Classifications

• • 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
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/717—Celluloses
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/116—Heterocyclic compounds
  • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/195—Antibiotics
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
  • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • 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
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
• • 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
  • A61K31/74—Synthetic polymeric materials
  • A61K31/765—Polymers containing oxygen
  • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Gastrointestinal (“Gl”) function disorders are caused by the invasion of pathogens, post treatment of broad-spectrum antibiotics, improper diet, stressful lifestyle and other causative factors. They are very common diseases, with conditions such as Irritable Bowel Syndrome (IBS) presenting in as much as 20% of the adult population in the USA. In Canada, IBS is second only to the common cold as the leading cause of time absent from school and work. So far, there is no effective medicine for the treatment IBS and Inflammatory Bowel Disease (IBD). Desirably, compositions for therapeutic purposes should meet the following criteria: Non-toxic, safe to use. • Not inhibiting or adversely affecting probiotic bacteria in the gut. Preferably very poor oral bioavailability (no systemic effects). Not causing bacterial resistance. Anti-inflammatory. Anti-diarrhoea, antisecretory. • Anti-motility. Strengthening immunity. Neutralizing toxins.
• This invention seeks to provide compositions and treatments for Gl functional disorders which meet one or more of the above criteria.
• the gastrointestinal (Gl) tract with an area of 300-400m 2 is the second largest surface connecting the body with the outside world. With consumption of 1 ⁇ 2kg of food every day, the Gl immune system is presented with the threat of ingested poisons and pathogens together with an enormous variety of harmless antigens.
• the Gl tract digests food and absorbs the nutrients that are beneficial to the body, while eliminating components that pose a potential risk to health.
• a large portion of the body's immune system is located in the Gl wall and the mesenteric lymph nodes, called gut-associated lymphoid tissue (GALT) system.
• Gl secretions are rich in antimicrobial factors such as lactoferrin and lysozyme and other factors, like important growth and mucosa healing factors such as epidermal growth factor (EGF).
• EGF epidermal growth factor
• the mucosa of the gut is normally covered by a unique protective layer of mucus and is colonized by microflora, which perform a key function in the regulation of the GALT system.
• the mucus serves to a large extent as a matrix for the indigenous protective flora.
• the intestines contain about 1 kg probiotic bacteria. The roles of these bacteria are to maintain the healthy ecology in the Gl tract, synthesizing vitamins, hormones, and other important factors, and to help to break down complex proteins and fiber into smaller molecules that can be absorbed by the mucosal cells.
• Pathogenic bacteria in the intestinal tract are an important aspect in the Gl functional disorders both as a causative factor and as a symptom. Other disorders can. actually cause the Gl tract to lose probiotic bacteria and allow pathogenic bacteria growth, eventually, resulting in changes to the intestinal ecology and further exacerbation of the Gl functional disorders.
• This invention relates to the treatment of Gl functional disorders and related conditions including IBS and IBD including colitis, Crohn's disease and coeliac disease.
• the treatment is expected to improve intestinal health and reduce symptoms including constipation, flatulence and diarrhoea. It acts as a Gl cleanser, strengthening the immune system, inhibiting and removing the pathogenic bacteria, and helping to restore a healthy ecology in the intestinal tract.
• the resulting healthy digestion system will support the healthy state of the body and healthy weight gain in animals including humans.
• Berberine is an isoquinoline quaternary alkaloid derived from a number of species of the barberry plant including Berberis aristata and Coptis chinensis.
• Structural analogues of berberine have been isolated from extracts of the Chinese medicinal plant, Acangelisia gusanlung.
• Berberine possesses antimicrobial 141 , anti- motility [8] and anti-secretory properties.
• Certain saturated lower dialdehydes also possess antibacterial activity toward sulfate-reducing bacteria.
• alcoholic sporicidal compositions containing similar saturated lower dialdehydes were taught.
• water-soluble dialdehyde starch can be incorporated into chewing gum compositions as a cariostatic agent
• a water insoluble dialdehyde polysaccharide being applied in medium at a concentration of at least about 0.1 weight per cent to inhibit the bacterial growth.
• Synthetic polymeric dialdehydes such as poly-(2-propenal, 2-propenoic acid) have been used in the treatment of gastrointestinal diseases. However, since the antimicrobial activities of these compounds are very weak, very high doses for treatment, such as 500 ⁇ 2500mg/kg body weight/day are required.
• compositions including compounds of Formula (1 ) below, (particularly berberine chloride), and compounds of Formula (2) below, (particularly oxidized cellulose), are each useful for the treatment of the Gl functional disorders and related conditions as well as for a method of promoting weight gain in animals including humans.
