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.

A review of 29 incidents involving 4-aminopyridine in non-target species reported to the ASPCA Animal Poison Control Center.

4-Aminopyridine (4-AP) is an avicide used in products that are approved by the Environmental Protection Agency (EPA) to control populations of various birds. Pharmaceutical 4-AP is also used in humans to treat neural and muscular dysfunctions associated with multiple sclerosis. Although strict restrictions for its use are in place, exposures to 4-AP bait by non-target species still occur. Twenty-nine exposures of 4-AP bait involving non-target species were identified and retrieved from the ASPCA Animal Poison Control Center medical record database. Canines were the most commonly exposed (86 %) species followed by felines (10 %). The highest frequency of exposures was reported from Colorado (22 %). Most commonly reported clinical signs in canines were tremors, hypersalivation, seizures, tachycardia, and ataxia. The onset time of signs ranged from 5 to 300 min with an average of 89 min. Clinical signs lasted from 15 to 84 h with an average of 37 h. Patient outcome was known in six cases; one dog died 4 h after the exposure and five made full recovery with supportive care. Treatment of five surviving patients included administration of activated charcoal, use of anticonvulsants and muscle relaxants like diazepam and methocarbamol, and intravenous fluids. Diagnosis of 4-AP toxicosis can be supported by testing the gastric contents of the exposed patient. Due to the rapid absorption, samples need to be collected and frozen/chilled promptly. For successful patient outcome, treatment must be implemented quickly after an exposure.

4-aminopyridine toxicity: a case report and review of the literature.

INTRODUCTION: 4-Aminopyridine (4-AP) selectively blocks voltage-gated potassium channels, prolongs the action potential, increases calcium influx, and subsequently, enhances interneuronal and neuromuscular synaptic transmission. This medication has been studied and used in many disease processes hallmarked by poor neuronal transmission in both the central and peripheral nervous systems including: multiple sclerosis (MS), spinal cord injuries (SCI), botulism, Lambert-Eaton syndrome, and myasthenia gravis. It has also been postulated as a potential treatment of verapamil toxicity and reversal agent for anesthesia-induced neuromuscular blockade. To date, there have been limited reports of either intentional or accidental 4-AP toxicity in humans. Both a case of a patient with 4-AP toxicity and review of the literature are discussed, highlighting commonalities observed in overdose. CASE REPORT: A 37-year-old man with progressive MS presented with diaphoresis, delirium, agitation, and choreathetoid movements after a presumed 4-AP overdose. 4-AP concentration at 6 h was 140 ng/mL. With aggressive benzodiazepine administration and intubation, he recovered uneventfully. DISCUSSION: The commonalities associated with 4-AP toxicity conforms to what is known about its mechanism of action combining cholinergic features including diaphoresis, altered mental status, and seizures with dopamine-related movement abnormalities including tremor, choreoathetosis, and dystonia. Management of patients poisoned by 4-AP centers around good supportive care with definitive airway management and controlling CNS hyperexcitability aggressively with gamma-aminobutyric acid agonist agents. Adjunctive use of dopamine antagonists for extrapyramidal effects after sedation is a treatment possibility. As 4-aminopyridine recently received Federal Drug Administration approval for the treatment of ambulation in patients with MS, physicians should be keenly aware of its presentation, mechanism of action, and management in overdose.

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.

Opisthotonic posturing with neuromuscular irritability attributable to 4-aminopyridine ingestion by a healthy pediatric patient.

