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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 -
Experimental Brain Research Nov 2020Although L-DOPA revolutionized in the treatment of Parkinson's disease, most patients developed motor complications after several years of treatment. Adjunctive therapy...
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.
Topics: Amifampridine; Animals; Corpus Striatum; Dopamine; Levodopa; Oxidopamine; Rats
PubMed: 32870323
DOI: 10.1007/s00221-020-05912-w -
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 -
JCI Insight Jan 2020Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning...
Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration-approved potassium channel blocker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4-DAP improved respiration and extended survival at up to 5 LD50 BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A-, B-, and E-induced botulism. These findings make a compelling argument for repurposing 3,4-DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points.
Topics: Amifampridine; Animals; Antitoxins; Botulinum Toxins; Botulinum Toxins, Type A; Botulism; Disease Models, Animal; Female; Lethal Dose 50; Mice; Muscle, Skeletal; Paralysis; Potassium Channel Blockers; Serogroup; United States; United States Food and Drug Administration
PubMed: 31996484
DOI: 10.1172/jci.insight.132891 -
Expert Review of Clinical Pharmacology Nov 2019: Lambert-Eaton myasthenic syndrome is an autoimmune disease of the neuromuscular junction characterized by a presynaptic defect of neuromuscular transmission resulting... (Review)
Review
: Lambert-Eaton myasthenic syndrome is an autoimmune disease of the neuromuscular junction characterized by a presynaptic defect of neuromuscular transmission resulting in muscle weakness and fatigability. Diagnostic features are specific neurophysiological alterations and autoantibody detection. The present review is focused on the use of Amifampridine Phosphate to treat LEMS patients.: Medline search from 1990 to 2019 was examined using the free subject terms: Lambert-Eaton myasthenic syndrome, LEMS, Amifampridine, 3,4-diaminopyridine, which were then combined with Treatment, Therapy, Clinical Trial, Controlled Clinical Trial, Randomized Clinical Trial and Cochrane Review. The author has done a supervised analysis of the retrieved articles and focused on those subjectively evaluated as most relevant.: Data from randomized clinical trials and case series have demonstrated that Lambert-Eaton myasthenic syndrome symptoms were successfully treated by Amifampridine Phosphate. Hence, the drug represents a substantial step forward in the symptomatic treatment of the disease due to its efficacy, safety and reliable GMP formulation. As Amifampridine Phosphate works by enhancing the release of acetylcholine at the neuromuscular junction by blocking K+ efflux at the pre-synaptic membrane, it is also conceivable to use it for other diseases of the neuromuscular junction in which such an effect is searched for.
Topics: Amifampridine; Humans; Lambert-Eaton Myasthenic Syndrome; Neuromuscular Agents; Potassium Channel Blockers; Randomized Controlled Trials as Topic; Tablets
PubMed: 31639317
DOI: 10.1080/17512433.2019.1681972 -
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 -
Expert Review of Clinical Immunology Oct 2019: The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed. : All relevant literature identified through a... (Review)
Review
: The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed. : All relevant literature identified through a PubMed search under treatment of LEMS, aminopyridine, and amifampridine are reviewed. An expert opinion on AFP was formulated. : AFPs, 3,4-DAP and 3,4-DAPP, are the most studied drugs in neuromuscular diseases. Randomized and non-randomized studies showed the most effective drug as symptomatic medication for LEMS. AFPs are safe and tolerable. Thus, AFPs should be the drug of choice for the symptomatic treatment in LEMS. As long as the daily dose is less than 80 mg a day, there is no concern for the serious side-reaction, seizure. Because of short-acting drug effects, it should be given three or four times a day. Peri-oral and finger paresthesia, the most common side-reaction, is accepted as a sign of drug-intake by many patients. Gastro-intestinal side reactions, the next common side-reaction of AFPs, are tolerable. AFPs are also the drug of choice and life-saving for LEMS crisis. For the long-term usage, it is proven to be safe and AFPs can be supplemented with liberal amount of pyridostigmine to sustain a symptomatic improvement without any undue side-reaction.
