CN105324112A - 用于治疗腹泻的产品和方法 - Google Patents
用于治疗腹泻的产品和方法 Download PDFInfo
- Publication number
- CN105324112A CN105324112A CN201480022471.0A CN201480022471A CN105324112A CN 105324112 A CN105324112 A CN 105324112A CN 201480022471 A CN201480022471 A CN 201480022471A CN 105324112 A CN105324112 A CN 105324112A
- Authority
- CN
- China
- Prior art keywords
- bisfentidine
- receptor antagonist
- patient
- aforementioned
- diarrhoea
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010012735 Diarrhoea Diseases 0.000 title claims abstract description 102
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000000938 histamine H1 antagonist Substances 0.000 claims abstract description 57
- 229950002342 bisfentidine Drugs 0.000 claims description 54
- FXJAOWANXXJWGJ-UHFFFAOYSA-N n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(NC=NC(C)C)=CC=C1C1=CN=C(C)N1 FXJAOWANXXJWGJ-UHFFFAOYSA-N 0.000 claims description 54
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 40
- 229960001803 cetirizine Drugs 0.000 claims description 39
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims description 32
- 229960001596 famotidine Drugs 0.000 claims description 32
- 239000002552 dosage form Substances 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 208000019902 chronic diarrheal disease Diseases 0.000 claims description 15
- 210000003630 histaminocyte Anatomy 0.000 claims description 14
- 229960000620 ranitidine Drugs 0.000 claims description 14
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 9
- 208000010227 enterocolitis Diseases 0.000 claims description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- 229960000520 diphenhydramine Drugs 0.000 claims description 8
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 201000009840 acute diarrhea Diseases 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
- 239000000310 rehydration solution Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000003485 histamine H2 receptor antagonist Substances 0.000 abstract 1
- 230000013872 defecation Effects 0.000 description 40
- 230000003203 everyday effect Effects 0.000 description 36
- 208000002551 irritable bowel syndrome Diseases 0.000 description 13
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 10
- 230000007423 decrease Effects 0.000 description 10
- 239000000902 placebo Substances 0.000 description 10
- 229940068196 placebo Drugs 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 230000004044 response Effects 0.000 description 9
- 210000003608 fece Anatomy 0.000 description 8
- 208000015943 Coeliac disease Diseases 0.000 description 7
- 231100000957 no side effect Toxicity 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 206010009900 Colitis ulcerative Diseases 0.000 description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000005156 Dehydration Diseases 0.000 description 4
- 102000000543 Histamine Receptors Human genes 0.000 description 4
- 108010002059 Histamine Receptors Proteins 0.000 description 4
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 4
- 238000001574 biopsy Methods 0.000 description 4
- 239000000812 cholinergic antagonist Substances 0.000 description 4
- 229960001380 cimetidine Drugs 0.000 description 4
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000011505 plaster Substances 0.000 description 4
- 229940100618 rectal suppository Drugs 0.000 description 4
- 239000006215 rectal suppository Substances 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- 239000006189 buccal tablet Substances 0.000 description 3
- 229940046011 buccal tablet Drugs 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003792 electrolyte Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 208000029081 mast cell activation syndrome Diseases 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 210000001428 peripheral nervous system Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 201000009881 secretory diarrhea Diseases 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000006190 sub-lingual tablet Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229940098466 sublingual tablet Drugs 0.000 description 3
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 2
- 102000009660 Cholinergic Receptors Human genes 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- 206010014418 Electrolyte imbalance Diseases 0.000 description 2
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 2
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 2
- 206010025476 Malabsorption Diseases 0.000 description 2
- 206010071282 Mastocytic enterocolitis Diseases 0.000 description 2
- BXSVDJUWKSRQMD-ITMJLNKNSA-N O.O.CN1[C@@H]2CC[C@H]1C[C@H](C2)OC(=O)[C@H](CO)c3ccccc3.CN4[C@@H]5CC[C@H]4C[C@H](C5)OC(=O)[C@H](CO)c6ccccc6.OS(=O)(=O)O Chemical compound O.O.CN1[C@@H]2CC[C@H]1C[C@H](C2)OC(=O)[C@H](CO)c3ccccc3.CN4[C@@H]5CC[C@H]4C[C@H](C5)OC(=O)[C@H](CO)c6ccccc6.OS(=O)(=O)O BXSVDJUWKSRQMD-ITMJLNKNSA-N 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 229960000725 brompheniramine Drugs 0.000 description 2
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000001200 fecal consistency Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 201000009863 inflammatory diarrhea Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229960001508 levocetirizine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000008275 microscopic colitis Diseases 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 208000026775 severe diarrhea Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010061958 Food Intolerance Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000010538 Lactose Intolerance Diseases 0.000 description 1
- 102000001109 Leukocyte L1 Antigen Complex Human genes 0.000 description 1
- 108010069316 Leukocyte L1 Antigen Complex Proteins 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- ISFHAYSTHMVOJR-UHFFFAOYSA-N Phenindamine Chemical compound C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 ISFHAYSTHMVOJR-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010041969 Steatorrhoea Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 229940125714 antidiarrheal agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 229960004574 azelastine Drugs 0.000 description 1
- 229960002071 bepotastine Drugs 0.000 description 1
- YWGDOWXRIALTES-NRFANRHFSA-N bepotastine Chemical compound C1CN(CCCC(=O)O)CCC1O[C@H](C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 YWGDOWXRIALTES-NRFANRHFSA-N 0.000 description 1
- 229960004314 bilastine Drugs 0.000 description 1
- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940070318 chlo-amine Drugs 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000012321 colectomy Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 238000009112 empiric therapy Methods 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000000117 functional diarrhea Diseases 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 201000006592 giardiasis Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- 229960001144 mizolastine Drugs 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 229960004872 nizatidine Drugs 0.000 description 1
- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 201000009868 osmotic diarrhea Diseases 0.000 description 1
- 208000028719 osmotic diarrheal disease Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229960003534 phenindamine Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 230000000529 probiotic effect Effects 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960004466 quifenadine Drugs 0.000 description 1
- PZMAHNDJABQWGS-UHFFFAOYSA-N quifenadine Chemical compound C1N(CC2)CCC2C1C(O)(C=1C=CC=CC=1)C1=CC=CC=C1 PZMAHNDJABQWGS-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960001520 ranitidine hydrochloride Drugs 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 229960005328 rupatadine Drugs 0.000 description 1
- WUZYKBABMWJHDL-UHFFFAOYSA-N rupatadine Chemical compound CC1=CN=CC(CN2CCC(CC2)=C2C3=NC=CC=C3CCC3=CC(Cl)=CC=C32)=C1 WUZYKBABMWJHDL-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 208000001162 steatorrhea Diseases 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂。
Description
相关申请的交叉引用
本申请要求2013年3月14日提交的、标题为“用于治疗腹泻的产品和方法”的美国临时申请号No.61/782,608的优先权,其全部内容通过引用在此并入,与本申请不一致之处除外。
背景
腹泻是一种常见状况,其特征为排便频率或流动性增加。腹泻可引起脱水和电解质紊乱,可能需要住院治疗,以补充丢失的体液和电解质,直至症状消失。持续的、未得到控制的腹泻能够引起如严重营养不良、电解质失衡和脱水,其可能最终会导致死亡。急性腹泻通常使用流体和电解质置换、饮食改变以及止泻剂或抗微生物剂治疗。急性腹泻的并发症可能导致严重的疾病,特别是在高危人群中,例如潜在的免疫抑制或高龄患者。慢性腹泻患者也需要止泻治疗。用于慢性腹泻的常规经验疗法包括:粪便改善剂(如车前草和纤维)、抗胆碱药、阿片制剂、抗生素和益生菌。
慢性腹泻可能是慢性疾病的症状,如肠易激综合征(IBS)。据估计慢性腹泻在美国的发病率是约5%。估计仅IBS就影响美国总人口的15-20%,并占据所有胃肠病医疗费用的至少30%。在很多情况下,慢性腹泻的病因是未知的,诊断仍不明确并且经验治疗是不成功的。因此,对在接受治疗以除去导致腹泻的原因的患者中,或者在导致腹泻的原因未知的患者中,有效阻止或极大减少排便和体液丧失的止泻剂存在持续的需求。
