A Single-center, Phase II Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Effect of S-adenosyl-L-methionine (SAMe) in Prevention of Hepatocellular Carcinoma Among Patients With Metabolic Dysfunction-associated Steatotic Liver Diseases (MASLD)-Related Cirrhosis

This study will evaluate the safety, feasibility, and preliminary effects of S-adenosyl-L-methionine (SAMe) compared with placebo in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis. Investigators will assess whether treatment is associated with changes in liver-related clinical measures, biologic markers, and other study outcomes relevant to disease progression. The goal of this study is to generate early data to determine whether SAMe should be studied further as a potential therapeutic strategy in patients with MASLD cirrhosis.

Start Date15 Apr 2026

Sponsor / Collaborator

Cedars-Sinai Medical Center

NCT07453472

/ Not yet recruitingPhase 3

Comparative Evaluation of the Effect of Topical Photodynamic Therapy Versus Topical Calcipotriol on the Clinical and Molecular Characteristics of Oral Leukoplakia: a Randomized Clinical Trial

(i)Rationale/ gaps in existing knowledge,: Oral cancer, one of the top three common cancers in India is usually preceded by Oral potentially malignant disorders in nearly two thirds of the cases like Oral leukoplakia. OL has a high prevalence and malignant transformation rates(0.13% - 40.8%). There are no universal protocols for management in OL ranging from preventive, conservative, medical and surgical interventions. They all have limitations and high recurrence rates requiring regular follow up.
(ii)Novelty: Removal of pathological lesions are believed to reduce the risk of malignant transformation in OL. Surgical methods are associated with morbidity and high recurrence rates. Non -invasive methods (like Photodynamic therapy) that can remove the abnormal lesions would be preferred as they are cheaper, convenient, safe with less morbidity and better patient acceptability. They also have the advantage of repeatability with minimum morbidity and damage to adjacent normal tissues. Non -invasive medical management involves topical application of retinoids which are associated with systemic toxicity, recurrence and development of resistance.
(iii)Objectives,
Primary objective:
To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy and topical calcipotriol (0.005%) on clinical response after completion of treatment at 4 weeks from baseline during management of Oral leukoplakia
Secondary objectives:
To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy with topical Calcipotriol (0.005%) on lesion size, lesion roughness/ whiteness, and oral health quality of life after completion of treatment at 4 weeks and 12 weeks from baseline during management of Oral leukoplakia To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy with topical Calcipotriol (0.005%) on salivary molecular markers ( IL6, TNF-α, PCNA, Survivin and VEGF) after completion of treatment at 4 weeks from baseline To compare the adverse events, time to complete response and recurrence rates between the two groups
(iv)Methods,: An open label randomized clinical trial where Group A (n=83) will receive 4 sessions of Toludine blue mediated photodynamic therapy (Fluence 15J/cm2); GroupB (n=83) will receive twice daily tropical application of Calcipotriol (0.005%) over a period of 4 weeks. The clinical response, lesion thickness/ whiteness, lesion size /area, OHIP-14 scores, adverse events and recurrence rates will be compared with baseline at 4 weeks and 12 weeks after completion of therapy. Sterile PVA ophthalmic sponges will be used to evaluate molecular markers ( IL6, TNF-α, PCNA, Survivin VEGF) from treatment site of lesion at baseline and 4 weeks after completion of treatment by ELISA. The data will be analyzed statistically using Intention to treat and as per protocol analysis at significance levels of p<0.05.
(v)Expected outcome.: The study will validate and verify the effectiveness of the TB mediated PDT protocol in the management of OL as compared to other non invasive method of topical Calcipotriol in terms of clinical response ( complete/ partial/ none), lesion thickness/ whiteness, lesion size and it's effect on oral health quality of life. Adverse events if any and recurrence rates or malignant transformation rates will also help in assessment of safety of the protocol. The molecular markers will help to monitor and determine prognosis of the lessons following treatment.

