New technologies are needed to help diagnose anxiety disorders. EVestG has facilitated the identification of numerous possible biomarkers of several psychiatric disorders. Some EVestG features seem to be caused by differences in low-frequency modulation that is consistent (both in frequency and behaviour) with the hippocampal rhythm (theta), which is known to play a role in anxiety. Critically, there is ample support in the literature for an anatomical and functional basis for the modulation of vestibular signals via theta. If anxiety could be measured continuously, perhaps throughout a patient's day, or throughout a task, it might be able to confirm an anxiety disorder. However, current techniques for measuring theta are highly invasive, performed rarely, and only in epilepsy patients. EVestG technology, however, is non-invasive, and could potentially record anxiety levels in any subject for extended periods of time. The proposed study will attempt to identify hippocampal theta in vestibular signals in healthy participants through a double-blind administration of two different drugs that are dissimilar both pharmacologically and in acute clinical effects but which are known to reduce the theta rhythm.

开始日期2023-10-16

申办/合作机构

University of Manitoba

NCT03360123 / CompletedN/AIIT

Oral Anxiolysis for the Older Pediatric Patient-Which Medication is Preferred?

This study will evaluate the perceptions of the effects of two anxiolytic medications commonly used during dental treatment in patients weighing 40 kilograms or more.

开始日期2018-01-26

申办/合作机构

University of Pittsburgh

NCT03246724 / Completed临床4期IIT

A Single-center, Randomized, Double-blind, Double-dummy, Parallel-group Study Comparing Oral Sedation to Intravenous Sedation for Ocular Procedures.

The purpose of this study is to evaluate patient satisfaction after eye surgery when given a capsule compared to an intravenous (IV) dose of sedation (calming medication).
Each subject will be given a capsule and an IV in the hospital before their procedure starts, however they will not know which one is the sedation route. Each subject will have their planned surgical procedure as previously discussed with their doctor. After the procedure is completed, the doctors will complete satisfaction surveys. The subject will also complete a satisfaction survey during their regularly scheduled visit the day after surgery. Once the subject completes this survey, their study participation will be complete.
The hypothesis is that there will be no difference in patient satisfaction when given a capsule in comparison to IV sedation. If the results of the study support this hypothesis, a capsule could be used in place of IV sedation. By using a capsule for ocular procedures, both patients and the medical practice would benefit: patient would be able to eat before their procedure, patient costs would be decreased, hospital costs would be reduced, and some of these procedures would be given the option to move to a procedure room (freeing up operating room time for other departments).

开始日期2017-10-16

申办/合作机构

Boston Medical Center

100 项与三唑仑相关的临床结果

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100 项与三唑仑相关的转化医学

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100 项与三唑仑相关的专利（医药）

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项与三唑仑相关的文献（医药）

2024-03-01·European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

Physiologically based pharmacokinetic modeling of ritonavir-oxycodone drug interactions and its implication for dosing strategy

Article

作者: Wang, Ling ; Hu, Wei ; Ni, Liang ; Dallmann, André ; Olkkola, Klaus T ; Zheng, Liang ; Zhang, Qian ; Zhang, Wei ; Zhao, Yingjie

The concomitant administration of ritonavir and oxycodone may significantly increase the plasma concentrations of oxycodone. This study was aimed to simulate DDI between ritonavir and oxycodone, a widely used opioid, and to formulate dosing protocols for oxycodone by using physiologically based pharmacokinetic (PBPK) modeling. We developed a ritonavir PBPK model incorporating induction and competitive and time-dependent inhibition of CYP3A4 and competitive inhibition of CYP2D6. The ritonavir model was evaluated with observed clinical pharmacokinetic data and validated for its CYP3A4 inhibition potency. We then used the model to simulate drug interactions between oxycodone and ritonavir under various dosing scenarios. The developed model captured the pharmacokinetic characteristics of ritonavir from clinical studies. The model also accurately predicts exposure changes of midazolam, triazolam, and oxycodone in the presence of ritonavir. According to model simulations, the steady-state maximum, minimum and average concentrations of oxycodone increased by up to 166% after co-administration with ritonavir, and the total exposure increased by approximately 120%. To achieve similar steady-state concentrations, halving the dose with an unchanged dosing interval or doubling the dosing interval with an unaltered single dose should be practical for oxycodone, whether formulated in uncoated or controlled-release tablets during long-term co-medication with ritonavir. The results revealed exposure-related risks of oxycodone-ritonavir interactions that have not been studied clinically and emphasized PBPK as a workable method to direct judicious dosage.

