Amifampridine overdose leading to refractory status epilepticus.

3,4-Aminopyridine or Amifampridine belongs to the aminopyridine class of drugs which is used to treat multiple sclerosis and Lambert-Eaton Myasthenic Syndrome (LEMS). Aminopyridine pharmaceuticals inhibit presynaptic potassium channels. This increases available acetylcholine in the nerve cleft which leads to improved strength in this patient population. While overdoses have been reported of 4-Aminopyridine, no case reports of acute 3.4-Aminopyridine overdose are currently available. A 67 year old man presented to the emergency department 30 min after ingesting 100 mg of amifampridine in a suicide attempt. Within an hour of ingestion he experienced tachycardia, tachypnea, hypertension and tremor. The patient then started to experience seizures and had a cardiac arrest 3 h after the ingestion. The patient achieved return of spontaneous circulation but proceeded to have refractory seizures. Despite significant and escalating doses of anti-epileptic medications, the patient continued to have seizures until 18 h after ingestion. His anti-epileptic medications were weaned over the following days and he had no more seizures. This is a report of a novel overdose of 3,4-Aminopyridine, a medication that belongs to the aminopyridine class of pharmaceuticals that have been well used for many years. Aminopyridine overdoses are commonly thought to carry low morbidity and mortality; however, our patient had both a cardiac arrest and refractory status epilepticus. Ultimately, this case suggests that patients who overdose on 3,4-Aminopyridine could become critically ill and their presentation may be far more severe than that of other medications of the same class.

A Massive Overdose of Dalfampridine.

Multiple sclerosis (MS) is an immune mediated inflammatory disease that attacks myelinated axons in the central nervous system. Dalfampridine (4-aminopyridine) was approved by the Food and Drug Administration in January 2010 for treatment of MS. Our patient was a 34-year-old male with a history of MS, who was brought to the emergency department after being found unresponsive. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri intravenous (IV) infusion. Fifteen minutes after arrival the patient seized. The seizures were refractory to benzodiazepines, barbiturates and phenytoin. The 4-AP level was 530 ng/mL (25 ng/mL and 49 ng/mL). The patient stopped seizing on hospital day 3 and was discharged 14 days later with normal mental status and neurologic exam. 4-AP is a potassium channel blocker that blocks the potassium ion current of repolarization following an action potential. The blockade of the potassium channel at the level of the membrane widens the action potential and enhances the release of acetylcholine, thus increasing post-synaptic action potentials. The treatment of patients with 4-AP overdose is supportive. Animal data suggest that patients with toxic levels of 4-AP may respond to phenytoin. Our case illustrates the highest recorded level of 4-AP in an overdose. Our patient appeared to be refractory to a combination of high doses of anticonvulsants and only improved with time.

Effects of the antitussive drug cloperastine on ventricular repolarization in halothane-anesthetized guinea pigs.

Cloperastine is an antitussive drug, which can be received as an over-the-counter cold medicine. The chemical structure of cloperastine is quite similar to that of the antihistamine drug diphenhydramine, which is reported to inhibit hERG K⁺ channels and clinically induce long QT syndrome after overdose. To analyze its proarrhythmic potential, we compared effects of cloperastine and diphenhydramine on the hERG K⁺ channels expressed in HEK293 cells. We further assessed their effects on the halothane-anesthetized guinea-pig heart under the monitoring of monophasic action potential (MAP) of the ventricle. Cloperastine inhibited the hERG K⁺ currents in a concentration-dependent manner with an IC50 value of 0.027 µM, whose potency was 100 times greater than that of diphenhydramine (IC50; 2.7 µM). In the anesthetized guinea pigs, cloperastine at a therapeutic dose of 1 mg/kg prolonged the QT interval and MAP duration without affecting PR interval or QRS width. Diphenhydramine at a therapeutic dose of 10 mg/kg prolonged the QT interval and MAP duration together with increase in PR interval and QRS width. The present results suggest that cloperastine may be categorized as a QT-prolonging drug that possibly induces arrhythmia at overdoses like diphenhydramine does.

Severe accidental overdose of 4-aminopyridine due to a compounding pharmacy error.

BACKGROUND: 4-Aminopyridine (4-AP) is a potassium channel-blocking drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction. It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from compounding pharmacies with a physician's prescription. Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, tremor, delirium, choreoathetosis, and seizures. OBJECTIVES: To report a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error. CASE REPORT: A 42-year-old man with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, taking 4-AP, presented to the Emergency Department with the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Toxicity due to 4-AP was suspected and the patient was treated symptomatically. He recovered with permanent short-term memory loss after a prolonged and complicated hospital course. Analysis of the pills, which had been prescribed for him by a physician and specially compounded by a pharmacist, showed that they contained approximately 10 times the dose indicated on the label, a dose that reliably produces severe toxicity. CONCLUSION: Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies, and that quality control of made-to-order drug compounding may not be up to the standard that is expected with mass-produced pharmaceuticals.

