Secretropin The Millennium Health Centers Inc A 100

® Secretropin The Millennium Health Centers, Inc. A 100% Natural Growth Hormone Secretagogue © 2006 -2013 Millennium Health Centers, Inc. 08 -01 -2013

Dr. Mark L. Gordon, M. D. Medical Director, Product Development Millennium Products ® Secretropin The Logical “First Step” in GH Therapy. © 2006 -2013 Millennium Health Centers, Inc.

1. Definition A secretagogue is a substance that causes another substance to be secreted. SRx Simulates GHRF © 2006 -2013 Millennium Health Centers, Inc. Growth Hormone

The Science of SRx Youthful production of GH and Older Production The number of pulses and the amplitude of hormone production decreases as we get older. © 2006 -2013 Millennium Health Centers, Inc.

2. The Homeostasis of Growth Hormone Positive Feedback SRIF Hypothalamus Growth Hormone Releasing Hormone (GHRH) + IGF-1 + Liver + GH - Negative Feedback Somatotropin Releasing Inhibiting Factor (SRIF) aka - Somatostatin © 2006 -2013 Millennium Health Centers, Inc. AP

The Science of SRx Low Dose GH Stimulation vs. High Dose Stimulation Somatostatin Over stimulation of the AP leads to an elevation in the production of Somatostatin with a corresponding decrease in the release of GHRH leading to down regulation in the production of growth hormone. © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx The Threshold Theory of GH Production 1. GH is a central and peripheral trigger of the feed-back loop. i. Down regulation of GHRH-receptors ii. Down regulation of Arcuate Nucleus production of GHRH iii. Up-regulation of Somatostatin (SRIF) from the Paraventricular nucleus of the hypothalamus. 2. IGF-1 is a peripheral trigger of the central feed-back loop. i. Down regulation of GHRH-receptors ii. Down regulation of Arcuate Nucleus production of GHRH iii. Up-regulation of Somatostatin (SRIF) from the Paraventricular nucleus of the hypothalamus. © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx The Threshold Theory of GH Production 1. When GH reaches the individual’s threshold for Negative Feedback: i. Somatostatin increases thereby downregulating GH production and release. 2. When IGF-1 reaches the individual’s threshold for Negative Feedback: i. Somatostatin increases thereby downregulating GHRH and GHRH-r production. © 2006 -2013 Millennium Health Centers, Inc.

Neuroendocrine Control of Growth Hormone Secretion. PHYSIOLOGICAL REVIEWS Vol. 79, No. 2, April 1999. Eugenio E. Muller, Vittorio Locatelli, Daniela Cocchi, Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan, Milan; and Department of Biomedical and Biotechnology Sciences, University of Brescia, Italy Somatostatin 's Impact on GH Production Ø Preliminary results, from a number of articles, indicate that there is a 40% decrease in intrinsic GH production when injectable GH is used for just 2 days. Ø Eventually 100% decrease. Ø Thereafter, the exogenous GH becomes the only source of the hormone. Ø Recovery can take over a year. © 2006 -2013 Millennium Health Centers, Inc.

Homologous Down-Regulation of Growth Hormone. Releasing Hormone Receptor m. RNA Levels* Endocrinology 138: 1058– 1065, 1997 Grazia Aleppo, Stanley F. MOSKAL II, Paula A. De Grandis, Rhonda D. Kineman, Lawrence A. Frohman, Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Illinois 60612 v Repeated stimulation of pituitary cell cultures with GH-releasing hormone results in diminished responsiveness, a phenomenon referred to as homologous desensitization. v One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular c. AMP. © 2006 -2013 Millennium Health Centers, Inc.

The Secretagogue Story

Many Secretagogues Arginine Vitamin D 3 Vitamin GHRFs GHRH DHEA Peptides Dopamine Non-Peptides Amino Acids © 2010 Millennium Health Centers, Inc. © 2006 -2013 Millennium Health Centers, Inc. Melatonin GH GH

