Drug-induced liver injury (DILI) can lead to potentially fatal complications, such as acute liver failure and even death. In clinical practice, glucocorticoids have been considered in some cases of DILI, especially patients with hyperbilirubinemia. However, the available evidence remains controversial and its quality is also very limited. Herein, a multicenter randomized controlled trial (RCT) has been designed to explore the efficacy and safety of glucocorticoids in patients with acute DILI and hyperbilirubinemia.

Start Date01 Jun 2025

Sponsor / Collaborator

The General Hospital of Shenyang Military Region

NCT06882473

/ Not yet recruitingNot ApplicableIIT

A Clinical Study of Pelvic Concurrent Chemoradiotherapy Combined with CT-guided Intracavitary Brachytherapy with Adaptive Simultaneous Dose Escalation for Locally Advanced Cervical Cancer

The standard treatment for locally advanced cervical cancer is cisplatin-based concurrent chemoradiotherapy with external beam radiotherapy (EBRT) and Brachytherapy (BT). overall treatment time (OTT) has been found to be an important predictor of treatment response. Some studies have shown that the acceleration of tumor cell regeneration during the extension of radiotherapy leads to poor local control. Prolonging the overall treatment time of cervical cancer radiotherapy for more than 8 weeks leads to an increase in pelvic local control failure. Therefore, shortening OTT has great potential benefits from both clinical efficacy and social benefits. Shortening OTT in radical cervical cancer radiotherapy includes hypofractionated EBRT and shortening the interval between BT and EBRT. However, further shortening OTT may lead to an increase in acute and late toxicity. Adaptive radiotherapy (ART) strategies systematically monitor variations in target and neighbouring structures to inform treatment-plan modification during radiotherapy. The application of image-guided adaptive brachytherapy (IGABT) has clearly demonstrated the advantages of this approach in the treatment of cervical cancer. Previous studies have shown that the implementation of IGABT can achieve personalized treatment, dose increase, improve clinical efficacy, reduce normal tissue toxicity and side effects, and strengthen international standardized quality control. In this study, online adaptive pelvic EBRT combined with IGABT based on uRT-linac was performed under online CT guidance.
The aim of this study is to evaluate the safety and efficacy of pelvic concurrent chemoradiotherapy combined with CT-guided intracavitary brachytherapy with adaptive simultaneous dose escalation in locally advanced cervical cancer.

Start Date15 Mar 2025

Sponsor / Collaborator

Peking University Third Hospital

CTR20244073

/ CompletedNot Applicable

丁二磺酸腺苷蛋氨酸肠溶片人体药代动力学比较研究

[Translation] Comparative study on the pharmacokinetics of enteric-coated adenosylmethionine butanedisulfonate tablets in healthy volunteers

主要目的：本试验为预试验，旨在研究空腹和餐后状态下单次口服重庆药友制药有限责任公司研制、生产的丁二磺酸腺苷蛋氨酸肠溶片〔0.5 g（以腺苷蛋氨酸计）〕的药代动力学特征；以ABBOTT LABORATORIES (M) SDN. BHD持证、ABBVIE S.R.L.生产的丁二磺酸腺苷蛋氨酸肠溶片〔思美泰®，0.5 g（以腺苷蛋氨酸计）〕为参比制剂，比较两制剂中药动学参数Cmax、AUC0-t、AUC0-∞，为正式试验的开展提供参考。次要目的：观察受试制剂和参比制剂在健康受试者中的安全性。

[Translation]

Main purpose: This trial is a pilot study, aimed at studying the pharmacokinetic characteristics of a single oral administration of enteric-coated tablets of 5-(4-methionine-1-butenesulfonate) (0.5 g (in terms of 5-methionine-1-butenesulfonate)) developed and produced by Chongqing Yaoyou Pharmaceutical Co., Ltd. under fasting and postprandial conditions; using enteric-coated tablets of 5-(4-methionine-1-butenesulfonate) (Simetai®, 0.5 g (in terms of 5-methionine-1-butenesulfonate) produced by ABBOTT LABORATORIES (M) SDN. BHD and ABBVIE S.R.L. as the reference preparation, comparing the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ of the two preparations, and providing a reference for the conduct of formal trials. Secondary purpose: To observe the safety of the test preparation and the reference preparation in healthy subjects.

Start Date12 Mar 2025

Sponsor / Collaborator

Chongqing Yao Pharmaceutical Co., Ltd.