H1和H2受体拮抗剂是两类抗组胺药。H1受体拮抗剂用于多种疾病的对症治疗,包括过敏性鼻结膜炎、在荨麻疹患者中缓解瘙痒和在慢性哮喘患者中使用。将新型的H1受体拮抗剂如西替利嗪称为第二代H1受体拮抗剂,其对于外周H1受体与第一代H1受体拮抗剂相比具有更高的选择性,其能够拮抗中枢和外周神经系统的H1受体以及胆碱能受体。这种选择性在显著降低药物不良反应(如镇静)发生的同时,仍能够有效缓解过敏性疾病。
H2受体拮抗剂主要用于治疗酸反流,或胃食道反流疾病的症状。H2受体拮抗剂减少胃酸的产生。通常将腹泻列为是H2受体拮抗剂的主要副作用。
已对将第一代H1受体拮抗剂苯海拉明与H2受体拮抗剂西咪替丁或雷尼替丁合用治疗急性过敏反应进行了研究。在第一项研究中(Rungeetal."Histamineantagonistsinthetreatmentofacuteallergicreactions"AnnEmergMed(Mar.1992)21:237-242),通过单次静脉内施用给予患者300mg西咪替丁和安慰剂、50mg苯海拉明和安慰剂或者苯海拉明加西咪替丁溶液;发现该治疗对于急性荨麻疹有效。在第二项研究中(Linetal."ImprovedoutcomesinpatientswithacuteallergicsyndromeswhoaretreatedwithcombinedH1andH2antagonists"AnnEmergMed(Nov.2000)36:462-468),通过单次胃肠外施用给予患者50mg苯海拉明和生理盐水或50mg苯海拉明和50mg雷尼替丁溶液;发现该治疗对于急性过敏症状有效。
概述
在第一个方面,本发明涉及一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂。优选地,所述H1受体拮抗剂包括西替利嗪和所述H2受体拮抗剂包括法莫替丁。
在第二个方面,本发明涉及一种在患者中治疗腹泻的方法,所述方法包括向所述患者使用H1受体拮抗剂和H2受体拮抗剂。优选地,所述H2受体拮抗剂不是雷尼替丁。
在第三个方面,本发明涉及一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂。
在第四个方面,本发明涉及一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂。优选地,所述患者不具有肥大细胞性小肠结肠炎。
在第五个方面,本发明涉及一种用于治疗腹泻的药物组合物,所述药物组合物包括H1受体拮抗剂和H2受体拮抗剂。优选地,所述H2受体拮抗剂不是雷尼替丁,和所述药物组合物是口服剂型。
在第六个方面,本发明涉及一种用于治疗腹泻的药物组合物,所述药物组合物包括H1受体拮抗剂和H2受体拮抗剂。优选地,所述H1受体拮抗剂不是苯海拉明。
在第七个方面,本发明涉及一种用于在患者中治疗腹泻的药物组合物,所述药物组合物包括H1受体拮抗剂和H2受体拮抗剂。优选地,所述患者不具有肥大细胞性小肠结肠炎。
在第八个方面,本发明涉及H1受体拮抗剂和H2受体拮抗剂用于制备治疗患有腹泻的患者的药物的用途。
定义
术语“腹泻”指粪便的流动性或频率增加。
术语“急性腹泻”指发生至多4周的持续腹泻。
术语“慢性腹泻”指超过4周的持续腹泻。
术语“单位剂型”指单一的、预先测定的剂量,并且包括片剂、丸剂、胶囊、包、混悬剂、透皮贴片和直肠栓剂。
附图简述
图1显示了IBS-D研究治疗组的参与者和应答情况。
详细描述
本发明利用了向患者施用H1受体拮抗剂和H2受体拮抗剂结果导致腹泻显著减轻或停止的发现。申请人发现将H1受体拮抗剂和H2受体拮抗剂联合给予腹泻患者结果产生85-90%的阳性应答者(参见实施例7和表1)。将阳性应答者定义为每日排便次数减少50%或更多或者粪便形式由液体变成固体。未报告不良反应或事件。对照组给予纤维和抗胆碱药在对照组中阳性应答者小于25%。
在一项此前的研究中(Jakate,etal.,"MastocyticEnterocolitis:Increasedmucosalmastcellsinchronicintractablediarrhea"ArchPatholLabMed(2006)130:362-367),向肥大细胞增加(每个高倍视野下的肥大细胞数大于20)并因此被作者鉴定为具有“肥大细胞性小肠结肠炎”的33名患者施用为期2周的方案:盐酸西替利嗪(H1受体拮抗剂)每日10mg和盐酸雷尼替丁(H2受体拮抗剂)300mg每日两次。在这33名患者的8名患者中,连续4至6周每日4次给予第三种药物200mg/10mL色甘酸钠(肥大细胞介质释放抑制剂)。针对症状的缓解、改善或持续情况对患者进行随访。未给予不具有肥大细胞性小肠结肠炎的患者这些药物。经随访,33名研究患者中的22名(67%)显示出腹泻停止或腹泻显著减少(定义为排便频率降低大于或等于50%或者粪便粘稠度改善大于或等于50%)。然而,由于在研究中未使用对照,并且由于在一些患者中使用了第三种药物,因而不可能针对选定患者确定治疗的有效性。安慰剂的作用导致至多约11名患者出现阳性结果和第三种药物导致至多8名患者出现阳性结果。未提供随访的时间范围。而且,未描述统计学分析或进一步的研究。
本发明包括通过联合施用H1受体拮抗剂和H2受体拮抗剂治疗腹泻。本发明还包括包含H1受体拮抗剂和H2受体拮抗剂的单位剂型、多剂量剂型和试剂盒。优选地,所述H1受体拮抗剂包括西替利嗪和所述H2受体拮抗剂包括法莫替丁。
腹泻可以是急性的或慢性的。还可以将腹泻进一步分类为:
分泌性腹泻:当肠管不能完全吸收来自肠腔内容物中的水和电解质吸收受损时发生的腹泻,通常由细菌毒素、手术导致肠吸收面积减少、显微镜结肠炎和肠腔促分泌素如缓泻剂和胆汁酸引起。
渗透性腹泻:摄入非电解质导致肠吸收障碍引起的腹泻。
炎性腹泻:其特征是在粪便中存在血和脓和可能出现粪便钙卫蛋白水平升高,以及在肠组织活检中显示出由例如克隆氏病和溃疡性结肠炎导致的炎症的腹泻。
IBS-腹泻型(“IBS-D”):伴有腹痛的慢性腹泻。患有IBS的患者必须在诊断之前已经开始出现6个月的症状,并且在过去的3个月中每个月至少有3天出现复发性腹痛或不适并且伴有下述中的两种或多种:排便改善;伴有排便频率改变的发作;伴有粪便形式改变的发作。一旦诊断为IBS,可以根据患者的主要症状对其进行进一步分类:腹泻(IBS-D)、或便秘(IBS-C)或者混合型(IBS-M)。
功能性腹泻:在不符合IBS标准并且也不能确定是由其他原因导致的患者中的慢性腹泻。也可以将这种类型的腹泻称为慢性特发性腹泻。
吸收不良性腹泻:由肠病如腹腔疾病(乳糜泻)和贾第鞭毛虫病引起的腹泻,其特征为气体过量、脂肪泻和/或体重减轻。
药物诱导的腹泻:由针对无关疾病状态的药物或治疗导致的腹泻,如化疗、放疗、抗生素治疗、抗溃疡治疗和草药治疗。
食物不耐受性腹泻:与膳食摄入相关的腹泻,如乳糖、糖替代物或其他食物。
特别常见的是与IBS相关的腹泻,这是一种慢性腹泻,也称为IBS-腹泻型或简称为“IBS-D”。一些研究者宣称已鉴定得到了IBS-D的亚型肥大细胞性小肠结肠炎,可以将其定义为每个高倍视野下具有大于20个肥大细胞的患者,其基于使用X400的原始放大倍率(放大倍率X40的物镜和放大倍率X10的目镜)检测来自肠粘膜随机部分的至少2个独立的组织活检碎片的平均10个高倍视野(Jakate,etal.,"MastocyticEnterocolitis:Increasedmucosalmastcellsinchronicintractablediarrhea"ArchPatholLabMed(2006)130:362-367)。在本发明的一个方面,所述患者不具有肥大细胞性小肠结肠炎。
H1受体拮抗剂阻断H1组胺受体;第一代H1受体拮抗剂阻断中枢和外周神经系统中的组胺受体以及胆碱能受体,而第二代H1受体拮抗剂选择性地针对外周神经系统中的H1组胺受体。第一代H1受体拮抗剂包括溴苯那敏、扑尔敏、右旋溴苯那敏、右扑尔敏、非尼拉敏、曲普利啶、卡比沙明、氯马斯汀、苯海拉明、美吡拉敏、异丙嗪、羟嗪、阿扎他定、赛庚啶和苯茚胺。第二代H1受体拮抗剂包括酮替芬、卢帕他定、咪唑斯汀、阿伐斯汀、依巴斯汀、比拉斯汀、贝他斯汀、特非那定、奎非那定、氮卓斯汀、西替利嗪、左西替利嗪、地氯雷他定、非索非那定和氯雷他定。优选地,所述H1受体拮抗剂是第二代H1受体拮抗剂,更优选地所述H1受体拮抗剂是西替利嗪或左西替利嗪,其中西替利嗪是特别优选地。还可以使用H1受体拮抗剂的混合物和组合。
可以使用的H1受体拮抗剂的量是在治疗过敏中使用的典型用量的0.1至10倍,例如用量为每剂量0.1至600mg、每剂量0.5至500mg、每剂量1.0至50或60mg,包括每剂量1.25、1.5、1.75、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40和45mg。优选地,所述H1受体拮抗剂每日施用1、2、3或4次。所述H1受体拮抗剂可以作为可注射剂型施用,例如静脉内、胃肠内或肌内;通过透皮贴片透皮;或者优选地作为粉剂、片剂或胶囊、口服溶液或混悬液、或者舌下或口含片口服。替代性的施用形式包括直肠栓剂、吸入、硬膜外、皮下、鼻喷雾、经粘膜和皮内制剂。
H2受体拮抗剂阻断H2组胺受体。H2受体拮抗剂包括西咪替丁、雷尼替丁、法莫替丁和尼扎替丁,其中法莫替丁是优选的。还可以使用H2受体拮抗剂的混合物和组合。
可以使用的H2受体拮抗剂的量是在治疗消化不良中使用的典型用量的0.1至10倍,例如用量为每剂量1.0至8000mg、每剂量2.0至1000mg、每剂量5.0至800mg,包括每剂量6.0、7.0、8.0、9.0、10、15、20、21、22、22.5、23、24、25、26、27、28、29、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、120、140、150、175、200、250、300、350、400、450、500、600和700mg。优选地,所述H2受体拮抗剂每日施用1、2、3或4次。所述H2受体拮抗剂可以作为可注射剂型施用,例如静脉内、胃肠内或肌内;通过透皮贴片透皮;或者优选地作为粉剂、片剂或胶囊、口服溶液或混悬液、或者舌下或口含片口服。替代性的施用形式包括直肠栓剂、吸入、硬膜外、皮下、鼻喷雾、经粘膜和皮内制剂。
