Cannabidiol/Dronabinol

关注并星标CPHI制药在线 植物大麻是最早被人类认识的成瘾物质之一，同时也有不可忽视的医疗潜力。大麻素是大麻发挥药理活性的主要成分，随着大麻活性成分的提纯以及内源性大麻素递质系统的发现，大麻素因其广泛的生理作用及潜在的临床应用价值日益受到重视。目前从植物中分离并鉴定出的大麻素以Δ9-四氢大麻酚(Δ9-Tetrahy drocannabinol, Δ9-THC)和大麻二酚（CBD）为主。Δ9-THC是大麻植物的主要精神活性成分，虽然具有有益的镇痛、抗炎和抗癫痫等作用，但其“高”精神活性导致的严重不良反应，如成瘾、认知障碍、运动不协调、焦虑等限制了它在临床的应用。CBD是大麻植物中主要的非精神活性成分，具有镇痛、抗炎、神经保护和抗精神病等作用，且不会产生典型的大麻素副作用，即具有非成瘾性，在人类以及动物体内有良好的耐受性；不影响人体运动、记忆等。因此，作为一种耐受性好、安全的天然化合物，CBD成为一个具有吸引力和临床应用前景的药物。 CBD是一种脂溶性多靶点药物，包括大麻素受体(Cannabinoid Receptor,CBR)、5-羟色胺1A 受体、瞬时受体电位受体1、腺苷和甘氨酸受体等。体内研究表明，CBD 对大麻素受体的亲和力比较低，而对5-羟色胺受体(5-Hydroxytryptamine Receptor, 5-HTR)、非内源性大麻素G蛋白偶联受体以及酶和某些离子通道等靶标具有更强的亲和力，对神经疾病包括焦虑、精神分裂症、成瘾、神经退行性疾病和新生儿低氧缺血性脑病均具有明显的改善作用。另外，在抗癫痫、抗肿瘤、抗炎、肝保护、糖尿病、疼痛的治疗上也表现出很好的应用前景。 1、大麻二酚与神经性疾病 大麻二酚具有广泛的生物效应，在神经系统中有多种潜在的作用部位，被评估为一种治疗神经疾病的药物。对焦虑、精神分裂症、成瘾、神经退行性疾病、缺氧缺血脑病等都有一定的效果。 ①抗焦虑作用 与大麻二酚抗焦虑作用相关的受体有CB1 受体、TRPV1 受体和5-HT1A 受体。CBD 对CB1受体的亲和力较低，但它作为一种间接激动剂发挥作用。CBD 在高浓度时充当TRPV1 激动剂，可能通过干扰花生四烯乙醇胺的失活来发挥作用。5-HT1A受体是目前已确定的抗焦虑靶点。动物试验表明，低剂量的大麻二酚通过激动5-HT1A 受体，来发挥抗焦虑作用；过量的大麻二酚则会激活TRPV1 受体，增加焦虑。另外，试验还发现大麻二酚可以使人产生抗焦虑作用，可以用来治疗社交焦虑障碍。 ②抗精神分裂症 抗精神病药物通过拮抗中枢多巴胺D2 受体发挥作用，虽然它们对大多数患者有效，但多达三分之一的患者治疗效果不佳。然而CBD 并不依赖于多巴胺D2 受体的拮抗，而是通过抑制脂肪酸酰胺水解酶、抑制腺苷酸再摄取、激动TRPV1 和5-HT1A 受体来发挥作用。研究发现CBD 可以改善对氟哌啶醇没有效果的病人的症状。研究报道额纹状体偶联下降是精神分裂症的中间表型，而CBD 导致额纹状体连接增加，提示CBD在精神分裂症患者中潜在的治疗用途。将CBD 作为辅助药物，加入到抗精神病的治疗中与对照组相比，产生了更好的治疗效果。患者的认知功能和整体功能水平有所提高，运动速度和行动能力的改善效果最为显著。但每组中有三分之一的患者出现了不良反应，例如血脂异常和恶心，不过副反应的症状大部分是轻微的，可自行解决，表明CBD 具有良好的耐受性。 ③抗成瘾性 研究大麻使用者成瘾性结果发现，单独使用THC 或二者合用均会造成精神损伤，而只使用CBD 则无精神损伤作用，且CBD 能改善低频率大麻使用者的精神症状，对高频率大麻使用者无效。评估40 名大麻依赖者对服用Nabiximols (27 mg/mL THC/25 mg/mL CBD)的耐受性和安全性。研究发现，Nabiximols有助于减少大麻的使用量，而不增加患者对大麻的渴望。此外，CBD也有利于烟草的戒断。 ④抗神经退行性疾病 大脑中铁的积累被认为是正常衰老的特征。然而，在阿尔茨海默氏症(AD)、帕金森症(PD)和亨廷顿氏症(HD)等神经系统疾病中，铁选择性地聚集在与相关的神经退行性过程有关的大脑区域，如海马、黑质、皮质和基底神经节。研究发现CBD 可以通过阻断铁诱导的细胞凋亡，来发挥神经保护作用，使得CBD 成为一种潜在的治疗神经退行性疾病的药物。此外，β-淀粉样肽聚集和微神经胶质细胞的激活与AD的发生联系紧密。CBD可通过Wnt/β-catenin信号转导通路抑制tau蛋白的高度磷酸化，从而避免β-淀粉样肽聚集所产生的毒害或通过阻止由β-淀粉样肽诱导的微神经胶质细胞的激活，实现对脑神经元的保护。CBD可通过神经元蛋白和trkA (神经生长因子受体）介导抑制与PD密切相关的神经毒物质MPP + (1-甲基-4-苯基-1,2,3,6-四氢吡啶）的作用，而MPP +可导致神经元细胞的死亡和神经突触的缺失。 ⑤抗新生儿低氧缺血性脑病 CBD对急性缺氧缺血后的神经具有保护作用，因此能够治疗新生儿缺氧缺血脑病。CBD 能够阻止钙的增加，减少谷氨酸的释放和NO 产生，抑制细胞核因子-κB (NF-κB)的转录活性，具有抗氧化结构及扩张血管的特点，具有神经胶质保护作用。CBD 能保护婴儿的大脑，不仅具有控制兴奋性、炎症和氧化应激的神经调节作用，还能减弱神经退化和有害神经胶质的激活。 2、大麻二酚与癫痫病 CBD对难治性癫痫具有一定的抑制效果，且能减少癫痫的发作频次。CBD能有效地减少Dravet 综合征模型小鼠的癫痫发作频率，但同时发现，癫痫发作次数减少了，生活质量提高了，CBD 的不良反应发生率也会增高，常见的不良事件包括嗜睡、厌食和腹泻。采用CBD治疗顽固性癫痫Sturge-Weber 综合症，所有受试者在CBD 治疗的大部分时间里生活质量改善了，其轻微的副作用可以被人体很好的耐受。目前，英国GW制药公司研制的Epidiolex(主要成分为CBD)和 Sativex(THC/CBD比值为1)这两种药物已在欧美市场销售，前者主要用于治疗婴儿严重肌阵挛性癫痫(Dravet)和儿童期弥漫性慢棘-慢波（小发作变异型）癫痫性脑病（Lennox-Gastaut)，后者主要治疗多发性硬化症。 3、大麻二酚与抗肿瘤作用 CBD对多种肿瘤细胞具有抑制作用，其抗肿瘤作用根据癌症组织类型不同，其作用机制各不相同。CBD对神经胶质瘤、白血病和前列腺癌具有一定的抑制作用。无血清条件下，CBD和他莫昔芬(tamoxifen,抗雌激素）与C6神经胶质瘤细胞共同孵化，对神经胶质瘤表现出一定的抑制作用。CBD通过半胱天冬酶的激活和活性氧的参与等机制诱导人类神经胶质瘤细胞U87和U373的凋亡。CBD通过对NOX4和P22phox的调控导致活性氧簇（ROS )的增加而实现对EL-4、Jurkat白血病细胞的抑制。CBD同样可阻滞前列腺癌细胞的增殖或诱导其凋亡。此外，CBD可通过调控AKT/mTOR/4EBPl、EGF/EGFR信号途径或通过诱导内质网激压力抑制乳腺癌细胞的生长和转移。 4、大麻二酚与代谢和免疫调节作用 CBD可通过调控炎性因子水平、控制干扰素的产生等起到代谢和免疫调节作用。CBD对糖尿病的发生或是早期糖尿病的治疗均有一定的控制效果。一方面，CBD可通过抑制胰腺炎的发生和炎性Th-1相关细胞因子的产生，将免疫反应从Th-1 (炎症性细胞因子占优势）模式转向Th-2 (抗炎症性细胞因子占优势)模式，从而降低糖尿病的发生几率，另一方面，针对早期糖尿病，CBD处理可大大降低促炎性因子IL-12水平，而抗炎性因子IL-10水平则显著升高，且胰岛组织学检查结果也优于对照组。