SK1272003A3 - Medicaments containing cilansetron for treating non-obstipated male IBS patients - Google Patents
Medicaments containing cilansetron for treating non-obstipated male IBS patients Download PDFInfo
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- SK1272003A3 SK1272003A3 SK127-2003A SK1272003A SK1272003A3 SK 1272003 A3 SK1272003 A3 SK 1272003A3 SK 1272003 A SK1272003 A SK 1272003A SK 1272003 A3 SK1272003 A3 SK 1272003A3
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- Prior art keywords
- cilansetron
- patients
- ibs
- male
- obstipated
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- 208000002551 irritable bowel syndrome Diseases 0.000 title claims abstract description 36
- 229960002099 cilansetron Drugs 0.000 title claims abstract description 32
- NCNFDKWULDWJDS-OAHLLOKOSA-N cilansetron Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C=3N4CCCC=3C=CC=2)=C4CC1 NCNFDKWULDWJDS-OAHLLOKOSA-N 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title description 3
- 229960003550 alosetron Drugs 0.000 claims abstract description 6
- FLZQKRKHLSUHOR-UHFFFAOYSA-N alosetron Chemical compound CC1=NC=N[C]1CN1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FLZQKRKHLSUHOR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 6
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 6
- PWWDCRQZITYKDV-UHFFFAOYSA-N 1-benzyl-2-piperazin-1-ylbenzimidazole Chemical compound C1CNCCN1C1=NC2=CC=CC=C2N1CC1=CC=CC=C1 PWWDCRQZITYKDV-UHFFFAOYSA-N 0.000 claims abstract description 3
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229950005951 azasetron Drugs 0.000 claims abstract description 3
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 claims abstract description 3
- 229960003413 dolasetron Drugs 0.000 claims abstract description 3
- 229960003727 granisetron Drugs 0.000 claims abstract description 3
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 claims abstract description 3
- MHNNVDILNTUWNS-XYYAHUGASA-N indisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CN(C[C@@H](C3)N4C)C)=NNC2=C1 MHNNVDILNTUWNS-XYYAHUGASA-N 0.000 claims abstract description 3
- 229950007467 indisetron Drugs 0.000 claims abstract description 3
- RWXRJSRJIITQAK-ZSBIGDGJSA-N itasetron Chemical compound C12=CC=CC=C2NC(=O)N1C(=O)N[C@H](C1)C[C@H]2CC[C@@H]1N2C RWXRJSRJIITQAK-ZSBIGDGJSA-N 0.000 claims abstract description 3
- 229950007654 itasetron Drugs 0.000 claims abstract description 3
- 229950009727 lerisetron Drugs 0.000 claims abstract description 3
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 claims abstract description 3
- 229950001588 ramosetron Drugs 0.000 claims abstract description 3
- 206010010774 Constipation Diseases 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- JXQUEAGLZNCBHC-QCUBGVIVSA-N cilansetron hydrochloride Chemical compound O.Cl.CC1=NC=CN1C[C@@H]1C(=O)C(C=2C=3N4CCCC=3C=CC=2)=C4CC1 JXQUEAGLZNCBHC-QCUBGVIVSA-N 0.000 claims description 6
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 235000012054 meals Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- -1 ondasetron Chemical compound 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 5
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 abstract description 2
- 229960005343 ondansetron Drugs 0.000 abstract description 2
- 229960003688 tropisetron Drugs 0.000 abstract description 2
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 abstract description 2
- FEROPKNOYKURCJ-ZDUSSCGKSA-N 4-amino-n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-5-chloro-2-methoxybenzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)N[C@@H]1C(CC2)CCN2C1 FEROPKNOYKURCJ-ZDUSSCGKSA-N 0.000 abstract 1
- 102000035037 5-HT3 receptors Human genes 0.000 abstract 1
- 108091005477 5-HT3 receptors Proteins 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 description 8
- 239000003826 tablet Substances 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 4
- 210000001015 abdomen Anatomy 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 208000004998 Abdominal Pain Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002547 anomalous effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
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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
- A61K31/495—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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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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
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Description
Oblasť technikyTechnical field
Predložený vynález rieši nové liečebné použitie cilansetróna alebo jeho kyslých adičných solí.The present invention provides a new therapeutic use of cilansetron or its acid addition salts.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Cilansetron je receptorom-antagonistom, ktorý spadá do rozsahu európskeho patentu EP 0 297 651 BI a ktorý nesie chemický názov (R)-(-)- 4,5,6,8,9,10 - hexahydro - 10 - [(2-metyl - 1H -imidazol -1 yl)metyl] -11 - H - pyrido [3,2,1 - jk] - karbazol - 11 - on.Cilansetron is a receptor antagonist which falls within the scope of European patent EP 0 297 651 B1 and bears the chemical name (R) - (-) - 4,5,6,8,9,10-hexahydro-10 - [(2- methyl-1H-imidazol-1-yl) methyl] -11-H-pyrido [3,2,1-jk] carbazol-11-one.
