This patent application is assigned to
The following quote was obtained by the news editors from the background information supplied by the inventors: "The immune system protects the body against infectious agents, including bacteria, viruses, fungi, and parasites. In addition, the immune system protects against cancer, as well as disease states that result from immune imbalance, opportunistic infections, and autoimmune disorders (Penney, U.S. Pat. No. 5,980,913). Stimulation of the immune system by pharmaceuticals is an important approach to the prevention and treatment of agents that cause immune suppressed states.
"The response by the immune system to an immunogen may be depressed as a consequence of certain diseases or pathological conditions. For example, patients infected with the human immunodeficiency virus (HIV-1) may develop acquired immune deficiency syndrome (AIDS) or AIDS related complex (ARC), and thus have depressed immune responses. This patient class is more susceptible to pathological infections or malignancies against which a normal immune system would have otherwise provided sufficient protection. Other such immunocompromised individuals include patients with cancer, or undergoing x-ray, surgery, or chemotherapy treatment.
"Current treatments used to prevent the development of immunodeficiency in individuals with viral infections, HIV for example, usually involve administration of compounds that inhibit viral DNA synthesis thereby slowing onset of viral-related immunosuppression. Treatments for HIV-infected patients often involves administration of compounds such as, for example, 3'-azido-3.sup.1-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC) and 2',3'-dideoxyinosine (DDI), zidovudine, didanosine, zalcitabine, stavudine, and viramune. More recent treatments against HIV include administration of protease inhibitors such as, for example, saquinovir, nefinavir, ritonavir, indinavir, and others. Cytokine therapy is also used in the treatment of AIDS patients, with research groups having demonstrated efficacy of interleukin-2 (IL2) in elevating the CD4 T-cell subset in HIV positive patients (Kovacs, et al.,
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventor's summary information for this patent application: "All cited patents, patent applications and references are hereby incorporated by reference in their entirety.
"Recent studies of met-enkephalin indicated that met-enkephalin activated gene transcription of IL2 (Wybran, et al., from Some Immunological Effects of Methionine-Enkephalin In Man: Potential Therapeutical Use Leukocytes and Host Defense. 205-212,
"Based on the above, however, there would be no expectation by one of skill in the art that the active agents of the present invention could be used in methods of treatment useful in producing a sustained immune response in a patient comprising administering the active agents on an intermittent dosage schedule to a patient in need of such treatment.
"The present invention is based on the surprising discovery that a regular dosing schedule of met-enkephalin is effective in promoting a sustained cell increase in immune system response including sustained cell levels, in a patient for at least one month after cessation of the dosing.
"The present invention provides, inter alia, for methods of treatment useful for inducing a sustained immune system response in an immunocompromised patient in need of such treatment wherein the method comprises administering to the patient an effective amount of an enkephalin peptide, either alone, combined, or in further combination with other compounds useful for increasing immune system response, including vaccines. In this context, 'immunocompromised' refers to any reduction in T-cell number or function.
"The present invention also provides, inter alia, for methods of treatment useful for inducing a sustained immune system response in an HIV-infected patient, wherein the method comprises administering to the HIV-infected patient an effective amount of an enkephalin peptide, either alone, combined, or in further combination with other compounds useful for slowing the progression of HIV proliferation or HIV-associated infections, including reverse transcriptase inhibitors such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC) and 2',3'-dideoxyinosine (DDI), zidovudine, didanosine, zalcitabine, stavudine, and viramune; protease inhibitors such as saquinovir, nefinavir, ritonavir, and indinavir; cytokines such as G-CSF, IL-11, IL-12, IL-2; and gamma interferon and antibiotics or other drugs used for the treatment or prevention of infections in HIV-infected patients.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
"Unless otherwise indicated, the term 'active agents' as used herein refers to the group of compounds comprising the class of enkephalin peptides.
"Unless otherwise indicated, the term 'enkephalin' or 'enkephalin peptides' includes any compound that falls into the general category of opioid peptide molecules, including compounds having the following peptide structure at one terminus:
"TABLE-US-00001 (SEQ ID NO: 1) Tyr-Gly-Gly-Phe-R
"where R is either Met or Leu. Exemplary enkephalin peptides are shown in Table 1.
