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1.
Int J Mol Sci ; 23(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36012286

RESUMO

Cell-cell communication via gap junction channels is known to be inhibited by the anesthetics heptanol, halothane and isoflurane; however, despite numerous studies, the mechanism of gap junction channel gating by anesthetics is still poorly understood. In the early nineties, we reported that gating by anesthetics is strongly potentiated by caffeine and theophylline and inhibited by 4-Aminopyridine. Neither Ca2+ channel blockers nor 3-isobutyl-1-methylxanthine (IBMX), forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester or H7 had significant effects on gating by anesthetics. In our publication, we concluded that neither cytosolic Ca2+i nor pHi were involved, and suggested a direct effect of anesthetics on gap junction channel proteins. However, while a direct effect cannot be excluded, based on the potentiating effect of caffeine and theophylline added to anesthetics and data published over the past three decades, we are now reconsidering our earlier interpretation and propose an alternative hypothesis that uncoupling by heptanol, halothane and isoflurane may actually result from a rise in cytosolic Ca2+ concentration ([Ca2+]i) and consequential activation of calmodulin linked to gap junction proteins.


Assuntos
Anestésicos Inalatórios , Anestésicos , Isoflurano , Anestésicos/farmacologia , Anestésicos Inalatórios/farmacologia , Cafeína/metabolismo , Cafeína/farmacologia , Cálcio/metabolismo , Calmodulina/metabolismo , Comunicação Celular , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Halotano/metabolismo , Halotano/farmacologia , Heptanol/metabolismo , Canais Iônicos/metabolismo , Isoflurano/farmacologia , Teofilina/farmacologia
2.
Int J Pediatr Otorhinolaryngol ; 159: 111187, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35660936

RESUMO

OBJECTIVES: Malignant hyperthermia (MH) susceptibility caries broad implications for the care of pediatric surgical patients. While precautions must often be taken for only a vague family history, two options exist to assess MH-susceptibility. We evaluate the use of MH precautions and susceptibility testing at a freestanding children's hospital. METHODS: This single institution retrospective cohort study identified patients of any age who received general anesthetics utilizing MH precautions over a five-year period. The electronic medical record was further queried for patients diagnosed with MH. The indication for MH precautions and uses of susceptibility testing are assessed. Secondary outcomes included a diagnosis of bona fide MH. RESULTS: A total of 125 patients received 174 anesthetics with MH precautions at a mean age of 114 months (0-363 months). Otolaryngology was the procedural service most frequently involved in the care of the cohort (n = 45; 26%). A reported personal or family history of MH (n = 102; 59%) was the most common indication for precautions, followed by muscular dystrophy (n = 29; 17%). No MH events occurred in the cohort and further review of ICD-9 and -10 diagnosis codes found no MH diagnoses. No study subjects received muscle biopsy and contracture testing and only 5 (4%) underwent genetic testing for genomic variants known to cause MH susceptibility. A case example is given to highlight the implications of a reported MH history. CONCLUSION: Otolaryngologists should maintain a familiarity with the precautions necessary to manage patients at risk for MH and MH-like reactions. Without an accessible test to rule out susceptibility, surgeons must rely on a careful history to appropriately utilize precautions. An inappropriate label of "MH-susceptible" may result in decreased access to care and treatment delays.


Assuntos
Hipertermia Maligna , Cirurgiões , Cafeína , Criança , Suscetibilidade a Doenças/complicações , Suscetibilidade a Doenças/diagnóstico , Halotano , Humanos , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/etiologia , Hipertermia Maligna/terapia , Estudos Retrospectivos
3.
J Perianesth Nurs ; 37(4): 435-444, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35414440

RESUMO

Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with RYR1, CACNA1S, or STAC3 mutations. And these genetic abnormalities often cause the imperfection of calcium release channels of skeletal muscle. The incidence of MH among different racial groups across the world ranges from approximately 1:5,000-1:250,000, but there is no national statistic MH incidence in China. It is not clear whether there are racial or regional differences in the incidence, but patients under 18 years old may be more affected. MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, "5C principles" were summarized as an algorithm to guide clinicians.


