溴隐亭对高泌乳素血症妇女促性腺激素诱导排卵的影响

目的:探讨比较高泌乳素血症患者促排卵治疗中溴隐亭应用时机对诱导排卵的影响。方法:回顾性分析62例高泌乳素血症患者促卵泡激素药物促排卵治疗方式,分为A、B两组,A组:溴隐亭与促排卵药物治疗同时进行。B组:溴隐亭治疗高泌乳素血症后促排卵治疗。结果:两组治疗方案,A组促排卵治疗用药量、用药时间明显增加,妊娠率低,流产率高,促排卵周期雌二醇水平较B组低;B组方案促排卵率高、妊娠率高,流产率低。结论:溴隐亭治疗高泌乳素血症后,使用促卵泡激素药物促排卵治疗不育疗效显著。     

色满醇类IKs钾通道阻断剂的三维定量构效关系研究

目的和方法本文运用自组织分子场分析法以35个色满醇类IKs阻断剂为训练集分子进行三维定量构效关系研究。结果计算结果显示,最优定量构效关系模型具有较高的交叉验证相关系数q2(0.698)以及线性回归系数r2(0701);同时以7个化合物作为测试集分子对该模型进行验证。结论计算结果表明该模型具有一定的预测能力,可应用于新型色满醇类IKs阻断剂的分子设计。     

Structure–activity relationships of arodyn,a novel acetylated kappa opioid receptor antagonist*,†

Abstract: We previously reported that the novel dynorphin A (Dyn A, Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile‐Arg‐Pro‐Lys‐Leu‐Lys‐Trp‐Asp‐Asn‐Gln) analog arodyn (Ac[Phe^1,2,3,Arg⁴,d ‐Ala⁸]Dyn A‐(1–11)NH₂, Bennett, M.A., Murray, T.F. & Aldrich, J.V. (2002) J. Med. Chem. vol. 45, pp. 5617–5619) is a κ opioid receptor‐selective peptide [K_i(κ) = 10 nm , K_i ratio (κ/μ/δ) = 1/174/583] which exhibits antagonist activity at κ opioid receptors. In this study, a series of arodyn analogs was prepared and evaluated to explore the structure–activity relationships (SAR) of this peptide; this included an alanine scan of the entire arodyn sequence, sequential isomeric d ‐amino acid substitution in the N‐terminal ‘message’ sequence, NMePhe substitution individually in positions 1–3, and modifications in position 1. The results for the Ala‐substituted derivatives indicated that Arg⁶ and Arg⁷ are the most important residues for arodyn's nanomolar binding affinity for κ opioid receptors. Ala substitution of the other basic residues (Arg⁴, Arg⁹ and Lys¹¹) resulted in lower decreases in affinity for κ opioid receptors (three‐ to fivefold compared with arodyn). Of particular interest, while [Ala¹⁰]arodyn exhibits similar κ opioid receptor binding as arodyn, it displays higher κ vs. μ opioid receptor selectivity [K_i ratio (κ/μ) = 1/350] than arodyn because of a twofold loss in affinity at μ opioid receptors. Surprisingly, the Tyr¹ analog exhibits a sevenfold decrease in κ opioid receptor affinity, indicating that arodyn displays significantly different SAR than Dyn A; [Tyr¹]arodyn also unexpectedly exhibits inverse agonist activity in the adenylyl cyclase assay using Chinese hamster ovary cells stably expressing κ opioid receptors. Substitution of NMePhe in position 1 gave [NMePhe¹]arodyn which exhibits high affinity [K_i(κ) = 4.56 nm ] and exceptional selectivity for κ opioid receptors [K_i ratio (κ/μ/δ) = 1/1100/>2170]. This peptide exhibits antagonistic activity in the adenylyl cyclase assay, reversing the agonism of 10 nm Dyn A‐(1–13)NH₂. Thus [NMePhe¹]arodyn is a highly κ opioid receptor‐selective antagonist that could be a useful pharmacological tool to study κ opioid receptor‐mediated activities.     

