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Molecules (Basel, Switzerland) Oct 2021UV-Vis spectroscopy was used to investigate two new charge transfer (CT) complexes formed between the K-channel-blocker amifampridine (AMFP) drug and the two...
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--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 (), molar extinction coefficients (), 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 CHCl. 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.
Topics: Amifampridine; Benzoquinones; Chemical Phenomena; Density Functional Theory; Electrons; Ethylenes; Molecular Structure; Nitriles; Potassium Channel Blockers; Solvents; Spectroscopy, Fourier Transform Infrared
PubMed: 34641581
DOI: 10.3390/molecules26196037 -
Asian Cardiovascular & Thoracic Annals Oct 2021We report a very rare case of cT1N0M0 lung adenocarcinoma reveling Lambert-Eaton myasthenic syndrome (LEMS). A 69-year-old nonsmoking woman, with several comorbidities...
We report a very rare case of cT1N0M0 lung adenocarcinoma reveling Lambert-Eaton myasthenic syndrome (LEMS). A 69-year-old nonsmoking woman, with several comorbidities consulted for cough and dyspnea. Chest radiograph and CT scanning detected a left lower lobe mass; Needle biopsy confirmed differentiated adenocarcinoma; 18FDG-PET scan and Brain MRI eliminated metastatic disease dissemination. Our patient underwent a left lower lobectomy with mediastinal lymphadenectomy (pT1N0M0), no adjuvant chemotherapy was administrated. One month later patient present a muscle weakness in both lower limbs and fatigability followed by an inability to walk. The diagnosis of LEMS was made from the distinctive electromyogram (EMG) findings and a treatment with Amifampridine (3, 4-diaminopyridine phosphate [3, 4-DAP]) was prescribed with evident efficacy for symptoms.
PubMed: 34605270
DOI: 10.1177/02184923211051796 -
BMC Neurology Sep 2021Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission. The objective was to examine the efficacy and safety of... (Meta-Analysis)
Meta-Analysis
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.
Topics: 4-Aminopyridine; Adult; Amifampridine; Humans; Lambert-Eaton Myasthenic Syndrome; Myasthenia Gravis; Randomized Controlled Trials as Topic
PubMed: 34563155
DOI: 10.1186/s12883-021-02405-3 -
Plastic and Reconstructive Surgery Aug 2021
Topics: Adult; Amifampridine; Botulinum Antitoxin; Botulinum Toxins, Type A; Botulism; Combined Modality Therapy; Cosmetic Techniques; Female; Humans; Injections; Middle Aged
PubMed: 34233341
DOI: 10.1097/PRS.0000000000008173 -
Biomedicine & Pharmacotherapy =... May 20213,4-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...
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.
Topics: Amifampridine; Animals; Behavior, Animal; Embryo, Nonmammalian; Glycogen Storage Disease Type II; Motor Activity; Muscle Fibers, Skeletal; Neuromuscular Junction; Receptors, Cholinergic; Zebrafish; alpha-Glucosidases
PubMed: 33724918
DOI: 10.1016/j.biopha.2021.111357 -
The Journal of Biological Chemistry 20213,4-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...
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.
Topics: Acetylcholine; Action Potentials; Amifampridine; Animals; Calcium Channels, L-Type; Calcium Channels, N-Type; Dose-Response Relationship, Drug; Female; Gene Expression; Male; Mice; Microelectrodes; Neuromuscular Agents; Neuromuscular Junction; Potassium Channel Blockers; Presynaptic Terminals; Rana pipiens; Shaw Potassium Channels; Tissue Culture Techniques
PubMed: 33465376
DOI: 10.1016/j.jbc.2021.100302 -
Muscle & Nerve Mar 2021
Topics: Amifampridine; Antineoplastic Combined Chemotherapy Protocols; Calcium Channels, P-Type; Calcium Channels, Q-Type; Cerebellar Diseases; Cerebellar Neoplasms; Female; Glucocorticoids; Humans; Immune Checkpoint Inhibitors; Immunoglobulins, Intravenous; Immunologic Factors; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Lymph Nodes; Magnetic Resonance Imaging; Middle Aged; Nerve Degeneration; Neuroendocrine Tumors; Neuromuscular Agents; Nivolumab; Positron Emission Tomography Computed Tomography; Prednisone; Radiosurgery; Radiotherapy; Rituximab; Small Cell Lung Carcinoma; Tomography, X-Ray Computed
PubMed: 33290581
DOI: 10.1002/mus.27141 -
Drugs of Today (Barcelona, Spain : 1998) Oct 2020Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic autoimmune disabling neuromuscular disease caused by antibodies against presynaptic voltage-gated calcium...
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.
Topics: Adult; Amifampridine; Child; Humans; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Small Cell Lung Carcinoma
PubMed: 33185628
DOI: 10.1358/dot.2020.56.10.3137144 -
Tremor and Other Hyperkinetic Movements... Oct 2020The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous...
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 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.
Topics: Adult; Amifampridine; Ataxia; Chorea; Dystonia; Electroencephalography; Female; Hallucinations; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Ocular Motility Disorders; Potassium Channel Blockers
PubMed: 33178487
DOI: 10.5334/tohm.549 -
Expert Opinion on Drug Metabolism &... Jan 2021The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous... (Review)
Review
INTRODUCTION
The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs.
AREAS COVERED
We describe and review data that more clearly defines the effects of haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for phenotype-dependent dosing strategies.
EXPERT OPINION
Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.
Topics: Acetylation; Amines; Arylamine N-Acetyltransferase; Genotype; Hepatocytes; Humans; Hydrazines; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 33094670
DOI: 10.1080/17425255.2021.1840551