Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lorazepam, a dichloro-3-hydroxy-1,4-benzodiazepine, has been shown to be a potent anticonvulsant in animal models of epilsepsy and has minimal depressant effects on respiration and circulation in humans. The effects of this compound were studied in status epilepticus. Twenty-five patients were given intravenous lorazepam during status epilepticus of varying cause. Four or 8 mg of the drug controlled status in 22 of the 25 patients. Although single seizures recurred in 5 of the 22 patients, none experienced recurrence of status during a prolonged follow-up period. Transient respiratory arrest occurred in 1 patient, but no other significant complications were observed. Studies of plasma drug levels suggest that most patients attain good seizure control at concentrations between 30 and 100 ng per milliliter. Clinical observations indicate that repetitive injections are not required for continuing control of seizures in patients whose seizures are initially controlled. Lorazepam appears to be an effective and safe drug for treatment of status epilepticus, with a duration of control longer than that achieved with diazepam.
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PMID:Lorazepam in status epilepticus. 4 12

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) mice were treated with 5 mg/kg lorazepam for 7 days via implanted osmotic mini pumps. Following chronic drug treatment, brains were assayed for GABA-mediated chloride flux (GABA-Cl-). Under control (drug naive) conditions, brain membranes prepared from WSP and WSR lines did not differ in flunitrazepam or ethanol stimulation of GABA-mediated 36Cl- uptake, but the WSP lines were more sensitive to inhibition of 36Cl- flux by the inverse agonist, FG-7142. Membranes from lorazepam tolerant WSP and WSR mice were resistant to flunitrazepam- and ethanol-stimulation of GABA-Cl-. Withdrawal from chronic treatment, by an acute injection with the benzodiazepine antagonist RO15-1788, returned flunitrazepam stimulation of GABA-Cl- to near control levels in WSR membranes but not in WSP membranes and restored ethanol modulation of the channel to control levels in both lines. Inhibition of chloride flux by the benzodiazepine partial inverse agonist, FG-7142 was greater in membranes from WSP mice compared with WSR mice. Tolerance to lorazepam increased sensitivity of the WSR membranes to FG-7142 without altering the response in the WSP line. Again, withdrawal restored the Cl- flux response to FG-7142 back to near control levels. Lorazepam tolerance lowered [3H]-flunitrazepam binding affinity slightly only in the WSR strain with no change in binding number. Withdrawal from chronic lorazepam treatment produced no significant change in binding affinity or number. The initial genotypic differences in benzodiazepine inverse agonist sensitivity, may be related to the selection for withdrawal seizure severity. Chronic administration of lorazepam reduces the coupling between the benzodiazepine agonist site and the chloride channel and concomitantly increases coupling between the channel and the inverse agonist site, while withdrawal resets the receptor coupling back to control response levels. However, for the WSP line, this drug environment dependent shift in channel coupling bias appears to be deficient compared with the WSR line.
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PMID:Effects of lorazepam tolerance and withdrawal on GABAA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity. 138 57

We report the results of treatment of intractable seizures with lorazepam in seven neonates. All of the patients were part of a prospective study, who failed to respond to 40 mg/k of phenobarbital. Lorazepam was given intravenously at 0.05 mg/k and repeated up to a total dose of 0.15 mg/k if necessary. The diagnosis of seizures and the efficacy of treatment was assessed clinically and by EEG during the administration of lorazepam in three patients and on clinical grounds in four patients. Six patients were full term and one was premature; there were five males and two females. Four patients had hypoxic-ischemic encephalopathy, two had intracranial hemorrhage, and one had bacterial meningitis. Two patients received one dose of lorazepam, three received two doses, and two received three doses. Six patients responded with a complete cessation of seizures within three minutes of their last dose; the remaining patient (who received two doses) had a reduction in seizures. No patients developed apnea or hypotension during or immediately after the infusion of lorazepam and no other adverse effects were observed. Four patients remained seizure-free for the rest of the neonatal period and no other anticonvulsant medications were added. Seizures recurred in one patient at 16 hours; subsequent intermittent seizures were managed with additional phenobarbital. In another patient, seizures recurred at 12 hours and subsequent intermittent seizures were managed with phenytoin. In one patient, seizures continued with reduction of frequency and duration. We conclude that lorazepam may be effective in the treatment of neonatal seizures refractory to phenobarbital and that further treatment with intravenous phenytoin may be unnecessary under these circumstances.
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PMID:Lorazepam in the treatment of refractory neonatal seizures. 194 Jan 33