Topics: Amifampridine; Cholinesterase Inhibitors; Drug and Narcotic Control; Guanidine; Humans; Lambert-Eaton Myasthenic Syndrome; Potassium Channel Blockers; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 31533480
DOI: 10.1080/1744666X.2020.1670061 -
The American Journal of Nursing Sep 2019
Topics: Adolescent; Amifampridine; Child; Female; Humans; Lambert-Eaton Myasthenic Syndrome; Male; Neuromuscular Agents
PubMed: 31449118
DOI: 10.1097/01.NAJ.0000580248.33784.dd -
Biopharmaceutics & Drug Disposition Sep 2019Lambert-Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4-Diaminopyridine (3,4-DAP)...
Lambert-Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4-Diaminopyridine (3,4-DAP) is the recommended therapy for the treatment of LEMS. However, estimations of 3,4-DAP pharmacokinetics in human and animals, such as rats, are rarely reported because 3,4-DAP is an orphan drug for the treatment of a very rare disease (LEMS). In particular, little is known about its tissue distribution. Therefore, the pharmacokinetics of 3,4-DAP were studied, with particular focus on tissue distribution, in rats. After intravenous administration of 3,4-DAP to rats, the half-life of 3,4-DAP was 15.9 ± 3.9 min and the volume of distribution at steady-state was 2.8 ± 0.7 L/kg. The tissue-to-plasma partition coefficient (Kp) was high in the kidney, heart, and muscle. In addition, with increased steady state plasma concentration (Css), a tendency toward increased Kp was found in most tissues. In the muscle, a likely target region of 3,4-DAP in LEMS patients, the Kp was higher than in the plasma. Furthermore, more than 68% of 3,4-DAP was distributed to the muscle as determined by the ratio of 3,4-DAP distribution calculated from the apparent volumes of distribution. Hence, 3,4-DAP may provide for more effective and long-lasting effects.
Topics: Administration, Intravenous; Amifampridine; Animals; Half-Life; Male; Neuromuscular Agents; Rats; Rats, Wistar; Tissue Distribution
PubMed: 31419315
DOI: 10.1002/bdd.2203 -
Current Opinion in Rheumatology Nov 2019This article provides an update on the most recent advances in diagnostic procedures and therapeutic approaches for myasthenia gravis, spanning from autoantibody and... (Review)
Review
PURPOSE OF REVIEW
This article provides an update on the most recent advances in diagnostic procedures and therapeutic approaches for myasthenia gravis, spanning from autoantibody and neuroelectrophysiological tests as diagnostic tools, to innovative and promising treatments based on biological drugs.
RECENT FINDINGS
Novel studies performed by cell-based assays (CBAs) indicate an improvement in the chance of identifying serum autoantibodies in myasthenic patients. Clinical trials on the use of biological drugs were recently concluded, providing important data on safety and efficacy of eculizumab, efgartigimod and amifampridine phosphate: the first, a complement blocker, showed long-term safety and efficacy in acetylcholine receptor (AChR)-positive myasthenic patients with refractory generalized disease; the second, the neonatal Fc receptor blocker, was well tolerated and clinically effective in both AChR-specific and muscle-specific kinase receptor (MuSK)-positive patients; the third, a blocker of presynaptic potassium channels, was found to be well tolerated and effective in MuSK-positive patients.
SUMMARY
CBAs can lead to a significant reduction of seronegative patients, improving myasthenia gravis diagnostic process. New biological drugs offer innovative approaches to treat myasthenic patients with generalized disease, promising to change the paradigm of treatment and to significantly enhance therapeutic success within a precision medicine framework.
Topics: Autoantibodies; Biological Factors; Electromyography; Humans; Immunosuppressive Agents; Myasthenia Gravis; Treatment Outcome
PubMed: 31385879
DOI: 10.1097/BOR.0000000000000647