-
Scientific Reports May 20244-aminopyridine (4AP) is a potassium (K) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K channels in...
4-aminopyridine (4AP) is a potassium (K) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K channels in demyelinated axons, reducing the leakage of intracellular K and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (pK = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value < 0.0001) and higher permeability to an artificial brain membrane (P = 88.1 ± 18.3 vs. 31.1 ± 2.9 nm/s, P-value = 0.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (IC = 36.2 ± 2.5 vs. 15.4 ± 5.1, P-value = 0.0003); the enzyme responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties as a candidate for PET imaging warranting additional investigation.
Topics: Potassium Channel Blockers; Humans; Positron-Emission Tomography; 4-Aminopyridine; Amifampridine
PubMed: 38750155
DOI: 10.1038/s41598-024-61465-w -
Cureus Jan 2024After a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, approximately 10-20% of patients are affected by the post-COVID syndrome (PCS). This...
After a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, approximately 10-20% of patients are affected by the post-COVID syndrome (PCS). This condition leads to a variety of functional complaints, including symptoms of fatigue. To date, there is still no adequate treatment option. Five patients are presented, including the self-observation of one of the authors, in whom the administration of amifampridine as an "off-label use" led to a normalization of the unphysiologically increased need for sleep with a simultaneous increase in the Bell score. This effect was confirmed in a double-blind discontinuation trial (the medication was discontinued on a trial basis) in two of the patients. The five patients, who were previously unable to lead a normal life due to their fatigue symptoms, were able to return to everyday life after treatment with amifampridine. This offers hope to millions of affected patients.
PubMed: 38406122
DOI: 10.7759/cureus.52935 -
The Journal of Pharmacology and... Jan 2024Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and...
Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP-mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties. SIGNIFICANCE STATEMENT: There is a critical need for fast-acting treatments to reverse respiratory paralysis in patients with botulism. This study used unrestrained, whole-body plethysmography and arterial blood gas analysis to show that aminopyridines rapidly restore ventilation and respiration and reverse respiratory acidosis when administered to mice at terminal stages of botulism. In addition to supporting the use of aminopyridines as first-line treatments for botulism symptoms, these data are expected to contribute to the development of new aminopyridine derivatives with improved pharmacological properties.
Topics: Mice; Humans; Animals; Botulism; Aminopyridines; Amifampridine; Acidosis, Respiratory; Botulinum Toxins, Type A; Paralysis; Respiration
PubMed: 37977816
DOI: 10.1124/jpet.123.001773 -
Pharmaceutics May 2023Amifampridine is a drug used for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United...
Amifampridine is a drug used for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United States (US) in 2018. It is mainly metabolized by -acetyltransferase 2 (NAT2); however, investigations of NAT2-mediated drug interactions with amifampridine have rarely been reported. In this study, we investigated the effects of acetaminophen, a NAT2 inhibitor, on the pharmacokinetics of amifampridine using in vitro and in vivo systems. Acetaminophen strongly inhibits the formation of 3--acetylamifmapridine from amifampridine in the rat liver S9 fraction in a mixed inhibitory manner. When rats were pretreated with acetaminophen (100 mg/kg), the systemic exposure to amifampridine significantly increased and the ratio of the area under the plasma concentration-time curve for 3--acetylamifampridine to amifampridine (AUC/AUC) decreased, likely due to the inhibition of NAT2 by acetaminophen. The urinary excretion and the amount of amifampridine distributed to the tissues also increased after acetaminophen administration, whereas the renal clearance and tissue partition coefficient (K) values in most tissues remained unchanged. Collectively, co-administration of acetaminophen with amifampridine may lead to relevant drug interactions; thus, care should be taken during co-administration.
PubMed: 37242713
DOI: 10.3390/pharmaceutics15051471 -
International Journal of Molecular... Feb 2023Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic... (Review)
Review
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.