患者通常在48至72小时内对治疗产生应答。但是,在急性腹泻的情况下治疗应当进行使得任意潜在病因缓解的时间,例如3至14天,或5至10天。在慢性腹泻的情况下,30天的试验期是合理的,并且如果导致腹泻的潜在病因不能被缓解,例如在IBS-D的情况下,则治疗应无限期的持续。
优选地,所述H1和H2受体拮抗剂以含有这两种受体拮抗剂的单位剂型的形式同时施用。单位剂型的示例包括口服组合物,如片剂(例如舌下或口含片)、胶囊(例如硬明胶和软明胶胶囊)、经粘膜和舌下贴片和膜剂、预称量粉包(saches)、加入调味剂和/或甜味剂的水溶液或混悬液。因为腹泻通常与脱水相结合,所以加入调味剂和/或甜味剂的水溶液或混悬液可以是口服补液溶液,或者是250ml、500ml或1升液体量的其中还含有钠和葡萄糖或含有葡萄糖的糖类的溶液。而且,可以提供含有所述受体拮抗剂以及钠(例如,氯化钠)和葡萄糖或含有葡萄糖的糖类,和任选地其他赋形剂、调味剂和/或甜味剂的预称量粉包,其在使用前可以容易地与水混合。优选地,口服单位剂型以每日一次的剂型存在。
口服剂型的示例包括片剂,其含有含量为5、10、15、20、22.5、25、30、35或40mg的法莫替丁作为核心和含量为2.5、5、8.5、10、15或20mg的西替利嗪包衣。另一个示例包括含有法莫替丁颗粒和在水溶性基质中的西替利嗪的胶囊。在另一个示例中,法莫替丁和西替利嗪作为混合物存在于基质中,其作为片剂或者在胶囊中。在这些示例中,可以使用其他H1和/或H2受体拮抗剂代替法莫替丁和/或西替利嗪,或者除了法莫替丁和/或西替利嗪以外还可以使用其他H1和/或H2受体拮抗剂。
还可以提供含有H1和H2受体拮抗剂的其他单位剂型。例如可以提供含有无菌溶液或混悬液的可注射制剂,包括用于静脉内、胃肠内或肌内施用的制剂。可以提供用于通过透皮贴片透皮施用的单位剂型。其他单位剂型包括直肠栓剂、吸入、硬膜外、皮下、鼻喷雾和皮内制剂。在口服和非口服的任意单位剂型中还可以包括赋形剂和助剂。
可以提供多剂量剂型,如含有2至30个、3至25个或者5至14个单位剂型,例如6、7、8、9、10、11、12、13、15、20、40、50或60个单位剂型的试剂盒。优选地,所述多剂量剂型含有足以施用2至30天、3至25天或者7至14ian,例如4、5、6、7、8、9、10、11、12、13、20或30天的单位剂型。还可以提供其中包括口服补液溶液,或者可以水化以形成口服补液溶液的粉剂的试剂盒,或者含有钠和葡萄糖或含有葡萄糖的糖类,以及其他赋形剂、调味剂和/或甜味剂和单位剂型的试剂盒。
实施例
实施例1:分泌性腹泻的治疗
患者#1,年龄65,因出现超过一周的与慢性腹泻相关的体重减轻和体液丢失入院。该患者每日排便20至40次并且出现严重危及生命的腹泻。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。其症状在48小时内消退,排便次数减少95%,患者出院。该患者对治疗产生应答,目前每日排便1次,偶尔2次,但不是腹泻。
实施例2:IBS腹泻的治疗
对7名年龄为26至80岁,每日排便3至18次的轻度至重度腹泻患者进行治疗。
患者#1,年龄80岁,出现轻度至重度痉挛,每日排便4至5次。每日一次,使用300mg雷尼替丁和10mg西替利嗪对该患者进行治疗。该患者报告排便次数减少了60%。
患者#2,年龄62岁,出现与腹泻相关的严重体重减轻(超过30磅),每日排便10至20次,并且其具有阿片类药物和类固醇依赖性。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗成功将排便次数减少了85至90%。该患者在治疗8个月后目前每日排便1至2次。
患者#3,年龄65岁,治疗前困居家中,每日排便4至5次,每次发作持续1至2小时。每日一次,使用300mg雷尼替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,该患者报告排便次数减少了90%。
患者#4,年龄67岁,出现中度腹泻和痉挛,每日排便4至5次。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者排便次数减少了75%,无痉挛和副作用。
患者#5,年龄26岁,出现中度至重度腹泻,每日排便7至8次。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了50%,降至每日3至4次,无副作用。
患者#6,年龄74岁,出现重度腹泻,每日排便8次并困居于家中。每日一次,使用300mg雷尼替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了75%,降至每日2次,无副作用。患者目前仅使用西替利嗪。
患者#7,年龄51岁,进行了结肠切除术,出现重度腹泻,每日排便15至20次。每日一次,使用300mg雷尼替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了94%,降至每日1至2次并且具有更好的粪便粘稠度,无副作用。
实施例3:慢性特发性腹泻
患者81岁,主诉中度腹泻并无其他诊断,每日排便4至6次,对其活动水平和生活方式造成干扰。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了70%,降至每日1至2次,大部分是1次,并且取消了结肠镜复查,因为症状已缓解。
实施例4:化疗诱发的腹泻
患者64岁,患有结肠癌并出现中度至重度腹泻,处于由化疗剂导致的虚弱状态,每日排便5至10次。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了80%,降至每日1至2次并且粪便具有正常的粘稠度,无副作用。
实施例5:炎性腹泻——溃疡性结肠炎/克隆氏病
对3名年龄为35至64岁出现了与溃疡性结肠炎或克隆氏病相关的重度腹泻患者进行治疗。
患者#1,年龄64岁,患有克隆氏病,每日排便12至15次并且出现重度腹泻。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是不成功的,患者的排便次数仅减少了5%。无副作用。
患者#2,年龄37岁,患有克隆氏病和结肠炎,出现重度腹泻,每日排便4至5次。每日一次,使用300mg雷尼替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了75%,降至每日1次并且粪便具有正常的粘稠度。
患者#3,年龄35岁,患有溃疡性结肠炎,出现重度腹泻,每日排便4至6次。每日一次,使用20mg法莫替丁和10mg西替利嗪对该患者进行治疗。治疗是成功的,患者的排便次数减少了50%。无副作用。
实施例6:腹腔疾病(乳糜泻)
患者#1,年龄57岁,患有腹腔疾病,出现轻度至中度腹泻,每日排便2至4次。该患者经过每日一次,使用20mg法莫替丁和10mg西替利嗪的治疗后未出现改善。无副作用。
患者#2,年龄26岁,患有腹腔疾病。该患者经过治疗后仅出现了较小改善。
实施例7:IBS-D治疗研究
研究人群的年龄为18至80岁,其为患有慢性无法解释的腹泻的患者,其来自已同意接受治疗的诊所的门诊患者人群和医疗中心的门诊患者。排除具有全身性或皮肤肥大细胞增多、具有可确定的腹泻病因(IBS-D或慢性特发性腹泻除外)如腹腔疾病、炎性肠病或乳糖不耐受,或者妊娠的患者。研究在经IRB批准后启动。
在转介至研究协调员并签署知情同意书后,将患者分配至两个研究组之一。对患者进行带组织活检的结肠镜检查,然后由对研究组处于盲态的病理学家进行评估。由研究协调员复核相应的病理结果和文档。向患者提供随机分配的治疗方法并且给予一个日志记录症状。定期进行电话随访和回访。在四周药物治疗期结束后,进行电话访问或访视。在八周时,收回日志并由协调员记录受试者记录的数据。有报告不良事件的程序,到目前为止无不良反应或事件的报告。
一个研究组每日一次给予法莫替丁(每日20mg)和西替利嗪(每日10mg)。另一个研究组每日一次给予纤维和抗胆碱能药表1显示了研究结果。表2和3显示了对研究结果的统计学分析。
表1:研究结果
阳性应答者=每日排便次数显著减少#
无应答者=每日排便次数无显著减少#
表2:分组统计学
表3:独立的样本检验
图1显示了治疗组的参与者和应答情况。左侧的柱子表示给予法莫替丁和西替利嗪的患者,右侧的柱子表示给予纤维和抗胆碱能药物的患者。如表和图中所示,90%给予法莫替丁和西替利嗪的患者对治疗产生了应答,而给予纤维和抗胆碱能药物的患者仅有10%对治疗产生了应答。
表4和5分别显示了法莫替丁和西替利嗪研究组以及双环胺和车前草研究组每日排便次数减少的百分率。
表4:法莫替丁和西替利嗪研究组每日排便次数减少的百分率
受试者数量 | 排便减少百分率 |
1 | 0% |
1 | 10-25% |
2 | 28-45% |
11 | 50-65% |
11 | 66-85% |
0 | >86% |
表5:双环胺和车前草研究组每日排便次数减少的百分率
受试者数量 | 排便减少百分率 |
6 | 0% |
0 | 10-25% |
1 | 28-45% |
1 | 50-65% |
0 | 66-85% |
0 | >86% |
实施例8:慢性腹泻治疗研究
研究人群的年龄为21至70岁,其为已同意接受治疗的已诊断为慢性腹泻的患者。如果患者对H1受体拮抗剂或H2受体拮抗剂敏感或过敏、肾损伤或有肾衰竭病史、诊断为炎性肠病(克隆氏病或溃疡性结肠炎)、已知有结肠活动性感染(如艰难梭状芽孢杆菌、贾第鞭毛虫或沙门氏菌)、组织活检证实有显微镜结肠炎(胶原性或淋巴细胞性结肠炎)或者在研究期间无法停止使用气体止泻剂,则将其排除。如果患者是妊娠或哺乳期妇女,或者如果患者正在使用阿扎那韦、伊曲康唑或酮康唑,则也许将其排除。研究在经IRB批准后启动。
