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1.
Saudi Med J ; 45(6): 626-632, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830658

RESUMO

OBJECTIVES: To shed some light on a potential therapeutic modality that may facilitate resolution of botulism symptoms, namely 3,4-diaminopyridine (3,4-DAP). METHODS: In Riyadh, Saudi Arabia, we recently encountered a foodborne botulism outbreak that, luckily, was discovered early. In Prince Sultan Military Medical city, we admitted, during a period of approximately 3 weeks, 15 probable cases, 2 of which were excluded due to more likely alternative diagnoses. We report in this case series 13 highly suspected cases of botulism that we encountered during the outbreak. RESULTS: A total of 12 out of 13 patients required intensive care unit (ICU) admission, one of which required intubation. Symptoms included cranial nerve palsies, gastrointestinal symptoms, limb and respiratory muscle weakness. Patients showed clinical improvement when received botulinum antitoxin and 3,4-DAP if given early in the course of the disease. CONCLUSION: Early admisntration of 3,4-DAP may facilitate recovery and prevent disease progression. Larger prospective trials should be carried out to confirm that.


Assuntos
Botulismo , Surtos de Doenças , Humanos , Botulismo/terapia , Botulismo/epidemiologia , Botulismo/diagnóstico , Masculino , Arábia Saudita/epidemiologia , Adulto , Feminino , Pessoa de Meia-Idade , Amifampridina , Antitoxina Botulínica/uso terapêutico , Adulto Jovem
2.
Pediatr Neurol ; 157: 5-13, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38833907

RESUMO

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS. METHODS: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. RESULTS: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America. CONCLUSIONS: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.


Assuntos
Amifampridina , Síndromes Miastênicas Congênitas , Fenótipo , Proteína 1 Associada à Membrana da Vesícula , Humanos , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Feminino , Masculino , Amifampridina/farmacologia , Proteína 1 Associada à Membrana da Vesícula/genética , Criança , Adolescente , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/farmacologia , 4-Aminopiridina/uso terapêutico , Pré-Escolar , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Lactente
3.
Sci Rep ; 14(1): 11105, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750155

RESUMO

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 (pKa = 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 (Pe = 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 (IC50 = 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.


Assuntos
Tomografia por Emissão de Pósitrons , Bloqueadores dos Canais de Potássio , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Humanos , Tomografia por Emissão de Pósitrons/métodos , 4-Aminopiridina/farmacologia , 4-Aminopiridina/química , 4-Aminopiridina/análogos & derivados , Amifampridina/metabolismo
4.
Am J Emerg Med ; 80: 231.e1-231.e2, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38693021

RESUMO

3,4-Aminopyridine or Amifampridine belongs to the aminopyridine class of drugs which is used to treat multiple sclerosis and Lambert-Eaton Myasthenic Syndrome (LEMS). Aminopyridine pharmaceuticals inhibit presynaptic potassium channels. This increases available acetylcholine in the nerve cleft which leads to improved strength in this patient population. While overdoses have been reported of 4-Aminopyridine, no case reports of acute 3.4-Aminopyridine overdose are currently available. A 67 year old man presented to the emergency department 30 min after ingesting 100 mg of amifampridine in a suicide attempt. Within an hour of ingestion he experienced tachycardia, tachypnea, hypertension and tremor. The patient then started to experience seizures and had a cardiac arrest 3 h after the ingestion. The patient achieved return of spontaneous circulation but proceeded to have refractory seizures. Despite significant and escalating doses of anti-epileptic medications, the patient continued to have seizures until 18 h after ingestion. His anti-epileptic medications were weaned over the following days and he had no more seizures. This is a report of a novel overdose of 3,4-Aminopyridine, a medication that belongs to the aminopyridine class of pharmaceuticals that have been well used for many years. Aminopyridine overdoses are commonly thought to carry low morbidity and mortality; however, our patient had both a cardiac arrest and refractory status epilepticus. Ultimately, this case suggests that patients who overdose on 3,4-Aminopyridine could become critically ill and their presentation may be far more severe than that of other medications of the same class.


Assuntos
Amifampridina , Overdose de Drogas , Bloqueadores dos Canais de Potássio , Estado Epiléptico , Humanos , Masculino , Idoso , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Bloqueadores dos Canais de Potássio/intoxicação , Tentativa de Suicídio , Anticonvulsivantes/intoxicação
5.
J Pharmacol Exp Ther ; 388(2): 637-646, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-37977816

RESUMO

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 CO2, 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.