Z európskeho patentu EP 0 601 345 BI je už známe použitie cilansetrónu medzi inými na výrobu farmaceutických prípravkov na liečenie funkčných porúch dolných črevných ciest u veľkých cicavcov a ľudí spojených so zvýšenou citlivosťou na bolesť a/alebo anomálne urýchleným priechodom stolice v oblasti hrubého čreva (tračníka). K funkčným poruchám, ktoré sú liečiteľné okrem iného cilansetrónom, sa radí napríklad tiež syndróm dráždivého čreva („Irritable Bowel Syndróme“ = IBS), predovšetkým v spojení s anomálne zrýchleným priechodom stolice hrubým črevom (tračníkom).European patent EP 0 601 345 B1 already discloses the use of cilansetron among others for the manufacture of pharmaceutical compositions for the treatment of functional disorders of the lower intestinal tract in large mammals and humans associated with increased sensitivity to pain and / or anomalously accelerated bowel passage in the colon ). Functional disorders that are treatable, inter alia, by cilansetron include, for example, Irritable Bowel Syndrome (IBS), particularly in conjunction with anomalously accelerated bowel passage through the colon.
V európskej patentovej prihláške, publikačným č. WO 99/17755, sú popísané receptory-antagonisti 5HT3, ktoré sa hodia obzvlášť dobre na liečenie ženských IBS-pacientov netrpiacich zápchou (teda skupinou prehánkovo predominantných IBS-pacientov; v protiklade ku skupine IBS - pacientov s predominantnou zápchou). Ako príklad je v publikácii WO 99/17755 uvedený alosetrón, ktorý pri klinických skúškach ukázal značné zlepšenú účinnosť u ženských IBS - pacientov, v porovnaní s účinnosťou u mužských IBS - pacientov. U mužských testovaných osôb liečených alosetrónom nebolo pri týchto klinických skúškach zistené žiadne výrazné vypovedajúce zlepšenie nálezu oproti skupine s placebom. V uskutočňovanej forme predmetu prihlášky WO/17755 sa okrem iného uvádza tiež cilansetron ako spadajúci do rozsahu tohto odhalenia.In European patent application, publication no. WO 99/17755 discloses 5HT 3 -receptor antagonists which are particularly well suited for treating female non-constipated IBS patients (i.e. a group of over-predominant IBS patients; as opposed to a group of IBS-predominant constipation patients). By way of example, WO 99/17755 discloses alosetron, which in clinical trials has shown a significantly improved efficacy in female IBS patients compared to efficacy in male IBS patients. No significant evidence of improvement was found in the male patients treated with alosetron in these clinical trials compared to the placebo group. In an embodiment of WO / 17755, cilansetron is also mentioned as falling within the scope of this disclosure.
