リン酸・リエストラジオール

WordNet

a salt of phosphoric acid (同)orthophosphate, inorganic_phosphate
carbonated drink with fruit syrup and a little phosphoric acid

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〈U〉リン酸塩 / 《複数形で》リン酸肥料

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/07 18:01:46」(JST)

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Polyestradiol phosphate (INN, trade name Estradurin) is an estrogen in form of a polymer^[2] used for the palliative treatment of prostate cancer.^[3]^[4] The drug has been marketed since 1960 by Pfizer in a number of European countries.^[5]^[6]

Medical use

Polyestradiol phosphate is used as an intramuscular injection for estrogen therapy of prostate cancer. It is available in combination with mepivacaine, a local anaesthetic, to avoid a burning sensation during application. After injection, it releases the active agent estradiol over several weeks.^[7]

Pharmacokinetics

Polyestradiol phosphate reaches the bloodstream within hours after the injection (90% after 24 hours), and is accumulated in the reticuloendothelial system.^[4] Estradiol is then cleaved from the polymer by phosphatases, although slowly because polyestradiol phosphate acts as a phosphatase inhibitor.^[8] With monthly injections, stable estradiol concentrations are reached after six to twelve months.^[4] Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome enzymes, and to a lesser extent in the kidneys, testicles and muscles.^[7] The metabolites are mainly excreted via the kidneys.

Mechanism of action

The growth of prostate cancer is generally stimulated by dihydrotestosterone (DHT); and unless the cancer is castration resistant, it can be treated by depriving it of DHT. Estradiol inhibits the action of DHT by several mechanisms. Firstly, it acts over the hypothalamic–pituitary–gonadal axis feedback loop by blocking secretion of luteinizing hormone, which reduces testosterone synthesis in Leydig cells in the testicle. It blocks testosterone uptake into prostate cells, where it would be metabolized to DHT by the enzyme 5α-reductase. Estradiol also inhibits 5α-reductase directly, blocks binding of DHT to androgen receptors, and exhibits cytotoxicity on prostate cancer cells.^[4]^[7]

Contraindications

The drug has the same contraindications as other forms of estradiol, including active thromboembolism (such as myocardial infarction) or high risk for thromboembolic events, asthma, and severe hepatic impairment.^[4]^[7]

Adverse effects

Although systematic studies of the drug's adverse effects are missing, it is assumed that they are identical to the effects observed under therapy with estradiol and other estrogens. These include nausea, headache, sodium and water retention, gain (but sometimes loss) of body weight, impaired glucose tolerance, and mood swings (in 40% of patients). Allergic reactions of the skin include itching, erythema multiforme and, rarely, Stevens–Johnson syndrome.^[4] As thromboembolic complications are associated mainly with oral estrogens and attributed to the first-pass effect, they are expected to occur less frequently under parenteral therapies such as polyestradiol phosphate.^[7]

Overdose typically manifests itself by reversible feminization.^[7]

Interactions

Estradiol levels may be increased by CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and grapefruit juice, and lowered by CYP3A4 inducers such as St John's wort, barbiturates, carbamazepine and rifampicin. The combination with COX-2 inhibitors can increase the risk for thromboembolism. Estradiol can also increase the effects of glucocorticoids.^[7]^[9]

Physical and chemical properties

Solubility

Polyestradiol phosphate is of very low solubility in water, acetone, chloroform, dioxane, and ethanol, but solves readily in bases, especially in aqueous pyridine.^[4]

Synthesis

Like polyphosphates of polyphenols, polyestradiol phosphate can be prepared from the monomer (in this case estradiol) and phosphoryl chloride. The latter reacts with both the phenolic hydroxyl group in position 3 and the aliphatic one in position 17. The molecular mass of the resulting polymer can be controlled by interrupting the reaction after a given time: the longer the reaction is allowed to continue, the higher the mass.^[8]^[10]

Estradiol

Phosphoryl chloride

History

Pharmacological experiments on estradiol phosphates conducted around 1950 gave rise to the hypothesis that estradiol 3,17-diphosphate acted as an inhibitor of kidney alkaline phosphatase.^[8] When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves,^[11] they accidentally created a polymer instead.^[10] This was later shown to exhibit the same anti-phosphatase properties as estradiol diphosphate, and so it was hypothesized that the original finding was due to contamination with estradiol phosphate polymers.^[8] Consequently, these polymers were studied in more detail, which resulted in marketing of polyestradiol phosphate in 1960.^[5] This drug is or has been marketed by Pfizer in Austria, Switzerland, Denmark, Finland, Latvia, Norway, and Sweden.^[6] As of 2012, it is no longer available in Austria.^{[citation needed]}

References

^ ^a ^b "Estradurin" (in German). Arzneimittel-Kompendium der Schweiz. August 2008. Retrieved 22 April 2012.
^ Johansson, CJ; Gunnarsson, PO (June 2000). "Pharmacodynamic model of testosterone suppression after intramuscular depot estrogen therapy in prostate cancer". Prostate 44 (1): 26–30. doi:10.1002/1097-0045(20000615)44:1<26::AID-PROS4>3.0.CO;2-P. PMID 10861754.
^ Mikkola, A; Aro, J; Rannikko, S; Ruutu, M; Finnprostate, Group (March 2007). "Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy". Prostate 67 (4): 447–55. doi:10.1002/pros.20547. PMID 17219379.
^ ^a ^b ^c ^d ^e ^f ^g Dinnendahl, V; Fricke, U, eds. (2010). Arzneistoff-Profile (in German) 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3.
^ ^a ^b "Produktresumé for Estradurin" [Summary of Product Characteristics for Estradurin] (PDF) (in Danish). 29 January 2010. Retrieved 21 April 2012.
^ ^a ^b Drugs.com: International Drug Names
^ ^a ^b ^c ^d ^e ^f ^g W, Jasek, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 2992–4. ISBN 978-3-85200-181-4.
^ ^a ^b ^c ^d Diczfalusy, E (April 1954). "Poly-estradiol phosphate (PEP); a long-acting water soluble estrogen". Endocrinology 54 (4): 471–7. doi:10.1210/endo-54-4-471. PMID 13151143.
^ Klopp, T, ed. (2011). Arzneimittel-Interaktionen (in German) (2011/2012 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-214-9.
^ ^a ^b Diczfalusy, E; Fernö, O; Fex, H; Högberg, B; Linderot, T; Rosenberg, Th (1953). "Synthetic high molecular weight enzyme inhibitors. I. Polymeric phosphates of phloretin and related compounds" (PDF). Act Chem Scand 7 (6): 921–7. doi:10.3891/acta.chem.scand.07-0913.
^ Picinelli, A; Dapena, E; Mangas, JJ (1995). "Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study". Journal of Agricultural and Food Chemistry 43 (8): 2273–78. doi:10.1021/jf00056a057.

English Journal

Effects of the standard and endoliquor injection of estradurin on the rat prostate.

Bordyushkov YN1, Kaplieva IV, Trepitaki LK.
Bulletin of experimental biology and medicine.Bull Exp Biol Med.2012 Aug;153(4):533-4.
The effects of intramuscular and endoliquor routes of administration of water-soluble antiandrogenic drug estradurin on proliferative activity of the prostate were studied. Estradurin injection via both routes produced a suppressive effect on the prostate. The effect of the minimum estradurin dose i
PMID 22977864

Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer: evaluation of cardiovascular events in a randomized trial.

Hedlund PO, Johansson R, Damber JE, Hagerman I, Henriksson P, Iversen P, Klarskov P, Mogensen P, Rasmussen F, Varenhorst E; SPCG-5 STUDY GROUP.
Scandinavian journal of urology and nephrology.Scand J Urol Nephrol.2011 Nov;45(5):346-53. doi: 10.3109/00365599.2011.585820. Epub 2011 May 31.
OBJECTIVE: This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardio
PMID 21627403

Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer.

Almasi CE1, Brasso K, Iversen P, Pappot H, Høyer-Hansen G, Danø K, Christensen IJ.
The Prostate.Prostate.2011 Jun 1;71(8):899-907. doi: 10.1002/pros.21306. Epub 2010 Nov 17.
BACKGROUND: The purpose of this study was to investigate the prognostic value of different forms of the urokinase receptor, uPAR, in serum from prostate cancer (PC) patients.PATIENTS AND METHODS: The uPAR forms were measured in samples from 131 metastatic PC patients. These constituted a subset of p
PMID 21456072

「リン酸ポリエストラジオール」

Polyestradiol phosphate
Systematic (IUPAC) name
	(17β)-Estra-1,3,5(10)-triene-3,17-diol, polymer with phosphoric acid
Clinical data
Trade names	Estradurin
AHFS/Drugs.com	International Drug Names
Pregnancy; category	N/A;
Routes of; administration	Deep intramuscular
Legal status	℞ (Prescription only);
Pharmacokinetic data
Protein binding	>95% (estradiol)
Metabolism	Mainly liver
Biological half-life	70 days
Excretion	Urine
Identifiers
CAS Number	28014-46-2
ATC code	L02AA02
PubChem	SID 51091766
ChemSpider	none
UNII	P14877CDX2
KEGG	D07434
ChEMBL	CHEMBL1201477
Chemical data
Formula	(C18H22)m(O4P)n; (m, n ≈ 80)
Molar mass	~26 g/mol
Physical data
Melting point	195 to 202 °C (383 to 396 °F)
(verify)

　　[★]

英: polyestradiol phosphate

「phosphate」

　　[★]

n.

(化合物)リン酸塩、リン酸エステル、ホスフェート、フォスフェート、リン酸

関: inorganic phosphate、orthophosphate、orthophosphoric acid、phospho、phosphoester、phosphoric、phosphoric acid、phosphoric acid ester、phosphorus

[Kompendium-CH-1] "Estradurin" (in German). Arzneimittel-Kompendium der Schweiz. August 2008. Retrieved 22 April 2012.

[pmid10861754-2] Johansson, CJ; Gunnarsson, PO (June 2000). "Pharmacodynamic model of testosterone suppression after intramuscular depot estrogen therapy in prostate cancer". Prostate 44 (1): 26–30. doi:10.1002/1097-0045(20000615)44:1<26::AID-PROS4>3.0.CO;2-P. PMID 10861754.

[pmid17219379-3] Mikkola, A; Aro, J; Rannikko, S; Ruutu, M; Finnprostate, Group (March 2007). "Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy". Prostate 67 (4): 447–55. doi:10.1002/pros.20547. PMID 17219379.

[Arzneistoff-Profile-4] ^ ^a ^b ^c ^d ^e ^f ^g Dinnendahl, V; Fricke, U, eds. (2010). Arzneistoff-Profile (in German) 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3.

[SPC_danish-5] "Produktresumé for Estradurin" [Summary of Product Characteristics for Estradurin] (PDF) (in Danish). 29 January 2010. Retrieved 21 April 2012.

[Drugs.com-6] Drugs.com: International Drug Names

[Austria-Codex-7] ^ ^a ^b ^c ^d ^e ^f ^g W, Jasek, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 2992–4. ISBN 978-3-85200-181-4.

[pmid13151143-8] Diczfalusy, E (April 1954). "Poly-estradiol phosphate (PEP); a long-acting water soluble estrogen". Endocrinology 54 (4): 471–7. doi:10.1210/endo-54-4-471. PMID 13151143.

[Arzneimittel-Interaktionen-9] Klopp, T, ed. (2011). Arzneimittel-Interaktionen (in German) (2011/2012 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-214-9.

[synthesis-10] Diczfalusy, E; Fernö, O; Fex, H; Högberg, B; Linderot, T; Rosenberg, Th (1953). "Synthetic high molecular weight enzyme inhibitors. I. Polymeric phosphates of phloretin and related compounds" (PDF). Act Chem Scand 7 (6): 921–7. doi:10.3891/acta.chem.scand.07-0913.

[Picinelli-11] Picinelli, A; Dapena, E; Mangas, JJ (1995). "Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study". Journal of Agricultural and Food Chemistry 43 (8): 2273–78. doi:10.1021/jf00056a057.

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案内

polyestradiol phosphate