2023-12-01·Psychopharmacology

Pharmaco-EEG analysis of ligands varying in selectivity for α1 subunit-containing GABAA receptors during the active phase in rats

Article

作者: Rowlett, James K ; Reeves-Darby, Jaren A ; Platt, Donna M ; Berro, Lais F ; Rüedi-Bettschen, Daniela ; Shaffery, James P

RATIONALE:

Benzodiazepines are known to evoke changes in cortical electrophysiological activity that can be correlated with action at distinct γ-aminobutyric acid type A (GABA_A) receptor subtypes.

OBJECTIVES:

We used electroencephalography (EEG) paired with electromyography (EMG) to evaluate the role of α1 subunit-containing GABA_A receptors (α1GABA_ARs) in benzodiazepine-induced sedation and changes in EEG band frequencies during the active phase of the light/dark cycle.

METHODS:

Male Sprague-Dawley rats (N = 4/drug) were surgically instrumented with EEG/EMG electrodes. The rats were injected i.p. with zolpidem, an α1GABA_AR-preferring compound, or L-838,417, which has selective efficacy for α2/3/5 subunit-containing GABA_ARs (i.e., α1GABA_AR-sparing compound), in comparison with the non-selective benzodiazepine, triazolam.

RESULTS:

All ligands evaluated induced changes in sleep-wake states during the active phase consistent with an increase in slow-wave sleep (SWS). The degree of SWS increase appeared to be related to the magnitude of delta power band changes induced by the ligands, with the strongest effects engendered by the α1GABA_AR-preferring drug zolpidem and the weakest effects by the α1GABA_AR-sparing compound, L-838,417. Consistent with other research, a selective increase in beta band power was observed with L-838,417, which may be associated with α2GABA_AR-mediated anxiolysis.

CONCLUSIONS:

Overall, these findings support the establishment of pharmaco-EEG "signatures" for identifying subtype-selective GABA_A modulators in vivo.

2023-10-01·Drug metabolism and disposition: the biological fate of chemicals

Analysis of the Bile Acid Composition in a Fibroblast Growth Factor 19-Expressing Liver-Humanized Mouse Model and Its Use for CYP3A4-Mediated Drug-Drug Interaction Studies.

Article

作者: Chang, Jae H ; Mezler, Mario ; Heikkinen, Aki T ; Sangaraju, Dewakar ; Foquet, Lander ; Pusalkar, Sandeepraj ; Goldman, Devorah C ; Jones, Robert S ; Mannila, Janne ; Chothe, Paresh P ; Scheer, Nico ; Hoffmann, Matthew

Numerous biomedical applications have been described for liver-humanized mouse models, such as in drug metabolism or drug-drug interaction (DDI) studies. However, the strong enlargement of the bile acid (BA) pool due to lack of recognition of murine intestine-derived fibroblast growth factor-15 by human hepatocytes and a resulting upregulation in the rate-controlling enzyme for BA synthesis, cytochrome P450 (CYP) 7A1, may pose a challenge in interpreting the results obtained from such mice. To address this challenge, the human fibroblast growth factor-19 (FGF19) gene was inserted into the Fah^-/- , Rag2^-/- , Il2rg^-/- NOD (FRGN) mouse model, allowing repopulation with human hepatocytes capable of responding to FGF19. While a decrease in CYP7A1 expression in human hepatocytes from humanized FRGN19 mice (huFRGN19) and a concomitant reduction in BA production was previously shown, a detailed analysis of the BA pool in these animals has not been elucidated. Furthermore, there are sparse data on the use of this model to assess potential clinical DDI. In the present work, the change in BA composition in huFRGN19 compared with huFRGN control animals was systematically evaluated, and the ability of the model to recapitulate a clinically described CYP3A4-mediated DDI was assessed. In addition to a massive reduction in the total amount of BA, FGF19 expression in huFRGN19 mice resulted in significant changes in the profile of various primary, secondary, and sulfated BAs in serum and feces. Moreover, as observed clinically, administration of the pregnane X receptor agonist rifampicin reduced the oral exposure of the CYP3A4 substrate triazolam. SIGNIFICANCE STATEMENT: Transgenic expression of FGF19 normalizes the unphysiologically high level of bile acids in a chimeric liver-humanized mouse model and leads to massive changes in bile acid composition. These adaptations could overcome one of the potential impediments in the use of these mouse models for drug-drug interaction studies.