Assuntos
Hipertermia Maligna , Adolescente , Cafeína , China , Halotano , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/terapia , Mutação
4.
Heart Vessels ; 37(10): 1808-1815, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35426504

RESUMO

Elevation of the head and expiratory negative airway pressure (ENAP) ventilation can both significantly alter cardiovascular hemodynamics. The impact of head-up tilt (HUT) position on mechanically regulated ENAP ventilation-induced hemodynamics was assessed in microminipigs under halothane anesthesia (n = 4) in the absence and presence of adrenergic blockade. Supine ENAP ventilation increased cardiac output, but decreased mean right atrial, systolic pulmonary arterial, and mean left atrial pressures without significantly altering heart rate or aortic pressure. With HUT, the magnitude of ENAP ventilation-induced reduction in right and left atrial pressures was attenuated. HUT minimally altered ENAP ventilation-induced increase in cardiac output and reduction in pulmonary arterial systolic pressure. In addition, with up to 10 cm of HUT there was a significant increase in mean right atrial pressure with and without the ENAP ventilation, whereas HUT did not alter the other hemodynamic variables irrespective of ENAP ventilation. These observations suggest that head elevation augments venous return from the brain irrespective of the ENAP ventilation. Additional studies with pharmacological adrenergic blockade revealed that ENAP ventilation-induced increases in cardiac output and decreases in pulmonary systolic pressure were minimally altered by sympathetic nerve activity, irrespective of the head position. However, the observed ENAP ventilation-induced decreases in right and left atrial pressures were largely dependent upon adrenergic activity. These experimental findings may provide insight into future clinical application of HUT and ENAP for patients with head injury and hypotension.


Assuntos
Halotano , Hipertensão Pulmonar , Adrenérgicos , Pressão Sanguínea/fisiologia , Halotano/farmacologia , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Humanos
5.
Arh Hig Rada Toksikol ; 73(1): 62-70, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35390237

RESUMO

Patient immobilisation with volatile anaesthetics (VA) during radiotherapy is sometimes unavoidable. Although it is known that both VAs and ionising radiation can have nephrotoxic effects, there are no studies of their combined effects on DNA damage. The aim of this in vivo study was to address this gap by investigating whether 48 groups of healthy Swiss albino mice (totalling 240) would differ in kidney cell DNA damage response (alkaline comet assay) to isoflurane, sevoflurane, or halothane anaesthesia and exposure to 1 Gy or 2 Gy of ionising radiation. We took kidney cortex samples after 0, 2, 6, and 24 h of exposure and measured comet parameters: tail length and tail intensity. To quantify the efficiency of the cells to repair and re-join DNA strand breaks, we also calculated cellular DNA repair index. Exposure to either VA alone increased DNA damage, which was similar between sevoflurane and isoflurane, and the highest with halothane. In combined exposure (VA and irradiation with 1 Gy) DNA damage remained at similar levels for all time points or was even lower than damage caused by radiation alone. Halothane again demonstrated the highest damage. In combined exposure with irradiation of 2 Gy sevoflurane significantly elevated tail intensity over the first three time points, which decreased and was even lower on hour 24 than in samples exposed to the corresponding radiation dose alone. This study confirmed that volatile anaesthetics are capable of damaging DNA, while combined VA and 1 Gy or 2 Gy treatment did not have a synergistic damaging effect on DNA. Further studies on the mechanisms of action are needed to determine the extent of damage in kidney cells after longer periods of observation and how efficiently the cells can recover from exposure to single and multiple doses of volatile anaesthetics and radiotherapy.


Assuntos
Anestésicos Inalatórios , Isoflurano , Anestésicos Inalatórios/toxicidade , Animais , Ensaio Cometa , Dano ao DNA , Halotano/toxicidade , Humanos , Isoflurano/toxicidade , Rim , Camundongos , Doses de Radiação , Sevoflurano/toxicidade
6.
J Pharmacol Sci ; 148(4): 343-350, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35300808

RESUMO

Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.


