Polydithicarbamate-containing non-targeting marcomolecules...

Details Polydithicarbamate-containing non-targeting marcomolecules... Polydithicarbamate-containing non-targeting marcomolecules...

1999-10-01

2003-11-18

Saunders, David (Department: 1644)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S009300, C424S009340, C424S009350, C514S002600, C514S04400A, C514S054000, C514S476000, C514S483000, C530S403000, C530S404000, C530S405000, C536S022100, C536S123000, C536S123100

Reexamination Certificate

active

06649591

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel non-targeting dithiocarbamate-containing compositions. In one aspect, the present invention relates to non-targeting dithiocarbamate-containing compositions wherein the dithiocarbamate is non-covalently associated with a macromolecule other than an antibody. Preferably, the macromolecule is non-immunogenic. In another aspect, the present invention relates to non-targeting dithiocarbamate-containing compositions wherein the dithiocarbamate is covalently crosslinked with a macromolecule other than an antibody that is preferably non-immunogenic. In yet another aspect, the present invention relates to diagnostic and therapeutic methods employing the novel non-targeting dithiocarbamate-containing compositions described herein.
BACKGROUND OF THE INVENTION
In 1984, Jolly et al., demonstrated the protection of reperfused myocardial tissue with the combinational use of superoxide dismutase and catalase (see, for example, Jolly et al., Cir. Res., 57:277, 1984). This observation implied that oxygen-derived free radicals are a cause of the reperfusion injury to the hypoxic myocardium. It is now known, however, that the phenomenon of ischemia/reperfusion injury is not restricted to the myocardium. Instead, ischemia/reperfusion injury is viewed as a general damaging event in any tissue or organ (such as brain, liver or kidney) subjected to a critical period of ischemia followed by perfusion with oxygenated whole blood.
Ischemia/reperfusion injury therefore results from the reintroduction of molecular oxygen at the time of organ reperfusion or restoration of the circulation. While the delivery of dissolved molecular oxygen sustains cellular viability, it also provides oxygen as a substrate for numerous enzymatic oxidation reactions that produce reactive oxygen species which cause oxidative damage, a phenomenon referred to as the “oxygen paradox” (see, for example, Hearse et al., in J. Mol. Cell. Cardiol., 10:641, 1978). Oxygen, a gaseous molecule essential for normal cellular metabolism, can, under certain conditions, be deleterious to life. The cell defends itself against oxidative insults through its antioxidant mechanisms including superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase and cellular antioxidants including glutathione, ascorbate and a-tocopherol (see, for example, Chan, in Stroke, 27:1124-29, 1996). However, when reactive oxygen species are generated at a rate that exceeds the capacity of the cell to defend itself against the resulting oxidative stress (such as in ischemia/reperfusion insults), the cell is irreversibly damaged, resulting in necrotic cell death or ischemic cell death.
Although the exact mechanism by which oxygen induces ischemic cell death is not yet clear, it is well known that reactive oxygen species cause a wide range of tissue damage. The hydroxyl radical (.OH), the most potent oxidant, is capable of initiating lipid peroxidation, causing protein oxidation and DNA damage in cells (see, for example, Lai and Piette, in Biochem. Biophys. Res. Commun., 78:51-59, 1977 and Dizdaroglu and Bergtold, in Anal. Biochem., 156:182, 1986). Albeit less reactive, superoxide anion radicals (.O
2
), on the other hand, participate in a repertoire of oxidative reactions which generate hydrogen peroxide and hydroxyl radical as follows:
.O
2
−
+.O
2
−
→H
2
O
2
  (1)
.O
2
−
+H
2
O
2
→.OH+OH
−
+O
2
  (1)
