Treatment and prevention of adhesions

Abstract

An inhibitor of adhesion formation which can be used to prevent adhesions within the abdominal cavity, particularly following surgical intervention, trauma or inflammation in the area is disclosed. Specifically, the most preferred compound of the present invention. Halofuginone, can be used to prevent collagen deposition from occurring within the peritoneum after surgical intervention, thereby inhibiting adhesion formation. Halofuginone, and related compounds, are useful in the prevention and treatment of both inflammatory and surgically induced adhesions, and in the treatment of congenital adhesions.

Description

FIELD AND BACKGROUND OF THE INVENTIONThe 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. ...

AI Technical Summary

Benefits of technology

Two different tests were performed to assess the effect of Halofuginone on the number and severity of adhesions in rats which underwent surgery. Both tests showed that Halofuginone reduced both the number and severity of adhesions. The experimental method was as follows. For the first test, three groups of rats were prepared as described above in Example 2. At the end of 21 days, the rats were weighed and the number and severity of adhesions were determined according to a double-blind procedure.

In the double-blind procedure, adhesions were classified according to the following grading: 0=no adhesions; I=a thin, filmy, easily separated adhesion; II=several thin adhesions; III=a thick, broad adhesion and IV=several thick adhesions. Clearly, 0 is the least severe and IV is the most severe grade.

Table 1 shows the results of Halofuginone treatment on the number and severity o

Problems solved by technology

Although the formation of granulation tissue is clearly an important protective mechanism, it can also lead to the formation of scars.

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, 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.

The formation of adhesions between organs of the abdominal or pelvic cavities is a frequent and undesirable complication of abdomino-pelvic surgery.

Adhesions can cause a number of further complications, such as intestinal obstruction.

Thus, these complications are serious and require substantial further treatment, thereby increasing both the trauma to the patient and the cost of the surgery.

Thus, clearly the problem of adhesion-related complications is growing and methods for treating and preventing adhesions are clearly needed.

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.

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.

Thus, currently available pharmacological methods are clearly not completely successful for the treatment or prevention of adhesions.

However, these barriers have only had limited success in animal models [Sawhney, A. S., et al., J. Biomed. Mater. Res., Vol 28, p.

Furthermore, barrier methods have the disadvantage of requiring direct internal application to the site of trauma, rather than allowing systemic application.

Unfortunately, only a few inhibitors of collagen synthesis are available, despite the importance of this protein in sustaining tissue integrity and its involvement in various disorders.

Unfortunately, none of these inhibitors are collagen-type specific.

Also, there are serious concerns about the toxic consequences of interfering with biosynthesis of other vital collagenous molecules, such as Clq in the classical complement pathway, acetylcholine esterase of the neuro-muscular junction endplate, conglutinin and pulmonary surfactant apoprotein.

Even a drug which was relatively more specific for collagen synthesis, cianidanol, proved to be toxic because of its effects on the synthesis of many types of collagen and because of its effect on other Fe++ ion-binding enzymes, in spite of its ability to decrease the number of post-surgical adhesions in rats [Rivkind, A. I., et al., Arch. Surg. Vol 118, p.

Thus, simply preventing adhesion formation alone does not make a compound useful if it is sufficiently non-specific to cause toxic side effects.

Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastic, another fibrous connective tissue protein, is also cross-linking.

However, none of these studied models adequately predicts the behavior of Halofuginone in the promotion of wound healing or the prevention of abdominal adhesions for a number of reasons.

Second, the prior art does not teach the efficacy of Halofuginone in the treatment or inhibition of adhesions, since tendons and abdominal tissues have very different structures and compositions.

However, none of these cells normally synthesize collagen.

These compounds also inhibit one portion of the mechanism of adhesion formation, yet they were not fully successful in preventing such formation.

Such lack of success is particularly surprising since these compounds inhibit a relatively early stage in the process, where the chance of success might be considered comparatively greater.

Thus, the mere inhibition of one step of adhesion formation does not appear to be sufficient to prevent such formation, or the related complications such as intestinal obstruction.

Thus, the ability of Halofuginone to prevent the formation of abdominal adhesions cannot be predicted from the prior art, since such adhesions could have arisen from any one of these different types of collagen.

However, such a route makes treatment with Halofuginone impractical, since the treatment can then only occur during a surgical intervention.

For certain types of adhesions, such as those caused by pelvic inflammatory disease, surgical intervention is not necessarily desirable.

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