Novel Off-label Use of Desipramine in Infantile Neuroaxonal Dystrophy: Targeting the Sphingolipid Metabolism Pathway to Reduce Accumulation of Ceramide.

This is a research study to find out if clinically prescribed desipramine is effective at improving the symptoms and slowing the progression of Infantile Neuroaxonal Dystrophy (INAD) in affected children.
Participants will receive an initial oral dose of study drug once a day. This dose may be changed depending on response to study drug Clinically collected data will be recorded for up to 5 years. Investigators will also ask for participant permission to obtain a sample of child's skin biopsy from unused clinical sample previously collected for standard of care.

开始日期2019-01-14

申办/合作机构

Duke University

NCT03548454

/ Recruiting临床4期IIT

Comparing Effectiveness of Duloxetine and Desipramine in Patients With Chronic Pain: A Pragmatic Trial Using Point of Care Randomization

Over 100 million Americans suffer from chronic pain resulting in annual cost of roughly $635 billion. Limited treatments are available for this widespread disease. The data supporting these treatments lack generalizability to patients with more serious medical and psychological comorbidities who are often excluded from explanatory efficacy trials. Our work aims to integrate randomized comparative effectiveness research with patient care. The investigators will randomize the patients and collect data using an open-source learning healthcare system already in use in our department to monitor patients' progress: Collaborative Health Outcomes Information Registry (CHOIR). Collaborative Health Outcomes Information Registry uses the National Institute of Health Patient Reported Outcomes Measurement Information System item banks for comparative metrics through computer adaptive testing. The investigators will leverage the advantage of this novel system to compare effectiveness of duloxetine and desipramine in decreasing pain in patients with chronic pain. The investigators will also compare adherence of patients to these two commonly used medications over a period of six months. This will evaluate feasibility of integrating randomized comparative effectiveness research with patient care in subspecialty clinics. Collaborative Health Outcomes Information Registry can then be applied for numerous future trials to advance our knowledge in perioperative and pain medicine.

开始日期2018-09-20

申办/合作机构

Stanford University

IRCT20160813029315N2

/ Completed临床2/3期IIT

Placebo-controlled randomized clinical trial testing the efficacy of desipramine in reducing craving in patients with methamphetamine use disorder

开始日期2016-06-03

申办/合作机构-

100 项与盐酸地昔帕明相关的临床结果

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100 项与盐酸地昔帕明相关的转化医学

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100 项与盐酸地昔帕明相关的专利（医药）

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11,563

项与盐酸地昔帕明相关的文献（医药）

2025-10-01·Talanta

Dimethyl itaconate: An effective antioxidant for promoting angiogenesis under oxidative stress

Article

作者: Liu, Suzhen ; Liu, Yicong ; Zhang, Miaomiao ; Song, Chunli ; Tang, Jilin ; Li, Zongjia

Angiogenesis is an important physiological process in the human body. When ischemic diseases occur, the ischemic and hypoxic environment induces excessive production of reactive oxygen species (ROS) within cells, which inhibits angiogenesis and leads to poor prognosis. Therefore, finding antioxidants that can eliminate excessive ROS to promote angiogenesis is crucial for the treatment of ischemic diseases. In this work, we investigate the antioxidant effects of dimethyl itaconate (DMI) by using an oxidative stress model in human umbilical vein endothelial cells (HUVECs). Our results demonstrate that DMI significantly reduces excessive ROS in cells under oxidative stress. DMI could protect mechanical properties of HUVECs from oxidative stress. The Young's modulus of HUVECs was 10.0 ± 1.4 kPa after treatment with H₂O₂. However, the Young's modulus increased to 24.42 ± 1.4 kPa when HUVECs were co-incubated with H₂O₂ and DMI (40 μg mL^-1). DMI also maintained cell morphology and cytoskeletal integrity. Meanwhile, DMI alleviates mitochondrial dysfunction by enhancing mitochondrial membrane potential (MMP) and increasing adenosine triphosphate (ATP) levels. The excellent antioxidant effects of DMI result from upregulating the expression levels of superoxide dismutase 2 and catalase, significantly leading to the removal of intracellular excessive ROS. With protecting HUVECs from oxidative stress damage, DMI promotes cell migration and angiogenesis. Consequently, this work not only elaborates on the mechanism by which DMI promotes angiogenesis by anti-oxidative stress, but also provides a new therapeutic option for the treatment of ischemic diseases.

2025-07-01·Biomaterials

Two-dimensionally cultured functional hepatocytes generated from human induced pluripotent stem cell-derived hepatic organoids for pharmaceutical research

Article

作者: Ueyama-Toba, Yukiko ; Asano, Rei ; Mizuguchi, Hiroyuki ; Nagai, Wakana ; Inui, Jumpei ; Imamura, Chiharu

Human induced pluripotent stem (iPS) cell-derived hepatocyte-like cells (HLCs) are expected to replace primary human hepatocytes (PHHs) as a new stable source of hepatocytes for pharmaceutical research. However, HLCs have lower hepatic functions than PHHs, require a long time for differentiation and cannot be prepared in large quantities because they do not proliferate after their terminal differentiation. To overcome these problems, we here established hepatic organoids (iHOs) from HLCs. We then showed that the iHOs could proliferate approximately 10⁵-fold by more than 3 passages and expressed most hepatic genes more highly than HLCs. In addition, to enable their widespread use for in vitro drug discovery research, we developed a two-dimensional culture protocol for iHOs. Two-dimensionally cultured iHOs (iHO-Heps) expressed most of the major hepatocyte marker genes at much higher levels than HLCs, iHOs, and even PHHs. The iHO-Heps exhibited glycogen storage capacity, the capacity to uptake and release indocyanine green (ICG), albumin and urea secretion, and the capacity for bile canaliculi formation. Importantly, the iHO-Heps had the activity of major drug-metabolizing enzymes and responded to hepatotoxic drugs, much like PHHs. Thus, iHO-Heps overcome the limitations of the current models and promise to provide robust and reproducible pharmaceutical assays.