本研究是一项交叉设计的、为期4周的随机、双盲、对照的试验。在签署知情同意书后,将患者随机分配至两个组(活性剂或安慰剂)之一,患者和医师均不知晓各患者的分组情况。向各患者提供随机分配的治疗方法并且给予一个日志记录症状。在治疗7天后,由处于盲态的研究组成员对参与研究的受试者进行电话访问。在治疗一周后对无应答者进行交叉。在第28天研究结束时,让患者完成详细的问卷调查。使用7分布里斯托粪便分类法(BristolStoolScale)对粪便质量进行评估。
“活性剂组”每日一次给予法莫替丁(24mg)和西替利嗪(9mg),这两种药物以单一胶囊的形式联用。“安慰剂组”每日一次给予一颗含有非活性成分的胶囊。
研究结果如表6所示。表中显示了27名患者的结果,其中安慰剂组12名和活性剂组15名。安慰剂组每日粪便(SPD)变化百分率的平均值为25.08,而活性剂组SPD变化百分率的平均值为46.00。活性剂组仅有3名患者同意进行交叉,而安慰剂组有9名患者同意进行交叉。该数据表明安慰剂组与活性剂组之间存在临床显著性差异,活性剂组中患者的生活质量得到了显著改善。
表6:慢性腹泻治疗研究结果
分组 | 患者数量 | 平均△%SPD |
安慰剂 | 12 | 25.08 |
活性剂 | 15 | 46.00 |
参考文献
SchillerLR,"SecretoryDiarrhea"CurrentGastroenterologyReports(1999)1:389-397.
Schiller,LR,HoganRB,Morawski,SG,SantaAna,CA,BernMJ,Nogaard,RP,Bo-Linn,GW,FordtranJS,"StudiesofthePrevalenceandSignificanceofRadiolabeledRiceAcidMalabsorptioninaGroupofPatientswithIdiopathicChronicDiarrhea"Gastroenterology(1997)92:151-160.
FordtranJS,SantaAnaCA,MorawskiSG,etal."Pathophysiologyofchronicdiarrhea:insightsderivedfromintestinalperfusionstudiesin31patients"GastroenterolClinNorthAm(1986)15:477-490.
LunardiC,BambaraLM,BiasiD,etal."Double-blindcross-overtrialoforalsodiumcromoglycateinpatientswithirritablebowelsyndromeduetofoodintolerance"ClinExpAllergy(1991)21:569-572.
FineKD,SchillerUR,"AGAtechnicalreviewontheevaluationandmanagementofchronicdiarrhea"Gastroenterology(1999)116:1464-1486.
O'Sullivanetal."Increasedmastcellsintheirritablebowelsyndrome"Neurogastroenterol.Mot.(2000)12:449-457.
SpillerRC,JenkinsD,ThornleyJP,HebdenJM,WrightT,SkinnerM,NealKR,"Increasedrectalmucosalenteroendocrinecells,Tlymphocytes,andincreasedgutpermeabilityfollowingacuteCampylobacterenteritisandinpost-dysentericirritablebowelsyndrome"Gut(Dec.2000)47(6):804-11.
TheoharidesTCCochraneDE,"CriticalroleofMastCellsininflammatorydiseasesandtheeffectofacutestress"JNeuroimmunol(2004)146:1-12.
BarbarsG,DeGiorgioetal."Newpathophysiologicalmechanismsinirritablebowelsyndrome"AlimentPharmacolTher(2004)20(suppl.2):1-9.
DunlopSP,Hebdenetal."Abnormalintestinalpermeabilityinsubgroupsofdiarrhea-predominantirritablebowelsyndromes"AmJGastroenterol(2006)101(6):1288-1294.
BarbaraG,StanghelliniVetal."Functionalgastrointestinsldisordersandmastcells:implicationsfortherapy"NeurogastroenterolMotil(2006)18:6-17.
HalvorsonHAetal."Postinfectiousirritablebowelsyndrome-ameta-analysis"AmJGastroenterol(2006)101:1894-1899.
PosserudIetal."Smallintestinalbacterialovergrowthinpatientswithirritablebowelsyndrome"Gut(2007)56:802-808.
Lewis,J,Candelora,J,Hogan,II,RB,Briggs,F,Abraham,S,"Crystal-StoringHistiocytosisDuetoMassiveAccumulationofCharcot-LeydenCrystals:AUniqueAssociationProducingColonicPolyposisina78-year-oldWomanWithEosinophilicColitis"AmJSurgPathol.(Mar.2007)321(3):481-485.
JakateS,etal."Mastocyticenterocolitisincreasedmucosalmastcellsinchronicintractablediarrhea"ArchPatholLabMed,(2006)130:362-367.
KirschRH,RiddellR,"Histopathologicalalterationsinirritablebowelsyndrome"ModemPathology(2006)19:1638-1645.
RamosL,VicarioM,SantosJ,"Stress-mastcellaxisandregulationofgutmucosalinflammation:fromintestinalhealthtoanirritablebowel"MedClin(Bare)(Jun.2007)129(2):61-69.
PicheT,Saint-PaulMCetal."Mastcellsandcellularityofthecolonicmucosacorrelatedwithfatigueanddepressioninirritablebowelsyndrome"Gut(2008)57:468-473.
VisserJ,Rozingetal."TightJunctions,intestinalpermeabilityandautoimmunityceliacdiseaseandtype1diabetesparadigms"AnnNYAcadSci(2009)1165:195-205.
WalkerMM,TalleyNJ,etal."Duodenalmastocytosis,eosinophiliaandintraepitheliallymphocytosisaspossiblediseasemerkersintheirritablebowelsyndromeandfunctionaldyspepsia"AlimentPharmacolTher(2009)29:765-773.
ThabaneM,MarshallJK,"Post-infectiousirritablebowelsyndrome"WorldJGastroenterol.(2009)15(29):3591-3596.
WalkerMM,SalehianSSetal."Implicationsofeosinophiliainthenormalduodenalbiopsy-anassociationwithallergyandfunctionaldyspepsia"AlimentPharmacolTher(2010)31:1229-1236.
KlookerTK,BraakB.KoopmanKEetal."Themastcellstabilizerketotifendecreasesvisceralhypersensitivityandimprovesintestinalsymptomsinpatientswithirritablebowelsyndrome"Gut(2010)59:1213-21.
MartinezC,etal."TheJejunumofDiarrhea-PredominantIrritableBowelSyndromeShowsMolecularAlterationsintheTightJunctionSignalingPathwayThatAreAssociatedWithMucosalPathobiologyandClinicalManifestations"AmJGastroenterol(2012)107:736-746.
TheoharidesTC,ShahrzadA,ChenJ,HuizingaJ,"IrritableBowelSyndromeandtheElusiveMastCell"AmJGastroenterol(2012)107:727-729.
SmithMJ,"IBSremainsamysteriousdisorderwithfeweffectiveRemedies"GastroenterologyandEndoscopyNews(April2012)Vol.63:4.
PylerisE,Giamarellos-BourboulisEJ,etal."Theprevalenceofovergrowthbyaerobicbacteriainthesmallintestinebysmallbowelculture:relationshipwithirritablebowelsyndrome"DigDisSci.(May2012)57(5):1321-9.
Vivinus-NebotM,DaineseR,etal."Combinationofallergicfactorscanworsendiarrheicirritablebowelsyndrome:roleofbarrierdefectsandmastcells"ACG(2012)107:74-81
AkhaveinA,PatelNR,etal."AllergicMastocyticGastroenteritisandcolitis:andunexplainedetiologyinchronicabdominalpainandgastrointestinaldysmotility"GastroenterResearchandPractice(2012)2012:950582.
MartinezC,LoboB,etal."Diarrhoea-predominantirritablebowelsyndrome:anorganicdisorderwithstructuralabnormalitiesinthejejunalepithelialbarrier"Gut(2012)[Epubaheadofprint:25May2012].
BraakB,KlookerTKetal."Mucosalimmunecellnumbersandvisceralsensitivityinpatientswithirritablebowelsyndrome:isthereanyrelationship?"AmJGastroenterol(2012)107:715-726.
TheoharidesTC,AsadiS,ChenJ,HuizingaJD,"Irritablebowelsyndromeandtheelusivemastcells"AmJGastroenterol(2012)107(5)727-729.
FarhadiA,FieldsJZ,KeshavarzianA,"Mucosalmastcellsarepivotalelementsininflammatoryboweldiseasethatconnectthedots:stress,intestinalhyperpermeabilityandinflammation"WorldJGastroenterol(2007)13(22):3027-3030.
JuckettG,TrivediR,"Evaluationofchronicdiarrhea"AmericanFamilyPhysician[serialonline].November15,2011;84(10):1119-1126.
Diarrhea[electronicresource]/NationalDigestiveDiseasesInformationClearinghouse.(2011).Bethesda,MD:U.S.Dept.ofHealthandHumanServices,NationalInstitutesofDiabetesandDigestiveandKidneyDiseases.
ForbesD,O'LoughlinE,ScottR,GallD,"Laxativeabuseandsecretorydiarrhoea"ArchDisChild(1985)60(1):58-60.
DuPont,H.L.etal.,"Diarrhea",NationalDigestiveDiseasesInformationClearinghouse,January2012.
Lever,D.D.,etal.,"AcuteDiarrhea",CenterforContinuingEducationpublications:DiseaseManagementProject,ClevelandClinic,August1,2010.
H2blockers,U.S.NationalLibraryofMedicine,NIH,updated:August11,2011.
Rungeetal."Histamineantagonistsinthetreatmentofacuteallergicreactions"AnnEmergMed(Mar.1992)21:237-242.
Linetal."ImprovedoutcomesinpatientswithacuteallergicsyndromeswhoaretreatedwithcombinedH1andH2antagonists"AnnEmergMed(Nov.2000)36:462-468.
He,Shuang;Li,Feng;Zhou,Dan;Du,Junrong;Huang,Yuan,Drugdevelopmentandindustrialpharmacy,(Oct.2012)38(10)1280-1289.
AkinC,ValentP,MetcalfeDD"Mastcellactivationsyndrome:Proposeddiagnosticcriteria"JAllergyClinImmunol.(2010)126(6):1099-104.
HamiltonMJ,HornickJL,AkinC,CastellsMC,GreenbergerNJ"Mastcellactivationsyndrome:anewlyrecognizeddisorderwithsystemicclinicalmanifestations"JAllergyClinImmunol.(2011)128(1):147-152.
ValentP“Mastcellactivationsyndromes:definitionandclassification”Allergy(2013)[Epubaheadofprint15Feb.2013].
Claims (31)
1.一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂,优选地其中所述患者不具有肥大细胞性小肠结肠炎。
2.一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂,其中所述H1受体拮抗剂包括西替利嗪和所述H2受体拮抗剂包括法莫替丁。
3.一种在患者中治疗腹泻的方法,所述方法包括向所述患者施用H1受体拮抗剂和H2受体拮抗剂,其中所述H2受体拮抗剂不是雷尼替丁。
4.H1受体拮抗剂和H2受体拮抗剂在用于制备治疗患有腹泻的患者的药物中的用途,优选地其中所述患者不具有肥大细胞性小肠结肠炎。
5.H1受体拮抗剂和H2受体拮抗剂在用于制备治疗患有腹泻的患者的药物中的用途,其中所述H1受体拮抗剂包括西替利嗪和所述H2受体拮抗剂包括法莫替丁。
6.H1受体拮抗剂和H2受体拮抗剂在用于制备治疗患有腹泻的患者的药物中的用途,其中所述H2受体拮抗剂不是雷尼替丁。
7.根据前述任意一项权利要求所述的方法或用途,其中所述H1受体拮抗剂包括第二代H1受体拮抗剂。
8.根据前述任意一项权利要求所述的方法或用途,其中所述H1受体拮抗剂包括西替利嗪、左旋西替利嗪或其混合物。
9.根据前述任意一项权利要求所述的方法或用途,其中所述H2受体拮抗剂包括法莫替丁、雷尼替丁或其混合物。
10.根据前述任意一项权利要求所述的方法或用途,其中所述H1受体拮抗剂和所述H2受体拮抗剂同时施用。
11.根据前述任意一项权利要求所述的方法或用途,其中所述H1受体拮抗剂和所述H2受体拮抗剂每日施用一次,至少施用2天。
12.根据前述任意一项权利要求所述的方法或用途,其中所述H1受体拮抗剂和所述H2受体拮抗剂每日施用一次,至少施用7天。
13.根据前述任意一项权利要求所述的方法或用途,其中所述患者患有慢性腹泻。
14.根据前述任意一项权利要求所述的方法或用途,其中所述患者患有IBS-D。
15.根据前述任意一项权利要求所述的方法或用途,其中所述患者患有急性腹泻。
16.根据前述任意一项权利要求所述的方法或用途,其中西替利嗪以5至20mg的量施用。
17.根据前述任意一项权利要求所述的方法或用途,其中所述法莫替丁以10至40mg的量施用。
18.根据前述任意一项权利要求所述的方法或用途,其中所述法莫替丁和所述西替利嗪作为单位剂型在一起使用。
19.根据前述任意一项权利要求所述的方法或用途,其中所述H2受体拮抗剂包括法莫替丁。
20.一种用于治疗腹泻的药物组合物,所述组合物包括:
H1受体拮抗剂,和
H2受体拮抗剂,
其中所述H2受体拮抗剂不是雷尼替丁,和
所述药物组合物是口服剂型。
21.一种用于治疗腹泻的药物组合物,所述组合物包括:
H1受体拮抗剂,和
H2受体拮抗剂,
其中所述H1受体拮抗剂不是苯海拉明。
22.一种用于在患者中治疗腹泻的药物组合物,所述组合物包括:H1受体拮抗剂,和H2受体拮抗剂,优选地其中所述患者不具有肥大细胞性小肠结肠炎。
23.根据前述任意一项权利要求所述的药物组合物,其中所述H1受体拮抗剂包括第二代H1受体拮抗剂。
24.根据前述任意一项权利要求所述的药物组合物,其中所述H1受体拮抗剂包括西替利嗪、左旋西替利嗪或其混合物。
25.根据前述任意一项权利要求所述的药物组合物,其中所述H2受体拮抗剂包括法莫替丁。
26.根据前述任意一项权利要求所述的药物组合物,其中所述H1受体拮抗剂包括西替利嗪,和所述H2受体拮抗剂包括法莫替丁。
27.根据前述任意一项权利要求所述的药物组合物,其中所述口服剂型包括单位剂型。
28.根据前述任意一项权利要求所述的药物组合物,其中所述口服剂型包括至少一种片剂或胶囊。
29.根据前述任意一项权利要求所述的药物组合物,其中所述口服剂型还包括钠和葡萄糖或含有葡萄糖的糖类。
30.根据前述任意一项权利要求所述的药物组合物,其中所述口服剂型还包括口服补液溶液。
31.根据前述任意一项权利要求所述的药物组合物,其中所述口服剂型包括多个单位剂型。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810755897.7A CN108939076A (zh) | 2013-03-14 | 2014-03-14 | 用于治疗腹泻的产品和方法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361782608P | 2013-03-14 | 2013-03-14 | |
