WO2021003553A1 - Composés de traitement de la diarrhée, de la maladie inflammatoire de l'intestin et leurs procédés - Google Patents

Composés de traitement de la diarrhée, de la maladie inflammatoire de l'intestin et leurs procédés Download PDF

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WO2021003553A1
WO2021003553A1 PCT/CA2020/050009 CA2020050009W WO2021003553A1 WO 2021003553 A1 WO2021003553 A1 WO 2021003553A1 CA 2020050009 W CA2020050009 W CA 2020050009W WO 2021003553 A1 WO2021003553 A1 WO 2021003553A1
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emoxypine
per
antagonist
glut2b
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Mark Williams
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Algernon Pharmaceuticals Inc.
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention relates to the use of compounds for treating inflammatory bowel disease, and in particular, the use of glutamate 2b receptor antagonists, and/or emoxypine, for treating inflammatory bowel disease, ulcerative colitis (UC), Crohn's Disease, and/or diarrhea.
  • glutamate 2b receptor antagonists and/or emoxypine
  • IBD Inflammatory Bowel Disease
  • Crohn's Disease UC.
  • IBD also includes indeterminate colitis. Indeterminate colitis is a term used when it is unclear if the inflammation is due to Crohn's disease or ulcerative colitis.
  • Crohn's disease is a type of inflammatory bowel disease (IBD) that primarily involves the small and large intestine, but may also affect any other part of the gastrointestinal tract. In its mild forms, Crohn's disease causes scattered, shallow ulcers in the inner surface of the bowel. In more serious cases, deeper and larger ulcers can develop, causing scarring and stiffness and possibly narrowing of the bowel, sometimes leading to obstruction. Deep ulcers can puncture holes in the bowel wall, leading to infection in the abdominal cavity (peritonitis) and in adjacent organs.
  • Common symptoms of IBD disease include abdominal pain, diarrhea, vomiting, fever, and weight loss. While the causes of IBD are unknown, genetic, environmental, and lifestyle factors are understood to contribute to IBD.
  • 5-aminosalicylic acid also known as 5-ASA
  • 5-ASA is currently a global standard for treatment of IBD. Used in combination with other drugs, the goal of such treatment is to reduce the inflammation that triggers the individual's signs and symptoms, and to improve long-term prognosis by limiting complications.
  • the murine models of intestinal inflammation are well-characterized experimental models of intestinal immune dysregulation that ultimately lead to colitis - a common characteristic of inflammatory bowel diseases.
  • the progression of colonic inflammation is highly predictable and reproducible, leading to significant infiltration of the lamina intestinal with inflammatory cells and tissue damage of the colonic mucosa (Kiesler et al., Experimental models of inflammatory bowel diseases, Cell Mol Gastroenterol Hepatol, 2015; 1 : 154-70).
  • TNBS 2,4,6-trinitrobenzene sulfonic acid
  • TNBS-induced colitis in mice constitutes an animal model of ulcerative colitis (UC) with high degree of similarity to the histopathological characteristics and distribution of inflammation described in human ulcerative colitis.
  • Diarrhea is a condition in which feces are discharged from the bowels frequently and in a liquid form .
  • the present invention provides a novel use of existing drugs, typically studied as potential therapies for neurological conditions, for the treatment and/or alleviation of IBD and/or diarrhea. Summary of Invention
  • the present invention provides methods and uses of Emoxypine for the treatment or prophylaxis of diarrhea, colitis, or inflammatory bowel disease (IBD) in a subject.
  • IBD inflammatory bowel disease
  • a glutamate 2b receptor (Glut2B or GluN2B) antagonist for the treatment or prophylaxis of diarrhea, colitis, or inflammatory bowel disease (IBD) and/or diarrhea in a subject.
  • the Glut2B antagonist may be one or more of Ifenprodil, Radiprodil, Traxoprodil, Rislenmdaz, Eliprodil, Ro-25-6981, and BMT-108908, EVT-101, CPlOl-606, MK-0657, EVT-103, and AZD 6765 (Annual Reports in Medicinal Chemistry (2012) Volume 47: 94-103).
  • the compounds of the invention are used in combination with the use of one or more of: anti
  • the inflammatory drugs may be one or more of corticosteroids and oral 5-aminosalicylates.
  • the immune system suppressors may be one or more of azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol and vedolizumab.