2025-04-01·Drug Metabolism and Disposition

In vitro–in vivo scaling of cytochrome P450-mediated metabolic clearance using a relative activity factor approach

Article

作者: Nozaki, Yoshitane ; Nagaya, Yoko

Quantitative prediction of hepatic clearance is a key element in predicting the human pharmacokinetic profile in the nonclinical stages. In the present study, we focused on the major cytochrome P450 (P450) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) and tested a relative activity factor (RAF) method to quantitatively predict in vivo hepatic intrinsic clearance (CL_h,int,vivo) and fraction metabolized (f_m) by the P450 isoforms directly from an in vitro recombinant P450 system. We selected multiple probe substrates for CYP1A2 (caffeine, tizanidine, phenacetin), CYP2C9 ((S)-acenocoumarol, glimepiride, lornoxicam, tolbutamide, (S)-warfarin), CYP2C19 ((S)-lansoprazole, omeprazole, pantoprazole), CYP2D6 (desipramine, metoprolol, nebivolol, tolterodine), and CYP3A4 (alprazolam, felodipine, midazolam, nisoldipine, sildenafil, triazolam) to calculate the representative RAF value for each P450 isoform based on the in vivo-to-in vitro clearance ratio of the multiple probe substrates. The most pronounced substrate dependency of the RAF values was noted for CYP3A4 (2698 [alprazolam] to 19073 [nisoldipine] pmol P450/kg). Using the geometric mean of the RAF values for each isoform, a within 3-fold prediction of the CL_h,int,vivo was obtained for all the 11 test drugs, except glibenclamide, which is a known substrate of hepatic uptake transporters. The f_m values of the responsible P450 isoform(s) could be well predicted for mexiletine, tamsulosin, risperidone, celecoxib, and glibenclamide. This simple, practical RAF method can be one of the useful nonclinical methods to estimate the CL_h,int,vivo and f_m mediated by the major P450 isoforms, which would promote earlier understanding of the impact of genetic polymorphisms and drug-drug interactions on the human pharmacokinetics of the substrate compounds. SIGNIFICANCE STATEMENT: The relative activity factor method has been used for extrapolating in vitro clearance from recombinant systems to liver microsomes, but this study utilized this method to predict in vivo hepatic clearance and fraction metabolized values. By applying relative activity factor values obtained from multiple probe substrates, this study was able to quantitatively predict the in vivo clearances mediated by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. This simple, practical method will help optimize metabolic clearances via the major cytochrome P450 isoforms in the nonclinical stages.