Assuntos
Acidose Respiratória , Toxinas Botulínicas Tipo A , Botulismo , Camundongos , Humanos , Animais , Botulismo/tratamento farmacológico , Aminopiridinas/farmacologia , Amifampridina/uso terapêutico , Acidose Respiratória/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Toxinas Botulínicas Tipo A/toxicidade , Paralisia/tratamento farmacológico , Respiração
6.
Dalton Trans ; 53(3): 1066-1086, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38099626

RESUMO

The different behaviors of the drug amifampridine (AMP) against Mn(II), Cu(II), Zn(II) and Cd(II) metal ions, in the presence and absence of tris(2-aminoethyl)amine (tren) was studied. The results showed that AMP successfully coordinates with Cu(II), Zn(II) and Cd(II) metal ions, but interestingly it undergoes an unexpected dimerization through a C-H activation in the presence of different Mn(II) salts. A four-coordinate complex of zinc(II), [Zn(AMP)2Cl2] (1), a binuclear complex of cadmium(II), [Cd2(AMP)2Cl4] (2), three five-coordinate tren-based metal complexes, [Cu(tren)(AMP)](ClO4)2 (8), [Zn(tren)(AMP)]Cl2 (9) and [Cd(tren)(AMP)](ClO4)2 (10), three pyridinium salts, [AmpDimer]X (X = Cl-, NO3-, ClO4-; (3, 4 & 5)), and also two four-coordinate metal complexes with this pyridinium cation, [Zn(AmpDimer)Cl3] (6) and [Cd(AmpDimer)Cl3] (7), were synthesized. All new compounds were characterized by elemental analysis and IR spectroscopy, and by 1H- and 13C-NMR spectroscopy (for 1, 2, 3, 6, 7, 9 & 10) and by X-ray crystal structure determinations (for 1, 3, 4, 5, 7, 8 & 10). Theoretical studies showed that the [M(tren)(AMP)]2+ cations act as pH-sensitive drug carriers of AMP and release it upon protonation. The molecular docking studies on the interaction of AMP and the above complexes/salts with DNA and the proteins of SARS-CoV-2 showed that the synthesized complexes/salts have greater anticancer and anti-covid-19 activities than AMP alone.


Assuntos
Cádmio , Complexos de Coordenação , Cádmio/química , Sais , Amifampridina , Complexos de Coordenação/farmacologia , Simulação de Acoplamento Molecular , Dimerização , Metais/química , Zinco/química , Íons
7.
Int J Mol Sci ; 24(4)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36835142

RESUMO

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 (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). 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.


Assuntos
Síndromes Miastênicas Congênitas , Simportadores , Humanos , Albuterol , Amifampridina , Inibidores da Colinesterase , Proteínas Mitocondriais/genética , Mutação , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/patologia , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Junção Neuromuscular/patologia , Receptores Colinérgicos/genética , Simportadores/genética , Transmissão Sináptica
8.
Continuum (Minneap Minn) ; 28(6): 1596-1614, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36537971

RESUMO

PURPOSE OF REVIEW: This article reviews the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and botulism, presynaptic disorders of neuromuscular transmission in which rapid diagnosis improves long-term outcomes. RECENT FINDINGS: Therapy for LEMS has seen significant advances in recent years due to the approval of amifampridine-based compounds. LEMS is likely still underdiagnosed, particularly when no underlying malignancy is identified. Clinicians must have a strong suspicion for LEMS in any patient presenting with proximal weakness and autonomic dysfunction. Botulism is another rare disorder of presynaptic neuromuscular transmission that is most commonly associated with improper storage or preservation of food products. Over the past 2 decades, wound botulism has been increasingly reported among users of black tar heroin. A high degree of clinical suspicion and electrodiagnostic studies can be beneficial in distinguishing botulism from other acute neurologic disorders, and early involvement of state and federal health authorities may assist in confirming the diagnosis and obtaining treatment. When botulism is suspected, electrodiagnostic studies can provide clinical evidence of disordered neuromuscular transmission in advance of serologic confirmation, and providers should not wait for confirmation of the diagnosis to initiate treatment. SUMMARY: A targeted clinical history and a thorough neurologic examination with support from serologic and electrodiagnostic studies are key to early diagnosis of LEMS and botulism. Early diagnosis of both conditions creates opportunities for therapy and improves outcomes.


