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)

We have investigated in mice the effects of several drugs which may be administered as part of an anaesthetic technique on the convulsive threshold to laudanosine and to strychnine, which is reported to have a similar mechanism of action. I.v. administered propofol, thiopentone and midazolam increased the dose of convulsant necessary to produce seizure when administered 2 min before the convulsive stimulus. In contrast, methohexitone and etomidate exhibited a proconvulsant effect, although with the latter this was significant only in laudanosine-treated mice. Pethidine was proconvulsant in both laudanosine- and strychnine-treated mice, but morphine was proconvulsant only in strychnine-treated mice. The effects of morphine, but not pethidine, were antagonized by naloxone 1 mg kg-1. Laudanosine, but not strychnine caused arousal from anaesthesia in subconvulsive doses. This and other evidence suggests that the mechanism of the CNS excitation produced by strychnine and laudanosine are not the same.
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PMID:Modification by drugs used in anaesthesia of CNS stimulation induced in mice by laudanosine and strychnine. 175 Dec 75

The present study was designed to investigate whether D,L-laudanosine (a breakdown product of the neuromuscular relaxant atracurium besylate) interacts with benzodiazepinergic receptors or muscarinic receptors, both of which are involved in epilepsy and other types of seizures. The ability of D,L-laudanosine (10(-10) to 5 X 10(-5) M) to displace ligands specific for these receptors from their binding sites was tested. D,L-Laudanosine failed to inhibit the binding of [3H]flunitrazepam to central benzodiazepine receptors in the cerebral cortex, the binding of [3H]PK 11195 to peripheral benzodiazepine binding sites in the cerebral cortex and kidney, the binding of [3H]Ro 5-4864 to peripheral benzodiazepine binding sites in the kidney, or the binding of [3H]quinuclidinyl benzilate to muscarinic receptors in the cerebral cortex. These results suggest that laudanosine does not exert its convulsive effect via interaction with benzodiazepinergic or muscarinic receptors.
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PMID:Laudanosine does not displace receptor-specific ligands from the benzodiazepinergic or muscarinic receptors. 253 52

The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg . kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 +/- 24 min (mean +/- SD) and a clearance of 25 +/- 8 ml . kg-1 . min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng . ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (less than 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg . kg-1 iv every 5 min. With cumulative doses of 2-8 mg . kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg . kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg . kg-1 iv) and returned to control levels 4 min later.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacology of laudanosine in dogs. 372 58

We examined the interactions of D,L-laudanosine, a potentially epileptogenic metabolite of the neuromuscular relaxant atracurium besylate, with gamma-aminobutyric acid (GABA) and opioid binding sites, all of which have been implicated in seizure activity. Laudanosine was almost ineffective at [3H]muscimol binding to high-affinity GABA receptors (IC50 = 100 microM). However, laudanosine displayed an inhibitory effect at the low-affinity GABA receptors labeled by [3H]bicuculline methochloride, with an IC50 value of 10 microM. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the mu 1, mu 2, delta, kappa 1, and kappa 3 receptors with Ki values of 2.7, 13, 5.5, 21, and 24 microM, respectively, concentrations seen clinically in blood and approaching those measured in cerebrospinal fluid. Saturation studies of mu 1, mu 2, delta, and kappa 3 sites in the presence of laudanosine revealed competitive interactions, with increases in the apparent Kd values but without significant changes in the maximal numbers of binding sites. In addition, we investigated whether the in vitro laudanosine-opioid receptor interaction would also be expressed by analgesic physiologic effects. We found that laudanosine elicited a dose-dependent analgesia in mouse tail-flick assay that was attenuated by coadministration of beta-funaltrexamine (mu 1- and mu 2-selective antagonist) and of naloxonazine (mu 1 antagonist), but not by nor-binaltorphimine (kappa 1-selective antagonist) or naltrindole (delta-selective antagonist), indicating a mu 1 mechanism for analgesia-mediated property of laudanosine. There is evidence suggesting mu 2 activity as well, but this is due to the ability of laudanosine to elicit analgesia when given intrathecally. We also observed cross-tolerance between laudanosine and morphine, as well as a partial effect of laudanosine on gastrointestinal transit. These results suggest an interaction between laudanosine and the low-affinity GABA receptor, as well as opioid mu 1 and mu 2 receptors.
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PMID:Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity. 806 69

Laudanosine is a metabolite of the neuromuscular-blocking drugs atracurium and cisatracurium with potentially toxic systemic effects. It crosses the blood-brain barrier and may cause excitement and seizure activity. Its interest in recent years has increased because of the recognized interaction with gamma-aminobutyric acid, opioid and nicotinic acetylcholine receptors. It has been shown to produce analgesia in animals. In the cardiovascular system, high plasma concentrations produce hypotension and bradycardia. In hepatic failure, its elimination half-life is prolonged but only moderate accumulation occurs in adults, whereas in infants and children plasma concentration are greater. In patients undergoing liver transplantation, laudanosine concentrations are increased during preanhepatic, anhepatic and postanhepatic stages. Patients with renal failure have higher plasma concentrations and a longer mean elimination half-life. In pregnancy, laudanosine crosses the placental barrier. The mean transplacental transfer is 14% of maternal blood concentrations. Except for prolonged administration of atracurium in intensive care units, laudanosine accumulation and related toxicity seem unlikely to be achieved in clinical practice. When cisatracurium is used, plasma concentrations of laudanosine are lower. Further studies are needed, especially around the interactions with gamma-aminobutyric acid, opioid and nicotinic acetylcholine receptors.
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PMID:Laudanosine, an atracurium and cisatracurium metabolite. 1211 8

Laudanosine, a degradation of neuomuscular blocking agent atracurium, crosses the blood-brain barrier and is indicted to trigger seizures at high concentration. In Xenopus Oocytes expressing nicotinic acetylcholine receptors (nAChRs), laudanosine has activating and inhibiting effects on nAChRs depending on its concentration. nAChRs is related to respiratory activities and thus, in the present study, we analyzed effects of laudanosine on central respiratory activities using isolated brainstem-spinal cord preparation of neonatal rats. The rhythmic inspiratory burst activity of the C4 spinal ventral root was recorded using a glass suction electrode as an index of respiratory rate. After superfusion with mock cerebrospinal fluid (CSF), the preparation was superfused with mock CSF containing laudanosine 1, 10 or 100 microM for 60 minutes. Laudanosine 1, 10 and 100 microM (n = 10 in each) did not induce any effects on C4 respiratory rate. In all 10 preparations, laudnosine 100 microM induced non-respiratory excitement activities that are possibly same as seizure observed in vivo study.
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PMID:Laudanosine has no effects on respiratory activity but induces non-respiratory excitement activity in isolated brainstem-spinal cord preparation of neonatal rats. 2021 44