4-Aminopyridine (fampridine) effectively treats amlodipine poisoning: a case report

Wilffert, Bob; Boskma, R. J.; Voort, Peter H. J. van der; Uges, Donald; Roon, van Eric; Brouwers, Jacobus

doi:10.1111/j.1365-2710.2007.00861.x

Cited by 7 publications

(3 citation statements)

References 5 publications

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“…Because 4-AP blocks voltage-activated K 1 channels only at millimolar concentrations (Wu et al, 2009), our study provides further evidence that 4-AP-induced increases in Ca 21 influx and neurotransmitter release in various experimental preparations are predominantly through its direct stimulating effect on HVA Ca 21 channels. In addition, 4-AP has been used to effectively treat patients who have overdosed on L-type Ca 21 channel blockers (ter Wee et al, 1985;Hofer et al, 1993;Wilffert et al, 2007). Our study thus provides a novel mechanistic basis for using 4-AP as an antidote to treat the overdose symptoms of L-type Ca 21 channel blockers.…”

Section: Ca 21 Channel Subunits and 4-aminopyridine Actionsmentioning

confidence: 99%

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Chen

et al. 2014

Molecular Pharmacology

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4-Aminopyridine (4-AP, fampridine) is used clinically to improve neuromuscular function in patients with multiple sclerosis, spinal cord injury, and myasthenia gravis. 4-AP can increase neuromuscular and synaptic transmission by directly stimulating high voltageactivated (HVA) Ca 21 channels independent of its blocking effect on voltage-activated K 1 channels. Here we provide new evidence that the potentiating effect of 4-AP on HVA Ca 21 channels depends on the specific combination of voltage-activated calcium channel a1 (Cava 1 ) and voltage-activated calcium channel b (Cavb) subunits. Among the four Cavb subunits examined, Cavb3 was the most significant subunit involved in the 4-AP-induced potentiation of both L-type and N-type currents. Of particular note, 4-AP at micromolar concentrations selectively potentiated L-type currents reconstituted with Cav1.2, a 2 d1, and Cavb3. In contrast, 4-AP potentiated N-type currents only at much higher concentrations and had little effect on P/Q-type currents. In a phrenic nerve-diaphragm preparation, blocking L-type Ca 21 channels eliminated the potentiating effect of low concentrations of 4-AP on end-plate potentials. Furthermore, 4-AP enhanced the physical interaction of Cav1.2 and Cav2.2 subunits to Cavb3 and also increased their trafficking to the plasma membrane. Site-directed mutagenesis identified specific regions in the guanylate kinase, HOOK, and C-terminus domains of the Cavb3 subunit crucial to the ability of 4-AP to potentiate L-type and N-type currents. Our findings indicate that 4-AP potentiates HVA Ca 21 channels by enhancing reciprocal Cav1.2-Cavb3 and Cav2.2-Cavb3 interactions. The therapeutic effect of 4-AP on neuromuscular function is probably mediated by its actions on Cavb3-containing L-type Ca 21 channels.

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Section: Ca 21 Channel Subunits and 4-aminopyridine Actionsmentioning

confidence: 99%

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Chen

et al. 2014

Molecular Pharmacology

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“…However, an additive effect of 4-AP and levosimendan on hemodynamics was not seen [32]. Nevertheless, case series demonstrating the effectiveness of 4-AP in the treatment of severe calcium channel blocker toxicity in humans have been published [33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

4-Aminopyridine Toxicity: a Case Report and Review of the Literature

et al. 2012

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“…shock and metabolic acidosis), which could be medicated with intravenous injection or infusion of calcium salts 93,94 , however it could be effective not in all cases. At intoxication by amlodipine or other CCBs it is recommended 4-aminopyridine (fampridine) use 95 .…”

Section: K Mitochondria As Amlodipine Drug Target: Ca 2+mentioning

confidence: 99%

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2012

IJPSR

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Amlodipine is the third generation calcium antagonist, 1,4-dihydropyridine derivative with the prolonged duration of the antihypertensive action, especially blocking L-type Ca 2+ ion channels. It promotes beneficial therapeutic effect by coronary and other blood vessel diseases and thus delays development of the atherosclerosis. It has several known trade names, the most mentioned is Norvasc. Amlodipine is well tolerated in the clinics, it could be used in combinations with other drugs-diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, statins. Amlodipine at nanomolar concentrations binds to the voltage-dependent L-type calcium channels. It possesses optimal lipophylicity. Amlodipine also influences the NO-dependent metabolic processes, stimulates NO synthesis and prolongs NO action duration. Results of the studies of the amlodipine pharmacological and clinical properties are summarized in several reviews. The present review contains opinion from the scientific works of the last decades about the multisided or pleiotropic amlodipine mechanisms of action, it contains information about sometimes controversial clinical studies of the amlodipine vaso-and cardioprotective activity. INTRODUCTION: Amlodipine is the third generation calcium antagonist, 1, 4-dihydropyridine (1, 4-DHP) compound with prolonged action. It has expressed properties of Ca 2+ channel (especially L-type and Ttype) blockers (CCB). Besides, it exerts multisided (pleiotropic, namely, when a drug has actions other than those for which the compound was specifically indicated or developed) effects on other metabolic processes. It is the basis for the beneficial therapeutic action at heart and vasculature diseases and delays the development of atherosclerosis 1-11. This drug is well tolerated by patients. It has no significant side effects. It could be used in the monotherapy, as well in combination with other drugs-diuretics, angiotensineconverting enzyme (ACE) inhibitors, antagonists of the angiotensine II receptors, statins 12, 13, 14, 15. Amlodipine at nanomolar concentrations binds to the voltage-dependent L-type calcium channels. It has optimal lipophylicity, and it has a free aminogroup, which garantees the good bioavailability 9. Amlodipine also influences the NO-dependent metabolic processes too, it stimulates NO synthesis and prolongs NO action duration 16. Results of the studies of amlodipine pharmacological and clinical properties are summarized in several reviews 9, 12, 17-20. This review summarizes outlook about experimental materials from the last decades concerning amlodipine pleiotropy in the action mechanism, as well sometimes controversial clinical observations about its cardioprotective and vazoprotective action.

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4-Aminopyridine (fampridine) effectively treats amlodipine poisoning: a case report

Cited by 7 publications

References 5 publications

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

4-Aminopyridine Toxicity: a Case Report and Review of the Literature

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