Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-03-04
2001-11-13
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06316423
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method of using certain adenosine amine congeners in the prevention and treatment of brain damage caused by ischemia, hypoxia, and anoxia.
BACKGROUND OF THE INVENTION
Despite intense research aimed at the development of effective therapeutic interventions, the means of preventing post-ischemic brain damage are still elusive. Among the numerous therapies currently under testing, approaches based on the stimulation of adenosine A
1
receptors offer a substantial promise in reducing ischemia-related structural and functional damage (for recent reviews, see Rudolphi et al.,
Cerebrovasc. Brain Metab. Rev
., 4, 346 (1992); Miller et al.,
J. Neurotrauma Suppl
., 2, S563 (1992); von Lubitz et al.,
N.Y. Acad. Sci
., 765, 163 (1995)).
Multiple studies have shown that acute stimulation of adenosine A
1
receptors results in decreased calcium influx, enhanced membrane hyperpolarization, suppressed release of neurotransmitters (including neurotoxic glutamate), and depression of NMDA receptor excitability (reviewed by Schubert et al.,
Neuroprotective mechanisms of endogenous adenosine action and pharmacological implications
, in:
Pharmacology of Cerebral Ischemia
, ed. J. Krieglstein, H. Oberpichler (Wissenschaftliche Verlagsgesselsschaft mbH, Stuttgart), 417 (1990); Rudolphi et al., supra; von Lubitz et al.,
J. Mol. Neurosci
., 2, 53 (1992); von Lubitz et al.,
Adenosine: a Drototherapeutic concept in neurodegeneration
, in
Neuroprotective agents: Clinical and Experimental Aspects
, B. Trembly and W. Slikker, Jr., (eds.)
Ann. N.Y. Acad. Sci
., 765, 163 (1995a)). As a result of these effects, neuronal excitability and firing rate are reduced causing, in turn, a substantial reduction of brain metabolic demands (Schubert et al., supra).
The events elicited by stimulation of adenosine A
1
receptors counteract several processes recognized as key participants in the generation of ischemic brain damage (see, von Lubitz et al., 1995a, supra; Bengtsson et al., Cell damage in cerebral ischemia:
physiological, biochemical, and structural aspects
, A. Schurr and B. M. Rigor (eds) in:
Cerebral Ischemia and Resuscitation
(CRC Press, Boca Raton), 1990; Choi,
J. Neurobiol
., 9, 1261 (1992)). Hence, several successful attempts have been made to demonstrate the neuroprotective value of treatment with agonists acting at this adenosine receptor subtype (see, von Lubitz et al., 1995 supra). Although most of these studies demonstrated unequivocally that both pre- and postischemically administered adenosine A
1
receptor agonists reduce postischemic neuronal loss (reviews by Miller et al., supra; Rudolphi et al., supra; von Lubitz et al., 1995, supra), a paucity of data describing the effect of these drugs on postischemic neurological recovery exists (see, e.g., Phillis and O'Regan, 1988; von Lubitz et al.,
J. Mol. Neurosci
., 2, 53 (1992), Heron et al.,
Brain Res
., 641, 217 (1994)).
It is well known that both focal and global ischemia may result in very significant disturbances of cognitive functions in both humans (Mohr et al.,
Middle cerebral artery
, in:
Stroke
, H. J. M. Barnett, J. P. Mohr, B. M. Stein, F. M. Yatsu (eds.) Churchill Livingstone, N.Y. 377 (1986); Mohr,
Posterior cerebral artery
, in:
Stroke
, H. J. M. Barnett, J. P. Mohr, B. M. Stein, F. M. Yatsu (eds.) Churchill Livingstone, N.Y.), 377 (1986)) and in animals subjected to an experimental cerebrovasculatory arrest (Bothe et al.,
Stroke,
17, 1160 (1985); Auer et al.,
Neurosci
. 9, 1641 (1989); le Peillet et al.,
Modified open-field activity test to study the protective activity of drugs in cerebral ischemia in rats
(4
vessel model
), in:
Pharmacology of Cerebral Ischemia
(1988), J. Krieglstein (ed.) (CRC Press, Boca Raton), 369 (1989); Jaspers et al.,
Neurosci. Lett
. 117, 149 (1990); Katoh et al.,
Brain Res
. 577, 57 (1992)). Short term and spatial memory appears to be particularly affected (Mohr et al., 1986a, supra).
