Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
1996-09-03
2001-03-20
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C424S043000, C424S600000, C424S450000, C424S085500, C514S006900, C514S037000, C514S253030, C514S255030, C514S354000, C514S492000, C514S669000, C514S924000
Reexamination Certificate
active
06203822
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of infections caused by intracellular pathogens, such as
M. tuberculosis
and others and to pathogens that cause chronic pulmonary infections. In particular, this invention relates to methods for inhibiting the growth of intracellular pathogens and pathogens causing chronic pulmonary infections using gallium-containing compounds, and to methods to test the capacity of these compounds to inhibit growth of these pathogens in mononuclear phagocytes.
BACKGROUND OF THE INVENTION
This invention was made with government support under agreement numbers AI33004 and AI34954 awarded by the National Institutes of Health. The government has certain rights to this invention.
Intracellular pathogens include, but are not limited to, Mycobacteria species including
M. tuberculosis, M. avium-intracellulare
(MAI), and other intracellular pathogens including
Legionella pneumophila, Histoplasma capsulatum,
Leishmania species including
L. chagasi, L. donovani
and
L. major,
and the like. These organisms are characterized by their ability to be phagocytosed and sequestered in macrophages in patients infected with these organisms. In general, intracellular sequestration makes these organisms more difficult to treat with standard anti-bacterial therapies.
Tuberculosis is caused principally by the pathogenic agent
Mycobacterium tuberculosis
(
M. tuberculosis
) and more rarely by
M. bovis
or
M. africanum. M. tuberculosis
is an exemplary intracellular pathogen in that it, like other intracellular pathogens is phagocytosed in vivo by mononuclear phagocytes and becomes sequestered and/or grows within the phagocytic cell. Tuberculosis continues to be a major cause of worldwide morbidity and mortality, especially in the elderly and in immunocompromised patients, such as HIV (human immunodeficiency virus)-infected persons. The World Health Organization estimates that 1.7 billion persons, or one third of the world's population, are infected with tuberculosis. New estimates indicate that there are approximately 10 million new cases of tuberculosis annually with three million deaths associated with tuberculosis worldwide.
The only current vaccine for
M. tuberculosis
is the BCG vaccine. This vaccine is a live attenuated strain of
Mycobacterium bovis.
The vaccine produces variable results and may rarely initiate active tuberculosis infection in compromised vaccinees. A significant problem associated with the vaccine is that it results in the conversion of the tuberculin skin test (PPD) from negative to positive. The tuberculin skin test is still the primary test of choice for diagnosing exposure to
M. tuberculosis.
Therefore, individuals receiving the BCG vaccine test positive using the tuberculin skin test making patient monitoring for
M. tuberculosis
exposure more difficult. Until such time that a uniformly effective vaccine exists, novel therapeutic approaches that significantly reduce the duration of therapy will have a major impact on compliance and ultimately on the transmission of this disease.
Current therapies to treat tuberculosis are becoming less satisfactory because of a growing incidence of drug-resistant strains of
M. tuberculosis.
Effective therapy for active tuberculosis requires multiple types of antibiotics taken for a minimum of six months. Each of these antibiotics causes sizable morbidity from drug toxicity. Further, poor compliance, in part due to the duration of treatment and side effects of the antibiotics, remains a critical issue in the treatment of tuberculosis. Improper treatment of
M. tuberculosis
infection has led directly to a growing incidence of multi-drug resistant tuberculosis leading to prolonged infectiousness and thereby enhanced transmission potential.
MAI is the most common mycobacterial pathogen in AIDs patients. Up to 50% of this population will develop infection due to MAI in their lifetime. MAI are inherently multi-drug resistant and treatment for these patients currently requires taking multiple types of antibiotics for life. Infections due to the other intracellular pathogens described above are also more commonly seen in the growing population of immunocompromised patients with significant morbidity and in some cases mortality. In these cases patients are also treated with multiple antimicrobial agents for a significant length of time.
The problems associated with Mycobacterium infection are also true for diseases associated with other intracellular pathogens. There is currently a need for new methods to treat intracellular pathogens such as
M. tuberculosis.
Patients with cystic fibrosis are at risk for a variety of pulmonary infections, including those due to mycobacterial pathogens and also including
Pseudomonas aeruginosa,
(
P. aeruginosa
) an extracellular pathogen that chronically inhabits the airways of the lungs in these patients requiring long term antibiotic therapy. Pseudomonas aeruginosa causes significant morbidity and mortality in cystic fibrosis patients (see Fick, R. B., Jr. Chest 96:158-164, 1989 and Hoiby, N.
Annu. Rev. Med.
44:1-10, 1993).
SUMMARY OF THE INVENTION
This invention relates to methods for treating intracellular pathogens infecting mononuclear phagocytes using gallium-containing compounds, including gallium nitrate. In a preferred embodiment of this invention, a method is disclosed for inhibiting growth of an intracellular pathogen comprising the step of delivering a therapeutically effective dose of a gallium-containing compound in a pharmaceutically acceptable buffer to a mammalian cell. In one embodiment the pathogen is inside a mammalian cell. In a preferred aspect of this embodiment, the method also includes the step of treating the cell with at least a second compound known to inhibit the growth of the intracellular pathogen. The second compound can be an antibiotic or another compound and where the second compound is an antibiotic, the antibiotic is preferably selected from the group consisting of streptomycin, isoniazid, rifampin, pyrazinamide and ethambutol.
In another preferred aspect of this embodiment, the pathogen is a member of the genus Mycobacterium and the pathogen can be a multi-drug resistant strain of the genus Mycobacterium. In yet another preferred aspect of this embodiment, the pathogen is selected from the group consisting of Legionella, Histoplasma and Leishmania.
The therapeutic ranges for the gallium-containing compounds include concentrations ranging from 16.25 &mgr;M to greater than 1000 &mgr;M. The literature indicates that safe doses of gallium nitrate for cancer patient therapy extends in one set of studies up to at least about 200 mg/m
2
/day. This invention employs therapeutically effective doses of at least 50 mg/m
2
/day and greater and limited only by toxicity studies in patient testing (see for example, Foster, et al.
Cancer Treatment Reports
70:1311-1319, 1986).
In another aspect of this invention the delivering step comprises delivering the therapeutically effective dose to a patient infected with the intracellular pathogen or delivering the therapeutic effective dose in vitro and preferably delivering the therapeutic effective dose to a cell in vitro. The therapeutically effective dose is preferably delivered intravenously, subcutaneously, by aerosol or orally. The therapeutically effective dose may be delivered using liposomes and in this application, the liposomes are preferably combined with the gallium-containing compound before the delivering step. The method can also additionally comprise the step of delivering interferon-&ggr; to the cell.
In another embodiment of this invention, the invention relates to a composition for inhibiting the growth of an intracellular bacterial pathogen where the composition comprises a gallium-containing compound and an antibiotic known to inhibit growth of the intracellular bacterial pathogen. In a preferred aspect of this embodiment, the gallium-containing compound is gallium nitrate and the antibiotic is preferably selected from the group consisting of strep
Britigan Bradley E.
Schlesinger Larry S.
Mueting Raasch & Gebhardt, P.A.
Pak John
University of Iowa Research Foundation
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