Systematic review of the pharmacological agents that have been tested against spreading depolarizations.

Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.

Use of neuromuscular monitoring to detect prolonged effect of succinylcholine or mivacurium: three case reports.

Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short-acting drugs like succinylcholine and mivacurium.

Characterization of renal toxicity in mice administered the marine biotoxin domoic Acid.

Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses≥0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.

[Residual relaxant block due to pseudocholinesterase deficiency - First manifestation in an elderly patient]. / Kasuistik: Relaxansüberhang durch Pseudocholinesterasemangel - Erstmanifestation in höherem Alter.

Pseudocholinesterase or butyrylcholinesterase (BChE) inactivates the relaxant drugs mivacurium and suxamethonium. A deficiency in plasma activity of this enzyme may result in prolonged muscular paralysis and subsequently the need for an extended duration of mechanical ventilation. We report the case of a 65-year-old patient who was diagnosed with butyrylcholinesterase deficiency for the first time during elective surgery. Neuromuscular monitoring constitutes a central diagnostic asset in ensuring patient safety.

Pharmacokinetic properties of succinylmonocholine in surgical patients.

Intoxications with succinylcholine (SUX) lead to a potentially lethal respiratory paralysis, and forensic cases involving accidental or deliberate SUX-application have been reported. Detection of SUX as well as its metabolite succinylmonocholine (SMC) is difficult: both substances are analytically challenging, and the extremely short plasma half-life of SUX additionally hampers detection of the parent compound. Pharmacokinetic data are scarce on SUX and non-existent on SMC. To enhance forensic knowledge concerning SUX intoxications, plasma pharmacokinetics of SMC were investigated in anesthetized patients. Fifteen subjects scheduled for a surgical procedure were included in this study. Muscle-relaxation was initialized with a bolus injection of 80-100 mg SUX. Blood sampling was performed within 6 h after SUX application using paraoxonized tubes. Collected plasma was processed according to a validated isotope dilution high-performance liquid chromatography-tandem mass spectrometry method using ion-pair solid-phase extraction. Pharmacokinetic parameters were derived from a user-defined as well as a three-compartment model. For SMC, peak plasma concentrations were reached after 0.03-2.0 min. In contrast to SUX, SMC was more slowly and more extensively distributed, featuring triphasic plasma concentration time profiles. Pharmacokinetic key parameters were subject to interindividual variation of potential forensic importance, with terminal half-lives of 1-3 h indicating a detection interval of 8-24 h for SMC in plasma. SMC was proven to be the only realistic SUX marker in a forensic context. The present work defines meaningful detection windows for plasmatic SMC after SUX application and offers guideline values for forensic toxicological casework.

Prolonged succinylcholine action during electroconvulsive therapy (ECT) after cytarabine, vincristine, and rituximab chemotherapy.

Succinylcholine is a depolarizing neuromuscular blocker frequently used during electroconvulsive therapy. In most patients, the duration of paralysis is brief, allowing for spontaneous respiration shortly after the therapy. We report a case of delayed return of neuromuscular function after succinylcholine administered during electroconvulsive therapy in a 72-year-old man receiving cytarabine, vincristine, and rituximab chemotherapy for chronic lymphocytic leukemia. We hypothesize that an interaction between succinylcholine and one of the chemotherapeutic agents caused the prolongation of paralysis and believe that this is the first reported case of prolonged duration of succinylcholine following this regimen of chemotherapy. Despite this unexpected prolonged neuromuscular blockade, the patient could be treated uneventfully, with attention paid to his respiratory support and with subsequent succinylcholine dose titration to effect.

In vivo seizure induction and affinity studies of domoic acid and isodomoic acids-D, -E and -F.