INTRODUCTION: 4-Aminopyridine (4-AP) is a potassium channel blocker used to increase muscle strength in the treatment of demyelinating diseases such as multiple sclerosis. We describe a case of ingestion by an 8-month-old child that resulted in severe but transient symptoms. CASE REPORT: An 8-month-old boy was found with greenish saliva, and a capsule with green 4-AP powder was missing. On arrival to an emergency department, he was jittery, tachycardic, and tachypneic. Activated charcoal, a cathartic, and midazolam (0.5 mg/kg) were administered before transfer to a tertiary pediatric hospital. On arrival, the infant remained tachycardic and tachypneic. His eyes deviated upward and he was noted to have 3+ deep tendon reflexes bilaterally. He was administered 0.9% normal saline (20 mL/kg) for a wide pulse pressure with low diastolic blood pressure. The patient developed dramatic opisthotonic posturing and vermiform tongue fasciculations. The symptoms responded well to repeated intravenous doses of benzodiazepines. In this case, we used 2 doses of lorazepam (0.05 mg/kg each). During opisthotonic posturing, an electroencephalogram performed in the intensive care unit revealed no evidence of seizure activity. Within 20 hours after admission, the patient became asymptomatic. CONCLUSION: This case is, to our knowledge, the first documented pediatric 4-AP ingestion. Clinical signs and symptoms are described as well as the response to therapy with benzodiazepines. The electroencephalogram performed while the patient was symptomatic was negative for seizures.

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.

Intoxicación por 4-aminopiridina: Caso clínico / Intoxication by 4-aminopyridine. Case report

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Atypical presentation of 4-aminopyridine overdose.

4-Aminopyridine (4-AP) is an investigational drug for the treatment of neurologic disorders including multiple sclerosis (MS). Until recently, relatively little was known about 4-AP toxicity in overdose; the only recorded cases involved neurologic symptoms ranging from mild parasthesias to tonic-clonic seizures. We report a case of accidental 4-AP overdose that resulted in continuous, dystonic, choreoathetoid-type movements that responded to treatment with standard anticonvulsant dosages of benzodiazepines.

[Severe poisoning by 4-aminopyridine in a body builder]. / Ernstige intoxicatie met 4-aminopyridine bij een bodybuilder.

A 22-year-old man was admitted to hospital with severe, accidental intoxication with 4-aminopyridine, a medicine which increases the acetylcholine concentration in the synapses and has a limited application in the treatment of some neurological diseases. The patient acted on the assumption of body-building capacities of this 'amino'. Apart from the previously documented symptoms of intoxication such as an epileptic attack and confusion, he showed cardiac arrhythmias, conduction disorders and severe hypertension. The serum concentration of 4-aminopyridine was 335 mg/l, while the therapeutic level is 25-75 mg/l.

Cardiac arrest following an iatrogenic 3,4-diaminopyridine intoxication in a patient with Lambert-Eaton myasthenic syndrome.

Syndromes with impaired neuromuscular transmission are frequently treated with pyridine derivates. 3,4-diaminopyridine is thought to have fewer side effects than the commonly used, but less potent, 4-aminopyridine. We describe a patient with an initially unrecognized iatrogenic intoxication with 3,4-diaminopyridine. Except for a life threatening arrhythmia, symptoms were similar to a 4-aminopyridine intoxication. The patient made a full recovery with symptomatic treatment and withdrawal of the drug.

Characterization of 4-aminopyridine in overdose.

We report three cases of 4-aminopyridine overdose resulting in seizure activity. All patients were on therapeutic regimens for the treatment of multiple sclerosis. All patients were responsive to intensive supportive care, although the length of toxicity was prolonged more than 24 hours in one patient. Seizure activity was responsive to benzodiazepine and phenytoin therapy.

A high-performance liquid chromatography method for determination of 4-aminopyridine in tissues and urine.

An analytical method was developed to measure 4-aminopyridine in tissues and urine to determine appropriate diagnostic samples in acute poisoning cases. Tissues from rats dosed with 4-aminopyridine were extracted with methylene chloride. Extracts were analyzed by high-performance liquid chromatography using an isocratic solvent system of acetonitrile and aqueous solution (15/85 v/v) consisting of 0.015 M sodium salt of l-heptane-sulfonic acid, 0.002 M tetramethylammonium bromide, and 0.01 M sodium dihydrogen phosphate adjusted to pH 3.0 with phosphoric acid. We concluded that suitable diagnostic samples for acute poisoning cases include stomach contents, kidney, liver, and urine.