  • the antibiotics may be one or more of iprofloxacin and
  • the inflammatory bowel disease is Crohn's disease.
  • the inflammatory bowel disease is ulcerative colitis.
  • Figure 1 is a line graph comparing the mean percentage change in body weights from baseline ( ⁇ the standard error of the mean, or SEM) for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 2 is a line graph comparing the mean Disease Activity Index (DAI) data, which includes daily measurement of body weight and evaluation of stool consistency, from baseline ( ⁇ the standard error of the mean, or SEM) for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive” control group, the "TN BS-Vehicle” control group, and the "5-ASA” positive control group.
  • DAI Disease Activity Index
  • Figure 3 is a line graph comparing the mean fecal consistency from baseline ( ⁇ the standard error of the mean, or SEM) for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 4 is a line graph comparing the mean occult positivity from baseline ( ⁇ the standard error of the mean, or SEM) for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 5 is a column graph showing an indication of disease severity with a comparison of the mean colon length in centimeters for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 6 is a column graph showing an indication of disease severity with a comparison of the mean colon weight in grams for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 7 is a column graph showing an indication of disease severity with a comparison of the mean colon weight/length ratio in milligrams/centimeter for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS- Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 8 is a line graph showing an indication of disease progression with a comparison of the daily survival rate in percentage for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TNBS-Vehicle” control group, and the "5-ASA” positive control group.
  • Figure 9 is a column graph showing a Histopathology severity score, which evaluats of colitis, bowel wall inflammation, leukocyte infiltration, high vascular density, bowel wall thickening, disruption of normal crypt architecture and epithelial ulceration, with a comparison of the Histopathology Scores for the experimental treatment groups of mice, test compounds Emoxypine, Ifenprodil and Radiprodil, compared to the "Naive" control group, the "TN BS-Vehicle” control group, and the "5-ASA” positive control group.
  • the inventor has found that a number of pharmacologic compounds approved for use in other pathologies are useful in inhibiting or alleviating colitis and may be useful in the prophylaxis and/or treatment of inflammatory bowel disease.
  • a number of pharmacologic compounds approved for use in other pathologies are useful in inhibiting or alleviating colitis and may be useful in the prophylaxis and/or treatment of inflammatory bowel disease.
  • the level of colonic inflammation is inhibited or alleviated.
  • the compounds described herein will be useful in some embodiments in the prophylaxis and/or treatment of diarrhea, colitis, or inflammatory bowel disease.
  • inflammatory bowel disease is administering the pharmacologic compound 5-ASA, which was used as a positive control in the experimental examples described herein.
  • 5-ASA 5-Aminosalicylic Acid
  • 5-Amino-2-hydroxybenzoic acid is an aminosalicylate anti-inflammatory drug known in the art for treating inflammatory bowel disease such as ulcerative colitis and for maintaining remission in Crohn's disease.
  • the chemical structure of 5-Aminosalicylic Acid is as follows:
  • Emoxypine 2-Ethyl-6-methyl-3-hydroxypyridine
  • the chemical structure of Emoxypine is as follows:
  • the present invention provides a use and method of treatment or prophylaxis of diarrhea, colitis, or inflammatory bowel disease (IBD) in a subject with Emoxypine or a pharmaceutically acceptable salt thereof.
  • the IBD may be Crohn's disease or ulcerative colitis, among others.
  • the amount of Emoxypine used is between 0.1 to 30 mg per kg of the subject.
  • the amount of Emoxypine used is between 5 to 20 mg per kg of the subject.
  • the amount of Emoxypine used is about 13 mg per kg of the subject.
  • Emoxypine, or pharmaceutically acceptable salt thereof may be administered to the subject orally, intravenously or in a manner known in the art.
  • the Emoxypine, or pharmaceutically acceptable salt thereof may also be
  • Glutamate 2b receptor antagonists a category of glutamate NMDA receptor antagonists, work to inhibit the action of the N-methyl-d-aspartate receptor (the NMDA receptor). Studies have focused on their application in neurological disorders, such as depression, Parkinson's disease, epilepsy,
  • selective NR2B antagonists consists of a central tertiary amine, linked to a (substituted) aromatic ring on two sides as shown below.
  • N MDA receptors are composed of different combinations of multiple protein subunits.
  • the physiological receptor is a heteromer containing an NR1 subunit with one or more of the different NR2 subunits.
