関: fadrozole hydrochloride hydrate

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/16 19:52:49」(JST)

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Fadrozole (INN, marketed as Afema by Novartis) is an aromatase inhibitor^[1] that has been introduced in Japan for the treatment of breast cancer.

It is selective.^[2]

References

^ Raats JI, Falkson G, Falkson HC (January 1992). "A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer". J. Clin. Oncol. 10 (1): 111–6. PMID 1530798. http://www.jco.org/cgi/pmidlookup?view=long&pmid=1530798.
^ Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A (February 1991). "Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease". J. Med. Chem. 34 (2): 725–36. doi:10.1021/jm00106a038. PMID 1825337.

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1. 思春期早発症の治療 treatment of precocious puberty
2. 転移性ホルモン受容体陽性乳癌に対する治療アプローチ：内分泌療法 treatment approach to metastatic hormone receptor positive breast cancer endocrine therapy

English Journal

Role of Aromatase in Sex-Specific Cerebrovascular Endothelial Function in Mice.

Zuloaga KL1, Davis CM, Zhang W, Alkayed NJ.Author information 1Oregon Health & Science University.AbstractStroke risk and outcome are strongly modified by estrogen. In addition to ovaries, estrogen is produced locally in peripheral tissue by the enzyme aromatase, and extra-gonadal synthesis becomes the major source of estrogen after menopause. Aromatase gene deletion in female mice exacerbates ischemic brain damage after stroke. However, it is not clear which cell type is responsible for this effect, since aromatase is expressed in multiple cell types, including cerebrovascular endothelium. We tested the hypothesis that cerebrovascular aromatase contributes to sex differences in cerebrovascular endothelial function. Cerebrocortical microvascular responses to the endothelium-dependent vasodilator acetylcholine (ACh) were compared between male and female wild-type (WT) and aromatase knockout (ArKO) mice by measuring laser-Doppler perfusion in vivo through a closed cranial window. Additional studies were performed in WT mice treated with the aromatase inhibitor fadrozole or vehicle. WT female mice had significantly greater responses to ACh compared to WT males (p<0.001), which was associated with higher aromatase expression in female compared to male cerebral vessels (p<0.05). ACh responses were significantly lower in ArKO compared to WT females (p<0.05) and in WT females treated with fadrozole vs. vehicle (p<0.001). Conversely, ACh responses were significantly higher in ArKO vs. WT males (p<0.05). Levels of phosphorylated eNOS were lower in ArKO vs. WT female brains, but were not altered by aromatase deletion in males. We conclude that cerebrovascular endothelial aromatase plays an important and sexually dimorphic role in cerebrovascular function, and that aromatase inhibitors in clinical use may have cardiovascular consequences in both males and females.
American journal of physiology. Heart and circulatory physiology.Am J Physiol Heart Circ Physiol.2014 Feb 7. [Epub ahead of print]
Stroke risk and outcome are strongly modified by estrogen. In addition to ovaries, estrogen is produced locally in peripheral tissue by the enzyme aromatase, and extra-gonadal synthesis becomes the major source of estrogen after menopause. Aromatase gene deletion in female mice exacerbates ischemic
PMID 24508640

Transdifferentiation of differentiated ovary into functional testis by long term treatment of aromatase inhibitor in Nile tilapia.

Sun LN1, Jiang XL, Xie QP, Yuan J, Huang BF, Tao WJ, Zhou LY, Nagahama Y, Wang DS.Author information 1Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Science, SW University, 400715, Chongqing, P.R. China;AbstractFemales with differentiated ovary of a gonochoristic fish, Nile tilapia, were masculinized by long term treatment with an aromatase inhibitor (Fadrozole) in the present study. The reversed gonads developed into functional testes with fertile sperm. The longer the fish experienced sex differentiation, the longer treatment time was needed for successful sex reversal. Furthermore, Fadrozole induced sex reversal, designated as secondary sex reversal (SSR), was successfully rescued by supplement of exogenous 17β-estradiol. Gonadal histology, immunohistochemistry, transcriptome and serum steroid level were analyzed during SSR. The results indicated that spermatogonia were transformed from oogonia or germline stem cell-like cells distributed in germinal epithelium; while Leydig and Sertoli cells probably came from the interstitial cells and granulosa cells of the ovarian tissue, respectively. The transdifferentiation of somatic cells, as indicated by the appearance of Dmrt1 (pre-Sertoli cells) and Cyp11b2 (pre-Leydig cells) positive cells in the ovary, provided micro-niche for the transdifferentiation of germ cells. Decrease of serum 17β-estradiol was detected earlier than increase of serum 11-ketotestosterone, indicating decrease of estrogen was the cause while increase of androgen was the consequence of SSR. The sex reversed gonad displayed more similarity in morphology and histology with a testis while the global gene expression profiles remained closer to the female control. Detailed analysis indicated that transdifferentiation was driven by suppression of female pathway genes and activation of male pathway genes. In short, SSR provides a good model for study of sex reversal in teleosts, and for understanding of sex determination and differentiation in non-mammalian vertebrates.
Endocrinology.Endocrinology.2014 Jan 17:en20131959. [Epub ahead of print]
Females with differentiated ovary of a gonochoristic fish, Nile tilapia, were masculinized by long term treatment with an aromatase inhibitor (Fadrozole) in the present study. The reversed gonads developed into functional testes with fertile sperm. The longer the fish experienced sex differentiation
PMID 24437491

Acute and chronic effects of an aromatase inhibitor on pair-maintenance behavior of water-restricted zebra finch pairs.

