Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-10-03
1997-11-18
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, A61K 3800
Patent
active
056887710
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to immunomodulating oligopeptides which can modulate the body's immune system response to invading foreign substances and micro-organisms or malignant cells.
The present invention is more particularly concerned with lipophilic desmuramyl-type peptide analogues of muramyl dipeptide and similar oligopeptides with lipophilic alkyl chains.
BACKGROUND OF THE INVENTION
Vertebrate animal immune systems are designed to protect the body from assault by parasites. These pathogens include acellular virus and cellular parasites such as bacteria, mycoplasms, fungi, unicellular protozoa and multicellular protozoa. The immune system also defends the organism against cancerous cells.
Control and fine tuning of the immune system is a goal of medical therapists. Stimulation or suppression of the immune system is often called for in the treatment or prevention of medical conditions. Control is accomplished by chemicals, such as synthetic organics, biologicals, or macromolecules from natural sources, such as glycoproteins.
Immunomodulators, thus, offer a powerful tool for the control of infectious diseases. These chemicals modulate (stimulate or suppress) the immune system in a non-specific manner. Stimulation of immunity is also important in the host*s defense against cancer. The latter occurs, for example, upon activation of tumoricidal macrophages in response to immunomodulators. Immunomodulators may also be used in the treatment of diseases caused by immune system disorders such as arthritis. They may also be used in the treatment of individuals with a compromised immune system in order to enhance their immune response. This group of patients includes surgery patients, burn victims, patients undergoing radiotherapy or chemotherapy and patients with immune disorders such as AIDS.
In general, these immunocompromised patients can be affected by viral infections such as cytomegalovirus (CMV), influenza, herpes zoster, herpes simplex, respiratory syncytial virus (RSV) and potentially hepatitis. Immunomodulators can be used to stimulate the immune system and help in fighting the viral infection. Immunomodulators can also be used as prophylactic agents in prevention of such infections.
Non-specific stimulation of the immune system also finds veterinary application as evidenced, for example, by the treatment of equine respiratory disease with a crude mycobacterial cell wall preparation.
Some immunomodulators are known in the prior art. For example, Freund's Complete Adjuvant, a water-in-oil emulsion of killed tubercle bacilli, is a well-known immunomodulator capable of increasing both the humoral and cell-mediated immune response. Its properties have been well documented for example, J. Freund, Adv. Tuberc. Res., 7, 130, 1956. However, this preparation is so toxic that its present use in humans is proscribed and its use in animals is restricted. Muramyl dipeptide (MDP; N-acetylmuramyl-L-alanyl-D-isoglutamine) is the minimal chemical structure which is both capable of replacing the mycobacterial cells present in Freund's adjuvant, while still maintaining immunomodulating activity. MDP is part of the peptidoglycan structure of bacterial cell walls. It is a unique rigid polymer which forms a net around the bacterium. MDP possesses a number of immunologic activities. For example, it is a macrophage activator and B-cell mitogen. Therefore, MDP has significant activity as an immunomodulator. MDP augments immunologic protective mechanisms against Gram negative and Gram positive bacteria, fungal parasites, viruses and tumors. MDP also produces uveitis (intraocular inflammation) in rabbits. Arthritis, an autoimmune reaction, can be produced in rats by the subcutaneous application of MDP. Muramyl dipeptide also increases the humoral response to a number of vaccines. However, MDP, like Freund's Adjuvant, is toxic. E. Lederst, in the Journal of Medicinal Chemistry, 23, 819, 1980 states that the toxic effects of MDP include pyrogenicity, transitory leukopenia, thrombocytolysis, and sens
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Penney Christopher
Zacharie Boulos
Biochem Pharma Inc.
Davenport Avis M.
Haley, Jr. James F.
Marks Andrew S.
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