100 Clinical Results associated with Ademetionine 1,4-Butanedisulfonate

100 Translational Medicine associated with Ademetionine 1,4-Butanedisulfonate

100 Patents (Medical) associated with Ademetionine 1,4-Butanedisulfonate

11,342

Literatures (Medical) associated with Ademetionine 1,4-Butanedisulfonate

01 Sep 2025·METABOLIC ENGINEERING

Insights into the methanol utilization capacity of Y. lipolytica and improvements through metabolic engineering

Article

Author: Newell, William ; Ledesma-Amaro, Rodrigo ; Jiang, Wei ; Borah Slater, Khushboo ; Liu, Long ; Haritos, Victoria ; Liu, Jingjing ; Bell, David ; Coppens, Lucas ; Peng, Huadong

Methanol is a promising sustainable alternative feedstock for green biomanufacturing. The yeast Yarrowia lipolytica offers a versatile platform for producing a wide range of products but it cannot use methanol efficiently. In this study, we engineered Y. lipolytica to utilize methanol by overexpressing a methanol dehydrogenase, followed by the incorporation of methanol assimilation pathways from methylotrophic yeasts and bacteria. We also overexpressed the ribulose monophosphate (RuMP) and xylulose monophosphate (XuMP) pathways, which led to significant improvements in growth with methanol, reaching a consumption rate of 2.35 g/L in 24 h and a 2.68-fold increase in biomass formation. Metabolomics and Metabolite Flux Analysis confirmed methanol assimilation and revealed an increase in reducing power. The strains were further engineered to produce the valuable heterologous product resveratrol from methanol as a co-substrate. Unlike traditional methanol utilization processes, which are often resource-intensive and environmentally damaging, our findings represent a significant advance in green chemistry by demonstrating the potential of Y. lipolytica for efficient use of methanol as a co-substrate for energy, biomass, and product formation. This work not only contributes to our understanding of methanol metabolism in non-methylotrophic organisms but also paves the way for achieving efficient synthetic methylotrophy towards green biomanufacturing.

01 Aug 2025·JOURNAL OF BIOTECHNOLOGY

Genome mining of an endophytic natural yeast isolate Rhodotorula sp. Y090 and production of the potent antioxidant ergothioneine

Article

Author: Chen, Chao ; Zhao, Xin-Qing ; Li, Yu-Zhen ; Wang, Qi ; Zhang, Feng-Li ; Li, Jun ; Cheng, Cheng ; Zou, Yue

Endophytic yeast strains are promising sources of various valuable bioactive compounds. However, studies on endophytic strains derived from lichen samples remain limited. In this study, we isolated and characterized Rhodotorula sp. Y090 from a Usnea longissima lichen sample, and investigated its biosynthetic potential. Genome mining revealed distinct genetic features that differed from its closest relative strain R. graminis WP1. Ergothioneine (EGT) is a potent antioxidant and rare sulfur-containing histidine derivative. However, so far, the EGT biosynthetic enzymes by natural yeast strains have been limitedly studied. In this study, combining genome mining and transcriptomic analysis, genes encoding the potential enzymes for the production of EGT and xylose utilization were identified in Rhodotorula sp. Y090. Further studies demonstrated that Rhodotorula sp. Y090 was capable of producing EGT using xylose, glucose, glycerol, or sucrose as the sole carbon source, and the highest titer reached 363.6 mg/L in shake flask culture, which is significantly higher than that of the most reported levels in the other natural yeasts. Rhodotorula sp. Y090 also exhibited a good ability of EGT export, which could facilitate cost-effective production. These findings suggest that the lichen-derived endophytic yeast Rhodotorula sp. Y090 represents a promising natural candidate for bio-production of the potent antioxidant.

01 Jul 2025·VETERINARY PARASITOLOGY

The GLI3 may be involved in the damage process of Eimeria tenella to chicken cecal tissue

Article

Author: Li, Ping ; He, Ye ; Chen, Ying ; Wang, Bi ; Cheng, Zhentao ; Yu, Yongmei ; Xiang, Wanjiang

Eimeria tenella (E. tenella) is the most pathogenic avian coccidial species that targets the cecal epithelial cells of chickens. During the peak period of E. tenella oocyst shedding, the release of a large number of oocysts causes great damage to the cecal tissue. This study uses scanning electron microscopy to observe morphological changes in the host cecum during this period. Subsequently, the metabolic status and transcription level of the cecal tissue were analyzed to gain a comprehensive understanding of the interaction mechanism between E. tenella and the host. The results show substantial cecal tissue damage during the peak oocyst shedding period. The test group shows widespread epithelial cell sloughing, lamina propria exposure, widened intercellular spaces, and a scattered arrangement of absorptive epithelial cells. Combined analysis of the metabolome and transcriptome revealed that primary metabolic pathways, including amino acid metabolism, nucleic acid metabolism and lipid metabolism, were significantly altered in the process of E. tenella damage to cecal tissue. The transcription factor GLI-Kruppel family member 3 (GLI3) may be involved in regulation of primary metabolic pathways through mTORC1 signaling pathway. This study elucidates how E. tenella affects the host through physiological, metabolic and transcriptional changes in chicken cecal tissue. It provides valuable insights into the mechanisms of host immune response and the molecular dynamics of parasite-host interaction.