Assuntos
Doenças do Sistema Nervoso Autônomo , Botulismo , Síndrome Miastênica de Lambert-Eaton , Humanos , Síndrome Miastênica de Lambert-Eaton/diagnóstico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Botulismo/diagnóstico , Botulismo/terapia , Amifampridina/uso terapêutico , Doenças do Sistema Nervoso Autônomo/complicações
9.
Mol Med ; 28(1): 61, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35659174

RESUMO

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 LD50 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 LD50 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.


Assuntos
Antitoxinas , Botulismo , Amifampridina/uso terapêutico , Animais , Antídotos/farmacologia , Antídotos/uso terapêutico , Antitoxinas/uso terapêutico , Botulismo/tratamento farmacológico , Camundongos , Paralisia/tratamento farmacológico , Ratos
10.
J Neurol ; 269(11): 5858-5867, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35763114

RESUMO

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.


Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Amifampridina/uso terapêutico , Estudos Cross-Over , Feminino , Humanos , Masculino , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Qualidade de Vida , Atrofias Musculares Espinais da Infância/tratamento farmacológico
11.
Curr Opin Neurol ; 34(5): 648-657, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34914667

RESUMO

PURPOSE OF REVIEW: To give an overview of the recent data on three autoimmune neuromuscular junction disorders with the recent Food Drug Administration (FDA) approval of amifampridine [3,4-Diaminopyridine (3,4-DAP) and 3,4-diaminopyridine phosphate (3,4-DAPP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS). RECENT FINDINGS: In LEMS, the most important recent development is the introduction of FDA approved amifampridine for the symptomatic treatment. Randomized controlled studies showed an extremely effective improvement with amifampridine with daily dose of ≤ 80 mg with minimal side reactions. The next important development is in the electrodiagnostic criteria. Now 10 s exercise and an incremental response ≥ 60% either after 10 s exercise or at the high-rate stimulation in the repetitive nerve stimulation test are recommended as the standard tests.In 2016, myasthenia-gravis Lambert-Eaton overlap syndrome (MLOS) was coined as new syndrome for patients with myasthenia gravis and LEMS combined symptoms in same patients.In Isaacs syndrome, voltage gated calcium channel antibody order is no longer recommended because of low specificity for immunotherapy responsive disorders. Instead, ' leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated like-2 (CASPR2) autoantibody tests' are recommended. SUMMARY: In LEMS, amifampridine (3,4 DAP and 3,4-DAPP) is approved by the FDA as an effective symptomatic treatment. MLOS is coined as new syndrome recently. In Isaacs syndrome, LGI1 and CASPR2 antibody tests are recommended.


Assuntos
Síndrome Miastênica de Lambert-Eaton , Miastenia Gravis , Amifampridina , Anticorpos , Humanos , Síndrome Miastênica de Lambert-Eaton/diagnóstico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Miastenia Gravis/tratamento farmacológico
12.
Molecules ; 26(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641581

RESUMO

UV-Vis spectroscopy was used to investigate two new charge transfer (CT) complexes formed between the K+-channel-blocker amifampridine (AMFP) drug and the two π-acceptors 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tetracyanoethylene (TCNE) in different solvents. The molecular composition of the new CT complexes was estimated using the continuous variations method and found to be 1:1 for both complexes. The formed CT complexes' electronic spectra data were further employed for calculating the formation constants (KCT), molar extinction coefficients (εCT), and physical parameters at various temperatures, and the results demonstrated the high stability of both complexes. In addition, sensitive spectrophotometric methods for quantifying AMFP in its pure form were proposed and statistically validated. Furthermore, DFT calculations were used to predict the molecular structures of AMFP-DDQ and AMFP-TCNE complexes in CHCl3. TD-DFT calculations were also used to predict the electronic spectra of both complexes. A CT-based transition band (exp. 399 and 417 nm) for the AMFP-TCNE complex was calculated at 411.5 nm (f = 0.105, HOMO-1 → LUMO). The two absorption bands at 459 nm (calc. 426.9 nm, f = 0.054) and 584 nm (calc. 628.1 nm, f = 0.111) of the AMFP-DDQ complex were theoretically assigned to HOMO-1 → LUMO and HOMO → LUMO excitations, respectively.


