MXPA97010002A - New med use - Google Patents

Abstract

A method for the prophylaxis and treatment of desensitizing symptoms using certain type 1 angiotensin II receptor antagonists and a pharmaceutical preparation comprising these compounds

Description

NEW MEDICAL USE Field of the invention The present invention relates to the use of angiotensin II type 1 receptor antagonists for the prophylaxis and / or treatment of dyspeptic symptoms and for the preparation of pharmaceutical preparations with effects on dyspeptic symptoms.

BACKGROUND OF THE INVENTION The present invention has found a new medical use known in the art for angiotensin II type 1 receptor antagonists. However, nothing has been reported or is known in general as regards the pharmacological properties and / or Therapeutics of these compounds with respect to effects on dyspeptic symptoms. An angiotensin II receptor antagonist type 1 of the general formula I is used in connection with the present invention: REF: 25343 A is 1: 4 L8 The compounds listed above could be used in racemic form or in the form of a substantially pure enantiomer; these could be used in neutral form or in the form of a salt, preferably a physiologically acceptable salt such as sodium, potassium, ammonium, calcium or magnesium. Where the applicable compounds listed above can be used in the form of a hydrolysable ester. The compound of formula I wherein A is the radical 1: 1 has the generic name losartan and is known from European patent no. 253 310. The compound of the formula I wherein A is the radical 1: 5 has the generic name candesartan cilexetil, code no. TCV-116 and is known from EP-459 136. The compound of the formula I wherein A is the radical 1: 9 is known under the generic name of irbesartan. The compound of formula I wherein A is 1:13 radical has the generic name candesartan and is known from EP-459 136. Functional disorders of the gastrointestinal tract are common and have a large number of medical consultations. On an annual basis of approximately 30% of a western population experienced such dyspeptic symptoms ranging from moderate indigestion to severe pain. The symptomatology could be due to an organic disease (for example peptic ulcer disease) or, more commonly, to be no known origin (eg absence of organic pathology in the upper intestine as evidenced by various diagnostic procedures). In clinical routine the last symptom-syndrome is commonly called "dyspepsia without ulcer", "functional dyspepsia", "non-organic dyspepsia" etc. The treatment of dyspepsia of unknown origin involves a variety of pharmacological principles (eg, neutralization of gastric acidity, drugs that affect the mobility of the intestinal wall, etc.), some of which have doubtful efficacy and sometimes with severe side effects. The dyspepsia due to peptic ulcers can be cured by the admission of antacids and inhibitors of gastric acid secretion. The dyspeptic symptoms similar to the ulcer without pathology of the mucosa, are also usually sensitive to a similar treatment. This subpopulation of dyspeptic symptoms (acid-related dyspepsia) is thus defined by symptom-relief in association with the ingestion of neutralizing agents or the inhibition of gastric acid production by the use of proton pump inhibitors or histamine type 2 receptor antagonists. However, the main trainer is short-lived and neutralizing drugs must be administered repeatedly during the day. The latter drugs have disadvantages of being expensive and exert a great impact on the physiology of the intestine as the gastric conditions antacids increase the risk for intestinal and / or systemic infections. Prokinetic drugs (such as cisapride a or) or anticholinergic compounds are other pharmaceutical principles that are used for dyspeptic symptoms, usually with variable effect and high frequency of side effects. Following the drug regimens that are available to treat dyspeptic symptoms are decoupled by serious disadvantages. Compounds that interfere with the renin-angiotensin system (RAS) are well known in the art and are used to treat cardiovascular diseases, particularly hypertension and heart failure mainly, the RAS can be interfered by inhibition of the enzymes that synthesize angiotensin or blocking the receptors in the active sites. Today, renin antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor (AII-receptor) antagonists are available. In addition for cardiovascular effects, some of these compounds have been claimed to exert effects in "gastrointestinal disorders" not specified.

Description of the invention The above exact mechanisms related to the acid that cause pain in the upper gastrointestinal tract are currently unknown. However, it is a prerequisite that luminal acid has access to the surface of mucous cells. This is not the case under normal conditions, such as a continuous transport of fluid and bicarbonate that provides a neutral compartment of the mucosal surface. This important process that neutralizes the acid is governed by a complex network of different regulatory mechanisms. The invention describes a new method for treating dyspeptic symptoms by modulating the surface-neutralizing capacity of the gastroduodenal mucosa, by pharmacological interference with RAS.

Angiotensin-renin system (RAS): It is known that the RAS, according to the sympathetic nervous system decreases the neutralizing capacity of gastroduodenal acid. As will be clear from the above form, several different methods can be used to interfere with RAS. It has now been surprisingly found that pharmacological obstruction of specific type I AII receptors with receptor-type angiotensin II antagonists reverses the inhibitory effects of AII to increase the neutralizing capacity of gastroduodenal acid. Thus, high concentrations of AII plasma in the presence of angiotensin II type I receptor obstructs the strengthening of superficial neutralizing capacity, rather than eliminating a prerequisite for the induction of symptoms by luminal acid. The present application discloses that the administration of type I AII specific receptor blockers, by an improvement in the acid neutralizing capacity of the gastroduodenal mucosa, are used to treat dyspeptic symptoms. Thus the present invention relates to a new method of treatment of dyspepsia by pharmacological interference by the renin-angiotensin system using known compounds of the general formula I above. Thus, compounds of the general formula I have unexpectedly been found where A is L4 - Lll or a physiologically acceptable salt and / or a stereochemical isomer thereof are effective in the prophylaxis and / or treatment of dyspeptic symptoms. Since the effects on the neutralizing capacity of gastroduodenal acid have been established in animals by the intravenous route, it is believed that the effect is a systemic effect which is not dependent in any way on the administration that is used, and therefore the The effect will also be seen with other routes of administration such as rectal or oral administration. The dose of a compound according to formula I to be administered in prophylaxis and / or treatment of dyspeptic symptoms will vary depending on factors such as the severity of the disease and the condition of the patient. The dosage range in oral, rectal as well as intravenous administration will be in the range of 1 to 500 mg per day. The preferred mode of the invention is the use of a compound of the formula I wherein A is 1: 1 (Losartan) or 1: 5 (T CV-116).

Scientific tests To study the neutralizing capacity of gastroduodenal acid, the following experiments were performed on anesthetized rats. Intravenous administration of AII in the untreated animals was followed by a slight decrease in the ability to neutralize the acid. In animals pretreated with the Losartan IIA receptor obstruction, an improved acid neutralizing capacity was found in response to the same dose of AII.

Table 1 Neutralizing acid capacity of the duodenal mucosa in anesthetized rats before and during intravenous administration of AIs Non-treated animals treated with Losartan (tfEq / h X Ctn) (i ± Eq / h x cm) Vaseline 12 ± 1.5 13 ± 1.2 During infusion-AII 10 ± 3 22 ± 2,3 * The results are given by ± SEM, n = 6 + 6. The significant inter-group difference (student t-tests, unpaired samples) is indicated by an asterisk. The intravenous administration of AII results in a neutralizing capacity of the uncoupled acid in untreated animals. In animals, which are pretreated with the blocking agent of the angiotensin II receptor losartan, the same dose of All significantly increases the neutralizing capacity of the acid in the duodenal mucosa.

Pharmaceutical preparations Conventional pharmaceutical preparations can be used. The pharmaceutical preparations are preferably in the form of injectable solutions, but it is also possible to use other types of preparation, such as oral solutions, or suspensions, tablets or capsules. Alternative routes of administration are sublingual tablets or solutions and rectal solutions, suspensions or rectiols. The pharmaceutical preparation contains between lmg and 500 mg of active substance, preferably 10 to 250 mg.

Claims (10)

Claims

1. - The use of a compound of the general formula I characterized in that A is MESS or a physiologically acceptable salt and / or a stereochemical isomer thereof for the manufacture of a medicament with effect on dyspeptic symptoms.

2. - The use according to claim 1 of a compound of the formula I, characterized in that A is 1: 1.

3. The use according to claim 1 of a compound of the formula I, characterized in that A is 1: 5.

4. - A pharmaceutical preparation for use in the prophylaxis and / or treatment of dyspeptic symptoms, characterized in that the active ingredient is a compound as defined in claim 1.

5. - A pharmaceutical preparation according to claim 4, characterized in that dosage in unitary form.

6. - A pharmaceutical preparation according to claims 4-5, characterized in that it comprises the active ingredients in association with a physiologically acceptable vehicle.

7. - A pharmaceutical preparation according to claims 4-6, characterized in that it comprises as active ingredients a compound of the formula I wherein A is 1: 1.

8. - A pharmaceutical preparation according to claims 4-6, characterized in that it comprises as active ingredients a compound of the formula I wherein A is 1: 5.

9. - A method for the prophylaxis and treatment of dyspeptic symptoms in mammals, including man, characterized in that an effective amount of a compound as defined in claim 1 is administered to a host in need of such prophylaxis and treatment.

10. - A method according to claim 9, characterized in that the administration of a compound of the formula I wherein A is 1: 1 or 1: 5.