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WO2000028984A1 - Remedes agissant contre un trouble fonctionnel du tractus digestif - Google Patents

Remedes agissant contre un trouble fonctionnel du tractus digestif Download PDF

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Publication number
WO2000028984A1
WO2000028984A1 PCT/JP1999/006363 JP9906363W WO0028984A1 WO 2000028984 A1 WO2000028984 A1 WO 2000028984A1 JP 9906363 W JP9906363 W JP 9906363W WO 0028984 A1 WO0028984 A1 WO 0028984A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrochloride
drug
salt
gastrointestinal
gastrointestinal dysfunction
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.)
Ceased
Application number
PCT/JP1999/006363
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English (en)
Japanese (ja)
Inventor
Hideo Kato
Kouji Morikawa
Norikatsu Kato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Japan Co Ltd
Original Assignee
Hokuriku Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hokuriku Pharmaceutical Co Ltd filed Critical Hokuriku Pharmaceutical Co Ltd
Priority to AU11804/00A priority Critical patent/AU1180400A/en
Publication of WO2000028984A1 publication Critical patent/WO2000028984A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a medicament for treating and / or preventing gastrointestinal dysfunction at the time of drug administration, and a pharmaceutical composition in which gastrointestinal dysfunction is reduced.
  • side effects include gastrointestinal dysfunction, such as stomach stomach after meals, stomach distension, anorexia, nausea, vomiting, gastric dyskinesia, gastritis, ulcers, Many induce digestive symptoms such as diarrhea, constipation, and enteritis.
  • gastrointestinal dysfunction such as stomach stomach after meals, stomach distension, anorexia, nausea, vomiting, gastric dyskinesia, gastritis, ulcers, Many induce digestive symptoms such as diarrhea, constipation, and enteritis.
  • the indications of these drugs are wide-ranging and their pharmacological mechanisms of action are also diverse. For example, they are widely found in drugs in many fields such as central nervous system, inflammation and immune system, and circulatory system. .
  • the gastrointestinal tract expresses coordination by orderly increasing or decreasing smooth muscle tone, controlling food storage, digestion, and transport. Abnormalities in the functioning of the gastrointestinal tract impede the transfer of contents and cause various complaints of gastrointestinal irregularities.
  • Is also prostaglandin F 2a to contract gastrointestinal smooth muscle the site of action is the intestinal tract, in order to improve the delayed gastric emptying are not used.
  • metoclobramide has been used for a long time as a drug to enhance gastrointestinal motility.
  • the agent may known is a dopamine D 2 receptor antagonist, has also antiemetic action with gastrointestinal motility enhancing effect, whereas the central migration is high
  • it is known that it exerts central side effects such as extrapyramidal disorders due to dopamine D 2 receptor antagonism.
  • Domperidone has emerged as a dopamine D 2 receptor antagonist by improving its central translocation and reducing side effects.
  • Dopamine is inhibiting biological Amin inhibition liberated movement Asechirukorin from nerve stimulates dopamine D 2 receptors, domperidone by dopamine D 2 receptor antagonism, to improve the free inhibition of Asechirukori down digestion It enhances ductal motility and has an antiemetic effect based on dopamine D 2 receptor antagonism.
  • An antiemetic effect based on dopamine D 2 receptor antagonism is a suitable effect for reducing nausea and vomiting, which is one of the symptoms of indefinite complaints of the digestive system.
  • cisapride is a relatively new drug that has a 5-111 " 4 receptor stimulatory action as a mechanism of action, that is, an action that stimulates acetylcholine release from nerves and thereby enhances gastrointestinal motility.
  • Itopride (rINN List32) or a salt thereof is a compound disclosed in Japanese Examined Patent Publication No. 5-37982, and is a drug commercially available for its effect of "improving various digestive symptoms in chronic gastritis". It is. Itopride is classified as a gastrointestinal motility enhancer based on its pharmacological effects, and it is reported in Pharmacology and Therapy, 21, p. 303, 1993 that it enhances gastric emptying in patients with chronic gastritis. Gastroenterology, 99, 401, 1990, reported that itopride antagonizes the gastric motility-suppressing action of dopamine in dogs, and it is reported in Gastroenterology, 99, 401, 1990.
  • Asechi Le cholinesterase is an enzyme degrading inactivate acetylcholine is the most important neurotransmitter in the contraction of the gastrointestinal tract smooth muscle
