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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 -
DNA and Cell Biology Oct 2020In this work, we have investigated the strength and mechanism of amifampridine (3,4-Diaminopyridine/3,4-DAP) interaction with calf thymus DNA (ct-DNA). The existence and...
In this work, we have investigated the strength and mechanism of amifampridine (3,4-Diaminopyridine/3,4-DAP) interaction with calf thymus DNA (ct-DNA). The existence and the strength of interaction are evaluated using circular dichroism (CD), UV-vis absorption, and differential pulse voltammogram studies. Results from UV-vis absorption technique indicate that amifampridine can significantly interact with DNA through a binding constant of = 1.66 × 10 M at 298 K. The mechanism of the interaction between amifampridine and DNA is also studied using ionic effect investigations, competitive fluorescence experiments, viscosity measurements, and molecular docking studies. The viscosity results indicate that amifampridine can bind to DNA via intercalation binding mode. Competitive fluorescence experiments using Acridine Orange (AO) and Hoechst 33258 (HO) probes also reveal that amifampridine binds to DNA via an intercalation mode of binding. Finally, the molecular docking studies also suggest that amifampridine tends to bind with the G-C rich region of DNA.
PubMed: 33090906
DOI: 10.1089/dna.2020.5618 -
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 -
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 -
Continuum (Minneapolis, Minn.) Dec 2022This article reviews the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and botulism, presynaptic... (Review)
Review
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.
Topics: Humans; Lambert-Eaton Myasthenic Syndrome; Botulism; Amifampridine; Autonomic Nervous System Diseases
PubMed: 36537971
DOI: 10.1212/CON.0000000000001205 -
Pharmacology Research & Perspectives Feb 2015The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl...
Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.
The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.
PubMed: 25692017
DOI: 10.1002/prp2.99 -
Neurology Aug 2004
Topics: 4-Aminopyridine; Amifampridine; Animals; Calcium Channels; Calcium Channels, N-Type; Calcium Channels, P-Type; Calcium Channels, Q-Type; Cerebellar Cortex; Female; Gravitation; Haplorhini; Humans; Male; Mice; Mice, Knockout; Models, Neurological; Nystagmus, Pathologic; Otolithic Membrane; Potassium Channel Blockers; Reflex, Abnormal; Reflex, Vestibulo-Ocular
PubMed: 15326227
DOI: 10.1212/01.wnl.0000138374.62591.f3 -
Postgraduate Medical Journal Sep 1999The Lambert-Eaton myasthenic syndrome is a neuromuscular disorder characterised by defective neurotransmitter release at autonomic neurones and presynaptic terminals of... (Review)
Review
The Lambert-Eaton myasthenic syndrome is a neuromuscular disorder characterised by defective neurotransmitter release at autonomic neurones and presynaptic terminals of the neuromuscular junction. It is caused by an IgG autoantibody formed against especially the P/Q type of voltage-gated calcium channels (VGCC) which is an essential component of the mechanism of neurotransmitter release. Many patients have an associated small cell carcinoma of the lung which appears to provide the antigenic stimulus for antibody production, although there is another group with no underlying malignancy. Both groups show an association with immunological disorders. Assay of VGCC antibody titres and electrophysiological tests help to differentiate Lambert-Eaton myasthenic syndrome from other disorders of the neuromuscular junction. Several drugs and therapeutic interventions capable of producing significant clinical improvement are currently available. Patients should also be investigated for underlying tumours, the specific treatment of which can result in remission or amelioration of symptoms.
Topics: 4-Aminopyridine; Amifampridine; Anti-Inflammatory Agents; Autoantibodies; Calcium Channels; Carcinoma, Small Cell; Genetic Predisposition to Disease; HLA-B8 Antigen; Humans; Immunoglobulins, Intravenous; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Plasma Exchange; Potassium Channels; Prednisolone
PubMed: 10616683
DOI: 10.1136/pgmj.75.887.516 -
Cureus Aug 2019Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune-mediated neurological disorder that manifests as muscle fatigue, diminished tendon reflexes, with symptoms of... (Review)
Review
Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune-mediated neurological disorder that manifests as muscle fatigue, diminished tendon reflexes, with symptoms of cholinergic overactivity. It can be associated with certain neoplastic conditions, the most common being small cell lung carcinoma (SCLC). The basic pathophysiology involved is antibody-mediated targeting of voltage-gated calcium channels (VGCC), which decreases the release of acetylcholine in the synaptic junction. Multiple treatment options have been introduced in the past and, recently, a new drug, amifampridine, has been approved by the Food and Drug Administration (FDA) for the treatment of weakness associated with these patients. We summarize this newly introduced drug with a brief description of other treatment options available.
PubMed: 31637147
DOI: 10.7759/cureus.5450 -
Revue Neurologique Feb 2004The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile... (Review)
Review
The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure), augmentation of strength during initial voluntary activation, and depressed tendon reflexes with post-tetanic potentiation. The disorder is paraneoplastic (small cell lung cancer) in about 60p. cent (P-LEMS); no cancer is associated in the remainder (NP-LEMS). LEMS affects all races. NP-LEMS can occur in childhood as well as adult life; P-LEMS is unusual at<30 Years. The weakness results from a reduction in the quantal release of acetylcholine from motor nerve terminals, caused by autoantibodies to P/Q-type voltage-gated calcium channels (VGCCs) that are provoked by tumour VGCCs in P-LEMS; the stimulus in NP-LEMS is not known. These antibodies may be implicated in the rarely associated cerebellar degeneration. The diagnosis can be confirmed by detecting the specific antibody in a radioimmunoprecipitation assay, and by finding a reduced compound muscle action potential amplitude that increases by>100p. cent following maximum voluntary activation. Most patients benefit from 3,4-diaminopyridine; pyridostigmine is less effective. Specific tumour therapy in P-LEMS will often ameliorate the neurological disorder. In those with severe weakness, IVIg or plasmapheresis confers short-term benefits. Prednisone alone or combined with azathioprine or cyclosporin can achieve long-term control of the disorder.
Topics: 4-Aminopyridine; Amifampridine; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Calcium Channels, P-Type; Calcium Channels, Q-Type; Carcinoma, Small Cell; Cholinesterase Inhibitors; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Neoplasm Proteins; Plasmapheresis; Potassium Channel Blockers; Pyridostigmine Bromide
PubMed: 15034474
DOI: 10.1016/s0035-3787(04)70888-7