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

Description:
This application is a 371 of PCT/SE96/01733 filed Dec. 20, 1996. 
    
    
     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 account 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 &#34;non-ulcer dyspepsia&#34;, &#34;functional dyspepsia&#34;, or &#34;non-organic dyspepsia&#34;. 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 have doubtful efficacy and sometimes have 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 histamine 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 symptoms, 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 interferred with by inhibition of the enzymes synthesizing angiotensins or by blocking the corresponding receptors at the effector sites. Available today are renin antagonists, inhibitors of the angiotensin converting enzyme (ACE) and angiotensin II-receptor (AII-receptor) antagonists. In addition to cardiovascular effects, some of these compounds have been claimed to exert effects on unspecified &#34;gastrointestinal disorders&#34;. 
    
    
     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 &#34;non-ulcer dyspepsia,&#34; functional dyspepsia or &#34;non-organic dyspepsia&#34;) 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 
     cilazapril 
     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 
     lyciurmin A 
     lyciumin B 
     mixanpril 
     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 
     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 abdominal 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.