项与盐酸地昔帕明相关的新闻（医药）

2025-04-18

·药智网

GLP-1药物制备的关键溶剂介绍

1,3-二甲基-2-咪唑烷酮（1,3-Dimethyl-2-Imidazolidinone，DMI），又名二甲基乙烯脲（Dimethylethyleneurea，DMEU），是一种强极性非质子溶剂。由于它具有出色的溶解能力、稳定性和高品质，因此它在医药化工领域中的应用日渐得到广泛的重视。尤其是近年来，它在GLP-1受体激动剂和Akt激酶抑制剂等新药合成方面的应用屡见报道。1用于原料药的合成由于DMI具有很高介电常数和很强的溶剂化作用，可加速阴离子亲核反应以及伴随发生阳离子溶剂化的反应。同时DMI还具有热稳定性和化学稳定性，对许多有机和无机化合物都具有出色的溶解能力。因此，它在药物合成涉及的许多的反应类型中，作为优良的反应溶剂，发挥很重要的作用。1.羟醛缩合反应在抗炎剂亚苄基衍生物的合成中用作反应溶剂，使产物收率提高到84%。[1]图片来源：参考文献12.硝酸酯化反应在合成抗骨关节炎药萘普西诺的最后一步反应时，采用DMI作反应溶剂，可以使产物收率得到明显提高。[2]图片来源：参考文献2下表列出与采用其他溶剂时不同效果的比较：数据来源：参考文献3.烷基化反应（1）作为γ-丁内酯烷基化合物合成中的反应助剂，使产物收率达90%以上。[3]图片来源：参考文献3（2）在合成药物中间体取代乙炔类化合物的反应中，用作反应助剂，与其他有机溶剂相比，也有明显的促进作用。[4]图片来源：参考文献4上式中，A：一个1至20个碳原子的饱和或不饱和脂肪烃残基。X：一个卤素原子或芳基磺酰氧基。M：一个碱金属原子。B：H、一个烃残基或－C≡C－M。下表列出与采用其他溶剂时不同效果的比较：数据来源：参考文献4.甲硅烷基醚化反应在合成医药中间体甲硅烷基醚类化合物时，用作反应溶剂。[5]图片来源：参考文献5与采用其他溶剂时不同效果的比较见下表：数据来源：参考文献5.酰胺水解反应在合成如下所示的一种GLP-1受体激动剂类的药物时，其中间体由A到B的酰胺键酸性水解反应，在DMI的促进下进行，效果较好。[6]图片来源：参考文献66.肼置换反应文献[7]则报道了在一项Akt激酶抑制剂的合成试验中，以DMI为溶剂，成功地实现了公斤级的肼置换反应，在DMI的作用下，6-氯-3-苯基-1,5-萘啶-2(1H)-酮与浓度为35%的水合肼反应，得到2.585公斤纯度为98.4 wt%的产品6-肼基-3-苯基-1,5-萘啶-2(1H)-酮，反应收率为84%。[7]图片来源：参考文献77.多肽的环合反应多有文献报道DMI用于有生物活性、可作为潜在药物开发的多肽或环肽的人工合成。有研究表明，DMI在如下潜在药物的合成中，作为溶剂，取得了较好的效果。[8]如，(S)-2-(2-羟基-N-甲基乙酰胺基)-3-苯基-N-((3R,6S,9S,123.15S,2iS,24S,27S)-6,15,21-三苄基-24-异丁基-3-(巯基甲基)-9,10,12,16,19,25-六甲基-2,5,8,11,14,17,20,23,26-九氧代-1,4,7,10,13,16,19,22,25-九氮杂三十烷-27-基)丙酰胺（化合物P-151）1-((6R,12S,15S,18R)-15-[1H-吲哚-3-基)甲基)-6-氨基-18-(叔丁基二硫烷基)甲基)-12-(4-(二甲氨基)丁基)-2,2-二甲基-7,10,13,16-四氧代-3,4-二硫杂-8,11,14,17-四氮杂十九烷)吡咯烷-2-甲酸(S)-2-((S)-6-氨基-1-(S)-4-(苄基硫)-1-((S)-2-氨基甲酰基吡咯烷-1-基)-1,4-二氧代丁-2-烷基氨基)-1-氧代己-2-烷基氨基)-2-氧代乙酯（化合物SP605）(S)-N-((3R,6S,9S,12R,16S,19S)-6-((1H-吲哚-3-yl)甲基)-16-((S)-2-氨基甲酰基吡咯烷-1-羰基)-9-(4-(二甲基氨基)丁基)-3,12-双(巯甲基)-2,5,8,11,14,18-六氧代-1,4,7,10,13,17-六氮杂二十三烷-19-基)-1-(2-羟乙酰基)吡咯-2-甲酰胺（化合物SP617）(S)-N-((3S,6S,9S,12S,155,18S,2IS,24S,27S)-3,12-苄基-1,24-二异丁基-6,9,10,13,15,19,21,22-八甲基-2,5,8,11,14,17,20,23,26-九氧代-1,4,7,10,13,16,19,22,25-九氮杂环三十一烷-27-基)-2-(2-羟基乙酰胺)-3-苯基丙酰胺(化合物SP664)(2R)-2-氨基-3-(叔丁基二硫基)-N-(4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,32S)-5,23,32-三苄基]-2-((叔丁基二硫基)甲基)-11,17-二异丁基-13,14,16,20,22,25,26,29-八甲基-3.6,9,12,15,18,21,24,27,30,33-十一氧代-1-氧杂-4,7,10,13,16,19,22,25,28,31-十氮杂环三十三烷-8-基丁基)丙酰胺（化合物SP665）等。图片来源：参考文献82用于透皮吸收制剂（1）安定是一种镇静剂用于治疗焦虑症和一般性失眠。以DMI 72g、已烷25g和安定3g配成药剂，以小老鼠腹部皮肤作透皮测试，在8h内的透皮吸收量是391μg／cm2，大于仅以安定3g和甲基乳酸酯97g配得溶剂的透皮量。可见由DMI和极性物质的组合能够促进药物在皮肤中的传输吸收。由安定1％、乙醇74％和DMI 25％能配制成一种肌肉松弛剂。[9]（2）尼索地平是一种钙离子拮抗剂，用于治疗脑血管疾病。以苯乙烯-异戊二烯聚合物28％、石蜡油17.5％、聚丁烯5％、石油树脂32％和钛白17.5％（按重量比）调配成涂敷剂底料。再在底料中加入尼索地平（活性药物）10％、辅料1-癸基氮杂环壬-2-酮（1-decylazaclononan-2-one）5％以及DMI 10％，所得涂敷剂均匀涂在聚乙烯薄膜的表面，测试透皮性能，有较好的效果。