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Patent Abstract
A method for minimizing scarring and preventing excessive scar formation
at an injury site is disclosed. The method involves the topical
and/or local application of a therapeutically effective amount of
a defibrinogenating agent or of a fibrinolytic agent that may be
delivered in an appropriate vehicle in a controlled- or timed-release
manner. In accordance with the principles of the invention, the
defibrinogenating agent or fibrinolytic agent is applied as a coating
on, or is irradiated or impregnated into or onto a delivery vehicle
such as, for example, sutures, dissolvable sutures, bandages, gauze
pads, or other types of first aid bandaging materials. Such application
may take the form of a controlled- or timed-release aspect of either
the vehicle, the delivery material or the therapeutic agent, such
that the release of the therapeutic agent may be regulated to produce
an appropriate therapeutic pattern or defibrinogenation or fibrinolysis.
In a preferred aspect of the invention, the defibrinogenating agent
is ancrod, and the mode of application is as ancrod-coated sutures.
Patent Claims
1. A method for minimizing scarring and/or preventing excessive
scar formation at an injury site, the method comprising applying
to the injury site a first aid bandaging material that has been
coated, irradiated or impregnated with a therapeutically effective
amount of a defibrinogenating agent.
2. The method of claim 1 wherein said first aid bandaging material
is a bandage or gauze pad.
3. The method of claim 1 wherein said defibrinogenating agent is
chosen from the group consisting of ancrod, urokinase, streptokinase,
phenobarbital and valproic acid.
4. A method for minimizing scarring and/or preventing excessive
scar formation at an injury site, the method comprising applying
to the injury site a first aid bandaging material that has been
coated, irradiated or impregnated with, a therapeutically effective
amount of a fibrinolytic agent.
5. The method of claim 4 wherein said fibrinolytic agent is chosen
from the group consisting of tissue-plasminogen activator (t-PA),
recombinant tissue-plasminogen activator (rt-PA), advance-generation
fibrates and a fibrinolytic derivative of recombinant tissue-plasminogen
activator.
6. The method of claim 5 wherein said fibrinolytic derivative of
recombinant tissue-plasminogen activator is chosen from the group
consisting of reteplase (rPA), lanoteplase (nPA) and tenecteplase
(TNK-tPA).
7. The method of claim 5, wherein said advance-generation fibrate
is fenofibrate.
8. A method for minimizing scarring and/or preventing excessive
scar formation at an injury site, the method comprising the use
of sutures or dissolvable sutures to close the wound site, wherein
said sutures or dissolvable sutures have been coated, irradiated
or impregnated with a therapeutically effective amount of a defibrinogenating
agent.
9. The method of claim 8 wherein said defibrinogenating agent is
chosen from the group consisting of ancrod, urokinase, streptokinase,
phenobarbital and valproic acid.
10. The method of claim 9 wherein said defibrinogenating agent
is ancrod.
11. A method for minimizing scarring and/or preventing excessive
scar formation at an injury site, the method comprising the use
of sutures or dissolvable sutures that have been coated, irradiated
or impregnated with a therapeutically effective amount of a fibrinolytic
agent, to close the wound site.
12. The method of claim 11 wherein said fibrinolytic agent is chosen
from the group consisting of tissue-plasminogen activator (t-PA),
recombinant tissue-plasminogen activator (rt-PA), fibrinolytic derivatives
of recombinant tissue-plasminogen activator, advance-generation
fibrates.
13. The method of claim 12 wherein said fibrinolytic derivative
of recombinant tissue-plasminogen activator is chosen from the group
consisting of reteplase (rPA), lanoteplase (nPA) and tenecteplase
(TNK-tPA).
14. The method of claim 11 wherein said fibrate is fenofibrate.
Patent Description
FIELD OF THE INVENTION
[0001] The present invention relates to the use of a defibrinogenating
agent, such as ancrod and fibrinolytic agents irradiated, impregnated
or coated in or on suture material and other first-aid bandaging
materials for the minimization of scarring and the prevention of
excessive topical and/or local scar formation.
BACKGROUND OF THE INVENTION
[0002] Fibrinogen is a protein that is a precursor to fibrin formation.
Fibrin is a protein that initiates blood clots at wound sites. Fibrinogen
and fibrin are believed to play key roles in scar formation at the
injury site. Inflammation is the normal acute reaction of the tissues
after any injury. The immediate response of the blood supply to
the area is a nervous constriction of the vessels. This is followed
immediately by vasodilation that allows fluid to exit the capillaries
and flood the area. The fluid, plasma, contains fibrinogen which
is cleaved to form fibrin strands that form substantial portions
of the blood clot. Eventually, the clot is replaced by granulation
tissue, a connective tissue with a rich blood supply. Collagen and
ground substance (proteoglycans) are produced by the fibroblasts
within the granulation tissue, and a scar forms. Defibrinogenating
agents, which function to reduce or remove circulating fibrinogen,
which converts to fibrin at the injury site, as well as fibrinolytic
agents, which act directly to deplete fibrin, represent a new strategy
for minimizing scarring and/or preventing excessive scarring.