Recent advances in small molecule gonadotrophin-releasing hormone receptor antagonists

Targeting the gonadotrophin-releasing hormone (GnRH) receptor for treatment of a variety of reproductive hormone-dependent diseases has yielded great success so far, with the use of peptide agonists. However, based on the current understanding of GnRH receptor biology, peptide agonists inevitably cause some side effects, such as the ‘flare’ effect and delayed action. By contrast, peptide or small molecule GnRH receptor antagonists should be devoid of the above-mentioned side effects. Furthermore, a small molecule antagonist is more preferable than a peptide antagonist because it also provides the possibility of oral administration, therefore allowing dose flexibility and better patient acceptance. Thus, it is not surprising to see that many patent applications on small molecule GnRH receptor antagonists have emerged over the last 10 years. This review summarises the patent applications of small molecule human GnRH receptor antagonists from 1994 to August 2003. If available, the biological data associated with patent structures are also cited from publications.     

The place of medical treatment of acromegaly: current status and perspectives

Introduction: Acromegaly is characterized by elevated growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels and by progressive somatic disfigurement and systemic manifestations, which lead to a mortality rate higher than the general population. Therefore, diagnosis and properly treatment should be performed as soon as possible.

Areas covered: This article focuses on the state of the art of acromegaly medical treatment. Somatostatin analogs, dopamine agonists and GH receptor antagonist were reviewed. Somatostatin analogs, the first-choice pharmacotherapy, can be used as primary or pre-operative treatment or as secondary therapy after failed surgery. Dopamine agonists have been used in patients with slightly elevated hormone levels and/or mixed GH/prolactin adenomas. Pegvisomant is indicated for resistant to somatostatin analogs/dopamine agonists. Combined treatment is also an option for resistant cases. Other non-conventional therapies and perspectives of treatment were also been discussed.

Expert opinion: The control of disease activity in acromegaly is of paramount importance. Medical treatment is an important option for cases in which surgery was unsuccessful or not indicated. Despite the achievements in medical treatment, somatotropic tumor aggressiveness and/or resistance to the drugs currently available remain a concern. Therefore, novel therapy targets based on molecular pathogenesis of GH-secreting tumors are currently in development, aiming at fulfilling this important gap.     

Induction de l’ovulation par administration pulsatile de GnRH en 2014 : revue de la littérature et synthèse des pratiques courantes

The hypogonadotropic hypogonadism is an easily treatable form of female infertility. The most common cause of hypogonadotropic hypogonadism is functional hypothalamic amenorrhea. The GnRH pump is a simple and effective treatment to restore fertility of patients with hypothalamic amenorrhea: cumulative pregnancy rate is estimated between 70 and 100% after 6 cycles, compared to a low rate of complications and multiple pregnancies. While only 2.8 cycles are on average required to achieve a pregnancy with a pump, this induction of ovulation stays underused in France. The objective of this paper is to propose a practical manual of pulsatile GnRH, in order to improve the accessibility of pulsatile GnRH for patients with hypogonadotropic hypogonadism.     

Interview: Dr Iain Frame,director of research,prostate cancer UK

Sophia Maprayil, Commissioning Editor for Expert Review of Anticancer Therapy, talks to Dr Iain Frame, Director of Research for Prostate Cancer UK.

Iain is Prostate Cancer UK’s first Director of Research, responsible for overseeing the development and implementation of the charity’s ambitious new research strategy. He joined Prostate Cancer UK in 2012 from Diabetes UK where he held the post of Research Director for 5 years. Since joining Prostate Cancer UK in 2012 Iain has overseen a dramatic increase in the charity’s research spend, from 2 million a year, to 7.5 million a year. Previously Iain worked in research management at the Wellcome Trust and before that as a parasitologist and researcher exploring various aspects of molecular biology of a number of different parasites.