NOVEL MEDICAL USE OF AN ACE-INHIBITOR FOR TREATMENT OF DYSPEPTIC SYMPTOMS

Abstract: A method for the prophylaxis and treatment of dyspeptic symptoms of unknown origin using ACE-inhibitors and a pharmaceutical preparation comprising these compounds.

Description: Novel medical use of an ACE-inhibitor for treatment of dyspeptic symptoms . Field of invention The present invention is related to the use of ACE-inhibitors for the prophylaxis and/or treatment of dyspeptic symptoms of unknown origin and to the manufacture of medicaments with effect on such dyspeptic symptoms. Background of the invention Functional disorders of the gastrointestinal tract are common and accounts for a very large number of medical consultations. On an annual basis approximately 30% of the western population experience such functional dyspeptic symptoms varying from mild indigestion to severe pain. The symptomatology may be due to an organic disease (for example peptic ulcer disease) or, more commonly, be without any known origin (i.e. absence of organic pathology in the upper gut as evidenced by various diagnostic procedures). In clinical routine the latter symptom-syndrome is commonly called "non-ulcer dyspepsia", "functional dyspepsia", or "non-organic dyspepsia". Current treatment of dyspepsia with unknown origin involves a variety of pharmacological principles, e.g. neutralization of gastric acidity or affecting the motility of the gut wall, some of which having doubtful efficacy and sometimes having severe side effects. Dyspepsia due to peptic ulcer can be cured by intake of antacids and inhibitors of gastric acid secretion. Ulcer-like dyspeptic symptoms, also without mucosal pathology, usually respond to similar treatment. This sub-population of dyspeptic symptoms (acid-related dyspepsia) is thus defined by the symptom-relief in association with intake of neutralizing agents or of inhibition of gastric acid production by use of proton pump inhibitors or hista ine H2-receptor antagonists. However, the former treatment is short-lasting and neutralizing drugs must be administered repeatedly during the day. The latter treatment has disadvantages of being expensive and exerting an impact on the gut physiology, as the antacid gastric conditions increase the risk for intestinal and/or systemic infections. Prokinetic drugs (such as cisapride) or anticholinergic compounds are other agents that are utilized to cure dyspeptic symtoms, usually with variable efficiency and high frequency of side effects. It follows that available drug regimens for treating dyspeptic symptoms are impaired by certain disadvantages. The present invention relates to a new method of treating dyspepsia with unknown origin by pharmacological interference with the renin-angiotensin system (RAS). Prior art Compounds that interfere with the renin-angiotensin system (RAS) are well known in the art and are used to treat cardiovascular diseases, particularly arterial hypertension and cardiac failure. Principally, the RAS can be interf erred with by inhibition of the enzymes synthesizing angiotensins or by blocking the corresponding receptors at the effector sites. Available today are rerun antagonists, inhibitors of the angiotensin converting enzyme (ACE) and angiotensin D-receptor (AJI-receptor) antagonists. In addition to cardiovascular effects, some of these compounds have been claimed to exert effects on unspecified "gastrointestinal disorders". Detailed description of the invention It has surprisingly been found that antihypertensive treatment by use of an angiotensin converting enzyme (ACE) inhibitor decreases the frequency and severity of dyspeptic symptoms of unknown origin (such as "non-ulcer dyspepsia," functional dyspepsia or "non- organic dyspepsia") and can act in a prophylactive manner against these symptoms. The invention describes a new method to treat dyspeptic symptoms of unknown origin by administration of an ACE-inhibitor which interferes with the synthesis of angiotensin II. The ACE-inhibitor can be administered orally, rectally or parenterally, in neutral form or in the form of a salt. While the effects on dyspeptic symptoms have been established by the peroral route, it is considered that the effect of ACE-inhibitors is a systemic effect, which is not dependent on mode of administration. The dose of ACE-inhibitors to be administered for the treatment of dyspeptic symptoms will vary depending on factors such as the severity of the disease and the status of the patient. The dosage range at oral, rectal as well as intravenous administration will preferably be in the range from 0.01 to 50 mg per day. Examples of ACE-inhibitors which can be used for the prophylaxis and for treatment of dyspeptic symptoms are the following: alacepril alatriopril altiopril calcium ancovenin benazepril benazepril hydrochloride benazeprilat benzazepril benzoylcaptopril captopril captopril-cysteine captopril-glutathione ceranapril ceranopril ceronapril cϋazapril cilazaprilat converstatin delapril delapril-diacid enalapril enalaprilat enalkiren enapril epicaptopril foroxymithine fosfenopril fosenopril fosenopril sodium fosinopril fosinopril sodium fosinoprilat fosinoprilic acid glycopril hemorphin-4 idrapril imidapril indolapril indolaprilat libenzapril lisinopril lyciurnin A ly umin B rnixanpril moexipril moexiprilat moveltipril muracein A muracein B muracein C pentopril perindopril perindoprilat pivalopril pivopril quinapril quinapril hydrochloride quinaprilat ramipril ramiprilat spirapril spirapril hydrochloride spiraprilat spiropril spiropril hydrochloride temocapril temocapril hydrochloride teprotide trandolapril trandolaprilat utibapril zabicipiil zabiciprilat zofenopril zofenoprilat Where applicable, a compound listed above may be used in racemic form or in the form of a pure or substantitally pure enantiomer. Pharmaceutical formulations Conventional pharmaceutical preparations can be used. The pharmaceutical preparations may be in the form of injection solutions, oral solutions, rectal solutions, suspensions, tablets for oral or sublingual use or capsules. The pharmaceutical preparation contains between 0.001 mg and 100 mg of active substance, preferably 0.1 to 50 mg. Case report Case. Male, 37 years old, self employed in yacht construction, has for long time suffered from abdorninal discomfort, especially during years of economical recession. The patient was subjected to a single-blind test During one fortnight he consumed placebo and during another fortnight he received the ACE-inhibitor enalapril (2.5 mg once daily). During enalapril-treatment the subject noted clear, symptom-relief and decreased his consumption of antacids compared to the placebo-period.