Extraordinary conservation, gene loss, and positive selection in the evolution of an ancient neurotoxin.

The recent determination of the genetic basis for the biosynthesis of the neurotoxin, saxitoxin, produced by cyanobacteria, has revealed a highly complex sequence of reactions, involving over 30 biosynthetic steps encoded by up to 26 genes clustered at one genomic locus, sxt. Insights into evolutionary-ecological processes have been found through the study of such secondary metabolites because they consist of a measurable phenotype with clear ecological consequences, synthesized by known genes in a small number of species. However, the processes involved in and timing of the divergence of prokaryotic secondary metabolites have been difficult to determine due to their antiquity and the possible frequency of horizontal gene transfer and homologous recombination. Through analyses of gene synteny, phylogenies of individual genes, and analyses of recombination and selection, we identified the evolutionary processes of this cluster in five species of cyanobacteria. Here, we provide evidence that the sxt cluster appears to have been largely vertically inherited and was therefore likely present early in the divergence of the Nostocales, at least 2,100 Ma, the earliest reliably dated appearance of a secondary metabolite. The sxt cluster has been extraordinarily conserved through stabilizing selection. Genes have been lost and rearranged, have undergone intra- and interspecific recombination, and have been subject to duplication followed by positive selection along the duplicated lineage, with likely consequences for the toxin analogues produced. Several hypotheses exist as to the ecophysiological role of saxitoxin: as a method of chemical defense, cellular nitrogen storage, DNA metabolism, or chemical signaling. The antiquity of this gene cluster indicates that potassium channels, not sodium channels, may have been the original targets of this compound. The extraordinary conservation of the machinery for saxitoxin synthesis, under radically changing environmental conditions, shows that it has continued to play an important adaptive role in some cyanobacteria.

Electrocardiographic abnormalities associated with poisoning.

This article will review the cardiovascular toxicities of various medications, stressing the electrocardiographic presentation--both rhythm and morphological issues--and emphasizing recognition and management issues. Cardiovascular toxins are grouped into categories causing similar electrocardiographic effects, including the potassium efflux blockers, sodium channel blockers, sodium-potassium adenosine triphosphatase blockers (ie, digitalis compounds), calcium channel blockers, and beta-adrenergic blockers. This article reviews the various electrocardiographic abnormalities associated with these 5 classes of agents, ranging from morphological abnormalities and conduction blocks to brady- and tachyarrhythmias.

Dendrotoxin poisoning in a neurobiochemist.

BACKGROUND: Dendrotoxin is a highly potent blocker of KV1.1, KV1.2, and KV1.6 potassium channels that is derived from the venom of the green mamba (Dendroaspis angusticeps). It is commonly used to inhibit the function of whole nerve preparations in vitro. Despite the widespread use and potency of this compound, neurotoxicity in humans has not been described from refined toxin. We report a case of dendrotoxin toxicity from dermal exposure. CASE REPORT: A healthy 40-year-old female neurobiochemist presented with complaints of progressive numbness of the left malar region and lateral orbit that progressed to include the medial orbit and tongue. One hour prior to presentation she used her bare hands to remove residual petroleum jelly from a dish that had previously contained 500 nanoliters of 500 nanomolar dendrotoxin. She recalled rubbing her left eye prior to the onset of symptoms. Before touching the dish, she had washed it with running water and then 70% ethanol while using latex gloves. Physical examination was remarkable only for weakness to superior gaze and some mild tongue fasciculations. Within 12 hours of exposure, she was completely asymptomatic. CONCLUSION: Dendrotoxin is a highly potent neurotoxin that can cause localized impairment of nerve function after mucous membrane exposure.

4-aminopyridine poisoning of crows in the Chicago area.

Poisoning of crows with the avicide 4-aminopyridine is reported. Seven crows had frequent vocalization and nervous signs; 6 died. Postmortem examination of 4 found evidence of trauma and corn-based bait present in the gastrointestinal tract. The bait contained 4-aminopyridine, a rapidly fatal nervous system toxin. When utilized by pest control professionals using manufacturer's recommendations, 4-aminopyridine has little risk of direct or relay toxicosis to non-target species. Treatment of exposed individuals involves symptomatic care and control of seizures.