Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0031—Rectum, anus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• This invention relates to novel compositions and novel methods of treating inflammatory bowel disease (IBD). More particularly, this invention pertains to novel compositions containing N-acetylglucosamine (NAG) as an active IBD treating agent and a pharmacologically and colonically suitable carriers for the NAG, and a method of administering the compositions to the colon to treat IBD in a person afflicted with IBD.
• IBD inflammatory bowel disease
• the "bowel” extends from the stomach to the anus and comprises the small intestine and the large intestine.
• the small intestine comprises three main sections, the duodenum (which is adjacent to the stomach), the jejunum (which is intermediate) and the ileum (which is distant to the stomach).
• the large intestine (which is termed the colon) is joined to the remote end of the ileum of the small intestine by the ileocecal valve.
• the large intestine (colon) comprises two main sections, the caecum (which is connected to the ileum of the small intestine), and the rectum, which is the remote part of the large intestine (colon). The remote end of the rectum is connected to the anus.
• IBD inflammatory bowel disease
• Ulcerative colitis is a chronic, non-specific inflammatory bowel disease which involves ulcerative lesions of the colon.
• Chronic proctitis comprises inflammation of the colon and often the rectum.
• Crohn's disease appears as several types of intestinal inflammation but most often the term refers to inflammation of the terminal portion of the ileum.
• Crohn's disease Synonyms of Crohn's disease are regional enteritis (the intestine) or regional iletis, although the latter is not always apt since Crohn's disease is not limited to the ileum. Crohn's disease often involves diseases, fistulas (deep sinnous passages or tracts in the colon), perianal ulcerations and narrowing of the intestinal lumen (strictures). Surgical removal of the diseased portion of the intestine (termed a colectomy, or ileectomy) is reserved for those cases which are most resistant to treatment, since about half of those treated by surgery experience a recurrence of the disease in another segment of the intestine. The most common clinical symptoms of Crohn's disease include abdominal pain, fever, anorexia, weight loss and a right lower quadrant "fullness".
• IBD Inflammatory bowel disease
• GAGs vascular and matrix glycosaminoglycans
• S.H. Murch, et al., Reference 3 in Bibliography Organ culture shows this disruption is due to the presence of matrix degrading enzymes (see S.L. Pender, et al., Reference 6 in Bibliography).
• inflammatory bowel disease has conventionally been treated by the use of steroidal anti-inflammatory drugs such as cortisone or sulphasalazine, or antispasmodic agents such as propantheline and dicyclomine, supplemented with laxative or anti-diarrheal drugs, as well as drugs which reduce intestinal motility, depending on symptoms.
• steroidal anti-inflammatory drugs such as cortisone or sulphasalazine
• antispasmodic agents such as propantheline and dicyclomine
• drugs which reduce intestinal motility depending on symptoms.
• 5-aminosalicylic acid (5- ASA) and related drugs which are considered the active moiety of sulphasalazine, have been found to be effective in the treatment of inflammatory bowel disease.
• Their action may be related to an ability to remove irritating superoxide radicals formed in inflamed tissues.
• immunosuppressant drugs such as azathioprine
• the invention is directed to a composition for treating inflammatory bowel disease in a patient suffering from inflammatory bowel disease comprising:
• the N-acetylglucosamine can be present in the composition in an amount ranging from 0.5 gram to 5 grams.
• the carrier can be any medium which delivers the N-acetylglucosamine to the diseased area of the bowel.
• the carrier can be distilled or purified water, a foam suitable for rectal administration, a suppository base which can surround the N-acetylglucosamine, or an orally ingestible time-release substance which can withstand degradation by the gastric acids of the stomach and can release the N-acetylglucosamine in the bowel or colon.
• the water can be present in sufficient quantity to comprise an analeptic enema.
• the foam can comprise N-acetylglucosamine, a surfactant, an adjuvant and a blowing agent.
• the carrier can comprise one or more substances selected from the group consisting of propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, ethoxylated cetyl and stearyl alcohols, stearath-10, cetyl alcohol, methyl paraben, propyl paraben, trolamine, purified water, cetyl alcohol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether, methyl and propyl parabens, propylene glycol, dry ethanol amine, de-ionized water and suitable propellents.