Novo Nordisk’s Report on Secretagogues Growth hormone secretagogues: recent advances and applications. DRUG DISCOVERY TODAY 1999 Nov; 4(11): 497 -506 Ankersen Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malov, Denmark. q The discovery of a new class of compounds that stimulate the release of growth hormone (GH) in a manner distinctly different from growth hormonereleasing hormone (GHRH) is advancing the understanding of the mechanisms that control GH secretion. q These compounds, the GH secretagogues, act at both pituitary and hypothalamic levels, and even elicit effects in the CNS and peripheral systems. © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Growth Hormone-Releasing Peptide (GHRP). Cell Mol Life Sci. 1998; 54(12): 1316 -29. Bowers CY. Tulane University Medical School, New Orleans, Louisiana 70112, USA. q Growth Hormone-Releasing Peptides and Non -Peptides are a chemical class of Growth Hormone secretagogues with a chemistry that ranges from small synthetic peptides to peptidomimetics (natural) substances. q They have no structural homology with (GHRH) but act via specific receptors, which are present at both the pituitary and hypothalamic levels. © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Specific receptors for synthetic GH Secretagogues in the human brain and pituitary gland. Journal of Endocrinology (1998) 157, 99– 106. G Muccioli, Et Al. Department of Anatomy, Pharmacology and Forensic Medicine, Department of Biomedical Sciences and Human Oncology, Department of Internal Medicine, University of Turin, Italy, Pharmacia and Upjohn, Stockholm, Sweden, Europeptides, Argenteuil, France, and Faculty of Pharmacy, University of Montreal, Canada. Ø A number of research centers have identified specific receptors in the human brain and pituitary gland that are unique for s. GHS. Ø These compounds are believed to be the synthetic counterpart of an endogenous GH secretagogue involved in the neuroendocrine control of GH secretion ( Ghrelin). © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Endocrine and non-endocrine activities of growth hormone secretagogues in humans. Hormone Research. 1999; 51 Suppl 3: 9 -15. Ghigo E; Arvat E; Broglio F; Giordano R; Gianotti L; Muccioli G; Papotti M; Graziani A; Bisi G; Deghenghi R; Camanni F Department of Internal Medicine, University of Turin, Italy. Ø Furthermore, these secretagogues (s-GHS) have been found to possess strong, dosedependent and reproducible GH releasing effects. © 2006 -2013 Millennium Health Centers, Inc.

Dehydroepiandrosterone modulates GHRH, Somatostatin, and angiotensin II action at the pituitary level. Journal of Endocrinology (2005) 185, 165 – 172 C Suárez, J Vela, I García-Tornadú and D Becu-Villalobos Instituto de Biología y Medicina Experimental, CONICET, V, Obligado 2490, Buenos Aires 1428, Argentina. q DHEA in vitro, directly or indirectly through conversion into metabolites, is able to modulate the hormonal response of the pituitary to hypothalamic regulators. q DHEA enhances pituitary prolactin release and induces GH secretion. q These effects could help explain some of the beneficial side effects observed in patients on prolonged DHEA treatments, and therefore, should be taken into account when considering its use. © 2006 -2013 Millennium Health Centers, Inc.

Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement. Clin Endocrinol (Oxf). 2006; 65(5): 673 -80, Brooke AM; Centre for Clinical Endocrinology, William Harvey Research Institute, St. Bartholomew's Hospital, QMUL, London, UK. q DHEA replacement in female patients lead to a 20% reduction in the dose of GH for a constant serum IGF-I. q This was maintained for 12 months and there was a significant fall in serum IGF-I two months after withdrawal of DHEA. q Therefore, take at night and not in the morning to enhance GH production. © 2006 -2013 Millennium Health Centers, Inc.

Allelic variations of the D 2 dopamine receptor gene in children with idiopathic short stature. J Hum Genet. 1999; 44(1): 26 -9. Miyake H, Nagashima K, Onigata K, Nagashima T, Takano Y, Morikawa A. Department of Pediatrics, Gunma University School of Medicine, Japan. q The Dopamine receptor (DRD 2) plays a major role in growth hormone (GH) secretion. q Binding to D 2 R increases the production and release of Growth Hormone. © 2006 -2013 Millennium Health Centers, Inc.

Stimulation of Human-Growth-Hormone Secretion by L-Dopa. N Engl J Med 1970; 283: 1425 -1429 Dec. 24, 1970. A. E. Boyd, III, M. D. , Harold E. Lebovitz, M. D. , and John B. Pfeiffer, M. D. From the divisions of Endocrinology and Neurology, Department of Medicine, Duke University Medical Center. q The effect of L-dopa, on GH secretion was studied in a group of patients with Parkinson's disease undergoing treatment with the drug. q The rise in plasma GH persisted for 120 minutes after the administration of the drug. ( The L-dopa-induced rise in plasma GH could not be blocked by either oral or intravenous glucose administration. ) © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Use of amino acids as growth hormone-releasing agents by athletes. Nutrition. 2002 Jul-Aug; 18(7 -8): 657 -61. Chromiak JA, Antonio J. Department of Health, Physical Education, Recreation and Sport, Mississippi State University, PO Box 6186, Mississippi State, MS 39762 -6186, USA. Ø Specific amino acids, such as arginine, lysine and ornithine, have been shown to stimulate GH release when infused intravenously or administered orally. ØAlthough parenteral administration consistently leads to increased circulating GH concentration, oral doses that are great enough to induce significant GH release are also likely to cause GI discomfort and diarrhea. © 2006 -2013 Millennium Health Centers, Inc.