Assuntos
Halotano , Síndrome do QT Longo , Animais , Arritmias Cardíacas/induzido quimicamente , Cães , Halotano/efeitos adversos , Ventrículos do Coração , Humanos , Síndrome do QT Longo/induzido quimicamente , Memantina/efeitos adversos
7.
Anesthesiology ; 136(5): 823-826, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35180293

RESUMO

Effect of Nitrous Oxide and of Narcotic Premedication on the Alveolar Concentration Required for Anesthesia. By , Eger EI II. Anesthesiology 1964; 25:302-6. Hyperthermia during Anesthesia. By Saidman LJ, Havard ES, Eger EI II. JAMA 1964; 190:1029-32. The minimum alveolar concentration (MAC) of an inhaled anesthetic preventing movement in response to a surgical incision as a measure of equipotency was "invented" in 1964 at the University of California, San Francisco. The principal advantage of MAC is that it allows the pharmacologic effects of inhaled anesthetics to be compared against each other at a similar anesthetic depth. Thus, if the hemodynamic effect (hypotension, decreased cardiac output) of anesthetic "A" is greater than that of anesthetic "B," the anesthesiologist may elect to use "A" in patients with myocardial dysfunction. A rare side effect of a volatile anesthetic is that in some patients, malignant hyperthermia may occur with or without succinylcholine use. This phenomenon was detected in a patient in whom halothane MAC was being measured. The availability of the Severinghaus blood gas device allowed for the first ever measurement of the metabolic and respiratory acidemia that accompanies malignant hyperthermia.


Assuntos
Anestésicos Inalatórios , Isoflurano , Hipertermia Maligna , Anestésicos Inalatórios/farmacologia , Halotano/farmacologia , Hemodinâmica , Humanos , Isoflurano/farmacologia , Óxido Nitroso
8.
Anesthesiology ; 135(4): 724-727, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34499097

RESUMO

The Solubility of Halothane in Blood and Tissue Homogenates. By Larson CP, Eger EI, Severinghaus JW. Anesthesiology 1962; 23:349-55. Measured samples of human and bovine blood, human hemoglobin, and tissue homogenates from human fat and both human and bovine liver, kidney, muscle, whole brain, and separated gray and white cortex were added to stoppered 2,000-ml Erlenmeyer flasks. To each flask, 0.1 ml of liquid halothane was added under negative pressure using a calibrated micropipette. After the flask was agitated for 2 to 4 h to achieve equilibrium between the gas and blood or tissue contents, a calibrated infrared halothane analyzer was used to measure the concentration of halothane vapor. Calculated partition coefficients ranged from 0.7 for water to 2.3 for blood and from 3.5 for human or bovine kidney to 6 for human whole brain or liver and 8 for human muscle. Human peritoneal fat had a value of 138. The human blood-gas partition coefficient of 2.3 as determined by this equilibration method was well below the previously published value of 3.6.


Assuntos
Anestésicos Inalatórios/metabolismo , Pesquisa Biomédica/normas , Halotano/metabolismo , Anestésicos Inalatórios/química , Animais , Bovinos , Halotano/química , Humanos , Solubilidade/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
9.
Int J Radiat Biol ; 97(10): 1425-1435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34328801

RESUMO

PURPOSE: Patient immobilization by general volatile anesthesia (VA) may be necessary during medical radiology treatment, and its use has increased in recent years. Although ionizing radiation (IR) is a well-known genotoxic and cytotoxic agent, and VA exposure has caused a range of side effects among patients and occupationally exposed personnel, there are no studies to date comparing DNA damage effects from combined VA and single fractional IR dose exposure. MATERIAL AND METHODS: We investigate whether there is a difference in white blood cells DNA damage response (by the alkaline comet assay) in vivo in 185 healthy Swiss albino mice divided into 37 groups, anesthetized with isoflurane/sevoflurane/halothane and exposed to 1 or 2 Gy of IR. Blood samples were taken after 0, 2, 6 and 24 h after exposure, and comet parameters were measured: tail length, tail intensity and tail moment. The cellular DNA repair index was calculated to quantify the efficiency of cells in repairing and re-joining DNA strand breaks following different treatments. RESULTS: In combined exposures, halothane caused higher DNA damage levels that were dose-dependent; sevoflurane damage increase did not differ significantly from the initial 1 Gy dose, and isoflurane even demonstrated a protective effect, particularly in the 2 Gy dose combined exposure. Nevertheless, none of the exposures reached control levels even after 24 h. CONCLUSION: Halothane appears to increase the level of radiation-induced DNA damage, while sevoflurane and isoflurane exhibited a protective effect. DNA damage may have been even greater in target organs such as liver, kidney or even the brain, and this is proposed for future study.


