Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-10
2001-04-24
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06221903
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods of treating fungal infections and methods of killing or inhibiting growth of fungi with an amiodarone compound.
BACKGROUND OF THE INVENTION
Overview
Pathogenic fungi occur world wide and are major agricultural and health pests. Fungal infections in humans range from superficial and cutaneous to deeply invasive and disseminated. Treatment of fungal infections has lagged behind bacterial chemotherapy. There are substantially fewer antifungal drugs than antibacterial drugs.
In the last two decades, nearly 12 million people have died of acquired immunodeficiency syndrome (AIDS) after being infected with HIV, the human-immunodeficiency virus. AIDS is defined by the occurence of at least one of more than two dozen opportunistic infections. Fungal opportunistic infections such as candidiasis, cryptococcosis, and histoplasmosis, occur frequently in patients with AIDS. Among the opportunistic infections, fungal infections caused by Pneumocystis, Candida, Cryptococcus, or Histoplasma were the first to occur in more than 50% of persons with AIDS; and at time of death, nearly 85% of decedents had a fungal infection (Jones, et al., 1999, MMWR 48: 1-22).
Cryptococcus neoformans
is an opportunistic yeast pathogen that infects individuals with a compromised immune system, such as those with AIDS or those undergoing cancer chemotherapy (Kwon-Chung and Bennett, 1992, in
Medical Mycology
, pp. 397-446; Mitchell and Perfect, 1995
, Clin. Microbiol. Rev
. 8: 515-548; Sugar, 1991
, Mycopathologia
114: 153-157). Its normal habitat is worldwide in pigeon droppings, and one variety is associated with eucalyptus trees (Ellis and Pfeiffer, 1992
, Eur. J. Epidemiol
. 8: 321-325; Levitz, 1991
, Reviews of Infect. Dis
. 13: 1163-1169; Pfeiffer and Ellis, 1991
, J. Infect. Dis
. 163: 929-930). The most common infection caused by this yeast is a lethal meningitis (Chuck and Sande, 1989
, N. Engl. J. Med
. 321: 794-799; Kovacs, et al., 1985
, Ann. Intern. Med
. 103: 533-538; Rozenbaum, et al., 1994
, Clin. Infect. Dis
. 18: 369-380; Stanseld, 1993
, Semin. Respir. Infect
. 8: 116-123; Zuger, et al., 1986
, Ann. Intern. Med
. 104: 234-240). Infection with
C. neoformans
begins with inhalation of infectious particles, and is first established in the lungs. Cryptococcosis is one of the defining diseases associated with AIDS, and nearly 10% of all AIDS patients have cryptococcosis.
Treatments for fungal infections include azole antifungal drugs, such as clotrimazole, ketaconazole, fluconazole, and itraconazole (for a review, see Graybill, 1996
, Clin. Infect. Dis
. 22: S166-S178). The azoles act by inhibiting an enzyme, lanosterol demethylase, that participates in the synthesis of ergosterol, an essential component of fungal membranes. Other commonly used drugs include flucytosine and amphotericin B. Amphotericin B is one of the most effective antifungal drugs but must be given intravenously and causes serious side effects. Resistance to antifungals has become more apparent in recent years and may worsen with the increase in prophylatic therapy.
There is intense interest in identifying new drugs with different modes of action against fungal infections. The current repertoire of antifungals has limitations such as insufficient efficacy, the need for intravenous administration, serious side effects, or the appearance of resistant fungal strains. Importantly, most of the current treatments are fungistatic, that is, they inhibit fungal growth but do not cause outright death. Subsequent clearing of these inhibited fungi is inadequate in patients with defective immune systems. Thus, it is imperative to identify fungicidal agents and, if possible, their cellular targets that, when impaired, lead to fungal cell death.
Fungi and Antifungal Agents
Fungi are eukaryotic cells that may reproduce sexually or asexually and may be biphasic, with one form in nature and a different form in the infected host. Fungal diseases are referred to as mycoses. Some mycoses are endemic, i.e. infection is acquired in the geographic area that is the natural habitat of that fungus. These endemic mycoses are usually self-limited and minimally symptomatic. Some mycoses are chiefly opportunistic, occurring in immunocompromised patients such as organ transplant patients, cancer patients undergoing chemotherapy, burn patients, AIDS patients, or patients with diabetic ketoacidosis.
Fungal infections are becoming a major health concern for a number of reasons, including the limited number of antifungal agents available, the increasing incidence of species resistant to older antifungal agents, and the growing population of immunocompromised patients at risk for opportunistic fungal infections. The incidence of systemic fungal infections increased 600% in teaching hospitals and 220% in non-teaching hospitals during the 1980's. The most common clinical isolate is
Candida albicans
(comprising about 19% of all isolates). In one study, nearly 40% of all deaths from hospital-acquired infections were due to fungi. (Sternberg, 1994
, Science
266: 1632-1634).
Neutropenic patients (due to, e.g., chemotherapy, immunosuppressive therapy, infection, including AIDS, or an otherwise dysfunctional immune system) are predisposed to the development of invasive fungal infections, most commonly including Candida species and Aspergillus species, and, on occasion, Fusarium, Trichosporon and Dreschlera. Cryptoccocus infection is also common in patients on immunosuppressive agents.
The majority of known antifungal agents fall into one of three main groups. The major group includes polyene derivatives, including amphotericin B and the structurally related compounds nystatin and pimaricin, which are only administered intravenously. These are broad-spectrum antifungals that bind to ergosterol, a component of fungal cell membranes, and thereby disrupt the membranes, leading to cell death. Amphotericin B is usually effective for systemic mycoses, but its administration is limited by toxic effects that include fever and kidney damage, and other accompanying side effects such as anemia, low blood pressure, headache, nausea, vomiting and phlebitis. The unrelated antifungal agent flucytosine (5-fluorocytosine), an orally absorbed drug, is frequently used as an adjunct to amphotericin B treatment for some forms of candidiasis and cryptococcal meningitis. Its adverse effects include bone marrow depression with leukopenia and thrombocytopenia.
The second major group of antifungal agents includes azole derivatives which impair synthesis of ergosterol and lead to accumulation of metabolites that disrupt the function of fungal membrane-bound enzyme systems (e.g., cytochrome P450) and inhibit fungal growth. Significant inhibition of mammalian P450 results in important drug interactions. This group of agents includes ketoconazole, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, terconazole, fluconazole and itraconazole. These agents may be administered to treat systemic mycoses. Ketoconazole, an orally administered imidazole, is used to treat nonmeningeal blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis in non-immunocompromised patients, and is also useful for oral and esophageal candidiasis. Adverse effects include rare drug-induced hepatitis; ketoconazole is also contraindicated in pregnancy. Itraconazole appears to have fewer side effects than ketoconazole and is used for most of the same indications. Fluconazole also has fewer side effects than ketoconazole and is used for oral and esophageal candidiasis and cryptococcal meningitis. Miconazole is a parenteral imidazole with efficacy in coccidioidomycosis and several other mycoses, but has side effects including hyperlipidemia and hyponatremia.
The third major group of antifungal agents includes allylamnines-thiocarbamates, which are generally used to treat skin infections. This group includes tolnaftate and naftifine.
Another antifungal agent is griseoflulvin, a fungistatic agent which is adminis
Burns Ian F.
Spivack Phyllis G.
University and College of Nevada, Reno
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