Teraz bolo prekvapivo nájdené, že cilansetron je rovnakou mierou vhodný na liečenie zápchou netrpiacich mužských a ženských pacientov, ktorí trpia syndrómom dráždivého čreva (= IBS).It has now surprisingly been found that cilansetron is equally suitable for the treatment of constipation in non-suffering male and female patients suffering from irritable bowel syndrome (= IBS).
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom vynálezu je preto použitie cilansetrónu alebo jeho farmakologicky znášanlivých kyslých adičných solí a/alebo solvátov na výrobu farmaceutických prípravkov na liečenie a/alebo ochrane proti syndrómu dráždivého čreva (- IBS) u zápchou netrpiacich mužských pacientov.It is therefore an object of the invention to use cilansetron or its pharmacologically tolerable acid addition salts and / or solvates for the manufacture of pharmaceutical compositions for the treatment and / or protection against irritable bowel syndrome (IBS) in constipation of non-suffering male patients.
IBS označuje skupinu príznakov (symptómov) prichádzajúcich s bolesťami a/alebo pocitom nevoľnosti v bruchu, ako aj zmenenými črevnými aktivitami, ako sú prehánka, zápcha (= konstipácia) alebo striedavo prehánka a zápcha. Keďže až doposiaľ neboli ešte uvedené žiadne jednoznačne uchopiteľné či zrozumiteľné fyziologické alebo iné organické nálezy ako príčina pre IBS, opiera sa lekárska diagnóza tejto choroby obvykle o neprítomnosť radu symptómov, na ktoré sa pozerá všeobecne ako na typické pre IBS, a ktoré sú napr. zachytené v „rímskych kritériách“ (W. G. Thompson et. al., Gastrocent. Int. 2_( 1989) 92 - 95; W. G. Thompson et. al., Gut 45/ Π (1999) II43 1147; W. G. Thompson, Lancet 341 (1993) (1569 - 1572).IBS refers to a group of symptoms (symptoms) that come with pain and / or a feeling of nausea in the abdomen, as well as altered intestinal activities such as diarrhea, constipation, or alternately diarrhea and constipation. Since so far no unambiguous physiological or other organic findings as a cause of IBS have been reported yet, the medical diagnosis of this disease is usually based on the absence of a number of symptoms which are generally regarded as typical of IBS and which are e.g. captured in "Roman criteria" (WG Thompson et. al., Gastrocent. Int. 2_ (1989) 92-95; WG Thompson et. al., Gut 45 / Π (1999) II43 1147; WG Thompson, Lancet 341 (1993) (1569 - 1572).
Podľa vynálezu môže byť cilansetrón používaný prednostne vo forme hydrochloridu cilansetrónu. Obvykle sa používa monohydrát hydrochloridu cilansetrónu. Ďalšie farmakologicky znášanlivé kyslé adičné soli cilansetrónu sú známe z EP 0 297 651 BI.According to the invention, cilansetron may preferably be used in the form of cilansetron hydrochloride. Usually, cilansetron hydrochloride monohydrate is used. Other pharmacologically tolerable acid addition salts of cilansetron are known from EP 0 297 651 B1.
Klinické výskumné dáta dokladujú prekvapivý sklon cilansetrónu na liečenie neobstipatívnych (zápchou netrpiacich) IBS - pacientov rovnakou mierou u mužského ako ženského pohlavia:Clinical research data demonstrate the surprising tendency of cilansetron to treat non-obstructive (constipated non-constipated) IBS patients equally in male and female:
V 12 - týždennej placebom kontrolovanej klinickej dvojitej slepej štúdii s náhodným výberom a paralelnými skúšobnými skupinami bol vyšetrovaný účinok cilansetrónu na zápchou netrpiacich IBS - pacientov obidvoch pohlaví. Na ako zápchou netrpiacich pacientov bolo v rámci tejto štúdie pozerané na tých IBS - pacientov, ktorých symptómy choroby zodpovedali zhora uvedeným „rímskym kritériám“, a ktorých povaha a frekvencia stolice spĺňala nasledujúce kritériá:In a 12-week placebo-controlled clinical double-blind, randomized and parallel study group, the effect of cilansetron on constipation in non-IBS patients of both sexes was investigated. In this study, constipation-free patients were considered to be those IBS - patients whose symptoms of the disease corresponded to the above-mentioned “Roman criteria” and whose nature and frequency of stool met the following criteria:
i) < 25% zápchou zhoršované či poškodzované javy súvisiace s IBS.(i) <25% of constipation-impaired or damaged IBS-related events.