研究发现CBD 能够降低非肥胖型糖尿病小鼠的发病率，这种效应与减少的胰岛炎结合在一起，导致促炎细胞因子的水平降低。CBD 能够减少与糖尿病相关的氧化应激、炎症、细胞死亡和血管通透性。CBD 通过G蛋白偶联受体18 (GPR18)依赖性地恢复心脏的脂联素-蛋白激酶B-内皮型一氧化氮合酶(adiponectin-Akt-Enos)信号和减少心肌氧化应激，来减轻糖尿病诱发的心血管异常。此外，CBD 对糖病引发的抑郁也可以产生轻微的抑制作用。因此CBD 能够改善糖尿病及其并发症。此外，经CBD处理后的小鼠引流区淋巴结细胞的II型胶原特异性扩增水平和γ干扰素水平明显降低，滑膜细胞释放的a干扰素也相应减少，结果表明腹腔注射或口服CBD均能有效阻止关节炎的发展。  5、大麻二酚与肝保护功能 CBD可以减轻肝脏损伤，降低肝脏甘油三酯的水平，还可在细胞水平减轻油酸所致人肝脏细胞脂肪堆积，具有肝保护功能。CBD 可通过诱导脂解或增强线粒体活性来抑制脂肪肝，还可以改善胰岛素敏感性，这两种化合物可被用作治疗肥胖症和代谢综合征相关肝病。CBD可以通过降低醇介导的氧化应激，抑制JNK MAPK通路的激活和增加自噬等多种机制保护小鼠肝脏免受酒精诱导的脂肪变性。此外，CBD对于缺血性肝损伤和慢性酒精中毒引起的肝损伤也有一定的保护作用。在小鼠发生缺血性肝损伤一小时后经尾静脉注射5 mg/kg/天 CBD，两天后发现，对照组中出现了由缺血引起的一系列生化指标的升高，如血清丙氨酸氨基转移酶、肝组织丙二醛、TNF-a (肿瘤坏死因子-a )和一氧化氮水平等，而CBD组无上述现象，提示CBD可能可用于解决肝移植手术因短暂性缺血导致的肝组织损伤难题。CBD对慢性酒精中毒引起的肝损伤也有一定的保护作用，如CBD可减轻由长期的酒精刺激所导致的肝损伤（包括肝转氨酶水平的升高、甘油三酯和中性粒细胞的积累及炎性因子的表达等）。 参考资料: [1]郭蓉,陈璇,郭鸿彦.四氢 大麻酚和大麻二酚的药理研究进展[J].天然产物研究与开发, 2017, 029(008):1449-1453. [2]韩莎莎,张殿杭,李丽.大麻二酚的药理研究进展[J].药物资讯, 2019, 8(3):7. 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。 智药研习社近期直播预告 扫码领取CPHI & PMEC China 2025展会门票 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~

Single Ascending and Multiple Ascending Dose Trial Demonstrated AJA001 to be Safe and Well-tolerated, with Formulation Optimized for ASD Presentation at the 63rd Annual Meeting of the American College of Neuropsychopharmacology LITTLETON, Colo., Dec. 12, 2024 /PRNewswire/ -- DeFloria, a joint venture between Ajna BioSciences and Charlotte's Web (TSX: CWEB, OTCQX: CWBHF), reported positive results from a Phase 1 single ascending and multiple ascending dose trial of AJA001 in development for the treatment of symptoms of autism spectrum disorder (ASD) in a poster presentation at the 63rd Annual Meeting of the American College of Neuropsychopharmacology in Phoenix, Arizona. AJA001 is an orally delivered, multi-cannabinoid botanical drug product (BDP) designed to provide a broad therapeutic effect. In a poster entitled, "A Single and Multiple Ascending Dose and Food Effect Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AJA001, a Full-Spectrum Hemp-Derived Botanical Drug for Autism Spectrum Disorder, " Marcel O. Bonn-Miller, Ph.D., Chief Scientific Officer at Charlotte's Web and Board Member at DeFloria, presented the results from the recently completed Phase 1 randomized, double-blind, placebo-controlled trial that evaluated the tolerability and pharmacokinetic (PK) / pharmacodynamic (PD) profile of several dose levels of AJA001 in 70 healthy volunteers ranging from 19 to 55 years. Results demonstrated that AJA001 was well-tolerated at doses up to 680 mg per day administered as a single dose and up to 660 mg per day administered twice a day. In both the single and multiple ascending dose portions of the trial, AJA001 displayed dose-proportional PK for CBD and THC that matched or exceeded the plasma concentrations of the comparable cannabinoid therapeutics dronabinol, nabiximols, and Epidiolex®. PK data following multiple dose administration of AJA001 showed minimal accumulation of CBD or THC after 7 days. AJA001's PD effects were shown to be dose-dependent and correlated with peak plasma concentrations of THC and its active metabolite 11-OH-THC after administration of