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British Journal of Anaesthesia May 2011Mivacurium is metabolized by plasma pseudocholinesterase (PChE) enzyme, which is decreased in burns. We tested whether the decreased metabolism of mivacurium due to...
BACKGROUND
Mivacurium is metabolized by plasma pseudocholinesterase (PChE) enzyme, which is decreased in burns. We tested whether the decreased metabolism of mivacurium due to decreased PChE activity can overcome the pharmacodynamic resistance to non-depolarizing relaxants previously seen in major burns.
METHODS
Thirty adults with 35 (13)% [mean (sd)] burn were studied at 5-91 post-burn days and 31 non-burns matched controls. Mivacurium 0.2 mg kg(-1) was administered as a single bolus. Neuromuscular block was monitored with single-twitch response using TOF-Watch™. Onset time (drug administration to maximal twitch suppression) and spontaneous recovery were measured.
RESULTS
Onset time was significantly prolonged in burns when compared with non-burns (115 vs 90 s; P<0.001). The PChE levels were lower in burns [1432 (916) vs 2866 (731) IU litre(-1); P<0.001] and the neuromuscular recovery to 50% of baseline twitch height was prolonged in burns (41 vs 26 min; P<0.001). There was a significant correlation between PChE and time to 50% recovery for the whole group together (r=-0.6; P<0.001). The dibucaine numbers were not different.
CONCLUSIONS
The prolonged onset time suggests resistance to neuromuscular effects, whereas the prolonged recovery suggests increased sensitivity. This divergent response can be explained by qualitative and quantitative changes in acetylcholine receptor expression causing resistance and decreased PChE activity causing sensitivity. Despite using a relatively large dose of mivacurium (0.2 mg kg(-1)) in the presence of decreased PChE levels, this did not overcome the resistance resulting from up-regulated receptors.
Topics: Adolescent; Adult; Burns; Butyrylcholinesterase; Case-Control Studies; Electric Stimulation; Female; Humans; Isoquinolines; Male; Middle Aged; Mivacurium; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents
PubMed: 21354998
DOI: 10.1093/bja/aer023 -
Journal of Investigational Allergology... 2010
Topics: Administration, Topical; Adrenal Cortex Hormones; Diagnostic Errors; Dibucaine; Drug Eruptions; Exanthema; Female; Humans; Middle Aged
PubMed: 21314006
DOI: No ID Found -
Journal of Neurophysiology Apr 2011Recurring waves of peri-infarct depolarizations (PIDs) propagate across gray matter in the hours and days following stroke, expanding the primary site of injury....
Recurring waves of peri-infarct depolarizations (PIDs) propagate across gray matter in the hours and days following stroke, expanding the primary site of injury. Ischemic depolarization (termed anoxic depolarization or AD in live brain slices) is PID-like but immediately arises in the more metabolically compromised ischemic core. This causes dramatic neuronal and astrocyte swelling and dendritic beading with spine loss within minutes, resulting in acute cell death. AD is evoked in rodent neocortical slices by suppressing the Na(+)/K(+)-ATPase pump with either oxygen/glucose deprivation (OGD) or exposure to ouabain. The process driving AD and PIDs remains poorly understood. Here we show that dibucaine is a potent drug inhibiting AD because of its high binding affinity to the Na(+) channel. Field recording reveals that, when superfused with ouabain (5 min), neocortical slices pretreated with 1 μM dibucaine for 45 min display either no AD or delayed AD onset compared with untreated controls. If ouabain exposure is extended to 10 min, 1 μM dibucaine is still able to delay AD onset by ∼ 60%. Likewise, it delays OGD-evoked AD onset by ∼ 54% but does not depress action potentials (APs) or evoked orthodromic field potentials. Increasing dibucaine to 10 μM inhibits AP firing, gradually putting the slice into a stasis that inhibits AD onset but also renders the slice functionally quiescent. Two-photon microscopy reveals that 10 μM dibucaine pretreatment prevents or helps reverse ouabain-induced structural neuronal damage. Although the therapeutic range of dibucaine is quite narrow, dibucaine-like drugs could prove therapeutically useful in inhibiting PIDs and their resultant neuronal damage.
Topics: Action Potentials; Animals; Astrocytes; Dendrites; Dibucaine; Enzyme Inhibitors; Female; Hypoxia-Ischemia, Brain; Male; Mice; Mice, Transgenic; Models, Animal; Neurons; Ouabain; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium-Potassium-Exchanging ATPase; Stroke
PubMed: 21273307
DOI: 10.1152/jn.00817.2010 -
Changes in mitochondrial surface charge mediate recruitment of signaling molecules during apoptosis.American Journal of Physiology. Cell... Jan 2011Electrostatic interactions with negative lipids contribute to the subcellular localization of polycationic proteins. In situ measurements using cytosolic probes of...
Electrostatic interactions with negative lipids contribute to the subcellular localization of polycationic proteins. In situ measurements using cytosolic probes of surface charge indicate that normal mitochondria are not noticeably electronegative. However, during apoptosis mitochondria accrue negative charge and acquire the ability to attract cationic proteins, including K-Ras. The marked increase in the surface charge of mitochondria occurs early in apoptosis, preceding depolarization of their inner membrane, cytochrome c release, and flipping of phosphatidylserine across the plasmalemma. Using novel biosensors, we determined that the increased electronegativity of the mitochondria coincided with and was likely attributable to increased exposure of cardiolipin, which is dianionic. Ectopic (over)expression of cardiolipin-binding proteins precluded the increase in surface charge and inhibited apoptosis, implying that mitochondrial exposure of negatively charged lipids is required for progression of programmed cell death.
Topics: Apoptosis; Cholestanols; Dibucaine; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria; Signal Transduction; Sphingosine; Surface Properties
PubMed: 20926778
DOI: 10.1152/ajpcell.00139.2010 -
Journal of Medical Toxicology :... Mar 2010Dibucaine is a potent, long-lasting local anesthetic (LA). Topical dibucaine ointments are marketed directly to consumers in the USA without prescription. Dibucaine...
INTRODUCTION
Dibucaine is a potent, long-lasting local anesthetic (LA). Topical dibucaine ointments are marketed directly to consumers in the USA without prescription. Dibucaine ointment is intended to treat discomfort associated with sunburn, eczema, minor rashes, minor scratches, insect bites, and poison ivy and is used alone or in combination with other active ingredients to treat pain associated with hemorrhoids or other anorectal disorders. Oral dibucaine toxicosis has been reported in children and includes gastrointestinal upset and neurologic and cardiovascular dysfunction.
CASE REPORT
An 18-month-old, female, Parson Russell terrier ingested approximately 23 g of 1% dibucaine ointment (approximately 38 mg/kg dibucaine) recommended to the owner for the treatment of hemorrhoids. Onset and resolution of clinical signs were relatively rapid, 5 min and 60 min, respectively. Clinical signs included vomiting, ptyalism, whole-body muscle fasciculations, disorientation, and severe ataxia.
DISCUSSION
Oral dibucaine toxicosis in dogs is similar to oral dibucaine toxicosis in children. Dibucaine ointment poses a real and potentially serious toxicological risk to pets and thus should be stored in a safe location.
Topics: Accidents; Administration, Oral; Anesthetics, Local; Animals; Antidotes; Ataxia; Charcoal; Confusion; Dibucaine; Dog Diseases; Dogs; Female; Poisoning; Sialorrhea; Spasm; Treatment Outcome; Vomiting
PubMed: 20224995
DOI: 10.1007/s13181-010-0036-3 -
Journal of Psychiatry & Neuroscience :... Mar 2010Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in...
BACKGROUND
Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.
METHODS
We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.
RESULTS
We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.
LIMITATIONS
This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.
CONCLUSION
Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.
Topics: Adolescent; Adult; Benzydamine; Brain; Caudate Nucleus; Cerebral Ventricles; Dibucaine; Drug Combinations; Female; Hippocampus; Humans; Hyaluronoglucosaminidase; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Nucleus Accumbens; Organ Size; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Substance-Related Disorders; Time Factors; Young Adult
PubMed: 20184807
DOI: 10.1503/jpn.090049 -
Acta Crystallographica. Section E,... Nov 2010The mol-ecular conformation of the title compound, C(20)H(29)N(3)O(2), is stabilized by an intra-molecular C-H⋯O hydrogen bond. The orientation of the amide group to...
The mol-ecular conformation of the title compound, C(20)H(29)N(3)O(2), is stabilized by an intra-molecular C-H⋯O hydrogen bond. The orientation of the amide group to the ring system is characterized by a C-C-C-O dihedral angle of 137.5 (3)°. In the crystal, inter-molecular N-H⋯O hydrogen bonds between the amide groups form C(4) chains running parallel to the a axis.
PubMed: 21589483
DOI: 10.1107/S1600536810045460 -
Journal of Pharmacy & Pharmaceutical... 2007To characterize the physicochemical properties of drug-loaded oil-in-water (o/w) and water-in-oil (w/o) Brij 97-based microemulsions in comparison to their blank...
PURPOSE
To characterize the physicochemical properties of drug-loaded oil-in-water (o/w) and water-in-oil (w/o) Brij 97-based microemulsions in comparison to their blank counterparts and to investigate the influence of microemulsion type on in vitro skin permeation of model hydrophobic drugs and their hydrophilic salts.
METHODS
The microemulsion systems were composed of isopropyl palmitate (IPP), water and a 2:1 w/w mixture of Brij 97 and 1-butanol. The samples were characterized by visual appearance, pH, refractive index, electrical conductivity, viscosity and determination of the state of water and IPP in the formulations using differential scanning calorimetry (DSC). Transdermal flux of lidocaine, tetracaine, dibucaine and their respective hydrochloride salts through heat-separated human epidermis was investigated in vitro using modified Franz diffusion cells.
RESULTS
The physicochemical properties of drug-loaded microemulsions and their blank counterparts were generally similar; however, slight changes in some physicochemical properties (apparent pH and conductivity) were observed due to the intrinsic properties of the drugs. The o/w microemulsions resulted in the highest flux of lidocaine, tetracaine and dibucaine as compared to the other formulations with in the same group of drugs.
CONCLUSIONS
The characterization results showed that incorporation of the model drugs into the microemulsions did not change the microemulsion type. The permeation data exhibited that the nature of the microemulsions was a crucial parameter for transdermal drug delivery. The o/w microemulsions containing hydrophobic drugs provided the highest skin permeation enhancement. In addition, skin permeation was depended on the molecular weight of the model drugs.
Topics: 1-Butanol; Administration, Cutaneous; Anesthetics, Local; Calorimetry, Differential Scanning; Dibucaine; Electric Conductivity; Emulsions; Epidermis; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Lidocaine; Molecular Weight; Palmitates; Permeability; Plant Oils; Polyethylene Glycols; Skin Absorption; Tetracaine; Viscosity; Water
PubMed: 17727792
DOI: No ID Found -
Biochimica Et Biophysica Acta Oct 2006Verapamil is used clinically as a Ca(2+) channel inhibitor for the treatment of various disorders such as angina, hypertension and cardiac arrhythmia. Here we study the... (Comparative Study)
Comparative Study
Verapamil is used clinically as a Ca(2+) channel inhibitor for the treatment of various disorders such as angina, hypertension and cardiac arrhythmia. Here we study the effect of verapamil on the bacterium Escherichia coli. The drug was shown to inhibit cell division at growth sub inhibitory concentrations, independently of the SOS response. We show verapamil is a membrane active drug, with similar effects to dibucaine, a local anesthetic. Thus, both verapamil and dibucaine abolish the proton motive force and decrease the intracellular ATP concentration. This is accompanied by induction of degP expression, as a result of the activation of the RpoE (SigmaE) extra-cytoplasmic stress response, and activation of the psp operon. Such effects of verapamil, as a membrane active compound, could explain its general toxicity in eukaryotic cells.
Topics: Anesthetics, Local; Bacterial Proteins; Calcium Channel Blockers; Dibucaine; Escherichia coli; Escherichia coli Proteins; Heat-Shock Proteins; Membrane Potentials; Periplasmic Proteins; Serine Endopeptidases; Sigma Factor; Transcription Factors; Verapamil
PubMed: 16836975
DOI: 10.1016/j.bbamem.2006.05.022 -
Acta Poloniae Pharmaceutica 2005Possible leakage of 5-fluorouracil from stable plurilamellar vesicles was monitored during storage of the liposomal concentrates, gels and lyophilized powders. Changes...
Possible leakage of 5-fluorouracil from stable plurilamellar vesicles was monitored during storage of the liposomal concentrates, gels and lyophilized powders. Changes in release profile of dibucaine were taken as indicator of instability. Release profiles were obtained using the dialysis technique for a freshly prepared liposomal concentrate, gel or reconstituted lyophilized powder (zero time) and storage for one, two and four weeks in well closed tubes at 4 degrees C for the liposomal concentrate or gel and at 25 degrees C for liposomal lyophilized powder. Aiming at increasing stability of 5-fluorouracil liposomal dispersion, freshly prepared liposomal concentrates were directly incorporated in hydroxypropyl methylcellulose gel. Stability release profiles of liposomal gels and concentrates indicated a significant increase in stability of liposomal formulations. Also, lyophilization increases the shelf life of liposomes by preserving it in a dry form as a lyophilized cake to be reconstituted immediately prior to administration or direct incorporation into a final dosage form. Release and physico-chemical stability studies showed superior potentials of the lyophilized product after reconstitution in comparison to concentrate and gel forms. It could be concluded that lyophilization of liposomes loaded with a water-soluble drug such as 5-fluorouracil could significantly increase the stability of the liposomal vesicles and decrease leakage from it.
Topics: Antimetabolites, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Drug Delivery Systems; Fluorouracil; Freeze Drying; Gels; Powders; Spectrophotometry, Ultraviolet
PubMed: 16459487
DOI: No ID Found