[10]（3）没药醇是一种钙离子拮抗剂。以没药醇（纯度87％）3％、DMI 7％以及镍5％配入底料85％中，制得药剂（按重量比）（底料是以丙烯酸和丙烯酸丁酯的共聚物溶入20％的丙酮而得）。该药剂涂于聚乙烯薄膜上测试得较好的透皮效果。[11]（4）盐酸普萘洛尔主要用于治疗心律不齐。以盐酸普萘洛尔（活性药物）1％、DMI74％、十二烷基烟碱25％（按重量比）配成药剂，在玻璃试管中测试它的透皮吸收性能。与以盐酸普萘洛尔1％和DMSO 99％配得药剂相比，透皮量要高出12.9倍，与以盐酸普萘洛尔1％和N-吡咯烷酮99％配得的药剂相比，透皮量要高出2.3倍。[12]（5）灭吐灵又名甲氧普胺、胃复安，是一种镇吐药。以灭吐灵1％、DMI 89％和十二烷基烟碱10％配得药剂，测试药物皮肤渗透量。与以药品1％和DMSO 99％配得的药剂相比，透皮量要高出15.8倍，与以药品1％和N-吡咯烷酮99％配得的药剂相比，透皮量要高出30倍。[13]（6）DMI具备配制软膏的溶剂所必须具备的多项条件，因此能用于配制各种药物软膏。如：立体异构或非立体异构各类治疗眼病的消炎药剂，心脏病药物、抗菌剂、抗病毒剂、激素、镇痛剂等等。在甾体激素软膏调制中，以DMI 3g、乙二醇3g、异丙基肉豆蔻2g、白凡士林92g，混合，再加入甾体激素B，配制成治疗软膏。图片来源：参考文献9用甾体激素A和甾体激素B分别与几种不同的有机物相容混，得到如下数据:数据来源：参考文献由此可知，与调制膏剂常用的其他有机溶剂相比，1,3-二甲基-2-咪唑烷酮对于甾体药物表现出极为出色的溶解能力。该项研究还通过对健康成年男子进行皮肤贴片测试，结果显示，加入了1,3-二甲基-2-咪唑烷酮的软膏基剂具有良好的皮肤亲和性，无过敏反应，且在保湿性和稳定性方面表现出色。[14]（7）DMI能够显著地增强视黄醇和视黄酸酯对角化细胞的增殖和变异的作用效果。单独的DMI对皮肤细胞并没有产生作用，但当它与视黄醇或视黄酸酯相混合后，DMI分子与视黄醇或视黄酸酯分子之间产生协同相互作用，从而显著地增强了对角化细胞的增殖和变异的作用效果。这种皮肤调节剂成分包括（a）一种视黄醇或视黄酸酯含量0.001％～10％，（b）DMI含量0.001％～10％，（c）a与b的含量比例可以从60∶1～1∶160均有较好效果。如以下药剂的配制：（按重量比）视黄醇0.5％，完全氢化的椰子油3.9％、DMI 0.2％、聚氧乙烯油脂5％、皂土油38％、七水合硫酸镁0.3％、丁基化羟基甲苯0.01％，香料适量，加水至100％，即可配制成一种促进角化细胞增殖的药剂。[15]（8）环孢菌素是一种免疫抑制药，它在生物体内的生物利用率很低，如果加入乳酸甘油脂AXOL、DMI等辅料后，能控制药物的释放，促进它在生物体内的传输吸收，提高它的生物利用率。DMI可以用于配制软胶囊、口服制剂、栓剂、乳剂等。其配比如下表。[16]数据来源：参考文献由以上这些例子可以说明，以DMI溶解药物和以DMSO或N-吡咯烷酮作溶剂相比，药物的透皮吸收量有较大的提高，如果在DMI中再加入少量极性物质（如十二烷基烟碱、乙醇等）则透皮性能更好。可以预计DMI在药物透皮吸收剂中的应用将会不断地得到扩展。3用于中间体的合成DMI在各类有机中间体（尤其是医药、农药中间体）的合成中有非常广泛的应用。1.作为溶剂用在苯醚的合成中，见于文献报道的四种苯醚产物的合成收率都在90%以上。[17,18,19,20]（1）图片来源：参考文献17（2）图片来源：参考文献18（3）图片来源：参考文献19（4）图片来源：参考文献202.胺类化合物的合成。[21,22,23]（1）图片来源：参考文献21（2）图片来源：参考文献22（3）图片来源：参考文献233.氟苯类化合物的合成。[24,25]（1）图片来源：参考文献24，25应用效果比较：数据来源：参考文献（2）图片来源：参考文献应用效果比较：数据来源：参考文献4.还原反应DMI有极强的溶解能力，不仅能溶解有机化合物及树脂材料，还能溶解金属氢化物，因此以NaBH4还原剂时，DMI是一种优良的溶剂。溶解在DMI中的NaBH4可用来还原睛、酰胺、羧酸和酯。[26]图片来源：参考文献265.氧化反应由于DMI在酸碱性条件下有很强生物稳定性，且对碱有活化作用，因此在碱性条件下用空气中的氧可以氧化含有活泼氢的芳香族化合物，而在碱性条件下和DMF和DMSO等都是不稳定的。[27]图片来源：参考文献276.柯尔贝-施密特反应在含有DMI的混合溶剂中，酚类的碱金属盐在加压下与CO2反应，可生成羟基苯甲酸，所得产物的收率比不用DMI时高很多。[28]图片来源：参考文献287.自缩合反应。[29]图片来源：参考文献298.二聚化反应。[30]图片来源：参考文献309.加成反应。[31]图片来源：参考文献3110.乌尔曼反应用DMI作反应溶剂，铜粉作催化剂，芳卤与芳胺乌尔曼发生反应，生成联苯胺，反应收率高达90%。[32]图片来源：参考文献32参考文献（上下滑动阅览）[1] Oda Katsuo. (SHIONOGI & CO) . Novel method for producing benzylidene derivative. WO2004089921A[2] Belli, A., Cannata, V., Villa, M., Hedberg, M., Westermark, A., Fonduca, T. (NicOx S.A.). Process for the Preparation of the (S)-naproxen 4-nitrooxybutyl ester. US2011034719A1[3] Bryan Li, Richard A. Buzon, and Michael J. Castaldi. Case Study of a γ-Butyrolactone Alkylation with 1,3-Dimethyl-2-imidazolidinone as a Promoter, Organic