Agomelatine:a potential novel approach for the treatment of memory disorder in neurodegenerative disease

Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B(MT/MT)and antagonist of 5-hydroxytryptamine 2C receptors.It is used clinically to treat major depressive episodes in adults.The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B,which work simultaneously to counteract depression and anxiety disorder.Moreover,by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors,agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex,increases the activity of dopamine and noradrenaline,and thereby reduces depression and anxiety disorder.The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression,anxiety,and disturbance of the circadian rhythm.Emotion and sleep are closely related to memory and cognitive function.Memory disorder is defined as any forms of memory abnormality,which is typically evident in a broad range of neurodegenerative diseases,including Alzheimer’s disease.Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases.Therefore,whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research“hotspot”.This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments.Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.

全新作用机制的抗抑郁药agomelatine

褪黑素类似物agomelatine,既是首个褪黑素受体激动剂,也是5-羟色胺2C(5-HT_(2C))受体拮抗剂。动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用,同时其不良反应少,对性功能无不良影响,也未见撤药反应。

Investigation of physicochemical properties and in-vitro in-vivo evaluation of agomelatine polymorphs

In the present study,Form I,Form II and Form III of agomelatine were prepared to investigate the variability of polymorphs,then the in-vitro in-vivo correlation were established.The presence of three polymorphs of agomelatine was corroborated through studies by XRPD,TGA and DSC.All the forms obtained were then subjected to the powder and intrinsic dissolution tests.The IDR ranked in the order of Form III>Form I>Form II.Form I and Form III both underwent solvent-mediated phase transformation(SMPT)to Form II during dissolution and the transition points were 62 and 45 min,respectively.Pharmacokinetic profiles were acquired after oral administration of tablets,showing that the ka and AUC0e12 h of Form I,Form II,Form III were 0.58
0.11,0.34
0.05,0.74
0.07 h1 and 296.25
49.39,186.05
45.93,331.16
54.74 ng*h/ml,respectively.Good linearities between IDR and ka,IDR and AUC were established,suggesting that the agomelatine polymorphic forms with faster dissolution rates in-vitro would increase the rate and extent of oral absorption in-vivo.These results demonstrated that IDR was predictive in estimating the relative bioavailability of agomelatine polymorphic forms.

Synthesis of Agomelatine by One-pot Catalytic Hydrogenation and Acetylation with NiO

Nano-NiO and bulk NiO were prepared from Ni(AC)_2·4 H_2O by coordination precipitation using aqueous ammonia and by a solid state reaction, respectively. The nickel oxide particles were characterized by X-ray Diffraction(XRD) and scanning electron microscopy(SEM). The results indicate that nano-sized NiO has a crystal phase with a standard face-centered cubic lattice structure, with a mean particle diameter of about 10 nm. The evaluation of the activity of nickel oxide nanoparticles in the catalytic hydrogenation of 7-methoxy-1-naphthylacetonitrile was carried out. The results demonstrate the efficient synthesis of the title compound by a one-pot catalytic hydrogenation and acetylation with NiO. The NiO nanoparticles displayed superior catalytic activity in the synthesis of agomelatine in the one-pot reaction.The total yield of agomelatine is over 81.8% with a purity of 99.2%, as determined by HPLC. The structure of agomelatine was confirmed by IR, MS, and 1 H NMR analysis.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

The aim of this study was to apply the reference-scaled average bioequivalence(RSABE)approach to evaluate the bioequivalence of 2 formulations of agomelatine,and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects.This was performed in a single-dose,randomized-sequence,open-label,four-way crossover study with a one-day washout period between doses.Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation.The formulations were considered bioequivalent if 90% confidence intervals(CIs)for the log-transformed ratios and ratio of geometric means(GMR)of AUC and C_(max) of agomelatine were within the predetermined bioequivalence range based on RSABE method.Results showed that both of the90% CIs for the log-transformed ratios of AUC and C_(max) of 7-desmethyl-agomelatine and 3-hydroxyagomelatine were within the predetermined bioequivalence range.The 90% CIs for natural logtransformed ratios of C_(max) ,AUC_(0–t)and AUC_(0–∞) of agomelatine(104.42–139.86,101.33–123.83 and97.90–117.94)were within the RSABE acceptance limits,and 3-hydroxy-agomelatine(105.55–123.03,101.95–109.10 and 101.72–108.70)and 7-desmethyl-agomelatine(104.50–125.23,102.36–111.50 and101.62–110.64)were within the FDA bioequivalence definition intervals(0.80–1.25 for AUC and0.75–1.33 for C_(max)).The RSABE approach was successful in evaluating the bioequivalence of these two formulations.

诺华公司决定中止对抗抑郁症药Agomelatine的进一步开发

近期,诺华公司宣称中止其＂未来的拳头产品＂——抗严重抑郁症药agomelatine（AGO178）的进一步的开发计划。Agomelatine具5-HT2c受体拮抗剂和褪黑激素受体激动剂双重活性,即可通过抑制5-HT2c受体,促进中枢神经系统中多巴胺和去甲肾上腺素的释放,并激活大脑皮质额叶区多巴胺能和肾上腺素能通路,且能有效激动褪黑激素受体MT1和MT2。该产品目前已在欧盟以商品名Valdoxan获准上市,成为首个褪黑激素能抗抑郁症药物,并有望于2013年在美国获准上市。

Possible Role of Exogenous Melatonin and Melatonin-Receptor-Agonists in the Treatment of Menopause―Associated Sleep Disturbances

One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms and changing reproductive hormone levels, circadian rhythm abnormalities, primary insomnia, mood disorders, coexistent medical conditions, and lifestyle. Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs with prolonged effects and slow-release melatonin preparations have been developed. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression associated insomnia. This article presents the currently available evidence regarding the effects of these compounds on sleep quality and their possible use in menopause associated sleep disturbances.