项与三唑仑相关的新闻（医药）

2024-06-24

·GlobeNewswire-Health Care

Helsinn Group announces AKYNZEO® (fosnetupitant/palonosetron) injection is now available in a ready-to-use vial in the US

Helsinn Group announces AKYNZEO® (fosnetupitant/palonosetron) injection is now available in a ready-to-use vial in the US Lugano, Switzerland – June 24, 2024 – Helsinn Group (“Helsinn”), a global pharmaceutical company with a track record of over forty-five years of commercial execution and a strong focus in supportive care, oncology and dermato-oncology, is pleased to announce that AKYNZEO® (fosnetupitant/palonosetron) injection is now available in the US in a ready-to-use vial. AKYNZEO injection (Ready-to-Use) is a new method of administration and contains the same formulation as the prior AKYNZEO Injection (To-be-Diluted). The features of the new ready-to-use presentation of AKYNZEO injection include: No reconstitution or dilution required; infuse directly from the vial using a built-in hanging strapNo refrigeration required at any point during distribution, storage, or preparationAccessible via automated dispensing machine, allowing the product to be stored and available near the location of patient care AKYNZEO injection is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. It has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. AKYNZEO injection does not contain polysorbate 80 or allergenic excipients such as soy or egg lecithin. It can be administered simultaneously with intravenous dexamethasone sodium phosphate. Dr. Melanie Rolli, Helsinn Group CEO, commented: “As a pioneer in cancer supportive care, Helsinn continues to be unwavering in our pursuit to help patients and clinicians in cancer care. We are very pleased to launch the new AKYNZEO Ready-to-Use vial, building on our legacy of innovation.” Ordering information Clinicians wishing to order the new vial should contact their GPO or distributor. The National Drug Code (NDC) number for AKYNZEO injection vial with hanger (Ready-to-Use) is 69639-106-01 and the J Code is J1454 (Injection, fosnetupitant 235 mg and palonosetron 0.25 mg); billing unit (single dose vial [SDV]). About AKYNZEO® AKYNZEO is the first and only 5-HT3 and NK1 receptor antagonists fixed combination approved for the prevention of chemotherapy-induced acute and delayed nausea and vomiting. A single dose of AKYNZEO given with dexamethasone has been shown to prevent chemotherapy-induced nausea and vomiting for up to 5 days. INDICATION AKYNZEO (fosnetupitant/palonosetron) injection is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Limitations of Use AKYNZEO injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. AKYNZEO is a combination of palonosetron, a serotonin-3 (5-HT3) receptor antagonist, and fosnetupitant, a substance P/neurokinin-1 (NK-1) receptor antagonist: palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. IMPORTANT SAFETY INFORMATION Warnings and Precautions Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the components of AKYNZEO, with or without known hypersensitivity to other 5-HT3 receptor antagonists.Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. Serotonin syndrome can be life threatening. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms. Patients should be monitored for the emergence of serotonin syndrome, and if symptoms occur, discontinue AKYNZEO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO is used concomitantly with other serotonergic drugs. Adverse Reactions Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema. The safety profile of AKYNZEO injection was generally similar to AKYNZEO capsules. Drug Interactions Use with caution in patients receiving concomitant medications primarily metabolized by CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co-administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days Dexamethasone doses should be reduced when given with AKYNZEO. A more than two- fold increase in the systemic exposure of dexamethasone was observed 4 days after a single infusion of fosnetupitant.Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) when administering with AKYNZEO. When administered with netupitant, the systemic exposure to midazolam was significantly increased. Avoid concomitant use of AKYNZEO in patients on chronic use of a strong CYP3A4 inducer such as rifampin as this may decrease the efficacy of AKYNZEO. Use in Specific Populations Avoid use of AKYNZEO in patients with severe hepatic impairment, severe renal impairment, or end-stage renal disease.Advise women of potential risk to fetus; limited data are available; may cause fetal harm. For more information about AKYNZEO® please see the full US Prescribing Information. About Helsinn Helsinn is a global pharmaceutical company that builds, manufactures, launches, and commercializes products to improve the quality of life for patients with cancer and chronic disease, with a focus on supportive care, oncology and dermato-oncology. Helsinn, headquartered in Lugano, Switzerland, has direct commercial operations in the U.S. and an extensive network of long-standing trusted partners enabling a commercial presence in more than 90 countries. Established in 1976, Helsinn is a third-generation family-owned company with broad pharmaceutical and technical expertise. Helsinn is proud of its history of operating with great integrity, passion and quality. The company is committed to continuously striving for innovation for its patients and embracing sustainable growth as a core element of its strategic vision. To learn more about Helsinn, please visit www.helsinn.com or follow us on LinkedIn and X. For more information: Helsinn Group Media Contact:Sabrina PerucchiGroup Communication ManagerLugano, Switzerland Tel: +41 (0) 91 985 21 21 Email: Info-hhc@helsinn.com