News (Medical) associated with Ademetionine 1,4-Butanedisulfonate

23 Aug 2024

·pharma.economictimes.indiatimes.com

Govt bans 156 medicines including antibiotics, painkillers, multivitamins: Here is the full list

New Delhi: In a significant move aimed at safeguarding public health, the Indian government has banned 156 fixed-dose combination (FDC) drugs, including a variety of antibiotics, painkillers, multivitamins, and medications for treating fever and hypertension. This decision marks the largest crackdown on FDCs since 2016, when 344 such drugs were prohibited. The Union Ministry of Health and Family Welfare issued a gazette notification on Thursday, officially prohibiting the manufacture, sale, and distribution of the banned FDCs. The ban was based on the recommendations of an expert panel that reviewed a total of 324 FDCs. Impact on Pharmaceutical Industry The banned FDCs include popular combinations such as mefenamic acid and paracetamol injections, commonly used for pain relief and fever, and omeprazole magnesium with dicyclomine HCl, used to treat abdominal pain. The ban is expected to impact major pharmaceutical companies, including Sun Pharmaceuticals, Cipla, Dr. Reddy's Laboratories, Torrent Pharmaceuticals, and Alkem Laboratories. Fixed Dose Combinations Drug Banned List Here is a table listing all 156 banned Fixed Dose Combinations (FDCs) SN Fixed Dose Combination (FDC) 1 Amylase + Protease + Glucoamylase + Pectinase + Alpha Galactosidase + Lactase + Beta-Gluconase + Cellulase + Lipase + Bromelain + Xylanase + Hemicellulase + Malt diastase + Invertase + Papain 2 Antimony Potassium Tartrate + Dried Ferrous Sulphate 3 Benfotiamine + Silymarin + L-Ornithine L-aspartate + Sodium Selenite + Folic acid + Pyridoxine hydrochloride 4 Bismuth Ammonium Citrate + Papain 5 Cyproheptadine HCl + Thiamine HCl + Riboflavine + Pyridoxine HCl + Niacinamide 6 Cyproheptadine Hydrochloride + Tricholine Citrate + Thiamine Hydrochloride + Riboflavine + Pyridoxine Hydrochloride 7 Rabeprazole Sodium (As enteric coated tablet) + Clidinium Bromide + Dicyclomine HCl + Chlordiazepoxide 8 Fungal Diastase + Papain + Nux vomica Tincture + Cardamom Tincture + Casein Hydrolysed + Alcohol 9 Mefenamic Acid + Paracetamol Injection 10 Omeprazole Magnesium + Dicyclomine HCl 11 S-adenosyl methionine + Metadoxine + Ursodeoxycholicacid BP + L-Methylfolate Calcium eq. to L- Methylfolate + Choline bitartratee + Silymarin + L-ornithine Laspartate + Inositol + Taurine 12 Silymarin + Thiamine Mononitrate + Riboflavin + Pyridoxine HCl + Niacinamide + Calcium pantothenate + Vitamin B12 13 Silymarin + Pyridoxine HCl + Cyanocobalamin + Niacinamide + Folic Acid 14 Silymarin + Vitamin B6 + Vitamin B12 + Niacinamide + Folic acid + Tricholine Citrate 15 Sodium Citrate + Citric Acid Monohydrate Flavored with Cardamom Oil, Caraway Oil, Cinnamon Oil, Clove Oil, Ginger Oil + Alcohol 16 Sucralfate + Acelofenac 17 Sucralfate + Domperidone + Dimethicone 18 Sucralfate + Domperidone 19 Tincture Ipecacuanha + Tincture Urgenia + Camphorated Opium Tincture + Aromatic Spirit of Ammonia + Chloroform + Alcohol 20 Ursodeoxycholic Acid + Metformin HCl 21 Weak Ginger tincture + Aromatic Spirit of Ammonia + Peppermint Spirit + Chloroform + Sodium Bicarbonate + Compound Cardamom + Alcohol 22 Sucralfate + Pantoprazole Sodium + Zinc Gluconate + Light Magnesium Carbonate 23 Aloe + Vitamin E Soap 24 Povidone Iodine+ Metronidazole + Aloe 25 Azelaic acid + Tea Tree Oil + Salicylic acid + Allantoin + Zinc oxide + Aloe vera + Jojoba oil + Vitamin E + Soap noodles 26 Azithromycin + Adapalene 27 Calamine + Aloes + Allantoin 28 Calamine + Diphenhydramine Hydrochloride + Aloe + Glycerine + Camphor 29 