Anti-protozoan methods and materials

Details Anti-protozoan methods and materials Anti-protozoan methods and materials

2001-06-08

2002-08-27

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S937000, C514S944000, C424S045000, C424S405000, C424SDIG001

Reexamination Certificate

active

06440936

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates generally to methods of treating protozoan infections by administration of bactericidal/permeabliity-increasing (BPI) protein products.
Protozoa are unicellular eukaryotic organisms that can infect and multiply in mammalian hosts. They may utilize more than one type of host, including insect hosts, during their life cycle. Parasitic protozoa account for a significant portion of all infectious diseases worldwide. Although the majority of protozoan infections occur in developing countries, these infections are seen increasingly in industrialized countries among immigrants and immunosuppressed or immunodeficient individuals. Frequently seen parasitic diseases include malaria, caused by the Plasmodia species, toxoplasmosis, caused by
Toxoplasma gondii
, leishmaniasis, caused by Leishmania species, and Chagas' disease (American trypanosomiasis), caused by
Trypanosoma cruzi
. AIDS patients are particularly susceptible to opportunistic protozoan infections such as
Pneumocystis carinii
and
T. gondii
. Treatment of protozoan infections is problematic due to lack of effective chemotherapeutic agents, in some instances, or in other instances because of excessive toxicity of the agents and increasingly widespread resistance to the agents.
Malaria is a major health problem in the tropics, and is caused by four Plasmodium species:
P. falciparum, P. vivax, P. ovale
and
P. malariae
. The developmental cycle of malaria parasites occurs in female mosquitos, which are the vector for spreading disease, and in humans. Female mosquitos inoculate sporozoites into humans during a blood meal. These sporozoites rapidly enter liver cells, where they develop immediately or after some delay into thousands of individual merozoites. In the relapsing malarias, such as
P. vivax
and
P. ovale
, the sporozoites can remain dormant for months to years before entering this proliferative stage. The merozoites rupture from the liver cells and enter the blood stream to invade erythrocytes. These merozoites can either proliferate asexually, or they can differentiate into sexual parasites which then are ingested by the mosquito, where they develop into the infectious sporozoites. After asexual proliferation within the erythrocytes, the merozoites develop through trophozoite forms into the dividing form, the schizont. Each mature schizont contains multiple merozoites which, upon rupture of the infected erythrocyte, are released to invade other erythrocytes and thus continue the cycle.
Clinically, the malaria parasite causes characteristic intermittent fevers and chills, anemia, kidney disease, and brain disease. High levels of parasites in the bloodstream, seen especially in the
P. falciparum
infection, causes serious complications including severe hemolytic anemia, renal failure, and coma. Thus, diagnosis and early treatment of
P. falciparum
is crucial. The drug regimen used for treatment of
P. falciparum
depends on the geographic origin of the infection and the known patterns of drug resistance. Chloroquine resistance is widespread, partial resistance to quinine is seen in many areas, and resistance to the combination of pyrimethamine and sulfadoxine is reported in some areas. Mefloquine is a new anti-malarial that may be effective against chloroquine-resistant
P. falciparum
. Since treatment failure may occur with any drug regimen, the course of the parasitemia must be followed closely. The non-
falciparum
parasites are usually treated with chloroquine or amodiaquine, followed by treatment with primaquine if infection is caused by
P. vivax
or
P. ovale.
Toxoplasmosis is a common disease among birds and small mammals, especially cats, that is caused by the protozoan
Toxoplasma gondii
. About 20 to 70% of adults in this country have positive serologic tests for Toxoplasma infection, depending on the specific population studied. Human infection usually occurs after exposure to infected cat feces or after consuming undercooked meat. Three forms exist in the life cycle of
T. gondii
: the cyst, the trophozoite and the oocyst. The trophozoite is an intracellular form that proliferates during acute infection. Cysts are forms containing several thousand trophozoites that develop within the host cells. They can be seen in any tissue, but are most commonly found in brain and muscle. Oocysts are forms that exist uniquely in the intestines of cats and are shed by cats. After ingestion, the Toxoplasma are liberated from the cysts or oocysts in the gastrointestinal tract. The trophozoites then disseminate through the blood stream or lymphatic system to infect any nucleated host cell.
The vast majority of people who are infected with Toxopkasma have no apparent clinical symptoms, but a small number develop symptoms including enlarged lymph nodes, fever and fatigue. Congenital infection with Toxoplasma has been estimated to cause 20 to 35% of the cases of retinochoroiditis in children and adults. In the immunodeficient patient, toxoplasmosis can appear as a severe disseminated disease that is rapidly fatal. A combination of pyrimethamine and sulfadiazine has been shown to be effective in inhibiting the replication of trophozoites. However, there are no drugs that will kill trophozoites or eradicate the cyst form. Pregnant women cannot be given pyrimethamine because of its potential to cause birth defects. For patients who cannot tolerate sulfadiazine and pyrimethamine, there are no clearly effective alternatives, although some studies suggest that trimethoprim alone or in combination with sulfa drugs may have some anti-toxoplasma activity.
Leishmaniasis is a protozoan infection caused by the genus Leishmania. This parasite exists in two forms: a mobile flagellated form called a promastigote, and a smaller non-mobile, non-flagellated intracellular form, the amastigote. The promastigotes are found in the gut of the sandfly, which is the vector for spreading disease, while amastigotes infect humans and other vertebrate hosts. In the infected animal, Leishmania are found only in macrophages, where they multiply, rupture the host cell, and infect new cells. When Leishmania are ingested by macrophages, they are enclosed within a phagocytic vacuole, where they proliferate. After the macrophages rupture, the amastigotes are taken up by adjacent cells or are transported to distant sites through the bloodstream or lymphatic system.
Visceral leishmaniasis, or kala-azar disease, is caused by the species
L. donovani
. Primarily affected organs are the liver, spleen, bone marrow and other elements of the reticuloendothelial system, which are enlarged due to the infected macrophages. Other symptoms include fever, weight loss, anemia, and skin lesions. After a few months to a year, the patient becomes emaciated and exhausted. Death is generally due to other concurrent infections. There is also a cutaneous form of leishmaniasis that manifests as ulcerating skin lesions. The drug of choice for treatment of leishmaniasis is pentavalent antimony. Second-line drugs for unresponsive or relapsed patients are pentamidine or amphotericin B. Although orally administered drugs such as rifampin, metronidazole and ketoconazole have been considered for treatment of cutaneous leishmaniasis on the basis of small uncontrolled trials, these drugs are inferior to antimony. Allopurinol analogs are being investigated, but their ultimate usefulness remains to be established.
L. donovani
has been found to possess heparin receptors on its cell surface. [Mukhopadhyay et al.,
Biochem. Journal,
264:517-525 (1989).] These heparin receptors have been localized to the flagellum. [Butcher et al.,
Experimental Parasitology,
71:49-59 (1990).] It has been shown that promastigotes and amastigotes of
L. donovani
bind heparin. Promastigotes in their infective stages bind substantially more heparin than their noninfective counterparts. [Butcher et al.,
J. Immunol.,
148:2879-2886 (1992).] It has also been found that promastigotes in culture produce a cell-associa

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