Process Research & Development , 5(6), 609-611(2001)[4] Saito Yuzuru, Yoshida Kokichi,. (TAKEDA CHEMICAL INDUSTRIES LTD). Production of substituted acetylenic compounds. EP0284237A1[5] Thomas C. Britton. (Eli Lilly and Company). Process for preparing 2,2-difluoroketene silyl acetals and α,α-difluoro-β- silyloxy-1,3-dioxolane-4-propanoic acid esters. US5618951A[6] Ayman D. et al., (Eli Lilly and Company). Process to make GLP1 RA and intermediates therefor. US20250042899[7] Pintipa Grongsaard, et al., Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor. Organic Process Research & Development , 16, 1069−1081(2012)[8] Peptide-compoud cyclization method（肽类化合物环合的方法）US20240166689A1[9] Base composition and Drug composition for external use.（基础成分与外用药成分）JPS58164520A[10] Drug composition. （药物组分）JPS6133128A[11] Pharmaceutical composition. （药物组分）JPS61129140[12] Composition for percutaneous administration.（经皮给药成分）EP0182635[13] Composition for exodermis administration.（外皮层给药组合物）JPS6287527A[14] Ointment bases and ointments.（软膏基质和软膏）EP0137212[15] Skin care compositions containing dimethyl imidazolidinone and retinol or retinyl ester.（含有二甲基咪唑烷酮和视黄醇或视黄醇酯的护肤组合物）US5536740[16] Medical preparations containing N-methylated cyclic undecapeptides. （含有N-甲基化环状十肽的药物制剂）US5670478A[17] Process for production of m-phenoxybenzyl alcohol（生产间苯氧苄基醇的工艺）US4694110[18] Method for Producing Nitrophenoxybenzene Amines（生产硝基苯氧基苯胺类化合物的方法）JPH0651662B2[19] Production of 4-biphenyl p-tolyl ether.（4-联苯对甲苯醚的生产方法）JP01160935A[20] Production of 4-nitrophenetole.（4-硝基苯醇的生产方法）JP03232841A[21] Production of anthraquinone compound（蒽醌类化合物的生产）JPH06247912A[22] Production of anthraquinone compound（蒽醌类化合物的生产）JPH05170713A[23] Production of N,N-diphentlacylamides.（N,N-二苯基酰胺的生产）JPS63165350A[24] Production of 3,4-difluorobenzonitrile.（二氟苯甲腈的生产）JPH03145449A[25] Production of polyfluorohalogenobenzenes. （多氟卤代苯的生产）JPH05117181A[26] Reducation of organic compounds.（有机化合物的还原反应）JPS54144301A[27] Preparation of ketone derivative.（酮衍生物的制备）JPS54144348A[28] Production of 3,5-dialkylsalicylic acid. （3,5-二烷基水杨酸的生产）JPH0390047A[29] Production of 3,3'-dinitro-5.5'-bis(trifluoromethyl)diphenyl ether.（3,3'-二硝基-5.5'-双（三氟甲基）二苯醚的生产）JPH05178796A[30] Production of 4,4'-dinitrostilbene-2,2'-disulfonic acid or its salt.（4,4'-二硝基二苯乙烯-2,2'-二磺酸或其盐的生产）JPH05230012A[31] Production of 3-cyano-3,5,5-trimethylcyclohexanone.（3-氰基-3,5,5-三甲基环己酮的生产）JPH04164057A[32] 胡爱国，华东理工大学硕士论文，1993,6声明：本内容仅用作医药行业信息传播，不代表药智网立场。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 史迪威合作、投稿 | 马老师 18323856316（同微信）阅读原文，是受欢迎的文章哦