ii) Ako zápchou netrpiace sú charakterizované podľa „rímskych kritérií“ (pozri vyššie) osoby, ktoré vykazujú nie < 3 pohyby čriev za týždeň a/alebo tvrdú/hrudkovitú povahu stolice.(ii) Constipation non-constipation is characterized according to the “Roman criteria” (see above) of persons who exhibit no <3 bowel movements per week and / or the hard / lumpy nature of stool.
iii) < 4 dni (za sebou idúce alebo nie za sebou idúce) bez pohybu čriev počas dvojtýždenného pozorovacieho obdobia (= „run-in periód“).(iii) <4 days (consecutive or non-consecutive) without bowel movement during a two-week observation period (= "run-in periods").
iv) Priemerná frekvencia stolice > (podľa „Bristolovej stupnice stolice) počas dvojtýždenného pozorovacieho obdobia.iv) Mean stool frequency> (according to the Bristol stool scale) over a two-week observation period.
Do štúdie boli rovnako zahrnutí takí pacienti, pokiaľ zodpovedali na otázku na bolesti/pocit nevoľnosti v brušnej krajine len < 50 % prípadov „nie“, alebo ktorí svoje bolesti/svoj pocit nevoľnosti v brušnej ]Patients were also included in the study if they responded to the question of pain / feeling sick in the abdomen only <50% of “no” cases, or who had their pain / feeling sick in the abdomen]
krajine posúdili na úrovni < 2 krát počas dvojtýždenného pozorovacieho obdobia ako „obmedzené“.country was assessed as “limited” at a level of <2 times during the two-week observation period.
Bol použitý cilansetrón v dávkach 1, 2, 8 a 16 mg. Každý týždeň boli pacienti kontrolovaní na „primeranú úľavu či zmiernenie“ (= primárny parameter účinnosti) svojich IBS-symptómov (bolesti brucha, anomálna činnosť čriev). Bolesti brucha, ako aj bolesti v bruchu, povaha a frekvencia stolice boli hodnotené pacientmi denne (= sekundárny parameter účinnosti).Cilansetron was used at doses of 1, 2, 8 and 16 mg. Every week, patients were checked for "adequate relief or alleviation" (= primary efficacy parameter) of their IBS symptoms (abdominal pain, anomalous bowel activity). Abdominal pain as well as abdominal pain, nature and stool frequency were evaluated by patients daily (= secondary efficacy parameter).
V predbežnom výsledku dvojitej slepej štúdie boli vyhodnocované dáta celkovo 454 pacientov (297 ženských pacientov a 157 mužských pacientov) a boli nanesené do nasledujúcej tabuľky. Podľa kritérií, ktoré sú základom dvojitej slepej štúdie, boli u oboch podskupín pacientov mužských a ženských IBS pacientov zistené podiely úspešnosti uvedené v nasledujúcej tabuľke, ktoré sa týkali primeranej úľavy či zmiernenia IBS-symptómov:In a preliminary double-blind study data, a total of 454 patients (297 female patients and 157 male patients) were evaluated and plotted in the following table. Based on the criteria underlying the double-blind study, the success rates reported in the following table for both male and female IBS patient subgroups were related to adequate relief or alleviation of IBS symptoms:
Tabuľka:Table:
„Primárny parameter účinnosti“ zodpovedá podielu úspešnosti (= „responder rate“) na pacientovi týždenne kladenú otázku, či v priebehu práve uplynulého týždňa pocítili „primeranú úľavu či zmiernenie“ svojich IBS-symptómov (bolestí/pocitu nevoľnosti v bruchu; anomálne črevné aktivity). Ako na „úspešnú osobu“ sa pozerá na pacienta či pacientku, ktorý/ktorá bola aspoň štyri týždne liečená, a ktorý/ktorá na jemu/jej položenú otázku, či sa dostavilo primerané „zmiernenie či úľava“ jeho/jej IBS-symptómov aspoň po polovicu jeho/jej liečebného obdobia, odpovedala „áno“.The "primary efficacy parameter" corresponds to the "responder rate" of the patient weekly questioned whether they have experienced "adequate relief or alleviation" of their IBS symptoms (pain / nausea in the abdomen; anomalous intestinal activities) during the past week. . A "successful person" is considered to be a patient who has been treated for at least four weeks and who has been asked by him / her whether the appropriate "alleviation or relief" of his / her IBS symptoms has occurred for at least half of his / her treatment period, responded "yes".