Topics: Humans; Albuterol; Amifampridine; Cholinesterase Inhibitors; Mitochondrial Proteins; Mutation; Myasthenic Syndromes, Congenital; NAV1.4 Voltage-Gated Sodium Channel; Neuromuscular Junction; Receptors, Cholinergic; Symporters; Synaptic Transmission
PubMed: 36835142
DOI: 10.3390/ijms24043730 -
Australian Prescriber Oct 2022
Review
PubMed: 36382167
DOI: 10.18773/austprescr.2022.056 -
Journal of Neurology Nov 2022Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission.
METHODS
SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics.
RESULTS
From 14 January 2019, 13 patients, mean age 34.5 years (range 18-53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes.
DISCUSSION
SMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients.
CLINICAL TRIAL REGISTRATION
NCT03781479; EUDRACT 2017-004,600-22.
Topics: Amifampridine; Cross-Over Studies; Female; Humans; Male; Muscular Atrophy, Spinal; Quality of Life; Spinal Muscular Atrophies of Childhood
PubMed: 35763114
DOI: 10.1007/s00415-022-11231-7 -
Molecular Medicine (Cambridge, Mass.) Jun 2022Botulinum neurotoxins (BoNTs) are highly potent, select agent toxins that inhibit neurotransmitter release at motor nerve terminals, causing muscle paralysis and death...
Botulinum neurotoxins (BoNTs) are highly potent, select agent toxins that inhibit neurotransmitter release at motor nerve terminals, causing muscle paralysis and death by asphyxiation. Other than post-exposure prophylaxis with antitoxin, the only treatment option for symptomatic botulism is intubation and supportive care until recovery, which can require weeks or longer. In previous studies, we reported the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses early botulism symptoms and prolongs survival in lethally intoxicated mice. However, the symptomatic benefits of 3,4-DAP are limited by its rapid clearance. Here we investigated whether 3,4-DAP could sustain symptomatic benefits throughout the full course of respiratory paralysis in lethally intoxicated rats. First, we confirmed serial injections of 3,4-DAP stabilized toxic signs and prolonged survival in rats challenged with 2.5 LD BoNT/A. Rebound of toxic signs and death occurred within hours after the final 3,4-DAP treatment, consistent with the short half-life of 3,4-DAP in rats. Based on these data, we next investigated whether the therapeutic benefits of 3,4-DAP could be sustained throughout the course of botulism by continuous infusion. To ensure administration of 3,4-DAP at clinically relevant doses, three infusion dose rates (0.5, 1.0 and 1.5 mg/kg∙h) were identified that produced steady-state serum levels of 3,4-DAP consistent with clinical dosing. We then compared dose-dependent effects of 3,4-DAP on toxic signs and survival in rats intoxicated with 2.5 LD BoNT/A. In contrast to saline vehicle, which resulted in 100% mortality, infusion of 3,4-DAP at ≥ 1.0 mg/kg∙h from 1 to 14 d after intoxication produced 94.4% survival and full resolution of toxic signs, without rebound of toxic signs after infusion was stopped. In contrast, withdrawal of 3,4-DAP infusion at 5 d resulted in re-emergence of toxic sign and death within 12 h, confirming antidotal outcomes require sustained 3,4-DAP treatment for longer than 5 d after intoxication. We exploited this novel survival model of lethal botulism to explore neurophysiological parameters of diaphragm paralysis and recovery. While neurotransmission was nearly eliminated at 5 d, neurotransmission was significantly improved at 21 d in 3,4-DAP-infused survivors, although still depressed compared to naïve rats. 3,4-DAP is the first small molecule to reverse systemic paralysis and promote survival in animal models of botulism, thereby meeting a critical treatment need that is not addressed by post-exposure prophylaxis with conventional antitoxin. These data contribute to a growing body of evidence supporting the use of 3,4-DAP to treat clinical botulism.
Topics: Amifampridine; Animals; Antidotes; Antitoxins; Botulism; Mice; Paralysis; Rats
PubMed: 35659174
DOI: 10.1186/s10020-022-00487-4