Assuntos
Dano ao DNA , Anestésicos Inalatórios/efeitos adversos , Animais , Halotano , Isoflurano/efeitos adversos , Camundongos , Radioterapia , Sevoflurano
10.
Ceska Slov Farm ; 70(1): 7-17, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237948

RESUMO

Since the advent of nitric oxide, diethyl ether, chloroform and cyclopropane, the greatest advancement in the area of general inhalational anesthetics has been achieved by the introduction of fluorinated anesthetics and the relevant chiral techniques. This progress led to marked decrease in mortality rates in anesthesia. In the group of chiral fluorinated compounds, halothane (Fluotan®), isoflurane (Foran®), desflurane (Supran®) and enflurane (Ehran®) are deployed as volatile anesthetics. Chiral anesthetics possess a stereogenic center in their molecules and thus exist as two enantiomers (S)-(+) and (R)-(-). Although these chiral anesthetics are used as racemates, it is crucial to study besides the bioactivities of the racemic compounds also the biological activity and other properties of the particular enantiomers. The present survey discusses the drug category known as inhalational anesthetics in regard to their chiral aspects. These compounds exhibit marked differences between the (R) and (S)-enantiomers in their pharmacodynamics, pharmacokinetics and toxicity. The main analytical technique employed in the enantioseparation of these compounds is gas chromatography (GC). This review lists the individual chiral phases (chiral selectors) used in the enantioseparation as well as in pharmacokinetic studies. The possibilities of preparation of these compounds in their enantiomerically pure form by means of stereoselective synthesis are also mentioned.


Assuntos
Anestésicos Inalatórios , Isoflurano , Enflurano , Halotano , Estereoisomerismo
11.
Nat Commun ; 12(1): 4293, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257294

RESUMO

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Cálcio/metabolismo , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Halotano/farmacologia , Isoflurano/farmacologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mutação/genética
12.
Med Gas Res ; 11(2): 53-57, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33818443

RESUMO

Induction of anesthesia using an inhalation agent remains a fundamental technique due to its rapid induction and emergence. Sevoflurane is preferred over halothane for its faster induction of anesthesia and lesser complications. Studies on sevoflurane in pediatrics have established it as safe and effective. However, its effectiveness in adults is very limited. Hence, this study was conducted to compare the induction and intubating conditions, hemodynamic profiles, and emergence from anesthesia with sevoflurane and halothane in adults and pediatric patients. This randomized clinical study was carried out for a period of 2 years (November 2006-September 2008) in the Anesthesiology Department of a Krishna Institute of Medical Sciences (Deemed to be) University. Eighty patients of American Society of Anesthesiologists Class I and II were randomly assigned to halothane group and sevoflurane group with 40 patients in each group. Patients were induced and intubated with increasing concentrations of halothane from 0.5% to 5% and sevoflurane 1% to 7% in 50% nitrous oxide and 50% oxygen mixture. Recordings of vitals including induction and intubation time, recovery characteristics, and recovery and discharge time was also recorded. There was a statistically significant difference between sevoflurane and halothane in the induction and intubation time indicating that sevoflurane had faster induction and shorter intubation time compared to that of halothane. Patients in halothane group had more incidence of coughing, intolerance, salivation, breathe holding, rigidity, and movement as compared to sevoflurane group. The mean time to consciousness, response to verbal commands, orientation, and recovery room discharge time was significantly shorter in sevoflurane group as compared to halothane group. Sevoflurane can be a suitable alternative to halothane for induction of anesthesia in patients with a shorter induction and intubation time with better hemodynamic stability. This study was approved by the Institutional Ethics Committee (KIMSDU/IEC-307/028/14/11/2006).


