Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reissue Patent
2000-12-08
2002-09-03
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reissue Patent
active
RE037828
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a composition and a method for the treatment and prevention of adhesions, and for the promotion of wound healing, and, more particularly, to a composition and a method for the treatment and prevention of pathological processes associated with wound healing, such as the formation of adhesions within the abdominal-pelvic cavity.
Wound healing is a complex process involving such factors as cells, extracellular matrix (ECM) components and the cellular microenvironment. Essentially, all wound healing involves the repair or replacement of damaged tissues. The precise nature of such repair or replacement depends upon the tissues involved, although all such processes involve certain basic principles. To illustrate these principles, cutaneous, or skin, wound healing will be described, it being understood that the discussion could also extend to all types of wound repair.
Skin has three layers, keratin, epidermis and dermis. If only the epidermis is damaged, as in most minor injuries, keratinocytes migrate from the edge of wound and eventually cover it, reforming the epidermis and keratin [D. R. Knighton and V. D. Fiegel, Invest. Radiol., Vol 26, p 604-611, 1991]. The risk of scar formation is thus relatively low for such minor injuries.
If all three skin layers are damaged or destroyed, new connective tissue, called granulation tissue, must first fill the wound space. This tissue is formed by deposition of ECM components by fibroblasts, which migrate into the wound space [D. R. Knighton and V. D. Fiegel, Invest Radiol., Vol 26, p. 604-611, 1991]. Although the formation of granulation tissue is clearly an important protective mechanism, it can also lead to the formation of scars. Production of ECM components, such as collagen, has been particularly linked to scar formation. Scars on the skin can be both a cosmetic and a functional problem. For example, scar formation following serious burns can restrict the nobility of joints. Scar formation within other types of tissue, such as in the lungs after a bacterial infection, or in many organ tissues following surgery, can be extremely dangerous. One reason scars within organ tissues are so dangerous is that the scar does not duplicate the functionality of the original organ tissue, so that the healing of the wound does not lead to a complete restoration of organ capacity and function. Thus, clearly scar formation can be a pathological process.
However, the deposition of ECM components, such as collagen, is currently believed to also be important for healing of the wound. Indeed, the prior art teaches that the strength of the healing wound is ultimately dependent upon collagen deposition [Haukipuro, K., et al., Ann. Surg., Vol 213, p. 75-80, 1991]. Thus, according to the prior art, collagen deposition must be present at a sufficient level to give the healing wound strength and support, yet not at such a high level to cause the formation of scars.
Another pathological process involved in the repair of damaged tissue is the formation of adhesions. The formation of adhesions between organs of the abdominal or pelvic cavities is a frequent and undesirable complication of abdomino-pelvic surgery. Surgical trauma to the tissue causes the release of a serosanguinous exudate, which forms a fibrous bridge that persists over the 4-5 days required for remesothelialization [Hill-West, J. L., et al., Obstet. Gynecol., Vol 83, p. 59-64, 1994; Sawhney, A. S., et al., Macromolecules, Vol 26, p. 581-587, 1993]. If the exudate is not absorbed or lysed within this period, it becomes ingrown with fibroblasts. Subsequent collagen production and deposition from these fibroblasts directly causes the formation of permanent scar tissue, which can connect the traumatized tissue to another organ, for example [Mahadevan et al., Fertil. Steril., Vol 44, p. 489-92, 1985]. Such permanent scar tissue is called an adhesion. Adhesions may be classified as either acquired (90%) or congenital (10%). The acquired type of adhesion is farther classified into inflammatory or post surgical, the majority being post surgical.
Hereinafter, the term “abdominal adhesion” will include adhesions in both the abdominal and pelvic cavities.
For example, patients undergoing multiple abdominal surgeries can have adhesion rates of up to 93% [Weibel, M. A. and G. Manjo, Am. J. Surg., Vol 126, p. 345-353, 1973]. Post-operative adhesions occur in 60-90% of patients undergoing major gynecological surgery [Monk, B. J. et al., Am. J. Obstet. Gynecol., Vol. 170, p. 1396-1403, 1994]. Thus, adhesions occur at an extremely high rate in patients who have undergone surgery in the abdominal area.
Adhesions can cause a number of further complications, such as intestinal obstruction. About 30-60% of patients who develop intestinal obstructions due to adhesions will require surgery, and a further 11-21% will develop recurrent obstructions [Menzies, D., Ann. Royal Col. Surg. Engl., Vol 75, p. 147-153, 1993]. Thus, these complications are serious and require substantial further treatment, thereby increasing both the trauma to the patient and the cost of the surgery. Indeed, in one surgical unit, 1% of all surgical admissions and 3% of all laparotomies were required for treatment of adhesions [Menzies, D., Ann. Royal Col. Surg. Engl., Vol 75, p. 147-153, 1993]. Furthermore, the frequency of intestinal obstructions caused by adhesions has increased steadily, from 7% in 1932 to about 60% in 1993[Vick, R. M., Br. Med. J., Vol 2, p. 546-548, 1932; Menzies, D., An. Royal Col. Surg. Engl., Vol 75, p. 147-153, 1993]. Thus, clearly the problem of adhesion-related complications is growing and methods for treating and preventing adhesions are clearly needed.
Other adhesion-related complications which can arise after pelvic surgery include chronic pelvic pain, voiding dysfunction and infertility [Monk, J. B. et al., Am. J. Obstet. Gynecol., Vol. 170, p. 1396-1403, 1994]. Adhesions can also arise from pelvic inflammatory disease, which is an important cause of infertility [Monk, J. B. et al., Am. J. Obstet. Gynecol., Vol. 170, p. 1396-1403, 1994]. Drugs such as cyclosporine can also cause adhesions and retroperitoneal fibrosis [D. M. Davies, ed., Textbook of Adverse Drug Reactions, Third Edition, Oxford University Press]. Thus, adhesions have many causes and can have serious and far-ranging consequences.
Unfortunately, no currently available method of treating and preventing adhesions is successful, particularly for blocking the mechanism of adhesion formation. For example, povidone-iodine was found to reduce the number of peritoneal adhesions after surgery by 35% in rats, but this effect was due to an anti-microbial effect, rather than a direct inhibition of adhesion formation [Gilmore, O. J. A. and C. Reid, J. Surg. Res., p. 477-481, 1978]. Another drug, dextran, was used by gynecological surgeons for adhesive prevention in infertility surgery but with little success [Holtz, G. et al., Fertil. Steril., Vol 33, p. 660, 1980]. Other compounds which have been tried include various plasminogen activators and fibrinolytic agents. These compounds were used because of the known fibrinolytic property of the peritoneum, resulting from the production of plasminogen activator. This production is reduced following trauma to the peritoneum, which may allow fibrin to form adhesions between traumatized areas [Raferty, A. T., Eur. Surg. Res., Vol 13, p. 397-401, 1981]. However, attempts to block fibrin deposition by using plasminogen activators and/or fibrinolytic agents has not proved routinely successful in rats, although some success was reported in rabbits [Rivkind, A. I., et al., Eur. Surg. Res., Vol 17, p. 254-258, 1985; Menzies, D. and H. Ellis, J. R. Soc. Med., Vol 82, p. 534-553, 1989]. Thus, currently available pharmacological methods are clearly not completely successful for the treatment or
Nagler Arnon
Pines Mark
Hadasit Medical Research Services & Development Co., Ltd.
Spivack Phyllis G.
Webb & Associates
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