• One of the most important findings of the invention is the existence of a synergic effect obtained by using combination of the compounds of Formula (1) and compounds of Formula (2) (see Example 4 and Example 8, below). This synergic effect provides the possibility of using lower dosage of the compounds, thereby achieving higher safety and economy. Disclosure of the Invention
• the present invention relates to a composition including a compound of Formula (1 ) and/or a polymeric dialdehyde, for the treatment of gastrointestinal (Gl) functional disorders and related conditions, including Irritable Bowel Syndrome (IBS); Inflammatory Bowel Disease (IBD), Colitis, Crohn's disease and coeliac disease; and/or for promoting weight gain in animals, where Formula (1 ) comprises:
• R 1 , R 2 , R 7 , R 8 , R 9 , and R 10 may be the same or different and are selected from H, CH 3 , OH, OCH 3 , C 2 H 5 , OC 2 H 5 OCH 2 Ph, OCH 2 PhN0 2 , F or CI;
• R 3 , R 4 , R 5 , R 6 may be the same or different and are selected from H, CH 3 ,
• R 5 and R 6 are the same or different and are selected from H, CH 3 , OCH 3 , C 2 H 5 ,
• R 3 and R 4 are the same or different and are selected from H, CH 3 , OCH 3 , C 2 H 5 ,
• X " is selected from the group consisting of CI, Br, SO 4 , I and R 13 COO, where
• R 13 is CH 3 or poly acids.
• the polymeric dialdehyde may be chosen from a wide range of suitable compounds.
• poly-(2-propenal, 2-propenoic acid) may be combined with a compound of Formula (1 ) to form the compositions of this invention.
• the polymeric aldehyde is a dialdehyde polysaccharide.
• Particularly preferred dialdehyde polysaccharides have a formula in accordance with Formula (2):
• each of the monomers R p and R r are independently selected from the group consisting of:
• each monomer R q is independently selected from the group consisting of:
• each R p and R r are (A) and R q is (D), so that the polymeric dialdehyde is oxidised cellulose.
• R 14 is CH 2 OH or CH 2 OCH 2 COOH.
• each R p and R r are (B) and R q is (E), so that the polymeric dialdehyde is oxidised starch or dextrin.
• each R p and R r are (C) and each R q is (F) or
• the compounds of Formula (2) preferably have a molecular weight of from 1 ,000 to 1 ,000,000. More preferably, they have a molecular weight of from 10,000 to 750,000. Where the compounds of Formula (2) are water-insoluble, they preferably have a particle size of from 5 ⁇ to 100 ⁇ , more preferably from 5 ⁇ to 30 ⁇ . For example, the diameter of microcrystalline oxidized cellulose is about 20 ⁇ .
• the oxidized rate of the Formula (2) is from 30-100%, preferably 40-100%, more preferably 40-60%. It was found that the compounds of the Formula (2) were non-toxic by oral administration. In particular, the oxidized celluloses are relatively stable in the Gl tract. Their high molecular weights prevent them being absorbed by gut. Their polydialdehyde functional groups interact and neutralize toxins. The compounds of the Formula (2) possess an anti-constipation effect. The compounds also promote ulcer healing. The compounds do not adversely affect the growth of probiotic bacteria in gut.
• Animals to which the composition may be administered include: primates including humans, birds including poultry, ungulates including cattle, sheep, horses, cervidae and swine, fish including crustaceans and molluscs, reptiles, rodents, canines and felines.
• the invention comprises using compounds of Formula (1 ) and compounds of Formula (2) in the manufacture of a medicament for the treatment of Gl functional disorders and related conditions including Irritable Bowel Syndrome (IBS); Inflammatory Bowel Disease (IBD) including Colitis, Crohn's disease and coeliac disease; and for promoting weight gain in animals including humans.
• IBS Irritable Bowel Syndrome
• IBD Inflammatory Bowel Disease
• Colitis, Crohn's disease and coeliac disease and for promoting weight gain in animals including humans.
• the invention comprises a method of treating gastrointestinal disorders including Irritable Bowel Syndrome (IBS); Inflammatory Bowel Disease (IBD), colitis, Crohn's disease and coeliac disease, including administering to an animal, including a human, suffering from a gastrointestinal disorder, effective amounts of a compound of Formula (1) and/or polymeric dialdehyde.
• the method of treatment comprises administering effective amounts of a compound of Formula (1 ) and polymeric dialdehyde in conjunction.
• treatment may comprise administering the compound of Formula (1 ) and the polymeric dialdehyde sequentially or simultaneously.
• the compound of Formula (1 ) is combined with the polymeric dialdehyde to form a composition which is then administered.
