Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-05-02
2003-01-21
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S114000, C514S561000, C424S423000, C424S422000
Reexamination Certificate
active
06509325
ABSTRACT:
BACKGROUND OF THE INVENTION
Systemic fungal diseases in humans, arising through fungal infections, may be chronic and even life-threatening. Many of the causative fungi which produce systemic mycoses in humans are opportunists: they are not usually pathogenic unless they enter a compromised host. Opportunistic fungal infections frequently occur in patients with acquired immune deficiency syndrome (AIDS), azotemia, bronchiectasis, bums, diabetes mellitus, emphysema, leukemia, lymphoma, or tuberculosis. Systemic mycoses affecting severely immunocompromised patients often result in rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination. Moreover, in immunocompetent patients, systemic mycoses typically have a chronic course. Amphotericin B remains the standard therapy for most life-threatening systemic mycoses, even though it is highly toxic and can result in impairment of renal functional [35].
Cryptococcosis, a typical opportunistic infection caused by the human pathogenic fungus
Cryptococcus neoformans
, frequently leads to chronic, life-threatening meningitis, but may also disseminate to the bones, skin, viscera, and other sites [35
]. Cryptococcus neoformans
is primarily a pathogen for immunocompromised individuals. In patients with impaired immune systems, cryptococcal meningitis is often incurable because existing antifungal agents are unable to eradicate the infection.
Cryptococcus neoformans
is a defining opportunistic pathogen in patients with AIDS, although patients with Hodgkin's or other lymphomas or sarcoidosis, or those receiving long-term corticosteroid therapy, are also at increased risk [35]. In the United States and Europe,
C. neoformans
causes meningoencephalitis, a life-threatening meningitis, in 5-10% of patients with AIDS [1, 2]. The incidence of cryptococcosis is significantly higher in sub-Saharan Africa [2] and Southeast Asia [3].
Although most cryptococcal infections have a self-limited, subacute, or chronic course, AIDS-associated cryptococcal infection may present with severe, progressive meningoencephalitis [35]. Patients with advanced human immunodeficiency virus (HIV) infection frequently relapse, despite successful initial treatment of cryptococcosis with antifungal agents [4, 5]. As a consequence, cryptococcosis in the setting of AIDS is currently considered incurable [6]. For meningitis in non-AIDS patients, the standard regimen is 6 weeks of 0.3 mg/kg/day of amphotericin B intravenously, combined with 100 to 150 mg/day of flucytosine. Renal and hematologic function must be evaluated before and regularly during therapy. AIDS patients more often have suboptimal therapeutic responses. Amphotericin B and flucytosine are recommended as initial treatment in AIDS patients, at least for two weeks. Oral fluconazole (200 to 400 mg/day) can be used thereafter. Most cases relapse if treatment is stopped, so chronic suppressive therapy is needed [35].
One of the important virulence factors in
C. neoformans
is its ability to synthesize melanin during infection [7, 8, 24, 25]. Melanins are amorphous, insoluble pigments that are stable free radicals; they also manifest distinct electron-spin resonance spectral features [9, 10]. Melanins are found in diverse species in all biological kingdoms, and have been associated with camouflage, drug binding, sexual display, and the absorption and dissipation of various forms of energy [11]. Melanin synthesis is a widespread phenomenon among microorganisms, including several important human and plant pathogens. Several pathogenic fungi, such as
Aspergillus fumigatus
and
Histoplasma capsulatum
, synthesize melanin. Among the plant pathogenic fungi, melanin synthesis appears to be necessary for cellular invasion [44]. Several bacteria, including
Mycobacterium leprae
, also make melanin pigments.
In
C. neoformans
, melanin appears to function in virulence by protecting the fungus against the host's immune system [14, 15]. Specifically, melanin has been shown to protect the fungus against oxidants [12, 13], defensins and protegrins [15], and macrophages in vitro [16], as well as extremes in temperature [17]. Additionally, melanogenesis has been shown to reduce the susceptibility of
C. neoformans
to amphotericin B, the primary antifungal drug [13, 14]. Melanized cryptococcal cells interfere with the development of a protective T-cell response in mice [18]. In addition, melanin-deficient mutants are avirulent in murine infections [19]. Currently, there are no compounds that are known to inhibit melanogenesis in
C. neoformans.
The prognosis for AIDS patients with cryptococcal disease continues to be extremely poor [40]. One development in the treatment of cryptococcosis is a monoclonal antibody against the major polysaccharide in the capsule of
C. neoformans
. This antibody is currently being evaluated for phase I clinical trials in the treatment of AIDS patients infected with
C. neoformans
[41]. Nevertheless, with growing numbers of immunocompromised individuals worldwide, further advances in the management of this disease are desperately needed.
Glyphosate (N-phosphonomethylglycine) is a synthetic crystalline amino acid with an empirical formula of C
3
H
8
NO
5
P. The compound, which is relatively nontoxic to humans, is used worldwide as a broad-spectrum systemic herbicide [28, 29], and is marketed as “Roundup” (Monsanto Company) in. the United States. Glyphosate inhibits synthesis of aromatic amino acids via the shikimate pathway. In particular, glyphosate is known to inhibit polymer formation in plants by blocking the metabolism of phenolic compounds [24, 25].
In addition to a herbicidal effect on plants, glyphosate inhibits many microorganisms. Recently, glyphosate was shown to inhibit the in vitro growth of several parasitic species of the phylum Apicomplexan [31]. Glyphosate has also been shown to inhibit growth of diverse fungal species, particularly those which are pathogenic to plants [33, 46, 47]. However, prior to the present invention, it was not known that glyphosate could inhibit melanogenesis in, and proliferation of, mammalian pathogenic fungi which use melanin in virulence.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that glyphosate inhibits both melanogenesis in
Cryptococcus neoformans
and growth and proliferation of
Cryptococcus neoformans
. This discovery will have implications in the treatment of infections, such as cryptococcosis, where the infectious microorganism is one which uses melanin in virulence. In particular, this finding will have important implications in the treatment of AIDS patients who are infected with
Cryptococcus neoformans.
Accordingly, the present invention provides a method for treating a subject infected with a mammalian pathogenic fungus which uses melanin in virulence, by administering to the subject an amount of glyphosate effective to treat the infection. The present invention further provides a method for inhibiting proliferation of a mammalian pathogenic fungus which uses melanin in virulence, by contacting the fungus with an amount of glyphosate effective to inhibit the proliferation of the fungus. Finally, the present invention further provides a method for inhibiting melanogenesis in a microorganism which produces melanin, by contacting the microorganism with an amount of glyphosate effective to inhibit melanogenesis in the microorganism.
Additional objects of the present invention will be apparent in view of the description which follows.
REFERENCES:
patent: 5656515 (1997-08-01), Camden
Butler and Day, Fungal melanins: a review. Can. J. Microbiol., 44(12):1115-36, Dec. 1998.
Doering et al., Melanin as a potential crypotococcal defence against microbicidal proteins. Med. Mycol., 37(3):175-81, Jun. 19
Casadevall Arturo
Nosanchuk Joshua D.
Ovalle Rafael
Albert Einstein College of Medicine of Yeshiva University
Amster Rothstein & Ebenstein
Nguyen Helen
Webman Edward J.
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