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CJC-1295 NO-DAC(MOD GRF 1-29)

Item 12646

CJC-1295

CJC-1295 is a Long acting GHRH analog. 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 hypothalamus by the arcuate nucleus. GHRH stimulates growth hormone (GH) secretion from the pituitary. GHRH is released in a pulsatile manner, stimulating pulsatile release of GH respectively.

In addition, GHRH also promotes slow-wave sleep .

The active portion of this GRF or GHRH peptide can be found as a 29 amino acid long peptide and is appropriately named GHRH1-29. This pulsatile release of various peptides is due to the negative feedback loop that is part of the hGH axis and controls the amount of hGH that your body produces to keep it in a homeostatic environment. Despite the effectiveness of GHRH to stimulate growth hormone release there are a number of problems associated with using it in vivo. The most noteworthy problem is the half life of the peptide, which has been shown to be ~7 minutes using advanced HPLC technologies that have proven to be very accurate. The reason for this relatively short half life is due to an enzyme called dipeptidylaminopeptidase IV (DPP-IV), which has a high affinity for the amino acids Ala and Pro and in the case of GHRH it cleaves the 1 and 2 positions that consist of Tyr-Ala, creating GHRH3-29, an inactive form of the peptide. To prevent the problems associated with natural GHRH, pharmaceutical companies looked at new ways to increase the half life and bioavailability of these smaller peptides with technologies that work far different than other technologies, such as PEGylation.
http://www.biochem.northwestern.edu/mayo/Lab%20GIF%20Images/GH-Axis.gif
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 is a relatively newer technology that 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. Once the CJC-1295 molecule has attached itself to albumin, it is given an extended half life and bioavailability thanks to the albumin preventing enzymatic degredation and kidney excretion. In fact, bioconjugation is so effective that there was less than 1% of CJC-1295 left unreacted in vivo and over 90% was stabilized after subcutaneous injection. This means that you get more of what you paid for working for you. There was no DPP-IV degredation observed on CJC-1295 in any of the various experiments conducted.

Various experiments have been conducted to test the effectiveness of CJC-1295 in vivo and the Journal of Clinical Endocrinology & Metabolism has reported dose-dependent increases in mean plasma GH concentrations by 2-10 fold for more than 6 days and increased IGF-1 concentrations 1.5-3 fold for 9-11 days after a single injection!

http://media.comrax.com/DBImages/gdila.co.il/41efd38acf31f03fbfeaa4f58607acf8.jpg
(from the same study) Subcutaneous administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30 or 60 µg/kg. There was evidence of a cumulative effect after multiple doses

Not only that but they proved the mean half life to be 5.8-8.1 days and after multiple doses showed mean IGF-1 levels remained above baseline for up to 28 days following! No serious adverse reactions were reported in any group.

Because of the long half-life and stability of the CJC-1295 analog it may only need to be taken 1-2 times per week. However research on GHRH knockout mice showed that e/d injections where superior in increasing GH vs every 48 or 72 hours. “GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48h and 72h reached higher body weight and length than placebo-treated animals, without full growth normalization.” These mice were treated for 5 weeks.
However the flaw in this study appears to be that the mice treated e/d were receiving a larger dose, so at minimum cjc-1295 is dose dependent. Whether or not a more frequent injection would prove to be beneficial is yet to be determined.

Growth Hormone Releasing Hormone (CJC-1295)

GHRH modified GRF 1-29 CJC-1295 Dose:

Light: 50mcg
Common: 100mcg
Large: 250mcg

Growth Hormone Releasing Hormone (GHRH) CJC-1295 is a synthetic secretalogue which stimulates HGH release. In the human body, large amounts of growth hormone are stored in the pituitary. GHRH affects the number of secreting cells and the amount they are able to secrete.

Dosing GHRH once at night for anti-aging purposes and multiple injections (1-3x) for anabolism. CJC-1295 has the ability to make the body produce its own GH as compared to using synthetic HGH. GHRP-6 use in conjunction with CJC-1295 is synergistic, amplifying the GH pulse considerably.

Researchers report positive effects much like that of HGH. Particularly energy, quality sleep, fat loss/metabolism, improved skin quality, pumps in the gym.

CJC-1295 is typically found in 2mg vials. Reconstitute with BW. Inject subcutaneously.

Most common desirable form to find and research with CJC-1295 (Growth Hormone Releasing Factor) is a modified GRF (1-29), lacking the DAC (drug affinity complex). This GHRH (mod GRF 1-29) has 30 minute half life, superior to that of Sermorelin. Post injection flush is common.

CJC-1295

 

CJC-1295 is a Long acting GHRH analog. 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 hypothalamus by the arcuate nucleus. GHRH stimulates growth hormone (GH) secretion from the pituitary. GHRH is released in a pulsatile manner, stimulating pulsatile release of GH respectively.

In addition, GHRH also promotes slow-wave sleep .

The active portion of this GRF or GHRH peptide can be found as a 29 amino acid long peptide and is appropriately named GHRH1-29. This pulsatile release of various peptides is due to the negative feedback loop that is part of the hGH axis and controls the amount of hGH that your body produces to keep it in a homeostatic environment. Despite the effectiveness of GHRH to stimulate growth hormone release there are a number of problems associated with using it in vivo. The most noteworthy problem is the half life of the peptide, which has been shown to be ~7 minutes using advanced HPLC technologies that have proven to be very accurate. The reason for this relatively short half life is due to an enzyme called dipeptidylaminopeptidase IV (DPP-IV), which has a high affinity for the amino acids Ala and Pro and in the case of GHRH it cleaves the 1 and 2 positions that consist of Tyr-Ala, creating GHRH3-29, an inactive form of the peptide. To prevent the problems associated with natural GHRH, pharmaceutical companies looked at new ways to increase the half life and bioavailability of these smaller peptides with technologies that work far different than other technologies, such as PEGylation.