US61/782,608 | 2013-03-14 | ||
PCT/US2014/027323 WO2014152420A2 (en) | 2013-03-14 | 2014-03-14 | Product and method for treating diarrhea |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810755897.7A Division CN108939076A (zh) | 2013-03-14 | 2014-03-14 | 用于治疗腹泻的产品和方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105324112A true CN105324112A (zh) | 2016-02-10 |
CN105324112B CN105324112B (zh) | 2018-08-17 |
Family
ID=50680150
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480022471.0A Active CN105324112B (zh) | 2013-03-14 | 2014-03-14 | 用于治疗腹泻的产品和方法 |
CN201810755897.7A Pending CN108939076A (zh) | 2013-03-14 | 2014-03-14 | 用于治疗腹泻的产品和方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810755897.7A Pending CN108939076A (zh) | 2013-03-14 | 2014-03-14 | 用于治疗腹泻的产品和方法 |
Country Status (20)
Country | Link |
---|---|
US (4) | US9717726B2 (zh) |
EP (3) | EP3581205A3 (zh) |
JP (4) | JP6313417B2 (zh) |
KR (4) | KR102449977B1 (zh) |
CN (2) | CN105324112B (zh) |
AU (3) | AU2014239878B2 (zh) |
BR (2) | BR122017004716A2 (zh) |
CA (1) | CA2906005C (zh) |
DK (1) | DK2968205T3 (zh) |
ES (2) | ES2655505T3 (zh) |
HK (2) | HK1213205A1 (zh) |
HU (1) | HUE035201T2 (zh) |
IL (3) | IL273377B2 (zh) |
MX (2) | MX350814B (zh) |
MY (1) | MY175326A (zh) |
PL (1) | PL2968205T3 (zh) |
PT (1) | PT2968205T (zh) |
RU (1) | RU2015143475A (zh) |
WO (1) | WO2014152420A2 (zh) |
ZA (1) | ZA201708539B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9717726B2 (en) * | 2013-03-14 | 2017-08-01 | Maregade Rx, LLC | Product and method for treating diarrhea |
WO2015073573A1 (en) * | 2013-11-14 | 2015-05-21 | Jacobs Michael M | Compositions and methods for the prevention and treatment of alcohol-induced hangover syndrome |
WO2018119464A1 (en) | 2016-12-23 | 2018-06-28 | Maregade Rx, LLC | Low dose product and method for treating diarrhea |
IT201900012645A1 (it) * | 2019-07-23 | 2021-01-23 | Eros Zanotti | Una composizione farmaceutica per l'uso nel trattamento delle chinetosi |
CN117293008A (zh) * | 2019-08-05 | 2023-12-26 | 株式会社日立高新技术 | 等离子处理装置 |
WO2023049205A1 (en) * | 2021-09-22 | 2023-03-30 | Hista Rx Llc | Compositions and methods for treating and preventing interstitial cystitis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101299996A (zh) * | 2005-09-30 | 2008-11-05 | 麦克内尔-Ppc股份有限公司 | 含有唾液诱生剂的口服组合物 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5204118A (en) | 1989-11-02 | 1993-04-20 | Mcneil-Ppc, Inc. | Pharmaceutical compositions and methods for treating the symptoms of overindulgence |
WO1995001792A1 (en) | 1993-07-06 | 1995-01-19 | Merck & Co., Inc. | H2 antagonist-antihistamine combinations |
US6264984B1 (en) * | 1999-12-06 | 2001-07-24 | Bristol-Myers Squibb Company | Effervescent histamine H2 antagonist composition |
US6656492B2 (en) * | 2000-06-30 | 2003-12-02 | Yamanouchi Pharmaceutical Co., Ltd. | Quick disintegrating tablet in buccal cavity and manufacturing method thereof |
RU2281326C2 (ru) | 2000-11-30 | 2006-08-10 | Дзе Байо Бэлэнс Корп. | ШТАММ БАКТЕРИЙ Escherichia coli, ПРЕДНАЗНАЧЕННЫЙ ДЛЯ НОРМАЛИЗАЦИИ ФИЗИОЛОГИЧЕСКОЙ АКТИВНОСТИ ЖЕЛУДОЧНО-КИШЕЧНОГО ТРАКТА, ПРОБИОТИЧЕСКАЯ КОМПОЗИЦИЯ, ПРЕДНАЗНАЧЕННАЯ ДЛЯ НОРМАЛИЗАЦИИ ФИЗИОЛОГИЧЕСКОЙ АКТИВНОСТИ ЖЕЛУДОЧНО-КИШЕЧНОГО ТРАКТА (ВАРИАНТЫ), И СПОСОБ ЕЕ ПОЛУЧЕНИЯ, СПОСОБ ВЫРАЩИВАНИЯ ШТАММА БАКТЕРИЙ Escherichia coli И ПИЩЕВОЙ ПРОДУКТ |
KR100967601B1 (ko) * | 2001-11-23 | 2010-07-05 | 얀센 파마슈티카 엔.브이. | 두개내압의 상승을 신속히 감소시키기 위한 항-히스타민제의 용도 |
SE528789C2 (sv) | 2004-09-10 | 2007-02-13 | Sandvik Intellectual Property | PVD-belagt skär av hårdmetall samt sätt att tillverka detta |
WO2007111945A2 (en) | 2006-03-22 | 2007-10-04 | Trustees Of Boston University | Method for management of diarrhea |
US8207188B2 (en) | 2006-04-07 | 2012-06-26 | Michalis Nicolaou | Treatment of diseases modulated by a H4 receptor agonist |
US20070254050A1 (en) * | 2006-05-01 | 2007-11-01 | Quart Barry D | Method for treatment of diarrhea-predominant irritable bowel syndrome |
US20090042972A1 (en) * | 2006-05-19 | 2009-02-12 | Somaxon Pharmaceuticals, Inc. | Methods of using low-dose doxepin for the improvement of sleep |
WO2008100539A1 (en) | 2007-02-12 | 2008-08-21 | Michalis Nicolaou | Treatment of copd, gastro-esophageal reflux disease (gerd), food allergies and other gastrointestinal conditions and disorders ameliorated by proper histamine management using a combination of histidine decarboxylase inhibitors, lra drugs, anti-h1 and/or anti-h2 drugs |
CA2721133C (en) * | 2007-04-13 | 2018-11-06 | Somaxon Pharmaceuticals, Inc. | Low-dose doxepin formulations and methods of making and using the same |
US8263581B2 (en) | 2009-07-03 | 2012-09-11 | Jdp Therapeutics, Inc. | Non-sedating antihistamine injection formulations and methods of use thereof |
US9856477B2 (en) | 2012-11-13 | 2018-01-02 | Codiak Biosciences, Inc. | Delivery of therapeutic agent |