Prior NH1, Yap KN2, Soma KK3.Author information 1Department of Zoology, University of British Columbia, Vancouver, BC, Canada. Electronic address: nhprior@zoology.ubc.ca.2Department of Psychology, University of British Columbia, Vancouver, BC, Canada.3Department of Psychology, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.AbstractZebra finches are highly social songbirds that maintain life-long monogamous pair-bonds. They rely heavily upon these pair-bonds to survive their ever-changing and unpredictable habitat in the Australian desert. These pair-bonds are maintained via a large repertoire of affiliative behaviors that for most of an individual's life are predominately associated with pair maintenance. Water restriction reduces circulating testosterone levels in male zebra finches and the size of the ovary and oviduct in female zebra finches, but water restriction has little or no effects on pair-maintenance behaviors and local levels of testosterone and estradiol in behaviorally-relevant brain regions. These data suggest that in water-restricted zebra finches, local synthesis of testosterone and estradiol in the brain may support the expression of pair-maintenance behaviors. Here, we directly test whether pair-maintenance behaviors are regulated by estradiol, acting via non-genomic or genomic mechanisms, in water-restricted (i.e., non-breeding) zebra finches. In two experiments, subjects were treated with an aromatase inhibitor (fadrozole) either acutely or chronically, and a variety of pair-maintenance behaviors were quantified. Additionally, we quantified the effect of acute fadrozole treatment on brain and circulating estradiol and testosterone levels. Acute fadrozole administration rapidly decreased estradiol levels in the circulation and brain of males and also rapidly increased testosterone levels in the circulation and brain of both males and females. However, neither the acute nor chronic fadrozole treatment decreased pair-maintenance behaviors. In one case, acute fadrozole treatment promoted affiliation. These data suggest that pair-maintenance behavior in non-breeding zebra finches is not promoted by estradiol acting via either non-genomic or genomic mechanisms.
General and comparative endocrinology.Gen Comp Endocrinol.2014 Jan 15;196:62-71. doi: 10.1016/j.ygcen.2013.10.018. Epub 2013 Nov 11.
Zebra finches are highly social songbirds that maintain life-long monogamous pair-bonds. They rely heavily upon these pair-bonds to survive their ever-changing and unpredictable habitat in the Australian desert. These pair-bonds are maintained via a large repertoire of affiliative behaviors that for
PMID 24231681

Japanese Journal

Effects of Aromatase Inhibitor (Fadrozole)-Induced Sex-Reversal on Gonadal Differentiation and mRNA Expression of P450arom, AMH and ERα in Embryos and Growth in Posthatching Quail

Koba Naomi,Mori Masahiko,Ha Yonju [他],MIZUSHIMA Shusei,TSUKADA Akira,SAITO Noboru,ONO Tamao,SHIMADA Kiyoshi
The journal of poultry science 45(2), 116-124, 2008-04-25
NAID 10021220131

Effects of Aromatase Inhibitor (Fadrozole)-Induced Sex-Reversal on Gonadal Differentiation and mRNA Expression of P450arom, AMH and ER.ALPHA. in Embryos and Growth in Posthatching Quail

Koba Naomi,Mori Masahiko,Ha Yonju,Mizushima Shusei,Tsukada Akira,Saito Noboru,Ono Tamao,Shimada Kiyoshi
The Journal of Poultry Science 45(2), 116-124, 2008
… The present study was conducted to investigate (1) the effective day of treatment with Fadrozole, nonsteroidal aromatase inhibitor (AI), during incubation for sex reversal, (2) the mRNA expression of aromatase (P450arom), anti-Müllerian hormone (AMH) and estrogen receptor α (ERα) in quail gonad and gonadal structures after the AI treatment before hatching and (3) the effects of AI on gonad growth, left-right asymmetry of the gonad and body weight gain between 1 to 7 weeks posthatch. …
NAID 130004938430

Sex Inversion of Sexually Immature Honeycomb Grouper(Epinephelus merra) by Aromatase Inhibitor(Reproductive Biology)

Bhandari Ramji Kumar,Komuro Hiroki,Higa Mikihiko [他],Nakamura Masaru
Zoological science 21(3), 305-310, 2004-03-25
… Female honeycomb groupers were implanted with various doses of Fadrozole (0, 100, 500 and 1000 μg/fish) in the non-breeding season, and resultant changes in the gonadal structures and the plasma levels of sex steroid hormones (estra-diol-17β, E2; … The Fadrozole could be an important tool for manipulating the sex of hermaphrodite fishes. …
NAID 110006281379

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リンク元	「ファドロゾール」
拡張検索	「fadrozole hydrochloride hydrate」

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Fadrozole
Systematic (IUPAC) name
	4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile
Clinical data
Pregnancy cat.	?
Legal status	℞ Prescription only
Routes	Oral
Identifiers
CAS number	102676-31-3
ATC code	None
PubChem	CID 59693
UNII	H3988M64PU
KEGG	D02451
ChEMBL	CHEMBL9298
Chemical data
Formula	C14H13N3
Mol. mass	223.27 g/mol
	SMILES C1CC(N2C=NC=C2C1)C3=CC=C(C=C3)C#N;
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