  • Asechiruko cholinesterase inhibitory effect of I Topurido includes a dopamine D 2 receptor antagonism It acts cooperatively and contributes to enhanced gastrointestinal motility.
  • the superiority of itopride in promoting gastrointestinal motility is a synergistic effect of the two mechanisms.
  • Gastrointestinal dysfunction for example, gastric dysmotility
  • Gastrointestinal dysfunction may have various causes. For example, idiopathic gastroparesis, secondary dyskinesias associated with diabetes, and the side effects of morphine drugs and anticholinergics, etc., may occur in Gastrointestinal 'Falma collodine'. Pharmacology), 21, 567, 1992.
  • GI dysfunctions such as gastric dysmotility, as described above, bezanecol and prostaglandin F 2 .
  • gastrointestinal motility stimulants are used, it should not be concluded that the efficacy of compounds having various mechanisms of action should be generally the same as in the previous report. Japanese Journal of Pharmacology, 56, 261 Page, 1991.
  • gastrointestinal motility enhancers when gastrointestinal dysfunction is applied to the above drugs, for example, gastrointestinal motility enhancers, whether or not all of them are similarly effective depends on the secondary gastric dysmotility model or gastric motility delay. It is important to make a judgment by widely confirming the effects of gastrointestinal motility enhancers on gastric motility suppression, for example, by inducing gastric motility suppression using an inducer.
  • Cisapride has recently reported It has a prolonged action, leading to lethal arrhythmia induction, and cisapride is metabolized by cytochrome P450 3A4 enzyme.Drug interaction with the concomitant drug increases the blood concentration of the concomitant drug and causes arrhythmia Triggering is known from the New England Journal of Medicine, 335, 290, 1996. Therefore, Cisapride has not yet solved the above problems.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, it was found that itopride or a salt thereof, which is a gastrointestinal motility stimulating agent, has a gastrointestinal leaning.
  • itopride or a salt thereof which is a gastrointestinal motility stimulating agent
  • has a gastrointestinal leaning We found that abnormalities in gastrointestinal tract function during administration of drugs that induce gastrointestinal motility decline, such as bloating, anorexia, nausea, and vomiting, were significantly suppressed and prevented.
  • a highly safe pharmaceutical composition in which a decrease in gastrointestinal motility is significantly reduced or suppressed can be provided by combining it or a salt thereof with a gastrointestinal tract hypofunction inducing agent. .
  • the present invention has been completed based on these findings.
  • the present invention provides a medicament for treating and / or preventing gastrointestinal dysfunction at the time of drug administration, which drug comprises itipride or a salt thereof as an active ingredient.
  • the drug that induces gastrointestinal dysfunction is an antidepressant, an antihistamine, an antiarrhythmic, an antihypertensive, or a drug for a psychiatric nerve, and these drugs are particularly preferably maprotiline hydrochloride,
  • a medicament for treating and / or preventing gastrointestinal dysfunction which is mexyldin, mexiletine hydrochloride, difludin, or etizolam.
  • the present invention provides, according to the present invention, a composition
  • a composition comprising ititride or a salt thereof and one or more of an antidepressant, an antihistamine, an antiarrhythmic agent, an antihypertensive, and a psychiatric agent.
  • Pharmaceutical compositions are provided. This pharmaceutical composition is characterized in that digestive tract dysfunction caused by these drugs is reduced or suppressed.
  • maprotiline hydrochloride, mexylidine, mexiletine hydrochloride, difludipine or etizolam are particularly preferred.
  • an itprid or a salt thereof for the manufacture of the medicament or the pharmaceutical composition for treating and / or preventing gastrointestinal dysfunction during drug administration;
  • a method for treating and / or preventing gastrointestinal dysfunction at the time of administration which comprises the step of administering a therapeutic and / or prophylactically effective amount of itopride or a salt thereof to a mammal, including a human.
  • the medicament of the present invention is a medicament for treating and / or preventing gastrointestinal dysfunction at the time of drug administration, preferably a medicament for treatment, characterized in that it contains itipride or a salt thereof as an active ingredient.
  • gastrointestinal tract should be interpreted in the broadest sense, including the stomach, duodenum, small intestine, and large intestine, but preferably refers to the stomach and duodenum, more preferably the stomach. I have.
