RESUMEN
OBJECTIVE: The present study aimed the functional recovery evaluation after long term of cardiac arrest induced by Custodiol (crystalloid-based) versus del Nido (blood-based) solutions, both added lidocaine and pinacidil as cardioplegic agents. Experiments were performed in isolated rat heart perfusion models. METHODS: Male rat heart perfusions, according to Langendorff technique, were induced to cause 3 hours of cardiac arrest with a single dose. The hearts were assigned to one of the following three groups: (I) control; (II) Custodiol-LP; and (III) del Nido-LP. They were evaluated after ischemia throughout 90 minutes of reperfusion. Left ventricular contractility function was reported as percentage of recovery, expressed by developed pressure, maximum dP/dt, minimum dP/dt, and rate pressure product variables. In addition, coronary resistance and myocardial injury marker by alpha-fodrin degradation were also evaluated. RESULTS: At 90 minutes of reperfusion, both solutions had superior left ventricular contractile recovery function than the control group. Del Nido-LP was superior to Custodiol-LP in maximum dP/dt (46%±8 vs. 67%±7, P<0.05) and minimum dP/dt (31%±4 vs. 51%±9, P<0.05) variables. Coronary resistance was lower in del Nido-LP group than in Custodiol-LP (395%±50 vs. 307%±13, P<0.05), as well as alpha-fodrin degradation, with lower levels in del Nido-LP group (P<0.05). CONCLUSION: Del Nido-LP cardioplegia showed higher functional recovery after 3 hours of ischemia. The analysis of alpha-fodrin degradation showed del Nido-LP solution provided greater protection against myocardial ischemia and reperfusion (IR) in this experimental model.
Asunto(s)
Soluciones Cardiopléjicas/farmacología , Paro Cardíaco Inducido/métodos , Lidocaína/farmacología , Reperfusión Miocárdica/métodos , Pinacidilo/farmacología , Compuestos de Potasio/farmacología , Animales , Western Blotting , Soluciones Cardiopléjicas/química , Proteínas Portadoras/análisis , Vasos Coronarios/fisiopatología , Glucosa/química , Glucosa/farmacología , Corazón/efectos de los fármacos , Masculino , Manitol/química , Manitol/farmacología , Proteínas de Microfilamentos/análisis , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Cloruro de Potasio/química , Cloruro de Potasio/farmacología , Compuestos de Potasio/química , Procaína/química , Procaína/farmacología , Ratas Wistar , Reproducibilidad de los Resultados , Factores de Tiempo , Resistencia Vascular/fisiología , Función Ventricular Izquierda/fisiologíaRESUMEN
Molecular Dynamic Simulations are performed to evaluate the interaction of lidocaine, procaine and tetracaine with a lipid membrane. The main interest is to evaluate the structural changes produced by these local anesthetics in the bilayers. Penetration trajectories, interaction energies, entropy changes and an order parameter are calculated to quantify the destabilization of the lipid configurations. We show that such structural parameters give important information to understand how anesthetic agents influence the structure of plasma membranes. Graphic processing units (GPUs) are used in our simulations.
Asunto(s)
1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , Anestésicos Locales/química , Lidocaína/química , Procaína/química , Tetracaína/química , 1,2-Dipalmitoilfosfatidilcolina/química , Entropía , Membrana Dobles de Lípidos/química , Conformación Molecular , Simulación de Dinámica MolecularRESUMEN
INTRODUCTION: Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. OBJECTIVE: To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM) uses low doses of sodium channel blocker (lidocaine), potassium channel opener (cromakalin), and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime). METHODS: Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK), Braile (G/A), and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. RESULTS: The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05). The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01). The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01). All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. CONCLUSION: Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.