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 is a relatively newer technology that 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. Once the CJC-1295 molecule has attached itself to albumin, it is given an extended half life and bioavailability thanks to the albumin preventing enzymatic degredation and kidney excretion. In fact, bioconjugation is so effective that there was less than 1% of CJC-1295 left unreacted in vivo and over 90% was stabilized after subcutaneous injection. This means that you get more of what you paid for working for you. There was no DPP-IV degredation observed on CJC-1295 in any of the various experiments conducted.

Various experiments have been conducted to test the effectiveness of CJC-1295 in vivo and the Journal of Clinical Endocrinology & Metabolism has reported dose-dependent increases in mean plasma GH concentrations by 2-10 fold for more than 6 days and increased IGF-1 concentrations 1.5-3 fold for 9-11 days after a single injection!

(from the same study) Subcutaneous administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30 or 60 µg/kg. There was evidence of a cumulative effect after multiple doses

Not only that but they proved the mean half life to be 5.8-8.1 days and after multiple doses showed mean IGF-1 levels remained above baseline for up to 28 days following! No serious adverse reactions were reported in any group.

Because of the long half-life and stability of the CJC-1295 analog it may only need to be taken 1-2 times per week. However research on GHRH knockout mice showed that e/d injections where superior in increasing GH vs every 48 or 72 hours. “GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48h and 72h reached higher body weight and length than placebo-treated animals, without full growth normalization.” These mice were treated for 5 weeks.
However the flaw in this study appears to be that the mice treated e/d were receiving a larger dose, so at minimum cjc-1295 is dose dependent. Whether or not a more frequent injection would prove to be beneficial is yet to be determined.

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 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
http://www.basskilleronline.com/images/ghrh/GHRH-Figure-1.gif

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
http://www.basskilleronline.com/images/ghrh/GHRH-Figure-2.gif

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
http://www.basskilleronline.com/images/ghrh/GHRH-Figure-3.gif

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
http://www.basskilleronline.com/images/ghrh/GHRH-Figure-4.gif

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
http://www.basskilleronline.com/images/ghrh/GHRH-Figure-5.gif

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

 

CJC-1295 Shows Promise as a Long-acting hGH Releaser

If you have used CJC-1295/CJC-1293 please post your results below. What dose did you use?

CJC-1295/CJC-1293 is a peptide analogue of GHRH. Because of the way CJC-1295 is engineered its half life has been extended from ~7 minutes to greater than 7 days!

Due to the extremely long half life of CJC-1295 it is plausible to use this peptide once per week with outstanding results. It would be wiser to use ½ dosages twice per week to keep serum levels high and to get maximal.

Various experiments have been conducted to test the effectiveness of CJC-1295 in vivo and the Journal of Clinical Endocrinology & Metabolism has reported dose-dependent increases in mean plasma GH concentrations by 2-10 fold for more than 6 days and increased IGF-1 concentrations 1.5-3 fold for 9-11 days after a single injection.

Not only that but they proved the mean half life to be 5.8-8.1 days and after multiple doses showed mean IGF-1 levels remained above baseline for up to 28 days following! No serious adverse reactions were reported in any group.

Another very positive benefit of CJC-1295/CJC-1293 is its ability to promote slow wave sleep. Slow wave sleep is also known as deep sleep and is the portion of sleep responsible for the highest level of muscle growth and memory retention. SWS are decreased significantly in older adults and also with people who tend to exercise later in the evening. This peptide has a benefit to side effect ratio that exceeds all others currently being legally sold and would make a great addition to ones training regimen or post cycle therapy.

CJC-1295 Shows Promise HGH Release

If you have used CJC-1295 please post your results below. What dose did you use?
CJC-1295 is a peptide analogue of GHRH. Because of the way CJC-1295 is engineered its half life has been extended from ~7 minutes to greater than 7 days!
Due to the extremely long half life of CJC-1295 it is plausible to use this peptide once per week with outstanding results. It would be wiser to use ½ dosages twice per week to keep serum levels high and to get maximal.

Various experiments have been conducted to test the effectiveness of CJC-1295 in vivo and the Journal of Clinical Endocrinology & Metabolism has reported dose-dependent increases in mean plasma GH concentrations by 2-10 fold for more than 6 days and increased IGF-1 concentrations 1.5-3 fold for 9-11 days after a single injection.

Not only that but they proved the mean half life to be 5.8-8.1 days and after multiple doses showed mean IGF-1 levels remained above baseline for up to 28 days following! No serious adverse reactions were reported in any group.

Another very positive benefit of CJC-1295 is its ability to promote slow wave sleep. Slow wave sleep is also known as deep sleep and is the portion of sleep responsible for the highest level of muscle growth and memory retention. SWS are decreased significantly in older adults and also with people who tend to exercise later in the evening. This peptide has a benefit to side effect ratio that exceeds all others currently being legally sold and would make a great addition to ones training regimen or post cycle therapy.

Quotes:
CJC 1295 is expensive whereas the GRF 1 – 29 & GHRP 6 are not, so I use GRF 1- 29 & GHRP 6 at doses of 100 mcg’s each morning. Before bedtime I inject 150 mcg’s of CJC 1295 & 100 mcg’s of GHRP 6. This seems to provide a good sleep & I wake in the morning feeling quite fresh & ready for another day at the uni.

