CJC-1295 + Ipamorelin Blend

Research and Clinical Studies

CJC-1295 and Ipamorelin Blend and Half-Life Determination

Clinical studies have been conducted on test subjects to determine the half-life and individual pharmacokinetic profiles of the two peptides. In a study from the late 1990s,(6) a clinical trial was conducted on eight male test subjects with a concentration escalation design. The level of growth hormones was monitored after each instance of peptide presentation. At the end of the study, researchers suggested that there was a single episode of growth hormone release with the highest peak at 0.67 hours, after which there was an exponential decline to negligible concentrations of the compound. This study concluded that the Ipamorelin peptide appeared to exhibit a short half-life of 2 hours, after which the potential action seemás to start diminishing.

CJC-1295, in contrast, appears to have a much longer half-life. Researchers comment that a single introduction of the peptide may upregulate growth hormone production by somatotropes for extended periods of time, thus apparently contributing "to an overall increase in [growth hormone] secretion … by 46%" and also potentially upregulating its main anabolic mediator insulin-like growth factor-1 (IGF-1) by 45% on average.(7) Another publication also observes that CJC-1295 may potentially upregulate "[growth hormone] concentrations by 2 to 10-fold," and estimates the peptide's half-life to range between 5.8 and 8.1 days.(8)

General Research on CJC-1295 and Ipamorelin Blend

In this study from the early 2000s,(7) a clinical trial was conducted on male test subjects between 20 and 40 years old. The test subjects were divided into two groups; one group was presented with the placebo and the other with the peptide. Blood samples were taken from the subjects one week before and after the presentation of the CJC-1295 peptide (and placebo) to monitor growth hormone pulsatility levels. At the end of the study, it was suggested that CJC-1295 contributed to a 7.5-fold increase in growth hormone pulsatility levels compared to that of the placebo. In addition to apparently affecting growth hormone synthesis, scientists also suggest that CJC-1295 may interact with the survival and proliferation of the cells that synthesize it: the somatotrope cells in the anterior pituitary gland.(9) In a study on murine models, authors commented that "CJC-1295 caused an increase in total pituitary RNA and GH mRNA, suggesting that somatotrope proliferation had occurred, as confirmed by immunohistochemistry images".

To exert these apparent effects, CJC-1295 appears to interact with specific binding sites on the GHRH receptor protein, leading to conformational changes in the receptor structure and potentially initiating a cascade of molecular events. The binding appears to activate intracellular signaling proteins that potentially act as molecular switches.(10) These proteins are often termed G proteins, which, when activated, could drive the generation of secondary messengers such as cyclic adenosine monophosphate (cAMP) or inositol triphosphate (IP3).(11) Secondary messengers like cAMP may set in motion protein kinases, enzymes believed to alter distinct proteins. These kinases possess a modulatory capacity for cellular activities and may phosphorylate transcription regulators or proteins that oversee gene modulation. Once phosphorylated, these transcription regulators could migrate to the nucleus of somatotrope cells, possibly impacting genes associated with growth hormone formation.(7)

On the other hand, Ipamorelin appears to interact with anterior pituitary gland cells through the N-terminus of GHS-R1a, which has binding sites that seem to recognize specific sequences in the secretagogue. When Ipamorelin encounters this receptor, it may bind in a non-permanent manner through forces like hydrogen bonds and inter-molecular forces called van der Waals forces. This binding could cause the receptor to change its shape, potentially initiating cellular signals, mainly those involving G proteins. GHS-R1a could work with a specific part of G proteins called Gαq/11.(12) A main process initiated by GHS-R1a involves an enzyme called phospholipase C (PLC). Gαq/11 interacts with PLC, which can split a fat-like molecule, phosphatidylinositol 4,5-bisphosphate (PIP2), into two messenger molecules: IP3 (Inositol triphosphate) and DAG (Diacylglycerol). IP3 appears to bind to places in a cellular part called the endoplasmic reticulum, causing the release of calcium ions (Ca2+). Additionally, DAG could activate an enzyme called protein kinase C (PKC), which can add phosphate groups to other signaling molecules. All these steps could end with the "activation" of proteins that help release growth hormone from certain cells in the pituitary gland.(13)

CJC-1295 and Ipamorelin Blend and Nitrogen Balance

The apparent synergistic action of CJC-1295 and Ipamorelin on growth hormone production by somatotrope cells in the anterior pituitary gland seemás to result in a positive nitrogen balance and a potential increase in lean mass in test models. In a particular study, researchers sought to test the metabolic capabilities of Ipamorelin within the context of certain liver markers related to alpha-amino-nitrogen processing during artificially provoked catabolism. The team evaluated the liver's ability to produce urea-N (CUNS), a potential metric of nitrogen processing within the liver. They examined observable levels of messenger RNA (mRNA) linked to urea cycle enzymes in the liver, measured the overall nitrogen balance, and postulated nitrogen quantities in different organs. It was proposed that Ipamorelin might have led to a 20% decrease in CUNS, in contrast to the catabolic condition that was artificially provoked by the researchers. Furthermore, it could possibly have decreased the manifestation of urea cycle enzymes, restored nitrogen balance, and theoretically adjusted or improved nitrogen values in organs.(14)

References

1. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822. https://pubmed.ncbi.nlm.nih.gov/9849822/
2. Lucie Jette et al, hGRF1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long Lasting GRF Analog, ResearchGate, January 2005.
3. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822 https://pubmed.ncbi.nlm.nih.gov/9849822/
4. The Discovery of Growth Hormone-Releasing Hormone: An Update https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01740.x
5. Jetté, L., Léger, R., Thibaudeau, K., Benquet, C., Robitaille, M., Pellerin, I., Paradis, V., van Wyk, P., Pham, K., & Bridon, D. P. (2005). Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology, 146(7), 3052–3058. https://doi.org/10.1210/en.2004-1286
6. Gobburu JV, Agersø H, Jusko WJ, Ynddal L (September 1999). “Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers”. Pharmaceutical Research. 16 (9): 1412–6. doi:10.1023/A:1018955126402
7. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/
8. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006 Mar;91(3):799-805. doi: 10.1210/jc.2005-1536. Epub 2005 Dec 13. PMID: 16352683. https://pubmed.ncbi.nlm.nih.gov/16352683/
9. Alba, M., Fintini, D., Sagazio, A., Lawrence, B., Castaigne, J. P., Frohman, L. A., & Salvatori, R. (2006). Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. American journal of physiology. Endocrinology and metabolism, 291(6), E1290–E1294. https://doi.org/10.1152/ajpendo.00201.2006
10. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
11. Newton, A. C., Bootman, M. D., & Scott, J. D. (2016). Second Messengers. Cold Spring Harbor perspectives in biology, 8(8), a005926. https://doi.org/10.1101/cshperspect.a005926
12. Yin, Y., Li, Y., & Zhang, W. (2014). The growth hormone secretagogue receptor: its intracellular signaling and regulation. International journal of molecular sciences, 15(3), 4837–4855. https://doi.org/10.3390/ijmás15034837
13. Bill, C. A., & Vines, C. M. (2020). Phospholipase C. Advances in experimental medicine and biology, 1131, 215–242. https://doi.org/10.1007/978-3-030-12457-1_9
14. Aagaard, N. K., Grøfte, T., Greisen, J., Malmlöf, K., Johansen, P. B., Grønbaek, H., Ørskov, H., Tygstrup, N., & Vilstrup, H. (2009). Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 19(5), 426–431. https://doi.org/10.1016/j.ghir.2009.01.001