Claims: CLAIMS 1. The use of an ACE-inhibitor or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of dyspeptic symtoms of unknown origin. 2. The use according to claim 1 of an ACE-inhibitor selected from the group consisting of alacepril alatriopril altiopril calcium ancovenin benazepril benazepril hydrochloride benazeprilat benzazepril benzoylcaptopril captopril captopril-cysteine captopril-glutathione ceranapril ceranopril ceronapril cilazapril cilazaprilat converstatin delapril delapril-diacid enalapril enalaprilat o enalkiren enapril epicaptopril foroxymi thine fosfenopril fosenopril fosenopril sodium fosinopril fosinopril sodium fosinoprilat fosinoprilic acid glycopril hemorphin-4 idrapril imidapril indolapril indolaprilat libenzapril -isinopril lydumin A lyciumin B ixanpril moexipril moexiprilat moveltipril muracein A muracein B muracein C pentopril perindopril perindoprilat pivalopril pivopril quinapril quinapril hydrochloride quinaprilat ramipril ramiprilat spirapril spirapril hydrochloride spiraprilat spiropril spiropril hydrochloride temocapril temocapril hydrochloride teprotide trandolapril trandolaprilat utibapril zabicipril zabiciprilat zofenopril zofenoprilat 3. A pharmaceutical preparation suitable for use in the prophylaxis and/or treatment of dyspeptic symtoms of unknown origin wherein the active ingredient is a compound as defined in any of claim 1 or 2. 4. The medicament according to claim 1 or claim 2, or a pharmceutical preparation according to claim 3 in dosage unit form. 5. The medicament according to claim 1 or claim 2, or a pharmaceutical preparation according to claims 3-4 comprising the active ingredient in association with a pharmaceutically acceptable carrier. 6. A pharmaceutical preparation according to claims 3-5 comprising as active ingredient a compound listed in claim 2. 7. A method for the prophylaxis or treatment of dyspeptic symptoms of unknown origin in mammals, including man, whereby an effective amount of a compound as defined in claim 1 as administered to a host in need of such prophylaxis or treatment. 8. A method according to claim 7 characterized by the administration of a compound as listed in claim 2.

Inventors: FAENDRIKS LARS, PETTERSSON ANDERS, FAENDRIKS, LARS, PETTERSSON, ANDERS
Applicants: ASTRA AB, FAENDRIKS LARS, PETTERSSON ANDERS, ASTRA AKTIEBOLAG (PUBL), FAENDRIKS, LARS, PETTERSSON, ANDERS
Application year: 1996
Main classification: A61K45
IPC codes: A61K31, A61K38, A61K45, A61K49, A61P1