Chlorphenesin + Zinc oxide + Starch 30 Clindamycin Phosphate + Zinc acetate 31 Gamma Benzene Hexachloride + Benzocaine 32 Glucosamine hydrochloride + Diacerein + Menthol + Camphor + Capsaicin 33 Hydroxyquinone 2.0%w/w + Octyl Methoxycinnamate 5.0% w/w + Oxybenzone 30 % w/w 34 Ketoconazole +Zinc Pyrithione +D-Panthenol +Tea Tree Oil +Aloes 35 Ketoconazole +Aloe vera+ Vitamin A Acetate 36 Ketoconazole +Aloes + ZPTO 37 Kojic Acid +Arbutin +Octinoxate +Vitamin E + Mulberry 38 Lornoxicam +capsaicin +menthol+ camphor 39 Lornoxicam + Thiocolchicoside +Oleum Lini +Menthol + Methyl salicylate 40 Menthol + Aloe vera Topical Spray 41 Menthol +Lignocaine HCl +Aloe vera gel +Clotrimazole +Diphenhydramine 42 Miconazole nitrate + Gentamicin + Fluocinolone Acetonide +Zinc Sulphate 43 Miconazole +Tinidazole 44 Minoxidil +Aminexil+ Alcohol 45 Minoxidil +Azelaic acid + saw palmetto 46 Minoxidil +Aminexil 47 Pine Bark extract+ Kojic acid +Sodium Ascorbyl Phosphate 48 Povidone Iodine +Tinidazole +Zinc sulphate 49 Povidone Iodine + Ornidazole + Dexpanthenol 50 Salicyclic acid +Aloe vera+ Allantoin +D-Panthenol 51 Silver sulphadiazine +Chlorhexidine Gluconate solution +Allantoin + Aloe vera gel +Vitamin E acetate 52 Sodium salicylate + Zinc gluconate + Pyridoxine HCl 53 Tetracycline + Colistin Sulphate 54 Clomiphene +Ubidecarenone 55 Combikit of Clomiphene Citrate + Estradiol Valerate 56 Flavoxate HCl +Ofloxacin 57 Clomiphene Citrate +N-Acetylcysteine 58 Primerose Oil +Cod liver oil 59 Sildenafil Citrate +Papaverine +L-Arginine 60 Tranexamic acid +Mefenamic acid + Vitamin K1 61 Divalproex Sodium +Oxcarbazepine 62 Divalproex Sodium + Levetiracitam 63 Ergotamine tartrate +Caffeine + Paracetamol +Prochlorperazine maleate 64 Piracetam + Ginkgo biloba extracts + Vinpocetin 65 Ginkgo biloba + methylcobalamin 66 Ginkgo biloba + methylcobalamin + Alpha lipoic acid +Pyridoxine HCl 67 Ginseng Extract +Dried extract of Ginkgo Biloba 68 Meclizine HCl+ Paracetamol + Caffeine 69 Nicergoline + Vinpocetine 70 Gamma Linolenic Acid + Methylcobalamin 71 Beclomethasone Dipropionate + Neomycin Sulphate + Clotrimazole + Lignocaine HCl 72 Boric acid+ Phenylephrine HCl + Naphazoline Nitrate + Menthol + Camphor 73 Naphazoline HCl + Chlorpheniramine Maleate + Zinc Sulphate + Hydroxy Propyl Methyl Cellulose 74 Chlorpheniramine Maleate + Naphazoline HCl + Zinc Sulphate + Sodium Chloride + Hydroxy Propyl Methyl Cellulose 75 Chlorpheniramine Maleate + Naphazoline HCl + Hydroxy Propyl Methyl Cellulose 76 Chlorpheniramine Maleate + Sodium Chloride + Boric Acid + Tetrahydrozoline HCl 77 Chlorpheniramine Maleate + Phenylephrine HCl + Antipyrine 78 Ketorolac Tromethamine + Chlorpheniramine Maleate + Phenylephrine HCl + Hydroxy Propyl Methyl Cellulose 79 Ketorolac Tromethamine + Flurometholone 80 Naphazoline HCl + Zinc Sulphate + Boric Acid + Sodium Chloride+ Chlorpheniramine Maleate 81 Naphazoline HCl + Hydroxy Propyl Methyl Cellulose + Boric Acid + Borax + Menthol + Camphor 82 Naphazoline HCl + Hydroxy Propyl Methyl Cellulose + Chlorpheniramine Maleate SN Fixed Dose Combination (FDC) 83 Diphenhydramine Hydrochloride + Phenylephrine Hydrochloride + Menthol + Camphor 84 Diphenhydramine Hydrochloride + Phenylephrine Hydrochloride + Sodium Chloride + Hydroxy Propyl Methyl Cellulose 85 Diphenhydramine Hydrochloride + Phenylephrine Hydrochloride + Sodium Chloride + Methylparaben 86 Methenamine + Sodium Benzoate + Benzyl Alcohol 87 Paracetamol + Phenylephrine Hydrochloride + Chlorpheniramine Maleate 88 Paracetamol + Phenylephrine Hydrochloride + Chlorpheniramine Maleate + Caffeine 89 Propoxyphene + Chlorpheniramine Maleate 90 Propoxyphene + Phenylephrine Hydrochloride + Chlorpheniramine Maleate 91 Propoxyphene + Diphenhydramine Hydrochloride + Phenylephrine Hydrochloride 92 Sodium Benzoate + Sodium Citrate + Citric Acid 93 Vitamin A Palmitate + Vitamin C + Vitamin E + Vitamin B6 + Vitamin B12 94 Vitamin A Palmitate + Vitamin C + Vitamin E + Niacinamide 95 Vitamin B6 + Vitamin B12 + Vitamin C 96 Vitamin B6 + Vitamin B12 + Niacinamide 97 Vitamin B12 + Vitamin B6 + Vitamin C + Folic Acid 98 Vitamin B12 + Vitamin B6 + Niacinamide + Folic Acid 99 Vitamin C + Vitamin E + Vitamin A + Niacinamide 100 Vitamin D + Calcium + Magnesium 101 Vitamin D + Calcium + Magnesium + Zinc 102 Calcium + Vitamin D + Vitamin K 103 Calcium + Vitamin D + Magnesium + Zinc 104 Calcium + Vitamin D + Vitamin K + Magnesium 105 Calcium + Vitamin D + Vitamin K + Magnesium + Zinc 106 Vitamin E + Vitamin A + Vitamin C + Niacinamide 107 Vitamin E + Vitamin A + Vitamin C + Folic Acid 108 Vitamin E + Vitamin A + Vitamin C + Biotin 109 Vitamin E + Vitamin A + Vitamin C + Vitamin B12 110 Vitamin E + Vitamin C + Folic Acid 111 Vitamin E + Vitamin C + Biotin 112 Vitamin E + Vitamin C + Vitamin B12 113 Vitamin E + Vitamin C + Zinc 114 Calcium + Vitamin D + Omega-3 Fatty Acids 115 Calcium + Vitamin D + Omega-3 Fatty Acids + Vitamin K 116 Calcium + Vitamin D + Omega-3 Fatty Acids + Vitamin K + Magnesium 117 Calcium + Vitamin D + Omega-3 Fatty Acids + Vitamin K + Zinc 118 Vitamin A + Vitamin C + Vitamin E + Beta-Carotene 119 Vitamin A + Vitamin C + Vitamin E + Beta-Carotene + Zinc 120 Vitamin C + Vitamin E + Beta-Carotene 121 Vitamin C + Vitamin E + Beta-Carotene + Zinc 122 Vitamin C + Vitamin E + Selenium 123 Vitamin D + Calcium + Vitamin K + Omega-3 Fatty Acids 124 Vitamin D + Calcium + Vitamin K + Omega-3 Fatty Acids + Magnesium 125 Vitamin D + Calcium + Vitamin K + Omega-3 Fatty Acids + Zinc 126 Vitamin D + Calcium + Vitamin K + Omega-3 Fatty Acids + Biotin 127 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Selenium 128 Vitamin E + Vitamin A + Vitamin C + Zinc 129 Vitamin E + Vitamin A + Vitamin C + Selenium 130 Vitamin E + Vitamin A + Vitamin C + Biotin 131 Vitamin E + Vitamin A + Vitamin C + Folic Acid + Niacinamide 132 Vitamin E + Vitamin C + Beta-Carotene + Zinc 133 Vitamin C + Vitamin E + Biotin + Folic Acid 134 Vitamin C + Vitamin E + Beta-Carotene + Folic Acid 135 Vitamin C + Vitamin E + Beta-Carotene + Selenium 136 Vitamin E + Vitamin C + Beta-Carotene + Biotin 137 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Biotin 138 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Selenium 139 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Vitamin B12 140 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Vitamin B6 141 Vitamin D + Calcium + Omega-3 Fatty Acids + Vitamin K + Folate 142 Calcium + Vitamin D + Magnesium + Vitamin K + Omega-3 Fatty Acids 143 Calcium + Vitamin D + Magnesium + Vitamin K + Biotin 144 Calcium + Vitamin D + Magnesium + Vitamin K + Selenium 145 Calcium + Vitamin D + Magnesium + Vitamin K + Vitamin B12 146 Calcium + Vitamin D + Magnesium + Vitamin K + Folate 147 Calcium + Vitamin D + Vitamin K + Omega-3 Fatty Acids + Vitamin B6 148 Calcium + Vitamin D + Vitamin K + Omega-3 Fatty Acids + Vitamin B12 149 Calcium + Vitamin D + Vitamin K + Omega-3 Fatty Acids + Folic Acid 150 Calcium + Vitamin D + Vitamin K + Omega-3 Fatty Acids + Biotin 151 Calcium + Vitamin D + Vitamin K + Omega-3 Fatty Acids + Selenium 152 Vitamin A + Vitamin C + Vitamin E + Omega-3 Fatty Acids 153 Vitamin A + Vitamin C + Vitamin E + Omega-3 Fatty Acids + Zinc 154 Vitamin A + Vitamin C + Vitamin E + Omega-3 Fatty Acids + Biotin 155 Vitamin A + Vitamin C + Vitamin E + Omega-3 Fatty Acids + Selenium 156 Vitamin A + Vitamin C + Vitamin E + Omega-3 Fatty Acids + Vitamin B12