  • the NR2 subunit that is coupled to the NR1 subunit alters the electrophysiological and
  • NMDA receptor pharmacological properties of the formed receptor channel. Additionally, activation of the NMDA receptor has an absolute requirement for glycine as a co-agonist.
  • glutamate 2b receptor antagonists are: Ifenprodil, Eliprodil, Radiprodil, Traxoprodil, Rislenemdaz, Ro-25-6981, BMT-108908, EVT-101, CPlOl-606, MK-0657, EVT-103, and AZD 6765 (Annual Reports in Medicinal Chemistry (2012) Volume 47: 94-103).
  • Ifenprodil 4-[2-(4-benzylpiperidin-l-ium-l-yl)-l-hydroxypropyl] phenol; 2,3,4-trihydroxy-4-oxobutanoate, is known in the art as a selective NMDA receptor (glutamate) antagonist. Ifenprodil was originally (in the early 1970's) developed as a vasodilator. Ifenprodil is currently being studied for treatment of adolescent PTSD. The chemical structure is as follows:
  • Ifenprodil hemitartrate having the following structure was used :
  • Eliprodil (4-chlorophenyl)-4-((4-fluorophenyl)methyl)-l- piperidineethanol
  • an NMDA receptor antagonist developed to have better oral bioavailability than Ifenprodil. It is currently being studied for therapeutic treatment of Parkinson's disease.
  • the chemical structure of Eliprodil is as follows:
  • Radiprodil 2-[4-[(4-fluorophenyl)methyl]piperidin-l-yl]-2-oxo-N-(2- oxo-3H-l,3-benzoxazol-6-yl)acetamide, is known in the art as an NMDA receptor antagonist. It has been used in trials studying the treatment of Infantile Spasms (IS) and Diabetic Peripheral Neuropathic Pain.
  • the chemical structure of Radiprodil is as follows:
  • Traxoprodil l-(( IS, 2S)- 1-hydroxy- l-(4-hydroxyphenyl)propan-2-yl)- 4-phenylpiperidin-4-ol, is known in the art as an NMDAR antagonist with unique NR2B specificity, potentially useful in treating Parkinson's disease, stroke, and major depressive disorders.
  • the chemical structure of Traxoprodil is as follows:
  • Rislenmdaz 4-methylbenzyl 3-fluoro-4-((pyrimidin-2- ylamino)methyl)piperidine-l-carboxylate, is known in the art as a selective NMDA receptor (glutamate) antagonist associated with potential therapeutic treatments of schizophrenia and depression .
  • the chemical structure of Rislenmdaz is as follows: [00047] Ro 25-6981 is known in art as a glutamate 2B receptor antagonist with the following chemical structure:
  • BMT-108908 is known in art as a glutamate 2B receptor antagonist with the following chemical structure:
  • the present invention provides a use and method of treatment or prophylaxis of diarrhea, colitis, or inflammatory bowel disease (IBD) in a subject with glutamate 2b receptor antagonists.
  • IBD inflammatory bowel disease
  • the IBD may be Crohn's disease or ulcerative colitis, among others.
  • the amount of glutamate 2b receptor antagonist used is between 0.2 and 40 mg per kg, preferably between 0.5 to 10 mg per kg of the subject.
  • the amount of glutamate 2b receptor antagonist used is between 1 to 5 mg per kg of the subject.
  • the amount of glutamate 2b receptor antagonist used is abut 2.5 mg per kg of the subject.
  • the glutamate 2b receptor antagonists may be one or more of Ifenprodil, Eliprodil, Radiprodil, Traxoprodil, Rislenmdaz, Ro-25,6981, or BMT-108908, EVT-101, CPlOl-606, MK-0657, EVT-103, and AZD 6765.
  • the glutamate 2b receptor antagonists may be administered to the subject orally, intravenously or in any manner known in the art.
  • the glutamate 2b receptor antagonists may also be administered with one or more pharmaceutically acceptable excipients.
  • ifenprodil is a known to exhibit NDMA receptor antagonism (GluN l and more specifically GlunN2B subunits) and sigma receptor agonist (more specifically subtype 1) activity.
  • Sigma receptors are intracellular chaperones that reside in the endoplasmic reticulum of a cell. Thus molecules with similar activity have anti-fibrotic effects and treat IPF.