Assuntos
Amifampridina/química , Benzoquinonas/química , Etilenos/química , Nitrilas/química , Fenômenos Químicos , Teoria da Densidade Funcional , Elétrons , Estrutura Molecular , Bloqueadores dos Canais de Potássio/química , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier
13.
BMC Neurol ; 21(1): 371, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563155

RESUMO

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission. The objective was to examine the efficacy and safety of 3,4-diaminopyridine (3,4-DAP) in patients with LEMS. METHODS: We searched several databases to identify relevant studies, including PubMed, EMBASE, Web of Science, MEDLINE, Cochrane Neuromuscular Disease Group Specialized Register and the Cochrane Central Register of Controlled Trials(CENTRAL). The primary outcome, quantitative myasthenia gravis (QMG) score and the secondary outcome, compound muscle action potentials (CMAP) amplitude were pooled by meta-analysis. RESULTS: Six randomised controlled trials (RCTs) involving 115 patients with LEMS were included. QMG score showed a significant decrease (improvement) of 2.76 points (95 % CI, -4.08 to -1.45, p < 0.001) after treatment with 3, 4-DAP. Moreover, the overall mean CMAP amplitude improved significantly in LEMS patients with 3, 4-DAP treatment, compared with placebo treatment (mean difference 1.34 mV, 95 % CI, 0.98 to 1.70, p < 0.001). The overall assessment of all included trials showed a low risk of bias and low heterogeneity. CONCLUSIONS: The pooled results of RCTs demonsrated with moderate to high evidence that 3,4-DAP has a significant effect on LEMS treatment, with improvements in muscle strength score and CMAP amplitude.


Assuntos
Síndrome Miastênica de Lambert-Eaton , Miastenia Gravis , 4-Aminopiridina/uso terapêutico , Adulto , Amifampridina , Humanos , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Miastenia Gravis/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Biomed Pharmacother ; 137: 111357, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33724918

RESUMO

3,4-Diaminopyridine (3,4-DAP) and its phosphate form, 3,4-DAPP have been used efficiently in the past years to treat muscular weakness in myasthenic syndromes with neuromuscular junctions (NMJs) impairment. Pompe disease (PD), an autosomal recessive metabolic disorder due to a defect of the lysosomal enzyme α-glucosidase (GAA), presents some secondary symptoms that are related to neuromuscular transmission dysfunction, resulting in endurance and strength failure. In order to evaluate whether 3,4-DAPP could have a beneficial effect on this pathology, we took advantage of a transient zebrafish PD model that we previously generated and characterized. We investigated presynaptic and postsynaptic structures, NMJs at the electron microscopy level, and zebrafish behavior, before and after treatment with 3,4-DAPP. After drug administration, we observed an increase in the number of acetylcholine receptors an increment in the percentage of NMJs with normal structure and amelioration in embryo behavior, with recovery of typical movements that were lost in the embryo PD model. Our results revealed early NMJ impairment in Pompe zebrafish model with improvement after administration of 3,4-DAPP, suggesting its potential use as symptomatic drug in patients with Pompe disease.


Assuntos
Amifampridina/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Junção Neuromuscular/efeitos dos fármacos , Animais , Comportamento Animal , Embrião não Mamífero , Atividade Motora/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Junção Neuromuscular/ultraestrutura , Receptores Colinérgicos/efeitos dos fármacos , Peixe-Zebra , alfa-Glucosidases/metabolismo
16.
J Biol Chem ; 296: 100302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33465376

RESUMO

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 µM in serum) are the Food and Drug Administration (FDA)-approved treatment for neuromuscular weakness caused by Lambert-Eaton myasthenic syndrome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the presynaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-target agonist effect on the Cav1 subtype ("L-type") of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAP's mechanism(s) of action, we first used the patch-clamp electrophysiology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-affinity (1-10 µM) partial antagonist effect of 3,4-DAP in addition to the well-known low-affinity (0.1-1 mM) antagonist activity. We also showed that 1.5-µM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5- or 100-µM 3,4-DAP broadened the AP waveform in a dose-dependent manner, independent of Cav1 calcium channels. Finally, we demonstrated that 1.5- or 100-µM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv channels to mediate AP broadening and enhance transmitter release at the NMJ.


