Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential hepatotoxicity resulting in fatal liver failure is of major concern in treating patients with valproate (VPA). Until now there is no relevant laboratory parameter allowing early detection of impending liver failure. The major routes of VPA biotransformation are glucuronidation and beta-oxidation. There are several other pathways of degradation with formation of mono- und di-unsaturated derivates. VPA dose, patients age, co-medication (anticonvulsants, aspirin), fasting and glucose supply influence the VPA metabolism. The clinical spectrum of VPA-associated hepatotoxicity reaches from slight increases of liver enzymes without clinical manifestations over reversible slight to severe liver dysfunction to fatal liver failure. With respect to pathogenesis attention has focused on depletion of beta-oxidation and change of biotransformation to other pathways with increased synthesis of toxic unsaturated VPA derivates. Several inborn errors of metabolism, acute infections and status epilepticus seem to predispose to liver failure. Another hypothesis lies in the possible VPA-induced depression of free radical scavenging enzyme activities. On this basis N-acetylcysteine has been used successfully in treating children with severe hepatotoxicity. In the presence of certain risk factors VPA should be avoided.
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PMID:[Valproate-associated hepatotoxicity--pathogenesis, clinical aspects, therapy and prevention]. 175 43

A previously healthy 2 1/2-year-old girl developed status epilepticus followed by cortical blindness during intravenous N-acetylcysteine therapy for paracetamol ingestion. The child's vision was almost completely recovered during the 18 months follow-up period. We assume that the cortical blindness was a postictal sequela after prolonged seizure episode, most probably due to respiratory depression induced by N-acetylcysteine.
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PMID:Status epilepticus following intravenous N-acetylcysteine therapy. 896 81

Cases of N-acetylcysteine overdose have been reported before. In some cases, these overdoses have led to death if an anaphylactoid reaction was present. A healthy 30-month-old girl allegedly ingested acetaminophen at 418 mg/kg. Because the emergency physician feared the time of ingestion might not be accurate, he decided to start the 20.5-hour intravenous N-acetylcysteine protocol 8 hours after ingestion. He mistakenly prescribed the maximum milliliter-per-kilogram volume of the dextrose 5% diluent for the milliliter-per-kilogram volume of N-acetylcysteine 20% to be administered. Five hours after the error was detected (19.5 hours postingestion), the patient started developing myoclonus on the left side of her body, with left eye deviation. This condition persisted intermittently for 3 hours despite treatment with diazepam, lorazepam, and phenytoin. A first computed tomographic scan result was normal. A few hours later, she sustained shorter recurrences of the myoclonus. At 30 hours after ingestion, she started to have irregular breathing and became unresponsive to pain. A repeated computed tomographic scan showed diffuse cerebral edema. A postmortem examination showed the presence of acute anoxic encephalopathy with marked cerebral edema and the beginning of uncal herniation that confirmed the clinical diagnosis of intracranial hypertension and brain death. A cumulative intravenous dose of 2,450 mg/kg of N -acetylcysteine was associated with status epilepticus, intracranial hypertension, and death in a child.
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PMID:Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. 1545 24

