Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-10-04
2003-01-21
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S141100, C424S450000
Reexamination Certificate
active
06509319
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the treatment of fungal infections in mammals. More particularly, the present invention provides methods of treating fungal infections in mammals using pharmaceutical preparations including chelator(s), antifungal agents, and/or monoclonal antibodies. The invention further provides pharmaceutical compositions useful for treating fungal infections.
2. Description of Related Art
Fungi, particularly species of Candida, Aspergillus, and Fusarium are a major cause of infection-related mortality in patients with leukemia and lymphoma. In addition, fungal infection is a major cause of mortality in patients with congenital and acquired deficiencies of the immune system.
For example, several species of Aspergillus are known to cause invasive sinopulmonary infections in seriously immunocompromised patients. Following inhalation of spores, clinical aspergillosis can occur in three major presentations. The first presentation, allergic bronchopulmonary aspergillosis, develops when Aspergillus species colonize the bronchial tree and release antigens that cause a hypersensitivity pneumonitis. The second presentation, aspergilloma or “fungus ball,” develops in pulmonary cavities, often in concert with other lung diseases such as tuberculosis. The third form, invasive pulmonary or disseminated aspergillosis, is a life threatening infection with a high mortality rate.
The drug of choice in treatment of invasive aspergillosis, as well as in most other systemic mycoses, is Amphotericin B. Amphotericin B is a polyene antibiotic produced from a strain of
Streptomyces nodosus.
It is a lipophilic compound which binds to ergosterols in fungal membranes, resulting in the formation of transmembrane channels which allow the escape of metabolites essential to maintaining the viability of the fungal cell. Mammalian cell membranes also contain sterols, and it is believed that this same mechanism of action is responsible for the damaging effects which Amphotericin B is known to exert on mammalian kidney, hematopoietic and central nervous system tissues.
Amphotericin B is not soluble in aqueous solution, and for this reason it is supplied commercially in the form of a colloidal suspension comprising Amphotericin B, desoxycholate, and buffers suspended in a glucose solution. This suspension is usually administered to the patient intravenously over a period of from two to six hours; faster infusions can result in cardiorespiratory arrest. Other possible untoward effects of administering Amphotericin B include fever, nausea and vomiting, diarrhea, renal dysfunction, anemia, hypotension, headache, vertigo, and loss of hearing. Amphotericin B is also available in the form of a phospholipid complex (ABELCET®, e.g.), which offers the advantage of somewhat reduced toxicity for those patients who do not tolerate free Amphotericin B well, although many of the same untoward side effects may be observed in patients receiving this lipid complex form of the drug.
As a consequence of the potential seriousness of its toxic side effects, there is a clear need for an alternative to treating systemic mycoses solely with Amphotericin B and/or other harsh antifungal agents.
SUMMARY OF THE INVENTION
The present invention provides an effective method of treating a systemic fungal infection comprising the steps of obtaining a therapeutically effective amount of a pharmaceutical composition comprising at least one chelator, at least one antifungal agent and a pharmaceutical excipient, diluent or adjuvant, and administering said pharmaceutical composition to a patient having a fungal infection.
For the purposes of this disclosure, the phrase “therapeutically effective amount” is defined as a dosage sufficient to induce a fungicidal or fungistatic effect upon fungi contacted by the composition. That amount of the pharmaceutical composition which is therapeutically effective will depend upon the ingredients comprising the composition, as well as the treatment goals.
For the purposes of this disclosure, the phrase “a chelator” denotes one or more chelators. As used herein, the term “chelator” is defined as a molecule comprising nonmetal atoms, two or more of which atoms are capable of linking or binding with a metal ion to form a heterocyclic ring including the metal ion.
For the purposes of this disclosure, the phrase “an antifungal agent” denotes one or more antifingal agents. As used herein, the term “antifungal agent” is defined as a compound having either a fungicidal or fungistatic effect upon fungi contacted by the compound.
As used herein, the term “fungicidal” is defined to mean having a destructive killing action upon fungi. As used herein, the term “fungistatic” is defined to mean having an inhibiting action upon the growth of fungi.
As used herein the terms “contact”, “contacted”, and “contacting”, are used to describe the process by which a pharmacological agent, e.g., any of the compositions disclosed in the present invention, comes in direct juxtaposition with the target cell.
Preferable chelators for use in the present invention include, but are not limited to, ethylenediamine-N,N,N′,N′-tetraacetic acid (EDTA); the disodiurn, trisodium, tetrasodium, dipotassium, tripotassiun, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; 1,3-diamino-2-hydroxypropane-N,N,N′,N′-tetraacetic acid; 1,3-diaminopropane-N,N,N′,N′-tetraacetic acid; ethylenediamine-N,N′-diacetic acid; ethylenediamine-N,N′-dipropionic acid dihydrochloride; ethylenediamine-N,N′-bis(methylenephosphonic acid)hemihydrate; N-(2-hydroxyethyl)ethylenediamine-N,N′,N′-triacetic acid; ethylenediamine-N,N,N′,N′-tetrakis(methylenephosponic acid); O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid; N,N-bis(2-hydroxybenzyl)ethylene diamine-N,N-diacetic acid; 1,6-hexamethylenediamine-N,N,N′,N′-tetraacetic acid; N-(2-hydroxyethyl)iminodiacetic acid; iminodiacetic acid; 1,2-diaminopropane-N,N,N′,N′-tetraacetic acid; nitrilotriacetic acid; nitrilotripropionic acid; the trisodium salt of nitrilotris(methylenephosphoric acid); 7,19,30-trioxa-1,4,10,13,16,22,27,33-octaazabicyclo[11,11,11]pentatriacontane hexahydrobromide; and triethylenetetraminie-N,N,N′,N″,N′″,N′″-hexaacetic acid. It is contemplated that any chelator which binds barium, calcium, cerium, cobalt, copper, iron, magnesium, manganese, nickel, strontiurn, or zinc will be acceptable for use in the present invention.
More preferably, the chelators for use in conjunction with the present invention may include ethylenediarnine-N,N,N′,N′-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; 1,3-diamino-2-hydroxypropane-N,N,N′,N′-tetraacetic acid; 1,3-diaminopropane-N,N,N′,N′-tetraacetic acid; O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid; and 7,19,30-trioxa-1,4,10,13,16,22,27,33-octatazbicyclo[11,11,11]pentatriacontane hexahydrobromide.
Most preferably, the chelators for use in the present invention may include ethylenediamine-N,N,N′,N′-tetraacetic acid (EDTA); the disodium salt of EDTA; 1,3-diaminopropane-N,N,N′,N′-tetraacetic acid; and O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid.
Many antifungal agents are known to those of skill in the art and may be useful in the present invention. For example, antifungal agents contemplated for use in the present invention include, but are not limited to, new third generation triazoles such as UK 109,496 (Voriconazole); SCH 56592; ER30346;
Hachem Ray
Raad Issam
Sherertz Robert
Board of Regents , The University of Texas System
Fulbright & Jaworski
Peselev Elli
LandOfFree
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