Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2000-11-20
2004-04-20
Saucier, Sandra E. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C424S773000, C424S093200
Reexamination Certificate
active
06723354
ABSTRACT:
TECHNICAL FIELD
The invention relates to methods and means for preventing, treating or reducing inflammation by inhibiting proteolytic activity, more specifically, for preventing or reducing inflammations of skin or intestine.
Inflammations of skin (dermatitis) or intestine (enteritis) are of various origin. Initially, allergic reactions, infections with pathogenic micro-organisms, excoriation by chemical or physical means, and other causes are instrumental in causing an inflammation. These causal events are immediately followed by the necessary reaction of the body, resulting in an interplay of actions and events aiming at restoration of the skin or intestine to its original state. In this interplay of cause and effect, various activities of proteolytic enzymes are seen. Granulocyte, mast cells, macrophages and other immediate actors in inflammatory responses and attracted by cytokines to a site of inflammation, contain and secrete proteases, such as chymotryptic protease and elastase, that act as mediators or are instrumental in cleaving and removing proteins derived from pathogens or from the surrounding degenerated tissue. Bacteria, either as primary causal agent or during a secondary infection, and other pathogenic micro-organisms, secrete proteases that damage the surrounding tissue for their purposes. In this battlefield between host and invader, excess proteolytic reactions are kept at bay by, often very specific, protease inhibitors. Well known are proteinase/proteinase inhibitor systems such as PMN-elastase/alpha-1-proteinase inhibitor and cathepsin G/alpha-1-antichymotrypsin.
Proteolytic enzymes in themselves, however, can also be a cause of inflammation. This is especially the case for digestive enzymes which are found in the intestinal tract. In order to degrade dietary protein, the stomach, the pancreas and the small intestinal brush border secrete several kinds of proteases. Pepsin from the stomach works optimal at pH 2, pancreatic and brush border enzymes, such as trypsin, chymotrypsin and elastase work optimal at pH 7-8. In adults, the small intestine has a length of seven meters and the transit time of its contents is about 3 hours. This part of the intestine is colonized by only a few bacteria but is filled with a watery mixture of food and a wide array and large quantities of digestive enzymes, such as lipases and proteases. However, in the large intestine, colon and caecum, the water content is greatly reduced and the activity of the enzymes is neutralized by bacteria. Neutralized and digested remnants of food and bacteria (feces) finally leave the body via the rectum. Only when the colon cannot effectively reduce the water content and neutralize the enzymes, the feces may still contain proteolytic activity, which, during periods of diarrhoea or fecal incontinence, may be very irritating to intra-anal and perineal skin.
The skin, especially of humans, is, although it is protected by the stratum corneum which consists mainly of keratine, as any other proteinaceous substance, very susceptible to the proteolytic action of proteases. Consequently, fluid-like small intestinal content may cause severe inflammation.
In babies and infants, the intestine is much less well developed, especially the colon, and functions different from that in adults. This is the reason why digestive enzymes in feces of babies and infants are not neutralized; the contents of feces resemble more the contents of the small intestine, albeit having passed the colon. Therefore, perineal (perianal) dermatitis is more often found with babies or infants than with adults. Also, hospitalized infants and children with gastro-intestinal disorders are prone to such a dermatitis. Such a dermatitis or prunitis, defined by itchiness, skin erythema, vesiculas, wetness, edema or disruption (excoriation) of perineal skin, is also found with diaper rash and can manifest itself in rather mild to very severe forms. With diaper rash, complicating factors are the accumulation of urine, whereby ureum is converted by fecal bacteria to ammonia, thereby raising the pH to an even better value for the activity of proteolytic enzymes. Since the skin is extremely susceptible to infections, care should be taken to prevent such inflammations related to fecal proteolytic activity.
Yet other cases of dermatitis are found with patients that have undergone resections of colon and/or ileum a-stoma. Pouchitis, an intestinal inflammation, is a major complication of ileoanal anastomosis with reservoir construction after colon resection and is characterized by clinical symptoms and inflammation of the reservoir (pouch). Peristomal (circumstomal) dermatitis is found with those patients that have been provided with an ileostoma that opens up at the surface of the abdomen, ending in an artificial reservoir that needs to be emptied daily. In inflammatory bowel diseases (IBD, such as Crohn's disease (CD), ulcerative colitis (UC) and pouchitis) and inflammation with an unknown etiology, the role of the intestinal flora and pathogens, proteolytic enzymes derived from these micro-organisms and endogenous (e.g., pancreatic or leukocyte/granulocyte) proteolytic enzymes and their contribution to degradation of protecting mucoglycoproteins and the underlying tissues, is not understood.
Especially in the above cases where the colon is removed or its function is affected or immature, it is evident that the proteolytic activity is still very high when the feces are excreted, leading to various degrees of perineal dermatitis.
It goes without saying that many medications and personal care items have been developed in order to remedy the severely itchy and often painful consequences of the above-discussed inflammations. General anti-inflammatory therapy often resorts to treatment with corticosteroids, despite the serious side-effects that are often seen with these medicaments. Other ways of treating are mainly based on providing either a protective layer to the skin, e.g., by applying a lipid-based ointment containing additives such as zinc, or by frequently cleaning an area at risk. Special personal care items have been developed, varying from specific wet wipes for perineal care, diapers that stay very dry despite heavy soiling by the child or patient, to products (stoma care appliances), such as adhesive, absorbing discs and stoma rinsing fluid that are specifically designed for stoma care patients with ileostomy or ileo-anal anastomosis.
However, none of these treatments can really do more than alleviate one or more of the above- and below-described clinical symptoms.
SUMMARY OF THE INVENTION
The invention provides a method for treating, reducing or preventing an inflammation or pruritis by subjecting a mammal to a treatment with at least one inhibitor which is capable of inhibiting proteolytic activity. Preferably, the invention provides a method whereby a protease produced or secreted, for example, granulocytes mastcells, macrophages and other actors in inflammatory processes, is inhibited. The invention is applicable to human and veterinary medicine and care.
A preferred embodiment of the invention is wherein the mammal is a human suffering from, for example, dermatitis or pruritis. Treating for example a dermatitis with a protease inhibitor reduces the proteolytic activity of the proteases involved in the inflammation pruritis. Especially when, in the interplay of causes and effects seen during inflammation, the activity of proteolytic enzymes is too high, the invention provides a method to reduce this activity (be it from host or from invader) by treatment with at least one inhibitor which is capable of inhibiting proteolytic activity.
The treatment is provided by applying the inhibitor in an ointment, cream, gel, powder, or any other suitable form to the location of the inflammation. These substances can, for example, also be carried on wipes impregnated with an inhibitor, in sprays or in rinsing fluid.
In a preferred embodiment of the invention, treatment is provided for an inflammation which is intestinal, perineal or peristom
Laman Jon Daniël
Ruseler-van Embden Johanna Geertruida H.
van Lieshout Leonarda Maria C.
Afremova Vera
Erasmus Universiteit Rotterdam
Saucier Sandra E.
TraskBritt
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