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2024-07-25

·生物探索

Nature | 闫创业/袁亚飞团队揭示去甲肾上腺素转运蛋白再摄取与抑制的分子基础

引言去甲肾上腺素 (Norepinephrine 或 noradrenaline；NE) 、多巴胺 (Dopamine；DA) 和血清素 (Serotonin ；或5-羟色胺5-hydroxytryptamine, 5-HT) 是重要的单胺类神经递质，影响着包括运动、激素分泌、奖惩和情绪相关的复杂行为和生理过程。这些神经递质在突触前膜去极化后释放到突触间隙，随后激活突触后膜上的受体并触发影响神经元兴奋性、突触可塑性和各种生理过程的细胞内信号级联。正常生理情况下，从突触前神经元释放的神经递质，在完成信号传导后必须及时高效地从突触间隙被清除，从而实现信号终止。通过突触前神经元或者神经胶质细胞质膜上的单胺类神经递质转运蛋白（Monoamine transporters; MATs），可以将单胺类神经递质再摄取回突触前膜从而终止其对下游受体的激活状态。目前，MATs家族抑制剂主要在医药市场上用作抗抑郁药，可根据其化学结构和作用方式分为不同的类别（图1）。图 1 单胺能神经元中神经递质的传递过程及不同抗抑郁药物的作用方式（Credit: Acta Neuropsychiatr）【1】 MATs属于神经递质钠同向转运蛋白（Neurotransmitter: sodium symporter; NSS）家族成员，其利用膜外/内钠离子Na+的浓度梯度来完成对神经递质的同向跨膜运输，这一过程可能依赖于氯离子Cl-同向转运以及钾离子K+的反向转运。近年来对MATs 中底物转运及抗抑郁药物调节机制的研究进展迅速，其中果蝇多巴胺转运蛋白dDAT和人源血清素转运蛋白SERT的不同构象以及与多种抗抑郁药物分子结合的结构已经得到解析。但关于人源去甲肾上腺素转运蛋白NET的结构研究相对进展缓慢，这大大阻碍了抗抑郁药物的进一步优化和开发。 2024年7月24日，清华大学生命科学学院/北京生物结构前沿研究中心闫创业/袁亚飞团队在Nature杂志发表了题目为Molecular basis of human noradrenaline transporter reuptake and inhibition”（人类去甲肾上腺素转运蛋白再摄取与抑制分子基础）的研究论文。该工作通过结构生物学和生物化学方法阐明了NET转运底物NE和DA的机制，首次报道了NET中的第二个底物结合位点和NSS家族的钾离子结合位点，揭示了四种不同类别的常用上市抗抑郁药物的选择性抑制机制，为进一步开发靶向MATs的药物奠定了基础。该团队利用冷冻电镜技术成功解析了人源NET蛋白的八个高分辨率结构，包括天然状态、结合底物（NE、DA）和四种常用上市抗抑郁药物（托莫西汀：Atomoxetine，ATX；地昔帕明：Desipramine，DSP；艾司西酞普兰：Escitalopram，ESC；安非他酮：Bupropion，BPP）的结合状态。这些结构是天然蛋白在未使用任何基准标记或突变的情况下获得，分辨率在2.5到3.5埃之间（图2）。图2. 人源NET天然状态、结合两种底物和四种抗抑郁药物复合物的冷冻电镜结构（Credit: Nature）研究发现 NET中央口袋S1处识别NE或DA的方式与报道的果蝇dDAT不同，其儿茶酚环上的两个羟基主要通过水介导的氢键识别（图3a，b）。此外，研究在NET与两种底物结合的结构中都观测到了第二个底物的密度（S2位点）。值得注意的是，与已报道的SERT中的S2位点显著不同，NET中的S2位点位于TM1b C末端，且仅存在于向内闭合或开放的构象中，向外开放构象转变会导致S2位点被破坏（图3c）。通过生化实验发现，S2位点内的某些突变显著影响转运蛋白的转运速度。推测NET中S2位点的功能可能是提前加载底物，从而加快底物转运效率。图3. NET中心口袋S1的底物结合方式（a-b）、S2位点（c）及K+离子结合位点（d）（Credit: Nature） MATs成员是离子耦合的膜蛋白，作为次级主动转运蛋白，它们共享两个保守的Na+结合位点（Na1和Na2）和一个保守的Cl-结合位点，利用跨膜离子梯度的能量来催动神经递质的运输（图3a）。早在1979年时K+离子就被提出参与MATs的转运循环，但直到现在实验结构仍未确定特定的K+结合位点【3】。研究人员在向内开口的NET-DSP-KCl结构的 Na1 位点处发现了K+的额外密度，而该密度在 NaCl 条件下的NET内向开口构象中并不存在。据此，该研究首次通过结构验证了NSS 家族中 K+ 离子的结合位点。这一K+ 离子位点恰好是Na1位点，该位点在向内开口释放Na+离子之后，局部残基构象发生改变，使得该位点更偏好螯合K+离子（图3d）。尽管确认了 Na1 处 K+ 的存在及其在运输中的作用，但其触发构象转变的确切机制仍需要进一步研究。深入了解不同抗抑郁药物对MATs的选择性抑制的分子基础对于抗抑郁药物的开发和应用具有重要意义。托莫西汀是一种NE再摄取抑制剂（NRI），其对 NET 的选择性比 SERT 和 DAT 高约 30 倍和 130 倍；地昔帕明是三环类抗抑郁药（TCA），其对NET的选择性比SERT高约20倍；安非他酮是典型的NE和DA再摄取抑制剂（NDRI）；而艾司西酞普兰是一种典型的选择性血清素再摄取抑制剂（SSRI），其对SERT的选择性比NET高约2600倍。该研究通过解析四种不同类型的抗抑郁药物的高分辨率结构，为理解其对NET、DAT和SERT选择性提供了分子基础。通过不同抑制剂浓度的[3H]-NE摄取测定，该研究进一步揭示了托莫西汀的竞争性抑制及其它三种抑制剂的混合型抑制机制与结合不同构象相关。这些研究为理解靶向MATs的抗抑郁药物选择性提供了重要见解，MATs抗抑郁药独特的结合模式和多靶点特性值得制药行业特别关注。综上，研究人员提出了NET的转运过程模型（图4）。在向外开放的构象中，Na+、Cl-和底物NE与中央口袋结合，启动 NET 的闭合，进入闭合状态。在这个转变过程中，第二个底物可以提前结合到新形成的膜外S2位点中。随后，TM1a 的打开（向内开放构象的标志特征）促进底物与两个Na+一起从中央口袋释放。在转变回向外开放构象的过程中，S2 位点的局部结构将受到破坏，导致S2位点处底物的释放。释放的底物可能直接进入到中央口袋，开始下一个转运循环。这一过程与两个 Na+ 离子和一个 Cl- 离子进入细胞质以及可能一个 K+ 离子进入细胞外基质的转运耦合。而不同类别的抗抑郁药物占据 S1 位点阻碍底物转运。图4. NET的交替开放转运模型和抑制机制（Credit: Nature）该研究亮点：首次发现了NET的第二个底物结合位点以及NSS家族的K+结合位点，揭示了NET底物识别机制、交替开放转运模型、以及不同类别抗抑郁药物选择性抑制的分子机制，为抗抑郁药物的进一步研发提供了基础。参考文献 1.Pereira, V. S. & Hiroaki-Sato, V. A. A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatr 30, 307-322 (2018). 2. Cheng, M. H. & Bahar, I. Monoamine transporters: structure, intrinsic dynamics and allosteric regulation. Nat Struct Mol Biol 26, 545–556 (2019). 3.Rudnick, G. & Sandtner, W. Serotonin transport in the 21st century. J. Gen. Physiol 151, 1248-1264 (2019). https://www.nature.com/articles/s41586-024-07719-z 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-05-06

·BioSpace

Boehringer Ingelheim shares positive results from the first study worldwide in diabetic macular ischemia