Po skončení dvojitej slepej štúdie mohli byť vyhodnotené dáta celkom 471 pacientov (308 ženských pacientov a 163 mužských pacientov). Konečné podiely úspešnosti boli stanovené na 40% pre skupinu s placebom, 62 % pre dávku 1 mg cilansetrónu (TID), 53 % pre dávku 2 mg cilansetrónu, 55 % pre dávku 8 mg cilansetrónu (TĽD) a 63 % pre dávku 16 mg cilansetrónu (TID). Podiely úspešnosti boli u mužskej skupiny pacientov a u ženských pacientov veľmi podobné. Najväčšie rozdiely boli pozorované pri dávkovaní 1 mg cilansetrónu (TID).A total of 471 patients (308 female patients and 163 male patients) could be evaluated at the completion of the double-blind study. Final success rates were set at 40% for the placebo group, 62% for the 1 mg cilansetron (TID) dose, 53% for the 2 mg cilansetron dose, 55% for the 8 mg cilansetron (TĽD) dose, and 63% for the 16 mg cilansetron dose (TID). The success rates were very similar in the male group and in the female patients. The greatest differences were observed with 1 mg cilansetron (TID).
Z hora uvedených dát je zrejmé, že zápchou netrpiaci IBS-pacienti obidvoch pohlaví reagujú na liečenie cilansetrónom vo všetkých vyšetrovaných dávkovaniach.From the above data, it is evident that constipation-free IBS-patients of both sexes respond to cilansetron treatment at all dosages investigated.
Obzvlášť prekvapivá je účinnosť cilansetrónu pri liečení neobsipatívnych (prehánkovo predominantných) mužských IBS-pacientov doložená hore uvedenými prieskumovými výsledkami, pretože odborník z obsahu publikácie WO 99/17755 musel urobiť záver, že cilansetrón je vhodný práve tak ako alosetrón - prednostne len na liečenie zápchou netrpiacich ženských IBS-pacientov.Especially surprisingly, the efficacy of cilansetron in the treatment of non-manipulative (over-predominant) male IBS patients is supported by the above-mentioned research results, as the expert in WO 99/17755 had to conclude that cilansetron is as suitable as alosetron - preferably only for non-constipated medication female IBS patients.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Dopredu známe receptory-antagonisti 5HT3 sú na liečenie IBS obvykle podávané dvakrát denne („dávkovanie BED“). Ako výhodnejšie na liečenie IBS-pacientov oboch pohlaví sa však ukazuje podávať 5HT3 namiesto toho trikrát denne, napríklad v dávkovaniach od aktuálne 1 mg do 16 mg IBSpacientom oboch pohlaví (= dávkovanie TID). Obzvlášť uprednostnené je užívanie antagonistov 5HT3 rozdeliť na trikrát denne na celý deň a predpísať ich zvlášť na dobu po hlavnom jedle (ráno, na poludnie a večer). Príklady receptor-antagonistov 5HT3, ktoré môžu byť výhodnejšie podávané v trikrát dennom dávkovaní, obsahujú alosetrón, azasetrón, dolasetrón, granisetrón, indisetrón, itasetrón, lerisetrón, ondansetrón, ramosetrón, tropisetrón a ® - zacoprid. Ako obzvlášť výhodné na liečenie IBS- pacientov oboch pohlaví sa ukazuje podávať pacientom trikrát denne cilansetrón alebo jeho farmakologicky znášanlivé kyslé adičné soli a/alebo solváty, napríklad