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Striated MusclesSkeletal and Cardiac Muscles
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The anaerobic bacterium Clostridium botulinum produces an exotoxin that inhibits acetylcholine release from cholinergic nerves. Consequences include gastrointestinal and urinary dysfunction, blurred vision and paralysis, which spares limbs but affects respiratory muscles. Aminopyridines may be used to treat the paralysis. Clostridium tetani toxin (tetanus toxin) also prevents acetylcholine release, as well as produces generalized muscle spasms by removing spinal cord inhibition.
Neurobiology of the Gustatory Zone of Nucleus Tractus Solitarius
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
These complex firing patterns are mediated by different ionic conductances. Ionic channel blockers have now been used to characterize the conductances involved in the intrinsic firing properties of rNTS neurons.19 Application of 4-aminopyridine, used to block K channels, results in reduction or elimination of the delay in firing of Group II neurons. Voltage-clamp recordings of Group II neurons reveal that the firing delay is due to a transient outward K+ current partially inactivated around the resting membrane potential and blocked by 4-aminopyridine (Figure 3). Hyperpolarization removes this inactivation causing a delay in the firing of the neuron. Based on its pharmacology and voltage dependence, this current is similar to the A-current (IKA) previously described in many other CNS neurons including the caudal NTS.20-23
Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, Ajay K. Singh, Nizamettin Gul, Frank J. Lebeda
The inability of 3,4-DAP infusion to produce complete reversal of BoNT/A-mediated paralysis in the infusion studies may have resulted from the dose being too low. Higher doses could not be examined because the dose used was at the limit of aqueous solubility, indicating a need for a more potent K+ channel blocker. To achieve this aim, a series of aminopyridines, from both commercial and custom sources, were tested in the mouse phrenic nerve–hemidiaphragm assay by Adler and Borrell (unpublished observations). Table 14.1 shows a sample of the compounds tested and the percentage potentiation of twitch tension achieved. Test compounds were added at 100 µM after tensions were depressed to ~20% of control by exposure to 2 pM BoNT/A. Most compounds were weak or inactive in this assay, as exemplified by 6-aminopyridine-3-carboxylic acid. The remaining compounds, including those with single amine groups (2-aminopyridine [2-AP], 3-aminopyridine [3-AP], 4-aminopyridine [4-AP]) or two amine groups (2,3-diaminopyridine [2,3-DAP]), were all found to be less potent than 3,4-DAP. These results agree with those of Molgó et al. (1985) and indicate the difficulty of discovering aminopyridine analogs more potent than 3,4-DAP for blocking K+ channels at motor nerve terminals.
6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chhabi Lal Chaudhary, Dongchul Lim, Prakash Chaudhary, Diwakar Guragain, Bhuwan Prasad Awasthi, Hee Dong Park, Jung-Ae Kim, Byeong-Seon Jeong
Numbers of research for the discovery of selective FGFR4 inhibitors have underlined the covalent interaction between Cys552 residue in the middle-hinge domain of the ATP-binding site of FGFR4 and acrylamide moiety of small molecule compounds, which was supported by X-ray co-crystal structures. BLU9931 (1) was discovered as a notable compound to possess potent FGFR4 inhibitory activity with good selectivity over FGFR1 ∼ 3. After that, a number of analogues of BLU9931 were designed and prepared, where fisogatinib (BLU554) (2) with better physicochemical properties has been evaluated in a clinical trial for the treatment of HCC. In addition, other Cys552 − acrylamide inhibitors such as H3B-6527 (3), aminopyrimidines (4), and aminopyridines (5) are undergoing either preclinical or clinical studies in recent years (Figure 1) 17–26. Multiple pan-FGFR inhibitors have shown weak efficacy against FGFR4 together with toxicity (hyperphosphatemia and soft tissue mineralization) due to activity against FGFR1 ∼ 3, which indicates a strong need for the discovery of FGFR4-selective inhibitors27.
Clinical trials in pediatric ALS: a TRICALS feasibility study
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Tessa Kliest, Ruben P.A. Van Eijk, Ammar Al-Chalabi, Alberto Albanese, Peter M. Andersen, Maria Del Mar Amador, Geir BrÅthen, Veronique Brunaud-Danel, Lev Brylev, William Camu, Mamede De Carvalho, Cristina Cereda, Hakan Cetin, Delia Chaverri, Adriano Chiò, Philippe Corcia, Philippe Couratier, Fabiola De Marchi, Claude Desnuelle, Michael A. Van Es, JesÚs Esteban, Massimiliano Filosto, Alberto GarcÍa Redondo, Julian Grosskreutz, Clemens O. Hanemann, Trygve HolmØy, Helle HØyer, Caroline Ingre, Blaz Koritnik, Magdalena Kuzma-Kozakiewicz, Thomas Lambert, Peter N. Leigh, Christian Lunetta, Jessica Mandrioli, Christopher J. Mcdermott, Thomas Meyer, Jesus S. Mora, Susanne Petri, MÓnica Povedano, Evy Reviers, Nilo Riva, Kit C.B. Roes, Miguel Á. Rubio, FranÇois Salachas, Stayko Sarafov, Gianni SorarÙ, Zorica Stevic, Kirsten Svenstrup, Anette Torvin MØller, Martin R. Turner, Philip Van Damme, Lucie A.G. Van Leeuwen, Luis Varona, Juan F. VÁzquez Costa, Markus Weber, Orla Hardiman, Leonard H. Van Den Berg
Since the revocation of the waiver for ALS in 2015, four PIPs have been submitted by pharmaceutical companies to the EMA (Table 1). Two of the four PIPs received a waiver. One waiver was based on the disease not occurring in children as the drug, synthetic ribonucleic acid oligonucleotide (EMEA-002403-PIP01-18), aims to target a subset of patients with a superoxide dismutase 1 (SOD1) mutation (14). The second granted waiver for PIP EMEA-001266-PIP04-19 was based on no expected therapeutic effect of the compound, mastinib, in children (17). The other two PIPs (EMEA-001748-PIP02-18 and EMEA-002469-PIP01-18) for the compounds, arimoclomol citrate (15) and pyrimidinyl-aminopyridine dual leucine zipper kinase inhibitor (16), were not granted a waiver due to a potential therapeutic benefit in the pediatric population.
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Amifampridine (marketed as Firdapse) is currently approved for the treatment of Lambert-Eaton myasthenic syndrome, an autoimmune disorder in which antibodies target voltage-gated Ca2+ channels, resulting in a pre-synaptic pathology of NMJs. Amifampridine acts by blocking pre-synaptic K+ channels thus increasing duration of acetylcholine release in the NMJ cleft [50]. Amifampridine has also been successfully used to treat the post-synaptic NMJ disorder muscle-specific kinase myasthenia gravis and thus appears to be effective in treating both pre- and post-synaptic defects. NMJ defects are a key component in the SMA pathology, as demonstrated both in preclinical and in clinical studies [51–53]. A phase 2 randomized cross-over study to evaluate the safety, tolerability, and efficacy of amifampridine in ambulatory SMA3 patients is currently ongoing (NCT03781479). A cross-over study in adult ambulant SMA3 patients using a similar compound, an extended-release formulation of 4-aminopyridine, that blocks voltage-sensitive potassium channels in the central and peripheral nervous system is now completed and results are pending (NCT01645787).