• the suppository base can be selected from the group consisting of theobroma oil, glycerinated gelatin, hydrogenated vegetable oil, polyalkyl glycol, fatty acid ester of poly alky lene glycol, coconut oil base, hydrogenated fatty acid, hydrogenated vegetable oil, monoglyceride, cocoa butter, petroleum oil, beeswax, glycerine, polyethylene glycol 600 dilaurate, hydrogenated cocoa glyceride and polyethylene glycol.
• the time release substance can be selected from the group consisting of an acrylic-based resin coating, a methacrylic acid copolymer, an acrylic-based resin mixed with a suitable non-medicinal carrier such as lactose, magnesium stearate, polyethylene glycol, polyvinyl pyrolidone, or sodium starch glycolate, cellulose or ethyl cellulose, a matrix composition comprised of a hydrophilic polymer and an enteric polymer, a cellulose derivative, polyvinyl acetate phthalate, or polyvinyl acetate phthalate mixed with a plasticizer, a polysaccharide which is decomposable in the bowel, a locust bean gum or a guar gum, a film-forming polymer having hydrophilic groups, a film-forming acrylic polymer in admixture with a polysaccharide comprising from 30 to 100% by weight of at least one monomer selected from the group consisting of lower alkyl esters of acrylic acid and lower alkyl esters
• the foam can comprise 0.5 to 5 grams of N-acetylglucosamine as the active ingredient and 20 grams of a foam containing propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben and propylparaben, trolamine, purified water and inert propellents, dichlorodifluoromethane or dichlorotetrafluoroethane.
• composition can comprises between about 0.1 % by weight to about
• N-acetylglucosamine 90% by weight of N-acetylglucosamine, coated with about 5% by weight to about 29% by weight of a hydrophilic polymer, and from about 0.5% by weight to about
• the invention is also directed to a method of treating a patient suffering from inflammatory bowel disease comprising administering to the bowel of said patient a composition comprising a therapeutic amount of N-acetylglucosamine and a bowel compatible and pharmacologically acceptable carrier.
• the N-acetylglucosamine can be present in an amount between about 0.5 gram and 5 grams per enema.
• the pharmacologically acceptable carrier can be distilled or purified water, a bowel compatible foam which can coat the colon, a suppository which can be solid at room temperature but melt at body temperature, or an orally ingestible time-release substance which can withstand degradation by the gastric acids of the stomach and release the N-acetylglucosamine in the bowel. - 6 -
• the enema can be administered to said patient by an enemator.
• Figure 1 depicts a histological section of rectal tissue prior to treatment with N-acetylglucosamine.
• Figure 2 depicts a histological section of rectal tissue after treatment with N-acetylglucosamine.
• Figure 3 depicts a higher magnification of the histological section depicted in Figure 1.
• Figure 4 depicts a higher magnification of the histological section depicted in Figure 2.
• IBD inflammatory bowel disease
• NAG N-acetylglucosamine
• a bowel and pharmacological acceptable carrier which can be distilled or purified water, a foam enema, a suppository, or a time-release carrier which can be ingested orally and passes largely unscathed through the stomach and releases the N-acetylglucosamine in the upper bowel or colon.
• the time release coating protecting the N-acetylglucosamine from attack by the gastric stomach acids can be an acrylic-based resin coating which delays release of the N-acetylglucosamine until the acrylic-based resin coated N-acetylglucosamine reaches the upper intestine or lower intestine, depending on the nature of the carrier.
• a suitable acrylic acid can be Eudragit STM, which is a methacrylic acid copolymer.
• the N-acetylglucosamine which is coated by the acrylic-based resin can be mixed with a suitable non-medicinal carrier such as lactose, magnesium stearate, polyethylene glycol, polyvinyl pyrolidone, or sodium starch glycolate.
• the gastric acid resistant coating can also be a matrix composition which is comprised of a hydrophilic polymer and an enteric polymer.
• the enteric polymer is impermeable to gastric fluids of the stomach and aids in retarding release of the N-acetylglucosamine in regions of low pH, thereby allowing lower levels of N-acetylglucosamine to be employed.
• the hydrophilic polymer and enteric polymer dissolve and thereby release the N-acetylglucosamine in the bowel.
• a specific formulation can comprise between about 0.1 % by weight to about 90% by weight of the N-acetylglucosamine, coated with about 5% by weight to about 29% by weight of a hydrophilic polymer, and from about 0.5% by weight to about 25% by weight of an acrylic polymer which dissolves at a pH in the range of about 5.0 to about 7.5.
