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Neurology Jan 1986Mammalian motor and sensory fibers respond differently to the potassium channel-blocking agent, 4-aminopyridine (4-AP). The action potentials of the motor fibers...
Mammalian motor and sensory fibers respond differently to the potassium channel-blocking agent, 4-aminopyridine (4-AP). The action potentials of the motor fibers increase in duration after 4-AP, while the sensory fibers respond with bursts of action potentials after a single stimulus. These differences may account for the paresthesias reported by patients with multiple sclerosis following treatment with 4-AP.
Topics: 4-Aminopyridine; Action Potentials; Aminopyridines; Animals; Axons; Motor Activity; Multiple Sclerosis; Nerve Fibers; Paresthesia; Rats; Rats, Inbred Strains; Sensation; Spinal Nerve Roots
PubMed: 3001584
DOI: 10.1212/wnl.36.1.117 -
Brain Research Nov 1988Whole cell voltage-clamp recordings were made from cultured rat neostriatal neurons. Depolarizing voltage commands evoked transient and sustained outward K-currents. The...
Whole cell voltage-clamp recordings were made from cultured rat neostriatal neurons. Depolarizing voltage commands evoked transient and sustained outward K-currents. The transient K-current was activated by depolarizing commands beyond -50 mV; peak current was dependent upon holding potential. Bath application of 4-aminopyridine, but not inorganic calcium channel blockers (Cd, Co, Mn), attenuated the transient current. Reversal was near the K-equilibrium potential. These properties suggest that this transient K-current is similar to the A-current described in a number of other neurons.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Cells, Cultured; Corpus Striatum; Electric Stimulation; Membrane Potentials; Potassium; Rats; Rats, Inbred Strains
PubMed: 2850087
DOI: 10.1016/0006-8993(88)90334-4 -
Brain Research Apr 19814-aminopyridine (4-AP) is known to produce large increases in quantal acetylcholine release from stimulated motor nerve terminals. It has been suggested that the drug...
4-aminopyridine (4-AP) is known to produce large increases in quantal acetylcholine release from stimulated motor nerve terminals. It has been suggested that the drug might act directly on Ca2+ channels to increase Ca2+ influx. This possibility was tested at frog neuromuscular junctions depolarized in elevated [K+]out. The 4-AP did not increase miniature end-plate potential frequencies. Also, 4-AP did not alter the increase in frequency that follows a rise in [Ca2+]out at a depolarized junction. Therefore, under these conditions, 4-AP does not appear to change Ca2+ entry into or elimination from the nerve terminal. The results support the hypothesis that 4-AP acts by lengthening the nerve terminal action potential.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Calcium; Motor Neurons; Neuromuscular Depolarizing Agents; Neuromuscular Junction; Potassium; Rana pipiens
PubMed: 6971693
DOI: 10.1016/0006-8993(81)90928-8 -
Journal of Neurotrauma May 2018Myelin damage is a hallmark of spinal cord injury (SCI), and potassium channel blocker (PCB) is proven effective to restore axonal conduction and regain neurological...
Myelin damage is a hallmark of spinal cord injury (SCI), and potassium channel blocker (PCB) is proven effective to restore axonal conduction and regain neurological function. Aiming to improve this therapy beyond the U.S. Food and Drug Administration-approved 4-aminopyridine (4-AP), we have developed multiple new PCBs, with 4-aminopyridine-3-methanol (4-AP-3-MeOH) being the most potent and effective. The current study evaluated two PCBs, 4-AP-3-MeOH and 4-AP, in parallel in both ex vivo and in vivo rat mechanical SCI models. Specifically, 4-AP-3-MeOH induced significantly greater augmentation of axonal conduction than 4-AP in both acute and chronic injury. 4-AP-3-MeOH had no negative influence on the electrical responsiveness of rescued axons whereas 4-AP-recruited axons displayed a reduced ability to follow multiple stimuli. In addition, 4-AP-3-MeOH can be applied intraperitoneally at a dose that is at least 5 times higher (5 mg/kg) than that of 4-AP (1 mg/kg) in vivo. Further, 5 mg/kg of 4-AP-3-MeOH significantly improved motor function whereas both 4-AP-3-MeOH (1 and 5 mg/kg) and, to a lesser degree, 4-AP (1 mg/kg) alleviated neuropathic pain-like behavior when applied in rats 2 weeks post-SCI. Based on these and other findings, we conclude that 4-AP-3-MeOH appears to be more advantageous over 4-AP in restoring axonal conduction because of the combination of its higher efficacy in enhancing the amplitude of compound action potential, lesser negative effect on axonal responsiveness to multiple stimuli, and wider therapeutic range in both ex vivo and in vivo application. As a result, 4-AP-3-MeOH has emerged as a strong alternative to 4-AP that can complement the effectiveness, and even partially overcome the shortcomings, of 4-AP in the treatment of neurotrauma and degenerative diseases where myelin damage is implicated.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Male; Neural Conduction; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries
PubMed: 29228863
DOI: 10.1089/neu.2017.5297 -
Anesthesia and Analgesia Apr 1982The electroencephalographic (EEG) effects of 4-aminopyridine (4-AP) given intravenously in therapeutic doses were studied in four conscious human volunteers. 4-AP (0.2...