Boehringer Ingelheim today presented positive data from the HORNBILL Phase I/IIa study of BI 764524, the first ever study exploring a potential treatment for people living with diabetic macular ischemia (DMI). The study found that BI 764524 was well tolerated following intravitreal administration of single and multiple doses, meeting its primary safety endpoints and showed early signs of potential efficacy.1 DMI is a common, irreversible complication of diabetic retinopathy (DR) that may lead to blindness.12,3,4 It can develop when the light sensitive tissues of the central retina do not receive adequate blood supply over a longer time. There are currently no approved treatments for DMI. The current standard of care for advanced DR includes intravitreal anti-VEGF treatment or invasive laser treatment. However, some patients’ conditions progress despite this treatment.5 BI 764524 uses a novel mode of action by inhibiting the Sema3A pathway to re-vascularize ischemic areas and potentially overcome the limitations of anti-VEGF and laser treatments.1 “The results from the HORNBILL study are really encouraging. They suggest there may be a pathway for earlier intervention that could decrease the risk of, and maybe even prevent, people with diabetic retinopathy from developing irreversible and vision-threatening complications, such as DMI,” said Quan Dong Nguyen, MD, MSc, FARVO, FASRS, Professor of Ophthalmology at the Byers Eye Institute, Professor of Medicine and of Pediatrics at Stanford School of Medicine, and Principal and Coordinating Investigator of the trial. “Retinal non-perfusion is a key driver of vision loss in people living with diabetic retinopathy. However, until the HORNBILL study, retinal non-perfusion has not been explored as a potential treatment target.” “Vision loss associated with retinal conditions such as diabetic retinopathy and DMI has a devastating impact on quality of life. Today’s results are an important step towards achieving our aspiration of developing precision therapies delivering the right treatment for the right patient at the right time to prevent vision loss before irreversible damage occurs,” said Ulrike Graefe-Mody, Ph.D., Head of Retinal Health at Boehringer Ingelheim. “We’re looking forward to start a Phase IIb study to further explore the safety and efficacy of BI 764524.” HORNBILL is one of 23 abstracts being presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual meeting 2024, spanning Boehringer Ingelheim’s retinal health portfolio, including other studies of retinal non-perfusion and diabetic retinopathy, geographic atrophy and neovascular age-related macular degeneration. About the HORNBILL study The HORNBILL study consisted of two parts (single rising dose (SRD), N=12 and multiple dose (MD), N=31) both of which met the primary safety endpoints of number of patients with dose-limiting adverse events (SRD) and treatment-related adverse events(MD).1 The study also met its pre-specified criterion for early efficacy of foveal avascular zone area stabilization versus sham at week 16 (p<0.2).1 This suggests that BI 764524 may positively impact retinal non-perfusion and potentially halt the progression of capillary loss.1 The upcoming CRIMSON trial, a Phase IIb trial, will assess safety and efficacy of BI 764524 in patients with DR further and start recruiting later this year. Notes to Editors: About the trial (NCT04424290) This Phase I/IIa trial assessed the tolerability of BI 764524 in people with diabetic retinopathy (DR) with diabetic macular ischemia (DMI) who have previously been treated with panretinal photocoagulation.1 The trial consisted of a single rising dose (SRD) part followed by a multiple dosing (MD) part, with BI 764524 administered via intravitreal injection.1 Single rising dose part In the non-randomized, open-label, SRD part, 12 patients received intravitreal BI 764524 doses: 0.5 (n=3), 1.0 (n=3), or 2.5 mg (n=6).1 The primary endpoint was the number of patients with dose-limiting events (DLEs); secondary endpoints were the number of patients with drug-related adverse events (AEs) and any ocular AEs.1 Patients in the SRD part had a mean age of 61.8 years.1 No DLEs were reported in the SRD part.1 There were five ocular AEs in four patients in the study eye, none related to the study drug. The highest tested dose (BI 764524 2.5 mg) was considered safe and applied in the MD part.1 Multiple dosing part In the randomized, masked, sham-controlled, MD part, 31 patients received three intravitreal doses of BI 764524 2.5 mg (n=21) or sham injection procedures (n=10) at 4-week intervals (baseline, week 4, and week 8), followed by 14 weeks of follow-up until the end of study at week 22.1 The primary endpoint was the number of patients with drug-related AEs; secondary endpoints included number of patients with ocular AEs, change from baseline in foveal avascular zone (FAZ) area, best corrected visual acuity (BCVA) and central retinal thickness (CRT).1 Patients in the MD part had a mean age of 59.5 years.1 There were seven patients with ocular AEs (study eye; three patients with four AEs for BI 764524, four patients with six AEs for sham), one of which was reported as related to the study drug (vitreous floater).1 In addition, there was one systemic AE (increase deemed related to the study drug by the investigator). There were no cases of intraocular inflammation or occlusive retinal vasculitis.1 At baseline, mean BCVA was 65.2 letters, mean FAZ area was 0.65 mm, and mean CRT was 252 mm.1 The HORNBILL study met its pre-specified criterion for early efficacy of FAZ area stabilization versus sham at week 16 (p<0.2). Over the short trial period, other secondary efficacy endpoints showed no relevant change. About BI 764524 BI 764524 is a humanized monoclonal anti-Sema3A antibody intended to re-vascularize ischemic areas and reduce leakage in the retina, offering the potential to address retinal non-perfusion in retinal diseases. The compound was discovered and developed by Boehringer Ingelheim and is part of its research and development portfolio in retinal conditions. About diabetic retinopathy and diabetic macular ischemia Diabetic retinopathy affects 1 in 3 people with diabetes and is the leading cause of vision loss in adults of working age. It is a growing epidemic that is expected to increase as the incidence of diabetes escalates across the globe. Diabetic macular ischemia (DMI) is a complication of diabetic retinopathy which can lead to slowly progressing, irreversible vision loss. About Boehringer Ingelheim Boehringer Ingelheim is working on breakthrough therapies that transform lives, today and for generations to come. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term, sustainable perspective. More than 53,000 employees serve over 130 markets in the two business units Human Pharma and Animal Health. Learn more at Boehringer Ingelheim’s Intended Audiences Notice This press release is issued from our Corporate Headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where we do business. References 1 Nguyen QD, Jhaveri C, Habib MS. Oral presentation at the Association for Research in Vision and Ophthalmology (ARVO) 2024. Abstract number: 959 2 Marques IP, et al. Diabetes 2019;68:648–653 3 Sim DA, et al. Invest Ophthalmol Vis Sci 2013;54:2353–2360 4 Tey KY, et al. Eye Vis (Lond) 2019;6:37 5 Ip MS, et al. Ophthalmology 2014;122:367–374

