WO1993020819A1 - Treatment of delayed gastric emptying - Google Patents
Treatment of delayed gastric emptying Download PDFInfo
- Publication number
- WO1993020819A1 WO1993020819A1 PCT/EP1993/000781 EP9300781W WO9320819A1 WO 1993020819 A1 WO1993020819 A1 WO 1993020819A1 EP 9300781 W EP9300781 W EP 9300781W WO 9320819 A1 WO9320819 A1 WO 9320819A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gastric emptying
- treatment
- diphenylmethoxy
- piperidine
- prevention
- Prior art date
Links
- 206010021518 Impaired gastric emptying Diseases 0.000 title claims description 11
- 230000030136 gastric emptying Effects 0.000 claims abstract description 14
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims abstract description 7
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims abstract description 7
- 230000008485 antagonism Effects 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 201000006549 dyspepsia Diseases 0.000 claims description 4
- 208000001288 gastroparesis Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 230000001272 neurogenic effect Effects 0.000 claims description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 206010028813 Nausea Diseases 0.000 claims 1
- 230000008693 nausea Effects 0.000 claims 1
- 230000008673 vomiting Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 8
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000012054 meals Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- JHOLNMSWPGVEOI-UHFFFAOYSA-N 2-benzhydryloxy-1-[2-(1,3-benzodioxol-5-yl)ethyl]piperidine Chemical compound C=1C=C2OCOC2=CC=1CCN1CCCCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 JHOLNMSWPGVEOI-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000012258 Diverticular disease Diseases 0.000 description 1
- 206010013554 Diverticulum Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 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 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-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
- 206010030136 Oesophageal achalasia Diseases 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- VVWYOYDLCMFIEM-UHFFFAOYSA-N Propantheline Chemical compound C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 VVWYOYDLCMFIEM-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 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 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- WEUHJSOYWODZCN-MGYVYGPGSA-M ciclotropium bromide Chemical compound [Br-].C([C@H]1CC[C@@H](C2)[N+]1(C)C(C)C)C2OC(=O)C(C=1C=CC=CC=1)C1CCCC1 WEUHJSOYWODZCN-MGYVYGPGSA-M 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000013575 mashed potatoes Nutrition 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960000697 propantheline Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000243 solution 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
- 239000000725 suspension Substances 0.000 description 1
- 238000005303 weighing Methods 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Definitions
- This invention relates to treatment of medical conditions associated with delayed gastric emptying using 3R- or 3R,S-diphenylmethoxy-l-(3,4- - methylenedioxyphenethyl)piperidine, a compound disclosed in European Patent Application EP-A-0350309.
- Diphenylmethoxy-1-(3 ,4-methylenedioxyphenethyl)- piperidine is of formula (I) :
- the dose required for treating the above-mentioned diseases is typically 3.5 to 350 mg daily for an average human adult weighing 70 kg. It is known that muscarinic receptor antagonists, besides inhibiting small and large bowel motility, also tend to inhibit gastric emptying. Antagonists for which this effect has been discussed in the literature include propantheline (Hurwitz, Robinson and Herrin, 1977, Clin. Pharmacol. Therap. 2.206-210) , pirenzepine (Soffer, Kumar r Mridha, Das-Gupta r Britto and Wingate, 1988, Gastroenterol. 23.146-150) , atropine (Rashid and Bateman, 1990, Br. J. Clin. Pharmacol.
- 3R and 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine are capable of increasing gastric emptying rates when administered to patients at doses within the range which are likely to be used for treatment as muscarinic receptor antagonists.
- This effect which is quite contrary to what might have been expected from existing knowledge , renders this compound suitable for the treatment of a number of conditions in patients for whom inhibition of gastric emptying is undesirable. These conditions include non-ulcer dyspepsia, neurogenic and non-neurogenic gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting.
- UK-76,654 has a significant effect in increasing gastric emptying rate of doses within or less than the range of 3.5-350 mg, particularly at doses around the 10 mg level.
- the dose administered for treatment of non-ulcer dyspepsia, gastroparesis, ideopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting will be determined by a physician bearing in mind the age, weight, response and medical history of the patient but for average adults (70 kg) it is likely to be in the range of 1 to 100 mg.
- 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or its acid addition salts may be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- they may be administered orally in the form of tablets containing excipients such as starch or lactose or in capsules or ovules either alone or in combination with excipients or in the form of elixirs or suspensions containing flavouring or colouring agents.