Assuntos
Anestesia , Anestesiologia , Anestésicos Inalatórios , Éteres Metílicos , Pediatria , Adulto , Anestésicos Inalatórios/efeitos adversos , Criança , Éteres , Halotano/efeitos adversos , Humanos , Éteres Metílicos/efeitos adversos , Sevoflurano/efeitos adversos
13.
Heart Vessels ; 36(7): 1088-1097, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33763729

RESUMO

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.


Assuntos
Anestesia por Inalação/métodos , Fibrilação Atrial/tratamento farmacológico , Halotano/farmacologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ranolazina/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Feminino , Átrios do Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Infusões Intravenosas , Bloqueadores dos Canais de Sódio/administração & dosagem
14.
J Pharmacol Sci ; 145(3): 268-272, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33602507

RESUMO

We assessed concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables using a cross-over design in intact beagle dogs (n = 4). Elevation of inhaled halothane from 1.0% to 2.0% or isoflurane from 1.5% to 2.5% decreased the mean blood pressure and prolonged the QRS width without significantly altering the heart rate, PR interval or QT interval. However, the observed changes disappeared after regressions of both anesthetic conditions to their initial settings. These results indicate that hypotension-induced, reflex-mediated increase of sympathetic tone may have counterbalanced the direct negative chronotropic, dromotropic and repolarization slowing effects of the anesthetics.


Assuntos
Anestésicos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Halotano/administração & dosagem , Halotano/farmacologia , Hemodinâmica/efeitos dos fármacos , Isoflurano/administração & dosagem , Isoflurano/farmacologia , Administração por Inalação , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Cães , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Masculino , Sistema Nervoso Simpático/efeitos dos fármacos
15.
Can J Anaesth ; 68(6): 761-772, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33403543

RESUMO

PURPOSE: Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites. METHODS: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups. RESULTS: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement. CONCLUSION: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.


RéSUMé: OBJECTIF : L'hyperthermie maligne (HM) est une condition hypermétabolique potentiellement mortelle déclenchée par certains agents anesthésiques et causée par une homéostasie calcique perturbée des cellules musculaires squelettiques. Des données probantes récentes ont mis en lumière une atteinte de diverses voies biochimiques chez les patients susceptibles à l'HM en l'absence d'anesthésiques. Nous avons émis l'hypothèse que les différences cliniques entre les individus susceptibles à l'HM et des témoins se refléteraient dans des différences mesurables de métabolites myoplasmiques. MéTHODE : Nous avons réalisé un profilage métabolomique d'échantillons de muscles squelettiques provenant de personnes négatives à l'HM (témoins) et de patients susceptibles à l'HM subissant une biopsie musculaire dans le but de poser un diagnostic de susceptibilité à l'HM. Les métabolites cellulaires ont été extraits de 33 échantillons de muscles humains frais et de 87 échantillons congelés à l'aide d'une microextraction en phase solide et des plateformes de profilage biochimique non ciblées Metabolon®, respectivement. La chromatographie en phase liquide à haute performance et la spectrométrie de masse à haute résolution ont été utilisées pour l'identification et la validation des métabolites, puis suivies d'une analyse des différences dans les métabolites entre les groupes susceptibles à l'HM et les groupes négatifs à l'HM. RéSULTATS : Des différences significatives ont été observées entre les groupes susceptibles à l'HM et les groupes témoins dans les métabolites issus de diverses voies (P : de 0,009 à < 0,001). Ces différences comprenaient l'accumulation d'acylcarnitines à longue chaîne, de diacylglycérols, de phosphoénolpyruvate, de métabolites de la voie d'histidine, de lysophosphatidylcholine, de marqueurs de stress oxydatif, et de phosphoinositols, aussi bien que des taux réduits de monoacylglycérols. Les résultats des deux plateformes analytiques concordaient. CONCLUSION : Cette étude métabolomique indique un changement de l'utilisation des glucides vers les lipides pour la production d'énergie chez les personnes susceptibles à l'HM. Ce changement pourrait entraîner une inefficacité de la bêta-oxydation, ainsi qu'une augmentation du renouvellement des protéines musculaires, du stress oxydatif, et/ou des taux de lysophosphatidylcholine.