• the polymeric dialdehyde is a compound of Formula (2), more preferably oxidised cellulose, especially oxidised cellulose having an oxidation level of from 40% to 60%.
• the required dose of the composition containing Formula (1 ) and a polymeric dialdehyde is generally less than 50% of those separately using individual components.
• the dose of beberine is 6mg ⁇ 18mg/kg/day for adult.
• the use of 40% oxidized cellulose is 250mg ⁇ 750mg/kg/day.
• the required dose is berberine 0.5mg ⁇ 6mg/kg/day plus 40% oxidized cellulose 5mg ⁇ 200mg/kg/day.
• a dose of berberine 0.5mg ⁇ 3mg/kg/day plus 40% oxidized cellulose 5mg ⁇ 80mg/kg/day is used.
• the invention includes modified foods containing from 0.1 to 50 ppm of a compound of Formula (1 ) and from 1 to 400 ppm of a polymeric dialdehyde.
• the modified food contains from 2 to 10 ppm of a compound of Formula (1 ) and from 10 to 200 ppm of a compound of Formula (2); more preferably Formula (1 ) is berberine chloride and Formula (2) is oxidized cellulose.
• the present invention also comprises a kit including a quantity of a compound of Formula (1 ) and a quantity of a polymeric dialdehyde for the treatment of gastrointestinal (Gl) functional disorders and related conditions including Irritable Bowel Syndrome (IBS); Inflammatory Bowel Disease (IBD) including colitis, Crohn's disease and coeliac disease; and for promotion of weight gain in animals including humans.
• Gl gastrointestinal
• IBS Irritable Bowel Syndrome
• IBD Inflammatory Bowel Disease
• the weight ratio of the quantity of compound of Formula (1 ) to the quantity of polymeric dialdehyde ranges from 1 :1 to 1 :100, more preferably from 1 :10 to 1 :40.
• berberine selectively inhibits pathogenic bacteria such as Staphylococcus aureus, Streptococcus Group B, Vibrio cholerae, Clostridium perfringens, Candida albicans, but does not inhibit beneficial bacteria (probiotics) such as Lactobacillus plantarum at ⁇ 500 Dg/ml (see Table 1 ).
• beneficial bacteria probiotics
• Table 1 Antimicrobial Activities of berberine, oxidized cellulose and Erythromycin
• the research leading to the present invention also discloses the invention of treating Irritable Bowel Syndrome, Inflammatory Bowel Disorder, Colitis, Crohn's disease and ceoliac disease including administering an effective amount of a compound of Formula (1 ) or of Formula (2) to an animal, including a human, in need thereof.
• the invention also provides a method of promoting weight gain in animals including humans including administering an effective amount of a compound of Formula (1 ) and/or Formula (2).
• Gl tract cleansing compositions that include compounds of Formula (1 ) and compounds of Formula (2), and/or the pharmaceutically acceptable derivatives thereof may be referred to as GILAX cleansers.
• the amount of GILAX-cleanser required for use in treatment will vary with the nature of the condition being treated and the age condition of the animal including human patients, and will ultimately be at the discretion of the attendant veterinarian or physician.
• a GILAX-cleanser comprises the compounds of Formula (1 ) and the compounds of Formula (2) at a weight ratio of 1 :1-100, preferably at a weight ratio of 1 :10-40.
• the dose of GILAX-cleansers may be 275 ⁇ 1650mg/day orally.
• the dose taken is according to the Gl functional disorder condition. It is recommended for an adult to take 550mg once daily for IBS or post antibiotic Gl functional disorder, 275mg x 2 daily for IBD, 550mg x 4 daily for acute diarrhoea or other severe conditions.
• GILAX-cleansers may be used as food additives to promote growth.
• the composition is preferably 1 ⁇ 20ppm of berberine plus 10 ⁇ 400ppm of oxidized cellulose; more preferably, 5ppm of berberine plus 50ppm of oxidized cellulose.
• GILAX-cleansers can be used to protect piglets from diarrhoea.
• a composition including 0.5mg ⁇ 6mg of Formula (1 ) (berberine)/kg/day and 50mg ⁇ 200mg of Formula (2) (oxidized cellulose)/kg/day may be used.
• a GILAX-cleanser composition is preferably formed by combining the compounds of Formula (1 ) and the compounds of Formula (2) with one or more other ingredients, for example: vitamins, antibiotics, antiseptic agents, surfactants, antidiarrheal agents, anti-constipation agents, enzymes, (especially digestive enzymes), probiotic bacteria, herbs, vaccines, ulcer healing agents (e.g. gibberellins, glucans).