INTRODUÇÃO: Preservação do miocárdio durante cirurgias cardíacas abertas e de colheita para transplante são de grande importância. O coração ao final do processo tem de retomar as suas funções, logo que possível. Todas as soluções cardioplégicas são baseadas em potássio, para indução de parada cardioplégica. OBJETIVO: Comparar a uma solução cardioplégica sem adição de potássio à sua fórmula com duas outras soluções cardioplégicas disponíveis comercialmente. A avaliação comparativa foi baseada na citotoxicidade, preservação miocárdica (adenosina trifosfato, ATP) e atividade da caspase 3. A solução testada (LIRM) utiliza baixas doses de bloqueador de canal de sódio (lidocaína), abridor do canal de potássio (cromacalina) e inibidor da ponte actina/miosina (2,3-butanodiona monoxima). MÉTODOS: Ratos Wistar foram submetidos à toracotomia sob ventilação mecânica e três soluções diferentes foram utilizadas para perfusão in situ para a indução de parada cardioplégica: soluções Custodiol (HTK) Braile (G/A) e LIRM. Após parada cardíaca, os corações foram retirados e mantidos em câmara fria por 4 horas. Após esse período, o coração foi avaliado com microscopia de luz ótica, o conteúdo de ATP miocárdico e atividade da caspase 3. Todas as três soluções foram avaliadas quanto à citotoxicidade direta com células L929 e WEHI-164. RESULTADOS: A quantidade de ATP foi maior no grupo Custodiol em comparação às com outras duas soluções (P<0,05). A atividade de caspase foi menor no grupo HTK quando comparado às soluções LIRM e G/A (P<0,01). A solução LIRM demonstrou menor atividade da caspase em comparação à solução Braile (P<0,01). Todas as soluções não mostraram qualquer efeito de citotoxicidade após 24 horas de exposição das células às soluções cardioplégicas. CONCLUSÃO: Soluções cardioplégicas sem potássio são uma perspectiva e a adição de aminoácido pode ser uma estratégia interessante. Mais avaliações são necessárias para o desenvolvimento ideal da solução cardioplégica.
Asunto(s)
Animales , Ratas , Soluciones Cardiopléjicas/farmacología , Paro Cardíaco Inducido/métodos , Corazón/efectos de los fármacos , Preservación de Órganos/métodos , Adenosina Trifosfato/análisis , Soluciones Cardiopléjicas/química , /análisis , Supervivencia Celular/efectos de los fármacos , Glucosa/química , Glucosa/farmacología , Modelos Animales , Manitol/química , Manitol/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Cloruro de Potasio/química , Cloruro de Potasio/farmacología , Potasio/química , Potasio/farmacología , Procaína/química , Procaína/farmacología , Ratas Wistar , Reproducibilidad de los Resultados , Bloqueadores de los Canales de Sodio/química , Factores de TiempoRESUMEN
A simple capillary electrophoretic method with spectrophotometric UV detection at 236 nm has been developed for the selective separation and determination of 1-(2-chlorophenyl)piperazine (oCPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-chlorophenyl)piperazine (pCPP) in confiscated pills. Several cyclodextrin derivatives were tested to compose the background electrolyte (BGE). The optimized BGE contained 20 mmol/L phosphoric acid adjusted to pH 2.5 with triethylamine and 10 mmol/L α-cyclodextrin, which provided acceptable resolution of analytes and candidate interferents in less than 15 min. The analyses were performed at constant voltage of 25 kV in 60 cm (effective length 50 cm; 50 µm i.d.) uncoated fused-silica capillary maintained at 25°C with sample injection at 4,826 Pa for 8s. Procaine at a concentration of 0.1mg/mL was used as internal standard (IS). Possible interference from other drugs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, 1-(3-trifluoromethylphenyl)piperazine and cocaine was also examined. The analytical curves were linear (R(2)=0.9994-0.9995) in the range of 10-200 µg/mL (for oCPP and mCPP) and 20-200 µg/mL for pCPP. Limits of detection (LODs) were 2.0 µg/mL (oCPP), 2.5µg/mL (mCPP) and 3.5 µg/mL (pCPP). Intraday precision at three concentration levels and six replicates of each level (10, 100, 200 µg/mL of each analyte; n=18) was evaluated for the corrected peak area ratio of analyte to IS and the migration times giving RSDs ≤ 4.9%. The accuracy was estimated for mCPP by a recovery test at the same three concentration levels and recoveries varied from 101.0 to 101.6%. The method has been successively applied to the analysis of 17 confiscated pills based mostly on mCPP.
Asunto(s)
Ciclodextrinas/química , Electroforesis Capilar/métodos , Piperazinas/química , Isomerismo , Procaína/química , Estándares de Referencia , Comprimidos/químicaRESUMEN
INTRODUCTION: Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. OBJECTIVE: To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM) uses low doses of sodium channel blocker (lidocaine), potassium channel opener (cromakalin), and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime). METHODS: Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK), Braile (G/A), and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. RESULTS: The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05). The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01). The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01). All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. CONCLUSION: Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.
