Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/475—Growth factors; Growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• • 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
  • A61P1/10—Laxatives
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• Constipation which is the passage of less than 3 bowel movements per week with excessive straining at least 25% of the time, is the most common gastrointestinal complaint in the United States, resulting in about 2 million annual visits to the clinic. (See, National Digestive Diseases Information Clearinghouse, Constipation, Available at http://www.niddk.nih.gov/health/digest/pubs/const/const/htm, accessed on December 1, 1998.) In addition, Americans spend $725 million on laxatives each year without seeking medical help. According to the 1991 National Health Interview Survey, about 4.5 million people in the United States say they are constipated most or all of the time.
• Fig. 4 shows modal ease of passage rating after NT-3 administration.
• Fig. 5A and 5B show that NT-3 shortens gastric emptying half-time after NT-3 administration.
• Fig. 6A and 6B show small bowel transit time by period as affected by NT-3 administration.
• Fig. 7A-7D show that NT-3 increases gastrointestinal motility as evidenced by advancement of geometric center of fecal bolus.
• the present invention relates to the use of a neurotrophic factor, its analogues, mimetics, agonists and neurotrophin receptor activating antibodies for treating gastrointestinal hypomotility.
• a neurotrophic factor its analogues, mimetics, agonists and neurotrophin receptor activating antibodies for treating gastrointestinal hypomotility.
• gastrointestinal hypomotility including but not limited to, chronic constipation, obstipation, idiopathic abdominal distention, abdominal pain, abdominal cramps, irritable bowel syndrome, megacolon associated with hypothyroidism, pseudo- obstruction of the gastrointestinal tract, hypomotility of the colon associated with diabetes mellitus, neurological disorders, myopathic disorders, geriatric hypomotility disorders, jejunal-ileal bypass with secondary megacolon, hypomotility associated with cancer chemotherapy, hypomotility associated with severe burns and other major stresses, hypomotility associated with syndromes of depression, Parkinson's disease and other neuro-degenerative disorders, post-operative intestinal distension, and other pathological conditions, in a subject in need of such treatment.
• neutralizing antibody against a NT-3 receptor as used herein is intended to include those antibodies that block or diminish receptor activation including ligand receptor binding.
• NT-3 neutralizing antibody as used herein is intended to include those antibodies that diminish or abolish the physiological activities of a NT-3 molecule.
• NT-3 peptides, NT-3 chimeric molecules and peptide analogues of the invention can be purified by art-known techniques such as high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography and the like.
• the actual conditions used to purify a particular peptide or analogue will depend, in part, on factors such as net charge, hydrophobicity, hydrophilicity, etc., and will be apparent to those having skill in the art.
• adjuvants may be used to increase the immuno- logical response, depending on the host species, including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and potentially useful human adjuvants such as BCG (bacilli Calmette-Guerin) and Corynebacterium parvum.
• BCG Bacilli Calmette-Guerin
• Corynebacterium parvum bacilli Calmette-Guerin
• the optimum ratio in terms of efficiency of reaction in that there is no excess unreacted protein or polymer
• the desired degree of derivatization e.g., mono-, di-, tri-, etc.
• the molecular weight of the polymer selected whether the polymer is branched or unbranched, and the reaction conditions.
• the polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those skilled in the art. See for example, Magal, Method for Treating Sensorineural Hearing Using Glial Cell-Line-Derived Neurotrophic Factor (GDNF) Protein Product, U.S. Patent No.
• Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds which are sufficient to maintain therapeutic effect.
• dosage of NT-3 in the range of 25-500 ⁇ g/kg body weight is administered subcutaneously one to seven, preferably three, times per week. More preferably, the dosage is around 100-300 ⁇ g/kg, administered subcutaneously one to seven, preferably three, times per week.
• the effective local concentration of the compounds may not be related to plasma concentration.
• the amount of active ingredients administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
• the change in each measurement was obtained by substracting the pretreatment value from the end-of-treatment value for each subject.
• the changes in each measurement for each group of subjects were tested against a null hypothesis of zero change using paired t-test and paired Wilcoxon signed-rank tests.
• NT-3 caused an increase in stool frequency, ease of passage and softening in stool consistency in both groups of patients. The observed effect was not characterized as diarrhea in most cases. The onset of NT-3 induced effects in bowel function was rapid (within 24 hours) and lasted for several days after treatment ended. Increase of stool frequency.
• Figures 1-13 Data obtained from five of the six constipated patients and four of the six healthy volunteers are summarized in Figures 1-13.
• Fig. 1 shows that the stool number of constipated patients increased during and shortly after the treatment period.
• the increase of stool number by NT-3 treatment is also demonstrated in Fig. 2A which shows the weekly stool number before and during NT-3 treatment. Each line denotes one patient. The effect of NT-3 is not limited to constipated patients.
• Fig. 2B shows that NT3 treatment also increased weekly stool number in normal healthy volunteers.

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• Animal Behavior & Ethology (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Gastroenterology & Hepatology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
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• Toxicology (AREA)
• Neurology (AREA)
• Biophysics (AREA)
• Psychology (AREA)
• Immunology (AREA)
• Epidemiology (AREA)
• Nutrition Science (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Peptides Or Proteins (AREA)

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