Drug Approval

21 Aug 2023

·synapse.patsnap.com

Progress in the Research and Development of METTL3 Drug Targets

METTL3 is an RNA methyltransferase that catalyzes the methylation of RNA at N6-adenosine, making it a key player in this process. Abnormal expression of METTL3 can lead to various diseases, including cancer, cardiovascular disorders, and neurodegenerative diseases. Therefore, finding inhibitors of METTL3 could help further our understanding of the biological functions of this enzyme and aid in the development of new treatments. N6-methyladenosine (m6A) is one of the most common and abundant covalent modifications in messenger RNA. First discovered in bacterial and eukaryotic RNA back in 1958, approximately 0.1% to 0.5% of mRNA adenines are modified by m6A. In vitro data suggests that m6A modifications affect fundamental biological processes of mRNA, including expression, splicing, localization, and translation. The occurrence of m6A modifications demonstrates tissue specificity, with significant variations observed between healthy and diseased tissues. Timeline of m6A Discovery The METTL3, an RNA methyltransferase, is one of the primary enzymes catalyzing m6A modification of RNA, but not the only one. It coexists with METTL14 and Wilms Tumor 1 Associated Protein (WTAP) in the form of a heterotrimeric complex. METTL3 possesses catalytic activity, transferring methyl groups from cofactor S-adenosylmethionine to substrate RNA, while METTL14 facilitates the binding of the substrate RNA. WTAP locates the complex at a specific nuclear region and positions the RNA substrate onto the complex. METTL3 plays roles in various aspects of cancer development. Knocking out the METTL3 gene in lung cancer cell lines and Hela cells results in decreased growth, survival, and invasion of human lung cancer cells. In human bladder, the expression of METTL3 is significantly upregulated, and the knockout of METTL3 significantly reduces the proliferation, invasion, in vitro survival, and in vivo tumorigenicity of bladder cancer cells. Competitive Landscape By entering "Mettl3" into the Synapse database, the clinically relevant molecule STC-15 can be found. In addition, a batch of molecules is in the preclinical research stage, including SAM binding pocket inhibitors, conformation inhibitors, natural products, and adenine analogs. According to a review summarized by Professor Qidong You in "Drug Discovery Today", the binding pattern of METTL3-METTL14 with inhibitors can be divided into three parts: part A is the aromatic ring, part B is the connecting chain, part C is the amino hydrophobic chain. Furthermore, the available cocrystal structures of METTL3-METTL14 and its inhibitors can help rationally design new molecules. To achieve this goal, analyzing the cocrystal structures of METTL3-METTL14 and conformation inhibitors will provide new ways for the development of new tools and potential drugs. Accent Therapeutics, which is in the same field, was established in 2017 and has attracted attention from several capitals, and has had strong development momentum in recent years. The company announced in April 2020 that it completed a $63 million B round of financing to advance new precise cancer treatments for RNA modification proteins (including METTL3 and ADAR1). At present, the company has received more than $100 million in financing. In June of the same year, Accent announced a partnership with pharmaceutical giant AstraZeneca. Key DrugSTM2457 is the first METTL3 class small molecule inhibitor developed by the UK pharmaceutical company STORM THERAPEUTICS. Unlike other RNA methyltransferases, STM2457 has high specificity for METTL3 (IC50=51.7 μM). It can induce apoptosis in cells of AML patients and mouse AML models, but it does not induce apoptosis in normal non-leukemic hematopoietic cells. After treatment, it can reduce the number of human CD45 cells in the bone marrow and spleen of mice. STORM THERAPEUTICS had raised £30 million in its Series A financing and began human clinical trials for the latest generation METTL3 inhibitor, STC-15, on November 15, 2022. The study's indication is for advanced solid tumors. This study is a phase I, multi-center, open-label study with a 3+3 cohort design, expecting to recruit 66 patients. The aim is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of STC-15 in multiple escalating daily oral doses in the Q3W treatment cycle, with dose levels determined by the modified Fibonacci algorithm. The study aims to systematically assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of STC-15 in adult patients with advanced malignant tumors. The dose levels further evaluated in the expanded cohort will be selected based on available PK, pharmacodynamics, target activity, efficacy, safety, and tolerability data, including long-term safety data beyond Dose Limiting Toxicity (DLT). As METTL3 is a SAM-dependent methyltransferase, the earliest prototypes of METTL3 inhibitors were structural analogues of SAM. We are still in the early stage of discovering potent and selective METTL3 inhibitors, and many biological questions about the mechanism and function of the METTL3-METTL14 complex remain unanswered. STC-15 is the only drug that has entered the clinical stage. Interruption of METTL3-METTL14 activity could potentially lead to damage to fundamental physiological processes, resulting in harmful outcomes. To thoroughly validate METTL3-METTL14 as a manageable drug target, a multi-disciplinary approach is required to further elucidate its biological function in a broader context of epitranscriptomics.

03 Apr 2023

·www.eisai.com

EISAI ENTERS INTO AGREEMENT WITH NATIONAL CANCER CENTER TO COLLABORATE ON INVESTIGATOR-INITIATED CLINICAL RESEARCH FOR ANTICANCER AGENT TAZEMETOSTAT BASED ON “PATIENT-PROPOSED HEALTHCARE SERVICES” SYSTEM

