In isolated rat hypothalamic-neurohypophyseal explants, histrelin (10–100 nM) promotes the release of vasopressin (VP) [4]. In the rat hypothalamic-neurohypophyseal system, histrelin (100 nM) promotes the production of oxytocin (OT) [5].

In Csfmop/Csfmop mice, histrelin (0.1 mg/kg, subcutaneous injection) raises circulating LH concentrations [2]. Rabbit kidneys with subcutaneous injections of histrelin (10, 30, or 100 μg/day) have less intimal glands.

Animal/Disease Models: Csfmop/Csfmop mice [2]
Doses: 0.001, 0.05, and 0.1 mg/kg
Route of Administration: Results of subcutaneous injection: serum FSH concentration increased 4-fold.

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Animal/Disease Models: Rabbit [3]
Doses: 10, 30 or 100 μg/day
Route of Administration: subcutaneous injection for 4 weeks
Experimental Results: Caused endometrial glandular degeneration and stroma thinning.

Absorption, Distribution and Excretion
In 17 patients with advanced prostate cancer who received subcutaneous histamine relin (Vantas, Endo Pharmaceuticals) implantation (n = 17), the peak serum histamine relin concentration at 12 hours was 1.10 ± 0.375 ng/mL (mean ± standard deviation). The sustained subcutaneous release of the histamine relin implantation was confirmed by the stable serum concentrations throughout the 52-week dosing period. At the end of 52 weeks, the mean serum histamine relin concentration was 0.13 ± 0.065 ng/mL. In patients who received a second implantation at the end of 52 weeks, the serum histamine relin concentrations in the first eight weeks were similar to those detected at the time of the first implantation. In the 52-week study, the mean residual drug level of the histamine relin implantation (Vantas, Endo Pharmaceuticals) in 41 patients was 56.7 ± 7.71 mcg/day. Compared with healthy male volunteers receiving subcutaneous injection, the relative bioavailability of histamine resorcinol was 92% in prostate cancer patients with normal renal and hepatic function. In children with central precocious puberty (CPP, n=47) receiving subcutaneous histamine resorcinol implantation (Supprelin LA, Endo Pharmaceuticals), the median peak serum histamine resorcinol concentration during the study period was 0.43 ng/mL, which is expected to maintain gonadotropin levels at pre-pubertal levels. No pharmacokinetic differences were found between patients who had previously received luteinizing hormone-releasing hormone (LHRH) agonist therapy and those who had not. Food-drug interaction studies of histamine resorcinol products have not been conducted. Prostate cancer patients with mild to severe renal impairment had 50% higher serum histone concentrations compared with prostate cancer patients without renal or hepatic impairment; however, this difference is not clinically significant. Drug excretion studies of histamine resorcinol have not been conducted.
Following subcutaneous injection of histamine relin (Vantas, Endo Pharmaceuticals, 500 mcg) in healthy volunteers, the apparent volume of distribution of histamine relin was 58.4 ± 7.86 L.
In prostate cancer patients (n=17) who received histamine relin implantation (Vantas, Endo Pharmaceuticals), the apparent clearance was 174 ± 56.5 mL/min (mean ± standard deviation).
Oral histamine relin acetate was ineffective.
In patients with advanced prostate cancer, the median time to peak serum histamine relin concentration after subcutaneous implantation of histamine relin acetate was 12 hours; the drug was administered continuously at a rate of 50-60 μg daily for 12 months.
In patients with advanced prostate cancer (n = 17) who underwent subcutaneous implantation of a 50 mg Vantas (histamine relin) implant, peak serum drug concentrations occurred at 12 hours (median), with a mean of 1.10 ± 0.375 ng/mL (mean ± standard deviation).
During the 52-week dosing period, subcutaneous drug release was measured from 41 implants, with a mean release rate of 56.7 ± 7.71 μg/day.
For more complete data on absorption, distribution, and excretion of histamine relin (8 items), please visit the HSDB record page.

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Metabolism/Metabolites
As a synthetic peptide, histamine relin is expected to be metabolized by proteases in vivo. This will likely result in hydrolysis to produce multiple peptide fragments. In an in vitro drug metabolism study using human hepatocytes, a histamine relin metabolite generated by C-terminal dealkylation was identified.
An in vitro drug metabolism study using human hepatocytes identified a histamine relin metabolite produced by C-terminal dealkylation. Hydrolysis may also yield peptide fragments as metabolites.
Biological Half-Life

Following a single subcutaneous injection of a histamine relin metabolite in healthy volunteers, the terminal half-life was 3.92 ± 1.01 hours (mean ± standard deviation).
In healthy men, following a single subcutaneous injection of 500 micrograms of histamine relin metabolite, the mean terminal half-life of the drug was approximately 3.92 hours.

Hepatotoxicity
The incidence of elevated serum enzymes during histamine relinide treatment is similar to that of other gonadotropin-releasing hormone analogs. Elevated serum enzymes are usually mild, asymptomatic, and resolve spontaneously even without dose adjustment or discontinuation. The incidence of ALT elevation exceeding 3 times the upper limit of normal is less than 1%. Histamine relinide has been associated with one case of acute liver injury, but the report did not specify whether the case was accompanied by jaundice or other symptoms, thus other diagnoses remain possible. Therefore, histamine relinide can cause clinically significant liver injury, but this is extremely rare and usually self-limiting. No cases of acute liver failure, chronic hepatitis, or bile duct disappearance syndrome have been identified in association with histamine relinide or other GnRH analogs. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Protein binding In vitro measurements showed that the free fraction of histamine relinide (Vantas, Endo Pharmaceuticals) in plasma was 29.5% ± 8.9% (mean ± standard deviation).