  • Representative sigma receptor agonists include selective serotonin reuptake inhibitors (SSRI) such as fluvoxamine, fluoxetine, excitalpram and donepezil (J. Pharmacological Sciences (2015) 127 : 6-9).
  • SSRI selective serotonin reuptake inhibitors
  • the compounds of the invention may ameliorate the diarrhea complication that occurs in a significant number of patients taking Nintedanib.
  • Treatment be combined with Nintedanib may ameliorate the diarrhea complication that occurs in a significant number of patients on Nintedanib treatment (Corte T, Bonella F, Crestani B, et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res. 2015; 16: 116. doi : 10.1186/sl2931-015-0276-5).
  • the anti-diarrheal action may be due to the Sigma-1 receptor agonists, which have shown preliminary clinical anti-diarrheal activity (Volz H-P,
  • Ifenprodil is a Sigma 1 receptor agonist (Ishima T, Flashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by ifenprodil : the role of sigma-1 and IP3 receptors. PLoS One. 2012;7(5) :e37989. doi : 10.1371/journal pone.0037989).
  • the present invention provides a use and method of treatment or prophylaxis of colitis or inflammatory bowel disease in a subject with selective serotonin reuptake inhibitors, Emoxypine or glutamate 2b receptor antagonists in combination with one or more of: anti-inflammatory drugs, immune system suppressors, antibiotics, anti-diarrheals, pain relievers, iron supplements, vitamin B-12 shots, and calcium and vitamin D supplements.
  • the anti-inflammatory drugs are often used in the first step in the treatment of inflammatory bowel disease. They include corticosteroids and/or oral 5-aminosalicylates.
  • Oral 5-aminosalicylates include sulfasalazine (for example Azulfidine), which contains sulfa, and mesalamine (for example Asacol HD, Delzicol or others). While oral 5-aminosalicylates have been widely used in the past to treat Crohn's disease, it is now generally considered of limited benefit.
  • Corticosteroids such as prednisone and budesonide (for example Entocort EC), may help reduce inflammation in the body, though it has not been shown to work for everyone with Crohn's disease. It is prescribed, typically, only if the subject hasn't responded to other treatments. Corticosteroids may be used for short-term (three to four months) symptom improvement and to induce remission. Corticosteroids may also be used in combination with an immune system
  • Immune system suppressor also reduce inflammation in a subject, but they target the subject's immune system, which produces the substances that cause inflammation. For some, a combination of these drugs works better than one drug alone.
  • immunosuppressant drugs used with selective serotonin reuptake inhibitors, Emoxypine or glutamate 2b receptor antagonists may comprise one or more of azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol and vedolizumab.
  • Azathioprine for example Azasan or Imuran
  • mercaptopurine for example Purinethol or Purixan
  • Amathioprine for example Azasan or Imuran
  • mercaptopurine for example Purinethol or Purixan
  • Their use may also cause nausea and vomiting.
  • Infliximab for example Remicade
  • adalimumab for example Humira
  • certolizumab pegol for example Cimzia
  • TNF inhibitors or biologies work by neutralizing an immune system protein known as tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • Vedolizumab was recently approved for use in treatment of Crohn's disease. Vedolizumab works like natalizumab, but appears not to carry a risk of brain disease.
  • Antibiotics have been used in the past to reduce the amount of drainage and sometimes heal fistulas and abscesses in subjects with Crohn's disease. Some researchers also think antibiotics may help reduce harmful intestinal bacteria that may play a role in activating the intestinal immune system, leading to inflammation . Frequently prescribed antibiotics include ciprofloxacin (for example Cipro) and metronidazole (for example Flagyl).
  • Anti-diarrheals includes fiber supplements, such as psyllium powder (for example Metamucil) or methylcellulose (for example Citrucel), may be used to help relieve mild to moderate diarrhea by adding bulk to stool. For more severe diarrhea, loperamide (for example Imodium A-D) may be used.
  • Pain relievers for mild pain, such as acetaminophen (for example Tylenol or others) may be used.
  • acetaminophen for example Tylenol or others
  • other common pain relievers such as ibuprofen (for example Advil, Motrin IB and others) and naproxen sodium (for example Aleve) should not be used as these drugs tend to make a subject's symptoms worse, and can make the disease worse as well.
  • the subject may develop iron deficiency anemia and may need to take iron supplements.
