Therapeutic methods employing disulfide derivatives of...

Details Therapeutic methods employing disulfide derivatives of... Therapeutic methods employing disulfide derivatives of...

2000-05-05

2001-11-13

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S707000, C514S825000, C514S838000, C514S851000, C514S861000, C514S866000, C514S885000, C514S903000, C514S912000, C514S925000

Reexamination Certificate

active

06316502

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to therapeutic methods employing dithiocarbamates to reduce the level of species associated with disease states in mammals. In one aspect, the invention relates to compositions containing disulfide derivatives of dithiocarbamates and to therapeutic methods employing such compositions.
BACKGROUND OF THE INVENTION
In 1987, nitric oxide (·NO), a gaseous free-radical, was discovered in humans (see, for example, Ignarro et al., in
Proc. Natl. Acad Sci., USA
84:9265-69 (1987) and Palmer et al., in
Nature
327:524-26 (1987)). As an indication of the significance of this discovery for the understanding of human physiology and pathophysiology, Science magazine selected nitric oxide as the molecule of the year in 1992.
Nitric oxide is formed from the terminal guanidino nitrogen atom of L-arginine by nitric oxide synthase (NOS; see, for example, Rodeberg et al., in
Am. J Surg,
170:292-303 (1995), and Bredt and Snyder in
Ann. Rev. Biochem.
63:175-95 (1994)). Two major forms of nitric oxide synthase, constitutive and inducible enzymes, have been identified.
Under physiological conditions, a low output of ·NO is produced by the constitutive, calcium-dependent NOS isoform (cNOS) present in numerous cells, including endothelium and neurons. This low level of nitric oxide is involved in a variety of regulatory processes, e.g., blood vessel homeostasis, neuronal communication and immune system function. On the other hand, under pathophysiological conditions, a high output of ·NO is produced by the inducible, calcium-independent NOS isoform (iNOS) which is expressed in numerous cell types, including endothelial cells, smooth muscle cells and macrophages. These high levels of nitric oxide have been shown to be the etiology of endotoxin shock. This high output of ·NO further contributes to inflammation-related tissue damage, neuronal pathology, N-nitrosamine-induced carcinogenesis and mutations in human cells and bacteria via deamination reaction with DNA. Nitric oxide can therefore be seen to be a mixed blessing, being very desirable when present in small amounts, while potentially being highly detrimental when produced in excessive quantities.
Nitric oxide is a potent vasodilator (see, for example, Palmer in
Arch. Surg
128:396-401 (1993) and Radomski & Moncada in
Thromb. Haemos.
70:36-41 (1993). For example, in blood, ·NO produced by the endothelium diffuses isotropically in all directions into adjacent tissues. As ·NO diffuses into the vascular smooth muscle, it binds to guanylate cyclase enzyme, which catalyzes the production of cGMP, inducing vasodilation (see, for example, Ignarro, L. J.,
Ann. Rev. Toxicol.
30:535-560 (1990); Moncada, S.,
Acta Physiol. Scand.
145:201-227 (1992); and Lowenstein and Snyder,
Cell
70:705-707 (1992)). The overproduction of nitric oxide causes an extreme drop in blood pressure, resulting in insufficient tissue perfusion and organ failure, syndromes that are associated with many diseases and/or conditions (e.g., septic shock, overexpression of cytokines, allograft rejection, and the like). The overproduction of nitric oxide is triggered by a number of stimuli, such as, the overproduction of inflammatory cytokines (e.g., tumor necrosis factor (TNF), interleukin-1 (IL-1), interferons, endotoxin, and the like). Additionally, the overproduction of ·NO has been discovered to be one of the major side-effects of cytokine therapy (see, for example, Miles et al., in
Eur. J. Clin. Invest.
24:287-290 (1994) and Hibbs et al., in
J. Clin. Invest.
89:867-877 (1992)). Thus, abnormally elevated nitric oxide levels have been linked to many inflammatory and infectious diseases.
