RESUMO
BACKGROUND: Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model. METHODS: The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice. RESULTS: The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P < 0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P < 0.001] for Ca; mean ± SD; n = 9 each) but lower in Na current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P < 0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P < 0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P < 0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 10/µm (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 10/µm (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1. CONCLUSION: These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.
Assuntos
Anestésicos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Espasmo Brônquico , Inflamação/tratamento farmacológico , Lidocaína/análogos & derivados , Traqueia/efeitos dos fármacos , Traqueia/fisiopatologia , Animais , Modelos Animais de Doenças , Inflamação/fisiopatologia , Lidocaína/farmacologia , Camundongos , Ratos , Ratos WistarRESUMO
The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not known. In this study, we asked whether PSD increases tonic nociception in the formalin test, decreases the antinociceptive effect of morphine administered into the periaqueductal gray matter (PAG), and disrupts endogenous descending pain modulation. PSD for either 24 or 48 h significantly increased formalin-induced nociception and decreased mechanical nociceptive paw withdrawal threshold. The maximal antinociceptive effect induced by morphine (0.9-9 nmol, intra-PAG) was significantly decreased by PSD. The administration of a low dose of the GABAA receptor antagonist, bicuculline (30-300 pmol, intra-PAG), decreased nociception in control rats, but not in paradoxical-sleep-deprived ones. Furthermore, the administration of the cholecystokinin (CCK) 2 receptor antagonist, YM022 (0.5-2 pmol) in the rostral ventral medulla (RVM), decreased nociception in paradoxical-sleep-deprived rats but not in control ones. While a dose of the CCK 2 receptor agonist, CCK-8 (8-24 pmol intra-RVM), increased nociception in control rats, but not in paradoxical-sleep-deprived ones. In addition, the injection of lidocaine (QX-314, 2%, intra-RVM) decreased nociception in sleep-deprived rats, but not in control rats, while the lesion of the dorsolateral funiculus prevented the pronociceptive effect of PSD. Finally, PSD significantly increased c-Fos expression in the RVM. Therefore, PSD increases pain independently of its duration or of the characteristic of the nociceptive stimulus and decreases morphine analgesia at the PAG. PSD appears to increase pain by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity.
Assuntos
Nociceptividade , Dor/complicações , Dor/fisiopatologia , Privação do Sono/complicações , Privação do Sono/fisiopatologia , Animais , Bicuculina/farmacologia , Bicuculina/uso terapêutico , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Medição da Dor , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Privação do Sono/tratamento farmacológicoRESUMO
Inhalation of JMF2-1, an analog of lidocaine with reduced anesthetic activity, prevents airway contraction and lung inflammation in experimental asthma models. We sought to test if the JMF2-1 effects are a consequence of increased intracellular cAMP levels in asthma cell targets, such as smooth muscle cells and T cells. Functional effect of JMF2-1 on carbachol-induced contraction of intact or epithelial-denuded rat trachea was assessed in conventional organ baths. cAMP was quantified by radioimmunoassay in cultured guinea pig tracheal smooth muscle cells, as well as lymph node cells from BALB/c mice, exposed to JMF2-1. We found that JMF2-1 (0.1-1mM) concentration-dependently inhibited epithelium-intact tracheal ring contraction induced by carbachol challenge. The antispasmodic effect remained unaltered following epithelium removal or pretreatment with NG-nitro-L-arginine methyl ester (100µM), but it was clearly sensitive to 9-(tetrahydro-2-furyl) adenine (SQ22,536, 100µM), an adenylate cyclase inhibitor. JMF2-1 (300 and 600µM) also dose-dependently increased cAMP intracellular levels of both cultured airway smooth muscle cells and T lymphocytes. This effect was consistently abrogated by SQ22,536 and reproduced by forskolin in both systems. JMF2-1 induced apoptosis of anti-CD3 activated T cells in a mechanism sensitive to zIETD, indicating that JMF2-1 mediates caspase-8-dependent apoptosis. Furthermore, forskolin also inhibited anti-CD3 induced T cell proliferation and survival. Our results suggest that JMF2-1 inhibits respiratory smooth muscle contraction as well as T cell proliferation and survival through enhancement of intracellular cAMP levels. These findings may help to explain the anti-inflammatory and antispasmodic effects of JMF2-1 observed in previous studies.