Start Date01 Apr 2026

Sponsor / Collaborator

All India Institute of Medical Sciences

[+1]

ChiCTR2600119242

/ Not yet recruitingNot ApplicableIIT

Nerve Block-Based Opioid-Free Anesthesia versus Low-Dose Opioids in Laparoscopic Cholecystectomy: A Randomized Controlled Trial

Start Date01 Mar 2026

Sponsor / Collaborator

Chongqing Dazu District People's Hospital

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

9,318

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

01 Jul 2026·BRAIN BEHAVIOR AND IMMUNITY

Neonatal inflammation induces ventral hippocampal microglial priming via epigenetic regulation of BAG3 to enhance adult depression susceptibility in mice

Article

Author: Yao, Jun ; Zhu, Yichao ; Rong, Jing ; Zhou, Rong ; Yang, Yang ; Sha, Sha ; Du, Jun ; Zhang, Yujie ; Wang, Xiaoli

BACKGROUND:

Neonatal inflammation increases the risk of adult depression, but the mechanisms remain unclear. Under the two-hit hypothesis, early-life inflammation may enhance vulnerability to later-life stress. Whether neonatal inflammation induces depression susceptibility via microglial priming, and the molecular basis of this process, remain unknown.

METHODS:

Neonatal mice (postnatal day 4) received intraperitoneal injections of lipopolysaccharide (LPS; 10, 50, or 100 μg/kg) or saline. In adulthood, mice were exposed to a subthreshold 2-week chronic unpredictable mild stress (CUMS) paradigm. Depression-like behaviors, microglial priming, molecular alterations, and DNA methylation were assessed. Genetic (Bag3 knockout) and pharmacological (minocycline; S-adenosylmethionine, SAM) interventions were applied.

RESULTS:

Neonatal exposure to a moderate dose of LPS (50 μg/kg), but not lower or higher doses, selectively increased susceptibility to adult depression-like behaviors and induced microglial priming in the ventral hippocampus (vHPC). Subthreshold CUMS alone failed to induce microglial activation or depressive phenotypes, but robustly activated primed vHPC microglia, triggered neuroinflammation, and precipitated depressive-like behaviors in neonatally LPS-exposed mice; these effects were fully reversed by minocycline. Neonatal moderate LPS induced sustained BAG3 upregulation in the vHPC. Genetic deletion of Bag3 abolished microglial priming and depression susceptibility. At the epigenetic level, neonatal moderate LPS caused persistent hypomethylation of the Bag3 promoter, which was reversed by SAM supplementation.

CONCLUSION:

Moderate neonatal inflammation establishes a BAG3-dependent microglial primed state in the vHPC via persistent epigenetic remodeling, thereby enhancing vulnerability to adult stress-induced depression. These findings identify BAG3-centered epigenetic-microglial crosstalk as a critical mechanistic hub linking early-life inflammation to later depression susceptibility.

01 Apr 2026·JOURNAL OF MOLECULAR BIOLOGY

Importance of Riboswitch-regulated Genes for Pseudomonas aeruginosa

Article

Author: Côté, Jean-Philippe ; Jahangirnejad, Shirin ; Lafontaine, Daniel A

Riboswitches offer a promising avenue as targets for the development of novel bacterial antibiotics. For this approach to work, it requires that target riboswitches control the expression of essential genes for bacterial survival. However, the small number of essential riboswitch-regulated genes restrains the output of viable novel antimicrobial agents. Here, in an effort to increase the number of riboswitch potential targets, we have assessed the essentiality of Pseudomonas aeruginosa riboswitch-controlled genes in nutrient-limited growth conditions. Using a P. aeruginosa library containing inactivating transposons in riboswitch-controlled genes, we find that the majority of these genes are not required for growth in any tested conditions. However, we find that the inactivation of the S-adenosyl-homocysteine (SAH) hydrolase gene results in the complete lack of P. aeruginosa growth in nutrient-limited conditions. Importantly, bacterial growth is rescued when supplementing S-adenosyl-methionine, which is the precursor of SAH in catalyzed methylation processes. RT-qPCR assays show that although the SAH riboswitch is predicted to control translation initiation, mRNA levels are increased in the presence of SAH, suggesting an additional level of control. Lastly, in vitro structural analyses indicate that the riboswitch undergoes significant rearrangement upon SAH binding and exhibits an affinity toward SAH in the micromolar range. Together, our results provide an approach to discover novel riboswitch targets in nutrient-limited growth conditions and suggest that the SAH-sensing riboswitch constitutes a potential target to inhibit the growth of P. aeruginosa.

