更新于：2024-06-29
Pavinetant
更新于：2024-06-29
概要
基本信息
原研机构 |
在研机构- |
最高研发阶段终止临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
结构
分子式C26H25N3O3S |
InChIKeyQYTBBBAHNIWFOD-NRFANRHFSA-N |
CAS号941690-55-7 |
关联
5
项与 Pavinetant 相关的临床试验A Double-blind, Randomized, Parallel-group, Placebo-controlled Study of MLE4901 for the Treatment of Polycystic Ovary Syndrome (PCOS)
Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes
A Phase I, Randomized, Open Label, 2-Way Crossover Study in Healthy Subjects to Assess the Relative Bioavailability of AZD2624 (Tablet Versus Liquid Suspension) Followed by an Additional Period to Assess the Food Effect on the Tablet
100 项与 Pavinetant 相关的临床结果
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100 项与 Pavinetant 相关的转化医学
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100 项与 Pavinetant 相关的专利（医药）
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5
项与 Pavinetant 相关的文献（医药）2020-06-01Human reproduction (Oxford, England)1区 · 医学
Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome
1区 · 医学
Article
作者: Millar, Robert P ; Skorupskaite, Karolina ; Anderson, Richard A ; Veldhuis, Johannes D ; George, Jyothis T
Abstract:
STUDY QUESTION:
What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER:
Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.
WHAT IS KNOWN ALREADY:
PCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.
STUDY DESIGN, SIZE, DURATION:
The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.
MAIN RESULTS AND THE ROLE OF CHANCE:
NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.
LIMITATIONS, REASONS FOR CAUTION:
The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.
WIDER IMPLICATIONS OF THE FINDINGS:
These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.
STUDY FUNDING/COMPETING INTEREST(S):
Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.
TRIAL REGISTRATION NUMBER:
N/A.
2018-01-01Neuroendocrinology2区 · 医学
Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women
2区 · 医学
Article
作者: Jyothis T. George ; Richard A. Anderson ; Robert P. Millar ; Karolina Skorupskaite ; Johannes D. Veldhuis
Objectives: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. Methods: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. Results: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, <i>p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, <i>p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. Conclusions: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.
2015-02-01Lancet (London, England)1区 · 医学
Role of a neurokinin B receptor antagonist in the regulation of ovarian function in healthy women
1区 · 医学
Article
作者: Anderson, Richard A ; George, Jyothis ; Skorupskaite, Karolina
BACKGROUND:
Patients with loss-of-function mutation in neurokinin B (NKB) and its receptor show hypogonadotropic hypogonadism characterised by failure to progress through puberty, indicating the involvement of this newly described hypothalamic peptide in human reproduction. However the role of NKB in regulating ovarian function in adult women is unknown. We tested the hypothesis that a NKB antagonist would decrease gonadotropin secretion and inhibit folliculogenesis in healthy women.
METHODS:
Six healthy women with regular menstrual cycles were administered the NKB antagonist AZD4901 (AstraZeneca, London, UK) 40 mg orally twice daily for 5 days from cycle days 4-5. Transvaginal ultrasonography was performed at the end of drug administration, and serum gonadotropins and oestradiol measured. Cycle-day-matched results were compared with seven women who received no treatment (controls). The study received ethics committee approval, and all women gave written informed consent.
FINDINGS:
The diameter of the largest follicle was significantly smaller in women treated with NKB antagonist than in controls (mean 8·8 mm [SD 1·2] vs 11·9 [2·1], p=0·01). Serum oestradiol concentrations were also significantly reduced in the NKB antagonist group (mean 112·7 pmol/L [SD 56·0] vs 240·1 [73·6], p=0·005): in keeping with this finding endometrial thickness was also reduced (mean 3·5 mm [SD 0·5] vs 6·4 [3·2], p=0·05). Concentrations of luteinising hormone were not significantly altered after 5 days of NKB antagonist (mean pretreatment luteinising hormone 5·2 IU/L [SD 2·1] vs post-treatment 6·7 [3·8], p=0·2) or when compared with control women (6·0 [2·4], p=0·7). One woman had minimal vaginal bleeding; there were no adverse events.
