Use of hydroxyguanidines

Details Use of hydroxyguanidines Use of hydroxyguanidines

1999-05-26

2003-07-29

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

Reexamination Certificate

active

06599943

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the use of hydroxyguanidines in the prevention and treatment of a variety of diseases as well as to the protection of organs intended for transplantation. The present invention also relates to pharmaceutical compositions containing hydroxyguanidines intended for such use. Furthermore the invention relates to the manufacture of medicaments containing hydroxyguanidines useful for such prevention and treatment.
BACKGROUND OF THE INVENTION
Xanthine dehydrogenase (EC 1.1.1.204) and xanthine oxidase (EC 1.1.3.22) are closely related molybdenum, iron-sulphur and flavin containing enzymes that catalyze the oxidation of purines such as hypoxanthine and xanthine leading to formation of, respectively, xanthine and uric acid (Pritsos & Gustafson 1994; Hille and Nishino, 1995). It is presumed that xanthine oxidase is formed from the dehydrogenase both in vivo and in vitro by reversible and irreversible postranslational processes. This conversion may occur reversibly by sulfhydryl oxidation, and irreversibly by proteolytic processes (Amaya et al., 1990; Nishino, 1994). The enzymes are composed of two identical subunits of about 1330 amino acids each, which amino acid sequences among mammals are highly conserved (Amaya et al., 1990; Wright et al., 1993; Ichida et al. 1993; Hille and Nishino, 1995). The oxidase and dehydrogenase forms of the enzyme exhibit different reactivities towards molecular oxygen and NAD
+
, the former oxidant is preferred by the oxidase and the latter by the dehydrogenase (Hille and Nishino, 1995). When oxygen is used as electron acceptor both superoxide radicals (i.e., superoxide anions) and hydrogen peroxide may be generated both of which are considered to be harmful and capable of causing tissue damage (Hille and Nishino, 1995). In particular the oxygen radical is considered to be harmful when present in a living organism, because of its reactivity and the fact that when a radical reacts with a non-radical matter of the organism a new potentially harmful radical is being produced (Kooij, 1994). The superoxide radical may react with H
+
under formation of the perhydroxyl radical HO
2
. which is capable to react substantially faster than superoxide with tissue components (Kooji, 1994). Moreover, the perhydroxyl radical may form hydrogen peroxide which also may disintegrate to the extremely reactive hydroxyl radical .OH (Xia et al., 1996).
Both xanthine oxidase and xanthine dehydrogenase are capable of using oxygen as the oxidizing substrate whereby oxyradicals are formed. However, in the case of the dehydrogenase form NAD
+
is the preferred substrate. In the presence of NAD
+
the utilization of oxygen thus will be limited (Saugstad, 1996). Pathophysiological role of xanthine dehydrogenase/oxidase. Increased conversion of xanthine dehydrogenase to its oxidase form is implicated in pathological conditions of which diseases associated with hypoxia have attracted most attention. Conversion of the enzyme is assumed to contribute to tissue damage by generation of superoxide radicals produced from oxygen during the period of re-oxygenation of tissues after re-perfusion of an area previously deprived of blood flow (McCord, 1984; Nishino, 1994). According to this hypothesis the enzyme is converted to its oxidase form in conjunction with an ischemic period. Due to the inability of ATP-regeneration in the absence of adequate oxidative phosphorylation the cellular ATP pools will also become deprived and converted to hypoxanthine during ischemia. Upon eventual tissue reoxygenation (e.g. due to recovery of blood-circulation) xanthine oxidase will however start to utilize oxygen and then oxidize hypoxanthine to xanthine, and xanthine to uric acid, thus concomitantly generating toxic oxyradicals which may cause cell damage (Nishino, 1994; Saugstad, 1996). Hypoxia induced conversion of xanthine dehydrogenase to xanthine oxygenase has been shown experimentally in hepatocytes, Kupfer cells and endothelial cells (Wiezorek et al. 1994). The xanthine dehydrogenase/xanthine oxidase enzyme can be detected in a variety of tissues such as liver, kidney, heart, central nervous system, skeletal muscle, spleen, adrenal gland, intestine, skin, kidney, lung and placenta (Wajner and Harkness, 1989; Kooij, 1994). In particular interest has been focused on the fact that the enzyme may be present in endothelial cells (Moriwaki et al., 1993) and that damage to these cells may be involved in the pathology of reperfusion injuries by capillary leakage and formation of oedema. This sort of phenomenon could be involved in, for instance, induction of increased intracranial pressure in stroke and in high altitude sickness, and be the reason of the high mortality in these conditions.
Other abnormal conditions which have been associated with xanthine oxygenase induced oxyradical formation are complications seen in preterm infants such as periventricular leucomalacia (PVL), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP) (Russell et al., 1995).
It has also been shown that increased conversion of xanthine dehydrogenase to xanthine oxidase can be induced in endothelial cells in vitro by activated neutrophils (Wakabayashi et. al. 1995) and experimental evidence indicates that xanthine dehydrogenase/xanthine oxidase may be an causative enzyme under influence of a variety of inducing factors such as TNF, interferon-gamma, IL-6, IL-1, and dexamethasone (Pfeffer et al., 1994). Moreover, the promoter region of the rat xanthine dehydrogenase/xanthine oxidase gene has been isolated; its sequence suggests several possible regulatory elements, including an NF-IL6 motif upstream of the transcriptional start site (Chow et al., 1994). Moreover, pre-treatment of mice and bacterial lipopolysaccharide or interferon-alpha increases xanthine oxidase activity (see Saugstad, 1996). The results quoted here thus indicate a role of xanthine dehydrogenase/xanthine oxygenase in inflammation.
In this context the term “causative” and/or “induced” and/or “upregulated” is intended to mean that the content and/or activity of the xanthine oxidase/xanthine dehydrogenase enzyme becomes increased and/or is increased in a tissue compared to that of the normal level. A normal level is in this context intended to mean the level found in the corresponding tissue of a healthy individual.
Besides having the patophysiological roles described above it has been suggested that xanthine oxidase may be involved in a variety of other conditions such as xanthinuria, molybdenum-cofactor deficiency, gout, hyperuricemia, inflammation, airway obstruction, duodenal ulceration, arthritis, Parkinson's disease, Alzheimer's disease, paraquat intoxication, thermal skin injury, hyperthermia, pancreatitis, adult respiratory distress syndrome, nephrosis, adriamycin nephrosis, malaria, distant organ injury, cutaneous porphyrin photosensitation, inflammatory and autoimmune rheumatic diseases, rheumatoid arthritis, athereosclerosis, scleroderma and tumour promotion (see Kooji, 1994; Salim, 1994, Closa et al., 1994; Sakai et al., 1995; Misawa and Nakano, 1993; Misawa and Arai, 1993; Singh and Aggarwal, 1995; and references therein). Hepatotoxicity after viral infections (as well as after interferon treatment) was shown to be due to formation of xanthine oxidase and to oxyradical formation (see Saugstad, 1996).
Finally it should be mentioned that substantial amounts of xanthine oxidase may be released from the liver and intestine into the circulation during, e.g., hypoxia and/or shock, and that this circulating enzymatic activity may cause tissue damage at distant sites and organs of the body (Saugstad, 1996).
Known methods to prevent damage from xanthine dehydro-genase/xanthine oxidase derived free radicals. Due to the potential involvement of xanthine dehydrogenase/xanthine oxidase in the above mentioned conditions methods have been devised that are thought to interfere with xanthine dehydrogenase/xanthine oxidase or which may act on products(s) formed due to the ac

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