  • Vitamin B-12 shots may be used with selective serotonin reuptake inhibitors, Emoxypine or glutamate 2b receptor antagonists to help prevent anemia, promote normal growth and development, since Vitamin B-12 s is essential for proper nerve function.
  • Calcium and vitamin D supplements may also be used with
  • Emoxypine. Crohn's disease and the steroids used to treat it can increase a subject's risk of osteoporosis.
  • Calcium supplement with added vitamin D may help alleviate this osteoporosis.
  • test compounds Emoxypine and Ifenprodil were obtained from Toronto Research Chemicals, Toronto, ON, Canada M3J2K8. Radiprodil was obtained from Axon Medchem LLC, Mclean, VA 22102, USA. The Positive control 5- aminosalicylic acid (5-ASA) was obtained from Sigma Aldrich, USA. The vehicle used was 0.5% CMC.
  • the dose selected for the animal studies was determined by taking the maximum known human daily dose, dividing by the average weight if an adult ( ⁇ 60-70 kg) to get a human mg/kg dose. Then that number was multiplied by 12 to convert to a mouse dose based on conventional dosing tables. See Nair and Jacob, J Basic Clin Pharm March 2016-May 2016, 7(2) : 27-31.
  • mice Healthy young female SJL mice were used for the study. At the commencement of the study, the mice were between 8-9 weeks of age, weighing 20-22g. All the mice were obtained from The Jackson Laboratory, Bar Harbor,
  • mice were maintained in a controlled environment with a temperature of 70-72° F, humidity 30-70%, with a photo cycle of 12 hours of light and 12 hours of dark. They were provided with TEKLAD 2018-Global 18% diet and Arrowhead drinking water ad libitium.
  • mice were grouped according to their body weight. There was one group of ten mice and five groups of fifteen mice each. Five groups of fifteen mice each were challenged intra-rectally with 100 pi of 2.0% TNBS in 50 % EtOH and other group of ten mice were challenged intra- rectally with 100 pi of 50% EtOH and serve as No-TNBS control.
  • the experimental groups were as follows: [00080] Table 1 : Experimental Design
  • mice were challenged intra-rectally with 100 pi of 2% TNBS in 50% ethanol under light anesthesia with ketamine/xylazine.
  • the test compounds were administrated an hour prior to intra-rectal administration of TN BS as per scheduled daily dosing.
  • test compounds Emoxypine, Ifenprodil and Rediprodil were prepared in 0.5% CMC and administrated orally once-a-day from day 1 to 7.
  • 5-ASA was also prepared in 0.5% CMC and administrated orally once a day beginning on Day 1 to Day 7.
  • Vehicle and no-TNBS control groups received 0.5% CMC orally from Day 1 to Day 7.
  • the following measurements and assessments were taken for each mouse.
  • Body Weight The body weights were measured daily for 1-7 days using a laboratory balance.
  • Serum Collection on Day 8, blood samples were collected from all the surviving mice and were processed for serum and stored at -80°C.
  • Colon Length and Weight the mice were euthanized using CO2 asphyxiation and colon from the colocecal junction to the anus was removed, washed and cleaned of all fecal matter using PBS. The colon length and weight were measured and then preserved in 10% NBF for histopathology.
  • Histopathology Formalin fixed colon samples were submitted to affiliated histopathology laboratory for histopathological analysis subjected to hematoxylin and eosin (H & E) staining using standard techniques. Each colon was trimmed from both ends and mid. All three sections were stained and evaluated.
  • a board certified veterinarian pathologist assessed the presence of colitis and severity score according to the following criteria:
  • DAI Disease Activity Index
  • the percent survival data is presented in Figure 8 and Table 10. The percent survival was higher with the treatment group treated with Emoxypine (160 mg/kg) followed by Ifenorpdil (30 mg/kg), 5-ASA (100 mg/kg) and Rediprodil (30 mg/kg).
  • the 3 main categories include (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture.
  • Appendix A Body weight, g
  • Appendix E Colon Length and Weight
  • Emoxypine 160 Differenc 95% Cl of Row Factor Na ' ive mg/kg) e diff.
  • Rediprodil (30 Differenc 95% Cl of Row Factor Na ' ive rng/kg) e diff.