Sodium phenobarbitone (20 and 70 mg/kg) had a significant anticonvulsant action against pentylenetetrazole-induced seizures, which persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold below control level 24-48 h after the last dose of 70 mg/kg. Phenytoin (40 mg/kg) had a significant anticonvulsant action after 7 days of treatment and this persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold 48 h after the last dose. Lorazepam (0.1 mg/kg) had a significant anticonvulsant action, but the group tested after 21 days of treatment did not differ from the controls, indicating that tolerance had developed to this effect; on drug withdrawal there was a decrease in seizure threshold from 24 to 72 h. The only drug to increase aggressive behaviour was sodium phenobarbitone (70 mg/kg); this reached significance after 14 and 21 days of treatment and occurred 8 h after drug administration; 0.5 h after drug administration phenobarbitone (70 mg/kg) abolished aggressive behaviour. After 7 days of treatment phenobarbitone (70 mg/kg) increased social behaviour 0.5 h after administration and this was still increased after 21 days of treatment. On drug withdrawal, there were no changes in aggressive behaviour, but there were significant decreases in social behaviour 24 and 48 h after phenobarbitone (70 mg/kg) withdrawal and 24, 48 and 72 h after lorazepam (0.1 mg/kg) withdrawal.
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PMID:Changes in seizure threshold and aggression during chronic treatment with three anticonvulsants and on drug withdrawal. 230 12

Cerebral infarction, headache, and hypertension are well-known complications of carotid endarectomy (CEA). Seizures are a less frequent, but important complication. We describe eight patients with focal and generalized seizures following CEA. Seizures occurred 6 to 13 days after CEA. All began as focal motor seizures contralateral to the side of the CEA, and six patients developed generalized tonoclonic seizures. Lorazepam and phenytoin sodium controlled the seizures. Five patients without evidence of stroke on computed tomographic scan were normal in follow-up and had no further seizures. The other three patients had mild deficits. One developed a chronic seizure disorder. The pathogenesis of this syndrome following CEA remains unclear, but may involve cerebral hyperperfusion, cerebral embolization, or both.
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PMID:Seizures following carotid endarterectomy. 199 2

We studied the efficacy, pharmacokinetics, and brain entry of lorazepam in the treatment of status epilepticus (SE) using a rat model of secondarily generalized convulsive SE. Lorazepam entered the bloodstream rapidly following intraperitoneal injection. Brain concentrations peaked 10 minutes after peak serum levels were achieved. Lorazepam remained in brain longer than in serum, leading to increasing brain: serum ratios over time once peak serum levels had been reached. Free lorazepam was 9.1% of the total concentration in serum, a fraction similar to that which has been reported for humans. The median effective dose for control of generalized tonic-clonic seizures in this model was 0.94 mg/kg, which would produce a serum concentration of 196 ng/ml. Rats in SE had higher serum lorazepam concentrations than controls given the same doses, but lower brain: serum ratios, perhaps due to lactic acidosis during SE. Our data confirmed clinical reports of lorazepam's effectiveness as a treatment for SE and suggest that a target serum concentration of 200 ng/ml should be effective in most cases and provide seizure protection for 24 hours following treatment.
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PMID:Lorazepam treatment of experimental status epilepticus in the rat: relevance to clinical practice. 234 20

Benzodiazepines are potent and effective drugs for the management of acute seizures and status epilepticus. Lorazepam, diazepam, and clonazepam have been the most widely studied of the benzodiazepines in the treatment of status epilepticus. In 47 studies of these drugs involving 1,455 patients, lasting control of status epilepticus was achieved in 79% of the patients. None of these benzodiazepines is clearly superior to another for the effective control of status epilepticus. Differences in pharmacokinetic parameters, therefore, will influence the choice of drug. All three benzodiazepines are lipid-soluble and enter the brain within seconds to minutes after intravenous administration. Diazepam, however, is very lipid-soluble and highly protein-bound and thus has a very large volume of distribution of unbound drug. As a result, the effective duration of action of diazepam in status epilepticus is only 20 to 30 min, whereas that of lorazepam, which has a much smaller volume of distribution of unbound drug, is at least several hours after a single intravenous injection. This allows the orderly administration of an antiepileptic drug for long-term seizure control after status epilepticus has been controlled. For this reason, lorazepam is preferable for the initial management of status epilepticus. Continuous intravenous infusion of diazepam has been used successfully in the management of some patients with status epilepticus refractory to initial treatment.
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PMID:Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus. 267 May 37