Reaction (1) is catalyzed by SOD, while reaction (2) proceeds rapidly in the presence of trace iron metal (see, for example, Haber and Weiss, in Proc. R. Soc. Ser. A., 147:332, 1934). Superoxide anion radical is known to liberate iron from ferritin (see, for example, Wityk and Stem, in Crit. Care Med., 22:1278-93, 1994) which further facilitates the iron-catalyzed Fenton reaction in the reoxygenated tissue, generating damaging hydroxyl radicals, as shown in reactions (3) and (4), see, for example, Halliwell and Gutteridge, in Halliwell and Gutteridge. Free Radicals in Biology and Medicine, 2nd edition. Oxford: Clarendon Press, 15-19 (1989):
Fe
3+
+O
2
−
→Fe
2+
+O
2
  (3)
Fe
2+
+H
2
O
2
→.OH+OH
−
+Fe
3+
  (4)
In addition to reactive oxygen species, reactive nitrogen species such as nitric oxide (.NO) have also been observed to be excessively produced in ischemia/reperfusion organs (see, for example, Faraci and Brian, in Stroke, 25: 692-703, 1994). .NO is synthesized from the terminal guanidino nitrogen atom of L-arginine by nitric oxide synthase (NOS). Three different isoforms of NOS have been isolated, cloned, sequenced and expressed (see, for example, Nathan, in FASEB J., 6:3051-3064, 1992), i.e., eNOS, NNOS and iNOS. The eNOS (endothelial cell derived) and nNOS (neuronal cell derived) are expressed constitutively, and both enzymes require an increase in intracellular calcium for activation.
Under physiological conditions, a low output of .NO is released continuously from eNOS in endothelial cells and from nNOS in neuronal cells. This .NO serves to dilate blood vessels and, in concert with vasoconstrictor catecholamines, regulate blood flow and blood pressure. On the other hand, a high output of .NO is produced by the inducible, calcium-independent NOS (INOS) isoform upon activation with cytokines or endotoxin (see, for example, Moncada and Higgs, in New Engl. J. Med., 329:2002-2012, 1993). iNOS is expressed in numerous cell types, including endothelial cells, smooth muscle cells, microglial cells and macrophages. Abnormally elevated levels of nitric oxide have recently been associated with ischemia/reperfusion injury (see, for example, Kumura et al., in J. Cereb. Blood Flow and Metab., 14:487-491, 1994; Iadecola et al., J. Cereb. Blood Flow and Metab., 15:378-384, 1995).
In the central nervous system, nitric oxide has been discovered to function as both a neurotransmitter and a neurotoxin (see, for example, Faraci and Brian, in supra.). It mediates N-methyl-D-aspartate (NMDA) excitotoxicity. Elevated .NO levels in the brain have been measured during ischemia using an .NO electrode (for example, see Malinski et al., J Cereb.Blood Flow Metab., 13:355-358,1993), and by electron paramagnetic resonance spin trapping (for example, Sato et al., Biochim. Biophys. Acta, 1181:195-197, 1993). .NO levels began to increase within minutes after the onset of ischemia, presumably reflecting an increased activity of constitutive .NO synthase. However, as ischemia continues, .NO levels fall slowly but then increase again during reperfusion (see, for example, the recent review by Dawson and Dawson in Cerebrovascular Disease, H. Hunt Batjer, ed., Lippincott-Raven Publishers, Philadelphia, pp. 319-325 (1997)). The expression of iNOS gene was demonstrated in the rat brain to begin at 12 hours and peaked at 48 hours following the cerebral ischemia (Iadecola et al., supra).
.NO may have both beneficial and detrimental effects during cerebral ischemia. Increased .NO production during ischemia may be protective because .NO increases cerebral blood flow and inhibition of aggregation and adherence of platelets or leukocytes (see, for example, Samdani et al., in Stroke 28:1283-1288 (1997)). On the other hand, excessive .NO production during reperfusion is cytotoxic, either directly or after recombination with superoxide anion radical to form peroxynitrite according to reactions (5)-(7), as follows:
.O
2
−
+.NO→ONOO
−
  (5)
ONOO
−
+H
+
→ONOOH  (6)
ONOOH→[.OH]+.NO
2
  (7)
It has been demonstrated in cell-free systems that superoxide anion radical chemically reacts with nitric oxide to form the toxic anion, peroxynitrite, ONOO
−
(reaction (5), see, for example, Beckman et al., in Proc.Natl. Acad. Sci., USA 87:1620-1624, 1990). The rate constant for the reaction of nitric oxide with superoxide anion is 6.7×10
9
M
−1
S
−1
(see, for exam

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