US9717726B2 (en) | 2013-03-14 | 2017-08-01 | Maregade Rx, LLC | Product and method for treating diarrhea |
WO2018119464A1 (en) | 2016-12-23 | 2018-06-28 | Maregade Rx, LLC | Low dose product and method for treating diarrhea |
-
2014
- 2014-03-13 US US14/209,937 patent/US9717726B2/en active Active
- 2014-03-14 EP EP19169633.5A patent/EP3581205A3/en active Pending
- 2014-03-14 KR KR1020217004881A patent/KR102449977B1/ko active IP Right Grant
- 2014-03-14 AU AU2014239878A patent/AU2014239878B2/en active Active
- 2014-03-14 EP EP17189072.6A patent/EP3269364B1/en active Active
- 2014-03-14 PL PL14722445T patent/PL2968205T3/pl unknown
- 2014-03-14 WO PCT/US2014/027323 patent/WO2014152420A2/en active Application Filing
- 2014-03-14 CN CN201480022471.0A patent/CN105324112B/zh active Active
- 2014-03-14 JP JP2016502404A patent/JP6313417B2/ja active Active
- 2014-03-14 MY MYPI2015703092A patent/MY175326A/en unknown
- 2014-03-14 KR KR1020187021688A patent/KR20180088514A/ko not_active IP Right Cessation
- 2014-03-14 CA CA2906005A patent/CA2906005C/en active Active
- 2014-03-14 PT PT147224455T patent/PT2968205T/pt unknown
- 2014-03-14 MX MX2015011885A patent/MX350814B/es active IP Right Grant
- 2014-03-14 EP EP14722445.5A patent/EP2968205B1/en active Active
- 2014-03-14 KR KR1020207023569A patent/KR20200100211A/ko not_active Application Discontinuation
- 2014-03-14 CN CN201810755897.7A patent/CN108939076A/zh active Pending
- 2014-03-14 BR BR122017004716-7A patent/BR122017004716A2/pt not_active Application Discontinuation
- 2014-03-14 ES ES14722445.5T patent/ES2655505T3/es active Active
- 2014-03-14 RU RU2015143475A patent/RU2015143475A/ru not_active Application Discontinuation
- 2014-03-14 DK DK14722445.5T patent/DK2968205T3/da active
- 2014-03-14 HU HUE14722445A patent/HUE035201T2/hu unknown
- 2014-03-14 IL IL273377A patent/IL273377B2/en unknown
- 2014-03-14 ES ES17189072T patent/ES2743604T3/es active Active
- 2014-03-14 BR BR112015022513A patent/BR112015022513A2/pt not_active Application Discontinuation
- 2014-03-14 KR KR1020157029028A patent/KR101884506B1/ko active IP Right Grant
- 2014-03-14 MX MX2017011532A patent/MX366329B/es unknown
-
2015
- 2015-09-09 IL IL241372A patent/IL241372B/en active IP Right Grant
-
2016
- 2016-02-04 HK HK16101359.5A patent/HK1213205A1/zh unknown
- 2016-09-06 US US15/257,674 patent/US10034875B2/en active Active
-
2017
- 2017-10-24 AU AU2017251701A patent/AU2017251701B2/en active Active
- 2017-12-13 IL IL256300A patent/IL256300B/en active IP Right Grant
- 2017-12-15 ZA ZA2017/08539A patent/ZA201708539B/en unknown
-
2018
- 2018-03-22 JP JP2018054088A patent/JP6473254B2/ja active Active
- 2018-05-28 HK HK18106976.5A patent/HK1247557B/zh unknown
- 2018-07-06 US US16/029,384 patent/US11058681B2/en active Active
-
2019
- 2019-01-24 JP JP2019009896A patent/JP6790140B2/ja active Active
- 2019-02-28 AU AU2019201412A patent/AU2019201412A1/en not_active Abandoned
-
2020
- 2020-11-04 JP JP2020184294A patent/JP2021046400A/ja active Pending
-
2021
- 2021-05-28 US US17/333,525 patent/US20220047583A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101299996A (zh) * | 2005-09-30 | 2008-11-05 | 麦克内尔-Ppc股份有限公司 | 含有唾液诱生剂的口服组合物 |
Non-Patent Citations (6)
Title |
---|
ANDREAS ALY ET AL.: "Effect of an H2-Receptor Blocking Agent on Diarrhoeas after Extensive Small Bowel Resection in Crohn"s disease", 《ACTA MED SCAND》 * |
ELLIOT M. BERRY ET AL.: "Carcinoid myopathy and treatment with cyproheptadine (Periactin)", 《GUT》 * |
IVAR LöNNROTH ET AL.: "Chlorpromazine Reverses Diarrhea in Piglets Caused by Enterotoxigenic Escherichia coli", 《INFECTION AND IMMUNITY》 * |
JOSOPH D. FONDACARO ET AL.: "Cerectomized Rat: A model of Experimental Secretory Diarrhea in Conscious Animals", 《JOURNAL OF PHARMACOLOGICAL METHODS》 * |
SHRIRAM JAKATE等人: "Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea", 《ARCH PATHOL LAB MED》 * |
SPIEGEL DR ET AL.: "Treatment of irritable bowel syndrome with comorbid anxiety symptoms with mirtazapine", 《CLINICAL NEUROPHARMACOLOGY》 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105324112A (zh) | 用于治疗腹泻的产品和方法 | |
Selby et al. | Managing constipation in adults | |
CA3212135A1 (en) | Methods of treatment with selective cb2 receptor agonists | |
Baralo et al. | Review of Hematology-Oncology Emergencies for Internal Medicine Residents | |
Blandizzi et al. | Gastrointestinal drugs | |
Pushpa et al. | Pattern of Use of SGLT2 Inhibitors In Patient With Chronic Heart Failure In A Tertiary Care Hospital In South India 2021-22 | |
CA3233054A1 (en) | Compositions and methods for treating and preventing interstitial cystitis | |
CN105147958B (zh) | 一种治疗痛风的草药制剂 | |
Bennett | Diuretics: use, actions and prescribing rationale | |
CN101879167A (zh) | 抗高血压药物复方制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |