Drug repurposing for rare: progress and opportunities for the rare disease community

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 17, 2024

Repurposing is one of the key opportunities to address unmet rare diseases therapeutic need. Based on cases drug repurposing in small population conditions, and previous work repurposing, we analyzed most important lessons learned, such as sharing clinical observations, reaching out regulatory scientific advice at an early stage, public-private collaboration. In addition, current upcoming trends field were analyzed, including role these could play diseases’ ecosystem. Specifically, cover innovation platforms, use real-world data, artificial intelligence, initiatives patient engagement throughout project. The outcomes from emerging activities will help progress for benefit patients, public health medicines development.

Language: Английский

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Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 27, 2021

Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10–20 years, potential therapeutic solutions for diseases of complex etiology and with significant drug-resistance problems. Such agents that modulate targets simultaneously are developed aim enhancing efficacy improving safety relative to address only a single target combinations single-target drugs. Although this strategy has been proposed epilepsy therapy >25 years ago, my knowledge, one antiseizure medication (ASM), padsevonil, intentionally molecular entity could two different mechanisms. This novel exhibited promising effects numerous preclinical models difficult-to-treat seizures. However, recent randomized placebo-controlled phase IIb add-on trial treatment-resistant focal patients, padsevonil did not separate from placebo its primary endpoints. At about same time, ASM, cenobamate, several controlled trials such patients far surpassed any other newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening presumed dual mechanism action described recently. In review, I will survey vs. treatment prevention epilepsy. Most clinically approved ASMs already act at targets, but it be important identify validate new more effective drug-resistant eventually may prevent development progression

Language: Английский

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Update on Antiseizure Medications 2022

CONTINUUM Lifelong Learning in Neurology, Journal Year: 2022, Volume and Issue: 28(2), P. 500 - 535

Published: April 1, 2022

EDITOR’S NOTEABSTRACT The article “Update on Antiseizure Medications 2022” by Dr Abou-Khalil was first published in the February 2016 Epilepsy issue of Continuum: Lifelong Learning Neurology as “Antiepileptic Drugs,” and at request Editor-in-Chief updated for 2019 again this issue. PURPOSE OF REVIEW This is an update from antiepileptic drug therapy (now referred to antiseizure medication ) two previous Continuum issues epilepsy intended cover vast majority agents currently available neurologist management patients with epilepsy. Treatment starts monotherapy. Knowledge spectrum efficacy, clinical pharmacology, modes use individual medications essential optimal treatment addresses individually, focusing key pharmacokinetic characteristics, indications, use. RECENT FINDINGS Since most recent version published, new medications, cenobamate fenfluramine, have been approved US Food Drug Administration (FDA), indications some expanded. Older are effective but tolerability disadvantages. Several newer undergone comparative trials demonstrating efficacy equal least or better than older first-line focal list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, lacosamide. Pregabalin found be less lamotrigine. Lacosamide, pregabalin, eslicarbazepine successful conversion monotherapy Other a variety mechanisms action suitable adjunctive therapy. marketed since benefited FDA policy allowing drug’s adults extrapolated In addition, can children 4 years age older. Both extrapolations require data that has equivalent pharmacokinetics between its original Rational combinations should avoid unfavorable interactions pharmacodynamic related mechanism action. SUMMARY pharmacokinetics, profiles facilitates choice appropriate

Language: Английский

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Serotonin receptors in epilepsy: Novel treatment targets?

Epilepsia Open, Journal Year: 2022, Volume and Issue: 7(2), P. 231 - 246

Published: Jan. 25, 2022

Despite the availability of over 30 antiseizure medications (ASMs), there is no "one size fits it all," so a continuing search for novel ASMs. There are divergent data demonstrating that modulation distinct serotonin (5-hydroxytryptamine, 5-HT) receptors subtypes could be beneficial in treatment epilepsy and its comorbidities, whereas only few ASM, such as fenfluramine (FA), act via 5-HT. 14 different 5-HT receptor subtypes, most studies focus on one or these using animal models ligands. We reviewed available evidence each subtype MEDLINE up to July 2021. Our included medical subject heading (MeSH) free terms "5-HT subtype" separately relation "epilepsy seizures." Most research underlines activity 5-HT1A,1D,2A,2C,3 agonism 5-HT6 antagonism. Consistently, FA, which has recently been approved seizures Dravet syndrome, an agonist 5-HT1D,2A,2C receptors. Even though study focused seizure/epilepsy type generalization findings lead false interpretations, we believe preclinical clinical emphasize role serotonergic modulation, especially stimulation, promising avenue treatment.

Language: Английский

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Seizures Cause Prolonged Impairment of Ventilation, CO₂Chemoreception and Thermoregulation

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(27), P. 4959 - 4971

Published: May 9, 2023

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) patients caused a prolonged decrease hypercapnic ventilatory response (HCVR; measure of CO 2 chemoreception). We then studied Scn1a R1407X /+ (Dravet syndrome; DS) Scn8a N1768D (D/+) mice sexes, two models SUDEP, postictal ventilation severely depressed HCVR subset animals. Those with severe depression also exhibited transient hypothermia. A combination blunted abnormal thermoregulation is known occur dysfunction serotonin (5-hydroxytryptamine; 5-HT) system mice. Depleting 5-HT para -chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded HCVR, exacerbated hypothermia, increased mortality DS Conversely, pretreatment agonist fenfluramine reduced inhibition These results are consistent previous observation cause impairment serotonergic neuron function, which would be expected inhibit many aspects control dependent on 5-HT, including baseline HCVR. provide scientific rationale investigate interictal and/or as noninvasive biomarkers for those at high risk death, prevent SUDEP by enhancing tone. SIGNIFICANCE STATEMENT There increasing evidence contributes pathophysiology sudden (SUDEP). However, cellular basis not defined. Here, show impair chemoreception some patients. In mouse impaired chemoreception, induced effects reported dysfunction. The defects were chemical depletion fenfluramine, suggesting may due function. findings suggest because neurons contribute SUDEP.

Language: Английский

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Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 226, P. 107866 - 107866

Published: April 22, 2021

Language: Английский

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Sustainable production of active pharmaceutical ingredients from lignin-based benzoic acid derivatives via “demand orientation”

Green Chemistry, Journal Year: 2023, Volume and Issue: 25(10), P. 3791 - 3815

Published: Jan. 1, 2023

Catalytic production of several representative active pharmaceutical ingredients (APIs) from lignin.

Language: Английский

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Sigma-1 receptor and seizures

Pharmacological Research, Journal Year: 2023, Volume and Issue: 191, P. 106771 - 106771

Published: April 15, 2023

Over the last decade, sigma-1 receptor (Sig1R) has been recognized as a valid target for treatment of seizure disorders and seizure-related comorbidities. Clinical trials with Sig1R ligands are underway testing therapies drug-resistant seizures, developmental epileptic encephalopathies, photosensitive epilepsy. However, direct molecular mechanism by which modulates seizures balance between excitatory inhibitory pathways not fully elucidated. This review article aims to summarize existing knowledge its involvement in focusing on evidence obtained from knockout animals anti-seizure effects ligands. In addition, this includes discussion advantages disadvantages use compounds describes challenges future perspectives disorders.

Language: Английский

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Use of Zebrafish Models to Boost Research in Rare Genetic Diseases

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(24), P. 13356 - 13356

Published: Dec. 12, 2021

Rare genetic diseases are a group of pathologies with often unmet clinical needs. Even if rare by single disease (from 1/2000 to 1/more than 1,000,000), the total number patients concerned account for approximatively 400 million peoples worldwide. Finding treatments remains challenging due complexity these diseases, small and challenge in conducting trials. Therefore, innovative preclinical research strategies required. The zebrafish has emerged as powerful animal model investigating diseases. Zebrafish combines conserved vertebrate characteristics high rate breeding, limited housing requirements low costs. More 84% human genes responsible present an orthologue, suggesting that majority could be modelized zebrafish. In this review, we emphasize unique advantages models over other vivo models, particularly underlining throughput phenotypic capacity therapeutic screening. We briefly introduce how generation transgenic lines gene-modulating technologies can used Then, describe phenotyped using state-of-the-art technologies. Two prototypic examples illustrate play critical role deciphering underlying mechanisms their use identify solutions.

Language: Английский

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Serotonin-releasing agents with reduced off-target effects

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(2), P. 722 - 732

Published: Nov. 9, 2022

Abstract Increasing extracellular levels of serotonin (5-HT) in the brain ameliorates symptoms depression and anxiety-related disorders, e.g., social phobias post-traumatic stress disorder. Recent evidence from preclinical clinical studies established therapeutic potential drugs inducing release 5-HT via 5-HT-transporter. Nevertheless, current releasing compounds under investigation carry risk for abuse deleterious side effects. Here, we demonstrate that S -enantiomers certain ring-substituted cathinones show preference ex vivo vivo, exert 5-HT-associated effects behavioral models. Importantly, lead cathinone (1) do not induce substantial dopamine (2) display reduced off-target activity at vesicular monoamine transporters 2B -receptors, indicative low abuse-liability adverse events. Taken together, our findings identify these agents as may prove useful treatment disorders where elevation has proven beneficial.

Language: Английский

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