práve v dávkovaniach medzi 1 mg a 16 mg na príslušné podanie (dávku).Pre-known 5HT 3 -receptor antagonists are usually administered twice daily ("BED dosing") for the treatment of IBS. However, it is preferable to treat 5HT 3 instead of three times daily, for example at doses of currently 1 mg to 16 mg of IBS to both sexes (= TID dosing), to be more advantageous for the treatment of both sexes. It is particularly preferred to divide the use of 5HT 3 antagonists into three times a day for the whole day and prescribe them separately for the period after the main meal (morning, noon and evening). Examples of 5HT 3 receptor antagonists that may more preferably be administered in three times daily dosages include alosetron, azasetron, dolasetron, granisetron, indisetron, itasetron, lerisetron, ondansetron, ramosetron, tropisetron, and --zacoprid. It has proven to be particularly advantageous for the treatment of IBS-patients of both sexes by administering cilansetron or pharmacologically tolerable acid addition salts and / or solvates thereof three times a day, for example just at dosages between 1 mg and 16 mg for the respective administration (dose).
Ako liek môže byť cilansetrón alebo farmakologicky znášanlivá kyslá adičná soľ cilansetrónu podľa vynálezu obsiahnutý spolu s obvyklými farmaceutickými pomocnými a/alebo nosičmi obsiahnutý v pevných alebo kvapalných farmaceutických prípravkoch. Ako príklady pevných preparátov budú uvedené orálne aplikovateľné preparáty ako tabletky, dražé, kapsule, prášky alebo granuláty alebo tiež čipky. Tieto preparáty môžu obsahovať farmaceutický obvyklé anorganické a/alebo organické nosiče, ako napríklad mastenec, mliečny cukor alebo škrob vedľa farmaceutických obvyklých pomocných prostriedkov, napríklad klzných prostriedkov alebo napučiavadiel tabliet. Kvapalné preparáty ako suspenzie alebo emulzie cilanstrónu môžu obsahovať obvyklé riediace prostriedky, ako vodu, oleje a/alebo suspenzné prostriedky, ako sú polyetylénglykoly a podobne. Navyše môžu byť pridávané ďalšie pomocné látky, ako napríklad konzervačné prostriedky, látky korigujúce vôňu a podobne.As a medicament, the cilansetron or pharmacologically tolerable acid addition salt of cilansetron of the invention may be included together with conventional pharmaceutical auxiliary and / or carriers in solid or liquid pharmaceutical formulations. Examples of solid preparations will be mentioned orally administrable preparations such as tablets, dragees, capsules, powders or granules or also lace. These preparations may contain pharmaceutically customary inorganic and / or organic carriers, such as talc, milk sugar or starch, in addition to the usual pharmaceutical excipients, for example glidants or tablet swelling agents. Liquid preparations such as cilanstron suspensions or emulsions may contain conventional diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like. In addition, other excipients, such as preservatives, fragrance correcting agents and the like, may be added.