上市批准临床结果

2024-01-03

·CPHI制药在线

失眠药物治疗研究进展

关注并星标CPHI制药在线睡眠障碍是指睡眠质量异常或睡眠时发生某些临床症状，如睡眠减少或睡眠过多、睡眠相关运动障碍等，后者包括睡眠行走、睡眠惊恐、不宁腿综合征等。其中最主要最常见的是失眠障碍，以持续睡眠时间过短、早醒以及入睡困难为最主要的3个症状。失眠治疗有躯体治疗(包括药物治疗、物理治疗等) 、心理治疗或者心理治疗联合躯体治疗的综合治疗等。虽然美国内科医师学会将认知行为疗法确定为失眠的一线治疗方法。但由于认知行为疗法存在费用高、咨询时间长、缺乏训练有素的提供者及不能立竿见影等弊端，难以在临床开展。因此，药物治疗依然广泛应用于是失眠治疗。目前推荐在临床常用的治疗失眠药物包括苯二氮䓬受体激动剂、褪黑素及褪黑素受体激动剂、食欲素受体拮抗剂、组胺拮抗剂及抗焦虑、抗抑郁类药物。对单纯失眠患者，一般首选非苯二氮䓬类药物或褪黑素受体激动剂单药治疗，当单药治疗效果不佳时考虑联合不同作用机制的镇静催眠药治疗；对合并情绪障碍患者，需根据症状选择苯二氮䓬类药物或联合具有镇静作用的抗抑郁药、抗精神病药物治疗。 1、苯二氮䓬受体激动剂苯二氮䓬受体激动剂（benzodiazepine receptor agonists，BzRAs）作为临床上最常用于治疗失眠的药物，可分为苯二氮䓬类药物（benzodiazepine drugs，BZDs）与非苯二氮类药物（nonbenzodiazepine drugs，NBZDs）。临床常见用于失眠治疗的BZDs有阿普唑仑、艾司唑仑、劳拉西泮、氯硝西泮等，主要适用于入睡困难和睡眠维持障碍的成年患者，尤其适用于伴有焦虑症的失眠患者。BZDs 通过非选择性结合苯二氮䓬受体，增加γ- 氨基丁酸（gamma aminobutyric acid，GABA）受体的亲和力，促进氯离子内流，导致苯二氮䓬受体所在神经元出现超极化，起到镇静催眠、抗焦虑和肌肉松弛等药理作用。BZDs 可以缩短睡眠潜伏期，减少夜间觉醒，增加总睡眠时间，但深度睡眠时间减少，患者服用后虽然觉得入睡改善、睡眠时间延长，但睡眠质量仍较低。BZDs可能会导致日间思睡、头晕、乏力和认知功能下降，老年患者还可能增加跌倒、骨折的风险。长期使用BZDs 的患者可能形成心理和躯体依赖，且部分患者在停药后出现严重的戒断症状，出现反跳性失眠和焦虑情绪加重，因此长期服用BZDs 的患者需缓慢撤药。美国医师协会在失眠药物治疗指南列出批准治疗失眠的BZDs 有艾司唑仑、氟西泮、夸西泮、替马西泮和三唑仑。 NBZDs通过选择性结合苯二氮䓬受体，抑制睡眠中枢产生镇静催眠作用，但一般不具有抗焦虑作用。临床上常见的NBZDs 有唑吡坦、扎来普隆、佐匹克隆和右佐匹克隆， NBZDs的半衰期较短，白天残留镇静作用少见，尤其唑吡坦和扎来普隆对改善入睡困难效果满意，但对睡眠维持作用不大，佐匹克隆和右佐匹克隆半衰期稍长，对入睡困难和睡眠维持障碍均有作用。 2、褪黑素和褪黑素受体激动剂褪黑素作为重要的生理性睡眠调节因子，其昼夜节律的变化与睡眠节律密切相关。褪黑素由松果体分泌，呈昼少夜多的节律，凌晨2～3点分泌达到高峰，主要作用于下丘脑的褪黑素受体，调节睡眠-觉醒周期。研究发现，外源性褪黑素可能对缩短睡眠潜伏期、增加总睡眠时间有效，但临床观察发现大多数患者对于失眠治疗效果不满意，可能更适合睡眠节律失调的失眠患者。褪黑素主要通过2个高亲和力膜受体MT1和MT2发挥其生理作用。视交叉上核在光-暗循环周期的调控下，通过激活 MT1 和(或MT2) 受体反馈回细胞核以调节睡眠和昼夜节律周期。雷美替胺是首个获准上市的选择性褪黑素受体激动剂，已被 FDA 批准用于治疗失眠，主要改善入睡困难，但在国内未上市。该药物可缩短睡眠潜伏期，增加总睡眠时间，不良反应有头晕、思睡、疲劳、头痛、恶心，加重原发性抑郁症患者的抑郁症状和自杀观念等。阿戈美拉汀是国内仅有的一种褪黑素受体激动剂，具有激动褪黑素受体（MT1/MT2）和5-HT2C受体拮抗的双重机制，研究发现，阿戈美拉汀可改善睡眠维持障碍，增加深睡眠和总睡眠时间、减少入睡后总觉醒时间、提高睡眠效率，因此对有入睡困难患者需联合苯二氮䓬受体激动剂效果更佳。由于该药同时是抗抑郁药，对失眠伴轻中度焦虑抑郁患者可起到改善睡眠和情绪的双重作用，但需注意使用该药物需监测肝功能，对肝功能损害者禁止使用。 3、食欲素受体拮抗剂食欲素( Orexins，OX) 主要由下丘脑外侧、背侧和弯窿区分泌，又称下丘脑分泌素，被称为下丘脑的"觉醒启动区"，可促进食欲且具有促醒作用，对维持长期觉醒很重要，食欲素的生成减少将导致发作性嗜睡和不规则快速眼动睡眠。研究表明，大鼠脑脊髓液内和下丘脑外侧、丘脑内侧的细胞外食欲素A水平呈显著的日节律变化，在黑暗期慢慢上升，在光照期慢慢下降。说明食欲素可调节睡眠-觉醒周期，正常睡眠的控制有赖于下丘脑的食欲素的调节。食欲素能神经元投射最密集的地方是蓝斑核，食欲素A可以通过激活蓝斑去甲肾上腺素能细胞促进觉醒，单胺能和胆碱能神经核是食欲素受体富集区，食欲素神经元在睡眠时保持静息，在即将觉醒前开始放电，在觉醒和睡眠剥夺时活跃。睡眠剥夺通过突触前和突触后机制可以改变食欲素神经元的兴奋性，食欲素可促使前额皮层神经元放电，并通过激活组胺能、去甲肾上腺素能和血清素促进觉醒。食欲素受体拮抗剂只选择性地阻断食欲素受体，食欲素的拮抗剂可改善失眠，提高睡眠质量，没有BZDs类药物的不良反应，却比传统安眠药有更强的药理活性。双食欲素受体拮抗剂( Suvorexant、Almorexant 等) 可通过促进REM睡眠增加总睡眠时间，具有较好的临床疗效和耐受性，已获得FDA批准用于治疗失眠。 4、组胺拮抗剂组胺是一种促进清醒的神经递质，在中枢神经系统中产生于下丘脑的结节乳头核中。因此拮抗组胺受体可促进睡眠。在组胺的4个受体中，H1受体是控制睡眠的关键靶点。有证据表明，敲除 H1 受体的小鼠，在给予 H1 受体拮抗剂多塞平和苯海拉明能够增加 NREM时间和发作次数。而酮替芬则通过增加δ波功率来降低REM 并增加 NREM。从以上数据可推测，组胺拮抗剂对睡眠的影响主要作用于NREM 阶段。但服用抗组胺药可引发抗胆碱能作用，包括发热、脓毒症、视力模糊、口干、便秘、尿潴留、心动过速、肌张力障碍和精神错乱等不良反应。组胺拮抗剂目前对于治疗人类失眠的数据较少，其中多塞平是组胺拮抗剂中用来控制失眠最常用的药物，其能延长 NREM 但减少 REM，但易造成恶心、呼吸道感染等不良反应。 5、抗焦虑、抗抑郁类药物抗焦虑、抗抑郁类药物主要是 5-羟色胺受体( 5-HT1A ) 受体部分激动剂。主要代表有丁螺环酮和坦度螺酮，属于抗焦虑药，由于其对5-HT1A具有良好的亲和力，能够激活突触前5-HT1A受体抑制神经元放电，减少 5-HT1A 的合成与释放，主要用于治疗各种焦虑症以及各种伴发的焦虑症。在治疗焦虑性失眠上，临床使用坦度螺酮较多。该类药物的优点在于镇静作用轻，对认知功能影响较小，无蓄积性，相较于BZDs类药物产生的不良反应更少。但起效相对较慢，为2～4 周。临床研究表明在镇静催眠药上加用坦度螺酮对伴有焦虑症状的失眠患者有更好的治疗作用，联合用药的症状改善效果更好。大部分失眠患者治疗效果不佳的原因可能是忽略了焦虑、抑郁等情感状态的障碍，虽然并无直接证据表明抗抑郁、抗焦虑药物能直接改善失眠，但在由心理、精神因素造成的睡眠问题上，能够起到有效的改善作用，因此在治疗时应充分把握患者病情，必要时应同时考虑抗焦虑、抗抑郁治疗。相关阅读：《失眠障碍新药获批上市，更多创新药很快就到！》参考资料 [1]冯庭宇,许晓伍.失眠症的药物治疗进展[J].世界睡眠医学杂志,2023,10(03):691-696. [2]胡金,韦姗姗,姜海洲等.失眠的药物治疗研究进展[J].中国中药杂志,2023,48(19):5122-5130. [3]沈阳阳,周俊英.失眠药物治疗及进展[J].中国临床医生杂志,2023,51(12):1394-1397. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习社1月直播预告来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床结果

2023-12-06

·药渡Daily

如何拯救3亿国人的睡眠焦虑？

你肯定失眠过，或为考试的焦虑，或为工作的烦恼，或为生活的琐碎，那种辗转反侧难以入眠的感觉足以让人抓狂。有数据统计，中国人的睡眠时间越来越短，失眠的人越来越多。更值得注意的是，越来越多的失眠患者，为了寻求安稳的睡眠，正在加速寻求通过药物进行治疗。但市场上现有的各类失眠症药物都存在不良反应和药物依赖等问题，已到了急需更新换代的时候。然而，面对这样一个广阔的市场，布局者却不多，研发进展也久未见成效，以至于当一款失眠症创新药获批时，便能引起广泛关注。16年来首突破近日，国家药监局批准了1类创新药地达西尼的上市申请，用于失眠患者的短期治疗。地达西尼（EVT201）是一种（GABA）A受体的部分正向别构调节剂，选择性作用于(GABA)A受体α1亚型，既能对受体产生激活作用并迅速抑制神经系统，又能避免过度激活受体而产生深度抑制，引发神经副作用。一项随机、多中心、双盲、安慰剂对照研究显示，与安慰剂相比，EVT201分组剂量1.5mg和2.5mg分别增加总睡眠时间（TST）33.1分钟和45分钟，分别减少入睡后的觉醒（WASO）16.7和25.7分钟，分别减少持续睡眠的潜伏期（LPS）17分钟和20.7分钟，并分别减少觉醒次数1.2次和2.6次，研究结果均显著有效。两种剂量均改善了睡眠质量，早晨自测嗜睡与安慰剂没有差异，耐受性良好，没有报告严重或意外的不良事件。并且，与唑吡坦、扎来普隆和三唑仑等短效失眠症药物（平均半衰期1-3小时）最优剂量相比，地达西尼消除半衰期（3-4小时）更长，从而维持睡眠的作用时间更久；而对比右佐匹克隆、替马西泮等中效失眠症药物（平均半衰期6小时及以上），地达西尼产生残留效应的可能性更小。地达西尼部分临床数据来源：京新药业官网地达西尼最早由Roche研发，随后Evotec获得全球独占权并将其开发用于治疗失眠症，于2008年在国外完成I、II期临床。2010年京新药业与Evotec签署协议，获得地达西尼在中国的独家专利许可和开发权。地达西尼的出现，一举打破了中国失眠症药物赛道长达16年的沉寂，有望率先抢占失眠创新药增量市场。迭代空间巨大随着生活节奏加快和社会压力增大，越来越多的人精神长期处于高度紧张状态，睡眠问题日益严重。《2022中国国民健康睡眠白皮书》显示，近四分之三的受访者表示曾有睡眠困扰，入睡困难成头号问题。其中，在备受睡眠困扰的人中，有33.1%为入睡难，25.8%为易醒，23.5%为失眠，21.8%为打鼾，20.5%为多梦。调查显示，青少年人群当中，有超六成的青少年用睡眠时间来玩手机、打游戏和追剧，仅有27%的青少年压缩睡眠时间来写作业、学习；25-60岁之间的人群，随着年龄增加，平均睡眠时长逐渐减少，睡眠时长超过6小时的占比也逐步降低，生活压力为失眠的主要因素；老年人群中，有42%的老年人入睡时长超过半小时，失眠率高达21%，影响睡眠的首要因素为健康问题。根据Frost&Sullivan数据，2017-2021年中国失眠症患者由2.5亿人增加到2.8亿人，4年复合增长率为2.9%，约占中国总人口的1/5；预计到2030年，患者人数将增加至3.3亿。中国不同年龄段网民失眠情况调查来源：银河证券研报基于此，科学家们研发了各种类型的镇静催眠药，主要通过抑制中枢神经系统实现稳定情绪或促进和维持生理睡眠，目前已经经历了四代更迭。第一代药物主要包括巴比妥酸合成物和苯巴比妥，这类药物镇静催眠效果不明显，且服用者易产生依赖性和抗药性，已逐渐被淘汰。第二代药物为苯二氮卓类（BZDs），主要代表为地西泮，相比第一代药物，苯二氮卓类治疗安全指数高，但长期服用仍会形成药物依赖，因此以唑批坦和扎来普隆为首的第三代非苯二氮卓类（NBZDs）药物在安全性上有所提高，久服并无依赖性，极大的提升患者睡眠质量。第四代药物以食欲素受体（Orexin）为代表，目前已有Suvorexant（2014年）、Lemborexant（2019年）和Daridorexant（2022年）问世，其他靶点目前仍处于临床试验阶段中。第四代食欲素靶向药物具有全新作用机制，药物安全性更高。失眠症药物分类及作用机制来源：头豹研究院研报在国内，目前国内仍处于第二代（BZDs）药物向第三代（NBZDs）过渡阶段，相较于欧美第四代药物的用药格局仍有差距。临床使用量占比较大的失眠症药物包括咪达唑仑、佐匹克隆、唑吡坦等，这些品种在国内上市时间均超过20年，并有多家仿制药上市。根据药渡数据，2022年，咪达唑仑在国内销售8.93亿元，同比增长5.96%；唑吡坦销售3.66亿元，增长19.47%；艾司唑仑销售3.51亿元，增长21.74%；佐匹克隆销售3.34亿元，增长20.64%等。相关精神类药物销售在新冠疫情结束后得以解禁，失眠症药物在过去的一年都取得不错的销售成绩。国内失眠症药物市场竞争格局来源：国泰君安研报根据头豹研究院数据显示，2017-2021年，中国失眠药物市场由102.8亿元增加至122.8亿元，年复合增长率为4.5%。由于中国已有16年无失眠创新药上市带动发展，市场规模保持较低水平，整个失眠药物市场始终处于需求未被完全满足的状态，未来随着新药上市将激发市场潜力，有望带动整体市场规模的爬升。预计到2025年市场规模可达到151.2亿元，2030年将达到211.9亿元。值得关注的是，虽然失眠药物市场中仿制药众多竞争激烈，但布局创新药的药企却十分稀少，未来迭代的空间巨大。一片蓝海对失眠症药物来说，不良反应是研究人员竭力改善的重大问题。一方面，焦虑症、失眠症致病原因相当复杂，致病原因可能涉及遗传因素、生理因素及心理因素等多个方面，如果研究人员不能充分理解各类致病原因，就很难根据具体病因研发出针对性药物；另一方面，目前临床应用的镇静催眠药都是直接作用于中枢神经，而一旦中枢神经习惯了药物刺激后，容易产生依赖性，一旦断药或减药，可能发生戒断综合征，因此很难做到完全避免副作用。因此，目前关于失眠症药物研发均是以克服依赖性为主要方向。褪黑素已经成为“网红”级助眠产品，在购物网站上某些品牌的月销量甚至可达5万以上。褪黑素又名美拉酮宁、抑黑素、松果腺素，化学名称为N-乙酰基-5-甲氧基色胺，是由哺乳动物和人类的松果体产生的一种胺类激素。1958年美国耶鲁大学皮肤病专家Aaron Lerner等首次从牛松果体中分离得到该物质，并证明了其生物活性。由于它能够使一种产生黑色素的细胞颜色变浅，因此被命名为褪黑素。根据较早之前的关于褪黑素与睡眠质量的研究荟萃分析发现，与安慰剂相比，褪黑素可使入睡时间平均缩短7.06分钟，总睡眠时间平均增加8.25分钟，并对睡眠质量有一定改善作用。但事实上，褪黑素改善睡眠的临床证据依然不足。而且有医生指出，长期大量服用褪黑素类保健品可能会对人体的免疫系统和生育系统产生影响。因此，对于处在生育期的成年男性与成年女性而言，不能长期大量服用褪黑素。雷美替胺首个应用于临床治疗失眠的褪黑素受体激动剂，用于治疗以入睡困难为特征的失眠症，最早于2005年在美国上市，目前原研药在中国未上市，但申报雷美替胺仿制药临床的企业达到26家，其中正大天晴的雷美替胺仿制药上市申请已于2022年递交，有望冲击国内首仿。但是在主流应用上，美国是把褪黑素作为膳食补充剂使用，而加拿大、英国、法国、意大利、爱尔兰等绝大多数国家和地区对褪黑素的使用持谨慎态度。在我国，褪黑素则仅被批准应用于保健品中。褪黑素分子式来源:参考资料食欲素也叫下丘脑泌素，是下丘脑分泌的一类激素。早在1998年，两组研究人员分别独立发现了食欲素体系，该体系能显著调节受试对象的进食行为，影响食欲。该体系包括两个G蛋白偶联受体：食欲素-1受体和食欲素-2受体，以及两个神经递质肽激动剂：食欲素-A和食欲素-B。食欲素A和食欲素B是一种神经肽类物质，均作用于G蛋白偶联受体食欲素-1受体和食欲素-2受体。随后就有研究发现患有发作性嗜睡病的犬类是由于其表达为食欲素-2受体的基因发生了突变，进而导致食欲素-2受体的功能紊乱。这一研究表明食欲素不但影响机体的摄食行为，还参与了睡眠-觉醒周期的调节。自此，研究者对失眠症的病因有了新的认识，即失眠症还可能是由于不恰当觉醒造成的。由此，食欲素受体拮抗剂便受到较大关注。2014年，首个食欲素受体拮抗剂苏沃雷生（Suvorexant）在美国获批。相关临床试验数据中，苏沃雷生展现出很好的安全性和耐受性，不良反应发生较少，试验中未发现患者服用苏沃雷生后有显著的依赖性。对比苯二氮类药物较高的身体依赖性、睡眠异常等不良反应，苏沃雷生具有疗效上的优势。目前苏沃雷生在中国暂未获批，但已于2023年4月被我国列入第二类精神药品目录。Lemborexant是由日本卫材研发的一款双重食欲素受体拮抗剂，于2019年12月在美国获批上市；Daridorexant是瑞士公司Idorsia Pharmaceuticals Ltd研发的一款双重食欲素受体拮抗剂，2022年先后在美国、意大利、德国上市。在中国，除了上述已获批的地达西尼之外，扬子江药业的YZJ-1139以及东阳光药的HEC83518，均为食欲素受体拮抗剂，分别处于临床III期和临床I期；此外先声药业已经引进Daridorexant，于2023年5月在国内申报临床，Lemborexant也已在2020年7月于中国香港获批上市。国内食欲素在研管线情况来源：国泰君安研报结语从健康角度出发，通过药物治疗失眠症并非首选，排查引起焦虑的因素并加以克服，才能从根本上解决失眠问题。但这就涉及到更加深层次的一系列问题，包括社会问题、心理问题等等，已超出本文的讨论范围。在本文讨论的失眠症药物市场中，总体来看，目前整体市场不仅空间较大，而且布局的药企非常少。在现有治疗药物已经存在较大替代需求的情况下，失眠症药物市场领域可以称之为一片蓝海。后续发展如何，药渡还将持续关注。参考资料京新药业官网、年报等国泰君安、财通证券、头豹研究院研报等《褪黑素有助睡眠但不是“神药”生物学作用机理亟待更深入研究》，中国数字科技馆，2019-11-08《3亿人的烦恼？270亿药物研发“无人区”，跑出两家稀缺龙头》，瞪羚社，2022-11-03

临床终止临床1期

100 项与三唑仑相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00387	三唑仑	N05CD05	DB00897

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
麻醉	日本	Pfizer Japan, Inc.	1982-12-15
入睡和睡眠障碍	美国	Pfizer Inc.	1982-11-15

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03246724 (CTgov)	临床4期	镇静	327	Sodium chloride 0.9%+Microcrystalline Cellulose+Triazolam+Midazolam (Cataract Procedures)	壓鏇製觸觸鑰衊齋鹹鏇(壓鹽鏇鹹選憲膚築鬱鏇) = 醖獵鏇衊選淵繭築繭範蓋築願鏇窪選築鏇窪壓 (顧壓艱衊鏇衊淵憲醖齋, 糧艱餘憲繭壓顧積鬱餘 ~ 觸網壓醖窪網淵衊壓遞) 更多	-	2020-08-19
				Sodium chloride 0.9%+Microcrystalline Cellulose+Triazolam+Midazolam (Retina Procedures)	壓鏇製觸觸鑰衊齋鹹鏇(壓鹽鏇鹹選憲膚築鬱鏇) = 鑰膚襯築範窪鑰鬱襯製蓋築願鏇窪選築鏇窪壓 (顧壓艱衊鏇衊淵憲醖齋, 襯積鑰選窪窪觸窪鑰鏇 ~ 鹹蓋鑰築獵鹽製鹹餘壓) 更多