GHRP down-regulation following prolonged GHRP administration in vivo in the rat was described by Bowers in his original description of GHRP efficacy. In the short-term, the administration of GHRP in vivo causes an immediate down-regulation of responsiveness to subsequent exposures to GHRP. For example, an infusion of GHRP results in a large initial release of GH, then after several hours a long-term down-regulation of GH secretion. We have published the only comparison of different patterns of GHRP exposure on longterm efficacy. The body gains weight from this experiment. The experiment showed a dramatic waning of anabolism after infusions of GHRP, while anabolism was maintained with GHRP injections.
Such observations should influence GHRP structure-activity considerations for GHRP candidate drugs, GHRP formulations and GHRP delivery. However it is clear that continuous exposure to GHRPs has not been seen as of key importance in GHRP drug design programmes. For example MK-677 was chosen for clinical development because of its "superior oral potency and duration of action". Given the persistence and thus long-lasting activity of this molecule it was always possible that this molecule may not have long lasting efficacy in humans. This possibiUty was recently confirmed when MK-677 failed to show a maintained acceleration of statural growth in children. A synergistic interaction between administered GRF and GHRP occurs in vivo, but apart from one study, such synergism has not been seen in vitro. It is likely that the dramatic effects of GHRPs on GH secretion in vivo, which are much more impressive than those in vitro, may be a reflection of this synergism and of an inhibition of somatostatin secretion. However the dramatic synergistic effects of GHRP and GRF on GH secretion have yet to be translated into dramatic synergistic effects on efficacy endpoints (growth, anabolism, reduced fat depot size) in vivo. Why this has not been the case is difficult to understand or discern. A rise in IGF-1 concentrations in blood, caused by a rise in GH secretion, has been assumed to be the "surrogate" marker of GHRP activity that would inevitably lead to efficacy in terms of GHRP mimicking the effects of administering GH on anabolism, growth or lipolysis.
It has been a salutary lesson in endocrinology that increases in IGF-1, the surrogate marker of increased GH activity, have not resulted in long-term effects of GHRP administration that are comparable to the effects of administering GH or IGF-1. Thus, IGF-1 levels do not seem to be a good surrogate marker for GHRP efficacy on anaboUsm, growth or lipolysis. The reason for this is unclear. It could be that GHRP administration changes the pattern of GH exposure, rather than the amount of GH exposure, causing a rise in IGF-1 levels. A more continuous GH exposure causes larger rises in blood IGF-1 levels than intermittent GH exposure, suggesting that a rise in IGF-1 levels following GHRP exposure is not predictive of GH-like efficacy. The pediatric literature now suggests that the growth response to treatment with injections of IGF-1 in children does not match the growth response that can be caused by GH treatment.
This confirms the animal data which has shown that IGF-1 administration does not show the full anabolic and growth promoting efficacy of treatment with GH. It is even unclear as to whether or not the blood IGF-1 response to GH treatment is predictive of the statural growth response in GH-deficient children. This series of experimental observations clearly illustrates the tenuous nature of the use of blood IGF-1 concentrations as a surrogate marker for GHRP efficacy. Therefore, the fact that the administration of a particular GHRP causes a rise in IGF-1 concentrations in animals cannot be taken as evidence pre-cUnically that a molecule will show long-term efficacy in animals or humans. In addition, a rise in IGF-1 concentrations in humans following the administration of GHRP should not be taken as predictive of long-term efficacy. The above discussion underscores what seems to be obvious, but has been perhaps ignored in the transition of the GHRPs from pre-clinical to clinical studies. This is that the actual endpoints that are intended to be achieved by GHRPs in humans should be shown in animals rather than relying on surrogate endpoints. For example, for GHRP use in pediatrics for statural growth, animal data showing a robust increase in epiphyseal cartilage growth or longitudinal bone growth would seem to be necessary. Given that these are the "classic" endpoints for GH action and activity, it is surprising that there is no literature showing dramatic "GH-like" effects of GHRP in vivo on bone growth in animals.
The recent human data, that GHRPs are relatively poor stimulators of bone growth, may be the reason why robust growth promoting animal data is lacking. In comparison, many more experiments have shown that GRF induces classic GH-like growth responses in animals. Clear structure-activity data of GHRP efficacy on long-term efficacy endpoints such as bone growth in animals, is needed. Such data should be predictive of superior GHRP efficacy in humans. Solutions to the issues identified above need to be found if future structure-activity analyses of GHRP are to identify clinically useful GHRPs. It is clear that the dramatic GH release that can be induced by GHRPs should be amenable to being harnessed for long-term clinical benefit. However, current GHRP molecules and/or modes of administration have not been able to translate effects on GH secretion into long-term efficacy on clinically desirable endpoints. It is also apparent that the lack of dramatic long-term GHRP efficacy in animals suggests that there are basic flaws in widely held concepts of GHRP activity and use. Key issues that need to be addressed are the importance of GHRP-induced ACTH release and long-term down-regulation, both of which may limit long-term GHRP efficacy. The relationship between the down-regulation, the mode of GHRP administration, and therefore of GHRP receptor exposure, are key related issues. Although the acute GH-releasing activity of the GHRPs is tantalizing, much more research is needed before a GHRP will become a pharmaceutical with acceptable GH-like efficacy in humans.
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