BPC-157 for Healing Gastric Ulcers and Superior Healing of ... · BPC 157 BPC 157 is the most...
Transcript of BPC-157 for Healing Gastric Ulcers and Superior Healing of ... · BPC 157 BPC 157 is the most...
Dr. Rob Kominiarek, DO FACOFPMedical Director, Renue Health
BPC-157 for Healing Gastric Ulcers and Superior Healing of Tendinopathies
What is a Peptide?
• A peptide is a short chain of amino acids that are linked together, and can be thought of as a small protein.
• To date, over 7,000 naturally-occurring peptides have been identified.
• In our bodies, these small proteins typically act as signaling molecules.
• They bind to receptors on the cell surface and tell other cells and molecules what to do.
What is a Peptide?
• Peptides are highly specific while also being safe and well-tolerated!
• As of January 2015, there were over 60 FDA-approved peptide medications, 140 peptide drugs being evaluated in clinical trials, and 500 in pre-clinical development.
• More peptides are created everyday!
Peptide Therapy Goal
Peptide therapy aimed at normalization of the serum IGF-1 is associated with significant improvements in serum triglycerides, LDL-C, total cholesterol, total cholesterol/HDL-C ratio, decrease in CIMT and atherogenic lipid profile, increase in CO, increase in EF, decrease in CVD, increased lean body mass, decreased inflammatory visceral fat, improvement in energy levels and emotional reaction, improved psychological well-being, improved skeletal mass and osteopenia/osteoporosis scores, decreased fatigability and greater vitality.
What are the Peptides?
Link to access list of peptides: http://crdd.osdd.net/raghava/thpdb/length.php
Peptides – Legalities & Regulations
EXEMPTION FD&C ACT
A compounded drug product intended for use in humans that meets the conditions of section 503A of the FD&C Act and its associated regulations is exempt from the requirements under sections 501(a)(2)(B), 502(f)(1), and 505 of the FD&C Act.
Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act HTTP://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
Peptides – Legalities & Regulations
EXEMPTION FD&C ACT
Sections 351 (a)(2)(B), 352 (f)(1), and 355 (NEW DRUGS) shall not apply to a drug product if the drug product is compounded for an identified individual patient based on the receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient, if the drug product meets the requirements of this section, and if the compounding—(1) is by—(A) a licensed pharmacist in a State licensed pharmacy or a Federal facility, or(B) a licensed physician,on the prescription order for such individual patient made by a licensed physician or other licensed practitioner authorized by State law to prescribe drugs;
https://www.law.cornell.edu/uscode/text/21/353a
Reasons compounded product is necessary for the identified patient:
• Allergens or dye sensitivity to commercially available products
• Failure of initial therapy on commercially available products
• Lifestyle request which commercially available products may not accommodate
• Patient adherence and compliance is necessary and un-achievable with commercially available products
• Micronization and modified release is necessary and un-achievable with commercially available products
Reasons compounded product is necessary for the identified patient:
• Patient has allergy to cottonseed oil, a component in brand name testosterone, Depo®-Testosterone
• Patient has a needle phobia, requiring use of creams
• Patient has sensitivity to alcohol based gels
Peptides – Legalities & Regulations
Federal law clearly states that licensed physicians may “manufacture, prepare, propagate, compound, or process drugs solely for use in the course of their professional practice” [21 USC 360(g)]. Furthermore, the Federal Food, Drug, and Cosmetic Act (FD&C) cannot regulate the therapeutic practices themselves.
The purpose of this lecture is to understand how peptides provide powerful therapeutic tools due to their receptor specificity and excellent low side effect profile, and which patients and conditions would likely benefit from peptide therapy and alternative treatment strategies.
• Short chain of amino acids from 2-50, but < 50 AA • Seemingly simple peptides are found to regulate
most every known process and system in the body in a tissue specific manner.
• While hormone therapy and optimization is a mainstay of age management, understanding that regulatory peptides are the master controllers of many functions of the body, including hormone production.
How many peptides?
How many peptides?
• The human body has about 293,700 peptides according to the Human Poteome Map
• Compared to about 30,000 proteins
Peptides that are Hormones
• ACTH
• ADH
• Atrial Natriuretic Peptide
• Calcitonin
• GHRH-44 amino acid peptide-7 min half-life
• Oxytocin
• Parathyroid Hormone
• Prolactin
Currently, peptides are available that are shown to safely and effectively improve and modulate specific parts of:
• Hormone production • Immune function• Sleep cycle• Production of inflammatory mediators• DNA replication• Cell division and renewal• Cancer cell destruction and apoptosis• Libido and sexual arousal• Tissue healing• Specific biological functioning of the brain, skin, eyes,
urinary and reproductive systems.
Hormones generally work on nuclear receptors withresultant gene activation and protein synthesis
Peptides are generally non-genomic that act onmembrane receptors to activate an intracellularsignaling cascade
Peptide signaling molecules generally have more of arapid response with less side-effects when comparedto hormones
Peptides have more precise tissue-selective effects,while hormones have less precise broader effects
The side effect profile and low cost of peptide repair therapies suggest a first treatment line option for many different types of muscle, ligament, and tendon injuries. Many of these options could be explored before more drastic treatment protocols.
Surgical and Pain Treatment Alternatives:
Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice.
What Is BPC-157?
BPC 157
• H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-AlaGly-Leu-Val-OH
• Accelerates the healing of many different wounds, including tendon, ligaments, muscles, nervous system and other organs
• BPC 157 increases growth hormone receptors
• BPC 157 also promotes the outgrowth of tendon fibroblasts, cell survival under stress, and the migration of tendon fibroblasts
• This peptide is also shown to decrease pain in damaged areas
BPC 157
• Protects and prevents gastric ulcers
• Improves digestive function
• Protects and heals inflamed intestinal epithelium (leaky gut)
• Eosinophilic esophagitis
• It has also been shown to help in Inflammatory bowel disease
• Protects liver from toxic insults (alcohol, antibiotics, etc) and promotes healing
• Traumatic brain injury
• May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal
• May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)
BPC 157: Potential target conditions
AgingAllergiesCFS/FibromyalgiaChemical sensitivityGI ulcers/inflammationInflammatory conditionsInflammatory bowel diseasePrevent/treat heart arrhythmiasAutoimmune disease (asthma, lupus)Chronic viral or intracellular infectionsLyme disease/HIV, especially in conjunction with TA1
CVDPost surgicalDiabetesLeaky gutH-pylori
Patient #1: Severe Esophageal Pain
50 yo male with constant, persistent esophageal pain and spasms for 2 years. Has had several EGDs and manometry. Has tried numerous therapies with minimal relief.
Patient #1: Severe Esophageal Pain
Patient #1: Severe Esophageal Pain
Patient #1: Severe Esophageal Pain
Patient was started on BPC-157 oral daily for 4 weeks.
Place on my “SSD” to shed 8-10 lbs.
Two week follow up demonstrated a 100% resolution of esophageal spasm and pain.
Patient #1: Severe Esophageal Pain
Patient #1: Severe Esophageal Pain
Patient #1: Severe Esophageal Pain
Patient #1: Severe Esophageal Pain
BPC 157
BPC 157 is the most stable gastric pentadecapeptide that is available in human gastric juice. It has remarkable effects in the lower and the upper GI tracts. It is also known for its side effect-free property.
BPC 157
“Stable gastric pentadecapeptide BPC 157 is an antiulcer peptidergic agent, safe in inflammatory bowel disease clinical trials and wound healing, stable in human gastric juice and has no reported toxicity. Particularly, it has a prominent effect on alcohol lesions (i.e., acute, chronic) and NSAIDs-lesions (interestingly, BPC 157 both prevents and reverses arthritis)… and acts as a free radical scavenger and exhibits neuroprotective properties.”
Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success is the potent and specific, yet safe, mode of action of peptides. The future development of peptide drugs will continue to build upon the strengths of naturally occurring peptides, with the application of traditional rational design to improve their weaknesses, such as their chemical and physical properties.
Peptides vs GH
Benefits of growth hormone secretagogues, relative to recombinant growth hormone:
• Simulate natural, pulsatile GH secretion
• Allow the pituitary to self regulate GH secretion
• Do not down regulate pituitary’s own GH secretion
• Safe for long-term use
PEPTIDES – GH Stimulation
Self Regulation / Negative Feedback
Patient #2: The Hobbler
35 y/o male who presents with chronic right ankle pain from eleven injuries. MRI demonstrates chronic inflammation of the anterior talofibular ligament and chronic sinus tarsi syndrome. Has tried numerous therapies, now orthopedist wants to scope to “clean and tighten”.
Treatment Strategy
He was put on BPC-157 for 3 months
PRP joint injection in the right ankle
Three months later is pain free
Patient #3: The Ex Jock
42 y/o at 6’2 and 240 lbs. male presents with complaint of right shoulder pain and weakness of bicep.
Examination reveals positive Yergason, positive O’Brion, positive Speed, positive empty can tests
Possible Treatment Options
This patient could:
• Hope it heals on its own
• Take NSAIDS and Steroids
• Go to physical therapy
• Consider surgery
• PRP
• Strategic use of BPC-157
Patient #3: The Ex Jock
Patient elects to proceed with Platelet Rich Plasma injection of biceps and supraspinatus tendons and strategic use of BPC-157.
Treatment Strategy
He was put on BPC-157 for 3 months
PRP joint injection in the right biceps and supraspinatus tendons
Approximately three months later is pain free with normal strength
The emerging peptide technologies, including multifunctional peptides, cell penetrating peptides and peptide drug conjugates, will help broaden the applicability of peptides as therapeutics. Taking all of the above into account, we are convinced that peptides offer enormous growth potential as future therapeutics for the treatment of unmet medical needs.
1. Lynch, H.E., et al., Thymic involution and immune reconstitution. Trends in Immunology, 2009. 30(7): p. 366-373.
2. Cremaschi, G.A., et al., Chronic stress influences the immune system through the thyroid axis. Life Sciences, 2000. 67(26): p. 3171-3179.
3. Skowera A., Cleare A., Blair D., Bevis L., Wessely S. C. and Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clinical & Experimental Immunology. 2004;135: 294–302.
4. Brenu E, van Driel M, Staines D, Ashton K, Ramos S, Keane J, Klimas N, Marshall-Gradisnik S. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/MyalgicEncephalomyelitis Journal of Translational Medicine 2011 9:81
5. Song C, Halbreich U, Han C, et al. Imbalance between pro- and anti-inflamatory cytokines, and between TH1 and TH2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 2009;42(5):182-8 Jackson, I.M.D., The Thyroid Axis and Depression. Thyroid, 1998. 8(10): p. 951-956.
6. Maes, M., Evidence for an immune response in major depression: A review and hypothesis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1995. 19(1): p. 11-38.
References:
7. Hichami, A.,Grissa, O., Mrizak, I., Benammar, C. Role of T-Cell Polarization and Inflammation and Their Modulation by n-3 Fatty Acids in Gestational Diabetes and Macrosomia. J Nutr Metab2016
8. Torres-Harding, S. Sorenson, M. Jason, L. A. Maher, K. Fletcher, M. A. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008. 16;3:19-33
9. Gross, D. M., Steere, A. C., Huber, B. T. T helper 1 response is dominant and localized to the synovial fluid in patients with Lyme arthritis. J Immunol. 1998. 160;2: 1022-8
10. Morozov, V.G. and V.K. Khavinson, Natural and synthetic thymic peptides as therapeutics for immune dysfunction. International. Journal of Immunopharmacology, 1997. 19(9-10): p. 501-505.
11. Ershler WB, Gravenstein S, Geloo ZS. Thymosin alpha 1 as an adjunct to influenza vaccination in the elderly. Annals of the New York Academy of Sciences. 2007 Sep 1;1112(1):375-84.
12. Li J, Liu CH, Wang FS. Thymosin alpha 1: biological activities, applications and genetic engineering production. Peptides. 2010 Nov 30;31(11):2151-8.
13. Garaci E, Favalli C, Pica F, SINIBALDI VALLEBONA PA, TERESA PALAMARA AN, Matteucci C, Pierimarchi P, Serafino A, Mastino A, Bistoni F, Romani L. Thymosin alpha 1. Annals of the New York Academy of Sciences. 2007 Sep 1;1112(1):225-34.
14. Qin Y, Chen FD, Zhou L, Gong XG, Han QF. Proliferative and anti-proliferative effects of thymosin α1 on cells are associated with manipulation of cellular ROS levels. Chemico-biological interactions. 2009 Aug 14;180(3):383-8.
References:
15. Schulof, R.S.e.a., A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer. J. Biol. Response Modif., 1985. 4: p. 12.
16. Blagaic, A.B., et al., The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. European Journal of Pharmacology, 2004. 499(3): p. 285-290.
17. Sikiric, P., et al., Stable Gastric Pentadecapeptide BPC 157: Novel Therapy in Gastrointestinal Tract. CPD, 2011. 17(16): p. 1612-1632.
18. Tudor, M., et al., Traumatic brain injury in mice and pentadecapeptide BPC 157 effect. Regulatory Peptides, 2010. 160(1-3): p. 26-32.
19. Ojo-Amaize, E.A., E.J. Conley, and J.B. Peter, Decreased Natural Killer Cell Activity Is Associated with Severity of Chronic Fatigue Immune Dysfunction Syndrome. Clinical Infectious Diseases, 1994. 18(Supplement 1): p. S157-S159.
20. Stricker, R.B. and E.E. Winger, Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunology Letters, 2001. 76(1): p. 43-48.
21. V. Kh. Khavinson, I. E. Bondarev, A. A. Butyugov, and T. D. Smirnova. Peptide Promotes Overcoming of the Division Limit in Human Somatic Cell. Bulletin of Experimental Biology and Medicine, Vol. 137, No. 5, May, 2004
References:
22. V. Kh. Khavinson, N. Goncharova, and B. Lapin. Synthetic tetrapeptide epitalon restores disturbed neuroendocrine regulation in senescent monkeys. Neuro Letters ISSN. 2001;22;4:251-254.
23. V. Kh. Khavinson, T. A. Lezhava, J. G. Monaselidze, et al. Effects of livagen peptide on chromatin activation in lymphocytes from old people. Bulletin of Exp. Bio and Med. 2002;134;10:451-455
24. V. N. Anisimov, V. K. Khavinson, I. G. Popovich, and M. A.Zabezhinski. Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats. Cancer Lett. 2002;183:1-8.
25. V. N. Anisimov, V. Kh. Khavinson, M. Provinciali, et al. Inhibitory effect of the peptide epitalonon the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int. J. Cancer. 2002;101;1:7-10.
26. V. Kh. Khavinson, I. E. Bondarev, and A. A. Butyugov, Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells. Ibid. 2003;135;6:692-695.
27. W. E. Wright and J. W. Shay. Historical claims and current interpretations of replicative aging Ibid. 2002;20;7:682-688.
References:
28. O. V. Korkushko, V. Kh. Khavinson*, V. B. Shatilo, and I. A. Antonyk-Sheglova. Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People: Results of 15-Year Follow-Up. Bulletin of Experimental Biology and Medicine, Vol. 151, No. 3, July, 2011
29. Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology. 2000 Oct 31;56(4):641-6
30. Dorr R, Lines R, Levine N, Brooks C, Xiang L, Hruby V, Hadley M. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996; 58(20): 1777-84.
31. Shadiack, Sharma S, Earle D, Spana C, Hallam T. Melanocortins in the Treatment of Male and Female Sexual Dysfunction Annette M. Current Topics in Medicinal Chemistry. 2007; 7: 1137-1144.
32. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006 Apr 30;27(4):921-30.
33. Li G, Zhang Y, Wilsey JT, Scarpace PJ. Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. Journal of endocrinology. 2004 Jul 1;182(1):123-32.
References:
34. Hadley ME. Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides. 2005 Oct 31;26(10):1687-9
35. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997 Jun 30;49(6):822-30.
36. Diamond LE, Earle DC, Garcia WD, Spana C. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology. 2005 Apr 30;65(4):755-9.
37. Results of Palatin Technologies’ PT-141 phase 2b study in men with erectile dysfunction, May 10, 2004. www.palatin.com.38. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT‐141: a melanocortin agonist for the treatment of sexual dysfunction. Annals of the New York Academy of Sciences. 2003 Jun 1;994(1):96-102.
39. Dorr R, Lines R, Levine N, Brooks C, Xiang L, Hruby V, Hadley M. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996; 58(20): 1777-84.
40. Positive data reported on treatment for female sexual dysfunction, September 26, 2002. www.palatin.com.
References:
41. Bradley et al, 2008; Tsuchida, 2008
42. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proceedings of the National Academy of Sciences. 2001 Jul 31;98(16):9306-11.
43. Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Science translational medicine.2009 Nov 11;1(6):6ra15
44. Calvo RM, Villuendas G, Sancho J, San Millán JL, Escobar-Morreale HF. Role of the follistatingene in women with polycystic ovary syndrome. Fertility and sterility. 2001 May 31;75(5):1020-3.
45. Eldar-Geva T, Spitz IM, Groome NP, Margalioth EJ, Homburg R. Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome. Human reproduction. 2001 Dec 1;16(12):2552-6.
46. J Nutr Health Aging. 2008 Aug-Sep
47. Journal of Clinical Endocrinol Metabolism. 2004 Jun;89(6):2724-7.
48. McPherron AC, Lawler AM., S.J. L Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387:83–90.
49. Myostatin Does not Regulate Cardiac Hypertrophy or Fibrosis Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
References:
50. Taylor WE, Bhasin S, Artaza J, Byhower F, Azam M, Willard DH Jr, Kull FC Jr, Gonzalez-CadavidN. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells
51. Artaza JN, Bhasin S, Magee TR, Reisz-Porszasz S, Shen R, Groome NP, Fareez MM, Gonzalez-Cadavid NF. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology.
52. Andreone P, Cursaro C, Gramenzi A, Margotti M, Ferri E, Talarico S, Biselli M, Felline F, Tuthill C, Martins E, Gasbarrini G, Bernardi M. In vitro effect of thymosin alpha 1 and interferon on Th1 and Th2 cytokine sythesis in patients with chronic hepatitis C. Journal of Viral Hepatitis. 2001.8.194-201
53. Silecchia G, Guarino E, Sinibaldi-Vallebona P, Pierimarchi P, Restuccia P, Spaziani E, Bernard P, Tuthill C, Garaci E, Rasi G. Efficacy of repeated cycles of chemo-immunotherapy with Thymosin α1 and interleukin-2 after intraperitoneal 5-fluorouracil delivery. Cancer Immunology, Immunotherapy. 1999;48;4:172–178
54. Shiau, A. L., Wu C. L., Huang K. Y. The effect of thymosin on experimental herpes simplex virus infections. Journal of Formosan Med. Ass. 1988;87:34-42
55. Gumen AV, Kozinets IA, Shanin SN, et al. Production of lympohcyte-activating factors by mouse macrophages during aging and under the effect of short peptides. Bull Exper Bio Med 2006;142(3):360-362
References:
56. Khavinson Vkh, Yakovleva ND, Popuchiev VV, et al. Reparative effect of epithalon on pineal gland ultrastructure in gamma-irradiated rats. Bull Exper Bio Med 2001;131(1):81-85.
57. Dilman VM, Anisimov VN, Ostroumova MN, et al. Increase in lifespan of rats following polypeptide pineal extract treatment. Exp Pathol 1979;17:539-545
58. Khavinson VKh, Morozov VG, Anisimov VN. Experimental studies of the pineal gland preparation Epithalamin. The Pineal Gland and Cancer: Neuroimmunoendocrine Mechanisms in Malignancy 2001:294-306
59. Krude H, Biebermann H, Grüters A. Mutations in the human proopiomelanocortin gene. Annals of the New York Academy of Sciences. 2003 Jun 1;994(1):233-9.
60. Results of Palatin Technologies’ Bremelanotide phase 2b study in men with erectile dysfunction, November, 2006. www.palatin.com.
61. Gregoire, Francine M., Cynthia M. Smas, and Hei Sook Sul. Understanding Adipocyte Differentiation. Physiol. Rev. 1998. 78: 783–809.
62. Vkh, Morozov VG. Peptides of pineal gland and thymus prolong human life. Neuro Endocrinol Lett. 2003 Jun-Aug;24(3-4):233-40
63. Khavinson V., Malinin V. Gerontological aspects of genome peptide regulation. Karger. 2005
References:
64. Anisimov VN, Khavison V KH. Peptide bioregulation of aging: results and prospects. Biogerontology 210;11:139-149.
65. http://www.fdanews.com/articles/85402-sciclone-s-zadaxin-granted-orphan-drug-designation.
66. Khavinson V. Peptidergic and ageing. Neuroendocrinology Letters. 2002
67. Khavinson V. et al. Synthetic tetrapeptide epitalon restores disturbed neuroendocrine regulation in senescent monkeys. Neuroendocrinology Letters 200122(4):251-4
68. Korkushko, O.V., Khavinson, V.K., Shatilo, V.B. et al.. Effect of Peptide Preparation Epithalamin on Circadian Rhythm of Epiphyseal Melatonin-Producing Function in Elderly People. Bulletin of ExpBiology Med 2004; 137(4)389–391
69. Anisimov V. et al. Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumor incidence in female CBA mice. Mechanisms of Ageing and Development. 2001;122:41–68
70. Clerici M, Shearer, GM. The Th1-Th2 hypothesis of HIV infection: new insights. Immunology Today 1994;15(12):575-581
71. Anisimo VNN, et al. Effect of synthetic thymic and pineal peptide on biomarkers of ageing, survival and spontaneous tumor incidence of female CBAmice. Mech Ageing Dev 2001;122(1):41-68.
References:
72. Ilia J. Elenkov and George P. Chrousos. Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease. Trends in Endocrinology & Metabolism , 1999, Volume 10 , Issue 9 , 359 – 368
73. Hemdan, N. Y. A., Emmrich, F., Faber, S., Lehmann, J. and Sack, U. (2007), Alterations of Th1/Th2 Reactivity by Heavy Metals. Annals of the New York Academy of Sciences, 1109: 129–137. doi:10.1196/annals.1398.015
74. Tomicˇ ic´ S, Fa¨ lth-Magnusson K, Fagera˚s Bo¨ ttcher M. Dysregulated Th1 and Th2 responses in food-allergic children – does elimination diet contribute to the dysregulation? Pediatr Allergy Immunol 2010: 21: 649–655.
75. Clerici M1, Shearer GM. The Th1-Th2 hypothesis of HIV infection: new insights. Cattedra di Immunologia, Universitá degli Studi, Milano, Italy.
76. Ilia J. Elenkov. Glucocorticoids and the Th1/Th2 Balance. Ann NY Acad Sci 2004; 1024:138–146
77. Uciechowski P, Kahmann K, Plumakers B, et al. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Exper Gerontology 2008;43:493–498.
References:
78. A. Skowera, A. Cleare, D. Blair, L. Bevis, S. C. Wessely & M. Peakman. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol 2004;135:294–302.
79. Torres-Harding S, Sorenson M, Jason, LA, et al. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008;16(3):19–33.
80. Charlton B, Lafferty KJ. The Thl/Th2 balance in autoimmunity. Current Opini in Imm1995;7:793-798.
81. Komalpreet Kaur. et al. / Asian Journal of Research in Chemistry and Pharmaceutical Sciences. 3(3), 2015, 75 - 88.
82. Keld, Fosgerau & Torsten, Hoffmann, Peptide therapeutics: current status and future directions. Drug Discovery Today Volume 20, Issue 1, January 2015, Pages 122-128
83. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/085635s030lbl.pdf
References: