Growth Hormone Releasing Hormone (GHRH)/CJC-1295

It increases protein synthesis and stimulates the growth of new muscle tissue.

- Allows for normal growth in short children with GH deficiency.
- Increases muscle mass (and physical strength if combined with moderate exercise).
- Reduces wrinkling of the skin and some other effects of skin aging.
- Re-grows internal organs that have atrophied with age.
- Causes hyperplasia, the increase of more muscle cells.
- It increases muscle mass through the creation of new muscle cells (which differs from hypertrophy).
- It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
- Increased bone density.
- Faster recovery from exercise, exertion, and injuries.
- Strengthen the immune system.

It is important to begin the discussion of CJC-1295 with a discussion of the parent of the Growth Hormone Releasing Factors which is somatocrinin., this peptide ultimately gave birth to the newer generations of Growth-hormone-releasing hormone peptides (CJC-1295).

Growth-hormone-releasing hormone (GHRH), also known as growth-hormone-releasing factor (GRF or GHRF) or somatocrinin, is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus. GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophysial portal circulation to the anterior pituitary gland where it stimulates growth hormone secretion. GHRH stimulates the production of growth hormone.

GHRH gave birth to a more compact growth hormone releasing factor known as Sermorelin which is a synthetic analogue of growth hormone releasing hormone, which is produced by the hypothalamus. Sermorelin acetate is the acetate salt of an amidated synthetic 29-amino acid peptide that corresponds to the amino-terminal segment of the naturally occurring human growth hormone-releasing hormone (GHRH or GRF) consisting of 44 amino acid residues.

The free base of sermorelin has the empirical formula C 149 H 246 N 44 O 42 S and a molecular weight of 3,358 daltons. Sermorelin stimulates the secretion of growth hormone by acting directly on the pituitary gland, in the brain. In contrast to GHRH which is a 44 amino acid sequence Sermorelin is a 29 amino acid peptide hormone and is also known as (GRF 1-29 NH2). Sermorelin was sold in the United States with the brand name GEREF by Serono Biotechnologies, which later was sold to Merck, they stopped production of Sermorelin in November 2002.

So, what was the problem with Sermorelin, or GHRH for that matter? The clinical use of growth hormone-releasing hormone (GHRH) is limited by its short half-life. Also it follows that Sermorelin faced the same difficulties and thus is limited by its short half life (approximately 12 min following intravenous injection in humans), mainly due to its susceptibility to rapid enzymatic degradation. Thus, the product quickly dissipated in the body and the peptide could not stay in the body long enough to have a medicinal impact. A Munafo, T X Q Nguyen, O Papasouliotis, H L?cuelle, A Priestley and M O Thorner (2005). There were attempts to resolve some of the short half-life issues with Sermorelin, in fact a PEGylated GHRH was developed. Even though PEGylated GHRH solved some of the degradation issues, the much more potent CJC 1295, rendered PEGylated GHRH obsolete.

Instead of using a PEGylated technology, the technology of bioconjugation was employed. In vivo bioconjugation to serum albumin is a useful tool to increase the half-life of small molecules or peptides in plasma. In vivo bioconjugation occurs when a strategically placed reactive group on a bioactive peptide reacts with a nucleophilic entity found in blood or in sc interstitium to form a stable bond. The foremost nucleophile is the thiol, and its most abundant source in these fluids is Cys34 on albumin. The thiol on Cys34 reacts with a Michael acceptor, such as a maleimido derivative, leading to a new bioactive protein construct that will adopt an extended half-life due to stabilization from enzymatic degradation) or reduced elimination through the kidney. It therefore became logical to combine the long-lasting effect of bioconjugation with the proper GRF analog. Lucie Jett?, Roger L?ger, Karen Thibaudeau, Corinne Benquet, Martin Robitaille, Isabelle Pellerin, V?ronique Paradis, Pieter van Wyk, Khan Pham and Dominique P. Bridon (2005).

CJC-1295

CJC-1295 is a synthetic modification of growth hormone releasing factor (GRF) with D-Ala, Gln, Ala, and Leu substitutions at positions 2, 8, 15, and 27 respectively. These substitutions create a much more stable peptide with the substitution at position 2 to prevent DPP-IV cleavage, position 8 to reduce asparagine rearrangement or amide hydrolysis to aspartic acid, position 15 to enhance bioactivity, and position 27 to prevent methionine oxidation. By applying the Drug Affinity Complex (DAC) technology to GRF, the peptide selectively and covalently binds to circulating albumin after subcutaneous (SC) administration, thus prolonging its half-life. These substitutions are key in increasing the overall half life of CJC-1295 but there lies an even greater reason as to why the half life has been extended from ~7 minutes to greater than 7 days. Bioconjugation takes a reactive group and attaches it to a peptide, which in turn reacts with a nucleophilic (usually a partially negative molecule) entity found in the blood to form a more stable bond. Albumin, one of the most abundant substances in the human body is chosen as the nucelophile by this particular peptide thanks to a Cys34 thiol group that attracts it. By combining the tetrasubstituted GHRH analogue with maleimodoproprionic acid using a Lys linker, you create a GHRH peptide with a high binding affinity for albumin.

So how effective is bioconjugation? How long will CJC-1295 stay in ones system? How will CJC-1295 impact IGF-1 levels? This is the exact question researchers asked and a study was conducted to determine the efficacy of CJC-1295. The objective of this study was to examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog. The study design was two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 days. Healthy subjects, ages 21-61 years old were studied. After a single injection of CJC-1295, there were dose-dependent increases in mean plasma GH concentrations by 2- to 10-fold for 6 days or more and in mean plasma IGF-I concentrations by 1.5- to 3-fold for 9-11 days. The estimated half-life of CJC-1295 was 5.8-8.1 days. After multiple CJC-1295 doses, mean IGF-I levels remained above baseline for up to 28 days. No serious adverse reactions were reported. Sam L. Teichman, Ann Neale, Betty Lawrence, Catherine Gagnon, Jean-Paul Castaigne and Lawrence A. Frohman (2006). What was the research dose used in the study? A particularly important question, the dosage was 30-60 micrograms per kilogram of bodyweight.

This bears repetition, GH remained elevated for up to six days! IGF-1 concentrations were up 1.5 to 3 fold for 9-11 days! And the estimated half-life of CJC-1295 is 5.8-8.1 days! IGF-1 levels were elevated up to 28 days! At a dosage of 30-60 micrograms per kilogram of bodyweight, with no significant side effects. Excuse all he emphasis but this is a truly remarkable research product, its ability for efficacy is self-evident.

So in sum, what is CJC-1295? CJC-1295 is a long-acting analog of GH-releasing hormone. CJC-1295 exhibits the same effects of Human Growth Hormone, it has the ability to promote muscle mass, increase bone density, improve protein synthesis, increase IGF-1 levels potently, strengthen immune systems, stimulate the production of bone marrow cells that produce red blood cells, and of course reduce excess body fat, especially abdominal fat. (The reduction of abdominal fat is the single most profound effect of HGH replacement.)

Peptide should be administered at least twice a week (so divide the research dose into two administrations on your research subject) this will help to keep blood levels consistent in your research subject, or in cellular culture, or in vitro.

Figure 1

Chemical structure of the CJC-1295 (DAC-GRF). The core therapeutic moiety is a tetrasubstituted GHRH-(1–29)NH2. The substituted amino acids are shown in italics. The linker is lysine, and the reactive chemical is maleimidoproprionic acid that binds covalently to the single unpaired cysteine (cysteine 34) in serum albumin.

Figure 2

Plasma disappearance curves of CJC-1295 after a single sc injection. Shown are the mean ± SD half-life. Drug concentrations were generally measurable for at least 12–14 d after injection.

Figure 3

GH responses to a single sc injection of CJC-1295. A, Serum GH concentrations (mean ± SD) are shown and suggest that pulsatile hormone secretion is maintained. B, Mean GH AUC0–7 d, expressed as a percent increase over placebo. *, P < 0.05 vs. placebo. Shown are the mean ± SD. Mean maximum concentrations of GH were 6.6, 9.6, 9.9, and 13.3 ng/ml in the 30, 60, 125, and 250 µg/kg groups; mean AUC were 758, 969, 977, and 1370 ng/ml·h, respectively.

Figure 4

IGF-I responses to a single sc injection of CJC-1295. A, Serum IGF-I concentrations (mean ± SD) are shown. B, Mean IGF-I AUC0–7 d, expressed as a percent increase over placebo. *, P < 0.05 vs. placebo. Shown are the mean ± SD. The shaded area marked is the upper limit of normal (U.L.N.) for age- and gender-matched cohorts. Mean maximum concentrations of IGF-I were 232, 319, 328, and 435 ng/ml in the 30, 60, 125, and 250 µg/kg groups; mean AUC were 91, 127, 119, and 172 µg/ml·h, respectively.

Figure 5

IGF-I responses to multiple sc injections of CJC-1295. Serum IGF-I concentrations (mean ± SE) are shown. Arrows indicate days of injection. A, Changes in serum IGF-I levels after three weekly injections of CJC-1295 or placebo. B, Changes in serum IGF-I levels after two biweekly injections of CJC-1295 or placebo. In both A and B, for d 0–7 and 14–21, the entire pooled placebo group (n = 4) is plotted, because all these subjects received placebo injections on d 0 and 14. In A, for the period from d 7–14, only the two subjects who received placebo injections on d 7 are plotted (i.e. three weekly injections). In B, for the period from d 7–14, only the two subjects who received placebo injections on d 0 and 14 are plotted (i.e. two biweekly injections).

RESEARCH DOSAGE:

30-60 mcg per kilogram of bodyweight.

Peptide should be administered at least twice a week (so divide the research dose into two administrations on your research subject) this will help to keep blood levels consistent in your research subject, or in cellular culture, or in vitro.

STORAGE:

REFRGIRATE UPON RECEIPT.

KEEP REFRIGERATED AFTER RECONSTITUTION ALLOW 24 HOURS FOR THE PEPTIDE TO SETTLE BEFORE BEGINNING YOUR RESEARCH.

Academic References & Further Information

A Munafo, T X Q Nguyen, O Papasouliotis, H L?cuelle, A Priestley and M O Thorner (2005). Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects. European Journal of Endocrinology, Vol 153, Issue 2, 249-256.

Lucie Jett?, Roger L?ger, Karen Thibaudeau, Corinne Benquet, Martin Robitaille, Isabelle Pellerin, V?ronique Paradis, Pieter van Wyk, Khan Pham and Dominique P. Bridon (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 Vol. 146, No. 7 3052-3058.

Sam L. Teichman, Ann Neale, Betty Lawrence, Catherine Gagnon, Jean-Paul Castaigne and Lawrence A. Frohman (2006). 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. The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 799-805