01 Apr 2026·VIRUS RESEARCH

Identification of key genes modules linking brain aging signatures and COVID-19-associated cognitive impairment

Article

Author: Wang, Ben ; Zhao, Yunfeng ; Wu, Xueling ; Xie, Cuiying ; Chen, Jiajun ; He, Teng

BACKGROUND:

Emerging evidence indicates that SARS-CoV-2 infection is associated with aging, particularly in memory-related domains. However, the molecular mechanisms underlying COVID-19-associated aging, often referred to as "brain fog," remain poorly understood. This study aimed to identify key genes implicated in post-COVID cognitive dysfunction.

METHODS:

Transcriptomic data from the frontal cortex, obtained from the GEO dataset GSE188847 and GSE164332, were analyzed using differential expression analysis to identify differentially expressed genes (DEGs) associated with brain fog. Functional enrichment analysis was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Machine learning techniques, including LASSO regression and weighted gene co-expression network analysis (WGCNA), were employed to identify hub genes. Drug-gene interactions were explored using the Comparative Toxicogenomics Database (CTD).

RESULTS:

A total of 81 up-regulated and 441 down-regulated DEGs were identified in COVID-19 patients compared to controls. Up-regulated genes were primarily enriched in pathways related to pulmonary fibrosis and immune activation (e.g., IL-17 signaling), while down-regulated genes were associated with synaptic transmission (e.g., GABAergic synapse, adjusted p = 0.003). Integration of LASSO and WGCNA analyses revealed five aging-related hub genes: SST, S100A9, SOCS3, FKBP5, and HBB. Notably, SST expression was significantly reduced, whereas the other four genes showed marked upregulation. CTD analysis identified seven potential therapeutic agents: fulvestrant, bucladesine, S-adenosylmethionine, valproic acid, folic acid, kaempferol, and quercetin.

CONCLUSIONS:

This study employed transcriptomic analysis and bioinformatics approaches to identify five key aging-related genes associated with COVID-19. These genes may serve as potential therapeutic targets for addressing COVID-19-associated aging.

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

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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
Metabolic Dysfunction Associated Steatohepatitis	Phase 3	France	Abbott Laboratories	01 Dec 2012
Metabolic Dysfunction Associated Steatohepatitis	Phase 3	Germany	Abbott Laboratories	01 Dec 2012
Metabolic Dysfunction Associated Steatohepatitis	Phase 3	Poland	Abbott Laboratories	01 Dec 2012
Metabolic Dysfunction Associated 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