For Print（180KB） April 3, 2023 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that it has entered into an agreement with the National Cancer Center to collaborate on investigator-initiated clinical research for the EZH2 inhibitor tazemetostat hydrobromide (generic name, product name “Tazverik® Tablets 200 mg”, “tazemetostat”) based on “Patient-Proposed Healthcare Services” system. This clinical research will be conducted by the National Cancer Center Hospital. The “Patient-Proposed Healthcare Services” system is a system under which medical treatment using unapproved drugs not covered by insurance is applied for to the government based on the patient's request, and is conducted as a clinical trial to confirm safety and efficacy. Under the terms of the agreement, Eisai will provide tazemetostat free of charge to the National Cancer Center Hospital as the drug to be used in “A clinical trial of Tazemetostat for pediatric and AYA* patients with malignant tumors which have no standard of care or and which is refractory to standard of care: Patients-Proposed Healthcare Service” to be conducted by the hospital under this program. Researched and developed by Eisai and Epizyme, Inc.,** an Ipsen (Headquarters: France) company, tazemetostat is a first-in-class, oral small molecule inhibitor of the epigenetic enzyme EZH2. It is one of the histone methyltransferases in the epigenetics-related protein group, and is thought to regulate the expression of cancer-related genes and suppress the growth of cancer cells by specifically targeting EZH2, which contributes to the cancer growth process.1 Eisai holds the rights for development and commercialization of tazemetostat in Japan, where it was approved for the indication of “relapsed or refractory EZH2 gene mutation-positive follicular lymphoma (only when standard treatment is not applicable)” in 2021, and manufactures and distributes the product. Eisai positions oncology as a key franchise area and aims to create innovative drugs that act towards curing cancer. Eisai is committed to expanding the potential clinical benefits of tazemetostat for cancer treatment, as it seeks to contribute to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families and healthcare professionals. * AYA (Adolescent & Young Adult): Patients between the ages of 15 and 39. ** Acquired by Ipsen in 2022 Media Inquiries: Public Relations Department, Eisai Co., Ltd. +81-(0)3-3817-5120 [Notes to editors] 1. About the “Patient-Proposed Healthcare Services” system The “Patient-Proposed Healthcare Services” system is a system that allows patients who wish to use unapproved drugs and other medications as uninsured treatment to do so promptly, based on the patient's request, while confirming the safety and efficacy of the drug and allowing access to the unapproved drugs at medical institutions close by. The objective is to accumulate data and scientific evidence for future insurance coverage. Ministry of Health, Labour and Welfare “Patient-Proposed Healthcare Services” (Moushide Ryouyou) System: https://www.mhlw.go.jp/moushideryouyou/ (Japanese only) 2. About tazemetostat hydrobromide (generic name, product name “Tazverik® Tablets 200 mg”) Tazemetostat is a first-in-class, oral small molecule inhibitor that targets EZH2 that was jointly researched and developed under the alliance agreement between Eisai and Epizyme, Inc., an Ipsen company, utilizing Epizyme, Inc.'s proprietary product platform. This agent selectively inhibits EZH2 in a competitive matter with S-adenosylmethionine (a methyl group donor) to suppress methylation of H3K27.1 Eisai is responsible for development and commercialization of this agent in Japan, where the drug was approved in June 2021 for the indication of “relapsed or refractory EZH2 gene mutation-positive follicular lymphoma (only when standard treatment is not applicable)”. Ipsen is responsible for the development and commercialization of this agent in the United States, where accelerated approval was granted for in January 2020 with the indication of “adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection”. In June of the same year, the accelerated approval was granted for this agent with the indication of “adult relapsed / refractory follicular lymphoma who had at least 2 regimens of prior treatment and whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test”, and of “adult relapsed / refractory follicular lymphoma for which there are no satisfactory alternative treatment options”. This agent is not approved outside of Japan and the United States. 3. About epigenetics Epigenetics is a branch of science that studies the mechanism for the acquired activation/inactivation of gene function and seeks to determine how gene function is inherited through cell division, irrespective of DNA base sequence alteration. Examples of modification that lead to the regulation of gene expression include methylation of DNA and modifications of histone (methylation, acetylation, phosphorylation, etc.). 4. About EZH2 EZH2 is one of the histone methyltransferases within a larger class of epigenetics-related proteins, and specifically catalyzes the methylation of histone H3 at lysine 27 (H3K27), thus controlling expression of various genes. It is indicated that an increase in methylation of H3K27 caused by EZH2 gain-of-function mutation, overexpression, or the dysfunction of the SWI/SNF (switch/sucrose non-fermenting) complex that reportedly inhibits EZH2 methylation activity, plays an important role in carcinogenesis.1 1 Sarah K. Knutson, Satoshi Kawano, Yukinori Minoshima, et al. Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma. Molecular Cancer Therapeutics. 2014 Apr; 13(4):842–854

License out/inDrug ApprovalAccelerated ApprovalClinical StudyAcquisition

100 Deals associated with Ademetionine 1,4-Butanedisulfonate

External Link

KEGG	Wiki	ATC	Drug Bank
-	Ademetionine 1,4-Butanedisulfonate	A16AA02	DB00118

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Liver Cirrhosis, Biliary	China	Abbott Laboratories	02 Nov 2000
Cholestasis	Italy	Abbott Laboratories	01 Jan 1975