Cilansetrón alebo farmakologicky znášanlivá kyslá adičná soľ cilansetrónu môžu byť miešané známym spôsobom s farmaceutickými pomocnými látkami a/alebo nosičmi. Na výrobu pevných liečivých foriem môže byť cilansetrón alebo kyslá adičná soľ napríklad miešaná obvyklým spôsobom s pomocnými látkami a/alebo nosičmi a potom na mokro alebo na sucho granulovaná. Granulát alebo príslušný prášok môžu byť plnené priamo do kapsúl alebo obvyklým spôsobom lisované do jadier tabliet. Tie môžu byť podľa priania známym spôsobom dražované.The cilansetron or pharmacologically tolerable acid addition salt of cilansetron may be mixed in a known manner with pharmaceutical excipients and / or carriers. For the manufacture of solid dosage forms, the cilansetron or acid addition salt may be mixed, for example, in the usual manner with excipients and / or carriers, and then wet or dry granulated. The granulate or the appropriate powder may be filled directly into capsules or compressed into tablet cores in a conventional manner. These can be auctioned in a known manner.
Nasledujúci príklad má vysvetliť výrobu farmaceutických prípravkov obsahujúcich hydrochlorid cilansetrónu.The following example is intended to explain the manufacture of pharmaceutical compositions containing cilansetron hydrochloride.
Príklad 1: TabletkyExample 1: Tablets
Zloženie:Ingredients:
Monohydrát hydrochloridu cilansetrónu 4 dielyCilansetron hydrochloride monohydrate 4 parts
Kukuričný škrob 30 dielovCorn starch 30 parts
Laktóza 70 dielovLactose 70 parts
Kollidón 25R 5 dielovKollidón 25 R 5 pieces
Stearan horečnatý 2 dielyMagnesium stearate 2 parts
Mastenec 3 dielyTalc 3 parts
Celkom: 114 dielovTotal: 114 parts
Predpis výroby:Production Code:
Účinná látka je zmiešaná v miešačke s kukuričným škrobom a jemne práškovanou laktózou. Vzniknutá zmes je prevlhčená vo vode zbavenej minerálov 20%-roztokom polyvinylpyrolidónu (Kollidón 25r firmy BASF). Pokiaľ je to nutné, pridá sa ďalšia voda zbavená minerálov. Vlhký . granulát sa precedí sitom 2 mm, pri 40°C sa vysuší na platni a nakoniec sa precedí sitom 1 mm (Frewittov stroj). Po premiešaní granulátu so stearanom horečnatým a mastencom sa z toho vylisujú tabletky s hmotnosťou 114 mg, takže každá tabletka obsahuje 4 mg účinnej látky.The active ingredient is mixed in a blender with corn starch and finely powdered lactose. The resulting mixture is moistened in a mineral-free water with a 20% solution of polyvinylpyrrolidone (Kollidon 25 r from BASF). If necessary, additional mineral-free water is added. Moist. The granulate is sieved through a 2 mm sieve, dried at 40 ° C on a plate and finally sieved through a 1 mm sieve (Frewitt machine). After mixing the granulate with magnesium stearate and talc, tablets of 114 mg are compressed, so that each tablet contains 4 mg of the active ingredient.
Práve tak môžu byť použité iné, napríklad z patentu EP 0 895 782 A2 známe farmaceutické prípravky cilansetrónu.Other pharmaceutical compositions of cilansetron known from EP 0 895 782 A2 may also be used.