Assuntos
Halotano , Hipertermia Maligna , Humanos , Hipertermia , Metabolômica , Músculo Esquelético
16.
J Surg Res ; 260: 325-344, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33373852

RESUMO

Case reports from as early as the 1970s have shown that intravenous injection of even a small dose of volatile anesthetics result in fatal lung injury. Direct contact between volatile anesthetics and pulmonary vasculature triggers chemical damage in the vessel walls. A wide variety of factors are involved in lung ischemia-reperfusion injury (LIRI), such as pulmonary endothelial cells, alveolar epithelial cells, alveolar macrophages, neutrophils, mast cells, platelets, proinflammatory cytokines, and surfactant. With a constellation of factors involved, the assessment of the protective effect of volatile anesthetics in LIRI is difficult. Multiple animal studies have reported that with regards to LIRI, sevoflurane demonstrates an anti-inflammatory effect in immunocompetent cells and an anti-apoptotic effect on lung tissue. Scattered studies have dismissed a protective effect of desflurane against LIRI. While a single-center randomized controlled trial (RCT) found that volatile anesthetics including desflurane demonstrated a lung-protective effect in thoracic surgery, a multicenter RCT did not demonstrate a lung-protective effect of desflurane. LIRI is common in lung transplantation. One study, although limited due to its small sample size, found that the use of volatile anesthetics in organ procurement surgery involving "death by neurologic criteria" donors did not improve lung graft survival. Future studies on the protective effect of volatile anesthetics against LIRI must examine not only the mechanism of the protective effect but also differences in the effects of different types of volatile anesthetics, their optimal dosage, and the appropriateness of their use in the event of marked alveolar capillary barrier damage.


Assuntos
Anestésicos Inalatórios/uso terapêutico , Anestésicos Intravenosos/efeitos adversos , Lesão Pulmonar/prevenção & controle , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Adolescente , Adulto , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/administração & dosagem , Animais , Biomarcadores/metabolismo , Ponte Cardiopulmonar , Evolução Fatal , Feminino , Halotano/administração & dosagem , Halotano/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Adulto Jovem
17.
Naunyn Schmiedebergs Arch Pharmacol ; 394(4): 581-589, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33064166

RESUMO

Donepezil, an inhibitor for acetylcholinesterase used for patients with Alzheimer's disease, has been shown to inhibit IKr, occasionally inducing torsade de pointes. In order to analyze the causal relationship between donepezil treatment and onset of lethal arrhythmias, we initially assessed electropharmacological effects of donepezil hydrochloride of 0.01, 0.1, and 1 mg/kg, i.v. over 10 min using the halothane-anesthetized intact dogs (n = 4), possibly providing subtherapeutic to supratherapeutic plasma concentrations. Although the low or middle dose did not exert any effect, the high dose transiently increased the ventricular refractoriness along with modest prolongation of the late repolarization period, indicating potential IKr inhibitory action in vivo. Moreover, the high dose induced the positive chronotropic, inotropic, and dromotropic actions along with the pressor effect and prolongation of early repolarization period, suggesting sympathicotonic condition in the central nervous system. Next, we examined proarrhythmic effects of donepezil hydrochloride of 0.1 and 1 mg/kg, i.v. over 10 min using the conscious chronic atrioventricular block dogs (n = 4). Although the low dose hardly affected the cardiovascular variables, the high dose increased the atrial and ventricular rate without significantly altering the repolarization period, possibly reflecting sympathicotonic condition. Importantly, the high dose induced non-sustained ventricular tachycardia in half of the animals. Thus, donepezil by itself did not induce torsade de pointes in vivo, which suggests that donepezil-induced sympathicotonic condition may induce Ca2+ overload, triggering the ventricular arrhythmias, but might indirectly attenuate its IKr inhibitory action, preventing excessive repolarization delay.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Inibidores da Colinesterase/efeitos adversos , Donepezila/efeitos adversos , Anestésicos Inalatórios , Animais , Arritmias Cardíacas/fisiopatologia , Bloqueio Atrioventricular , Cães , Feminino , Halotano , Ventrículos do Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
18.
J Pharmacol Sci ; 145(1): 16-22, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357775

