Exploring the Role of the GABAergic Modulation in Pain Transmission in Human. Effects of the GABAA Agonist N-desmethylclobazam on Central Sensitization: a Pharmacodynamic and Pharmacokinetic Study in Healthy Volunteers

Neuropathic pain affects about 7% of the general population in European countries. Meta-analyses indicate that only a minority of neuropathic pain patients has adequate response to drug therapy and management of neuropathic pain is still an unmet medical need. New insights into the contribution of defined subtypes of GABAA receptors (GABAARs) to the different clinical effects of benzodiazepines, including analgesia, have suggested that α1-sparing selective benzodiazepines, such as N-desmethylclobazam (NDMC), may be a new realistic alternative for the treatment of neuropathic pain. Results from our previous study in healthy volunteers assessing the antihyperalgesic and sedative effects of benzodiazepines on a UVB-induced pain model of central sensitization showed that, at the time of maximum effect, clobazam and clonazepam antihyperalgesic effect was greater than placebo by respectively 15.7% (95% CI 0.8 - 30.5) and 28.6% (95% CI 4.5 - 52.6), p<0.05. Moreover difference in sedation (VAS), as compared to placebo, was only significant for clonazepam 26.3mm (95%CI 15.0-37.7), p<0.001. Our preclinical data also demonstrate that, in recombinant receptors, NDMC has a better α2- over α1GABAARs activity ratio than clobazam and diazepam. And, unlike diazepam, NDMC caused no or modest sedation at antihyperalgesic doses in two strains of wild-type mice. In addition NDMC α2/α1 in vitro activity profile and long term clinical experience from its marketed parent compound (clobazam) make it an advisable clinical candidate for further proof-of-concept assessments in human. Therefore the Geneva University Hospitals have manufactured a new chemical entity and initiated a drug development program for NDMC starting with this proof-of-concept phase 1b randomized double-blind crossover (4 arms) study that will assess the analgesic and sedative effects of NDMC 20mg and 60mg compared to clonazepam 1.5 mg or placebo on a UVB-induced erythema pain model in healthy volunteers.

开始日期2017-03-30

申办/合作机构

Les Hôpitaux Universitaires de Genève

NCT00490516

/ Completed临床2期

A Six-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase II Study of the Efficacy and Safety of ACP-104 in Acutely Psychotic Subjects With Schizophrenia

This is a randomized, double-blind, placebo-controlled parallel-group, 6-week study, evaluating two dose levels of ACP-104 or Placebo twice a day in patients with schizophrenia who are experiencing an acute psychotic episode.

开始日期2007-06-01

申办/合作机构

ACADIA Pharmaceuticals, Inc.

NCT00628420

/ Completed临床1期IIT

A Randomized, Double Blind, Placebo Controlled, Single Oral Dose Study to Demonstrate the Safety, Tolerability, and Pharmacokinetics of ACP-104 (N-desmethylclozapine) in Schizophrenia, or Other Psychotic Disorders.

To determine the safety and tolerability of ACP-104 after oral administration of single doses in comparison with placebo to schizophrenia or other psychotic disorders.

开始日期2005-01-01

申办/合作机构

The University of Texas Southwestern Medical Center

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100 项与去甲氯氮平相关的临床结果

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100 项与去甲氯氮平相关的转化医学

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100 项与去甲氯氮平相关的专利（医药）

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601

项与去甲氯氮平相关的文献（医药）

2026-01-01·PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY

Population pharmacokinetic analysis for simultaneous fit of clozapine and norclozapine concentrations in adult psychiatric patients

Article

作者: Panić, Bojana ; Vučićević, Katarina ; Milovanović, Srđan ; Lukić, Vera ; Jovanović, Marija ; Miljković, Branislava

BACKGROUND:

Clozapine (CLZ) exhibits a high potential for pharmacokinetic interactions due to its extensive and complex metabolism. Additionally, several patient-related factors contribute to the pharmacokinetic variability, making treatment optimization even more challenging. The goal of this study was to develop a parent-metabolite population pharmacokinetic model for CLZ and its primary metabolite norclozapine (NCLZ) and to evaluate sources of variability in a real-world clinical setting.

METHODS:

Data from routine therapeutic drug monitoring (TDM) of 126 adult in- and out-patients with psychiatric disorders were used for the analysis. A nonlinear mixed-effects modeling approach was applied for data analysis to simultaneously fit CLZ and NCLZ concentrations.