The most popular dosage used by body builders seems to be 100 mcg injections of both CJC 1295 & GHRP 6 * 3 times each day. It really depends on a person’s goals, because some people use what I consider to be massive doses once or twice each week. The general opinion, however, seems to be that regular small doses are healthier & more effective. I’ve found that better sleep, & better digestion are the obvious results of using these products.

GHRP-6 is great for appetite stimulation and works very well taken with CJC-1295 and testosterone,Especially for those who have difficulty in gaining weight.
My vote goes to real hgh,lots of chinese brands have popped up these days.And like Sly Stallone said,hgh and testosterone should really be over the counter. your best way to go is to take 100mcg of GRF1-29 and 100mcgs GHRP6 in the morning upon waking up, post workout and pre-bed. The 2 peptides has a synergistic effect without the other it would be not 100% effective.

A GRF1-29 only wont do such…
A GHRP6 only will be a better choice…
But both will increase GH release 100%…

Try not to eat for about 30 minutes after administering the following peptides as fat affects the GH pulsations
Chris White

CJC-1295 & GHRP-6 (Basic Guides)

 



Introduction to the thread

What is growth hormone?

Synthetic Growth Hormone is an artificially created hormone "identical" to the major naturally produced (endogenous) isoform. It is often referred to by its molecular mass which is 22kDa (kilodaltons) and is made up of a sequence of 191 amino acids (primary structure) with a very specific folding pattern that comprise a three-dimensional structure (tertiary structure). This tertiary structure is subject to potential shape change through a process known as thermal denaturation. While many labs are capable of generating growth hormone (GH) with the proper primary structure not all will be capable of creating a tertiary structure identical to the major naturally occurring growth hormone. The tertiary structure can determine the strength with which the growth hormone molecule binds to a receptor which will in turn affect the "strength" of the intracellular signaling which mediates the events leading to protein transcription, metabolism, IGF-1 creation, etc. It is this inconsistency that accounts in part for the differences in effectiveness of various non-pharmaceutically produced synthetic growth hormone.

Naturally produced Growth Hormone is produced in the anterior pituitary and to a far lesser extent in peripheral tissue. It is made up of a blend of isoforms the majority of which is the 22kDa (191 amino acid) variety with which most are familiar. In addition an isoform that is missing the 15 amino acids that interact with the prolactin receptor is also produced. This form is known as 20kDa and although it binds differently to the growth hormone receptor it has been shown to be equally potent to 22kDa. It appears that 20kDa has lower diabetogenic activity then 22kDa. The pituitary releases a blend of these two isoforms with 20kDa averaging perhaps 10% of the total although this percentage increases post-exercise. Currently there is no synthetic produced for external administration for this isoform.

Growth hormone (GH) in the body is released in pulsatile fashion. It has been demonstrated that this pattern promotes growth. The pituitary is capable of rather quickly synthesizing very large amounts of growth hormone which it stores large amounts in both a finished and unfinished form. Adults rarely experience GH pulses (i.e. releases of pituitary stores) that completely deplete these stores. As we age we do not lose the ability to create and store large amounts of growth hormone. Rather we experience a diminished capacity to "instruct" their release. The volume of GH that is released can not be properly equated to the exogenous administration of synthetic GH for the reason that a set of behavioral characteristics accompany natural GH that differ from those of synthetic GH. Among those characteristics are concentrated pulsatile release which upon binding in mass to growth hormone receptors on the surface of cells initiate signaling cascades which mediate growth events by translocating signaling proteins to the nucleus of the cell where protein transcription and metabolic events occur.

These very important signaling pathways desensitize to Growth Hormone's initiating effects and need to experience an absence of Growth Hormone in order to reset and be ready to act again. The presence of GH released in pulsatile fashion is graphed as a wave with the low or no growth hormone period graphed as a trough. Therefore attempting to find a natural GH to synthetic GH equivalency is not very productive because in the end what is probably import is:

- the quantity &amp; quality of intracellular signaling events; and
- the degree to which GH stimulates autocrine/paracrine (locally produced/locally used) muscle IGF-1 &amp; post-exercise its splice variant MGF.

Synthetic GH versus Natural GH in IUs

An attempt has been made on my part and can be found at:

#8 - Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH (part I of II)

#9 - Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH (part II of II)

Rather than demonstrate absolute values this comparison articles should serve to demonstrate that the body can produce pharmacological levels of growth hormone.

Brief overview of natural GH release

The initiation of growth hormone release in the pituitary is dependent on a trilogy of hormones:

Somatostatin which is the inhibitory hormone and responsible in large part for the creation of pulsation;

Growth Hormone Releasing Hormone (GHRH) which is the stimulatory hormone responsible for initiating GH release; and

Ghrelin which is a modulating hormone and in essence optimizes the balance between the "on" hormone &amp; the "off" hormone. Before Ghrelin was discovered the synthetic growth hormone releasing peptides (GHRPs) were created and are superior to Ghrelin in that they do not share Ghrelin's lipogenic behavior. These GHRPs are GHRP-6, GHRP-2, Hexarelin and later Ipamorelin all of which behave in similar fashion.

In the aging adult these Ghrelin-mimetics or the GHRPs restore a more youthful ability to release GH from the pituitary as they turn down somatostatin's negative influence which becomes stronger as we age and turn up growth hormone releasing hormone's influence which becomes weaker as we age.

The exogenous administration of Growth Hormone Releasing Hormone (GHRH) creates a pulse of GH release which will be small if administered during a natural GH trough and higher if administered during a rising natural GH wave.