single doses. An analysis of participant responses on the Drug Effects Questionnaire (DEQ) demonstrated that the magnitude and time course of AJA001's subjective drug effects were moderate and transient in nature. The safety, PK, and PD findings support doses from 100 mg to 660 mg of AJA001 per day for Phase 2 trials in children, adolescents, and adults with ASD. This is equivalent to an upper limit of 395 mg CBD and 15 mg THC per day. The most common treatment emergent adverse events in the AJA001 treated groups were somnolence, anxiety, dizziness, and headache. One serious adverse event was reported by a participant receiving 906.4 mg of AJA001 who reported anxiety that resolved by the next day with no sequalae. A copy of the poster is available on the DeFloria website at . "We are extremely encouraged by these results from our Phase 1 single and multiple ascending dose trial, which demonstrate that AJA001 is well-tolerated across a range of doses and provides a favorable pharmacokinetic profile for both cannabidiol and tetrahydrocannabinol," said Dr. Bonn-Miller. "Importantly, the results from this trial inform the doses to be evaluated in upcoming Phase 2 clinical trials of AJA001 in children, adolescents, and adults with ASD." "We are excited to present this important data and look forward to initiating two Phase 2 trials of AJA001 in ASD in the second quarter of 2025," said Jared Stanley, CEO of DeFloria. "Despite its prevalence, ASD remains a difficult condition to treat. Moreover, currently available treatments for ASD are not well tolerated, making patient compliance a challenge. DeFloria is committed to supporting the ASD community and developing AJA001 to treat the behavioral symptoms associated with ASD with a drug product that is designed to provide broad therapeutic efficacy." About ASD Approximately 1 in 36 children may have ASD (Maenner et al 2023). ASD is characterized by core deficits in (1) social communication, (2) impaired reciprocal social interactions, and (3) restricted, repetitive and stereotyped patterns of behaviors or interests. Irritability, impulsivity, and "temper tantrums" are common symptoms and contribute to high caregiver burden (Lecavalier et al 2006). About AJA-001 AJA001 Oral Solution is a botanical drug product (BDP) containing full spectrum hemp extract (FSHE) botanical drug substance (BDS) derived from Cannabis sativa L proprietary CW1AS1 hemp cultivar. The primary cannabinoid is cannabidiol (CBD). As an innovative multi-cannabinoid formulation, it may provide broad therapeutic efficacy. Its full-spectrum composition has potential therapeutic applications across various medical conditions due to its varied mechanisms of action. About DeFloria DeFloria LLC, a collaboration between Charlotte's Web, Inc., AJNA BioSciences PBC, and British American Tobacco PLC (BAT), is on a mission to address crucial healthcare needs through groundbreaking innovations from multi-compound drugs originating in nature. With a combined century of experience in regulatory, research, and quality-controlled standardized manufacturing, DeFloria's ambitious endeavor aims to secure FDA approval for a novel cutting-edge