Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-17
2002-05-21
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S342000
Reexamination Certificate
active
06391899
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention provides a genus of compounds and pharmaceutical compositions that are protective for mitigating damage associated with tissue ischemia, particularly stroke (CNS ischemia), and ischemia of the myocardium. The present invention further provides a method for treating or preventing tissue damage precipitated by injury, disease or insult, particularly the tissue damage caused by ischemia. Lastly, the present invention provides a method for treating or preventing tissue damage by providing compounds that and compositions that inhibit or neutralize the cytotoxic activity of 3-aminopropanal.
BACKGROUND OF THE INVENTION
Cerebral ischemia, a leading cause of disability and mortality world-wide, is mediated by a cascade of molecular cytotoxins that kill potentially viable cells in the brain. The polyamines, spemine, spermidine, and putrescine, which are among the most abundant molecules in mammalian brain, have been implicated in the pathogenesis of ischemic brain damage (Zhang et al.,
Proc. Natl. Acad. Sci. USA
91:10883-10887, 1994; Harman and Shaw,
Br. J. Pharmac.
73:165-174, 1981; Bergeron et al.,
J. Med. Chem.
39:5257-5266, 1996; Glantz et al.,
J. Basic. Clin. Physiol. Pharmacol.
7:1-10, 1996; Dempsey et al.,
Neurosurg.
17:635-640, 1985; and Schmitz et al.,
Neurosurg.
33:882-888, 1993). Polyamine biosynthesis is increased following the onset of cerebral ischemia, due to an ischemia-mediated induction of ornithine decarboxylase, a key synthetic enzyme in the polyamine biosynthetic pathway. Spermine was linked to development of glutamate-mediated cytotoxicity, because it can bind to the NR1 subunit of the NMDA receptor and potentiate glutamate-mediated cell damage (Traynelis et al.,
Science
268:873-876, 1995; Traynelis and Cull-Candy.
J. Physiol. (Lond.)
433:727-763, 1991; and Sullivan et al.,
Neuron
13:929-936, 1994). Administration of experimental therapeutics which inhibit ornithine decarboxylase limit the development of ischemic brain damage in experimental animal models of stroke [ref]. Thus, the accumulation of polyamines in the ischemic brain occupies an important role in the pathogenesis of stroke (Kindy et al.,
J. Cereb. Blood Flow Metab.
14:1040-1045, 1994).
Brain spermine and spermidine levels are actually decreased by cerebral ischemia (Paschen,
J. Neurochem.
49:35-37, 1987; and Paschen,
Cerebrovasc. Brain Metab. Rev.
4:59-88, 1992). This observed decline of tissue spermine and spermidine levels is accompanied by an increase in brain levels of putrescine (Paschen,
Mol. Chem. Neuropathol.
16:241-271, 1992; Paschen,
Cerebrovasc. Brain Metab. Rev.
4:59-88, 1992; Morgan, Bachrach and Heimer, eds. CRC Publications, 203-229, 1989; and Paschen et al.,
Acta Neuropathol.
76:388-394, 1988). Further, intracerebral putrescine levels correlated significantly with the volume of brain cell death. Putrescine does not interact with the NMDA receptor, and does not potentiate its cytotoxic activity. A possible explanation for these results may reside in the catabolism of polyamines via the “interconversion pathway” which is dependent upon the activity of tissue polyamine oxidase (Seiler and Bolkenius,
Neurochem. Res.
10:529-544, 1985; Seiler et al.,
Med. Biol.
59:334-346, 1981; Bolkenius and Seiler,
Int. J. Dev. Neurosci.
4:217-224, 1986; and Bolkenius et al.,
Biochim. Biophys. Acta
838:69-76, 1985). This ubiquitous enzyme, which is present in high levels in brain and other mammalian tissues, cleaves spermine and spermidine via oxidative deamination to generate the end products putrescine and 3-aminopropanal (Seiler and Bolkenius,
Neurochem. Res.
10:529-544, 1985; Seiler, In Yu et al., eds. Elsevier Science, 333-344, 1995; Morgan,
Essays in Biochemistry
23:82-115, 1987; and Houen et al.,
Acta Chem. Scand.