Growth Hormone Releasing Peptides (GHRP-6, GHRP-2, Hexarelin) are capable of creating a larger pulse of GH on their own then GHRH and they do this with much more consistency and predictability without regard to whether a natural wave or trough of GH is currently taking place.

Synergy of GHRH + GHRP

It is well documented and established that the concurrent administration of Growth Hormone Releasing Hormone (GHRH) and a Growth Hormone Releasing Peptide (GHRP-6, GHRP-2 or Hexarelin) results in synergistic release of GH from pituitary stores. In other words if GHRH contributes a GH amount quantified as the number 2 and GHRPs contributed a GH amount quantified as the number 4 the total GH release is not additive (i.e. 2 + 4 = 6). Rather the whole is greater than the sum of the parts such that 2 + 4 = 10.

While the GHRPs (GHRP-6, GHRP-2 and Hexarelin) come in only one half-life form and are capable of generating a GH pulse that lasts a couple of hours re-administration of a GHRP is required to effect additional pulses.

Growth Hormone Releasing Hormone (GHRH) however is currently available in several forms which vary only by their half-lives. Naturally occurring GHRH is either a 40 or 44 amino acid peptide with the bioactive portion residing in the first 29 amino acids. This shortened peptide identical in behavior and half-life to that of GHRH is called Growth Hormone Releasing Factor and is abbreviated as GRF(1-29).

GRF(1-29) is produced and sold as a drug called Sermorelin. It has a short-half life measured in minutes. If you prefer analogies think of this as a Testosterone Suspension (i.e. unestered).

To increase the stability and half-life of GRF(1-29) four amino acid changes where made to its structure. These changes increase the half-life beyond 30 minutes which is more than sufficient to exert a sustained effect which will maximize a GH pulse. This form is often called tetrasubstituted GRF(1-29) (or modified) and unfortunately &amp; confusingly mislabeled as CJC-1295. If you prefer analogies think of this as a Testosterone Propionate (i.e. short-estered).

Note that some may also refer to this as CJC-1295 without the DAC (Drug Affinity Complex).

Frequent dosing of either the aforementioned modified GRF(1-29) or regular GRF(1-29) is required and as previously indicated works synergistically with a GHRP.

In an attempt to create a more convenient long-lasting GHRH, a compound known as CJC-1295 was created. This compound is identical to the aforementioned modified GRF(1-29) with the addition of the amino acid Lysine which links to a non-peptide molecule known as a "Drug Affinity Complex (DAC)". This complex allows GRF(1-29) to bind to albumin post-injection in plasma and extends its half-life to that of days. If you prefer analogies think of this as a Testosterone Cypionate (i.e. long-estered). However this is not accurate. CJC-1295 results in continual GH bleed. Although natural pulsation still occurs CJC-1295 does nothing to increase those pulses. Instead it raises base levels of GH and creates a more feminized pattern of release. This not desirable.

Modified GRF(1-29)however when combined with a GHRP brings about a substantial pulse which has desirable effects.

What follows on this first page of the thread is:

- A Basic Peptide Primer (which introduces the concept &amp; structure of peptides)

- A Brief Summary of Dosing and Administration (for someone that wants to know the "how to use" straight away)

If all of this is a bit unclear because a lot of new concepts are thrown at you one of my original very thorough articles is available:

Post #5 - Basic Guide: Growth Hormone Secretagogues

Post #6 - Basic Guide: Growth Hormone Secretagogues (part II)

I have only one pet-peeve and that is when someone refers to synthetic growth hormone as "real" growth hormone. The GH that your body produces is as real as it gets. It is what grew you from a fetus to a boy (girl) and from a boy (girl) to a man (woman). - DatBtrue


Basic Peptide Primer
Written by
Datbtrue

What is a peptide?

Peptides (proteins) are present in every living cell and possess a variety of biochemical activities. Some peptides are synthesized in the ribosomes of a cell by translation of mRNA (messenger RNA) into hormones and signaling molecules for example. Other peptides are assembled (rather then synthesized) and become enzymes with a vast variety of functions. Peptides also make up the structure of receptors which await binding of hormones &amp; signaling molecules.

A peptide is a molecule created by joining two or more amino acids. In general if the number of amino acids is less than fifty, these molecules are called peptides, while larger sequences are referred to as proteins.

So peptides can be thought of as tiny proteins. They are merely strings of amino acids.

Raw Constituents of Peptides (Amino Acids)

Amino acids are small molecules made up of atoms. As part of their structure they posses a grouping of a Nitrogen (N) atom bonded to two Hydrogen (H) atoms. This is called an amino group and written as (NH2). In addition their structure is also made up of a second grouping of a Carbon (C) atom bonded to two Oxygen (O) and one Hydrogen atom. This group is called a carboxyl group and is written as (COOH).

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Between these two groupings are atoms and bonds unique to each amino acid. In other words all amino acids possess the two groupings (amino &amp; carboxyl) as end-points between which are sandwiched a unique set of atoms.

Amino Acids

Inside the human body there are twenty standard amino acids used by cells in peptide biosynthesis (i.e. the cellular creation of peptides from amino acids). Our genetic code specifies how to synthesize peptides and proteins from these amino acids.

Amino acids are classified into two groups: essential amino acids and nonessential amino acids.

An essential amino acid is an indispensable amino acid which cannot be made by the body and must be supplied by food. These include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Another amino acid - histidine is considered semi-essential because the body does not always require dietary sources of it.