- They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
- one aspect of the invention comprises 3R- or 3R r S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine, or a pharmaceutically acceptable acid addition salt thereof, for use in the treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
- the invention also provides a method of treating conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying, which comprises adminstering to the patient an effective amount of 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or a pharmaceutically acceptable salt thereof.
- the above-mentioned conditions include non-ulcer dyspepsia, gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux r nausea and vomiting.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Use of 3R-and 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)-piperidine for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
Description
-4- TREATMENT OF DELAYED GASTRIC EMPTYING
This invention relates to treatment of medical conditions associated with delayed gastric emptying using 3R- or 3R,S-diphenylmethoxy-l-(3,4- - methylenedioxyphenethyl)piperidine, a compound disclosed in European Patent Application EP-A-0350309.
Diphenylmethoxy-1-(3 ,4-methylenedioxyphenethyl)- piperidine is of formula (I) :
Being an optically active compound, it exists as different stereoisomers and, as stated in EP-A-0350309, its 3R- form (known as compound UK-76,654) and its 3R,S- (racemic form) are gut-selective muscarinic receptor antagonists. They are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle, including irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease. Compound UK 76,654 and the corresponding racemate form acid addition salts and may be administered by conventional methods orally or by injection. The dose required for treating the above-mentioned diseases is typically 3.5 to 350 mg daily for an average human adult weighing 70 kg.
It is known that muscarinic receptor antagonists, besides inhibiting small and large bowel motility, also tend to inhibit gastric emptying. Antagonists for which this effect has been discussed in the literature include propantheline (Hurwitz, Robinson and Herrin, 1977, Clin. Pharmacol. Therap. 2.206-210) , pirenzepine (Soffer, Kumar r Mridha, Das-Gupta r Britto and Wingate, 1988, Gastroenterol. 23.146-150) , atropine (Rashid and Bateman, 1990, Br. J. Clin. Pharmacol. 3C).25-34) and cyclotropium bromide (Stacher, Bergmann, Gaupmann, Schneider, Kugi, Hobart, Binder and Mittelbach-Steiner 1990, Br. J. Clin. Pharmacol. ,3£ 839-845) . However, such inhibition is often undesirable for patients who otherwise benefit from treatment with muscarinic receptor antagonists, including those affected by irritable bowel syndrome.
It has now been found, unexpectedly, that 3R and 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine are capable of increasing gastric emptying rates when administered to patients at doses within the range which are likely to be used for treatment as muscarinic receptor antagonists. This effect, which is quite contrary to what might have been expected from existing knowledge , renders this compound suitable for the treatment of a number of conditions in patients for whom inhibition of gastric emptying is undesirable. These conditions include non-ulcer dyspepsia, neurogenic and non-neurogenic gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting.
The preparation of compound UK 76,654 or its racemate and the manner in which it may be administered to a patient, generally orally or by injection, are described in European Patent Application 0350309. The effect of the compound on gastric emptying may be demonstrated as follows, using the radiolabelled meal method described by Gustavsson (1982) r Acta Radiologica Diagnosis 21 639-643.
Healthy volunteers are given placebo or compound UK- 76654 or its 3R,S-racemic form orally in random order at varying doses followed 1 hour later by a meal typically consisting of two sausages, 120 g baked beans and mashed potato radioactively labelled with 2MBqTc99m. Gastric emptying is measured over the next 2 to 3 hours, gastric emptying curves calculated and the time (t%) to emptying half of the meal deduced.
It is found that UK-76,654 has a significant effect in increasing gastric emptying rate of doses within or less than the range of 3.5-350 mg, particularly at doses around the 10 mg level. The dose administered for treatment of non-ulcer dyspepsia, gastroparesis, ideopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting will be determined by a physician bearing in mind the age, weight, response and medical history of the patient but for average adults (70 kg) it is likely to be in the range of 1 to 100 mg.
For human use, 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or its acid addition salts may be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example they may be administered orally in the form of tablets containing excipients such as starch or lactose or in capsules or ovules either alone or in combination with excipients or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose to make the solution isotonic with blood.
Thus, one aspect of the invention comprises 3R- or 3RrS-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine, or a pharmaceutically acceptable acid addition salt thereof, for use in the treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
The invention also provides use of 3R- or 3R,S- diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine, or a pharmaceutically acceptable acid addition salt thereof, fortιtmaking a medicament for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
The invention also provides a method of treating conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying, which comprises adminstering to the patient an effective amount of 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or a pharmaceutically acceptable salt thereof.