Acute poisoning following ingestion of medications, both intentional and unintentional, is frequent and more or less severe. It is often unclear whether a toxic dose has been ingested. This review examines the initial management of patients with suspected acute poisoning, based on a review of the literature using the standard Prescrire methodology. We examined clinical practice guidelines, which are mostly based on observational, pharmacological and toxicological data, as well as empirical data. Few comparative trials are available. In life-threatening situations, the first priority is to call an emergency response mobile unit and to implement life-support techniques, i.e., resuscitation for cardiorespiratory arrest; respiratory support if necessary; and the left lateral head-down position and glucose injection if the patient is unconscious. Prompt, initial measures may also include: anticonvulsant injection for status epilepticus (diazepam, for example); a sedative for extreme agitation (diazepam or clorazepate if there is no risk of respiratory depression; otherwise haloperidol); atropine for severe bradycardia; elevating the legs for hypotension; and naloxone in case of respiratory depression due to opioids. Drug poisoning can be life-threatening.The extent of the risk should be assessed by questioning the patient and close contacts, examining the immediate environment, and carrying out a clinical examination to identify a major toxic condition. The severity of poisoning is assessed by gathering all information about the patient, the drug(s) ingested, the circumstances of ingestion, and any other substances ingested at the same time. A poison control centre may be called to assist with diagnosis, to predict the clinical consequences, and to guide patient management. Activated charcoal can reduce the gastrointestinal absorption of some drugs. It should be given as soon as possible, preferably within 2 hours after ingestion of a drug known to be adsorbed by activated charcoal, provided the patient is fully conscious and capable of swallowing safely. Gastric lavage carries a risk of serious adverse effects. It is only justified in the rare cases in which the patient's life is at risk following ingestion of a drug that is not adsorbed by activated charcoal. Ipecac syrup should not be used under any circumstances. Purging and gastric lavage are not part of initial management. Few antidotes are suitable for use in the early stages of poisoning. Acetylcysteine can be used for some cases of paracetamol poisoning, and naloxone for some types of opioid poisoning. Paracetamol poisoning can cause life-threatening hepatocellular necrosis. Activated charcoal should be administered as soon as possible. Acetylcysteine protects the liver when administered within 24 hours after paracetamol ingestion. Paracetamol serum assay can be useful for guiding patient management. In practice, acetylcysteine should be given when access to emergency medical intervention is not feasible within 8 to 10 hours after paracetamol ingestion. Intravenous naloxone is useful for respiratory depression due to opioid poisoning, but its duration of action is often shorter than that of opioids, making continuous monitoring necessary. Hospital monitoring is warranted in case of potentially severe poisoning; this includes patients at increased risk, patients having taken a potentially lethal substance at a toxic or unknown dose. Some pharmacological substances and formulations can have delayed effects. In case of self-poisoning, the risk of short-term relapse should be evaluated, even when the patient's condition is not life-threatening. Hospital admission should be proposed, or sometimes imposed, until the acute risk of suicide has subsided. In practice, when faced with acute drug poisoning, the first step is to implement life-support measures, to gather and communicate prognostic information and details of any treatments to the ambulance crew or hospital team.
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PMID:Acute poisoning following ingestion of medicines: initial management. How to treat life-threatening complications and to evaluate the risk of delayed effects and psychological distress. 2149 72

There is accumulating evidence that reactive oxygen species are involved in the development of seizures under pathological conditions, and antioxidant treatments are a novel therapeutic approach for epilepsy. The kainic acid (KA) model of induced seizures has been widely used to study temporal lobe epilepsy. However, research on the use of free radical scavengers following KA-induced status epilepticus (SE) is limited. We examined whether antioxidants already used in humans could reduce hippocampal neuronal cell loss, mossy fiber sprouting and the acquisition of hyperexcitability when administered as a single dose after SE. The antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) (30mg/kg) or N-acetylcysteine (NAC) (30mg/kg) was administered after KA-induced SE ceased by pentobarbital. We evaluated neuronal cell viability 1 week after SE, determined the threshold for seizures induced by inhalation of flurothyl ether 12 weeks after SE, and examined the extent of mossy fiber sprouting 12 weeks after SE. We found that edaravone or NAC prevented neuronal cell loss and mossy fiber sprouting, and increased the threshold for seizures induced by flurothyl ether, even when administered after KA-induced SE. These results demonstrate that a single dose of edaravone or NAC can protect against neuronal cell loss and epileptogenesis when administered after SE ceased by pentobarbital.
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PMID:3-Methyl-1-phenyl-2-pyrazolin-5-one or N-acetylcysteine prevents hippocampal mossy fiber sprouting and rectifies subsequent convulsive susceptibility in a rat model of kainic acid-induced seizure ceased by pentobarbital. 2485 22

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.
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PMID:Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. 3114 51

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.
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PMID:Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. 2857 53