[0003] By removing the clotting precursor, fibrinogen, from the
injury site, a reduction or alteration in fibrin formation and hence
fibrin deposition is seen. Controlled, patterned defibrinogenation
can be used as a strategy for controlling the timing, pattern and
amount of fibrin deposition occurring at an injury site in a way
that allows for sufficient normal fibrin deposition in the early
stages of healing, thereby promoting the initiation of the scarring
process, and then controlling further fibrin deposition to control,
reduce or minimize the extent of scarring as the process continues
to evolve. Since ancrod, as the preferred method, does not cause
the lysis of normal clots already formed, the initial fibrin deposition
to the wound site prior to the introduction of ancrod as a defibrinogenating
agent, is not adversely affected and ancrod administration will
not reverse the positive effects of early fibrin deposition.
[0004] A particularly effective defibrinogenating agent is Empire
Pharmaceutical's brand of ancrod (VIPRINEX.RTM., under license from
Abbott Laboratories Chicago, Ill. USA), a biological derived from
the venom of the Malayan pit viper. The agent consists of a glycosylated
234-amino acid protein.
[0005] Ancrod specifically functions by interfering with the fibrinogen
to fibrin conversion. It has a thrombin-like action with substrate
specificity for fibrinogen, while lacking any effect on Factor XIII,
other coagulation factors or platelets. Any fibrin polymers that
do arise, are rapidly digested by plasmin and eliminated from circulation
via the reticulo-endothelial system. The pharmacological consequence
of this action is the depletion of plasma fibrinogen and the reduction
of erythrocyte aggregation on blood viscosity. The endogenous fibrinolytic
system is strongly activated; indicated by a rise in fibrin degradation
products and other clear indicators of plasmin-mediated fibrinolysis.
[0006] The feasibility of various routes of administration of fibrinolysis-enhancing
agents for the prevention of surgical adhesions is described in
U.S. Pat. No. 6,461,640.
SUMMARY OF THE INVENTION
[0007] In accordance with the principles of the present invention,
Applicant has discovered that the direct application or controlled-
or timed-release local or topical administration of a therapeutically
effective amount of a defibrinogenating agent, such as, for example,
ancrod, urokinase, streptokinase and anticonvulsants such as, for
example, phenobarbital or valproic acid, provides effective treatment
for minimizing or preventing excessive topical and or local scarring
at an injury site.
[0008] In one aspect, therefore, the invention relates to a method
for minimizing scarring and/or preventing excessive scar formation
at an injury site, the method comprising applying to the injury
site a first aid bandaging material that has been coated, irradiated
or impregnated with a therapeutically effective amount of a defibrinogenating
agent. The first aid bandaging material may be any type of bandage
or gauze pad. The defibrinogenating agent is chosen from the group
consisting of ancrod, urokinase, streptokinase, phenobarbital and
valproic acid.
[0009] In another aspect, the invention relates to a method for
minimizing scarring and/or preventing excessive scar formation at
an injury site, the method comprising applying to the injury site
a first aid bandaging material that has been coated, irradiated
or impregnated with, a therapeutically effective amount of a fibrinolytic
agent. In this embodiment of the present invention, the fibrinolytic
agent is chosen from the group consisting of tissue-plasminogen
activator (t-PA), recombinant tissue-plasminogen activator (rt-PA),
advance-generation fibrates, such as fenofibrate and fibrinolytic
derivatives of recombinant tissue-plasminogen activator, such as
reteplase (rPA), lanoteplase (nPA) and tenecteplase (TNK-tPA).
[0010] The invention further provides for the minimization of external
scarring caused by wounds and/or incisions and/or by the use of
sutures in routine wound closure procedures or in the closing of
surgical incisions postoperatively, or any such locally or surgically
invasive procedure where scarring may develop at an incisions, wound
or sutured site.
