
low molecular weight substances).
,.
A pharmaceutical which contains these thrombin inhibitors
and, where appropriate, others of the indicated active
substances can be administered intravenously, orally,
intraocularly or topically (eye drops) before, during or
after operations. It can contain a thrombin inhibitor in
an amount of 0.01 to 20 mg/kg of body weight ~oral or
i.v. administration), preferably 0.05 to 5 mg/kg of body
weight, and of G.01 to 100 ~g/kg o~ body weight ~intra-
ocular, topical), pre~erably 0.1 to 10 ~g/kg of body
weight.
The active sobstances as for example inhibitors of plasmin and/or
plasminogen activator inhibitors which can be administered in
addition to the thrombin inhibitors can be used in an
amount of 0.001 to 50 mg/kg (oral/i.v.), preferably 0.01
to 10 mg/kg~ and of 0.001 to 100 ~g/kg, preferably 0.01
to 10 ~g/kg (in-traocular, topical).
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