Amino Acid Secretagogues Product(s) Response Arginine 250 mg/kg/day 60% increase in GH Ornithine 400% increase in baseline IV Ornithine 500% increase of GH over baseline. Alpha-Keto Glutarate Significant increase in GH in TBI patients. Glutamine 2 grams increase GH GABA 5 grams increase GH Glycine 6. 7 grams increased GH 300 -400% © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Arginine stimulates growth hormone secretion by suppressing endogenous Somatostatin secretion. Journal of Clinical Endocrinology & Metabolism, Vol 67, 1186 -1189, 1988. J Alba-Roth, OA Muller, J Schopohl, K von Werder Medizinische Klinik Innenstadt, University of Munich, West Germany. Ø Arginine administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arginine alone. ØThis indicated that the stimulatory effects of Arginine are mediated by suppression of endogenous Somatostatin secretion (SRIF). © 2006 -2013 Millennium Health Centers, Inc.

Vitamin D and growth hormone regulate growth hormone/insulin-like growth factor (GH–IGF) axis gene expression in human fetal epiphyseal chondrocytes. Growth Hormone & IGF Research Volume 19, Issue 3, June 2009, Pages 232– 237. M. Fernández-Cancio, Ø Vitamin D, dose-dependently, stimulated GHR, IGF-I , and IGFBP-3 expression. 24 © 2006 -2013 Millennium Health Centers, Inc.

Peripheral estrogen receptor alpha selectively modulates the waveform of GH secretory bursts in healthy women. Veldhuis JD, Keenan DM, Bowers CY. Am J Physiol Regul Integr Comp Physiol. 2007 Oct; 293(4): R 1514 -21. Epub 2007 Aug . Endocrine Research Unit, Mayo Medical and Graduate Schools, Clinical Translational Research Unit, Mayo Clinic, Rochester, MN 55905, USA. Ø Estradiol drives GH secretion via estrogen receptors (ER-α) located in the hypothalamus and pituitary gland. © 2006 -2013 Millennium Health Centers, Inc.

Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy. Eur J Endocrinol. 2005; 153(4): 577 -86 Veldhuis JD; et. Al, . Dept of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA. q Supraphysiological testosterone concentrations increase GH and IGF-I production in the elderly male without altering maximal somatotrope responses to single and combined GHRH and GHRP-2 drive, thus predicting multifactorial mechanisms of testosterone up-regulation. © 2006 -2013 Millennium Health Centers, Inc.

Other GH Influencers Item Increase Melatonin + Estradiol + Dopamine + DHEA + Testosterone + Tamoxifen © 2006 -2013 Millennium Health Centers, Inc. Decrease -- Sermorelin + Vitamin D + Alcohol -- FATS - Carbohydrates - Obesity --

The Science of SRx Summary - The research literature supports the ability of atypical substances to increase the production and release of Growth Hormone through a number of receptor pathways. - These substances have been found to be amino acids, non-peptides, synthetic peptides, DHEA, Dopamine, which enhance the activity level of Somatotropes increasing production of GH. - To work they must be introduced into a homeostatic hormonal environment. © 2006 -2013 Millennium Health Centers, Inc.

TBImedlegal. com Nano-Liposomal Delivery © 2010 Millennium Health Centers, Inc.

Nanoliposomal Encapsulation HCl Dopamine Amino Acids Melatonin DHEA Arginine HCl © 2006 -2013 Millennium Health Centers, Inc. Vitamin D Peptides Protection from Acid Destruction.

The Science of SRx Nano-Liposomes filled with SRx S © 2006 -2013 Millennium Health Centers, Inc. a m s e o d e iz ! r tt e Nano-spheres or emulsions to diffuse into the blood.

Analytical methods for the control of liposomal delivery systems. Revue Tr. AC. Trends in analytical chemistry, 2006, vol. 25, pp. 167 -178. Gomez-Hen. ; Fernandez. Romero J. M. q Liposomal delivery systems are effective vehicles to incorporate active agents into compartmentalized structures for the delivery of pharmaceutical, cosmetic, food and nutritional products. q A major benefit of liposomal delivery systems is that they allow for spatial and temporal distribution of a drug in the body, reducing unwanted toxic side effects and increasing efficiency of treatment. © 2006 -2013 Millennium Health Centers, Inc.