• the acrylic resin should be formulated so that it withstands dissolution and attack at a pH of less than 5, but decomposes at a pH ranging from about 5 to about 8.
• a further suitable coating can comprise a cellulose derivative such as polyvinyl acetate phthalate, or polyvinyl acetate phthalate, mixed with a plasticizer. The latter is normally decomposable at a pH in the range pH of about 3 to about 6.
• a further suitable coating can be a polysaccharide, which is decomposable in the colon, such as a locust bean gum or a guar gum, and a film- forming polymer preferably having hydrophilic groups. Such coatings are decomposed under the influence of glycosidic enzymes in the colon.
• the polysaccharide, which is decomposable in the colon should contain galactose and - 8 -
• the film-forming acrylic polymer in admixture with the polysaccharide should comprise from about 30 to 100% by weight of at least one monomer selected from the group consisting of lower alkyl esters of acrylic acid and lower alkyl esters of methacrylic acid.
• a further suitable coating used in the form of a membrane surrounding the core of the N-acetylglucosamine, and suitable non-medicinal carriers can be a pharmaceutically acceptable, film-forming anionic carboxylic polymer which is difficult to dissolve at a low pH of less than 4, but is soluble at a higher pH ranging from about 4 to about 7.5.
• a further suitable gastric acid resistant coating can be a hydrocoUoid gum obtained from higher plants, admixed with a suitable pharmaceutically acceptable binder.
• the suppository can be a small solid body shaped for ready introduc- tion into the rectum, made of the N-acetylglucosamine enclosed in a carrier substance which is hydrophilic and solid at ordinary ambient temperatures but melts at body temperature.
• the bases for the suppository can be theobroma oil, glycerinated gelatin, hydrogenated vegetable oil, a mixture of polyethylene glycols of various molecular weights, and/or fatty acid esters of polyethylene glycol.
• the body temperature melting coatings which envelope the N- acetylglucosamine can be selected from a wide group of materials and substances such as coconut oil base, hydrogenated fatty acids, or hydrogenated vegetable oils, formulated to be solid at ambient room temperature, but which dissolve at body temperature.
• Other suitable coatings can be monoglycerides, cocoa butter, vegetable and petroleum oils, beeswax, glycerine, polyethylene glycol 600 dilaurate, - 9 -
• the polymeric material should be dissolvable in body fluids, and preferably be capable of slowly releasing the N- acetylglucosamine into the rectal area while the polymeric material is dissolving in the body fluids.
• the film can comprise a water-soluble polymer which is bio- erodable and contains the active N-acetylglucosamine.
• the rectal foam can typically be 0.5 to 5 grams of N-acetylglucosamine as the active ingredient in 20 g of a foam containing propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben and propylparaben, trolamine, purified water and inert propellants, dichlorodifluoromethane and dichlorotetrafluoroethane.
• the foam should be hydrophilic and can be made up of propylene glycol, ethoxylated cetyl and stearyl alcohols, stearath-10, cetyl alcohol, methyl paraben, propyl paraben, trolamine and purified water, with dichlorodifluoromethane and dichlorotetrafluoroethane as propellents or blowing agents.
• foam causing carriers for the N-acetylglucosamine comprising a water miscible mucoadhesive foam base
• foam causing carriers for the N-acetylglucosamine comprising a water miscible mucoadhesive foam base
• the liquid vehicle which can create the foam should include at least one surfactant, a foaming propellent such as an environmentally benign halocarbon, and an adjuvant for the active ingredients, namely, N-acetylglucosamine, which is capable of suspending or solubilizing the N- acetylglucosamine in the foam.
• a foaming propellent such as an environmentally benign halocarbon
• an adjuvant for the active ingredients namely, N-acetylglucosamine, which is capable of suspending or solubilizing the N- acetylglucosamine in the foam.
• N-acetylglucosamine and its precursor, glucosamine, are classified biochemically as amino sugars.
• Amino sugars are essential biochemical compounds formed from blood glucose by most cells of the body through a series of biochemical reactions, which were elucidated many years ago. Other amino sugars include galactosamine and mannosamine and their N-acetyl-derivatives.
• N-acetylglucosamine is the precursor of N-acetylgalactosamine and N-acetylmannosamine and thus, - 10 -
• N-acetylglucosamine plays an important role in the availability of all amino sugars which are incorporated into functional complex carbohydrates, such as glycosaminoglycans (GAG's).
• GAG's glycosaminoglycans
• N- acetylglucosamine is available in commercial quantities at reasonable cost.
• N-acetylglucosamine and related amino sugars are components of a large number of high molecular weight complex polysaccharides, including the functionally important glycosaminoglycans and proteoglycans, formerly referred to as mucupolysaccharides.
• Glycosaminoglycans are composed of repeating disaccharide units of N-acetylglucosamine or related amino sugars, and glucuronic or iduronic acid.
• glycosaminoglycans examples include hyaluronic acid (which is made up of repeating units of N-acetylglucosamine and glucuronic acid), chondroitin sulphate, dermatan sulphate, keratan sulphate and heparin, all of which contain either N- acetylglucosamine or the amino sugar N-acetylgalactosamine, which is synthesized from N-acetylglucosamine.
• Glycosaminoglycans are also present in proteoglycans, which are structures containing a number of glycosaminoglycans chains linked to a polypeptide or protein core.
• N-acetylglucosamine plays an important role in the normal maintenance of cell function, including the permeability of cell membranes, the structural integrity of connective tissues such as skin and cartilage, and joint lubrication.
• glycosaminoglycans are essential to the formation of the glycocalyx of gastrointestinal cells and the mucous secreted by the intestinal goblet cells. As well, they are essential components of the extracellular fluid or "glue" which holds cells together, immunoglobulins, blood group antigens and a wide diversity of other biochemically and immunologically important substances.
• the extracellular matrix composed largely of proteoglycans containing
• N-acetylglucosamine is present in the basement membrane, as well as the lamina propia, and the submucosa of the gastrointestinal tract.
• Proteoglycans containing N- acetylglucosamine play an important function in anchoring cells to the - 11 -
• mucopolysaccharide layer on the epithelial cells lining the gastrointestinal tract as well as cell repair and intestinal permeability.
• N-acetylglucosamine is found in all cells and tissues of the body as a component of glycosaminoglycans and proteoglycans, it appears that, unlike glucose, significant concentrations of free N-acetylglucosamine or its precursor, glucosamine, are not available in the blood or intracellular fluids. Under normal conditions, the body utilizes all the available N-acetylglucosamine it produces. In disease states, such as those involving inflammatory reactions of the gastrointestinal tract (IBD), the body reserves of N-acetylglucosamine may be inadequate to support cellular repair and function at an optimal level. It has been demonstrated (see Burton et al.
• N-acetylglucosamine When N-acetylglucosamine is given to animals or humans, either intravenously or by mouth, it is quickly distributed throughout the body and incorporated within minutes into glycosaminoglycans and proteoglycans in most tissues and organs, including the intestinal tract and articular cartilage of joints. Free N-acetylglucosamine has a half-life in blood of less than ten minutes, but when incorporated into glycosaminoglycans, the N-acetylglucosamine contained in these complex molecules turns over very slowly, with a half-life measured in hours, and even days.
• N-acetylglucosamine is a natural amino sugar belonging to a class of compounds that are usually very well tolerated. Monosaccharides, and their simple derivatives, are widely used in medicine even at high doses. Even when given by intravenous administration, N-acetylglucosamine is considered to be very safe. Specifically, no mutagenicity, carcinogenicity or teratogenicity are to be expected. - 12 -
• N-acetylglucosamine Single intravenous or oral doses of N-acetylglucosamine of over 25 grams/kg body weight administered to mice or rats have resulted in no observed toxic effects. Intravenous dosing of 20 grams of N-acetylglucosamine to humans had no adverse effects, did not affect blood glucose or insulin levels, and is therefore considered safe for use by diabetics.
• N- acetylglucosamine is non-toxic at doses substantially greater than those used for most medicinal purposes. Oral administration at doses of up to 3 to 6 grams/kg body weight per day for 30 days had no toxic effects, and resulted in no gross or microscopic changes in various tissues and organs. N-acetylglucosamine has been used orally, as a human nutritional supplement, at doses of up to 3 grams per day without adverse effects. For the past several months, we have administered up to 4.5 grams per day orally, or 3 grams daily rectally, to children with no adverse consequences.
• N-acetylglucosamine is more readily absorbed into cells as a result of its passive diffusion across cell membranes, as compared to the apparent active transport mechanism (a complex, energy requiring system) required for the intracellular distribution of glucosamine.