• a pharmaceutical formulation including the GILAX-cleansers or pharmaceutically acceptable derivatives thereof may also contain one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients.
• the carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• compositions may be in any form suitable for administration to the gastrointestinal tract, including those suitable for oral, and rectal administration. While it is possible that for use in therapy, the GILAX-cleansers may be administered as the raw chemical(s), it is preferable to present the active ingredient(s) as a pharmaceutical formulation.
• the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods known in the art of pharmacy. Preferably, the methods include the step of bringing into association the active compound(s) with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulations.
• compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient(s); as a powder or granules; a solution, a suspension or as an emulsion.
• the active ingredient(s) may also be presented as a bolus, electuary or paste.
• Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
• the tablets may be coated according to methods known in the art.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non- aqueous vehicles (which may include edible oils), or preservatives.
• the compounds of GILAX-cleanser or pharmaceutically acceptable derivatives thereof may be administered by any of the methods and formulations employed in the art of administration to the gastrointestinal tract. Where desired, formulations adapted to give sustained release of the active ingredient may be employed.
• the compounds of the GILAX-cleansers may also be used in combination with other therapeutic agents, for example, anti-infection agents, such as antibiotics, or ulcer healing agents such as gibberellins, glucans, growth factors (EGF), and/or probiotic bacteria such as Lactobacillus plantarum.
• anti-infection agents such as antibiotics
• ulcer healing agents such as gibberellins, glucans, growth factors (EGF), and/or probiotic bacteria such as Lactobacillus plantarum.
• each compound When the compounds of GILAX-cleansers are used with a second therapeutic agent active in the treatment of Gl functional disorders and related conditions, the dose of each compound may either be the same as or differ from that employed when each compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
• GILAX-cleansers and their pharmaceutically acceptable derivatives may be prepared by any methods known in the art for the preparation of compounds of analogous structure.
• Example 1 Preparation of a compound of Formula (1), berberine chloride.
• Group A feed additive is 50ppm berberine chloride.
• Group B feed additive is 10ppm berberine chloride.
• Group C feed additive is 200ppm 40% oxidized cellulose.
• Group D feed additive is 100ppm 40% oxidized cellulose.
• Group E feed additive is 5ppm berberine chloride + 50ppm 40% oxidized cellulose.
• Example 4 demonstrates the synergic effect of the invention. From the results, it is clear that the composition of 5ppm berberine plus 50ppm oxidized cellulose gave the best growth promotion compared to 20ppm berberine or 10ppm berberine or 200ppm oxidized cellulose, or 100ppm oxidized cellulose alone. This synergic effect provides the possibility of using lower dosages of the compounds, thereby achieving higher safety and economy.
• Example 5 Preparation of GILAX-cleanser. a) Berberine chloride 50mg mixed with 40% oxidized cellulose 500mg was packed in a capsule for oral administration for adult for the treatment of IBS or post antibiotic Gl functional disorder or diarrhea. b) Berberine chloride 25mg mixed with 40% oxidized cellulose 250mg was packed in a capsule for oral administration for the treatment of IBD. Example 6.
• GILAX-cleanser from example 5 may be used sequentially or simultaneously with the preparation of probiotic bacteria.
• Compound of Formula (2) 40% oxidized cellulose as food additive to promote chicken growth.
• the chicken experiment was set up substantially as described in example 4, but with 6 chickens in each of the experimental and control groups.
• the feed additive was 1.OOOppm of 40% oxidized cellulose.
• hFUTI mouse model of colitis was used. It provides insights into the pathogenesis of Inflammatory Bowel Disease (IBD). These mice do not develop disease in a germ free environment. Immune dysfunction contributing to IBD in humans includes abnormal T cell reactivity and a loss of tolerance to gut bacteria.
• the compositions of Formula (1 ) and Formula (2) were given orally to mice to see the effectiveness on the altering the gut flora and lessening the severity of the colitis. The positive results indicated the compositions of Formula (1) and Formula (2) may have a therapeutic role in human IBD. A total five groups with ten mice per group were used as follows. 1 ) Control (without treatment). 2) Treated with compound of the Formula (1 ) (berberine chloride), 13.5mg /kg/day (o.s.).
• mice 30 male and 30 femal Balb-C mice were divided into groups of 10. 10 male and 10 female mice were in each of three groups as follows;
• tissue slides live, kidney, lung, intestine
• a randomized block design assigned sex-matched individual pens per treatment group at weaning. Each pen held 15 piglets (21 days old) three pens were used.
• GILAX cleanser treatment The piglets received in feed GILAX cleanser (5mg/kg/day berberine chloride+ 50mg/kg/day 40% oxidized cellulose) for 21 days.

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