Oral vs Liposomal Product to Delivery Absorption Vitamin C (1000 mg) Oral 19% Vitamin C (1000 mg) Liposomal 97% 1 gram of orally ingested Vitamin C had a 19% absorption while 1 gram in a Nanoliposomal based product had a 97% delivery. © 2006 -2013 Millennium Health Centers, Inc.

2001 – The Initial Testing q The original clinical testing of Secretropin was performed in 2001. The original formula delivered by nanoliposomes was found to increase the production of GH based upon a measurable increase in IGF-1. q At that time, IGF-1 was the only test used to monitor responsiveness to the product. Today IGFBP-3 has been shown to be logarithmically proportional to GH production. © 2006 -2013 Millennium Health Centers, Inc.

© 2010 Millennium Health Centers, Inc. © 2006 -2013 Millennium Health Centers, Inc.

2006 Follow-up Study The October 2006 Study Sequence The March 2008 Report. The March 2009 Report and pending March 2013. Ø Goal to have 100 patients followed for 6 – 12 months with labs drawn initially and monthly thereafter. © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx Initial 1 month 3 months 6 months 62. 9% 78. 6% 98. 7% © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx MK. 50 y/o Female 233% Stopped SRx due to increased muscularity. Levels dropped. Result 6/21/2007 3/22/2007 1/09/2007 IGF-1 125. 4 230. 8 213 99. 1 IGFBP-3 3652 5262 5147 4135 © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx JC, 47 y/o Male. 238% Increase TBI case, 5 TBI, 3 LOC, one hospitalization. Result Range 9/06/2007 4/04/2007 12/26/2006 IGF-1 246. 9 > 200 ng/ml 276. 2 290 122 IGFBP-3 5693 > 4000 ng/ml 6527 5450 © 2006 -2013 Millennium Health Centers, Inc.

The Science of SRx NJ: 34 y/o Male 199. 2% Cryptorchism. Result Range 1/10/2008 10/30/2007 2/20/2007 IGF-1 306. 9 > 200 ng/ml 290. 8 240 154 IGFBP-3 3824 > 4000 ng/ml 3767 3882 2830 © 2006 -2013 Millennium Health Centers, Inc.

Clinical Results IGF-1 Results at approx. 1 month intervals (3 mos) 350 Continuous 4 - sprays 300 250 200 6 5 4 150 100 50 Patient 1 Patient 2 Patient 3 Patient 4* 3 1 2 Patient 5 Patient 6 0 Generally speaking: High initial IGF-1/BP-3 are more prone to shut down then those with initial low IGF-1/BP-3 levels. © 2006 -2013 Millennium Health Centers, Inc.

Growth Hormone Algorithm Initial Treatment Secretropin (SRx) 1 mo Laboratory 3 mos Increase No Change/Decrease 3 mos Continue Glucagon Challenge Testing © 2006 -2013 Millennium Health Centers, Inc. Adjust Dosing Failed

Secretropin GH Protocol Program Secretropin Growth Hormone Initial Protocol 4 sprays to start None Combined protocol 4 sprays, adjust 0. 1 mg – 0. 3 mg Established GH Use 4 sprays to start. Reduce GH based upon response. Post-GH Shutdown 4 Sprays, adjust. None 1. In a GH deficient or insufficient patient start SRx and adjust dose for maximal response. Monitor over 3 months. 2. Starting a new patient on both GH and SRx allows for the use of a lower dose of GH with comparable results in both IGF-1 and BP-3 levels. 3. In a patient already on GH, add SRx and adjust for maximal IGF-1/BP-3 levels. You should have a spike in GH production within 3 months. 4. Patients who have been on GH for 6 months or more should start SRx having both IGF-1 and GH monitored. Before starting SRx, wait 4 weeks before taking initial IGF-1 and BP-3 levels for baseline. Monitor Q 3 months. © 2006 -2013 Millennium Health Centers, Inc.

Secretropin ® The Logical “First Step” in GH Therapy. ü 2013 data shows a 20% to a 650% increase in IGF-1 and BP-3 levels in over 89% of the patients. ü Over 11 years of Clinical Trials showing the efficacy based upon rising blood levels of IGF-1/BP-3. ü A Physician ONLY product. ü Logically, Secretropin before GH. ü Logically, cost considerations. ü Logically, avoid the requirements of legally prescribing GH. © 2006 -2013 Millennium Health Centers, Inc.