  • the term "digestive tract dysfunction J" needs to be interpreted in the broadest sense, including postprandial stomach leaning, stomach distension, anorexia, nausea, vomiting, etc.
  • a salt of itopride which is an active ingredient of the present invention
  • a pharmacologically acceptable salt is preferable.
  • mineral salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or acetic acid and maleic acid , Fumaric acid, malic acid, citric acid, oxalic acid, lactic acid, tartaric acid and the like, and particularly preferred salts are hydrochlorides.
  • the administration route of the medicament of the present invention is not particularly limited, and an appropriate administration route can be selected.
  • preparations for oral administration include tablets, capsules, powders, granules, fine granules, syrups, and solutions.
  • preparations for parenteral administration include injections. Preparations, drops, suppositories, inhalants, transdermal preparations and the like, but the pharmaceutical form of the medicament of the present invention is not limited to these.
  • One or more optional pharmaceutical additives available in the art can be used in the manufacture of these formulations.
  • the type of drug that induces gastrointestinal dysfunction to which the medicament of the present invention is applied is not particularly limited.
  • any one of an antidepressant, an antihistamine, an antiarrhythmic, an antihypertensive, and a psychiatric agent may be used.
  • Pharmaceuticals containing two or more are preferred.
  • Specific examples of these drugs include, for example, maprotiline hydrochloride, levomepromazine maleate, amoxabin, mianserin hydrochloride, amitriptyline hydrochloride, fluvoxamine hydrochloride, diphenhydramine hydrochloride, mexidine, promethazine hydrochloride, Cyproheppudin hydrochloride, chlorpheniramine maleate, clemastine fumarate, ketotifen fumarate, cetirizine hydrochloride, abrindine hydrochloride, pilsicainide hydrochloride, pilmenol hydrochloride, mexiletine hydrochloride, propaphenone hydrochloride, bepridyl hydrochloride, sibe succinate Nzoline, flecainide
  • the medicament of the present invention can be administered at any time or during a period before, during, and / or after the administration period of the agent that induces gastrointestinal dysfunction. Preferably, it can be administered in accordance with the administration period of the drug that induces gastrointestinal dysfunction.
  • the dose of the drug of the present invention can be appropriately selected according to the type and dose of the drug that induces gastrointestinal dysfunction, and the conditions such as the age and body weight of the patient.
  • ditopride hydrochloride is usually administered at a dose of 50 to 50 mg / day. Oral administration of about 300 mg is possible.
  • the above dose can be administered several times a day.
  • the pharmaceutical composition of the present invention comprises an ittide or a salt thereof and one or more of an antidepressant, an antihistamine, an antiarrhythmic agent, an antihypertensive, and a psychiatric agent. It is characterized by including.
  • the pharmaceutical composition of the present invention is a composition in which gastrointestinal dysfunction is substantially reduced or eliminated, and suppresses stomach leaning, stomach bloating, anorexia, nausea, vomiting, etc. in the gastrointestinal tract such as the stomach and duodenum. It can be used in therapy as a safe composition that does not cause.
  • a drug that induces a gastrointestinal dysfunction and itipride or a salt thereof those described above can be suitably used.
  • the amounts of the drug that induces gastrointestinal dysfunction and the amount of itopride or a salt thereof contained in the pharmaceutical composition of the present invention can be appropriately selected depending on the type of each active ingredient.
  • the examples in the present specification specifically describe an example of the effect of improving the gastrointestinal dysfunction induced by maprotiline hydrochloride, mexidin hydrochloride, mexiletine hydrochloride, difludipine or etizolam. Those skilled in the art can refer to this example in determining the amount of the active ingredient in the composition.
  • the administration route of the pharmaceutical composition of the present invention is not particularly limited, and an appropriate administration route can be selected.
  • Formulations for oral administration include, for example, tablets, capsules, powders, granules, fine granules, syrups, liquids, etc.
  • Formulations for non-periodic administration include, for example, injections, Examples include drops, suppositories, inhalants, and transdermal preparations, but the form of the pharmaceutical composition of the present invention is not limited thereto.
  • some of the formulation examples of the pharmaceutical composition are described, but the present invention is not limited thereto.
  • one or more arbitrary pharmaceutical additives available in the art can be used, but the pharmaceutical additives for producing the desired pharmaceuticals can be used.
  • the pharmaceutical additives for producing the desired pharmaceuticals can be used.
  • examples of pharmacologically and pharmaceutically acceptable excipients for pharmaceuticals include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coatings, pigments, diluents , Bases, solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants and adhesives, but are not limited to these.
  • Example 1 Action of the medicament of the present invention (awake dog)
  • Transducer 1 Male and female beagle dogs (weight around 10 kg) were anaesthetized (introduced under anesthesia with Tiopen Yuichi Lunatrium 30 mg / kg i.v. and maintained under anesthesia by mixed inhalation of laughter, oxygen and enflurane).
  • a transducer F-121S, Suichi Medical, hereinafter referred to as Transducer 1
  • Transducer 1 was chronically sewn in the direction of the cricoid muscle in the antrum (3 cm from the gastric pylorus).
  • the lead wire of the transducer was pulled out of the body from between the scapulas through the subcutaneous skin and protected by a jacket attached to the dog. The experiment was performed awake at least 10 days after the operation.
  • the lead wire from the transducer was connected to a contraction force measurement pump (FA-01, SUYU Medical), and the signal from the amplifier was recorded on the recorder, and at the same time it was input into the combi. Drug administration was performed at least 2 hours after the meal, during which rhythmic gastric contractile exercise continued.
  • the gastric contraction momentum was calculated by calculating the area under the curve of the contraction wave input to the computer using an analysis software (Eitos Yuichi, Star Medical) and expressed as a motor index. medicine
  • the comparison of the contraction momentum before and after the administration of the substance was as follows: the motor index 10 minutes before the continuous administration of each drug and the motor index 10 minutes after the administration of physiological saline or itipride hydrochloride (administered 20 minutes after the start of the continuous administration). %. Drugs used:
  • Itopride hydrochloride, maprotiline hydrochloride, and mexiletine hydrochloride were dissolved in physiological saline before use.
  • methyl gin and etizolam were dissolved in 0.1 mol / L hydrochloric acid and then diluted with physiological saline for use.
  • Nifidivin was dissolved in a 50% aqueous ethanol solution. The effect of each drug on gastric motility was evaluated by continuous intravenous administration.
  • Maprotiline hydrochloride 10 mg / kg-hr
  • etizolam 5 mg / kg-hr
  • mexidyne lmg / kg-hr
  • mexiletine hydrochloride 20 mg / kg -hr
  • difendipine Each dose of 0.3 mg / kg-hr was continuously administered intravenously at a dose rate of 30 ml / hr (difludin only 10 ml / hr). Itopride hydrochloride was intravenously administered at a dose of 3 mg / kg, a dose that sufficiently increased dog gastric locomotor activity during the postprandial period. Test results
  • Example 2 Formulation example of the pharmaceutical composition of the present invention (tablet)
  • the medicament of the present invention has an effect of suppressing gastrointestinal dysfunction caused by a drug that induces gastrointestinal dysfunction, and is useful for suppressing and preventing side effects of drugs that induce gastrointestinal dysfunction. Further, the pharmaceutical composition of the present invention has an excellent feature that side effects of gastrointestinal dysfunction are reduced or suppressed, and various diseases can be treated without causing gastrointestinal dysfunction.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention a trait à des substances médicamenteuses visant à traiter et/ou à prévenir un désordre fonctionnel du tractus digestif induits par d'autres médicaments, tels que des antidépresseurs, des agents antihistaminiques et des agents anti-arythmisants, ces substances médicamenteuses renfermant comme ingrédient actif de l'itopride ou l'un de ses sels. L'invention concerne également des compositions médicinales contenant à la fois un médicament induisant un trouble fonctionnel du tractus digestif et de l'itopride ou l'un de ses sels et ce, afin d'atténuer le trouble fonctionnel du tractus digestif ou de le réguler.
PCT/JP1999/006363 1998-11-16 1999-11-15 Remedes agissant contre un trouble fonctionnel du tractus digestif Ceased WO2000028984A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11804/00A AU1180400A (en) 1998-11-16 1999-11-15 Remedies for digestive tract functional disorder