botanical drug developed from Charlotte's Web proprietary hemp genetics that targets a neurological condition identified by the DeFloria leadership and research teams. Cautionary Note of Forward-Looking Statement This news release contains "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of 1995. Often, but not always, forward-looking statements can be identified by the use of words such as "plans", "expects" or "does not expect", "is expected", "estimates", "intends", "anticipates" or "does not anticipate", or "believes", or variations of such words and phrases or state that certain actions, events or results "may", "could", "would", "might" or "will" be taken, occur or be achieved. Forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of DeFloria, LLC to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained in this news release. Examples of such statements and uncertainties include statements with respect to future dose trial results, therapeutic efficacy, or approvals of AJA001 Oral Solution. Risks, uncertainties and other factors involved with forward-looking statements could cause actual events, results, performance, prospects and opportunities to differ materially from those expressed or implied by such forward-looking statements, including negative outcomes in future dose trials, therapeutic efficacy, or delays in approvals of AJA001 Oral Solution. In respect of the forward-looking statements, DeFloria, LLC has provided such statements in reliance on certain assumptions that it believes are reasonable at this time. Although DeFloria, LLC and its collaborators and partners believe that the assumptions and factors used in preparing the forward-looking statements in this news release are reasonable, undue reliance should not be placed on such information or statements and no assurance can be given that such events will occur in the disclosed time frames or at all. Should one or more of the foregoing risks or uncertainties materialize, or should assumptions underlying the forward-looking statements prove incorrect, actual results may vary materially from those described herein as intended, planned, anticipated, believed, estimated or expected. Although DeFloria, LLC has attempted to identify important risks, uncertainties and factors which could cause actual results to differ materially, there may be others that cause results not to be as anticipated, estimated or intended. The forward-looking statements included in this news release are made as of the date of this news release and DeFloria, LLCs does not undertake any obligation to publicly update such forward-looking statements to reflect new information, subsequent events or otherwise unless required by applicable securities laws. Investor/Media Contact Tiberend Strategic Advisors, Inc. Casey McDonald (646) 577-8520 [email protected] References: Maenner MJ, Warren Z, Williams AR, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ 2023;72(No. SS-2):1–14. Lecavalier L, Leone S, Wiltz J. The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders. J Intellect Disabil Res. 2006;50(Pt 3):172-83. SOURCE DeFloria, LLC WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED