Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-22
2002-11-26
Henley, Ray (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06486188
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of an angiotensin II type 1 receptor antagonist in the manufacture of a medicament for the prophylactic and/or therapeutic treatment of cardiovascular complications encountered in a patient in need of dialysis. The invention further relates to a method for prophylactic and/or therapeutic treatment of cardiovascular complications encountered in a patient in need of dialysis, comprising administering to the patient a therapeutically effective amount of an angiotensin II type 1 receptor antagonist.
BACKGROUND OF THE INVENTION
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 interfered with by inhibition of the enzymes synthesizing angiotensins or by blocking receptors at the effector sites. Available today are renin-antagonists, inhibitors of the angiotensin converting enzyme (ACE) and angiotensin II (AT II) receptor antagonists.
Angiotensin II type 1 receptor antagonists for which the present invention has found a new medical use are thus known in the art. However, nothing has been disclosed in connection with their potential effects in dialysis and more particularly hemodialysis.
Hemodialysis is a process for removing waste products and toxins from the blood of patients with renal malfunction or failure. Blood is removed from, and returned to, circulation, either through an artificial arterio-venous fistula or a temporary or permanent internal catheter, and passes through an “artificial kidney”, or dialyzer.
Dialyzers vary in design and performance, but all include a dialysis membrane and a dialys-ing solution. In dialysis, toxins are removed by diffusion through the dialysis membrane, thus essentially restoring blood to its normal state. The process, however, has to be repeated at regular intervals, e.g. two to three times per week for four to six hours per session.
Patients subject to hemodialysis are currently treated in hospitals, due to the high cost and the complexity of the dialysis equipment. For patients in hemodialysis, the prognosis has been improved over the last decades. One reason is improved dialysis equipment and procedures. Thus, new and more effective dialysis filters have been developed to allow more efficient dialysis with improved clearance of toxic substances. Another alternative to more effective dialysis filters is to use more frequent dialysis sessions. Currently, most patients are offered four hour dialysis sessions three times per week, all year round. Trials comparing frequency of dialysis sessions indicate that the survival rate will be improved if patients can accept such dialysis sessions four times per week. Understandably, all patients cannot manage such frequent hospital visits.
Mortality among patients treated with hemodialysis due to end-stage renal insufficiency is very high. A large proportion of these deaths, approximately 50 to 65%, are reported to be caused by cardiovascular complications. For example, in a Danish national registry report from 1996, cardiac causes of death and stroke were noted in 51% and 11% of the patients, respectively. Data from the European Registry, the so-called ERA-EDTA registry show that more than 44% of the hemodialyzed patients die of cardiac events, 33% of which from myocardial infarction and 23% from sudden death.
In most patients subject to hemodialysis, the non-functioning kidneys are left intact. The main reason for this, is that it involves major surgery to remove them.
It is likely that non-functioning kidneys excrete a number of kidney-derived toxic substances which increase the risk of cardiovascular complications in these patients.
Further support of this hypothesis, is that patients in hemodialysis who have had their kidneys removed seem to exhibit a reduced risk for such adverse effects on the cardiovascular system. Consequently, such patients run a reduced risk of cardiovascular complications.
Improved medical treatment of patients in hemodialysis has also resulted in prolonged survival as well as a reduced risk and duration of hospitalization due to complications. Although few large scale trials have been performed, treatment of cardiovascular diseases, such as hypertension, have improved. The infections which frequently occur in dialysis patients can nowadays be better managed. Furthermore, the restoration of red blood cell formation using e.g. recombinant erythropoetin (EPO) has improved the survival rate and increased quality of life (QoL).
Despite these medical advances, the prognosis for patients in dialysis, and especially chronic hemodialysis, remains poor. A medical treatment that can significantly reduce mortality and morbidity due to cardiovascular complications would clearly be a major therapeutic advance.
SUMMARY OF THE INVENTION
The inventors of the present invention, have surprisingly found that the cardiovascular complications, such as mortality and morbidity, encountered in patients subject to dialysis, especially chronic hemodialysis, due to end-stage renal disease can be reduced by using an angiotensin II type 1 receptor antagonist during and/or between the dialysis sessions. Thus, use of an angiotensin II type 1 receptor antagonist can significantly reduce mortality due to cardiovascular diseases and reduce the number and duration of hospitalizations due to cardiovascular complications.
The present invention thus relates to a new method of preventing and/or treating cardiovascular diseases and complications by pharmacological interference with the renin-angiotensin system (RAS) using an angiotensin II type 1 receptor antagonist.
Angiotensin II type 1 receptor antagonists are conventionally used for preventing and/or treating hypertension. The present invention, however, is directed to prevention and/or treatment of cardiovascular complications other than hypertension, e.g. mortality and morbidity as stated above. Further cardiovascular complications which may be prevented and/or treated with the present invention include, without limitation myocardial infarction (MI), stroke, vascular access dysfunction and amputations.
In one embodiment, the present invention relates to use of an angiotensin II type 1 receptor antagonist in the manufacture of a medicament for the prophylactic and/or therapeutic treatment of cardiovascular complications encountered during or between dialysis of a patient in need of such dialysis.
A further embodiment of the invention provides a method for prophylactic and/or therapeutic treatment of cardiovascular complications encountered in dialysis of a patient, comprising administering to a patient in need of such dialysis a therapeutically effective amount of an angiotensin II type 1 receptor antagonist.
DETAILED DESCRIPTION OF THE INVENTION
In preferred embodiments of the present invention use is made of an angiotensin II type 1 receptor antagonist of the general formula I:
wherein A is
or
The compound of the general formula I wherein A is the I:1 moiety has the generic name losartan and is known from European Patent No. EP 0 253 310 B1 to du Pont.
The compound of the general formula I wherein A is the I:5 moiety has the generic name candesartan cilexetil and is known from European Patent No. 459 136 B1 and U.S. Pat. No. 5,196,444 to Takeda Chemical Industries.
The compound of the general formula I wherein A is the I:9 moiety has the generic name irbesartan.
The compound of the general formula I wherein A is the I:13 moiety has the generic name candesartan and is known from European Patent No. 459 136 B1 and U.S. Pat. No. 5,703,110 to Takeda Chemical Industries.
In preferred embodiments of the present invention, use is made of a compound of the general formula I wherein A I:5 (candesartan cilexetil) or A is I:13 (candesartan). Candesartan cilexetil is currently manufactured and sold world-wide e.g. under the trade names Atacand®, Amias® and Blopress®.
When the angiotensin II type 1 receptor antagonists used in the pres
Luft Friedrich
Pedersen Erling Bjerregaard
Svensson Anders
Zannad Faies
AstraZeneca AB
Fish & Richardson PC
Henley Ray
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