• active transport mechanism a complex, energy requiring system
• glycosaminoglycans from the intestinal wall which results in the bowel wall becoming abnormally thick, or fibrotic. When this occurs, the permeability and function of the gut is impaired.
• Crohn's Disease is an inflammatory condition in which inflammation and ulcerations may be distributed along any part of the entire gut.
• fibrosis of the gut may be extensive causing luminal narrowing, resulting in bowel obstruction.
• Both ulcerative colitis and Crohn's Disease can become serious and may require intensive drug therapy or surgery.
• Patients with inflammatory bowel disease exhibit high cellular turnover in the gut wall, often leading to ulceration or fistulas.
• Diverticulitis is a more common, but less severe gastrointestinal condition that is often categorized with inflammatory bowel disease.
• This disorder is an inflammation of one or more diverticular, which are sac-like outpouchings of the colon wall that occur at weak points.
• the cell wall of the colon is primarily affected and the symptoms range from relatively minor discomfort to painful perforation of the intestinal lining. Diet has been implicated as a causative or contributing factor to the development of diverticulitis, which is also associated with increasing age, being uncommon in individuals under the age of 35.
• the disorder is progressive, developing from mild symptoms to painful inflammation. Early stages of diverticulitis may respond to a modified diet, but later stages require medication or surgery.
• GAG's glycosaminoglycans
• N-acetylglucosamine preventing or replacing the bowel wall glycosaminoglycans in inflammatory bowel disease, we have observed that N- acetylglucosamine has a significant effect in stimulating the synthesis of hyaluronic acid when applied to the intestinal epithelium or to human mesothelial cells isolated from the intestinal peritoneum.
• N-acetylglucosamine is a preferential precursor in the synthesis of the constituent glycosaminoglycans and proteoglycans in the inflamed and damaged tissues occurring in inflammatory bowel disease. This research suggests that the oral administration of N-acetylglucosamine supplements the body's supply of the essential amino sugars when under the stress of excessive tissue breakdown and loss.
• N-acetylglucosamine N-acetylglucosamine
• TAB trinitrobenzenesulfonic acid
• N-acetylglucosamine When N-acetylglucosamine was placed on the mucosal surface of the stomach, copious quantities of mucus were observed being released from the goblet cells of the stomach. On the basis of this observation, additional experiments were carried out in which it was found that in the presence of ethanol (which is a gastric irritant), N- acety lglucosamine , but not glucosamine , caused a significant reduction in the potential difference between the mucosal and serosal surfaces. This phenomenon may be a result of N-acetylglucosamine stimulating the synthesis of sulphated glycosaminoglycans. The effect of N-acetylglucosamine in stimulating mucus release by the stomach may explain the anecdotal clinical claims that N-acetylglucosamine is effective in the treatment of non-erosive gastritis.
• N-acetylglucosamine is a substrate for glycosaminoglycans production, but in addition to its role as a fuel in fibroblast matrix synthesis, there is evidence that N-acetylglucosamine can act intracellularly as an antagonist of O- phosphorylation and may thereby regulate many inflammatory pathways.
• N-acetylglucosamine would provide a significant clinical benefit.
• three with upper inflammatory bowel disease have responded well, with one child doing better than on any previous therapy.
• Three children with lower inflammatory bowel disease did not demonstrate significant therapeutic response with oral N-acetylglucosamine. This is not unexpected since only a small fraction of each oral dose would be expected to reach the diseased tissue in the lower bowel.
• N-acetylglucosamme In order to expose the inflamed colon to a higher concentration of N- acetylglucosamme, patients with lower inflammatory bowel disease have been administered N-acetylglucosamine by rectal enema at a dose of 1 to 2 grams three times a day. The initial three patients had symptomatic clinical improvement within forty-eight hours of initiating therapy. Pre- and post-biopsies of the colon of several children indicated that, after six weeks of rectal N-acetylglucosamine therapy, there was a significant improvement in the histopathology of the bowel wall.
• Figure 1 is a section from the pre-N-acety lglucosamine treatment biopsy, and clearly demonstrates that prior to N-acetylglucosamine therapy, an atrophic epithelium with heavy inflammatory infiltrate and fibrosis was present. Pre-treatment there was an almost complete void of villi and the epithelial membrane was virtually absent.
• the post-N-acetylglucosamine treatment biopsy (Figure 2) indicates the presence of significantly less inflammatory infiltrate, as well as an increase in the number of villi and an almost normal epithelial membrane.