The electroencephalographic (EEG) effects of 4-aminopyridine (4-AP) given intravenously in therapeutic doses were studied in four conscious human volunteers. 4-AP (0.2 mg/kg) caused an increase of the occipital alpha peak frequency of 0.4 to 1.0 Hz. In the dose range of 0.2 to 0.3 mg/kg there was neither evidence for epileptic activity in the EEG nor were any clinical side effects observed. This dose of 4-AP was also found to antagonize diazepam-induced sleep in four volunteers. In addition 4-AP (0.3 mg/kg) hastened the recovery by a factor of 4 in four patients having endoscopic procedures under diazepam-nitrous oxide anesthesia.
Topics: 4-Aminopyridine; Adult; Aminopyridines; Cardiovascular System; Diazepam; Electroencephalography; Humans; Male; Neuromuscular Depolarizing Agents
PubMed: 7199853
DOI: No ID Found -
Journal of Labelled Compounds &... Dec 2016The antimalarial compound MMV390048 ([ C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from...
The antimalarial compound MMV390048 ([ C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [ C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([ C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound.
Topics: Aminopyridines; Animals; Antimalarials; Carbon Radioisotopes; Female; Isotope Labeling; Male; Rats; Sulfones; Tissue Distribution
PubMed: 27646069
DOI: 10.1002/jlcr.3445 -
Brain Research Jun 1982The effects of bath-applied 4-aminopyridine on neurones and extracellular potassium and calcium concentrations were recorded in slices of guinea-pig olfactory cortex....
The effects of bath-applied 4-aminopyridine on neurones and extracellular potassium and calcium concentrations were recorded in slices of guinea-pig olfactory cortex. Neurones were orthodromically activated by stimulating the lateral olfactory tract. 4-Aminopyridine (3-10 microM) had the following effects: (1) an increase in the frequency and amplitude of spontaneous postsynaptic potentials; (2) a prolongation and oscillatory behaviour of orthodromically evoked postsynaptic potentials; (3) induction of spontaneous or stimulus-evoked seizure-type discharges which were accompanied by large rises in extracellular potassium and falls in calcium concentration; (4) a prolongation of the lateral olfactory tract population fibre spike. Prior to paroxysmal depolarization, membrane potential, input resistance and soma spike duration were unaffected. In the seconds before seizure discharges, a late hyperpolarizing potential (evoked by orthodromic stimulation) was reduced in amplitude or abolished. Diphenylhydantoin (50 microM) or magnesium ions (5 mM) prevented paroxysmal activity. Our results show that 4-aminopyridine can produce seizure-type discharges in a brain slice preparation. The role of increased spontaneous potentials and possible loss of synaptic inhibition as causal factors for such discharges is discussed.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Central Nervous System; Cerebral Cortex; Convulsants; Evoked Potentials; Female; Functional Laterality; Guinea Pigs; Male; Membrane Potentials; Neurons; Olfactory Pathways
PubMed: 7104708
DOI: 10.1016/0006-8993(82)91230-6 -
Journal of Neurology, Neurosurgery, and... Jul 1983
Topics: 4-Aminopyridine; Aged; Amifampridine; Aminopyridines; Female; Humans; Middle Aged; Myasthenia Gravis; Neuromuscular Junction; Synaptic Transmission
PubMed: 6310051
DOI: 10.1136/jnnp.46.7.684 -
Clinical Toxicology Jun 1980Four-aminopyridine is an acutely toxic avicide considered by the manufacturer to be a bird "repellant" because only a small number of birds are acutely poisoned, become...
Four-aminopyridine is an acutely toxic avicide considered by the manufacturer to be a bird "repellant" because only a small number of birds are acutely poisoned, become disoriented, and emit a distress cry frightening other members of the flock. Four-aminopyridine dramatically enhances transmission at the neuromuscular junction and other synapses, and has been employed clinically in the treatment of prolonged paralysis caused by antibiotics and muscle relaxants, and in the Eaton-Lambert syndrome. In this paper we report the results of an acute poisoning misadventure in three adult males. We review the animal toxicology, summarize the neurophysiological research using 4-AP as a potassium channel blocker, comment on clinical applications, and outline the management of overdose with this agent.
Topics: 4-Aminopyridine; Adult; Aminopyridines; Animals; Chromatography; Humans; Ion Channels; Male; Potassium
PubMed: 6250762
DOI: 10.3109/15563658008989978 -
Journal of Pharmaceutical Sciences Apr 1983The kinetics of reaction of trans-cinnamic anhydride or trans-cinnamoyl chloride with n-propyl alcohol, catalyzed by N-methylimidazole or 4-dimethylaminopyridine, were...
The kinetics of reaction of trans-cinnamic anhydride or trans-cinnamoyl chloride with n-propyl alcohol, catalyzed by N-methylimidazole or 4-dimethylaminopyridine, were studied spectrophotometrically at 25 degrees in methyl ethyl ketone, ethylene dichloride, methylene chloride, and toluene. The acid chloride reacted in all solvents via the intermediate formation of the N-acyl catalyst, which underwent reaction with the alcohol catalyzed by another molecule of the base. The anhydride did not form the intermediate in any of the solvents, but underwent direct general base catalysis. The rate of the anhydride reactions was not sensitive to solvent polarity, whereas the rate of the chloride reactions tended to increase as the solvent polarity decreased. A kinetic analysis is given of the effect of ion-pair formation on the kinetics of acyl transfer in systems where the charged N-acyl catalyst intermediate is formed.
Topics: 1-Propanol; 4-Aminopyridine; Acylation; Aminopyridines; Catalysis; Cinnamates; Imidazoles; Kinetics; Solvents
PubMed: 6864472
DOI: 10.1002/jps.2600720412