For example, cardiac arrest and cerebrovascular arrest involving either middle or posterior cerebral artery frequently result in retro- and anterograde amnesia in humans (Mohr, supra; Mohr et al., supra). Typically, all of these insults involve severe damage to the hippocampus, which is the brain region postulated to be intimately involved in learning processes related to spatial coding (O'Feefe et al.,
Med. Sci. Res
., 16, 897 (1978)). Amnesia, determined in a wide variety of learning paradigms, has also been reported in several animal species exposed to experimentally induced loss of the hippocampal formation (Mishkin,
Nature
, 273, 297 (1978); Morris et al.,
Nature
, 297, 681 (1982); Bothe et al., Supra; Hagan et al.,
Beh. Brain Res
., 41, 151-160 (1990); Jaspers et al., supra). Moreover, in many instances of brain ischemia, treatment is not available to the patient until hours, in stroke patients typically 3 to 6 hours, after the ischemic injury. Such a delay places great demands on any therapeutic regime designed to mitigate ischemic brain injury, and to date there exists no known method for effectively treating this damage, especially following these significant delays in initiating such treatment.
Unlike treatment of ischemic brain damage, adenosine-based treatment of cardiovascular diseases has reached its clinical reality, and drugs such as Adenocard™ or Persantine™ are now available worldwide to the community of cardiologists. Yet, apart from carbamazepine, whose antagonistic properties at adenosine A
1
receptors are marginal, and which is used in prophylaxis of affective disorders (van Calker et al.,
Drug Dev. Res
., 3, 354 (1993)), the treatment of neurodegenerative diseases with adenosine A
1
receptor active drugs is generally limited to experimental practice. While both the neuroprotective and anticonvulsant impact of acute administration of adenosine A
1
receptor agonists became fully recognized (reviews by Fredholm et al.,
TIBS
, 9, 130 (1995); von Lubitz et al.,
Adenosine
in:
a prototherapeutic concept in neurodegeneration, in Neuroprotective agents: Clinical and Experimental Aspects
, (eds.) B. Trembly and W. Slikker, Jr., Ann. N.Y. Acad. Sci. 765, 163 (1995), Von Lubitz et al.,
Behavioral effects of adenosine receptor stimulation
, in:
Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology
, L. Belardinelli and A. Pelleg, (eds.) Kluwer Academic Publ., Boston, 489 (1995)). The presence of disturbing side effects, e.g., bradycardia and hypotension (Williams,
Drug Dev. Res
., 28, 438 (1993)) has severely mitigated introduction of these drugs as clinically viable alternatives in treatment of such disorders as stroke or seizures.
Previous studies show that preischemic treatment with adenosine A
1
receptor agonists results in significant improvement in neuronal survival and mortality reduction (Rudolphi et al., supra; von Lubitz et al., 1995, in press). However, these studies required drug doses in the milligram range (reviews by Rudolphi et al., supra, and von Lubitz et al., supra) which result in disturbing and clinically unacceptable cardiovascular side effects including (but not necessarily limited to) bradycardia and hypotension. Such side effects are considered the most serious obstacle in clinical development of adenosine A
1
receptor stimulating agents (Williams, supra).
Therefore, there exists a need for a method of preventing and treating ischemic brain damage without the aforesaid undesirable side-effects associated, for example with selective A
1
adenosine receptor agonists that provide neuroprotective effects. The present invention seeks to provide such a method of preventing and treating ischemic, hypoxic, or anoxic brain damage. These and other objects and advantages of the present invention, as well as additional inventive features will be apparent from the description of the invention provided herein.
SUMMARY OF THE INVENTION
The present invention provides a method of treating ischemic, hypoxic, or anoxic brain damage in an animal, particularly
Jacobson Kenneth A.
von Lubitz Dag K. J. E.
Fay Zohreh
The United States of America as represented by the Departmant of
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