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/324596 1998-11-16
JP32459698 1998-11-16

Publications (1)

Publication Number Publication Date
WO2000028984A1 true WO2000028984A1 (fr) 2000-05-25

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PCT/JP1999/006363 Ceased WO2000028984A1 (fr) 1998-11-16 1999-11-15 Remedes agissant contre un trouble fonctionnel du tractus digestif

Country Status (2)

Country Link
AU (1) AU1180400A (fr)
WO (1) WO2000028984A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60188319A (ja) * 1984-03-07 1985-09-25 Kotobuki Seiyaku Kk 抗潰瘍剤
EP0306827A1 (fr) * 1987-09-05 1989-03-15 Hokuriku Pharmaceutical Co.,Ltd Amides, procédé pour leur préparation et composition pour l'activation des fonctions gastromotrices
JPH05139964A (ja) * 1991-11-14 1993-06-08 Takada Seiyaku Kk 塩酸メキシレチン腸溶性製剤
JPH08208483A (ja) * 1995-02-03 1996-08-13 Lion Corp メキタジン含有製剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60188319A (ja) * 1984-03-07 1985-09-25 Kotobuki Seiyaku Kk 抗潰瘍剤
EP0306827A1 (fr) * 1987-09-05 1989-03-15 Hokuriku Pharmaceutical Co.,Ltd Amides, procédé pour leur préparation et composition pour l'activation des fonctions gastromotrices
JPH05139964A (ja) * 1991-11-14 1993-06-08 Takada Seiyaku Kk 塩酸メキシレチン腸溶性製剤
JPH08208483A (ja) * 1995-02-03 1996-08-13 Lion Corp メキタジン含有製剤

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
AMERICAN HEART JOURNAL,, vol. 109, no. 6, 1985, pages 1281 - 1286 *
CHEMICAL ABSTRACTS, vol. 104, 1986, Columbus, Ohio, US; abstract no. 28720Z, BIANCHI PORRO G. ET AL.: "Effect of maprotiline on penta-gastrin stimulated acid secretion in man" XP002929932 *
CHEMICAL ABSTRACTS, vol. 126, 1997, Columbus, Ohio, US; abstract no. 301607R, KAKIUCHI MASATO ET AL.: "Pharmacological evaluation of itopride hydrochloride with drug-induced arrhytmia" XP002929933 *
CHEMICAL ABSTRACTS, vol. 131, 1999, Columbus, Ohio, US; abstract no. 477J, KATO MORIKATSU ET AL.: "Improving effect of gastrointestinal-prokinegic agent, itopride hydrochloride on drug-induced gastric dysmotility in conscious dogs" XP002929930 *
CHEMICAL ABSTRACTS, vol. 95, 1981, Columbus, Ohio, US; abstract no. 197359Q, YANO JOJI ET AL.: "Subacute toxicity and recovery tests of 10-(3-quinuclidinylmethyl)phenothiazine (mequitazine) in beagle dogs" XP002929931 *
DATABASE MEDLINE, 1985, KLEIN A.L. ET AL.: "Usefulness and safety of cimetidine in patients recieving mexiletine for ventricular arrhythmia" *
IWANAGA YUJI ET AL.: "A novel water-soluble dopamine-2 anta-gonist with anticholinesterase activity in gastrointestinal motor activity. Comparison with domperidone and neostigmine", GASTROENTEROLOGY,, vol. 99, no. 2, 1990, pages 401 - 408, XP002927613 *
IWANAGA YUJI ET AL.: "Stimulator effect of N-(4-(2-(dimetylamino)ethoxy)benzyl)-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion", JPN. J. PHARMACOL.,, vol. 56, no. 3, 1991, pages 261 - 269, XP002927614 *
J. TOXICOL. SCI.,, vol. 6, no. 2, 1981, pages 129 - 157 *
OSAKAFU BYOIN YAKUZAISHIKAIHEN, XX, XX, 5 February 1995 (1995-02-05), XX, pages 01 - 17, XP002929928 *
SCAND. J. GASTROENTEROL.,, vol. 20, no. 8, 1985, pages 912 - 916 *
YAKURI TO CHIRYO,, vol. 25, no. 3, 1997, pages 811 - 817 *
YAKURI TO CHIRYO,, vol. 27, no. 1, 1999, pages 95 - 101 *

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