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The Cochrane Database of Systematic... 2001Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have... (Review)
Review
BACKGROUND
Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS).
OBJECTIVES
To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS.
SEARCH STRATEGY
Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies.
SELECTION CRITERIA
Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints.
DATA COLLECTION AND ANALYSIS
We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers.
MAIN RESULTS
Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0).
REVIEWER'S CONCLUSIONS
Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.
Topics: 4-Aminopyridine; Amifampridine; Cross-Over Studies; Humans; Multiple Sclerosis; Potassium Channel Blockers; Randomized Controlled Trials as Topic
PubMed: 11687106
DOI: 10.1002/14651858.CD001330 -
The Cochrane Database of Systematic... 2002The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase nerve conduction in demyelinated nerve fibers, and have been proposed as a... (Review)
Review
BACKGROUND
The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase nerve conduction in demyelinated nerve fibers, and have been proposed as a symptomatic therapy for people with multiple sclerosis (MS).
OBJECTIVES
To determine the efficacy and safety of aminopyridines for neurological deficits in MS people.
SEARCH STRATEGY
We searched CENTRAL (Issue 2, 2002), MEDLINE (January 1966-July 2002), EMBASE (1974-July 2002), and the Cochrane MS Group's Specialised Register. We hand searched bibliographic references from retrieved studies and recent MS symposia reports, and contacted known studies' investigators.
SELECTION CRITERIA
We included trials fulfilling all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints.
DATA COLLECTION AND ANALYSIS
We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from 17 full-paper studies.
MAIN RESULTS
Six studies (eight publications, 198 participants, all crossover trials) were considered. Five studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. Treatment duration ranged from hours to six months. Median quality score of the studies was 3. Heterogeneity of outcome assessment and absence of information on individual study periods allowed quantitative pooling of results for few categorical variables. Of the 198 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Three studies (54 patients) assessed manual muscle testing, with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Nine out of 54 participants (17%) improved in ambulation during study treatment versus none during placebo (p<0.001). A lower EDSS score was found in 13/198 participants during study treatment (7%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in three trials assessing cognitive function. Finally, 47/136 MS people (35%) felt better when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0).
REVIEWER'S CONCLUSIONS
Currently available information allows no unbiased statement about safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs (more than 300 participants). We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.
Topics: 4-Aminopyridine; Amifampridine; Cross-Over Studies; Humans; Multiple Sclerosis; Potassium Channel Blockers; Randomized Controlled Trials as Topic
PubMed: 12804404
DOI: 10.1002/14651858.CD001330 -
Clinical Neuropharmacology 2012Aminopyridines are members of a family of monoamino and diamino derivatives of pyridine, and their principal mechanism of action is dose-dependent blockade of... (Review)
Review
Aminopyridines are members of a family of monoamino and diamino derivatives of pyridine, and their principal mechanism of action is dose-dependent blockade of voltage-gated potassium channels, in particular, fast voltage-gated potassium channels. To date, only 2 main broad-spectrum potassium channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been used as investigational new drugs in various neurological diseases. More recently, licensed versions of these compounds including dalfampridine extended release (Fampyra, Biogen Idec) for the improvement of walking in adult patients with multiple sclerosis, and amifampridine (Firdapse, Biomarin Europe Ltd) for the treatment of Lambert-Eaton myasthenic syndrome have been released, and the costs associated with using these new products highlights the importance of evaluating the clinically meaningful treatment effects of these drugs.The current review summarizes the evidence of aminopyridine use in neurological conditions and in particular presents a systematic review of all randomized trials of 3,4-DAP in Lambert-Eaton myasthenic syndrome to determine the efficacy of this treatment using meta-analysis of clinical and electrophysiological end points.
Topics: 4-Aminopyridine; Amifampridine; Aminopyridines; Animals; Humans; Lambert-Eaton Myasthenic Syndrome; Nervous System Diseases; Potassium Channel Blockers; Randomized Controlled Trials as Topic
PubMed: 22805230
DOI: 10.1097/WNF.0b013e31825a68c5 -
Bioorganic & Medicinal Chemistry Sep 2022A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino...