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cholestasis, Intrahepatic	Phase 3	Russia	Abbott Laboratories	01 Jun 2014
Nonalcoholic Steatohepatitis	Phase 3	France	Abbott Laboratories	01 Dec 2012
Nonalcoholic Steatohepatitis	Phase 3	Germany	Abbott Laboratories	01 Dec 2012
Nonalcoholic Steatohepatitis	Phase 3	Poland	Abbott Laboratories	01 Dec 2012
Nonalcoholic Steatohepatitis	Phase 3	Russia	Abbott Laboratories	01 Dec 2012
Liver Diseases, Alcoholic	Phase 3	United States	Abbott Laboratories	01 Sep 2005
disorder of aging	Preclinical	China	Qingdao University	01 Mar 2024
Depressive Disorder	Preclinical	United States	Meharry Medical College	13 Oct 2012

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


UEGW2023	Not Applicable	Lymphoproliferative Disorders	-	S-Ademetionine (Patients with CLPD receiving only CT)	xqajlhohsp(oiiqpulxki) = shimgcujqg rohdkvuboy (gprytaczyp )	-	15 Oct 2023
				Patients with CLPD receiving S-ademetionine	xqajlhohsp(oiiqpulxki) = axsrlfwkqd rohdkvuboy (gprytaczyp )
NCT04623034 (Pubmed \| BMC Pharmacol Toxicol)	Phase 1	-	34	MSI-195	nfpjdtjljm(qyrkclprho) = hivcpzbnsq qyqortpimm (mjzjezdqys )	-	14 Dec 2020
UEGW2019	Not Applicable	Colorectal Cancer	-	S-adenosylmethionine (SAM) 0 mmol/l	xpemotizsa(xnmaozwiab) = xdrtwsaoep yeaqlbbwlv (ismhrizpec )	-	01 Oct 2019
				S-adenosylmethionine (SAM) 0.5 mmol/l	xpemotizsa(xnmaozwiab) = peheeiyume yeaqlbbwlv (ismhrizpec )
NCT00513461 (CTgov)	Phase 2	Hepatocellular Carcinoma \| Hepatitis C	110	immunoenzyme technique+S-adenosyl-L-methionine disulfate p-toluene-sulfonate (Arm I (SAMe))	drehguslry(csumzdplpr) = eniwwtsjos ybpoiaqghl (zhjabszrsh, 20.304) View more	-	10 Aug 2018
				placebo (Arm II (Placebo))	drehguslry(csumzdplpr) = nzkkcgbntb ybpoiaqghl (zhjabszrsh, 29.207) View more
NCT00070941 (CTgov)	Phase 2/3	Parkinson Disease	29	SAM-e (SAM-e)	iowfnmcocc(edhykbtcrz) = vmbmxzqmjs cudnmjkuhl (zrwdjruwkl, 4.8) View more	-	13 Jul 2016
				oral escitalopram (Escitalopram)	iowfnmcocc(edhykbtcrz) = psftksyfxb cudnmjkuhl (zrwdjruwkl, 5.4) View more
NCT00093847 (CTgov)	Phase 2	Depressive Disorder, Treatment-Resistant	73	SAMe Tosylate (Adjunct Oral SAMe Tosylate 800mg PO BiD)	vptrcagwep = arbkmwgswd dqggckxvdx (gzlbygwaqi, stodpqugur - aorarpgwjb) View more	-	13 Oct 2014
				placebo (Oral Adjunct Placebo)	vptrcagwep = loczzysnpx dqggckxvdx (gzlbygwaqi, ipjwpugfwc - zmsjirbvat) View more
AACR2014	Phase 2	Liver Cirrhosis	110	SAMe	gjgcjfovte(mnttuxoxmv) = ylimmypgcw mkkbonxvne (rxcwrqkbtn )	Negative	01 Oct 2014
				Placebo	gjgcjfovte(mnttuxoxmv) = enewhdpfku mkkbonxvne (rxcwrqkbtn )
NCT00762268 (CTgov)	Not Applicable	Bipolar Disorder	23	SAMe (SAMe)	omtglffgpq(xwflngmgvr) = txwuczigav qoyxrswkhn (wdctrwdxwx, dezcdffefj - slhesvotko) View more	-	26 Aug 2014
				Placebo (Placebo)	omtglffgpq(xwflngmgvr) = jbqomsmnhq qoyxrswkhn (wdctrwdxwx, vhnadolsbf - gquvegskah) View more
NCT01140646 (SAMe, CTgov)	Phase 2	Hot Flashes	45	s-adenosyl-L-methionine	vtxljwglfz(eurpcrkhut) = yohurnwdqz scfhepmrnr (npyfdlwjak, jpszryyvzi - hjeqvqklum) View more	-	11 Apr 2014
NCT00694564 (CTgov)	Not Applicable	Abdominal Pain	8	S-adenosyl methionine (SAM-e)	skpciaqvea(xsxzyvoasz) = pxpfrnlfsd nknvldhkri (dyrflndqhb, 0) View more	-	13 Sep 2013
				Sam-e (Sam-e (Treatment))	liktpsltmz(mnhecklemm) = bxrtedmzdw nhbpbrqfjn (crsvshdvwf, dxcxyetgbg - yevqdaobog) View more

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