RESULTS:

A one-compartment model for the drug with an additional compartment for NCLZ was used to fit the concentration-time data. The population pharmacokinetic value of oral clearance for CLZ (CL/F) for a typical patient (female, non-smoker) was 26.4 L/h. Male sex and positive smoking status were associated with an increase in CL/F of 25.9 % and 29.2 %, respectively. The estimated value of metabolite clearance (CL_m/F) for a typical patient was 29.6 L/h, while male sex and valproic acid (VPA) use were associated with its increases for 45.1 % and 95.5 %, respectively.

CONCLUSION:

The developed population pharmacokinetic model describes the simultaneous disposition of CLZ and NCLZ in adult psychiatric patients, accounting for impact of patient and co-therapy factors. In addition to the well-established effects of sex and smoking status on CLZ pharmacokinetics, the model characterizes the significant impact of VPA co-therapy, primarily on NCLZ disposition.

2026-01-01·JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY

Adverse Reactions to Clozapine

Article

作者: Reeves, Suzanne ; Sanchez, Paula Liren Valbuena ; Flanagan, Robert James ; Rogers, Jonathan P. ; Evans, Lauren ; Kim, Alice Hyun Min ; Every-Palmer, Susanna ; Obee, Stephen John

Background::

In treatment-refractory schizophrenia, pre-dose plasma clozapine concentrations are, on average, lower in smokers than in nonsmokers. This may relate to the incidence of adverse drug reactions (ADR).

Methods::

Generalized estimating equation analyses were used to investigate clozapine TDM data from 1993 to 2017 for ADR with ≥30 mentions on request forms.

Results::

There were 1154 mentions of an ADR (1058 patients), 36,470 controls (“baseline” samples, 14,572 patients). In the ADR group, median plasma clozapine concentration (mg/L) was significantly lower in smokers (0.41, N=586) than nonsmokers (0.56, N=368) ( P <0.001). The constipation subgroup, for example, had higher median plasma clozapine concentrations [0.56 (0.22-1.27) mg/L] than the controls [0.45 (0.18-0.93) mg/L] ( P =0.025). Higher plasma clozapine concentrations were also associated with hypersalivation, hypotension, and neurological ADR (seizures and myoclonus), but no associations were found in relation to cardiac, low white cell count, metabolic, and nausea/vomiting subgroups. In the neurological ADR subgroup, plasma clozapine concentrations were higher in smokers ( P <0.001) and in nonsmokers ( P =0.019) compared with controls. In the constipation subgroup, plasma clozapine was only significantly higher in nonsmokers, while in the hypotension and sedation subgroups, the opposite applied. Plasma norclozapine showed a similar pattern of results to that of clozapine. The plasma clozapine:norclozapine ratio showed no consistent pattern between the ADR subgroups.

Implications::

ADR such as constipation and seizures may be more likely to occur at lower plasma clozapine concentrations in smokers. The underlying mechanism(s) require further investigation.

2026-01-01·BRAIN BEHAVIOR AND IMMUNITY

Atypical antipsychotics alter microglial functions via astrocyte-derived extracellular vesicles

Article

作者: McCrea, Liam T ; Sheridan, Steven D ; Song, Yoonjae ; Yeh, Hana ; Bowen, Joshua J ; Perlis, Roy H

A limited understanding of the underlying molecular mechanisms of atypical antipsychotics has hindered efforts to develop the next generation of treatments for schizophrenia. In particular, there has been little investigation of how medications like clozapine and olanzapine modulate human non-neuronal cells, including astrocytes and microglia. Recent postmortem and serum-based studies suggest that schizophrenia etiology involves dysregulated cellular communication through extracellular vesicles (EVs). Astrocytes are a major source of these EVs and are strongly implicated in the etiology of schizophrenia by convergent data from human postmortem, brain imaging, RNA-sequencing, and genome-wide association studies. We hypothesized that clozapine and olanzapine can affect microglia biology indirectly via astrocytic secretion of EVs. We used in vitro cellular models with human astrocytes and PBMC-derived microglial-like cells to investigate the downstream impact of isolated astrocyte-derived EVs (ADEVs) on microglial phenotypes relevant to schizophrenia, including microglial phagocytosis, motility, and morphology. To model microglia-mediated synaptic pruning in vitro, we utilized image-based quantification of microglia engulfment of isolated human synaptosomes. We found that treatment with ADEVs reduced microglial synaptosome phagocytosis in a dose-dependent manner. This reduction was reversed upon addition of ADEVs isolated from astrocytes treated with norclozapine or olanzapine. ADEVs isolated from clozapine-treated astrocytes increased microglial motility, indicating that clozapine alters microglial surveillance activity without affecting phagocytosis through these ADEVs. Together, these results suggest that atypical antipsychotics have distinct and indirect impact on microglia biology mediated by ADEVs. These results highlight a potentially critical role for ADEVs in regulating glial cell communication, and suggest they may be promising therapeutic targets for next-generation antipsychotic development.