Nonessential amino acids are made by the body from the essential amino acids or the routine breakdown of proteins. The nonessential amino acids are arginine, alanine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, proline, serine, and tyrosine.

All twenty amino acids are equally important in maintaining a healthy body. They are the raw constituents of peptides and proteins.

The standard abbreviations for amino acids come in two forms: a one letter form and a three letter form. They are:

A - Ala - Alanine
C - Cys - Cysteine
D - Asp - Aspartic Acid
E - Glu - Glutamic Acid
F - Phe - Phenylalanine
G - Gly - Glycine
H - His - Histidine
I - Ile - Isoleucine
K - Lys - Lysine
L - Leu - Leucine
M - Met - Methionine
N - Asn - Asparagine
P - Pro - Proline
Q - Gln - glutamine
R - Arg - Arginine
S - Ser - Serine
T - Thr - Threonine
V - Val - Valine
W - Trp - Tryptophan
Y - Tyr - Tyrosine


Amino acids exist in either D (dextro) or L (levo) form. Most of the amino acids found in nature (and all within human cells) are of the L-form. As a generality all amino acids except glycine have a mirror image of the L-form. This mirror image is called the D-form. It is common when referring to the L-form (naturally occurring form) to leave off the "L" designation whereas the "D" designation is always explicitly written.

D-amino acids are found naturally in bacterial cell walls and used in some synthetic peptides to make a peptide more stable or more resistant to degradation.

Amino Acid + Amino Acid = Peptide

The amino acids are joined together by what is known as a "peptide bond". A "peptide bond" is a linkage in which the nitrogen atom of one amino acid (from the amino group (NH2) binds to the carbon atom of another amino acid's carboxyl group (COOH).

During this binding process a molecule of water is released. This is called a condensation reaction.

The resulting CO-NH bond is called a peptide bond, and the resulting molecule is called an amide.

On the following image note that the COOH group gives up an Oxygen Hydrogen (OH) bond and the NH2 group gives up a Hydrogen (H). This forms H2O, which is a water molecule which is not part of the newly created peptide. NOTE: in the following image the C (carbon) symbol is missing as it is assumed so I indicate it with a blue square.

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This reaction creating a peptide bond between two amino acids creates a peptide. We can call this peptide (made up of two amino acids) a dipeptide.

This process can be repeated using the twenty amino acids as raw material to create longer peptide chains. Sometimes peptide chains consisting of fifty to 100 amino acids are called polypeptides. Often a peptide chain beyond 100 amino acids is called a protein.

GHRP-6 is a peptide made up of just six amino acids. It's structure is often written as His-DTrp-Ala-Trp-DPhe-Lys-NH2

Note that the Carboxyl grouping (COOH) is assumed in the first position and is usually not written. The amino group (NH2) is wrtitten in the last position. The "meat" or the part that makes GHRP-6 distinct is the seqence in the middle of histadine bonded to the "D" form of Tryptophan bonded to Alanine bonded to Tryptophan bonded to the "D" form of Phenylalanine bonded to Lysine.

Pepdide bonds are formed by water (H2O) condensation (removing water). The converse is also true. A peptide bond can be broken down by hydrolysis (adding water).

The Amino Acid Structures of Peptides discussed in this thread

Growth Hormone Releasing peptides (GHRPs) (GH pulse initiators):

- GHRP-6 (His-DTrp-Ala-Trp-DPhe-Lys-NH2)

- GHRP-2 (
DAla-D-2-Nal-Ala-Trp-DPhe-Lys-NH2)

- Hexarelin (His-D-2-methyl-Trp-Ala-Trp-DPhe-Lys-NH2)

- Ipamorelin (
Aib-His-D-2-Nal-DPhe-Lys-NH2) - Ref-1

NOTES:

Aib = Aminoisobutyryc acid
D-2-Nal = "D" form of 2’-naphthylalanine

Growth Hormone Releasing Hormone (GHRH) (amplifies the GHRP initiated pulse):

- Growth Hormone Releasing Hormone (GHRH) aka GRF(1-44) (Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2) = half-life "less then 10 minutes", perhaps as low as 5 minutes. - Ref-2


- GRF(1-29) aka Sermorelin (
Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2) - the biologically active portion of the 44 amino acid GHRH = half-life "less then 10 minutes", perhaps as low as 5 minutes. - Ref-3

- Longer-lasting analogs of GRF(1-29):

-- replace the 2nd amino acid Alanine w/ D-Alanine only to modify GRF(1-29), D-Ala2 GRF(1-29) (Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2) = half-life "closer to 10 minutes" - Ref-4


-- replace the 2nd, 8th, 15th &amp; 27th amino acids &amp; get modified GRF(1-29) or CJC-1295 w/o the DAC (i.e. the part that will bind to albumin &amp; make the half-life days) (
Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2) = Half-life at least 30 minutes or so - Ref-5

-- CJC-1295 (
Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-Lys-(Maleimidopropionyl)-NH2) = Half-life measured in days, - Ref-6

NOTES:

Lys = linker to the Drug Affinity Complex (aka (Maleimidopropionyl))

"Since GH is released in a pulsatile manner and a higher level of GH is observed between 15 and 30 min after subcutaneous administration of GH-RH analogues, hydrolysis by trypsin-like enzymes could not affect the result of stimulation." - Potent Trypsin-resistant hGH-RH Analogues, JAN IZDEBSKI, J. Peptide Sci. 10: 524–529 (2004)

The analog in the above quoted study resisted degradation for 30 minutes. The quote implies that if your analog can last 30 minutes it has tapped out the potential for a single pulse.