• Figures 3 and 4 are pictures of the same biopsies depicted in Figures 1 and 2, but at a higher magnification. An important finding is the significant reduction in the fibrosis of the bowel wall.
• NAG is of therapeutic efficacy in resistant IBD, with a mode of action distinct from conventional therapies. Its lack of known adverse effects makes it particularly suitable for therapeutic use.
• NAG N-acetylglucosamine
• SB Severe long-term inflammation of rectal stump, unresponsive to corticosteroid enemas, metronidazole and ciprofloxacin. Commenced NAG enemas April, 1997, dose 1 gram twice daily rectally. Only minor clinical improvement reported at 2 months, but significant histological response compared to - 20 -
• MS Intractable inflammation of rectal stump, unresponsive to cyclosporine, corticosteroids and antidiarrhoeals.
• NAG enemas (1 gram three times daily) initially in October, 1996, with substantial improvement. Biopsies were not performed at that time. The enemas were stopped because of good clinical progress in December, 1996, and his symptoms gradually returned. He was recommenced on NAG enemas in June, 1997 (1 gram twice daily) after pre-treatment biopsy.
• SE-K Severe persistent inflammation of rectal stump, resistant to topical and systemic steroids, metronidazole, ciprofloxacin. Commenced on rectal NAG (1.5 grams twice daily) in June, 1997. Pre-treatment biopsy showed anal mucosa thus post-treatment biopsy will be difficult to interpret. However the clinical response has been prompt and marked, and she has shown complete resolution of bleeding and discharge.
• RM Persistent inflammation of rectal stump, with severe perianal inflammation. Treatment (1 gram twice daily) discontinued at child's request after brief period because of pain on inserting enema catheter. - 21 -
• GN A boy with a similar history to GC (above) of intractable left sided Crohn's colitis. He had failed to respond to corticosteroids, aminosalicylates, enteral nutrition and azathioprine. He was commenced on NAG (lg three times daily by mouth) in April 1996. He had minimal response to this, and underwent subtotal colectomy in March, 1997.
• azathioprine and high dose corticosteroids and has also previously undergone hemicolectomy. He was demonstrated to have multiple critical strictures throughout the small bowel (small intestine), which represents a major therapeutic problem. He was commenced on NAG (1.5g three times daily by mouth) in February, 1997, in addition to continuing his previous treatment with azathioprine and enteral nutrition. He has shown gradual improvement, both in terms of his stricture related symptoms and his inflammatory indices. An early barium examination in March, 1997 showed no significant improvement in the strictures after one month on NAG. A follow up barium study will probably be performed in the autumn.
• NBL This girl has stricturing small bowel Crohn's disease, with a long terminal ileal stricture with pre-synoptic dilatation. She has been managed with enteral nutrition and aminosalicylates previously. She was commenced on NAG (1.5g three times daily) in April, 1997, in association with enteral nutrition. She is significantly improved clinically, with no current stricture associated symptoms when reviewed in June, 1997. We plan to perform a follow up barium study.
• NAG has definite therapeutic effect in the treatment of inflammatory bowel disease.
• NAG clearly shows efficacy by rectal administration in the defunctioning colitis following subtotal colectomy.
• Several of the NAG treated children reviewed have shown very prompt clinical improvement.
• follow up histological examination in three NAG treated children shows definite improvement.
• the children who had more extensive colitis developed evidence of rectal sparing which had not been there previously.
• NAG also appears to be of benefit in the stricturing variant of inflammatory bowel disease (IBD), particularly in upper small intestinal strictures. - 26 -
• IBD inflammatory bowel disease
• NAG has been instrumental in avoiding early stricture surgery in two children, who had critical strictures before commencing NAG treatment and they are currently asymptomatic.
• NAG neurodegenerative disease
• rectal treatment by NAG has shown marked improvement. The latter success is probably due to the fact that rectally administered NAG does not have to pass through the digestive process of the gut.
• Suitable carriers for rectal administration can be distilled or purified water, a foam suitable for rectal administration, or a suppository.
• a suitable carrier for oral administration is a coating, or a double coating, in which the NAG is protected, the coating or double coating withstanding acidic and enzymatic degradation by the stomach and small intestine, until the afflicted IBD area is reached. Then the coating is digested and the NAG is delivered unscathed to the afflicted area.

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