项与去甲氯氮平相关的新闻（医药）

2024-02-13

·PRNewswire

Keystone Lab Announces Addition of Tianeptine to Testing Menu

ASHEVILLE, N.C., Feb. 13, 2024 /PRNewswire/ --  Keystone Lab, a dual-CAP accredited and CLIA certified lab based in Asheville, NC, has officially added tianeptine to its in-house urine clinical toxicology menu. Keystone provides clinical and forensic toxicology testing services throughout the southeastern U.S. and is one of few labs in the southeast to offer testing for tianeptine. Continue Reading Keystone Logo Tianeptine is an atypical tricyclic antidepressant often used for addressing anxiety and irritable bowel disease. It is not approved for any use by the United States Federal Drug Administration (FDA). Tianeptine is often described as "gas-station dope" and products containing tianeptine commonly use the street names of "ZaZa" or "Tianna". The FDA recently warned consumers to avoid purchasing or using any Neptune's Fix products, which is illegally sold with claims to improve brain function and treat anxiety, depression, pain, opioid use disorder and other conditions. In addition to tianeptine and its metabolite, tianeptine metabolite MC5, Keystone has also added clozapine, N-desmethylclozapine, aripiprazole, aripiprazole metabolite OPC-3373, modafinil, diphenhydramine, loperamide, and 7OH-mitragynine to its in-house menu. "The ease of obtaining products with tianeptine, combined with effects of harm, overdosing, and death has been a major obstacle for many of our addiction clinic and recovery center clients throughout North Carolina", said Dr. James Bourland, Scientific Director of Keystone Lab. "By adding tianeptine testing in-house, Keystone is able to listen to its clients and provide the best service possible to their patients." If testing for tianeptine is a priority for your business, please contact Keystone Lab at 800-230-2991, or contact us directly on our website. Resources: About Keystone Lab: Keystone Lab is a dual CAP-accredited and CLIA certified lab providing clinical and forensic toxicology testing services for more than 35 years. Keystone has developed an innovative platform of services to ensure the success and growth of organizations throughout the United States. For more information about Keystone Lab, . Media Contact David Price Sales & Marketing Manager [email protected] 828-771-3107 SOURCE Keystone Lab

上市批准

2023-04-23

·生物制品圈

9:1赞成！ Brexpiprazole有望成为首个FDA批准用于AAD治疗的药物

01 阿尔茨海默病痴呆相关激越症状(AAD)药物brexpiprazole 近日，FDA咨询委员会以 9：1 投票赞成 Otsuka 和 Lundbeck 的药物 Rexulti® (brexpiprazole，图1) 用于阿尔茨海默病痴呆相关激越症状（AAD）。FDA预计于5月10日前完成此sNDA审查。若获批，brexpiprazole将成为首个获FDA批准用于AAD治疗的药物。 2015 年，Rexulti®首次批准用于治疗精神分裂症，并作为成人重度抑郁症抗抑郁药的辅助疗法，并在2018年先后在日本和美国获批上市。2021年12月，FDA批准Rexulti的补充新药申请，用于治疗13至17岁儿童患者的精神分裂症。在会议上，大冢制药公布：所有三项安慰剂对照 III 期试验都显示出Brexpiprazole对阿尔茨海默病适应症的疗效，并且安全性与其他抗精神病药物相当。尽管距离获得监管审批还有一段路要走，但一些分析师已经预测，brexpiprazole具有产生年销售额 5 亿美元的潜力。 Brexpiprazole 由 Otsuka 和 Lundbeck共同开发，被认为是aripiprazole (图1，Abilify®) 的替代升级药物。 02 Brexpiprazole特殊的“部分激动剂”身份 Brexpiprazole在药理学上特殊的一点在于，它是一种新型的“部分激动剂”（partial agonist）。具体说，它是多巴胺D2受体和血清素1A受体的“部分激动剂”，也称为血清素-多巴胺活性调节剂 (SDAM，serotonin-dopamine activity modulator)。除此之外，它还是血清素2A受体和去甲肾上腺素能 α 1B 和 2C 受体的强效拮抗剂。部分激动剂与其受体结合的过程中，可在不同环境下表现出阻断或激动这两种相反的功效。这种亦庄亦谐的效果正是部分激动剂特殊的地方，它的阻断活性与激动活性的比率，决定了其临床效果。与它的前身药物aripiprazole相比，brexpiprazole 对多巴胺受体具有更多的阻断作用以及更少的激动作用，这可能会降低其导致激越和烦躁的风险。具体来说，aripiprazole对多巴胺D2 受体具有 60%以上的固有激动效率，brexpiprazole 则只有约 45%。部分激动剂与内源性多巴胺（属于完全激动剂）竞争时，就可以起到“鸠占鹊巢”并阻断多巴胺下游信号通路的效果。 03 “部分激动剂”的药理学特性在药理学中，部分激动剂是结合并激活给定受体的药物，但相对于完全激动剂而言，该受体仅具有部分功效。它们也可以被认为是同时显示激动和拮抗作用的配体：当完全激动剂和部分激动剂同时存在时，部分激动剂就会摇身一变，从激动剂变成竞争性拮抗剂，与完全激动剂竞争结合受体，并导致受体激活减少。参见brexpiprazole在多巴胺存在的情况下，从多巴胺D2受体激动剂变成拮抗剂的例子。临床上，当内源性配体数量不足时，部分激动剂则可用于激活受体以产生内源性配体结合带来的额效应；而当存在过量内源性配体时，它们可以减少受体的过度刺激。也就是说，部分激动剂的激动还是拮抗效应，需要视完全激动剂是否在场以及完全激动剂的浓度而定。正是这种“见风使舵”的分裂属性，提供了治疗精神分裂症的益处。 3.1多巴胺受体“部分激动剂” 多巴胺受体“部分激动剂”，是一种与多巴胺受体结合，但内在活性低于内源性完全激动剂（即多巴胺）的药物。在性质上类似于多巴胺，但产生的反应数量小于多巴胺产生的反应。根据多巴胺的水平，“部分激动剂”药物可以充当功能性拮抗剂（functional antagonist）或功能性激动剂（functional agonist）(图2)。 ü功能性拮抗剂（functional antagonist） ·在存在过量多巴胺传输的情况下，功能性拮抗剂可以将这种传输降低到较低水平（图2）。 ·中脑边缘多巴胺通路中的功能性拮抗作用，解决了过度的多巴胺活性所导致阳性症状。 ü功能性激动剂（functional agonist） ·在低多巴胺水平的情况下，功能性激动剂可以再次将多巴胺神经传递增加到其内在活动的水平（图2）。 ·中脑皮质多巴胺通路中的功能性激动剂活性，缓解了因为多巴胺活性降低所导致的不良症状和认知障碍。多巴胺受体“部分激动剂”可以被认为是多巴胺调节剂，根据内源性多巴胺水平是过高还是过低，来调节多巴胺受体的激动和拮抗水平，这被称为调光开关效应（dimmer switch，图3）或金发女孩效应（Goldilocks effect）（Goldilocks效应来自于儿童故事《三只熊》，故事中一个名叫Goldilocks的小女孩品尝了三碗不同的粥，发现自己喜欢的粥既不太热也不太冷，温度恰到好处。“适度”概念很容易理解，并适用于广泛的学科，包括心理学、生物学、天文学、经济学和工程学。这也是中国古典哲学推崇的执两用中的“中庸之道”）。图3. 调光开关效应示意图。（图片来源：Psych Scene Hub）部分激动剂可能有助于降低长期服用 D2 拮抗剂时发生的 D2 受体上调导致的多巴胺超敏性精神病（DA supersensitivity psychosis）的风险。多巴胺超敏性精神病的潜在临床后果，是抗精神病药物可能逐渐失效，随着时间的推移需要越来越高的抗精神病药物剂量，增加不良反应风险。 