Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-10-13
2004-04-27
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Bacterium or component thereof or substance produced by said...
C424S093400, C424S184100, C435S252100
Reexamination Certificate
active
06726913
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods to treat viral infections, dermal tumors, and warts in humans using heat-killed bacterial compositions. Specifically, it relates to the subcutaneous or intralesional administration of heat-killed
Propionibacterium acnes
(
P. acnes
), to treat dermal tumors and warts, and to the oral administration of heat-killed
P. acnes
to treat virus induced infections of the respiratory tract in humans.
BACKGROUND OF THE INVENTION
The maintenance of a healthy and competent immune system is a prerequisite for resistance to and elimination of infectious and neoplastic diseases. Bacteria and their derivatives were among the first substances to be recognized as immunostimulators and are used as adjuvants in vaccines to boost the humoral immune response (e.g., complete Freund's adjuvant). Bacteria have also been used as non-specific enhancers of the immune system to increase resistance and rejection of cancers, parasites, and infectious organisms.
Gram positive, whole-cell bacteria such as
Propionibacterium acnes, Propionibacterium avidum, Propionibacterium lymphophilum, Propionibacterium granulosum, Cornynebacterium parvum
and
Arachnia propionica,
when inactivated have been shown to be potent non-specific immune stimulants in animals and humans. Specifically
Propionibacterium acnes
(
P. acnes
) has been shown to stimulate antineoplastic activity, adjuvant activity, antiviral activity, antibacterial activity, and stimulate hematopoiesis.
Preparations of
P. Acnes
have been shown to act as non-specific stimulators of immunogenic responsiveness in vivo.
P. Acnes
is known to act by stimulating macrophages and neutrophils, initiating endogenous production of lymphokines (including IL-2 and various interferons), and enhancing killer cell activity. The intranasal inoculation of mice with
P. acnes
have been shown to activate pulmonary macrophages (Jackson R A, et al.,
J Leukoc. Biol.,
40(5):575-87, 1986). At the cellular level,
P. acnes
acts upon monocytes and lymphocytes and improves the functional interaction between these cells (M. T. Scott,
Cell Immunol.,
17:141, 1975).
P. acnes
also functions as an immune adjuvant to weakly antigenic substances. These properties, while not completely understood, play an important role in regulation of the immune response. One mode of the interaction of inactivated
P. acnes
with the immune system is through its stimulation of the reticuloendothelial system (RES), i.e. liver, spleen, lymph nodes, lungs, and bone marrow (C. Adlam, and M. T. Scott,
J. Med Microbiol,
6:621 (1973), N. H. McBridge et al.,
Cell Immunol.,
7:290 (1973)).
This activity elicits enhanced resistance to bacterial and viral infections, and also to certain tumors. This mode of action appears to be the activation of macrophages followed by the recruitment of lymphocytes. The particulate nature of
P. acnes
appears important for macrophage activation. Unlike some synthetic biological response modifiers (BRM's), bacteria in vivo are fully degraded and catabolized in the body without the formation and excretion of toxic metabolites or retention of residues. This has obvious therapeutic advantages for
P. acnes,
and contributes to the therapeutic and prophylactic use of
P. acnes
against infectious diseases.
In animals, stimulation of the immune system results in short term protection against infection with certain viruses and bacteria. Used therapeutically in animals with chronic skin and respiratory disease,
P. acnes
shortens the course of the disease.
The anti-tumor activity of
P. acnes
has been studied in mice and other animals. Tumor cells injected into Balb/c mice together with heat-killed
P. acnes
cells were rendered nontumorigenic (Murano E A, et al,
Cancer Immunol Immunother,
29(1):7-16, 1989). The preventive effect of
P. acnes
on metastasis in mice rendered tolerant to tumor-associated transplantation antigens (TATA) has been detailed (Fujiwara H, et al.,
Gann,
71(5):692-8, 1980). Heat-killed suspension of several
P. acnes
strains were prepared and studied for their protective activity against viral infections in mice and for their immunomodulating properties (Zgorniak-Nowosielska I, et al,
Arch Immunol Ther Exp
(
Warsz
), 37(3-4):431-42, 1989).
There has been considerable data collected on the use of
P. Acnes
in domestic animals. In a randomized study conducted for the treatment of equine respiratory disease (ERDC), complete recovery within a 14 day period was observed in horses treated intravenously with
P. acnes
(D. R. Evans et al.,
Equine Practice,
10:17, 1988; C. D. Vail et al.,
Vet. Review,
November/December: 399, 1990). Additionally, inactivated
P. acnes
has also been shown to be a biological response modifier for treatment of non-specific respiratory diseases in horses where upon administration of
P. acnes
it was shown that CD4+ lymphocyte expression and lymphokine activated killer cell (LAK) activity increased (Flaminio M J, et al,
Vet Immunol Immunopathol,
63(4):303-15, 1998).
In a randomized, double blinded, placebo controlled study, dogs with a significant skin disease (chronic recurrent pyoderma) were treated with antibiotics plus
P. acnes
with significant improvement or complete remission of the lesions (A. Becker et al., J. Vet Intern. Med. 13:26 (1989)).
P. acnes
has been extensively used as a veterinary therapeutic in cattle with papilloma (warts) where the warts had been intralesionally injected with
P. acnes
(H. Hall et al.,
Therapeutic Immunology,
1:319, 1994). While, lesions in the control group which were injected with saline showed no regressions at the end of 16 weeks, 100% of the injected lesions in the treatment group had completely regressed at the end of 16 weeks.
Use of
P. acnes
in humans has, in general been limited to treatment of neoplastic diseases and pleural effusions with some limited success. Additionally,
P. acnes
has been administered orally in the rations of food production animals to promote better health through cell-mediated immunity and weight gain (U.S. patent application Ser. No. 08/912,026). It has been used experimentally in people to treat various cancers, plural effusion and chronic obstructive pulmonary disease. It has been used experimentally as an adjuvant with vaccines.
Based on these findings, a veterinary preparation of
P. acnes
was used as an injectable therapeutic agent against plantar warts caused by the human papilloma virus. However, significant pain upon injection was observed caused due to the alcohol content of the preparation. Thus, a preparation of
P. acnes
is needed that causes the regression of warts and dermal tumors in humans, but which may be administered without undue pain or harm to the patient. Additionally, this preparation must be administered via a route that allows regression of the warts while minimizing pain to the patient.
Although
P. acnes
has been used to treat respiratory diseases in horses and cattle, the oral administration of
P. acnes
with efficacy in humans has not been previously demonstrated. There is a need for a
P. acnes
preparation that can be safely administered to humans for the treatment of viral infections of the respiratory tract.
P. acnes
preparations have been administered primarily through intravenous, intraperitoneal, or intrathoracic routes. However, they may also be administered orally, subcutaneously, or intralesionally depending on the type of infection and the determined dosage.
P. acnes
has been used at higher dose levels in experimental animals to study the release of nitric oxide by cells or the liver and other body tissues, and has been combined with vaccines as an adjuvant for subcutaneous or intramuscular injection. Ethanol-saline suspended preparations of heat-killed
P. acnes
for veterinary use in treating pyoderma, a bacterial infection in dogs, and respiratory infections in horses have been used. However, these preparations had to be administered intravenously in order to be efficacious. In another case, a feed add
Edwards Bobby G.
Van Kampen Kent R.
Gilchrist Michael C.
Hunt Jason M.
Lankford , Jr. Leon B.
Laurenzo Brian J.
The Van Kampen Group, Inc.
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