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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 -
Clinical Therapeutics Jul 2015Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure.
METHODS
This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N-acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0-∞, AUC0-t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0-∞, AUC0-t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use.
FINDINGS
Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed.
IMPLICATIONS
At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.
Topics: 4-Aminopyridine; Administration, Oral; Adult; Amifampridine; Area Under Curve; Biological Availability; Cross-Over Studies; Eating; Fasting; Female; Food-Drug Interactions; Half-Life; Healthy Volunteers; Humans; Male; Middle Aged; Phosphates; Therapeutic Equivalency; Young Adult
PubMed: 26101174
DOI: 10.1016/j.clinthera.2015.05.498 -
The American Journal of Emergency... Jun 20243,4-Aminopyridine or Amifampridine belongs to the aminopyridine class of drugs which is used to treat multiple sclerosis and Lambert-Eaton Myasthenic Syndrome (LEMS)....
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.
Topics: Humans; Male; Aged; Drug Overdose; Status Epilepticus; Potassium Channel Blockers; Amifampridine; Suicide, Attempted; Anticonvulsants
PubMed: 38693021
DOI: 10.1016/j.ajem.2024.04.023 -
Dalton Transactions (Cambridge, England... Jan 2024The 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...
Complexation of drug amifampridine with Cu(II), Zn(II) and Cd(II) ions, and its dimerization with the magic of Mn(II) salts. Potential anti-COVID-19 and anticancer activities.
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)Cl] (1), a binuclear complex of cadmium(II), [Cd(AMP)Cl] (2), three five-coordinate tren-based metal complexes, [Cu(tren)(AMP)](ClO) (8), [Zn(tren)(AMP)]Cl (9) and [Cd(tren)(AMP)](ClO) (10), three pyridinium salts, [AmpDimer]X (X = Cl, NO, ClO; (3, 4 & 5)), and also two four-coordinate metal complexes with this pyridinium cation, [Zn(AmpDimer)Cl] (6) and [Cd(AmpDimer)Cl] (7), were synthesized. All new compounds were characterized by elemental analysis and IR spectroscopy, and by H- and C-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)] 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.
Topics: Cadmium; Salts; Amifampridine; Coordination Complexes; Molecular Docking Simulation; Dimerization; Metals; Zinc; Ions
PubMed: 38099626
DOI: 10.1039/d3dt03281g -
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 -
Nursing May 2020This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Topics: Amifampridine; Antibodies, Monoclonal; Azetidines; Benzyl Compounds; Diterpenes; Drug Approval; Heterocyclic Compounds, 3-Ring; Humans; Peptides, Cyclic; Polycyclic Compounds; Rifamycins; Thioglycolates; United States; United States Food and Drug Administration; alpha-MSH
PubMed: 32332502
DOI: 10.1097/01.NURSE.0000659300.97243.8f -
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 -
BMJ Case Reports Feb 2022Lambert-Eaton Myasthenic Syndrome (LEMS) is a neuromuscular junction defect that results in weakness. It is rarely seen in children and most commonly is associated with...
Lambert-Eaton Myasthenic Syndrome (LEMS) is a neuromuscular junction defect that results in weakness. It is rarely seen in children and most commonly is associated with small-cell lung cancer. Diagnosis of LEMS requires characteristic electromyogram (EMG) findings and the detection of antibodies directed against voltage-gated calcium channels. We report the case of an 8-year-old female child who presented with profound weakness found to have EMG evidence of a neuromuscular junction defect and detectable antivoltage-gated calcium channel antibodies. She received plasma exchange electrophoresis, intravenous immunoglobulin, oral steroids and amifampridine with some clinical improvement. We present a case of a child with a demonstrated autoimmune propensity and no evidence of malignancy, thereby adding to the 12 previously reported cases of LEMS in children.
Topics: Child; Female; Humans; Immunoglobulins, Intravenous; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Small Cell Lung Carcinoma
PubMed: 35228217
DOI: 10.1136/bcr-2021-245773 -
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 -
Neurologia I Neurochirurgia Polska Jun 2024Lambert-Eaton myasthenic syndrome (LEMS) is an ultrarare neuromuscular disease with a triad of symptoms: muscle paresis, dysautonomy, and areflexia. Amifampridine is the...
INTRODUCTION
Lambert-Eaton myasthenic syndrome (LEMS) is an ultrarare neuromuscular disease with a triad of symptoms: muscle paresis, dysautonomy, and areflexia. Amifampridine is the symptomatic treatment of LEMS.
AIM OF STUDY
To assess the effectiveness and safety of treatment in the real world.
MATERIAL AND METHODS
14 patients with non-neoplastic LEMS treated with amifampridine were enrolled in the study (female 42.9%, mean age 48.8 ± 11.4 years). The patients were assessed using the Quantitative Myasthenia Gravis (QMG) scale, QMG limb domain (LD) score, spirometry, Hand Grip Strength (GRIP) test, and repetitive nerve stimulation study (RNS) at baseline and at the end of follow-up. Diagnostic delay since first symptoms was from seven months up to 22 years. Treatment delay ranged from one to 26 years. The patients were treated and reevaluated after 21.1 ± 12.0 weeks (range 13-48).
RESULTS
All of the patients improved in QMG score. Mean improvement was 5.1 ± 2.0 (range 1-8) points (p < 0.001) and this showed no correlation with the duration of the disease before treatment (p = 0.477). 85.7% of patients (N = 12) improved ≥ 3 points (clinically meaningful) in QMG. 78.6% of the patients improved in QMG LD (mean 2.2 ± 1.6 points (p < 0.001)). Also, forced vital capacity (FVC) improved after treatment (p = 0.031). Mean improvement in GRIP test was 7.0 ± 7.1 kg in the right hand and 5.2 ± 7.5 kg in the left hand (p < 0.001). In RNS before treatment, facilitation ( > 100%) was observed in 78.6% (N = 11) of patients, and was higher before treatment (p < 0.001). Compound muscle action potential (CMAP) amplitude was higher after treatment (p < 0.001). Mean increase of CMAP amplitude was 2.1 ± 1.6 times. In 64.3% (N = 9) of patients lowering of corticosteroid dose was achieved.
CONCLUSIONS
Amifampridine is an effective treatment in non-neoplastic LEMS patients, regardless of disease duration. The treatment is well-tolerated and allows to reduce dose of corticosteroids in the majority of patients.
PubMed: 38935421
DOI: 10.5603/pjnns.99335