3.2 Brexpiprazole的药理学和作用机制 Brexpiprazole的药物发现过程集中在： ·增加血清素2A 受体的拮抗作用： ü拮抗血清素2A 受体可以增强夜间慢波睡眠来改善失眠，从而减少失眠和其他睡眠障碍。（例如药物米氮平Mirtazapine是一种血清素2A受体拮抗剂，可改善慢波睡眠） ü尽量减少静坐不能的发生（Akathisia，一种运动障碍，主要表现为内心烦躁不安和无法保持静止。） ·增强血清素1A受体的激动作用： ü突触后膜上的血清素1A受体被激动剂后，可增加额叶皮质中的多巴胺释放，从而改善抑郁和焦虑。这些协同的作用，推动了 brexpiprazole 的开发，其特点是对血清素1A受体、血清素2A受体和多巴胺D2 受体具有几乎同样高的亲和力。因此，基于以上活性，brexpiprazole 被归类为血清素-多巴胺活性调节剂 (SDAM，serotonin-dopamine activity modulator)。 3.3 Brexpiprazole受体概况（图4） 1）多巴胺 D2 受体的“部分激动剂”，活性水平低于aripiprazole。 2）血清素1A受体的“部分激动剂”，活性水平高于aripiprazole。 3）血清素2A受体的强效拮抗剂 4）血清素7 受体的拮抗剂 5）去甲肾上腺素 α 1B/2C 受体的强效拮抗剂。 6）对组胺 H1 受体和毒蕈碱 M1 受体具有中等亲和力。 04 “部分激动剂”上市和在研药物除了brexpiprazole之外，上市和在研的“部分激动剂”药物还包括： ·Buspirone丁螺环酮 Buspirone是一种新型抗焦虑药，作为突触前血清素1A 受体的完全激动剂，以及海马和皮质上表达的突触后血清素1A 受体的“部分激动剂”。 ·Buprenorphine丁丙诺啡 Buprenorphine被用于治疗对替代疗法无反应的剧烈疼痛，也用于阿片成瘾的维持治疗。它是一种μ-阿片受体的部分激动剂和 kappa-阿片受体的拮抗剂。它表现出对 μ-阿片受体的高亲和力，但与海洛因、羟考酮或美沙酮等其他μ-阿片受体的完全激动剂相比具有较低的内在活性。这意味着丁丙诺啡可以优先结合阿片受体，并取代那些低亲和力的阿片类药物，而不将受体激活到过高的程度。在临床上，这种调节作用会导致起效缓慢，产生一种被称为“天花板效应”的临床现象，即一旦达到一定剂量，丁丙诺啡的效应就会达到平稳状态。这种效果可以是有益的，因为呼吸抑制、镇静和中毒等与剂量相关的副作用也在 32 mg的剂量左右得到稳定，因此与美沙酮和其他完全激动剂阿片类药物相比，过量服用的风险较低。“天花板效应”还这意味着，依赖阿片类药物的患者不会像使用更强效的阿片类药物时产生那种镇静或欣快感，从而改善患有剧烈疼痛的患者的生活质量，并尽可能减少药物滥用的可能性。 ·Nalmefene纳美芬纳美芬Nalmefene是一种阿片受体拮抗剂。更确切地说，它是 μ-阿片受体和 δ-阿片受体的拮抗剂，以及 kappa-阿片受体的“部分激动剂”。在欧洲，纳美芬口服片剂用于减少酒精依赖成人的饮酒量。12纳美芬于 1995 年在美国获准用作阿片类药物使用过量的解毒剂。纳美芬注射液用于管理阿片类药物过量。它用于完全或部分逆转阿片类药物的作用，包括由天然或合成阿片类药物引起的呼吸抑制。 ·Norclozapine去甲氯氮平 Norclozapine是一种用于治疗精神分裂症的在研药物。它具有M1 毒蕈碱受体的激动作用、血清素2A 受体的反向激动作用，以及多巴胺D2 和 D3 受体的部分激动作用，可引起多巴胺 D2 和 D3 受体的微弱激活，并让它具有比大多数其他抗精神病药物更少的运动副作用。主要参考文献 [1] Brennan, Z. FDA adcomm votes in favor of first drug for agitation associated with Alzheimer's dementia. Endpoints News. 14, 04, 2023. [2] Otsuka HD places top priority on development of OPC-34712. Chemical Business Newsbase. 01, 03, 2011. [3] Maeda, K. et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. The Journal of Pharmacology and Experimental Therapeutics. 2014, 350, 589–604. [4] Clarke, W. P. et al. The elusive nature of intrinsic efficacy. Trends in Pharmacological Sciences. 1998, 19, 270–276.[5] Calvey, N. et al. Partial agonists. Principles and Practice of Pharmacology for Anaesthetists. 2009. p 62.

临床3期临床2期临床结果

100 项与去甲氯氮平相关的药物交易

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