Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Reexamination Certificate
1998-12-15
2001-11-06
LeGuyader, John L. (Department: 1635)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C424S520000, C424S529000, C424S535000, C514S002600, C514S007600, C514S04400A
Reexamination Certificate
active
06312602
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel compositions containing peptides, which are useful as antiviral agents, and as agents useful in treating auto immune diseases, and to methods of making and using same. More particularly, the invention pertains to modified formulations, of the type described, with an improved ability to stimulate phagocytosis in humans for treatment of viruses and the like, and to methods of making and using same.
2. Description of Background Art
In the art there is at least one conventionally known formulation containing peptides and peptones, which is distributed under the trademark Reticulose™, which has been used as antiviral agent for humans in relation to treatment of viral infections/diseases such as influenza, herpes, infectious mononucleosis, hepatitis A and B, and most recently HIV. The known formulation is referred to as “conventional peptide-peptone composition” hereinafter.
U.S. Pat. No. 5,420,472 has recently issued on what is believed to be a method of using the conventional peptide-peptone composition to treat a specific disease. The disclosure of U.S. Pat. No. 5,420,472 is hereby incorporated by reference.
See also Anderson R. H. & Thompson R. N., Treatment of Viral Syndromes With A Lipoprotein Nucleic Acid Formulation (Reticulose), VIRGINIA MED. MONTH. 84, 347-353, 1957; Wegryn S. P., Marks R. A. and Baugh J. R., Herpes Gestations, Am J. Obst. & Gynecol. 79, 812-814, 1960; Reynolds M. R., Generalized Vaccinia Successfully Treated With Lipoprotein-Nucleic acid Complex (Reticulose) Arch Pediatrics 77, 421-422,1960; Medoff L. R. Use Of A Lipoprotein-Nucleic Acid Formulation In Treatment Of Infectious Mononucleosis, Clin. Med. 69, 1-4, 1962; Catterall R. A., A New Treatment Of herpes Zoster, Vaccinia And Chicken Pox, J. Roy. Coll. Gen. Practit. 19, 182-183, 1970; Friedland B., In Vitro Antiviral Activity Of A Peptide-Nucleic Acid Solution Against The Human Immonodeficiency Virus And Influenza A Virus, J. Royal Soc. Health 111, 170-171, 1991; Hirschman S. Z. and Chen W., Peptide Nucleic Acids Stimulate Gamma Interferon And Inhibit Replication Of Human Immunodeficiency Virus, Proc. Biomedicine '96, Washington D.C., U.S.A., May 3-6, 1996. Thompson R. M., A Lipo-Protein Nucleic Acid Complex In The Treatment Of radiation Injury, The Military Surgeon, 110, 51-58, 1952; Strickland W. N., Summary Of peptide-Nucleic acid Studies Conducted at The University of Wisconsin Biotechnology Center, Reticulose, Commonwealth Pharmaceuticals, Trenton, 1995, pp. 19-35; Friedland, B., In Vitro Antiviral Activity of a Pepti-Nucleic Acid Solution Against The Human Immunodeficiency Virus and Influenza Virus, J. ROY SOC. HEALTH, V. 111, No. 5, PP170, 171, 1991; and Cohen M. The Efficacy of a Pepti-Nucleic Acid Solution (Reticulose™) For The Treatment of Hepatitis A and Hepatitis B-A Preliminary Controlled Human Clinical Trial, J. ROY SOC. HEALTH, V. 112, No. 6, PP. 266-270 1992.
The conventional composition containing peptides and peptones, also generally referred to as nucleophosphoprotein and a lipoprotein nucleic acid solution, was originally conceived by Dr. Vincent LaPenta around 1934 and was commercially available in the U.S. for a lengthy period, ending in 1962. The conventional composition containing peptides and peptones is known to be formulated through a mixture of casein, beef peptone, ribonucleic acid (RNA), beef serum (blood) albumin, sodium hydroxide and distilled water which is processed through heat, pressurization and filtration to a solution that is of such a small molecular weight as to be compatible with any human blood type, as discussed further hereinbelow. Essentially, the conventional composition is a peptide-peptone solution in which peptone fragments are combined with short chain peptides, and wherein the molecular weight of the active components ranges from approximately 1 to 25 kDa. Presently, the conventional composition is still manufactured according to its original formulation by Advanced Viral Research Corp., in Miami, Fla. This composition was formerly believed and understood to contain peptides and nucleic acids, and thus was previously referred to as being in the class of peptide-nucleic acids (PNAs), but the thinking on this has been reevaluated, and it is no longer clear that the final product contains nucleic acids.
Although the exact nature of the antiviral activity caused by compositions such as the conventional composition containing peptides and peptones is unknown, it appears to act either by an ability to inhibit the viruses or by alteration of a host cell response in preventing virus multiplication, and a capacity to increase antiviral, antibody response in humans, which exerts a positive therapeutic effect in both acute and chronic infection. Also very significantly, the conventional peptide-peptone composition has been shown to be substantially free from side effects and systemic toxicity, unlike most other antiviral agents, including AZT and beta interferon.
Although the conventional peptide-peptone has certain advantageous characteristics as discussed above, its effectiveness as antiviral agent is known to be limited and erratic, especially when compared to other known antiviral agents including AZT, Ribavarin, Dideoxyadenosine (DDI) and Dideoxycytidine (DDC). There remains a need in the art for an antiviral agent which is, like the conventional peptide-peptone composition, substantially free of ill side effects and systemic toxicity, but which also has improved effectiveness as an antiviral agent in comparison to the conventional peptide-peptone composition.
SUMMARY OF THE INVENTION
The present invention has been developed to fulfill the above-discussed need in the art.
According to a first preferred embodiment of the invention, there is provided a peptide peptone formulation whose active components consist essentially of molecules having a molecular weight in a range from at least about 8 kDa to about 25 kDa. Preferably, the formulation comprises peptides without aromatic portions, and has an absorption band in the interval of &Dgr;&lgr;=200-235 nm, with a maximum absorbtion at &lgr;
max
=205 nm. Most preferably, the formulation according to the invention will stimulate phagocytic activity of neutrophils above a predetermined quantity of the formulation.
Applicant has determined that the conventional peptide-peptone composition, which contains active components with a molecular weight ranging from approximately 1 to 25 kDa, exhibits a phenomenon of inhibition of neutrophil phagocytic activity in humans by different groups of active components contained therein.
Surprisingly, when the conventional peptide-peptone composition is separated into two fractions, according to the molecular weight of the components thereof, applicant has discovered that the primary antiviral activity of the peptide-peptone composition is caused by heavier molecules (MW>8-15 kDa), in the portion of the composition which will be called Fraction A throughout the present specification, including peptides without aromatic components, which stimulate phagocytosis.
Conversely, a peptide-peptone-concentration dependent inhibition is caused by small peptone fragments, which appear to be associated with peptides containing aromatic amino acids (MW<8-15 kDa), working as phagocytosis inhibitors. This lighter weight fraction of the composition will be referred to throughout the present specification as Fraction B.
Based on such discovery, applicant has modified the conventional peptide-peptone composition by separating the composition into two new compositions based on the molecular weight of the components thereof, a first composition (Fraction A) containing those active components with the molecular weight greater than 8-15 kDa so that the resulting or modified peptide-peptone formulation exhibits mainly stimulatory effects on the phagocytic activity of neutrophils, and a second composition (Fraction B) containing those active components with a molecular weight of 8 kDa or less.
S
Blackman William D.
Carrier Joseph P.
Carrier Blackman & Associates P.C.
Larson Thomas G.
LeGuyader John L.
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