The above-mentioned conditions include non-ulcer dyspepsia, gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal refluxr nausea and vomiting.
Claims
1. Use of 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)-piperidine, or a pharmaceutically acceptable acid addition salt thereof> for making a medicament for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
2. 3R- or 3R,S-diphenylmethoxy-l-(3,4-methylene- dioxyphenethyl)-piperidine, or a pharmaceutically acceptable acid addition salt thereof, for use in treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.
3. A method of treating conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying which comprises administering to a patient an effective amount of 3R- or 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine or a pharmaceutically acceptable salt thereof.
4. Use according to claim 1, or a method according to claim 3, in which said condition is non-ulcer dyspepsia, neurogenic or non-neurogenic gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux, nausea or vomiting.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929208230A GB9208230D0 (en) | 1992-04-14 | 1992-04-14 | Treatment of delayed gastric emptying |
| GB9208230.4 | 1992-04-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993020819A1 true WO1993020819A1 (en) | 1993-10-28 |
Family
ID=10714037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1993/000781 WO1993020819A1 (en) | 1992-04-14 | 1993-03-29 | Treatment of delayed gastric emptying |
Country Status (7)
| Country | Link |
|---|---|
| AU (1) | AU3891093A (en) |
| GB (1) | GB9208230D0 (en) |
| IL (1) | IL105313A0 (en) |
| MX (1) | MX9302142A (en) |
| TW (1) | TW219331B (en) |
| WO (1) | WO1993020819A1 (en) |
| ZA (1) | ZA932583B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561127A (en) * | 1994-12-19 | 1996-10-01 | Allelix Biopharmaceuticals, Inc. | Muscarinic receptor ligands |
| WO2008144602A1 (en) * | 2007-05-18 | 2008-11-27 | Auspex Pharmaceuticals, Inc. | Deuterated zamifenacin derivatives |
| US8152821B2 (en) | 2000-03-03 | 2012-04-10 | C.R. Bard, Inc. | Endoscopic tissue apposition device with multiple suction ports |
| US9149270B2 (en) | 2004-08-27 | 2015-10-06 | Davol, Inc. (a C.R. Bard Company) | Endoscopic tissue apposition device and method of use |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0350309A1 (en) * | 1988-07-08 | 1990-01-10 | Pfizer Limited | Piperidine derivatives |
-
1992
- 1992-04-14 GB GB929208230A patent/GB9208230D0/en active Pending
-
1993
- 1993-03-29 AU AU38910/93A patent/AU3891093A/en not_active Abandoned
- 1993-03-29 WO PCT/EP1993/000781 patent/WO1993020819A1/en active Application Filing
- 1993-04-05 IL IL105313A patent/IL105313A0/en unknown
- 1993-04-12 TW TW082102729A patent/TW219331B/zh active
- 1993-04-13 ZA ZA932583A patent/ZA932583B/en unknown
- 1993-04-13 MX MX9302142A patent/MX9302142A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0350309A1 (en) * | 1988-07-08 | 1990-01-10 | Pfizer Limited | Piperidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| BR. J. PHARMACOL. vol. 30, 1990, pages 839 - 845 STACHER ET AL. 'Fat preload delays gastric emptying: reversal by cisapride' cited in the application * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561127A (en) * | 1994-12-19 | 1996-10-01 | Allelix Biopharmaceuticals, Inc. | Muscarinic receptor ligands |
| US5674877A (en) * | 1994-12-19 | 1997-10-07 | Allelix Biopharmaceuticals Inc. | Muscarinic receptor ligands |
| US8152821B2 (en) | 2000-03-03 | 2012-04-10 | C.R. Bard, Inc. | Endoscopic tissue apposition device with multiple suction ports |
| US9149270B2 (en) | 2004-08-27 | 2015-10-06 | Davol, Inc. (a C.R. Bard Company) | Endoscopic tissue apposition device and method of use |
| WO2008144602A1 (en) * | 2007-05-18 | 2008-11-27 | Auspex Pharmaceuticals, Inc. | Deuterated zamifenacin derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3891093A (en) | 1993-11-18 |
| ZA932583B (en) | 1994-10-13 |
| IL105313A0 (en) | 1993-08-18 |
| TW219331B (en) | 1994-01-21 |
| MX9302142A (en) | 1994-05-31 |
| GB9208230D0 (en) | 1992-05-27 |
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