[0011] In a related aspect, therefore, the present invention relates
to a method for minimizing scarring and/or preventing excessive
scar formation at an injury site, the method comprising the use
of sutures or dissolvable sutures to close the wound site, wherein
said sutures or dissolvable sutures have been coated, irradiated
or impregnated with a therapeutically effective amount of a defibrinogenating
agent such as ancrod, urokinase, streptokinase, phenobarbital and
valproic acid or defibrinlytic agent such as tissue-plasminogen
activator (t-PA), recombinant tissue-plasminogen activator (rt-PA),
advance-generation fibrates, such as fenofibrate and fibrinolytic
derivatives of recombinant tissue-plasminogen activator, such as
reteplase (rPA), lanoteplase (nPA) and tenecteplase (TNK-tPA.
DETAILED DESCRIPTION OF THE INVENTION
[0012] All patents, applications, publications and other references
cited herein are hereby incorporated by reference in their entirety
into the present application.
[0013] The invention applies to the treatment of any prospective
site of scarring, irrespective of the potential degree of scarring
severity, and may include, but is not limited to, applications involving
the potential for excessive scarring in the form of hypertropic
scars, for example.
[0014] In a preferred aspect of the invention, the defibrinogenating
agent is ancrod, available commercially, for example, under the
trade names ARVIN.RTM. or VIPRINEX.RTM. (Empire Pharmaceuticals,
Inc., New York, USA).
[0015] As used herein, the term "ancrod" encompasses
not only products prepared from the ancrod protease isolated from
snake venom, but also any products containing ancrod proteins obtained
through genetic manipulation.
[0016] Methods for the preparation of ancrod from snake venom are
well known, and include, but are in no way limited to, the methods
taught in U.S. Pat. Nos. 6,200,791; 3,743,722 and 3,879,369; Great
Britain Patent documents 1,094,301; 1,177,506 and 1,293,793; and
German patent documents 2,428,955 and 2,734,427. Methods for the
preparation of ancrod products through genetic manipulation are
taught, for example, in U.S. Pat. No. 6,015,685.
[0017] As a further aspect of the invention, Applicant has discovered
that fibrinolytic agents such as tissue-plasminogen activator (tPA),
recombinant tissue-plasminogen activator (rt-PA), fibrinolytic derivatives
of recombinant tissue-plasminogen activator, such as, for example,
reteplase (rPA), lanoteplase (nPA) and tenecteplase (TNK-tPA), as
well as various advance-generation fibrates such as hypocholesterolemic
drugs, such as, for example, fenofibrate, also effectively eliminate
fibrinogen from blood, thereby interfering with the formation of
fibrin and any resulting scarring.
[0018] According to the principles of the invention, the defibrinogenating
or fibrinolytic agent may be administered to the wound site in the
form of a pharmaceutical dosage unit for local administration. Such
dosage unit may take the form of a controlled- or timed-release
aspect of either the vehicle, the delivery material or the therapeutic
agent, such that the release of the administered agent may be regulated
to produce an appropriate therapeutic pattern of defibrinogenation
or fibrinolysis. The pharmaceutical may, for example, be in the
form of sutures, dissolvable sutures, bandages, gauze pads or any
other topical first aid bandaging materials, any of which have been
coated, irradiated or impregnated with the defibrinogenating or
fibrinolytic agent of choice. Preferably, the pharmaceutical dosage
unit will be in the form of ancrod-coated, irradiated or impregnated
sutures (SCARLESS SUTURES.TM., Empire Pharmaceuticals, Inc., New
York, USA).
[0019] To determine if ancrod applied locally to a sutured wound
exerts a systemic defibrinogenating effect and to evaluate the influence
of locally applied ancrod on wound healing and scarring, the following
study is performed.
[0020] Study Design
[0021] Four groups of six rats are studied (24 rats total). Prior
to the study, baseline fibrinogen levels are measured in each rat.
Each rat receives two identical surgically-induced abdominal wounds
which are then sutured. Prior to treatment with a defibrinogenating
agent, fibrinogen levels are then measured at one and two-hours
post-suturing. Subsequently, the animals are treated as follow:
[0022] Group A: IV ancrod is administered to each animal
[0023] Group B: Ancrod is applied locally to one wound and the
other wound is untreated
[0024] Group C: Ancrod is applied locally to both wounds
[0025] Group D: No treatment is administered
[0026] Fibrinogen levels are then measured at 1, 2, 3, 4, 6 and
9 hours post-treatment.
[0027] Evaluation
[0028] Fibrinogen levels are charted and compared between groups.
Wounds are evaluated for dehiscence and bleeding throughout the
study, and the time and duration of each event in relation to the
treatment is recorded. Wounds/scars are photographed and evaluated
for the following parameters at 3, 7, 10 and 14 days post-suturing,
with comparisons being made between scars in each animal and between
scars in groups of animals:
[0029] Overall appearance
[0030] Size
[0031] Color
[0032] Texture
[0033] Intensity
[0034] Fading
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