Mice were given chronic treatment with lorazepam 10 mg/kg PO or FG 7142 40 mg/kg IP once a day for 14 days. The pretreatments with lorazepam and FG 7142 did not change the sensitivity of the mice to the convulsant effect of DMCM. Lorazepam pretreated mice showed a significantly lower sensitivity to the anticonvulsant effects of the benzodiazepine (BZ) receptor ligands lorazepam, ZK 93423, ZK 91296, Ro 15-1788 and ZK 93426 administered acutely by the IP route when challenged with DMCM 24 hr after the last dose of lorazepam. FG 7142 pretreated mice showed a significantly lower sensitivity to the anticonvulsant effect of the two agonists lorazepam and ZK 93423 and to the antagonist Ro 15-1788, whereas the effects of ZK 91296 and ZK 93426 were left unchanged. The reduced DMCM antagonistic effects of the BZ receptor ligands may indicate that these ligands may either have lost some of their affinity to those BZ receptors being responsible for the DMCM-induced seizures or they may have lost some efficacy in allosterically inhibiting DMCM binding or as a third possibility may have lost efficacy at a BZ receptor site downstream to the seizure-inducing center in the brain.
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PMID:Lorazepam and FG 7142 induce tolerance to the DMCM antagonistic effect of benzodiazepine receptor ligands. 282 7

In day 4 female rats lorazepam, diazepam and clonazepam produced dose-related increases in forward walking and loss of righting and diazepam produced a dose-related increase in paddling. Lorazepam and diazepam increased jerks of the fore- and hind-limbs and the whole body, and clonazepam increased the latter two; these increases were not dose-related. Some doses of lorazepam and the lowest dose of diazepam increased tonic-clonic movements. Thus the benzodiazepines were observed to have two kinds of stimulant effect in day 4 rats. One is to cause hyperactivity and this effect is dose-related. The other is to cause a type of seizure-like behavior, although this action is not dose-related and the responses can be distinguished from those caused by convulsant compounds. The effects of the benzodiazepine antagonist Ro 15-1788 resembled those of the benzodiazepines. It increased hind-limb and whole body jerks, forward walking, paddling, loss of righting and tonic-clonic movements. CL 218,872, which is selective for type 1 benzodiazepine receptors, was devoid of significant effects. This suggests that the behavioral changes observed with the other compounds were mediated by the type 2 receptors.
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PMID:The effects of benzodiazepines in newborn rats suggest a function for type 2 receptors. 302 17

Treatment of mice with lorazepam 10 mg/kg p.o. or FG 7142 40 mg/kg i.p. once a day for 14 days changed the effects of benzodiazepine (BZ) receptor ligands injected acutely on the threshold of pentylenetetrazol (PTZ)-induced seizures. The effects of the two pretreatments differed qualitatively as well as quantitatively. Lorazepam elicited a shift in the effects of all BZ receptor ligands tested, whereby the agonists lorazepam and ZK 93423 now acted like partial agonists given acutely, the partial agonist ZK 91296 acted like an antagonist and the antagonists Ro 15-1788 and ZK 93426 like partial inverse agonists. The proconvulsant effects of the partial inverse agonist FG 7142 and the full inverse agonist DMCM on the PTZ-induced seizures did not change. However, FG 7142 became a full inverse agonist i.e. became convulsant, and DMCM may have increased in potency as a convulsant. After FG 7142 pretreatment lorazepam and ZK 93423 behaved like partial agonists given acutely whereas there was no change in effect for ZK 91296, Ro 15-1788 and ZK 93426. FG 7142 became convulsant (i.e. kindling occurred) and the potency of DMCM as a convulsant was non-significantly increased, while their proconvulsant effects with respect to PTZ-induced seizures were not altered. The fact that the effects of the two very different pretreatments on the BZ receptor ligand continuum were in the same direction may be explainable by assuming two different mechanisms, both of which may involve the GABA receptors.
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PMID:Chronic treatment with lorazepam and FG 7142 may change the effects of benzodiazepine receptor agonists, antagonists and inverse agonists by different mechanisms. 303 Jul 77


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