Pharmacological use of AII-receptor antagonists

Details Pharmacological use of AII-receptor antagonists Pharmacological use of AII-receptor antagonists

1996-08-28

1999-05-04

MacMillan, Keith D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514269, 514303, 514258, 514311, 514210, 514921, A61K 3141

Patent

active

059004282

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is related to the use of angiotensin II type 1 receptor antagonists for the prophylaxis and/or treatment of multiple system organ failure (MOF) and to the manufacture of pharmaceutical preparations with effects on MOF.


BACKGROUND OF THE INVENTION

Angiotensin II type 1 receptor antagonists for which the present invention has found a new pharmacological use are known in the art. However, nothing has been reported or is known concerning the pharmacological and/or therapeutic properties of these compounds with respects to effect on MOF.
In connection with the present invention an angiotensin II type 1 of the general formula I is employed: ##STR1## wherein A is ##STR2##
The compounds listed above may be used in racemic form or in the form of a substantially pure enantiomer; they may 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 applicable the compounds listed above can be used in hydrolysable ester form.
The compound of the formula I wherein A is the I:1 moiety has the generic name losartan and is known from European patent no 253 310.
The compound of the formula I wherein A is the I:5 moiety has the generic name candesartan cilexetil, code no TCV-116 and is known from European patent no 459 136.
The compound of the formula I wherein A is the I:9 moiety is known under the generic name irbesartan.
The compound of the formula I wherein A is the I:13 moiety has the generic name candesartan and is known from European patent no 459 136.
Hemorrhage and/or trauma elicits a vasoconstrictive response that preferentially reduces blood flow to mesenteric organs. If severe, hemorrhage may propagate to circulatory shock, a condition in which oxygen delivery becomes insufficient to maintain tissue integrity and function. Manifestations of circulatory shock in mesenteric organs include collapse of the gut permeability barrier, enabeling gut pathogens to cross the intestinal mucosa and eventually spread to systemic compartments via lymphatics and blood vessels. The barrier dysfunction with microbial translocation, together the initially compromised systemic circulation, leads to functional failure of various organ systems (e.g. kidneys, heart, lungs, hemostasis). Such a sequential development of devastating sequele is defined as multiple system organ failure (MOF).
The treatment of MOF is very costly and results in long term treatments at intensive care units. Therapeutic efforts in MOF treatment today are aimed at life sustaining treatments, such as antibiotics, blood volume expansion and respiration assistance. However, a therapeutical approach in order to maintain mesenteric blood flow and oxygen delivery is not available today.
Reduction of mesenteric blood flow in the critically ill patient is mainly mediated by activation of the renin-angiotensin system with elevated plasma angiotensin II (AII) levels. Administration of compounds which blocks the formation of AII (i.e. angiotensin converting enzyme inhibitors, (ACE-inhibitors) have been shown to improve mesenteric oxygenation during severe shock.
The use of ACE inhibitors for treatment of severe shock is, however hampered by the fact that they act as nonspecific enzyme inhibitors and result in the accumulation of several vasoactive peptides e.g. (bradykinin, subst. P, endogenous opoids). This consequence may lead to an instable blood pressure regulation as well as increased risk for allergic manifestations and upper airway irritation.
It will be appreciated therefore that there is need for alternative and improved methods for the prophylaxis and/or treatment of multiple system organ failure.


DISCLOSURE OF THE INVENTION

It has unexpectedly been found that known compounds of the general formula ##STR3## wherein A is ##STR4## or a physiologically acceptable salt and/or a stereochemical isomer thereof are effective in the prophylaxis and/or treatment of multiple system organ failure (MOF).
It has been found that

REFERENCES:
patent: 5155118 (1992-10-01), Carini et al.
patent: 5538991 (1996-07-01), Ashton et al.

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