Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-12-22
2002-07-16
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S307000, C514S365000, C514S367000, C514S374000, C514S394000, C514S412000, C514S415000, C514S438000, C514S461000
Reexamination Certificate
active
06420430
ABSTRACT:
The use of inhibitors of the sodium-hydrogen exchanger for preparing a medicament for preventing age-related organ dysfunction and age-related disorders, and for prolonging life.
The invention describes the use of inhibitors of the cellular sodium-hydrogen exchanger in human and veterinary medicine for preventing age-related functional disturbances and dysfunctional changes of body organs and for preventing age-related disorders, and for prolonging life while preserving an improved quality of life.
Within the last years, inhibitors of the sodium-hydrogen exchanger (NHE) have been characterized in numerous preclinical studies as substances which, in cases of hypoperfusion of the heart, are suitable in a superior manner for protecting the heart tissue at risk from the acute onset of the ischemia event from destruction. The protection of heart tissue by NHE inhibitors embraces all types of damage caused by the hypoperfusion, from cardiac arrhythmia to hypercontraction of the heart muscle and temporary loss of function to necrosis of heart tissue and associated permanent damage.
The mechanism of action of the NHE inhibitors, which is important in acute ischemic events, consists in that they reduce the increased influx of sodium ions which takes place in acute hypoperfused tissue by activation of NHE owing to intracellular acidification. This delays the situation of a sodium overload of the tissue. Since in heart tissue sodium and calcium ion transport are coupled with each other, this prevents the life-threatening calcium overload of the heart cells.
In the same manner as at the heart, most of the patents cited here also describe protection of the central nervous system under the influence of NHE inhibitors, and such active compounds protect the CNS similarly to the heart against acute ischemic states. These states are caused by an acute hypoperfusion and thus by insufficient supply of nutrients, oxygen, minerals, etc. Such ischemic damage of the CNS is particularly pronounced in the case of central infarcts, such as stroke.
Consequently, in accordance with expectations, in the case of normal healthy perfusion it was of course not possible to observe any protective effects of NHE inhibitors against these acute events, since there was no acute onset of ischemic tissue damage of the heart or the CNS.
Thus, it was surprising that NHE inhibitors, in addition to the protective effects against acute ischemic events and the subsequent likewise acutely stressing reperfusion events, also have direct therapeutically utilizable effects against disorders and disturbances of the entire organism of mammals which are connected with the manifestations of the chronic aging process and which are independent of acute states of hypoperfusion and which occur under normal non-ischemic conditions. These pathological age-related manifestations such as diseases, infirmity and death, which occur during the long period of aging and which are now accessible to treatment with NHE inhibitors are disorders and disturbances which are caused mainly by age-related changes of vital organs and their function and which become more and more important in the aging organism. NHE inhibitors such as, for example, cariporide act on such age-related disorders and disturbances of organs and their functions by a cascade of primary and secondary mechanisms whose mechanism has not yet been elucidated completely. It was therefore not possible to expect or predict a life-prolonging and antiaging effect for the NHE inhibitors, not to mention that such pronounced and strong effects have, according to our knowledge, not yet been shown in a comparable manner for any of the classes of active compounds known to date. It is true that recently a life-prolonging effect of ACE inhibitors, in particular under ramipril treatment, has been reported (Linz W, Jessen T, Becker RHA, Schölkens BA, Wiemer G. Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation. 1997; 96: 3164-3172). However, this life-prolonging effect only relates to hypertensive rats and organisms which, owing to their high blood pressure, have a reduced life expectancy compared with normotensive rats and organisms, respectively. Thus, the life-prolonging effect of ACE inhibitors relates only to animals suffering from high blood pressure and can, in the best case, only achieve the lifespan of a normotensive organism. Since at least a considerable part of the activity of the ACE inhibitors is caused by their hypotensive effect on individuals suffering from high blood pressure, the lack of a life-prolonging effect of ACE inhibitors on normotensive individuals came as no surprise. Likewise, ACE inhibitors did not show to a comparable extent an inhibiting action on age-related organ damage or the onset of cancer induced by the aging process.
Disorders associated with an age-related functional disturbance or with age-related manifestations of wear and tear of organs are, for example, the insufficient responsiveness and reactivity of the blood vessels to contraction and relaxation reactions. This age-related decrease of vessel reactivity on constrictory and relaxing stimuli, which are an essential process of the cardiovascular system and thus of life and health, can be eliminated or reduced significantly by NHE inhibitors. An important function and a measure for the maintenance of vessel reactivity is the blockage or delay of age-related progressive endothelial dysfunction which can be eliminated by NHE inhibitors in a highly significant manner.
An example of another measurement which characterizes the aging process is the reduction of the contractility of the heart and the decreased adaptation of the heart to a required pumping performance of the heart. This reduced ability of the heart to perform, as a consequence of the aging process, is in most cases associated with heart dysfunction caused, inter alia, by incorporation of connective tissue into heart tissue. This incorporation of connective tissue is characterized by an increase in the weight of the heart, by an increased heart size and by impaired heart function. It was surprising that such an aging of the organ's heart could be inhibited almost completely.
Whereas the earlier patents and patent applications claimed the treatment of various forms of cancerous diseases which have already become manifest, it was now extremely surprising that it is not only possible to treat a manifest cancerous disorder by inhibition of proliferation, but that it was also possible to prevent and delay in a highly significant manner the age-related frequency of the occurrence of cancer by using NHE inhibitors. Particularly noteworthy is the finding that age-related disorders of all organs and not only of certain forms of cancer can be prevented, or delayed in a highly significant manner.
What is found now is not only a delay of the onset of age-related disorders of all organs examined, including heart, vessels, liver, etc., delayed in a highly significant manner for more than the statistical norm, and a highly significant delay of age-related cancer. Rather, life is surprisingly prolonged to an extent which hitherto has not been achieved by any other group of medicaments or any natural substances.
This unique effect of the NHE inhibitors makes it also possible, in addition to using the active compound on its own in humans and animals, to combine these NHE inhibitors with other gerontologically applied principles of action, measures, substances and natural substances which are based on a different mechanism of action. Such classes of active compounds used in gerontological therapy are: in particular vitamins and antioxidants. Since there is a correlation between caloric stress or food intake and the aging process, a combination with dietary measures, for example with appetite suppressants, is possible. Also feasible is a combination with hypotensive medicaments, such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca
2+
antagonists, etc., or with medicaments which have a normalizing action on the met
Kelety Bela
Lang Hans-Jochen
Linz Wolfgang
Schmid Peter
Aventis Pharma Deutschland GmbH
Weddington Kevin E.
LandOfFree
Use of inhibitors of the sodium-hydrogen exchanger for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of inhibitors of the sodium-hydrogen exchanger for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of inhibitors of the sodium-hydrogen exchanger for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2840029