INTERPRETATION:
We have shown for the first time, to our knowledge, that NKB antagonist is a potent suppressor of follicle development and oestradiol secretion in women. This effect is likely to be mediated by reduced secretion of gonadotropin-releasing hormone and our results support the involvement of NKB in the control of human reproduction: further analysis will explore in detail effects on secretion of follicle-stimulating hormone and luteinising hormone. Our findings have potential for translational application, for example in endometriosis and contraception.
FUNDING:
Wellcome Trust through the Scottish Translational and Therapeutics Initiative.
100 项与 Pavinetant 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 多囊卵巢综合征 | 临床2期 | 美国 | 2016-07-01 | |
| 精神分裂症 | 临床2期 | 美国 | 2008-05-01 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床2期 | 55 | Placebo (Placebo Treatment Arm) | 製夢糧網衊蓋壓憲繭築(鏇鏇淵糧廠鹽艱衊鑰鏇) = 淵選膚範淵製顧顧顧觸 鏇窪夢選築鑰壓範蓋壓 (膚糧醖積衊簾繭觸窪繭, 窪顧蓋襯壓範製選醖廠 ~ 窪膚窪膚憲鬱醖積築範) 更多 | - | 2020-06-16 | ||
(MLE4901 Treatment Arm) | 製夢糧網衊蓋壓憲繭築(鏇鏇淵糧廠鹽艱衊鑰鏇) = 壓襯糧製築築齋膚襯淵 鏇窪夢選築鑰壓範蓋壓 (膚糧醖積衊簾繭觸窪繭, 獵鑰淵簾鹽觸鹽顧憲網 ~ 觸廠顧築糧廠襯顧憲獵) 更多 | ||||||
临床2期 | 28 | NK3R antagonist (MLE4901) | 簾構鬱淵淵鏇衊壓繭鏇(鏇觸積遞襯製鹹醖醖遞) = 糧範積願醖範鏇艱繭製 構窪齋蓋蓋廠願壓廠糧 (壓觸鏇艱壓構鹹鹹窪遞 ) | 积极 | 2020-02-01 | ||
Placebo | 簾構鬱淵淵鏇衊壓繭鏇(鏇觸積遞襯製鹹醖醖遞) = 憲艱積憲網獵願糧壓遞 構窪齋蓋蓋廠願壓廠糧 (壓觸鏇艱壓構鹹鹹窪遞 ) | ||||||
临床2期 | 37 | 觸鏇鑰繭廠願範艱簾簾(糧餘選夢遞壓廠繭範簾) = 廠夢蓋壓簾選積觸簾鹹 糧遞製簾觸憲鬱襯憲憲 (憲選獵觸廠製糧鏇廠鑰, 15.99 ~ 23.42) | 积极 | 2017-05-06 | |||
Placebo | 觸鏇鑰繭廠願範艱簾簾(糧餘選夢遞壓廠繭範簾) = 齋醖範窪觸選夢齋製醖 糧遞製簾觸憲鬱襯憲憲 (憲選獵觸廠製糧鏇廠鑰, 40.81 ~ 58.56) | ||||||
临床2期 | 67 | 鑰鏇遞繭壓觸齋顧餘鹽(顧衊願繭艱膚窪獵衊鏇) = 齋淵範顧構選醖繭簾糧 艱觸鏇網製鬱鹹遞鏇齋 (觸淵齋選蓋齋簾鬱糧糧 ) | 积极 | 2016-11-01 | |||
Placebo | - | ||||||
临床2期 | 106 | (AZD2624) | 選網壓糧壓衊醖鑰鹽範(鏇鏇構鑰築齋鬱蓋積網) = 築膚齋餘鬱觸鑰顧遞願 醖廠衊積廠衊蓋鹹糧衊 (醖鏇獵夢遞餘選鹹壓簾, 鑰簾醖築網選廠範獵鏇 ~ 鏇鹹範鬱選壓衊顧淵壓) 更多 | - | 2011-06-23 | ||
Placebo (Placebo) | 選網壓糧壓衊醖鑰鹽範(鏇鏇構鑰築齋鬱蓋積網) = 衊繭鹽鹹襯醖廠襯襯構 醖廠衊積廠衊蓋鹹糧衊 (醖鏇獵夢遞餘選鹹壓簾, 醖簾齋鬱鹹醖簾鬱願鬱 ~ 選夢選襯鹽製廠構簾夢) 更多 |
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