Inflammatory cytokines (e.g., TNF, interleukins or interferons) and infectious agents (e.g., endotoxin) induce nitric oxide overproduction by inducing transcription of the inducible nitric oxide synthase gene, leading to the production of inducible nitric oxide synthase, which in turn results in the overproduction of nitric oxide. The production of nitric oxide by the above-described pathway can be disrupted in a variety of ways. Thus, for example, there have been attempts to develop monoclonal antibodies (e.g., anti-endotoxin antibodies, anti-cytokine antibodies, anticytokine receptor antibodies, and the like) in efforts to block the ·NO production pathway at the transcriptional level. Unfortunately, however, such efforts have met with very limited success (see, for example, Glauser et al., in
Clin. Infect. Dis.
18:S205-16 (1994) and St. John & Dorinsky, in
Chest
103:932-943 (1993)). At least one reason for the relative lack of success in the art is the fact that the production of inflammatory cytokines is short-lived (see, for example, Wange & Steinsham in
Eur. J. Haematol.
50:243-249 (1993)), while overproduction of nitric oxide lasts several days, causing systemic hypotension, insufficient tissue perfusion and organ failure.
Thus, for example, during endotoxemia, TNF production peaks at about 1-2 hours. Therefore, in order to be effective, anti-TNF antibodies would have to be administered at an early stage after infection. Indeed, in many clinical settings, patients are likely to already have been infected with bacteria prior to being admitted. Accordingly, such therapeutic methods have met with only limited success.
Currently, many pharmaceutical companies have turned their attention to the design and development of substrate or product analogue inhibitors of the enzyme, NOS, in efforts to treat the overproduction of ·NO. However, recent data show that the inhibition of NOS is detrimental to subjects. For example, rodent studies show that inhibition of the production of nitric oxide causes intrauterine growth retardation and hind-limb disruptions in rats (see, for example, Diket et al., in
Am. J. Obstet. Gynecol.
171:1243-1250 (1994)). Furthermore, the inhibition of nitric oxide synthesis during endotoxemia has also been shown to be detrimental (see, for example, C. O. Corso et al., J. Hepatol. 28:61-69, 1998; K. Kaneda et al. Acta Anaesthesiol. Scand. 42:399-405, 1988; R. I. Cohen, et al. Crit. Care Med. 26:738-747, 1998. Similar results have been reported in larger animal studies, such as dogs and swine (see, for example, Statman et al., in
J. Surg. Res.
57:93-98 (1994); Mitaka et al.,
Am. J. Physiol.
268:H2017-H2023 (1994); Robertson, et al.,
Arch. Surg.
129:149-156 (1994); and Henderson et al.,
Arch. Surg.
129:1271-1275 (1994)).
Dithiocarbamates such as pyrrolidine dithiocarbamate have been determined to be potent inhibitors of nuclear factor kappa B (NF&kgr;B) in intact cells (see, for example, R. Schreck et al., in
J. Exp Med
175:1181-1194 (1992). In addition, NF&kgr;B has also been shown to up-regulate the expression of cell adhesive molecules, including the vascular cell adhesive molecule-1 (VCAM-1; see, for, example, M. F. Iademarco et al.,
J. Biol Chem
267:16323-16329 (1992)). Interestingly, in view of these known inhibitory effects of dithiocarbamates on NF&kgr;B, and the known ability of NF&kgr;B to induce expression of VCAM-1, Medford et al. propose the allegedly new use of dithiocarbamates to treat cardiovascular diseases mediated by VCAM-1, through the inhibition of the NF&kgr;B pathway (see U.S. Pat. No. 5,380,747).
It is also beneficial to remove cyanide (CN), a fast acting toxic compound, from subjects exposed thereto. Cyanide is frequently used in suicides, homicide, and chemical warfare (see, for example, Salkowski et al., in Vet. Hum. Toxicol. 36:455-466 (1994) and Borowitz et al., in B. Somani (Ed.), Chemical Warfare Agents, Academic Press, New York, pp. 209-236 (1992)). Cyanide toxicity can arise from a variety of sources, e.g., from inhalation of smoke produced by the pyrolysis of plastics or nitrile-based polymer fibers, materials that are commonly used in construction and for furniture manufacture. Cyanide toxicity can also occur from ingestion of plant extracts containing cyanogenic glycosides (such as cassava), or from inhalation of airborne vapors encountered in industrial or occupa

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