48:52-60, 1994). 3-Aminopropanal is known for its cytotoxicity to primary endothelial cells, fibroblasts, and a variety of transformed mammalian cell lines (Bouzyk and Rosiek,
Cancer Lett.
39:93-99, 1988; Brunton et al.,
Toxic. in Vitro
8:337-341, 1994; Gaugas and Dewey,
Br. J. Cancer
39:548-557, 1978; Morgan et al.,
J. Biochem.
236:97-101, 1986; and Ferrante et al.,
J. Immunol.
133:2157-2162, 1984). 3-Aminopropanal has also been implicated as a mediator of programmed cell death in murine embryonic limb buds, and may contribute to the development of necrosis in some tumors (Parchment and Pierce,
Cancer Res
49:6680-6686, 1989; and Kurihara et al.,
Neurosurg.
32:372-375, 1993). Inhibition of polyamine oxidase with aminoguanidine blocked generation of 3-aminopropanal in cell cultures following the addition of spermine, and prevented subsequent cytotoxicity (Ferrante et al.,
J. Immunol.
133:2157-2162, 1984; Morgan,
Essays in Biochemistry
23:82-115, 1987; and Parchment and Pierce,
Cancer Res.
49:6680-6686, 1989). On a molar basis, the LD
50
concentration of 3-aminopropanal to cells is similar to the cytotoxicity of glutamate. In contrast, putrescine is not cytotoxic to cells, even in the millimolar range, but its rate of production through polyamine oxidation correlates directly with the formation of a directly cytotoxic aldehyde, 3-aminopropanal.
In addition, in the data first being reported herein in glial cells, 3-aminopropanal mediates apoptosis by activation of an interleukin-1 beta converting enzyme (ICE)-dependent signaling pathway, whereas in neurons it causes necrotic cell death.
Cerebral ischemia (stroke) is a debilitating condition resulting from a sudden cessation of blood flow to an area of the brain, resulting in a loss of brain tissue. There are no available therapies to reverse the neurological deficits caused by neuronal death in the infarct zone. Stroke is a major public health problem in the United States wherein about 550,000 strokes occur each year. Cerebral ischemia afflicts individuals of all age groups, but the incidence doubles with each decade over 45 and reaches 1-2% per year in the population of individuals over 75 years of age. If a patient survives, major disability can result with loss of ability to communicate, ambulate, see, coordinate and/or reason. Standard therapy is often ineffective at preventing brain infarction and is meant to support cardiovascular and respiratory function, control intracranial pressure, and prevent recurrent stroke. There is also a class of protease enzymes that are designed to dissolve blood clots, only for those strokes caused by blood clots potentially useful in brain ischemia but (as opposed to bleeding) and these agents only function to restore some blood flow in limited situations.
During the evolution of cerebral infarction (stroke), a core of densely ischemic tissue becomes rapidly and irreversibly damaged. Cellular damage in the surrounding area, termed the “ischemic penumbra,” progresses more slowly.
Following an ischemic insult, the process of tissue destruction may not be completed for hours or even days (Kirino et al.,
Acta Neuropathol.
64:139-147, 1984; and Petito et al.
Neurology
37:1281-1286, 1987). There is a temporary window of opportunity for an intervention to prevent ischemic tissue from progressing to infarction. In humans, this window is thought to extend from about 2-4 hours following the onset of ischemia, after which time the efficacy decreases rapidly (Ginsberg and Pulsinelli,
Ann. Neurol.
36:553-554, 1994). During the therapeutic window, the target for therapeutic neuroprotection is the ischemic penumbra, a volume of brain tissue around the ischaemic core, which receives reduced blood flow and contains compromised, but potentially viable tissue. Studies have identified important cytotoxic mediators that cause cell death in the early hours after the onset of ischemia.
A number of molecular substrates of normal brain, as well as extrinsic factors delivered by the circulation, contribute to the development of cell cytotoxicity during ischemia. These include, but are not limited to, glutamate, aspartate, nitric oxide, calcium, free radicals, zinc, cytokines, arachidonic acid meta
Al-Abed Yousef
Bucala Richard J.
Ivanova Svetlana
Tracey Kevin J.
Amster Rothstein & Ebenstein
Gerstl Robert
North Shore-Long Island Jewish Research Institute
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