Hexarelin
Also known as: Examorelin, EP-23905, MF-6003, Hexarelin acetate
Evidence: Clinical
Overview
Highly potent synthetic hexapeptide GH secretagogue that also showed direct cardioprotective effects in animal work; desensitizes the GH axis with continuous use.
Hexarelin (examorelin) is a GHRP-6 analog with a methylated D-Trp. In 12 healthy men, 1 mcg/kg IV released about twice the GH of 1 mcg/kg GHRH; it was also active SC (1.5-3 mcg/kg), intranasally and orally (Ghigo 1994). A double-blind rising-dose study put the IV ED50 near 0.5 mcg/kg (Imbimbo 1994). Intranasal 60 mcg/kg three times daily raised growth velocity from 5.3 to 8.3 cm/year in eight short children (Laron 1995). Sixteen weeks of 1.5 mcg/kg SC twice daily in adults produced a partial, reversible blunting of the GH response and no change in IGF-1 or body composition (Rahim 1998). It also has GH-independent cardiac actions: protection of hypophysectomized rat hearts from ischemia-reperfusion (Locatelli 1999) and higher ejection fraction and cardiac output in bypass patients (Broglio 2002, n=24). Not developed as a drug.
Benefits
GH release about 2x that of GHRH (human, n=12), growth velocity in short children (human, n=8, intranasal), cardiac output during bypass surgery (human, n=24), protection from ischemia-reperfusion injury (rat)
Dosing reference
- Research dose
- 1-2 mcg/kg IV or 1.5-3 mcg/kg SC in human GH studies (about 100-200 mcg for 70 kg); 1.5 mcg/kg SC 2x daily for 16 weeks in the longest adult trial
- Range
- 100 to 200 mcg, 1-2x daily
- Reconstitution
- 2 mL bacteriostatic water
- Common vial sizes
- 2 mg, 5 mg
Subcutaneous in research; human studies used IV, SC, intranasal and oral routes. GH peaks about 30 min after an IV bolus (Imbimbo 1994). With 16 weeks of twice-daily SC dosing the GH response fell by about half by week 4 and recovered within 4 weeks of stopping (Rahim 1998).
Mechanism
Hexarelin is an agonist at the ghrelin receptor GHS-R1a on pituitary somatotrophs and hypothalamic neurons, releasing GH by a pathway independent of GHRH; GHRH co-administration potentiates the response in young and old men (Arvat 1994). Its cardiac effects do not depend on GH: they persist in hypophysectomized rats (Locatelli 1999), and in mice they are mediated by the scavenger receptor CD36, to which hexarelin binds in the heart (Bodart 2002). Chronic exposure partially down-regulates the pituitary GH response, reversibly (Rahim 1998).
Evidence
Clinical: at least one published human trial or an approved drug
- 1 mcg/kg IV released about 2x the GH of 1 mcg/kg GHRH in 12 healthy men; SC bioavailability 77% by GH response (Ghigo et al., 1994)
- Double-blind rising-dose study: GH peaked at 30 min, ED50 about 0.5 mcg/kg IV (Imbimbo et al., 1994)
- Intranasal 60 mcg/kg 3x daily raised growth velocity from 5.3 to 8.3 cm/year in 8 short children (Laron et al., 1995)
- 16 weeks of 1.5 mcg/kg SC 2x daily: partial reversible blunting of GH response, no change in IGF-1 or body composition (Rahim et al., 1998)
- Acute 2 mcg/kg IV raised ejection fraction and cardiac output in 24 bypass-surgery patients; GHRH and GH did not (Broglio et al., 2002)
- Human-trial status: small human physiology studies only; not approved anywhere
References
- Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. Ghigo E, Arvat E, Gianotti L, et al., Journal of Clinical Endocrinology & Metabolism, 1994
- Growth hormone-releasing activity of hexarelin in humans. A dose-response study. Imbimbo BP, Mant T, Edwards M, et al., European Journal of Clinical Pharmacology, 1994
- Growth hormone status during long-term hexarelin therapy. Rahim A, O'Neill PA, Shalet SM, Journal of Clinical Endocrinology & Metabolism, 1998
- Intranasal administration of the GHRP hexarelin accelerates growth in short children. Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A, Clinical Endocrinology (Oxford), 1995
- Growth hormone-independent cardioprotective effects of hexarelin in the rat. Locatelli V, Rossoni G, Schweiger F, et al., Endocrinology, 1999
- Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery. Broglio F, Guarracino F, Benso A, et al., European Journal of Pharmacology, 2002
- CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Bodart V, Febbraio M, Demers A, et al., Circulation Research, 2002
- Radioimmunoassay for hexarelin, a peptidic growth hormone secretagogue, and its pharmacokinetic studies. Roumi M, Marleau S, du Souich P, et al., Peptides, 1995
Side effects
In trials the main finding was a partial, reversible blunting of the GH response after weeks of dosing (Rahim 1998); children treated intranasally for up to 8 months had no reported adverse effects (Laron 1995). Water retention, appetite increase, lethargy, joint aches and reduced insulin sensitivity are commonly reported (anecdotal).
Storage
- Storage
- Refrigerated (2-8C)
- Lyophilized
- 24+ months refrigerated
- Reconstituted
- 28-30 days refrigerated
Pharmacology
- Half-life
- ~120 min terminal (dog, IV; Roumi 1995); no human PK located. GH peaks ~30 min after IV bolus in men (Imbimbo 1994)
- Bioavailability
- SC ~77%, intranasal ~5%, oral ~0.3% (human; GH-response-based estimates, Ghigo 1994)
- Molecular weight
- 887 Da
- Sequence
- H[D-2-Me-W]AW[D-F]K[NH2]