Claims (8)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10036645 | 2000-07-26 | ||
| DE10123447A DE10123447A1 (en) | 2000-07-26 | 2001-05-14 | Cilansetron-containing medicines for the treatment of non-obstipative male IBS patients |
| PCT/EP2001/008260 WO2002007713A2 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
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| Publication Number | Publication Date |
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| SK1272003A3 true SK1272003A3 (en) | 2003-07-01 |
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| SK127-2003A SK1272003A3 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male IBS patients |
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| Country | Link |
|---|---|
| EP (1) | EP1307195A2 (en) |
| JP (1) | JP2004504343A (en) |
| CN (1) | CN1444479A (en) |
| AR (1) | AR028970A1 (en) |
| AU (1) | AU2001276409A1 (en) |
| BR (1) | BR0112690A (en) |
| CA (1) | CA2417677A1 (en) |
| CZ (1) | CZ2003158A3 (en) |
| HU (1) | HUP0301479A2 (en) |
| IL (1) | IL153972A0 (en) |
| MX (1) | MXPA02012917A (en) |
| NO (1) | NO20030373D0 (en) |
| PL (1) | PL363517A1 (en) |
| RU (1) | RU2003104798A (en) |
| SK (1) | SK1272003A3 (en) |
| WO (1) | WO2002007713A2 (en) |
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| GB0216027D0 (en) | 2002-07-10 | 2002-08-21 | Arachnova Therapeutics Ltd | New therapeutic use |
| WO2005073220A1 (en) * | 2004-01-30 | 2005-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | Remedy for irritable bowel syndrome with diarrhea |
| NZ541656A (en) * | 2004-01-30 | 2008-05-30 | Astellas Pharma Inc | The use of ramosetron hydrochloride for diarrhea-predominant irritable bowel syndrome |
| JP4632204B2 (en) * | 2005-09-21 | 2011-02-16 | アステラス製薬株式会社 | Antidiarrheal irritable bowel syndrome treatment |
| US7662831B2 (en) | 2006-07-27 | 2010-02-16 | Wyeth Llc | Tetracyclic indoles as potassium channel modulators |
| US7601856B2 (en) | 2006-07-27 | 2009-10-13 | Wyeth | Benzofurans as potassium ion channel modulators |
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| GB9721139D0 (en) * | 1997-10-07 | 1997-12-03 | Glaxo Group Ltd | Medicaments |
| GB9930077D0 (en) * | 1999-12-20 | 2000-02-09 | Glaxo Group Ltd | Medicaments |
-
2001
- 2001-06-21 AR ARP010102958A patent/AR028970A1/en unknown
- 2001-07-18 EP EP01954044A patent/EP1307195A2/en not_active Withdrawn
- 2001-07-18 SK SK127-2003A patent/SK1272003A3/en unknown
- 2001-07-18 JP JP2002513449A patent/JP2004504343A/en active Pending
- 2001-07-18 HU HU0301479A patent/HUP0301479A2/en unknown
- 2001-07-18 RU RU2003104798/15A patent/RU2003104798A/en not_active Application Discontinuation
- 2001-07-18 BR BR0112690-3A patent/BR0112690A/en not_active Application Discontinuation
- 2001-07-18 CA CA002417677A patent/CA2417677A1/en not_active Abandoned
- 2001-07-18 CZ CZ2003158A patent/CZ2003158A3/en unknown
- 2001-07-18 IL IL15397201A patent/IL153972A0/en unknown
- 2001-07-18 AU AU2001276409A patent/AU2001276409A1/en not_active Abandoned
- 2001-07-18 MX MXPA02012917A patent/MXPA02012917A/en unknown
- 2001-07-18 CN CN01813307A patent/CN1444479A/en active Pending
- 2001-07-18 WO PCT/EP2001/008260 patent/WO2002007713A2/en not_active Application Discontinuation
- 2001-07-18 PL PL01363517A patent/PL363517A1/en not_active Application Discontinuation
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2003
- 2003-01-24 NO NO20030373A patent/NO20030373D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002007713A2 (en) | 2002-01-31 |
| MXPA02012917A (en) | 2003-05-14 |
| IL153972A0 (en) | 2003-07-31 |
| EP1307195A2 (en) | 2003-05-07 |
| PL363517A1 (en) | 2004-11-29 |
| HUP0301479A2 (en) | 2003-09-29 |
| BR0112690A (en) | 2003-06-24 |
| AR028970A1 (en) | 2003-05-28 |
| WO2002007713A3 (en) | 2002-11-14 |
| NO20030373L (en) | 2003-01-24 |
| AU2001276409A1 (en) | 2002-02-05 |
| JP2004504343A (en) | 2004-02-12 |
| RU2003104798A (en) | 2004-06-27 |
| CN1444479A (en) | 2003-09-24 |
| NO20030373D0 (en) | 2003-01-24 |
| CZ2003158A3 (en) | 2003-08-13 |
| CA2417677A1 (en) | 2003-01-27 |
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