RESUMO

We compared dl-sotalol-induced electrocardiographic responses in intact dogs using a repeated-measures design among 1% halothane anesthesia, 1.5% isoflurane anesthesia with nitrous oxide (N2O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N2O or in conscious state, reflecting sympathetic nerve suppression for the atrioventricular node by halothane. Both anesthetics exhibited longer basal QRS width than conscious state, suggesting their ventricular INa inhibition. Also, both anesthetics showed longer basal QT interval, QTcF and Tpeak-Tend than conscious state, indicating their ventricular IKr inhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N2O and in conscious state, which was less great in halothane, suggesting further sympathetic nerve suppression for the atrioventricular node might be limited in halothane. dl-Sotalol prolonged QT interval and QTcF >3 times greater in either of the anesthetics than in conscious state; moreover, dl-sotalol prolonged Tpeak-Tend similarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N2O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward IKr suppression. Thus, isoflurane with nitrous oxide could be useful for in vivo IKr assay like halothane.


Assuntos
Anestesia/métodos , Estado de Consciência/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Halotano , Isoflurano , Óxido Nitroso , Sotalol/farmacologia , Animais , Estado de Consciência/fisiologia , Cães , Halotano/farmacologia , Isoflurano/farmacologia , Masculino , Óxido Nitroso/farmacologia
19.
Heart Vessels ; 36(3): 424-429, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33136260

RESUMO

Lamotrigine has been used for patients with epilepsy and/or bipolar disorder, overdose of which induced the hypotension, elevation of the atrial pacing threshold, cardiac conduction delay, wide complex tachycardia, cardiac arrest and Brugada-like electrocardiographic pattern. To clarify how lamotrigine induces those cardiovascular adverse events, we simultaneously assessed its cardiohemodynamic and electrophysiological effects using the halothane-anesthetized dogs (n = 4). Lamotrigine was intravenously administered in doses of 0.1, 1 and 10 mg/kg/10 min under the monitoring of cardiovascular variables, possibly providing subtherapeutic to supratherapeutic plasma concentrations. The low or middle dose of lamotrigine did not alter any of the variables. The high dose significantly delayed the intra-atrial and intra-ventricular conductions in addition to the prolongation of ventricular effective refractory period, whereas no significant change was detected in the other variables. Lamotrigine by itself has relatively wide safety margin for cardiohemodynamics, indicating that clinically reported hypotension may not be induced through its direct action on the resistance arterioles or capacitance venules. The electrophysiological effects suggested that lamotrigine can inhibit Na+ channel in the in situ hearts. This finding may partly explain the onset mechanism of lamotrigine-associated cardiac adverse events in the clinical cases. In addition, elevation of J wave was induced in half of the animals, suggesting that lamotrigine may have some potential to unmask Brugada electrocardiographic genotype in susceptible patients.


Assuntos
Anestesia Geral/métodos , Doenças Cardiovasculares/induzido quimicamente , Eletrocardiografia , Halotano/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Cães , Sistema de Condução Cardíaco/fisiopatologia , Lamotrigina/toxicidade
20.
Naunyn Schmiedebergs Arch Pharmacol ; 394(3): 559-560, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33230575

RESUMO

Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and IKr inhibition in cardiomyocytes caused by donepezil are believed to mediate this effect.


Assuntos
Doença de Alzheimer , Bloqueio Atrioventricular , Doença de Alzheimer/tratamento farmacológico , Animais , Arritmias Cardíacas/induzido quimicamente , Inibidores da Colinesterase , Cães , Donepezila , Halotano , Indanos , Piperidinas
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