Domoic acid and its isomers are produced via algal blooms and are found in high concentrations in shellfish. Here, we assessed the acute seizurogenic potencies of isomers-D, -E and -F and their binding affinities at heterogeneous populations of KA receptors from rat cerebrum. In addition, binding affinities of all six isomers (Iso-A through -F) were assessed at AMPA receptors. Radioligand displacement studies indicated that the seizurogenic potency of Iso-F (E-configuration) closely correlates with its affinities at both KA and AMPA receptors, whereas isomers-D (Z) and -E (E), which exhibit distinctly lower seizurogenic potencies, are quite weak displacers. Previously observed functional potencies for isomers-A, -B and -C (Sawant et al., 2008) correlated with AMPA receptor affinities observed here. Taken together, these findings call into question previous structure-activity rules. Significantly, in our hands, Iso-D was ten-fold less potent than Iso-F. To further explain observed links between structural conformation and functional potency, molecular modeling was employed. Modeling results closely matched the rank order of potency and binding data observed. We further assessed the efficacy of isomers-D, -E and -F as pharmacological preconditioning agents. Acute preconditioning with low-dose Iso-D, -E or -F, before high-dose DA failed to impart behavioural tolerance. This study has shed new light on structural conformations affecting non-NMDA ionotropic glutamate receptor binding and functional potency, and provides a foundation for future work in areas of AMPA and KA receptor modeling.

Determination of suxamethonium in a pharmaceutical formulation by capillary electrophoresis with contactless conductivity detection (CE-C(4)D).

A simple method based on capillary electrophoresis with a capacitively coupled contactless conductivity detector (CE-C(4)D) was developed for the determination of suxamethonium (SUX) in a pharmaceutical formulation. A hydro-organic mixture, consisting of 100mM Tris-acetate buffer at pH 4.2 and acetonitrile (90:10, v/v), was selected as background electrolyte (BGE). The applied voltage was 30kV, and the sample injection was performed in the hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 microm and a total length of 64.5cm. Under these conditions, a complete separation between SUX, sodium ions and the main degradation products (choline) was achieved in less than 4min. The presence of acetonitrile in the BGE allowed a reduction of SUX adsorption on the capillary wall. The CE-C(4)D method was validated, and trueness values between 98.8% and 101.1% were obtained with repeatability and intermediate precision values of 0.7-1.3% and 1.2-1.6%, respectively. Therefore, this method was found appropriate for controlling pharmaceutical formulations containing suxamethonium and degradation products.

Pharmacokinetic-pharmacodynamic modeling of the influence of chronic phenytoin therapy on the rocuronium bromide response in patients undergoing brain surgery.

BACKGROUND: Antiepileptic drugs decrease the intensity of the effect of neuromuscular blocking agents. The objective of this study was to evaluate the influence of chronic phenytoin therapy (CPT) on the pharmacokinetics (PK) and pharmacodynamics (PD) of rocuronium. METHODS: A total of 21 patients undergoing intracranial surgery were enrolled in the study. Ten of these were under CPT. Rocuronium was administered intravenously. Arterial blood samples were drawn, and the T1% (percentage change from the response to the supramaximal stimulus) derived from electromyogram was continuously recorded. NONMEM: software was used to construct, evaluate and validate the PKPD models. RESULTS: The PKPD of rocuronium was described using a three-compartment PK model and effect compartment model. The CPT therapy was found to increase the total plasma clearance from 0.26 to 0.75 L min(-1). The PD model parameter estimates were k(e0)= 0.073 min(-1), IC(50) (the steady-state plasma concentration eliciting half of the maximum response) = 836 ng mL(-1) and gamma = 3.13. CONCLUSIONS: Chronic phenytoin therapy increases the clearance of rocuronium from 0.26 to 0.75 L min(-1) but has no effect on the k(e0), IC(50) or gamma parameters.

[Interaction between mivacurium and succinylcholine from a different point of view]. / Interacción entre mivacurio y succinilcolina: vista desde otra perspectiva.