Since another pulse won't be generated for about 2.5 - 3 hours analogs that last more than 30 minutes up to 3 hours are not any more beneficial.

You would need an analog that kept growth hormone releasing hormone around beyond 3 hours to have it trigger a second pulse.

Otherwise dosing the 30 minute analog every 3 hours will maximize GH output OR you could just use an analog such as CJC-1295 which lasts for many days and will trigger several GH pulses a day for several days on a single dose.

References:

Ref-1 - "lack of effect on ACTH and cortisol plasma levels" -
Ipamorelin, the first selective growth hormone secretagogue , K Raun, European Journal of Endocrinology, 1996 Vol 139, Issue 5, 552-561

Ref-2 -
Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus, Frohman LA, J Clin Invest. 1986 78:906–913 and Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-3 -
Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus, Frohman LA, J Clin Invest. 1986 78:906–913 and Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-4 -
Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-5 -
See: Posts within this thread

Ref-6 -
See: Posts within this thread



A Brief Summary of Dosing and Administration

Dosing GHRPs

The saturation dose in most studies on the GHRPs (GHRP-6, GHRP-2, Ipamorelin &amp; Hexarelin) is defined as either 100mcg or 1mcg/kg.

What that means is that 100mcg will saturate the receptors fully, but if you add another 100mcg to that dose only 50% of that portion will be effective. If you add an additional 100mcg to that dose only about 25% will be effective. Perhaps a final 100mcg might add a little something to GH release but that is it.

So 100mcg is the saturation dose and you could add more up to 300 to 400mcg and get a little more effect.

A 500mcg dose will not be more effective then a 400mcg, perhaps not even more effective then 300mcg.

The additional problems are desensitization &amp; cortisol/prolactin side-effects.

Ipamorelin is about as efficacious as GHRP-6 in causing GH release but even at higher dose (above 100mcg) it does not create prolactin or cortisol.

GHRP-6 at the saturation dose 100mcg does not really increase prolactin &amp; cortisol but may do so slightly at higher doses. This rise is still within the normal range.

GHRP-2 is a little more efficacious then GHRP-6 at causing GH release but at the saturation dose or higher may produce a slight to moderate increase in prolactin &amp; cortisol. This rise is still within the normal range although doses of 200 - 400mcg might make it the high end of the normal range.

Hexarelin is the most efficacious of all of the GHRPs at causing an increase in GH release. However it has the highest potential to also increase cortisol &amp; prolactin. This rise will occur even at the 100mcg saturation dose. This rise will reach the higher levels of what is defined as normal.

Desensitization

GHRP-6 can be used at saturation dose (100mcg) three or four times a day without risk of desensitization.

GHRP-2 probably at saturation dose several times a day will not result in desensitization.

Hexarelin has been shown to bring about desensitization but in a long-term study the pituitary recovered its sensitivity so that there was not long-term loss of sensitivity at saturation dose. However dosing Hexarelin even at 100mcg three times a day will likely lead to some down regulation within 14 days.

If desensitization were to ever occur for any of these GHRPs simply stopping use for several days will remedy this effect.

Chronic use of GHRP-6 at 100mcg dosed several times a day every day will not cause pituitary problems, nor significant prolactin or cortisol problems, nor desensitize.

GHRH

Now Sermorelin, GHRH (1-44) and GRF(1-29) all are basically GHRH and have a short half-life in plasma because of quick cleavage between the 2nd &amp; 3rd amino acid. This is no worry naturally because this hormone is secreted from the hypothalamus and travels a short distance to the underlying anterior pituitary and is not really subject to enzymatic cleavage. The release from the hypothalamus and binding to somatotrophs (pituitary cells) happens quickly.

However when injected into the body it must circulate before finding its way to the pituitary and so within 3 minutes it is already being degraded.

That is why GHRH in the above forms must be dosed high to get an effect.

GHRH analogs

All GHRH analogs swap Alanine at the 2nd position for D-Alanine which makes the peptide resistant to quick cleavage at that position. This means analogs will be more effective when injected at smaller dosing.

The analog tetra or 4 substituted GRF(1-29) sometimes called CJC w/o the DAC or referred to by me as modified GRF(1-29) has other amino acid modifications. They are a glutamine (Gln or Q) at the 8-position, alanine (Ala or A) at the 15-position, and a leucine (Leu or L) at the 27-position.

The alanine at the 8th position enhances bioavailability but the other two amino substitutions are made to enhance the manufacturing process (i.e. create manufacturing stability).

For use in vivo, in humans, the GHRH analog known as CJC w/o the DAC or tetra (4) substituted GRF(1-29) or modified GRF(1-29) is a very effective peptide with a half-life probably 30+ minutes.

That is long enough to be completely effective.

The saturation dose is also defined as 100mcg.

Problem w/ Using any GHRH alone

The problem with using a GHRH even the stronger analogs is that they are only highly effective when somatostatin is low (the GH inhibiting hormone). So if you unluckily administer in a trough (or when a GH pulse is not naturally occurring) you will add very little GH release. If however you luckily administer during a rising wave or GH pulse (somatostatin will not be active at this point) you will add to GH release.

Solution is GHRP + GHRH analog

The solution is simple and highly effective. You administer a GHRH analog with a GHRP. The GHRP creates a pulse of GH. It does this through several mechanisms. One mechanism is the reduction of somatostatin release from the hypothalamus, another is a reduction of somatostatin influence at the pituitary, still another is increased release of GHRH from the brain and finally GHRPs act on the same pituitary cells (somatotrophs) as do GHRHs but use a different mechanism to increase cAMP formation which will further cause GH release from somatotroph stores.

GHRH also has a way of reciprocally reinforcing GHRPs action.

The result is a synergistic GH release.

The GH is not additive it is synergistic. By that I mean:

If GHRH by itself will cause a GH release valued at 2
and GHRP itself will cause a GH release valued at 5

Together the GH is not 7 (5+2) it turns out to say 16!

A solid protocol

A solid protocol would be to use a GHRP + a GHRH analog pre-bed (to support the nightime pulse) and once or twice throughout the day.

For anti-aging, deep restful restorative sleep, the once at night dosing is all you need. For an adult aged 40+ it is enough to restore GH to youthful levels.

However for bodybuilding or fatloss or injury repair multiple dosings can be effective.

The GHRH analog can be used at 100mcg and as high as you want without problems.

The GHRP-6 can always be used at 100mcg w/o problems but a dose of 200mcg will probably be fine as well.

Again desensitization is something to keep an eye on particularly with the highest doses of GHRP-2 and all doses of Hexarelin.

So 100 - 200mcg of GHRP-6 + 100 - 500mcg+ of a GHRH analog taken together will be effective.

This may be dosed several times a day to be highly effective.

A solid approach is a bit more conservative at 100mcg of GHRP-6 + 100mcg of a GHRH analog dosed either once, twice, three or four times a day.

When dosing multiple times a day at least 3 hours should separate the administrations.

The difference is once a day dosing pre-bed will give a youthful restorative amount of GH while multiple dosing and or higher levels will give higher GH &amp; IGF-1 levels when coupled with diet &amp; exercise will lead to muscle gain &amp; fatloss.

Dose w/o food

Administration should ideally be done on either an empty stomach or with only protein in the stomach. Fats &amp; carbs blunt GH release. So administer the peptides and wait about 20 minutes (no more then 30 but no less then 15 minutes) to eat. AT that point the GH pulse has about hit the peak and you can eat what you want.

Modified GRF 1-29

 

In the healthy human body, large amounts of growth hormone are stored in the pituitary. The cells within the pituitary release growth hormone in response to signaling by GHRH (Growth Hormone Releasing Hormone), Ghrelin (of which GHRPs - Growth Hormone Releasing Peptides - are mimetics), and are inhibited from releasing these stores by Somatostatin. GHRH and Ghrelin act on different populations of somatotropes (GH releasing cells). GHRP/Ghrelin increases the number of somatotropes releasing GH but not the amount released by each cell; GHRH affects both the number of secreting cells and - more so - the amount they each secrete. [1] GHRH and Ghrelin are released in specific patterns that vary depending on event and environment: post-exercise, in response to slow wave sleep, in certain stages of life and physical development, and so on.


Most people (even the diseased) continue to possess the ability to make GH in the pituitary. The problem is in the signalling of the pituitary to release it and make more. Even most people with diseases that affect growth hormone secretion retain the ability to continue to make GH in their pituitaries. The disease states and symptoms result, most typically, in altered (dysfunctional) GH release signaling and this also affects the ability of the pituitary to continue to make more GH. [2]


Endogenous-type GHRH, which has a forty-four amino acid long chain (and a specific shape - thus making it a peptide as well as a hormone), has been marketed for the longest as Sermorelin in comparison to the other GHRH-type peptides. However, Sermorelin has been demonstrated to be degraded rapidly in the body and is cost-inefficient. But because most patients in need of GH therapy do retain the ability to produce and secrete their own GH, treatment with a GHRH-type analog remained hypothetically preferable to exogenous GH treatment. GH itself when administered exogenously results not only in "unnatural" release patterns, it results universally in down regulation of endogenous GH production - as do many hormones when applied exogenously.[3]


Sermorelin's limitations naturally resulted in a variety of formulations of GHRH analogs for therapeutic usage. CJC-1295, discussed in another article, is a GHRH analogue with attached MPA (aka DAC), binds to albumin in the bloodstream and circulates for a week or longer. Modified GRF 1-29, which is also called D-Ala2-GHRH-(1-29), [Nle27]-hGHRH(1-29)-NH2, GHRH (1-29)NH2, or ModGRF1-29, is the bioactive portion of GHRH(1-44) with fifteen amino acids subtracted and four amino acids replaced at the weakest points in the peptide structure.


Soule et al write that "D-Ala2 substitution contributes to the enhancement of biological activity by reducing metabolic clearance." [3] In a comparison study with synthetic exogenous GH for treating prepubertal GH deficiency, Lanes and Carillo concluded that "GHRH (1-29) at the dose and schedule used is generally effective in the treatment of GH deficiency." [4]


Campbell et al explain both GHRH(1-44)'s shortcomings in treatment as well as advantages offered by Modified GRF (1-29) and specific structural differences:

