Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-19
2003-05-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S081000, C514S263400
Reexamination Certificate
active
06559148
ABSTRACT:
This application is a 371 of PCT/EP99/08999, filed Nov. 23, 1999 published as WO 00/32198, Jun. 8, 2000.
OBJECT OF THE INVENTION
The present invention relates to the use of a specific class of compounds for the prevention of damages and mortality caused by global cerebral ischemia and ischemia-reperfusion and for the treatment of acute and chronic cerebrovascular diseases.
STATE OF THE ART
When cerebral blood flow is reduced to about 10-20% of the normal flow, neurons and astrocytes consume their cellular energy metabolites and lose their capacity of regulating transmembrane ionic gradients (Hansen A. J.,
Physiol. Rev
. 1985; 65:101-148). As a consequence, ionic homeostasis results to be jeopardized and all types of cells degenerate, as a consequence of the ischemic infarction (Ginsberg M.,
The Neuroscientist
, 1995; 1:95-103). It has been estimated in rodents that a cerebral ischemic injury reaches its peak 4-8 hours after the arterial occlusion, but it is possible to reduce the extent of the infarction without changing the duration or the intensity of the insult. As a matter of fact, the ischemic injury can be alleviated by the modulation of a wide range of parameters, such as: closing calcium channels associated to NMDA receptor (Siesjo B. et al.,
Ann. Thorac. Surg
. 1995; 59:1316-1320); reducing intracellular free calcium (Tymianski M. et al.,
Neuron
1993; 11:221-235); reducing production of free radicals (Chan P.,
Brain Pathol
. 1994; 59-65); lowering brain temperature (Dietrich W. et al.,
Cellular and molecular mechanism of ischemic brain damage
. Siesjo B., Wieloch T., eds., 177-198. Philadelphia: Lippincott-Raven).
Adenosine, an endogenous nucleoside that binds to purinoceptors of P
1
type, exerts a neuromodulating activity in several areas of the central nervous system of mammals. It is moreover involved in the regulation of cerebral blood flow (Rudolphi K. A. et al.,
Cerebrovascular brain metabolism reviews
, 1992; 4:346-369; Rudolphi K. A. et al.,
Trends in Pharmacol. Sci
. 1992; 13:439-445; Fredholm B. B.,
Neuroprotective agents and cerebral ischemia
, Green A. R., Cross A. J. eds., pp. 259-280, Academic Press 1997, San Diego). Adenosine acts as a neuroprotective agent during the onset of cerebral ischemic damage. It uses several mechanisms such as, for instance: inhibition of the neuronal activity by the reduction of both the excitatory amino acid release and the calcium ion influx; stabilization of the membrane potential by hyperpolarization; inhibition of the free radicals production; increase in blood supply by vasodilatation; inhibition of platelet aggregation and adhesion of neutrophils to endothelial cells (Miller, L. P., Hsu C.,
J. of Neurotrauma
, 1992; 9:S563-S577; Rudolphi K. A. et al.,
Trends in Pharmacol. Sci
. 1992; 13:439-445).
Unlike the direct involvement of P
1
purinoceptors in the neuroprotective action played by adenosine, as at today little is known about a potential role of P
2
purinoceptors (preferred for ATP; Burnstock G.;
Neuropharmacology
1997; 36, 11427-1139) in the onset or protection from cerebral ischemic damage.
U.S. Pat. No. 5,733,916 describes a method for the treatment of the damages caused by ischemia-reperfusion in organs intended for transplant or surgery. This method concerns the administration of an antagonist of the A1 adenosine receptor and/or an antagonist of P
2
purinoceptors. In particular, said antagonist for P
2
receptors is PPADS, utilized in described cases of lung ischemia. U.S. Pat. No. 5,733,916 concerns ischemia-reperfusion and in particular lung ischemia, which affects an organ that requires a drastic reduction in the blood supply, when it is subjected to transplant or surgery. Such drastic reduction causes ischemic damages that may be localized and severe. According to what is reported in U.S. Pat. No. 7,733,916, such damages are advantageously treated by administering PPADS (15 mg/kg) 30 minutes before ischemia, and/or an antagonist of the A1 adenosine receptor. U.S. Pat. No. 5,733,916 describes intravenous administration of PPADS, which allows the compound to reach the lung wherein ischemia has taken place.
OBJECTS OF THE INVENTION
Object of this invention is to provide a class of compounds that allow to reduce the damages and the mortality caused by cerebral ischemic injury and reperfusion-induced ischemia, with the ensuing possibility of an effective treatment of acute and chronic cerebrovascular diseases.
Another object of this invention is to provide a class of compounds allowing to modulate several physiological functions, for instance energy metabolism, neuronal activity, cell survival.
Another object of the present invention is to provide a class of compounds allowing to prevent the mortality caused by ischemic stress either induced or suffered. Another object of the present invention is to provide a class of compounds allowing to reduce mortality caused by cerebral ischemic insult and such as to be easily administered and to pass the blood-brain barrier. Still another object of the present invention is to provide a class of compounds representing a valid pharmacological alternative to agents that are already used for the treatment of ischemic insult, reperfusion and acute and chronic cerebrovascular diseases, either induced or suffered.
REFERENCES:
patent: 5733916 (1998-03-01), Neely
patent: WO 95/26728 (1995-10-01), None
patent: WO 97/04760 (1997-02-01), None
patent: WO 98/03178 (1998-01-01), None
“alteration in cardiac sarcolemmal atp receptors by oxyradicals”, Musat et al, Ann. N.Y. Acad. Sci. 1996, 793(myocardial preservation), abstract.*
“p2 purinoceptor-mediated dilations in the rat middle cerebral artery after ischemia-reperfusion”, Marrelli et al., american Journal of physiology, 1999, 276 (1 pt 2) h33-41, abstract.*
Volonte C et al: “Selected P2 Purinoceptor Modulators Prevent Glutamate-Evoked Cytotoxicity in Cultured Cerebellar Granule Neurons” Journal of Neuroscience Research,US,Wiley-Liss, vol. 45, No. 2, Jul. 15, 1996, pp. 183-193, XP002048687 ISSN: 0360-4012.
Burnstock G.: “Hypoxia, endothelium, and purines.” Drug Development Research, (1993) 28/3 (301-305)., XP000892583.
Dunwiddie T V (Reprint) et al: “Purinoceptors in the central nervous system” Drug Development Research, (Nov.-Dec. 1996) vol. 39, No. 3-4, pp. 361-370. Publisher Wiley-Liss, Div John Wiley & Sons Inc, 605 Third Ave, New York NY 10158-0012. ISSN: 0272-4391., XP000892584 Univ Milan, Inst Pharmacol Sci, Via Balzaretti 9, I-20133 Milan, Italy (Reprint).
Sigma-Aldrich Certificate of Analysis: Product No. R115, Product Name: Reactive Blue 2.
Product Descriptin from Sigma-Aldrich catalog of Product No.: R115, Product Name: Reactive Blue 2.
Bernardi Giorgio
Sancesario Giuseppe
Volonte′ Cinzia
Consiglio Nazionale delle Ricerche
Fay Zohreh
Kwon Brian-Yong
Millen White Zelano & Branigan P.C.
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