clemizole / Eiger - LARVOL DELTA

CLEAN-1: Safety and Tolerability Study of Clemizole Hydrochloride to Treat Hepatitis C in Subjects Who Are Treatment-Naive (clinicaltrials.gov) - P1b; N=12; Completed; Sponsor: Eiger BioPharmaceuticals; Phase classification: P1 ➔ P1b

Phase classification • Hepatitis C • Hepatology • Infectious Disease

Clemizole HCl for Subjects With Hepatocellular Carcinoma (clinicaltrials.gov) - P2a; N=12; Enrolling by invitation; Sponsor: Eiger Group International, Inc.

Clinical • New P2a trial • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • Transplantation • AFP

Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. (PubMed, Elife) - "These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a non-conductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5."

Journal • CNS Disorders • Depression • Mood Disorders • Nephrology • Psychiatry • Renal Disease

Synthesis and therapeutic potential of imidazole containing compounds. (PubMed, BMC Chem) - "The derivatives of 1, 3-diazole show different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities, etc. as reported in the literature. There are different examples of commercially available drugs in the market which contains 1, 3-diazole ring such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), astemizole (antihistaminic agent), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal), metronidazole, nitroso-imidazole (bactericidal), megazol (trypanocidal), azathioprine (anti rheumatoid arthritis), dacarbazine (Hodgkin's disease), tinidazole, ornidazole (antiprotozoal and antibacterial), etc. This present review summarized some pharmacological activities and various kinds of synthetic routes for imidazole and their..."

Journal • Review • Immunology • Inflammatory Arthritis • Oncology • Pain • Rheumatoid Arthritis • Rheumatology

Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome. (PubMed, Expert Opin Drug Discov) - "Experimental data and results from initial clinical studies have brought attention to several drugs with various mechanisms of action including: ataluren (a suppressant of premature stop codons; under clinical evaluation), EPX-100, EPX-200, fenfluramine (serotonin modulators), soticlestat (an 24-hydroxylase cholesterol enzyme inhibitor), SPN-817 (an inhibitor of acetylcholinesterase), verapamil (a voltage-dependent calcium channel inhibitor) and STK-001 (an antisense oligonucleotide). The latter is scheduled for clinical evaluation."

Journal • CNS Disorders • Epilepsy

Therapeutic advances in Dravet syndrome: a targeted literature review. (PubMed, Expert Rev Neurother) - "Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs."

Journal • CNS Disorders • Epilepsy • Gene Therapies • Rare Diseases

A Trial of EPX-100 (Clemizole Hydrochloride) as an Add-on Therapy in Children With Dravet Syndrome (clinicaltrials.gov) - P2; N=24; Recruiting; Sponsor: Epygenix; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Network analysis, sequence and structure dynamics of key proteins of coronavirus and human host, and molecular docking of selected phytochemicals of nine medicinal plants. (PubMed, J Biomol Struct Dyn) - "Among the predicted drugs compounds, clemizole, monorden, spironolactone and tanespimycin showed high binding energies; among the studied repurposing compounds, remdesivir, simeprevir and valinomycin showed high binding energies; among the predicted acidic compounds, acetylursolic acid and hardwickiic acid gave high binding energies; while among the studied anthraquinones and glycosides compounds, ellagitannin and friedelanone showed high binding energies against 3-Chymotrypsin-like protease (3CL), Papain-like protease (PL), helicase (nsp13), RNA-dependent RNA polymerase (nsp12), 2'-O-ribose methyltransferase (nsp16) of SARS-CoV-2 and DNA-PK and CK2alpha in human. Finally, medicinal plants with phytochemicals such as caffeine, ellagic acid, quercetin and their derivatives could possibly remediate COVID-19. Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Novel Coronavirus Disease

A Phase II Trial of EPX-100 (Clemizole HCl) as Adjunctive Therapy in Children With Dravet Syndrome (clinicaltrials.gov) - P2; N=24; Not yet recruiting; Sponsor: Epygenix

Clinical • New P2 trial

Critical Components for Spontaneous Activity and Rhythm Generation in Spinal Cord Circuits in Culture. (PubMed, Front Cell Neurosci) - "Such intrinsic activity was completely blocked at all electrodes by both the I blocker riluzole as well as by the I blocker flufenamic acid (FFA) and the more specific TRPM4 channel antagonist 9-phenanthrol...Other antagonists of unspecific cation currents or calcium currents had no suppressing effects on either intrinsic activity (gadolinium chloride) or spontaneous bursting (the TRPC channel antagonists clemizole and ML204 and the T channel antagonist TTA-P2). Combined patch-clamp and MEA recordings showed that Hb9 interneurons were activated by network bursts but could not initiate them. Together these findings suggest that both I through Na-channels and I through putative TRPM4 channels contribute to spontaneous intrinsic and repetitive spiking in spinal cord neurons and thereby to the generation of network bursts."

Journal • Preclinical

Changing Landscape of Dravet Syndrome Management: An Overview. (PubMed, Neuropediatrics) - "Clobazam, valproate, levetiracetam, topiramate, zonisamide, ketogenic diet, and vagus nerve stimulation had been shown to be effective, but even with polytherapy, only 10% of patients get adequate seizure control...In recent years, the treatment paradigm of DS is changing with the approval of pharmaceutical-grade cannabidiol oil and stiripentol...Several agents targeted for DS are in the developmental stage: TAK935, lorcaserin, clemizole, huperzine analog, ataluren, selective sodium channel modulators and activators, antisense oligonucleotide therapy, and adenoviral vector therapy. As DS is associated with a high risk of sudden unexpected death in epilepsy, seizure detection devices can be used in this population for testing and clinical validation of these devices."

Journal

Study of Safety and Pharmacokinetics of Oral Doses of EPX-100 in Healthy Subjects. (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Epygenix; Recruiting ➔ Completed

Clinical • Trial completion

Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells. (PubMed, Cells) - "The application of the TRPC4 blocker ML204, TRPC5 blocker clemizole hydrochloride, and TRPC4 and 5 blocker Pico145, all significantly inhibited persistent firing...Taken together these results indicate that TRPC4 and 5 channels support persistent firing in CA1 pyramidal neurons. Finally, we discuss possible scenarios causing these controversial observations on the role of TRPC channels in persistent firing."

Journal

Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors. (PubMed, Eur J Med Chem) - "To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC HO-1 >100 μM, IC HO-2 = 3.4 μM), while the HO-2 nonselective inhibitors described herein possess IC HO-2 values ≤ 10 μM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target."

Journal • Review

Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome. (PubMed, Brain Commun) - "Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs."

Journal

Muscarinic receptor-induced contractions of the detrusor are impaired in TRPC4 deficient mice. (PubMed, Sci Rep) - "Cholinergic responses, induced by electric-field stimulation (EFS), bath application of the cholinergic agonist carbachol, or the acetylcholinesterase inhibitor neostigmine were all significantly smaller in TRPC4 detrusor strips than wild-type...However, TRPC5 expression was up-regulated in these preparations and, in contrast to wild-type, EFS responses were reduced in amplitude by the TRPC5 channel inhibitor clemizole hydrochloride. This study demonstrates that TRPC4 channels are involved in spontaneous and cholinergic-mediated contractions of the murine detrusor. TRPC5 expression is up-regulated in TRPC4 detrusor strips, and may partially compensate for loss of TRPC4 channels."

Journal • Preclinical

Endothelial cell transient receptor potential channel C5 (TRPC5) is essential for endothelium-dependent contraction in mouse carotid arteries. (PubMed, Biochem Pharmacol) - "...TRPC5 inhibitors clemizole and ML204 also reduced the EDC...Our present study demonstrated that TRPC5 in endothelial cells contributes to EDC by stimulating the production of COX-2-linked prostanoids. The finding extends our knowledge about EDC."

Journal • Preclinical