NCT04623034 (Pubmed \| BMC Pharmacol Toxicol)	Phase 1	-	34	MSI-195	ookogvzojn(cuvqibhirp) = wuyylujoyq xbrjlkxbur (cbkxkuqqrz )	-	14 Dec 2020
NCT00769002 (Pro00000226, CTgov)	Not Applicable	Influenza, Human	18	Influenza Vaccine (Influenza Vaccine FluShield, FluMist)	mfjbvbapvs(xnviqlwnol) = ogzpmhkbxi bvjymppzfh (muvlkyebrn, xcbasehoni - dtuwjhuciz) View more	-	19 Oct 2020
				flu vaccine (Cytokine Profiling FluShield, FluMist)	mfjbvbapvs(xnviqlwnol) = xvjuzulxer bvjymppzfh (muvlkyebrn, ezqzpetpsc - ipayedlfbr) View more
NCT00513461 (CTgov)	Phase 2	Hepatocellular Carcinoma \| Hepatitis C, Chronic	110	immunoenzyme technique+S-adenosyl-L-methionine disulfate p-toluene-sulfonate (Arm I (SAMe))	bymcoktrrb(vkxzkscdvg) = fbrddogrwf vpzzriwjqb (awdvvqjbxg, 20.304) View more	-	10 Aug 2018
				placebo (Arm II (Placebo))	bymcoktrrb(vkxzkscdvg) = cchmztwrax vpzzriwjqb (awdvvqjbxg, 29.207) View more
NCT00070941 (CTgov)	Phase 2/3	Parkinson Disease	29	SAM-e (SAM-e)	rvltechkov(ujfnsuivgw) = dukyjhsuwm ozkzlzdopg (iqqugudmgu, 4.8) View more	-	13 Jul 2016
				oral escitalopram (Escitalopram)	rvltechkov(ujfnsuivgw) = xxigadmlaz ozkzlzdopg (iqqugudmgu, 5.4) View more
NCT00093847 (CTgov)	Phase 2	Depressive Disorder, Treatment-Resistant	73	SAMe Tosylate (Adjunct Oral SAMe Tosylate 800mg PO BiD)	zcbhlsdgdd = msevkifcnc ufswvrewfn (bsvqrpaeoo, yjhymvcxak - qlvczdubat) View more	-	13 Oct 2014
				placebo (Oral Adjunct Placebo)	zcbhlsdgdd = nvpkmfldgw ufswvrewfn (bsvqrpaeoo, ixzmbacryq - medjgqvbuo) View more
AACR2014	Phase 2	Liver Cirrhosis	110	SAMe	frgcnuwfng(ixbjorvlwr) = mwdjmeflwi rutbhxbmca (luykimvidt )	Negative	01 Oct 2014
				Placebo	frgcnuwfng(ixbjorvlwr) = wnywerzijb rutbhxbmca (luykimvidt )
NCT00762268 (CTgov)	Not Applicable	Bipolar Disorder	23	SAMe (SAMe)	zlwhdravyp(cbaoqfbnmv) = phzbzowkvc gbuevrotua (vtkdhlgnpj, seyjrbpdvl - wrfsreddis) View more	-	26 Aug 2014
				Placebo (Placebo)	zlwhdravyp(cbaoqfbnmv) = myblinuhsj gbuevrotua (vtkdhlgnpj, spfxgloccu - fwligcbmau) View more
NCT01140646 (SAMe, CTgov)	Phase 2	Hot Flashes	45	s-adenosyl-L-methionine	qoesaqxrac(pzqizoujuw) = yeiwdvinnt rbvjlwghqr (tfbwffbhxm, vqckaxnmrc - xdzecedzme) View more	-	11 Apr 2014
NCT00694564 (CTgov)	Not Applicable	Abdominal Pain	8	S-adenosyl methionine (SAM-e)	zjulfjwgnp(vjhfzmgldp) = seharrgtap xziuizsppq (grgdfyhtvy, 0) View more	-	13 Sep 2013
				Sam-e (Sam-e (Treatment))	eqqauiagrb(mbnpwklnih) = hpiobogdyn uibqkcaoer (wvvbscbmgj, qhatnxnqdc - wnluvlgqte) View more
NCT00573313 (CTgov)	Phase 3	Liver Diseases, Alcoholic	94	S-adenosylmethionine (S-adenosylmethionine (SAMe))	owyqrxdjyw(oxyyjpewtp) = tyayrnizdq oimxucpazs (lqkmvxnpdg, lamuxddmyk - lxomwbgqvg) View more	-	10 Jun 2013
				Placebo (Sugar Pill)	owyqrxdjyw(oxyyjpewtp) = xaklfbmjnp oimxucpazs (lqkmvxnpdg, qepbcaqumt - ncjynvzdin) View more

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