Assuntos
Anti-Inflamatórios/farmacologia , AMP Cíclico/metabolismo , Lidocaína/análogos & derivados , Parassimpatolíticos/farmacologia , Adenilil Ciclases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/metabolismo , Carbacol/farmacologia , Caspase 8/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colforsina/farmacologia , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Cobaias , Inflamação/prevenção & controle , Lidocaína/farmacologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismoRESUMO
The aim of this study is to determine the concentrations of lidocaine and its metabolite, monoethylglycine xylidide (MEGX), and of the enantiomers of bupivacaine in maternal and fetal compartments. Ten healthy pregnant women were submitted to epidural anesthesia. Drug concentrations were determined in the maternal vein, fetal umbilical artery and vein, and the placental intervillous space. The highest concentrations of the bupivacaine enantiomers lidocaine and of lidocaine and of its MEGX metabolite were detected in maternal plasma and in the placental intervillous space. The placental transfer was 33% for the (+)-(R)-bupivacaine enantiomer and 31% for the (-)-(S)-bupivacaine enantiomer. For lidocaine and its MEGX metabolite, respective placental transfers were 60% and 43%. Lidocaine concentration in the fetal umbilical vein was 1.46 times higher than in the fetal umbilical artery. The highest concentrations of lidocaine and its metabolite and of the enantiomers of bupivacaine were detected in the placental intervillous space. The higher lidocaine concentrations in the fetal umbilical vein than in the fetal umbilical artery suggest that there was tissue uptake of the drug or drug metabolization by the fetus.
Assuntos
Anestésicos Locais/farmacocinética , Bupivacaína/farmacocinética , Lidocaína/análogos & derivados , Lidocaína/farmacocinética , Adulto , Anestesia Epidural/métodos , Anestesia Obstétrica/métodos , Anestésicos Locais/química , Bupivacaína/química , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Placenta/metabolismo , Gravidez , Estereoisomerismo , Distribuição Tecidual , Artérias Umbilicais/metabolismo , Veias Umbilicais/metabolismo , Adulto JovemRESUMO
BACKGROUND: Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1. OBJECTIVE: We tested the hypothesis that JMF2-1 would prevent allergen-induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro. Methods Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2-1 (0.05-2%) or saline was aerosolized twice a day during the ovalbumin (OVA)-provocation period (19-21 days post-sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2-1 (100-600 µm) at the cellular level. RESULTS: OVA challenge resulted in lung recruitment of CD4(+) T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2-1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2-1 treatment did not alter levels of CD4(+) or CD8(+) T cells in the thymus or lymph nodes of naïve mice, although it inhibited OVA-induced IL-13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA-activated lymphocytes in a mechanism sensitive to z-VAD, indicating that JMF2-1 mediates caspase-dependent apoptosis. CONCLUSION: Inhalation of JMF2-1 prevents the cardinal features of asthma by reducing T(H) 2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2-1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics.
Assuntos
Anti-Inflamatórios/farmacologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Lidocaína/análogos & derivados , Ovalbumina/antagonistas & inibidores , Ovalbumina/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Hiper-Reatividade Brônquica/patologia , Citocinas/biossíntese , Citocinas/imunologia , Dexametasona/farmacologia , Inflamação/imunologia , Inflamação/prevenção & controle , Lidocaína/síntese química , Lidocaína/química , Lidocaína/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Linfócitos T/imunologiaRESUMO
The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.
Assuntos
Analgésicos não Narcóticos/farmacologia , Analgésicos Opioides/farmacologia , Comportamento Animal/efeitos dos fármacos , Dor/induzido quimicamente , Dor/psicologia , Óleos de Plantas/farmacologia , Articulação Temporomandibular/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Dipirona/farmacologia , Relação Dose-Resposta a Droga , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Morfina/farmacologia , Mostardeira , Ratos , Tramadol/farmacologiaRESUMO
BACKGROUND: Peridural blockade with lidocaine, bupivacaine, and fentanyl is an anesthetic procedure extensively used in obstetrics, justifying the pharmacokinetic study of these drugs during labor. OBJECTIVE: To investigate the influence of the physiopathological changes of gestational diabetes mellitus (GDM) on the pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women subjected to peridural anesthesia. PATIENTS AND METHODS: Ten normal pregnant women (group 1) and six pregnant women with GDM (group 2) were studied, all of them at term. The patients received 200 mg 2% lidocaine hydrochloride without a vasoconstrictor by the peridural locoregional route. Maternal blood samples were collected at predetermined times for the analysis of lidocaine and MEGX by chromatography and pharmacokinetic analysis. RESULTS: The median pharmacokinetic parameters of lidocaine for groups 1 and 2 (P
Assuntos
Anestesia Epidural , Anestésicos Locais/farmacocinética , Diabetes Gestacional/metabolismo , Lidocaína/análogos & derivados , Adulto , Anestésicos Locais/administração & dosagem , Anestésicos Locais/sangue , Anestésicos Locais/uso terapêutico , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Diabetes Gestacional/sangue , Diabetes Gestacional/enzimologia , Feminino , Humanos , Lidocaína/administração & dosagem , Lidocaína/sangue , Lidocaína/farmacocinética , Lidocaína/uso terapêutico , Taxa de Depuração Metabólica , Gravidez , Fatores de Tempo , Adulto JovemRESUMO
The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.
