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.


CONTEXT:
Therapeutic use of GHRH to enhance GH secretion is limited by its short duration of action.

OBJECTIVE:
The objective of this study was to examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog.

DESIGN:
The study design was two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 d.

SETTING:
The study was performed at two investigational sites.

PARTICIPANTS:
Healthy subjects, ages 21-61 yr, were studied.

INTERVENTIONS:
CJC-1295 or placebo was administered sc in one of four ascending single doses in the first study and in two or three weekly or biweekly doses in the second study.

MAIN OUTCOME MEASURES:
The main outcome measures were peak concentrations and area under the curve of GH and IGF-I; standard pharmacokinetic parameters were used for CJC-1295.

RESULTS:
After a single injection of CJC-1295, there were dose-dependentincreases in mean plasma GH concentrations by 2- to 10-fold for 6 d or more and in mean plasma IGF-I concentrations by 1.5- to 3-fold for 9-11 d. The estimated half-life of CJC-1295 was 5.8-8.1 d. After multiple CJC-1295 doses, mean IGF-I levels remained above baseline for up to 28 d. No serious adverse reactions were reported.

CONCLUSIONS:
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 microg/kg. There was evidence of a cumulative effect after multiple doses. These data support the potential utility of CJC-1295 as a therapeutic agent.






J Clin Endocrinol Metab. 2006 Mar;91(3):799-805. Epub 2005 Dec 13.

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Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog.



CONTEXT:
Pulsatile GH secretion is considered important for many of the hormone’s physiological effects. Short-term GHRH infusions enhance GH pulsatility and increase IGF-I, but the short GHRH half-life limits its therapeutic use. A synthetic GHRH analog (CJC-1295) that binds permanently to endogenous albumin after injection (half-life = 8 d) stimulates GH and IGF-I secretion in several animal species and in normal human subjects and enhances growth in rats.

OBJECTIVE:
Our objective was to assess GH pulsatility after a single injection of CJC-1295 and determine which GH secretion parameters correlated to the increase in IGF-I production.

METHODS:
GH pulsatility was assessed by 20-min blood sampling during an overnight 12-h period in healthy 20- to 40-yr-old men before and 1 wk after injection of either 60 or 90 microg/kg CJC-1295.

RESULTS:
GH secretion was increased after CJC-1295 administration with preserved pulsatility. The frequency and magnitude of GH secretory pulses were unaltered. However, basal (trough) GH levels were markedly increased (7.5-fold; P < 0.0001) and contributed to an overall increase in GH secretion (mean GH levels, 46%; P < 0.01) and IGF-I levels (45%; P < 0.001). No significant differences were observed between the responses to the two drug doses. The IGF-I increases did not correlate with any parameters of GH secretion.

CONCLUSIONS:
CJC-1295 increased trough and mean GH secretion and IGF-I production with preserved GH pulsatility. The marked enhancement of trough GH levels by continuous GHRH stimulation implicates the importance of this effect on increasing IGF-I. Long-acting GHRH preparations may have clinical utility in patients with intact pituitary GH secretory capability.







J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. Epub 2006 Oct 3.



So in basic terms the use of higher dose CJC1295 (GHRH) will raise basel and IGF-1 levels




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CJC-1295 Decay Rate Chart

A single dose of CJC-1295 “decays” by about 10% a day. So that single dose will follow the “effectiveness” percentages indicated below over the week:
_______Dose (2mg)
Day 0 – 100% (2mg)
Day 1 – 90% (1.8mg remaining)
Day 2 – 81% (1.6mg remaing)
Day 3 – 73% (1.4mg remaining
Day 4 – 65% (1.3mg remaining)
Day 5 – 59% (1.1mg remaining)
Day 6 – 53% (1mg remaining)
Day 7 – 47% (.9mg remaining)
Day 8 – 43% (.8mg remaining)

So a once a week dosing protocol would result in less consistent GH blood levels then the twice a week dosing indicated below (especially so after the initial buildup):

______Dose #1_(1mg)__________Dose #2_(1mg)__________Dose #3_(1mg)
Day 0 – 100% (1mg)
Day 1 – 90% (.9mg remaining)
Day 2 – 81% (.8mg remaing)
Day 3 – 73% (.7mg remaining)
Day 4 – 65% (.6mg remaining) + 100% (1mg) = 1.6mg
Day 5 – 59% (.5mg remaining) + 90% (.9mg remaining) = 1.4mg
Day 6 – 53% (.5mg remaining) + 81% (.8mg remaing) = 1.3mg
Day 7 – 47% (.4mg remaining) + 73% (.7mg remaining) = 1.1mg
Day 8 – 43% (.3mg remaining) + 65% (.6mg remaining) + 100% (1mg) = 1.9m