"TABLE-US-00002 TABLE 1 Opioid peptides and their Precursors and structures Precursors Peptides Structures Pro- .alpha.-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr- Opiomelanacortin Pro-Leu-Val-Thr (SEQ ID NO: 2) (PCMC) .gamma.-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr- Pro-Leu-Val-Thr-Leu (SEQ ID NO: 3) .beta.-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr- (human) Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys- Asn-Ala-Tyr-Lys-Lys-Gly-Glu (SEQ ID NO: 4) Proenkaphalin A Leu-enkaphain Tyr-Gly-Gly-Phe-Leu (SEQ ID NO: 5) Met-enkephalin Tyr-Gly-Gly-Phe-Met (SEQ ID NO: 6) Heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Gly (SEQ ID NO: 7) Octapeptide Tyr-Gly-Gly-Phe-Met-Arg-Gly-Leu (SEQ ID NO: 8) Peptide E Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-Gly-Arg-Pro-Glu- (bovine) Trp-Trp-Met-Asp-Tyr-Gln-Lys-Arg-Tyr-Gly-Gly-Phe- Leu (SEQ ID NO: 9) Prodynorphin Dynorphin A(1-8) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile (SEQ ID NO: 10) (Proenkaphalin B) Dynorphin A(1-17) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu- (porcine) Lys-Trp-Asp-Asn-Gln (SEQ ID NO: 11) Dynorphin B(1-13) Tyr-Gly-Gly-Phe-Leu-Arg-Gln-Phe-Lys-Val (porcine) Val-Thr (SEQ ID NO: 12) .alpha.-Neo-endorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys (SEQ ID NO: 13) .beta.-Neo-endorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro (SEQ ID NO: 14) New dynorphin Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val- (ieumorphin) Val-Thr-Arg-Ser-Gln-Glu-Asp-Pro-Asn-Ala-Tyr-Tyr- (porcine) Glu-Glu-Leu-Phe-Asp-Val (SEQ ID NO: 15) Others .sub.B-Casomorphin Tyr-Pro-Phe-Pro-Gly-Pro-Ile (SEQ ID NO: 16) Dermorphin Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH.sub.2 (SEQ ID NO: 17) Kyotorphin Tyr-Arg (SEQ ID NO: 18)
"Enkephalin analogues also fall within the scope of the invention, and are described in the following references which are incorporated by reference: U.S. Pat. No. 4,468,383, to Rodbard et al., issued
"As used herein, the term 'sustained immune system response' is taken to mean maintaining in a patient an increase from the baseline of serum levels of cells and molecules associated with the immune system, including T-cells such as CD3, CD4, CD8, CD56, CD 25, and CD38 and molecules such as the interleukins and interferons.
"As used herein, the term 'baseline' or 'base level response' is taken to mean the serum levels in a patient before administration of active agent of cells and molecules associated with the immune system, including T-cells such as CD3, CD4, CD8, CD56, CD 25, and CD38 and molecules such as the interleukins and interferons.
"The phrase 'intermittent dose schedule' of enkephalin peptides as used herein refers to an initial routine of repeated administration of a enkephalin peptides, ranging from a daily to a weekly basis for some defined period of time (or, alternatively, a compound that promotes in vivo production of enkephalin peptides for some defined period of time) (collectively referred to as an 'initial dosage regimen'), followed by a period of time when such administration is discontinued. Additional enkephalin peptides (or compounds that promote in vivo production of enkephalin peptides) are administered thereafter on an intermittent basis.
"Exemplary intermittent dose schedules include, but are not limited to, administration of enkephalin peptides from one to five times a week over the course of a 12 week period, then discontinued for a period of time ranging from 4 to 24 weeks. Thereafter, based on some defined criteria, booster doses are given, up to 5 times a week for 1 to 4 weeks. Other examples of intermittent dose schedules that fall within the scope of this invention include administration of enkephalin peptides from 1 to 5 times a week over 4 weeks, then discontinued for a period of time ranging from 4 to 16 weeks. Thereafter, booster doses are given, up to 5 times a week for 1 to 4 weeks, depending on the level of sustained response measured. Other intermittent schedules may also be utilized.
"As used herein, the term 'HIV' includes all variants and types of HIV-1, HIV-2, and other synonymous retroviruses, such as human T-lymphotropic virus type III (HTLV-III) and lymphadenopathy associated virus (LAV-1 and LAV-2).
"As used herein, the term 'AIDS' refers to acquired immune deficiency syndrome, AIDS-related complex (ARC), and decreased lymphocyte numbers in HIV-infected individuals.
"As used herein, the term 'treating or preventing AIDS' includes preventing or decreasing the immunosuppression caused by AIDS, for example, by decreasing HIV levels in the patient's peripheral blood lymphocytes, or by increasing lymphocyte numbers; replenishing the bone marrow; increasing survival of HIV-infected patients; as well as preventing or decreasing the associated symptoms, disorders, and infections associated with HIV infection, including but not limited to susceptibility to pathogenic and opportunistic organisms and infections, anemia, thrombocytopenia, and lymphopenia.
"As used herein, the term 'opportunistic infection' refers to infections with an organism that would not normally be pathologic in patients with properly functioning immune systems.
"Many of the peptides contemplated in the instant invention are commercially available, but alternatively may be synthesized by any conventional method, including, but not limited to, those set forth in
"In general, these methods involve the sequential addition of protected amino acids to a growing peptide chain (U.S. Pat. No. 5,693,616, herein incorporated by reference in its entirety). Normally, either the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is then either attached to an inert solid support, or utilized in solution, and the next amino acid in the sequence, also suitably protected, is added under conditions amenable to formation of the amide linkage. After all the desired amino acids have been linked in the proper sequence, protecting groups and any solid support are removed to afford the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to yield the final product.
"The peptides can synthesized according to standard solid-phase methodologies, such as may be performed on an Applied Biosystems Model 430A peptide synthesizer (
"Alternatively, the peptides may be produced via conventional molecular biological methods."
URL and more information on this patent application, see: PLOTNIKOFF,
Keywords for this news article include: Antiinfectives, Antivirals, Drugs, Therapy, Viruses, Virology, Cytokines, Ritonavir, Treatment, Dynorphins, Endorphins, Amino Acids, Enkephalins, Interferons, Lymphocytes, Interleukins, Legal Issues, Opioid Peptides,
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