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino sidechain is reported. A rapid and simple protocol was developed to access these inhibitors in excellent yields. Neuronal nitric oxide synthase (nNOS) is a novel therapeutic target for the treatment of various neurological disorders. The major challenges in designing nNOS inhibitors in humans focus on potency, selectivity over other isoforms of nitric oxide synthases (NOSs), and blood-brain barrier permeability. In this context, we discovered a promising inhibitor, 6-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-methylpyridin-2-amine dihydrochloride, that exhibits excellent potency for rat (K = 46 nM) and human nNOS (K = 48 nM), respectively, with 388-fold human eNOS and 135-fold human iNOS selectivity. It also displayed excellent permeability (P = 17.3 × 10 cm s) through a parallel artificial membrane permeability assay, a model for blood-brain permeability. We found that increasing lipophilicity by incorporation of fluorine atoms on the backbone of the inhibitors significantly increased potential blood-brain barrier permeability. In addition to measuring potency, isoform selectivity, and permeability of NOS inhibitors, we also explored structure-activity relationships via structures of key inhibitors complexed to various isoforms of nitric oxide synthases.
Topics: Aminopyridines; Animals; Enzyme Inhibitors; Humans; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Protein Isoforms; Rats
PubMed: 35772285
DOI: 10.1016/j.bmc.2022.116878 -
Chemistry, An Asian Journal May 2022We developed a facile, efficient method for synthesizing highly substituted 2-aminopyridines from unstable vinyl carbodiimides generated in situ in a one-pot...
We developed a facile, efficient method for synthesizing highly substituted 2-aminopyridines from unstable vinyl carbodiimides generated in situ in a one-pot transformation. A series of novel highly substituted 3-functionalized 2-aminopyridines were produced in good yields. Reaction mechanism studies, which included control experiments and density-functional theory (DFT) calculations, demonstrated that Rh and potassium carbonate played key roles in the cyclization step.
Topics: Aminopyridines; Azides; Cyclization; Ketones
PubMed: 35277925
DOI: 10.1002/asia.202200083 -
Annals of Neurology 1994Because the symptomatic treatments for multiple sclerosis (MS) are limited, new approaches have been sought. Anatomical studies of MS lesions show a relative... (Review)
Review
Because the symptomatic treatments for multiple sclerosis (MS) are limited, new approaches have been sought. Anatomical studies of MS lesions show a relative preservation of axons, and clinical studies suggest that some of the neurological impairment in patients with MS is physiological. Electrophysiological studies suggest that demyelination exposes axonal potassium channels that decrease action-potential duration and amplitude, hindering action-potential propagation. Potassium channel blockers, including aminopyridines, have been shown to improve nerve conduction in experimentally demyelinated nerves. Two potassium channel blockers, 4-aminopyridine (AP) and 3,4 diaminopyridine (DAP) have been tested in patients with MS. Preliminary studies of AP demonstrated benefit in many temperature-sensitive patients with MS, and improvement of function was found in a large randomized double-blind, placebo-controlled crossover trial of 3 months of oral treatment in 68 patients with MS. An open-label trial of DAP showed improvement in some deficits, and a double-blind placebo-controlled trial showed significant improvements in prospectively defined neurological deficits. A crossover comparison of the two agents suggested that AP produces more central nervous system side effects (dizziness and confusion), whereas DAP produces more peripheral side effects (paresthesias and abdominal pain). Both agents have rarely caused seizures. These studies suggest that aminopyridines may provide a new approach to the symptomatic treatment of MS.