OBJECTIVES: Succinylcholine (SCH) may first be used and continue with mivacurium (MIV). MIV has been suggested as a pretreatment. Conflicting results arises from studies on SCH-MIV interaction. The following trial revisits this interaction. PATIENTS AND METHODS: The patients were intubated after randomized administration of 100 microg x Kg(-1) of mivacurium (group 1) or 1 mg x Kg(-1) of succinylcholine and, after 50% recovery, 100 microg x Kg(-1) of mivacurium (group 2). A third group received the same regimen as group 2, preceded by pretreatment with 10 microg x Kg(-1) of mivacurium. Maximum effect (MAX), onset time, the 10%-25% recovery index, and duration of effect of mivacurium were determined by electromyography. In groups 2 and 3, the corrected MAX was defined as the difference between the actual MAX effect and the residual block after administration of succinylcholine, and speed of action was defined as the ratio between MAX or corrected MAX and onset time. Data were subjected to analysis of variance and Student-Newman-Keuls and t tests for bivariate comparisons. A value of P less than 0.05 was considered significant. RESULTS: Groups 2 and 3 had significantly greater MAX effects (97% and 98%, respectively) in comparison with group 1 (93%), shorter onset times (135 and 158 seconds in groups 2 and 3 vs 279 seconds in group 1), and greater speed of action without changes in duration of effect. MAX was halved when corrected (to 47% and 49% in groups 2 and 3, respectively), and speed of action was significantly reduced (from 1.34 and 1.62 seconds/% in groups 2 and 3 respectively, to 2.69 and 3.36 seconds/%). Mivacurium pretreatment did not produce relevant clinical changes. CONCLUSIONS: When mivacurium is used before the effects of succinylcholine disappear, a residual effect is not usually taken into consideration. This study corrected MAX and calculated speed of action, demonstrating a reduction in net block and speed of action, consistent with an antagonistic action when the 2 blockers are administered sequentially.

Tissue distribution and effects of heat treatments on the content of domoic acid in blue mussels, Mytilus edulis.

The effect of heat treatment on domoic acid (DA) content in soft tissues of mussels Mytilus edulis was investigated using high performance liquid chromatography. DA concentrations in whole flesh, hepatopancreas and tissue remainder were measured in fresh, steamed and autoclaved mussel flesh. Relative decreases in DA and tissue fluid following heat treatments of whole flesh were similar resulting in approximately equal concentrations of DA pre- and post-treatment. DA concentration decreased in the hepatopancreas and increased in tissue remainder suggesting some organ disruption of mussels during heat treatment. These findings suggest that heat treatments using either conventional steaming or autoclaving at 121 degrees C are not appropriate techniques to reduce DA in mussels during commercial processing. We also conclude that sample pre-treatment has a minimal effect on the result of a DA analysis on whole mussel tissues. The stability of DA at different temperatures within a shellfish matrix was separately tested. Reductions in DA concentration (ca. 3-7%) compensate for some of the discrepancies between what was found in the cooking fluids in the initial study and what was expected based on the whole flesh concentration of the uncooked material.

A study of the in vitro interaction between lidocaine and premedications using human liver microsomes.

OBJECTIVE: To investigate potential interactions between lidocaine (lignocaine) metabolism and premedication drugs, i.e. psychotropic and antianxiety agents (diazepam, midazolam), hypnotics (pentobarbital, thiamylal), depolarizing neuromuscular blocking agents (vecuronium, pancuronium and suxamethonium), an antihypertensive agent (clonidine) and an H2-receptor blocking agent (cimetidine) using human liver microsomes in vitro. METHODS: The interaction effects between lidocaine and premedication were examined using human liver microsomal preparations and monitored for enzyme activity. The lidocaine and its main metabolite (monoethylglycinexylide) were measured by HPLC/UV. RESULTS: Lidocaine metabolism was non-competitively inhibited by midazolam (Ki = 77.6 microM). Thiamylal was a competitive inhibitor of lidocaine metabolism (Ki = 885 microM). Cimethidine, pancuronium and vecuronium weakly inhibited lidocaine metabolism in a concentration-depend manner over the therapeutic range in human liver microsomes. On the contrary, suxamethonium, pentobarbital and clonidine did not inhibit lidocaine metabolism over the therapeutic range in human liver microsomes. CONCLUSION: These results show that the interactions between lidocaine and midazolam and thiamylal are of potential toxicological and clinical significance.

Consequences of inadvertent perioperative hypothermia.

Perioperative hypothermia triples the incidence of adverse myocardial outcomes in high-risk patients. Mild hypothermia significantly increases blood loss and augments allogeneic transfusion requirement, but the molecular pathophysiology of this effect remains to be elucidated. Only 1.9 degrees C core hypothermia triples the incidence of surgical wound infection following colon resection and increases the duration of hospitalization by 20%. Hypothermia adversely affects antibody- and cell-mediated immune defences, as well as the oxygen availability in the peripheral wound tissues. Mild perioperative hypothermia changes the kinetics and action of various anaesthetic and paralysing agents, increases thermal discomfort, and is associated with delayed post-anaesthetic recovery. Finally, mild core hypothermia influences pulse oximetry monitoring and various electrophysiological indices of the nervous system, with questionable clinical significance, as yet.

[Succinylcholine--update]. / Succinylcholin-Update.

The action profile of succinylcholine is unmatched even 50 years after its introduction into anaesthestic practice. This is probably why succinylcholine, despite its many and partly life-threatening side-effects, is still considered to be indispensable by many anaesthetists and emergency doctors. The main indication for succinylcholine--the facilitation of endotracheal intubation in patients considered to be at an increased risk of aspiration of gastric fluid, e.g. patients undergoing a Caesarean section or presenting with an ileus--remains undisputed. Some of the side-effects of succinylcholine can be diminished by precurarisation. However, just like priming, this technique holds some considerable dangers (such as a clinically significant attenuation of the protective reflexes) and has become a matter of increasing controversy. Rocuronium (> or = 1 mg/kg) is currently the best alternative to succinylcholine for rapid sequence induction. The routine use of succinylcholine as a relaxant for intubation is questionable, mainly because there are a number of modern anaesthetic techniques (laryngeal mask airway) and new drugs (rocuronium, mivacurium, remifentanil) which make succinylcholine quite dispensable except for a few situations (e.g. re-positioning of fractures). In the case of an expected difficult airway no muscle relaxant should be given, because severe hypoxaemia in these patients probably can only be prevented by a professional airway management. Succinylcholine is no longer an option in elective paediatric anaesthesia. The drug, however, retains its value in critical situations where a rapid onset but a short duration of action is of prime importance.

Depuration and anatomical distribution of the amnesic shellfish poisoning (ASP) toxin domoic acid in the king scallop Pecten maximus.

The depuration kinetics of the domoic acid of four body fractions (digestive gland, adductor muscle, gonad+kidney and gills+mantle) of the scallop Pecten maximus was studied over 295 days. The scallops, which had acquired the toxins during a Pseudo-nitzschia australis episode that took place the week before the beginning of the experiment, were maintained in tanks with running seawater. All the body fractions, except the adductor muscle, decreased their domoic acid burden throughout the experiment. The amount of toxin in the muscle dropped sharply at the start of the experiment but increased again at the end, to levels that were higher than the initial ones. Several dynamic models of depuration kinetics, which included the depuration of each fraction (excluding the adductor muscle) and the transfers between them, were constructed, implemented and fitted to the data to obtain their parameters. The estimated depuration rates were very low, both considering and not considering the transfer of toxin between organs or the effect of weight loss. There were strong differences in the domoic acid burden of the body fractions studied but not between their depuration rates. No net transfer from the digestive gland, the tissue with highest domoic acid concentration, to the other fractions was found, as the inclusion of these processes in the models produced only a marginally better fit to the data. The depuration of domoic acid was slightly, but significantly, affected by biomass. Weight loss induced domoic acid loss, suggesting that part of the depuration may be produced by the direct loss of bivalve cells. The concentration or dilution effect, due to decreases or increases in biomass, documented for other species and toxins, has little importance in Pecten maximus.

Spatial effects in modeling pharmacokinetics of rapid action drugs.

We develop a model to describe the time course of plasma concentration of neuromuscular blocking agents used as anesthetics during surgery. This model, which overcomes the limitations of the classical compartment models routinely used in pharmacokinetics, incorporates spatial effects due to heterogeneity in the circulation: it takes the form of a dispersion equation on a circular domain, with a time-dependent leakage term. This term is fitted to the functional form desired once first-stage transients have died out. Comparisons are made with clinical data by adjusting three parameters in the model.