Native human GRF(1-44)-NH2(hGRF44) is subject to biological inactivation by both enzymatic and chemical routes. In plasma, hGRF44 is rapidly degraded via dipeptidylpeptidase IV (DPP-IV) cleavage between residues Ala2 and Asp3. The hGRF44 is also subject to chemical rearrangement (Asn8-->Asp8, beta-Asp8 via aminosuccinimide formation) and oxidation [Met27-->Met(O)27] in aqueous environments, greatly reducing its bioactivity. It is therefore advantageous to develop long-acting GRF analogues using specific amino acid replacements at the amino-terminus (to prevent enzymatic degradation): residue 8 (to reduce isomerization) and residue 27 (to prevent oxidation). Inclusion of Ala15 substitution (for Gly15), previously demonstrated to enhance receptor binding affinity, would be predicted to improve GRF analogue potency. Substitution of [His1,Val2]-(from the mouse GRF sequence) for [Tyr1,Ala2]-(human sequence) in [Ala15,Leu27]hGRF(1-32)-OH analogues completely inhibited (24-h incubation) DPP-IV cleavage and greatly increased plasma stability in vitro. Additional substitution of Thr8 (mouse GRF sequence), Ser8 (rat GRF sequence), or Gln8 (not naturally occurring) for Asn8 (human GRF sequence) resulted in analogues with enhanced aqueous stability in vitro (i.e., decreased rate of isomerization). These three highly stable and enzymatically resistant hGRF(1-32)-OH analogues, containing His1, Val2, Thr/Gln8, Ala15, and Leu27 replacements, were then bioassay for growth hormone (GH)-releasing activity in vitro (rat pituitary cell culture) and in vivo (SC injection into pigs). Enhanced bioactivity was observed with all three hGRF(1-32)-OH analogues. In vitro, these analogues were approximately threefold more potent than hGRF44, whereas in vivo they were eleven- to thirteen fold more potent.[5]


Just as GHRH and Ghrelin work in conjunction through different means for maximal GH release within the body, exogenous GHRH such as Modified GRF (1-29) results in a synergistic effect when used with a Ghrelin mimetic, such as the hexapeptide known as GHRP-6. [6] Pandya et al also conclude that "GHRH is necessary for most of the GH response to GHRP-6 in humans." [6] Massoud et al conclude that "Hexarelin and GHRH-(1-29)-NH2 are synergistic" [7] (Ed note: Hexarelin is another Ghrelin mimetic).


Sawada writes that "findings suggest that the KP-102-induced GH secretion largely depends on GRF and the secretagogue potentiates the GRF effect by antagonizing the SS action at the level of somatotropes. It is concluded that KP-102 alone or in combination with GRF provides a means of stimulating GH secretion in the face of elevated inhibitory tone mediated by SS." [8] (Ed note: KP-102 is the Ghrelin mimetic GHRP-2)


An abstract of a review by Hamilton touches on the main advantage of GRF(1-29) over, for example, CJC-1295 or synthetic GH:

Growth hormone secretion occurs in a rhythmic pattern regulated by intricate interactions between two neurohormones: growth hormone-releasing hormone (GHRH) and somatotropin release-inhibiting factor (SRIF).[...] research also indicates that there are sexual differences in the pattern of growth hormone release and that growth hormone regulates its own secretion by means of a negative feedback system. [9]

By mimicking natural release patterns with properly dosed and timed GHRPs (Ghrelin mimetics) and GHRH-analogues, negative feedback and undesirable side effects that are typically seen in synthetic GH therapy or even with past forms of GHRH administration (such as constant low-dose administration via pump) can be avoided.


For achieving ends other than restoring natural GH release in diseased patients, optimized rhythmic or pulsatile dosing of GHRH with or without a GHRP may be useful, as Vittone et al write about their findings on GHRH applied to healthy elderly men:

Data suggest that single nightly doses of GHRH are less effective than multiple daily doses of GHRH in eliciting GH- and/or IGF-I-mediated effects. GHRH treatment may increase muscle strength, and it alters baseline relationships between muscle strength and muscle bioenergetics in a manner consistent with a reduced need for anaerobic metabolism during exercise. Thus, an optimized regimen of GHRH administration might attenuate some of the effects of aging on skeletal muscle function in older persons.[10]

references:

[1] Lewis UJ. Growth hormone: what is it and what does it do? Trends Endocrinol Metab 1992;3:117–121

[2] J Izdebski, J Pinski, JE Horvath, G Halmos, K Groot and AV Schally. Synthesis and Biological Evaluation of Superactive Agonists of Growth Hormone-Releasing Hormone. Proceedings of the National Academy of Sciences, Vol 92, 4872-4876.

[3] Soule S, King JA, Millar RP. Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men. J Clin Endocrinol Metab. 1994 Oct;79(4):1208-11.

[4]Lanes R, Carrillo E. Long-term therapy with a single daily subcutaneous dose of growth hormone releasing hormone (1-29) in prepubertal growth hormone deficient children. J Pediatr Endocrinol. 1994 Oct-Dec;7(4):303-8.

[5] Campbell RM, Stricker P, Miller R, Bongers J, Liu W, Lambros T, Ahmad M, Felix AM, Heimer EP. Enhanced stability and potency of novel growth hormone-releasing factor (GRF) analogues derived from rodent and human GRF sequences. Peptides. 1994;15(3):489-95.

[6]Pandya N, DeMott-Friberg R, Bowers CY, Barkan AL, Jaffe CA. Growth hormone (GH)-releasing peptide-6 requires endogenous hypothalamic GH-releasing hormone for maximal GH stimulation. J Clin Endocrinol Metab. 1998 Apr;83(4):1186-9.

[7]Massoud AF, Hindmarsh PC, Matthews DR, Brook. The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity. Clin Endocrinol (Oxf). 1996 May;44(5):555-62.

[8] Sawada H. Effect of newly developed analogue of growth hormone releasing peptide [D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2 (KP-102)] on growth hormone secretion in adult male rats (Trans. from Japanese). Nippon Ika Daigaku Zasshi. 1995 Apr;62(2):142-9.

[9] Hamilton J. A question of rhythm: recent advances in growth hormone research. CMAJ. 1995 Sep 1;153(5):585-8.

[10] Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart KJ, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RG. Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men. Metabolism. 1997 Jan;46(1):89-96.



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