Nafarelin

Absorption

Rapidly absorbed into the systemic circulation after intranasal administration. Bioavailability from a 400 μg dose averaged 2.8% (range 1.2 to 5.6%). Not absorbed after oral administration.

Toxicity

In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a μg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs.

Description

Nafarelin is a gonadorelin analogue. It produces an initial phase of stimulation followed by down-regulation of gonadotrophin-releasing hormone receptors, thus reducing the release of FSH and LH, leading to inhibition of androgen and oestrogen production.

Chemical properties

Nafarelin is a synthetic analogue of gonadotrophin-releasing hormone (GnRH), which is about 200 times more potent than the native hormone and is more resistant to proteolysis Chrisp and Goa (1990), Parker and Schimmer (2001). Like GnRH, it binds with high affinity to the GnRH receptor on anterior pituitary cells, where it acts as an agonist. 

Originator

Nafarelin Acetate,Bachem AG

The Uses of Nafarelin

LHRH agonist.

Indications

For treatment of central precocious puberty (true precocious puberty, GnRH-dependent precocious precocity, complete isosexual precocity) in children of both sexes and for the treatment of endometriosis.

Background

Nafarelin is a potent synthetic agonist of gonadotropin-releasing hormone with 3-(2-naphthyl)-D-alanine substitution at residue 6. Nafarelin has been used in the treatments of central precocious puberty and endometriosis.

brand name

Synarel (Searle).

Therapeutic Function

Gonadotropic

Biological Functions

Acutely, Nafarelin stimulates the secretion of LH and FSH from the anterior pituitary, but prolonged, continuous exposure leads to inhibition of secretion by desensitization of the pituitary gonadotropes Vickery (1985). The initial stimulation of gonadotrophin secretion results in an increase in serum concentrations of estradiol in females and testosterone in males. These then decrease to very low concentrations equivalent to those found in menopausal women and castrated men respectively.

Pharmacokinetics

Nafarelin is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. After nafarelin therapy is discontinued, pituitary and ovarian function normalize and estradiol serum concentrations increase to pretreatment levels. Recurrences of endometriosis are frequent after cessation of any hormonal therapy, or surgery that leaves the ovaries and/or uterus intact.

Clinical Use

Nafarelin has potential wide therapeutic applications in the treatment of endometriosis, uterine leiomyoma (fibroids), malignant neoplasms, and in assisted reproduction protocols. However, its use is currently restricted to the treatment of endometriosis and in assisted reproduction protocols.

Side Effects

Nafarelin does not have the same androgenic adverse effects as danazol, but it can cause menopausal symptoms. The most commonly reported symptoms are hot flushes, vaginal dryness, altered libido and headaches. Treatment for 6 months results in a loss of bone density. The vertebral trabecular bone density falls by nearly 9% and may not return to normal after treatment. Nafarelin also has a similar effect to oestrogen deficiency on blood lipids e.g. concentrations of total cholesterol and triglycerides may increase.

Synthesis

i. 1 mmol from preparation A was placed in the reaction vessel of a 5 L Vega 296 automatic solid phase peptide synthesizer.
ii. Following amino acids were added to the Preparation A resin:
Nα-Boc-Pro 2 equiv.
Nα-Boc-Arg 2 equiv.
Nα-Boc-Leu 2 equiv.
Nα-Boc-D-NaI 1.5 equiv.
Nα-Boc-Tyr 1.5 quiv
Nα-Boc-Ser(tBu) 2 equiv.
Nα-Boc-Trp 1.75 equiv.
Nα-Boc-His(tos) 1.75 equiv.
(pyro)Glu 2.5 equiv.
iii. Crude peptide was dissolved in 2M acetic acid and converted to acetate salt by passage through a column of AG3-X4A resin.
iv. Acetate was dissolved in minimal amount of methanol.
v. It was then reprecipitated using acetone.
vi. It was then purified using HPLC to get the Nafarelin.

Metabolism

Enzymatic hydrolysis.