  • Row Factor Difference t P value Summary 1.000 0.0000 0.0000 P > 0.05 ns 2.000 0.6300 0.3161 P > 0.05 ns 3.000 -0.8600 0.4316 P > 0.05 ns 4.000 0.1100 0.05520 P > 0.05 ns 5.000 0.1700 0.08531 P > 0.05 ns 6.000 -0.8100 0.4065 P > 0.05 ns
  • Row Factor Difference t P value Summary 1.000 0.0000 0.0000 P > 0.05 ns 2.000 -0.5000 0.2509 P > 0.05 ns 3.000 -2.630 1.320 P > 0.05 ns 4.000 1.020 0.5118 P > 0.05 ns 5.000 -0.4800 0.2409 P > 0.05 ns 6.000 -1.710 0.8581 P > 0.05 ns 7.000 -0.8600 0.4316 P > 0.05 ns
  • Emoxypine 160 mg/kg
  • Emoxypine 160 Ifenoprodil (30 Differenc 95% Cl of
  • Emoxypine 160 mg/kg
  • Emoxypine 160 Rediprodil (30 Differenc 95% Cl of
  • Row Factor Difference t P value Summary 1.000 0.0000 0.0000 P > 0.05 ns 2.000 -2.050 1.029 P > 0.05 ns 3.000 -2.480 1.244 P > 0.05 ns 4.000 -2.280 1.144 P > 0.05 ns 5.000 -2.030 1.019 P > 0.05 ns 6.000 -2.430 1.219 P > 0.05 ns 7.000 -2.810 1.410 P > 0.05 ns
  • Emoxypine 160 Differenc 95% Cl of Row Factor Naive rng/kg) e diff.
  • Rediprodil (30 Differenc 95% Cl of Row Factor Naive mq/kq) e diff.
  • Emoxypine 160 Ifenoprodil (30 Differenc 95% Cl of
  • Emoxypine 160 mg/kg
  • Emoxypine 160 Rediprodil (30 Differenc 95% Cl of
  • Emoxypine 160 Differenc 95% Cl of Row Factor Naive rng/kg) e diff.
  • Rediprodil (30 Differenc 95% Cl of Row Factor Naive mg/kg) e diff.
  • Emoxypine 160 mg/kg
  • Emoxypine 160 Ifenoprodil (30 Differenc 95% Cl of
  • Emoxypine 160 mg/kg
  • Emoxypine 160 Rediprodil (30 Differenc 95% Cl of

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Abstract

La présente invention concerne des antagonistes de récepteur du glutamate 2b, et/ou l'émoxypine et/ou les inhibiteurs du reprélèvement sélectif de la sérotonine, utilisés pour traiter la maladie inflammatoire de l'intestin, la rétrocolite hémorragique (UC), la maladie de Crohn, et/ou la diarrhée. En particulier, l'émoxypine est utilisée pour le traitement ou la prophylaxie de la diarrhée, de la colite ou de la maladie inflammatoire de l'intestin telle que la rétrocolite hémorragique (UC) et la maladie de Crohn chez un sujet ; comprenant les combinaisons d'émoxypine avec un ou plusieurs médicaments anti-inflammatoires, suppresseurs du système immunitaire, antibiotiques, antidiarrhéiques, agents de soulagement de la douleur, suppléments en fer, injections de vitamine B 12 et suppléments de calcium et de vitamine D.
PCT/CA2020/050009 2019-07-10 2020-01-03 Composés de traitement de la diarrhée, de la maladie inflammatoire de l'intestin et leurs procédés WO2021003553A1 (fr)

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US201962872555P 2019-07-10 2019-07-10
US62/872,555 2019-07-10
US201962873570P 2019-07-12 2019-07-12
US62/873,570 2019-07-12
US201962938659P 2019-11-21 2019-11-21
US62/938,659 2019-11-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2674286C1 (ru) * 2018-03-20 2018-12-07 Исмагилов Искандар Халиуллович Средство для лечения заболевания, обусловленного нарушением окислительного стресса
WO2020006629A1 (fr) * 2018-07-06 2020-01-09 Algernon Pharmaceuticals Inc. Composés pour le traitement de la maladie intestinale inflammatoire et procédés associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2674286C1 (ru) * 2018-03-20 2018-12-07 Исмагилов Искандар Халиуллович Средство для лечения заболевания, обусловленного нарушением окислительного стресса
WO2020006629A1 (fr) * 2018-07-06 2020-01-09 Algernon Pharmaceuticals Inc. Composés pour le traitement de la maladie intestinale inflammatoire et procédés associés

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène

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