[1]. Histrelin: in advanced prostate cancer. Drugs. 2010 Mar 26;70(5):623-30.

[2]. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. Mol Endocrinol. 1997 Oct;11(11):1636-50.

[3]. Development of an animal model for quantitatively evaluating effects of drugs on endometriosis. Fertil Steril. 1985 Sep;44(3):410-5.

[4]. Vasopressin release from the rat hypothalamo-neurohypophysial system: effects of gonadotrophin-releasing hormone (GnRH), its analogues and melatonin. J Physiol Pharmacol. 2010 Aug;61(4):459-66.

[5]. Hypothalamic gonadotropin-releasing hormone receptor activation stimulates oxytocin release from the rat hypothalamo-neurohypophysial system while melatonin inhibits this process. Brain Res Bull. 2010 Jan 15;81(1):185-90.

Therapeutic Uses
Gonadotropin-Releasing Hormone Agonist
/Histidine Relin/Indicated for the palliative treatment of advanced prostate cancer. /US Product Label Contains/
/Histidine Relin/ is a gonadotropin-releasing hormone (GnRH) agonist indicated for the treatment of central precocious puberty (CPP) in children. /US Product Label Contains/

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Drug Warnings
/Histidine Relin is contraindicated in patients with known hypersensitivity to histidine Relin or any component of the formulation, other gonadotropin-releasing hormone (GnRH) agonists, or GnRH.
As with other GnRH agonists, histidine Relin causes a transient increase in serum testosterone levels during the first week of treatment. Signs and/or symptoms of prostate cancer may worsen, and/or new manifestations (such as bone pain, neuropathy, hematuria, ureteral or bladder outlet obstruction) may occur, which may occur during the first few weeks of treatment. There have been reports that the use of gonadotropin-releasing hormone agonists (GnRH agonists) can cause ureteral obstruction and spinal cord compression, leading to paralysis, with or without fatal complications. Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely monitored during the first few weeks of treatment. If spinal cord compression or renal impairment occurs, standard treatment measures should be implemented immediately. There have been reports that synthetic gonadotropin-releasing hormone (GnRH) or GnRH agonists can cause allergic reactions. For more complete data on drug warnings for HISTRELIN (16 in total), please visit the HSDB record page.

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Pharmacodynamics
Histrelin inhibits gonadotropin secretion by reversibly downregulating gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and desensitizing pituitary gonadotropin cells. In children with central precocious puberty (CPP), long-term use of histamine acetate can suppress the luteinizing hormone (LH) response to GnRH, reducing LH levels to pre-pubertal levels within one month of treatment. This can reduce ovarian and testicular steroid production, slowing linear growth and thus increasing the likelihood of reaching expected adult height. Oral histamine acetate is ineffective. Both histamine acetate products (Vantas and Supprelin LA from Endo Pharmaceuticals) cause a transient increase in serum estradiol concentration in women and serum testosterone concentration in both men and women during the first week of treatment. Laboratory tests to monitor hormone levels are recommended. For children with CPP treated with histamine acetate (Supprelin LA from Endo Pharmaceuticals), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol or testosterone levels should be monitored. For patients with advanced prostate cancer treated with histamine relin (Vantas from Endo Pharmaceuticals), testosterone and prostate-specific antigen (PSA) levels should be monitored regularly. There have been reports of implantation failure, difficulty in implant positioning and removal, and other issues. The Supprelin LA (Endo Pharmaceuticals) product label warns users that patients receiving GnRH agonist therapy have reported cases of psychiatric events, seizures, and idiopathic intracranial hypertension (pseudotumor brain tumor). The Vantas (Endo Pharmaceuticals) product label warns users that male patients receiving GnRH agonist therapy have reported cases of spinal cord compression and urinary tract obstruction, as well as an increased risk of hyperglycemia/diabetes and cardiovascular disease.

C66H86N18O12

1323.50244

1322.667

76712-82-8

Histrelin acetate;220810-26-4

25077993

White to off-white solid powder

1.5±0.1 g/cm3

1800.6ºC at 760 mmHg

1042.8ºC

1.701

0.09

15

15

34

96

2660

9

CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2=CN(C=N2)CC3=CC=CC=C3)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC5=CNC6=CC=CC=C65)NC(=O)[C@H](CC7=CN=CN7)NC(=O)[C@@H]8CCC(=O)N8

HHXHVIJIIXKSOE-QILQGKCVSA-N

InChI=1S/C66H86N18O12/c1-4-70-64(95)55-17-11-25-84(55)65(96)48(16-10-24-71-66(67)68)76-58(89)49(26-38(2)3)77-62(93)53(30-43-34-83(37-74-43)33-40-12-6-5-7-13-40)81-59(90)50(27-39-18-20-44(86)21-19-39)78-63(94)54(35-85)82-60(91)51(28-41-31-72-46-15-9-8-14-45(41)46)79-61(92)52(29-42-32-69-36-73-42)80-57(88)47-22-23-56(87)75-47/h5-9,12-15,18-21,31-32,34,36-38,47-55,72,85-86H,4,10-11,16-17,22-30,33,35H2,1-3H3,(H,69,73)(H,70,95)(H,75,87)(H,76,89)(H,77,93)(H,78,94)(H,79,92)(H,80,88)(H,81,90)(H,82,91)(H4,67,68,71)/t47-,48-,49-,50-,51-,52-,53+,54-,55-/m0/s1

(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-3-(1-benzylimidazol-4-yl)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)