临床结果临床2期

100 项与盐酸地昔帕明相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D00812	盐酸地昔帕明	N06AA01	DB01151

研发状态

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适应症	国家/地区	公司	日期
抑郁症	美国	Validus Pharmaceuticals LLC	1964-11-20

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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


NCT01899326 (CTgov)	N/A	难治性多发性骨髓瘤	10	Laboratory Biomarker Analysis+Filgrastim+Desipramine Hydrochloride	醖艱餘淵襯鏇鏇醖積廠(鹽積範糧淵餘製繭窪膚) = 餘鏇襯餘繭廠鹽廠糧鹽構鏇膚顧顧齋襯遞鑰襯 (壓壓製鹽顧糧衊獵簾簾, 襯衊鹽鬱憲鹹築積積選 ~ 襯廠鹽網顧構窪網齋選) 更多	-	2023-03-28
ISTH2021	N/A	-	-	Desipramine	醖顧製艱獵範窪觸積鏇(廠鹽廠範範製鑰窪顧壓) = 繭鏇齋鏇積鑰糧簾願窪蓋糧簾鹹鹽夢築齋壓廠 (簾夢夢築獵製艱衊壓蓋 )	-	2021-07-17
				PRP pre-incubated with 10μM desipramine	醖顧製艱獵範窪觸積鏇(廠鹽廠範範製鑰窪顧壓) = 醖獵遞鹹鑰衊網鑰積夢蓋糧簾鹹鹽夢築齋壓廠 (簾夢夢築獵製艱衊壓蓋 )
NCT03726996 (CTgov)	临床4期	神经轴索营养不良	4	Desipramine	艱膚選襯鏇憲網積遞夢(醖鑰網鏇顧選願膚積餘) = 壓顧窪鬱顧壓觸鹽觸遞獵襯膚觸築鹹構蓋淵選 (壓觸鹽鬱鏇鏇繭醖鏇憲, 積餘淵艱鏇夢構選壓鹹 ~ 遞製觸憲鹽積顧積壓襯) 更多	-	2020-10-14
NCT01358968 (CTgov)	临床1期	肿瘤	20	Desipramine+Gemcitabine+LY2603618+Pemetrexed	構鏇觸構積願糧襯繭鹽(積鑰蓋蓋艱鏇簾膚艱醖) = 鏇鏇衊鹹選壓襯夢製艱衊餘鹹繭糧繭艱簾築觸 (簾膚糧鹹餘網顧蓋淵繭, 網齋網鹹餘憲觸餘夢顧 ~ 膚顧齋鹽觸鹹醖艱醖餘) 更多	-	2018-10-25
NCT01411085 (RADIAUS, CTgov)	临床2期	酗酒 \| 精神分裂症	12	Risperidone+Desipramine	觸壓觸衊鬱網蓋膚糧鹹(獵鹹壓網鑰選簾鬱糧鹽) = 構積糧鑰鹹鹹餘鏇糧膚積製齋廠範膚鏇構艱膚 (鹽鑰獵廠淵構糧構壓憲, 簾窪顧艱糧壓衊顧鑰繭 ~ 鏇蓋繭廠網艱築餘繭廠) 更多	-	2018-03-23
NCT00338962 (CTgov)	临床3期	酗酒 \| 抑郁症 \| 创伤后应激障碍	88	paroxetine+Naltrexone (Paroxetine and Naltrexone)	憲齋築鑰鹽獵網範觸齋(選願夢範夢獵壓顧鹹簾) = 製壓淵築願鑰糧餘範艱蓋繭獵鑰餘繭遞壓廠繭 (窪廠夢鹽繭範觸遞齋鏇, 膚觸蓋範衊鹹鹽襯憲網 ~ 製餘鹽廠壓蓋醖廠膚選) 更多	-	2016-02-05
				Placebo+paroxetine (Paroxetine and Placebo)	憲齋築鑰鹽獵網範觸齋(選願夢範夢獵壓顧鹹簾) = 顧餘鏇夢膚獵餘鬱夢顧蓋繭獵鑰餘繭遞壓廠繭 (窪廠夢鹽繭範觸遞齋鏇, 鏇淵顧網蓋鏇襯壓齋醖 ~ 簾壓襯鹹鹹壓鑰積製蓋) 更多
NCT00166114 (CTgov)	临床4期	重度抑郁症	40	Escitalopram (Escitalopram)	(糧餘選艱鹽憲選鬱願鑰) = 齋蓋鹹齋網製鑰淵醖繭憲艱夢餘製範夢鏇獵製 (艱遞觸構襯構獵鬱鏇網, 範製鑰齋廠遞壓繭蓋築 ~ 襯淵鹹繭壓積鬱壓願鹹) 更多	-	2015-07-23
				Desipramine (Desipramine)	(糧餘選艱鹽憲選鬱願鑰) = 鑰願鬱餘齋顧鏇衊網築憲艱夢餘製範夢鏇獵製 (艱遞觸構襯構獵鬱鏇網, 製願製壓壓齋廠觸廠壓 ~ 積積齋壓糧齋壓壓築膚) 更多
NCT00000271 (Pubmed \| Drug Alcohol Depend)	临床2期	抑郁症	111	Desipramine	憲淵製製製鬱獵觸膚選(齋簾淵夢網憲壓窪繭鬱) = 製餘築遞築繭觸淵製膚構壓齋衊願繭膚廠糧觸 (積壓憲顧鹽選鏇糧憲築 )	-	2005-11-01
				Placebo	憲淵製製製鬱獵觸膚選(齋簾淵夢網憲壓窪繭鬱) = 鹹糧簾淵醖築艱憲繭鹹構壓齋衊願繭膚廠糧觸 (積壓憲顧鹽選鏇糧憲築 )