Assuntos
Anestésicos Locais/síntese química , Anestésicos Locais/farmacologia , Lidocaína/análogos & derivados , Lidocaína/síntese química , Lidocaína/farmacologia , Parassimpatolíticos/síntese química , Parassimpatolíticos/farmacologia , Anestésicos Locais/química , Animais , Técnicas de Química Combinatória , Relação Dose-Resposta a Droga , Histamina/farmacologia , Lidocaína/química , Estrutura Molecular , Parassimpatolíticos/química , Ratos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Prior reports show that nebulized lidocaine might be an effective treatment for asthma. OBJECTIVE: We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity. METHODS: Blockade of Na(+) currents was assayed in cultured GH(3) cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro. RESULTS: The 50% inhibitory concentration values for blockade of Na(+) currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue. CONCLUSION: Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung. CLINICAL IMPLICATIONS: Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.
Assuntos
Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Anestésicos/farmacologia , Animais , Linhagem Celular , Histamina/metabolismo , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Ovalbumina , Ratos , Ratos Wistar , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Convulsões/induzido quimicamente , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/fisiopatologiaRESUMO
Evidence is accumulating which supports a role for ATP in the initiation of pain by acting on P2X receptors expressed on nociceptive afferent nerve terminals. To investigate whether these receptors play a role in temporomandibular (TMJ) pain, we studied the presence of functional P2X receptors in rat TMJ by examining the nociceptive behavioral response to the application of the selective P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) into the TMJ region of rat. The involvement of endogenous ATP in the development of TMJ inflammatory hyperalgesia was also determined by evaluating the effect of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on carrageenan-induced TMJ inflammatory hyperalgesia. Application of alpha,beta-meATP into the TMJ region of rats produced significant nociceptive responses that were significantly reduced by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314, (2%) or of the P2 receptor antagonist PPADS. Co-application of PPADS with carrageenan into the TMJ significantly reduced inflammatory hyperalgesia. The results indicate that functional P2X receptors are present in the TMJ and suggest that endogenous ATP may play a role in TMJ inflammatory pain mechanisms possibly by acting primarily in these receptors.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Artralgia/metabolismo , Lidocaína/análogos & derivados , Nociceptores/metabolismo , Fosfato de Piridoxal/análogos & derivados , Receptores Purinérgicos P2/metabolismo , Transtornos da Articulação Temporomandibular/metabolismo , Articulação Temporomandibular/fisiopatologia , Trifosfato de Adenosina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artralgia/fisiopatologia , Artrite/induzido quimicamente , Artrite/metabolismo , Artrite/fisiopatologia , Carragenina/antagonistas & inibidores , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Lidocaína/farmacologia , Masculino , Nociceptores/efeitos dos fármacos , Agonistas do Receptor Purinérgico P2 , Antagonistas do Receptor Purinérgico P2 , Fosfato de Piridoxal/farmacologia , Ratos , Ratos Wistar , Receptores Purinérgicos P2X , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiopatologia , Articulação Temporomandibular/inervação , Transtornos da Articulação Temporomandibular/induzido quimicamente , Transtornos da Articulação Temporomandibular/fisiopatologiaRESUMO
Temporomandibular joint (TMJ) pain conditions are poorly understood. Since formalin is a noxious stimulus widely used in animal behavioral experiments for studying pain mechanisms, the aim of this study was to develop a behavioral model to study the TMJ pain conditions by characterizing the nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats. NaCl (0.9%) or different concentrations of formalin (0.5, 1.5, 2.5 or 5%) were administrated into the TMJ region. The formalin-induced behavioral responses characterized by moving the mandible, rubbing the orofacial region and flinching the head quickly were quantified for 45 min. The TMJ injection of formalin significantly increased the asymmetrical orofacial rubbing and head flinching behaviors, but not the movement of the mandible with concentrations of 1.5% and above (P<0.05, Dunn's test) when compared with the NaCl (0.9%) injection. These responses were significantly reduced (P<0.05, Mann-Whitney test) by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314 (2%), and by the administration of intraperitoneal morphine (4 mg/kg) 30 min prior to the TMJ formalin injection. This study demonstrates that the injection of formalin into the TMJ region of rats produces quantitative nociceptive behaviors constituting a novel behavioral model for TMJ pain.
Assuntos
Comportamento Animal , Modelos Animais de Doenças , Lidocaína/análogos & derivados , Dor/fisiopatologia , Ratos Wistar , Articulação Temporomandibular/fisiopatologia , Analgésicos Opioides/farmacologia , Anestésicos Locais/farmacologia , Animais , Lidocaína/farmacologia , Masculino , Morfina/farmacologia , Nociceptores/fisiologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor , RatosRESUMO
Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.
Assuntos
Lidocaína/análogos & derivados , Antagonistas Nicotínicos/farmacologia , Proadifeno/análogos & derivados , Receptores Nicotínicos/metabolismo , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Animais , Sítios de Ligação , Clorisondamina/metabolismo , Clorisondamina/farmacologia , Etídio/metabolismo , Etídio/farmacologia , Hexametônio/metabolismo , Hexametônio/farmacologia , Lidocaína/metabolismo , Lidocaína/farmacologia , Camundongos , Antagonistas Nicotínicos/metabolismo , Oniocompostos/metabolismo , Oniocompostos/farmacologia , Pempidina/metabolismo , Pempidina/farmacologia , Proadifeno/metabolismo , Proadifeno/farmacologia , Quinacrina/metabolismo , Quinacrina/farmacologia , Compostos de Tritil/metabolismo , Compostos de Tritil/farmacologiaRESUMO
Our aim was to compare standard liver function tests (serum bilirubin, serum albumin and prothrombin concentration), with lidocaine and monoethylglycinexylidide pharmacokinetic parameters, after oral lidocaine administration, to assess hepatic function of cirrhotic individuals. Twenty-one consecutive cirrhotic patients, nine consecutive acute hepatitis patients, and nine healthy individuals received oral lidocaine. Lidocaine and monoethylglycinexylidide serum concentrations were determined by the TDx system. Cirrhotic patients had higher lidocaine and lower monoethylglycinexylidide serum concentrations and differences in its pharmacokinetic variables, compared to control and hepatitis groups (P < 0.05). Sensitivity of lidocaine serum determinations (100%) was greater than sensitivity of serum bilirubin (57%), serum albumin (62%), and prothrombin concentrations (43%) and monoethylglycinexylidide serum concentrations (57%) in differentiating cirrhotic individuals from controls. In conclusion, after oral administration, lidocaine and monoethylglycinexylidide pharmacokinetic parameters are significantly altered in cirrhotic patients compared to normal and acute hepatitis subjects. Lidocaine pharmacokinetic parameters would be better than those of monoethylglycinexylidide and standard liver function tests in the evaluation of liver function of cirrhotic patients.
Assuntos
Lidocaína/análogos & derivados , Lidocaína/farmacocinética , Cirrose Hepática/sangue , Testes de Função Hepática/normas , Administração Oral , Adulto , Análise de Variância , Área Sob a Curva , Bilirrubina/sangue , Feminino , Meia-Vida , Hepatite A/sangue , Hepatite A/metabolismo , Hepatite A/fisiopatologia , Hepatite B/sangue , Hepatite B/metabolismo , Hepatite B/fisiopatologia , Humanos , Lidocaína/administração & dosagem , Lidocaína/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Sensibilidade e Especificidade , Albumina Sérica , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To evaluate hepatic drug metabolism, as determined by the formation of monoethylglycinexylidide (MEGX) after lidocaine injection and indocyanine green (ICG) clearance, in patients with sickle cell disease. STUDY DESIGN: A case-control study including 19 patients with homozygous hemoglobin S, and 13 age- and sex-matched black control subjects. Serum MEGX concentration was measured after intravenous injection of 1 mg/kg (maximum 50 mg) lidocaine. ICG (0.5 mg/kg) was injected concomitantly and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: MEGX formation at 15 minutes was decreased in patients with sickle cell disease compared with formation in the control subjects (39.9 +/- 18.0 vs 65.6 +/- 50.0 micrograms/L, respectively, p < 0.02). The volume of distribution of ICG was increased in patients with sickle cell disease compared with that in the control subjects (0.21 +/- 0.09 vs 0.11 +/- 0.03 L/kg, p < 0.01). This partly accounts for the decreased MEGX formation. The ICG half-life was similar in both groups (3.8 +/- 1.5 vs 3.1 +/- 1.0 min). Hepatic blood flow, derived from ICG clearance, was increased in sickle cell patients compared with that of the control subjects (12.2 +/- 4.5 vs 8.1 +/- 2.1 ml/kg/min, p < 0.01). CONCLUSION: Hepatic drug metabolism, as assessed by MEGX formation after lidocaine injection, is impaired in patients with sickle cell disease. This impairment may have clinical implications when using hepatically metabolized medications in patients with sickle cell disease.
Assuntos
Anemia Falciforme/metabolismo , Lidocaína , Fígado/metabolismo , Adulto , Anemia Falciforme/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Corantes , Técnica de Diluição de Corante , Feminino , Meia-Vida , Homozigoto , Humanos , Verde de Indocianina , Lactente , Lidocaína/análogos & derivados , Lidocaína/metabolismo , Lidocaína/farmacocinética , Fígado/fisiopatologia , Circulação Hepática , Testes de Função Hepática , Masculino , Fatores de TempoRESUMO
Mechanisms of ion channel blockade by noncompetitive inhibitors of the nicotinic acetylcholine receptor (AChR) have been particularly difficult to elucidate. We have combined here transient expression of embryonic, adult, and a mutated adult muscle AChR associated with a slow channel syndrome (Ohno, K., Hutchinson, D. O., Milone, M., Brengman, J. M., Bouzat, C., Sine, S., and Engel, A. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 758-762) with single channel recordings to determine subunit specificity and mechanisms of action of the prototype glucocorticoid hydrocortisone (HC). HC affected in a similar manner the gating kinetics of all types of muscle AChR, producing briefer openings with normal amplitudes. We postulate that this steroid acts as a noncompetitive inhibitor of the AChR and that its mechanism of action can be interpreted in terms of blocking models. The forward rate constant for the blocking process was also similar for all channel types, indicating that the structural differences between them are not responsible for the effect. The reduction in the channel open time was not dependent on agonist concentration; it was slightly voltage dependent, suggesting that HC binds to a site located inside the membrane that senses the electric field. Recordings at high acetylcholine concentration in the presence of HC showed a reduced number of openings per activation period and the long closed times typically observed in the desensitization phenomenon. In competition studies with the classical open channel blocker QX-222, HC induced an early termination of the burst, suggesting that the two act at different sites. Taken together the results support the existence of specific sites sensed by the membrane field, different from those of open channel blockers and probably located at the lipid-protein interface. From this site(s), glucocorticoids and other hydrophobic noncompetitive inhibitors could allosterically mediate channel blockade.
Assuntos
Hidrocortisona/farmacologia , Músculos/metabolismo , Receptores Nicotínicos/metabolismo , Adulto , Regulação Alostérica , Linhagem Celular , Humanos , Técnicas In Vitro , Rim/embriologia , Cinética , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Mutagênese Sítio-Dirigida , Técnicas de Patch-Clamp , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genéticaAssuntos
Humanos , Feminino , Gravidez , Anestésicos Locais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrofotometria , Sangue Fetal/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Análise Química do Sangue , Anestésicos Locais/metabolismo , Bupivacaína/metabolismo , Bupivacaína/sangue , Lidocaína/análogos & derivados , Lidocaína/metabolismo , Lidocaína/sangue , Mepivacaína/metabolismo , Mepivacaína/sangueRESUMO
In this paper some of the new antiarrhythmic drugs are reviewed. The origin, electrophysiologic effects, mechanisms of action, pharmacokinetic properties, hemodynamic changes, clinical utilization with indications and contraindications as well as the collateral effects of: Verapamil Amiodarone, Aprindine, Encainide, Mexiletine and Tocainide are analyzed. A conclusion is drawn for each one of these drugs in accordance with the available information in the literature and the author's criteria and experience.