Topics: 4-Aminopyridine; Amifampridine; Clinical Trials as Topic; Double-Blind Method; Humans; Multiple Sclerosis; Placebos; Prospective Studies
PubMed: 8017870
DOI: 10.1002/ana.410360728 -
Journal de Pharmacologie 1985In this review the effects of aminopyridines and chemically related compounds are documented in an attempt to analyse the mechanism underlying their presynaptic actions... (Comparative Study)
Comparative Study Review
In this review the effects of aminopyridines and chemically related compounds are documented in an attempt to analyse the mechanism underlying their presynaptic actions at the vertebrate neuromuscular junction. Aminopyridines and related compounds are of particular interest because they greatly increase the amount of acetylcholine released in response to both conducted nerve impulses and electrotonic depolarizations of tetrodotoxin blocked motor nerve terminals. The apparent rank order of potency for increasing quantal transmitter release evoked by nerve impulse at physiological pH was as follows: 3,4-diaminopyridine greater than 4-aminopyridine greater than 4-aminoquinoline greater than 3-aminopyridine greater than 2,6-diaminopyridine greater than 2-aminopyridine greater than 4-nitropyridine greater than 4-aminopyridine N-oxyde greater than 4-hydroxypyridine greater than 2,4-dihydroxypyridine. The fact that both pyridine and aniline were found to be inactive indicate that both a pyridine ring and an amino-substituent are necessary for activity. A common site of action for the drugs here reported should be rationalized on the basis that their protonated molecular forms generate a common electrostatic potential field pattern. This results together with those concerning the dependence of pyridine activity on extracellular pH leads to the conclusion that this family of compounds exert its activity at the internal face of the motor nerve terminal membrane. Aminopyridines in concentrations that increase transmitter release evoked by nerve impulses block potassium conductance in motor nerve terminals and lengthen the presynaptic action potential, this effect leads to an enhanced calcium influx and consequently to an increase in acetylcholine release. The fact that aminopyridines had no consistent effect on transmitter release at junctions depolarized by elevated potassium ions strongly supports the view that these drugs have no direct effect on voltage-dependent calcium channels and that their primary site of action is on voltage-sensitive potassium channels of motor nerve terminals.
Topics: 4-Aminopyridine; Acetylcholine; Amifampridine; Aminopyridines; Aminoquinolines; Animals; Anura; In Vitro Techniques; Ion Channels; Membrane Potentials; Motor Endplate; Neuromuscular Junction; Potassium; Pyridines; Synaptic Transmission; Vertebrates
PubMed: 2417060
DOI: No ID Found -
Journal of Medicinal Chemistry Aug 2021Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified...
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound , with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
Topics: Aminopyridines; Animals; Anti-Inflammatory Agents; Class Ib Phosphatidylinositol 3-Kinase; Female; Humans; Inflammation; Molecular Structure; No-Observed-Adverse-Effect Level; Protein Kinase Inhibitors; Pyrazines; Rats, Sprague-Dawley; Structure-Activity Relationship; Rats
PubMed: 34384024
DOI: 10.1021/acs.jmedchem.1c00986 -
Organic & Biomolecular Chemistry May 2022We report a method for gold(III)/sodium diphenylphosphinobenzene-3-sulfonate (TPPMS)-catalyzed direct amination of benzhydrols using 2-aminopyridines with poor...
We report a method for gold(III)/sodium diphenylphosphinobenzene-3-sulfonate (TPPMS)-catalyzed direct amination of benzhydrols using 2-aminopyridines with poor nucleophilic character in water. Various functional groups such as electron-withdrawing nitro, cyano and halogen groups were tolerated well to form the desired -benzylated 2-aminopyridine compounds. On the basis of mechanistic studies including kinetic profiles, Hammett study and isotope effects, we propose a pathway in which a Lewis acidic gold cation species activates the sp C-O bond of the alcohol in the rate-determining step.
Topics: Amination; Aminopyridines; Benzhydryl Compounds; Catalysis; Cations; Electrons; Gold; Water
PubMed: 35537142
DOI: 10.1039/d2ob00673a -
Anaesthesia and Intensive Care May 19824-aminopyridine is the first of the aminopyridines to be used in clinical practice. It blocks potassium channels and thereby increases acetylcholine, and possibly... (Review)
Review
4-aminopyridine is the first of the aminopyridines to be used in clinical practice. It blocks potassium channels and thereby increases acetylcholine, and possibly noradrenaline, release at nerve terminals. In man the drug has a significant action at the neuromuscular junction, but has little effect on the autonomic nervous system or muscle (smooth, skeletal, or cardiac) although such actions have been demonstrated in animals. It may be clinically useful in the reversal of nondepolariser blockade and a role in antibiotic associated block has been proposed. It may be used effectively as an analeptic agent. It appears to be a useful therapeutic agent in myasthenia gravis and Eaton Lambert syndrome, although of limited use in botulism. It effects on the central nervous system are considerable. These account for the major side effects of the drug which include tremor, excitability and convulsions.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Botulism; Central Nervous System; Humans; Ion Channels; Myasthenia Gravis; Neuromuscular Blocking Agents; Neuromuscular Depolarizing Agents; Neuromuscular Diseases; Neuromuscular Junction; Structure-Activity Relationship
PubMed: 6285756
DOI: 10.1177/0310057X8201000205