Assuntos
Amifampridina/farmacologia , Fármacos Neuromusculares/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Canais de Potássio Shaw/metabolismo , Acetilcolina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo N/genética , Canais de Cálcio Tipo N/metabolismo , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Masculino , Camundongos , Microeletrodos , Junção Neuromuscular/metabolismo , Terminações Pré-Sinápticas/metabolismo , Rana pipiens , Canais de Potássio Shaw/antagonistas & inibidores , Canais de Potássio Shaw/genética , Técnicas de Cultura de Tecidos
17.
Muscle Nerve ; 63(3): E18-E21, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33290581

Assuntos
Doenças Cerebelares/induzido quimicamente , Neoplasias Cerebelares/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Síndrome Miastênica de Lambert-Eaton/induzido quimicamente , Degeneração Neural/induzido quimicamente , Tumores Neuroendócrinos/terapia , Nivolumabe/efeitos adversos , Amifampridina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Canais de Cálcio Tipo P , Canais de Cálcio Tipo Q , Doenças Cerebelares/tratamento farmacológico , Doenças Cerebelares/imunologia , Doenças Cerebelares/fisiopatologia , Neoplasias Cerebelares/secundário , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Linfonodos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Degeneração Neural/tratamento farmacológico , Degeneração Neural/imunologia , Degeneração Neural/fisiopatologia , Tumores Neuroendócrinos/secundário , Fármacos Neuromusculares/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prednisona/uso terapêutico , Radiocirurgia , Radioterapia , Rituximab/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/secundário , Carcinoma de Pequenas Células do Pulmão/terapia , Tomografia Computadorizada por Raios X
18.
Drugs Today (Barc) ; 56(10): 623-641, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33185628

RESUMO

Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic autoimmune disabling neuromuscular disease caused by antibodies against presynaptic voltage-gated calcium channels. It reduces the quantal release of acetylcholine (Ach), causing muscle weakness, reduced or absent reflex and dysautonomia. About half of LEMS patients have associated small cell lung cancer. For symptomatic treatment, amifampridine (3,4-diaminopyridine [3,4-DAP]) is ideal because it increases the release of Ach at the presynaptic membrane. Since the first use of 3,4-DAP in LEMS patients in the 1980s, 136 LEMS patients were treated with amifampridines in the open-label studies and 208 patients in the eight randomized studies. These studies showed that amifampridine is the most effective drug for symptomatic treatment in LEMS. Now, 3,4-DAPP (3,4-DAP phosphate) is approved for adult LEMS patients and 3,4-DAP for pediatric patients. The recommended dose is 80 mg a day, divided 3 or 4 times a day. Side effects are usually mild, and the most frequently reported are paresthesia.


Assuntos
Amifampridina/farmacologia , Síndrome Miastênica de Lambert-Eaton , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adulto , Criança , Humanos , Síndrome Miastênica de Lambert-Eaton/diagnóstico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico
19.
Artigo em Inglês | MEDLINE | ID: mdl-33178487

RESUMO

The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the KCNMA1 gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.


Assuntos
Ataxia/genética , Coreia/genética , Distonia/genética , Alucinações/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Transtornos da Motilidade Ocular/genética , Adulto , Amifampridina/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/fisiopatologia , Coreia/tratamento farmacológico , Coreia/fisiopatologia , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Eletroencefalografia , Feminino , Alucinações/tratamento farmacológico , Alucinações/fisiopatologia , Humanos , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/fisiopatologia , Bloqueadores dos Canais de Potássio/uso terapêutico
20.
Exp Brain Res ; 238(11): 2539-2548, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870323

RESUMO

Although L-DOPA revolutionized in the treatment of Parkinson's disease, most patients developed motor complications after several years of treatment. Adjunctive therapy to L-DOPA with drugs related to dopaminergic signaling may reduce its dose without decreasing the therapeutic efficiency and thus ameliorates its adverse effects. It has been shown that 3,4-diaminopyridine (3,4-DAP), a K channel blocker, increased dopamine release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The current study investigates whether 3,4-DAP may enhance L-DOPA-induced dopamine (DA) release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The effects of L-DOPA and 3,4-DAP on spontaneous DA and DOPAC release were tested in vitro, on acute rat striatal slices prepared from non-treated and 6-hydroxydopamine-pre-treated rats. DA and DOPAC levels were determined by HPLC methods. When 3,4-diaminopyridine was combined with L-DOPA, the observed effect was considerably greater than the increases induced by L-DOPA or 3,4-DAP alone in normoxic and neurodegenerative conditions produced by FeSO4 and 6-hydroxydopamine. Furthermore, L-DOPA plus 3,4-DAP also ameliorated DOPAC levels in neurodegenerative conditions. These data indicate that 3,4 DAP plus L-DOPA activates striatal dopaminergic terminals by increasing the DA release and, thus, could be considered as a promising finding in treatment of acute and chronic injury in dopaminergic neurons.


Assuntos
Corpo Estriado , Amifampridina , Animais , Dopamina , Levodopa/farmacologia , Oxidopamina/toxicidade , Ratos
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