Asunto(s)
Soluciones Cardiopléjicas/farmacología , Paro Cardíaco Inducido/métodos , Corazón/efectos de los fármacos , Preservación de Órganos/métodos , Adenosina Trifosfato/análisis , Animales , Soluciones Cardiopléjicas/química , Caspasa 3/análisis , Supervivencia Celular/efectos de los fármacos , Glucosa/química , Glucosa/farmacología , Manitol/química , Manitol/farmacología , Modelos Animales , Daño por Reperfusión Miocárdica/prevención & control , Potasio/química , Potasio/farmacología , Cloruro de Potasio/química , Cloruro de Potasio/farmacología , Procaína/química , Procaína/farmacología , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Bloqueadores de los Canales de Sodio/química , Factores de TiempoRESUMEN
Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the α(3)ß(4) nAChR heterologously expressed in KXα3ß4R2 cells. Affinity values (log[1/IC50]) of these compounds for the α(3)ß(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity.
Asunto(s)
Anestésicos Locales/farmacocinética , Procaína/farmacocinética , Receptores Nicotínicos/química , Anestésicos Locales/química , Animales , Procaína/análogos & derivados , Procaína/química , Relación Estructura-Actividad Cuantitativa , Ratas , Receptores Nicotínicos/metabolismoRESUMEN
In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters logP(n) and logP(i) (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pK(a) and pK(a)(oct), were obtained from logD-pH profiles measured at pH values ranging from 2 to 12. The difference between logP(i) and logP(n) values (i.e. difflogP) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflogP values varied nearly over one log unit, ranging from -2.40 to -3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features.
Asunto(s)
Enlace de Hidrógeno , Procaína/química , Aminas/química , Concentración de Iones de Hidrógeno , Iones/química , Lípidos/química , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
Carbomer (C) and procaine (P) were selected respectively as models of polyelectrolyte (PE) and basic drug (B) of low stability in aqueous solution. The purpose of this investigation was to test if a (C-P) aqueous system provides a microenvironment in which P is less exposed to hydroxyl ion catalyzed degradation, its main degradation pathway over a wide pH range. It was determined that in (C-P) a high fraction of P was present in the form of ion pairs [RCOO-PH+] with the carboxylate groups of C. The [RCOO-PH+] fraction was above 97% for compositions containing higher than 50 mol% of P. The chemical stability of C-P was assayed at two selected pHs (7.5 and 8.5) in comparison with conventional reference solutions (RS) without C. Procaine in (C-P) was 4.2 and 6.2 times more stable than in its respective RS at the two conditions assayed. The stabilizing factor was calculated as the ratio of the rate constants k(obs)(RS)/k(obs)(C-P).Since C-B systems exhibit negative electrokinetic potential that attracts positive ions such as (H+) and repels negative ones such as (OH(-)), the stabilizing effect would be associated with the higher acidity of (C-P) environment, in which PH+ molecules attached to the PE should also have lower kinetic energy than those in the bulk medium.
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Resinas Acrílicas/química , Estabilidad de Medicamentos , Hidrogeles/química , Procaína/química , Agua/química , Excipientes/química , Concentración de Iones de Hidrógeno , Hidrólisis , Iones , Solubilidad , Factores de TiempoRESUMEN
A set of potential Class III antiarrhythmic agents of structure p-HOOC-R-CO-NH-C(6)H(4)-CO-X-C(2)H(5)-N(C(2)H(5))(2) were isolated as crystalline solids of the amide and ester derivatives, I: succinylprocainamide (X=-NH-, R=-C(2)H(4)-); II: succinylprocaine (X=-O-, R=-C(2)H(4)-); III: maleylprocainamide (X=-NH-, R=-C(2)H(2)-) and IV: maleylprocaine (X=-O-, R=-C(2)H(2)-). Although compounds I-IV exhibit similar solution properties (i.e. acid-base speciation, with zwitterionic (+-) to neutral (00) form ratios higher than 10(4)), aqueous solubility of -NH- derivatives is significantly higher than that of -O- derivatives and also, solvent effects on solubility (i.e. the change of water by ethanol) is clearly different in both series. Solution and solid-state properties of I-IV were characterized to account for the observed differences. Results indicate that procainamide derivatives I and III crystallizes as (+-)(s) but procaine derivatives II and IV as (00)(s). Besides, I is anhydrous but II-IV are hydrates. Aqueous solubility and solvent effect on solubility are controlled by the intrinsic solubility of the species (+-) in I and III and (00) in II and IV. The rise of hydrophilicity of species (00) due to the structural change from -O- to -NH- would determine the change in the structure of the precipitating crystals from (00)(s) to (+-)(s). Solid structure (zwitterionic or neutral), as well as composition (anhydrous or hydrated) may be recognized as the main factors in determining the rank of aqueous solubility of the set: (+-)>(+-.H(2)O)>(00.H(2)O).
Asunto(s)
Antiarrítmicos/química , Procainamida/química , Procaína/química , Antiarrítmicos/síntesis química , Radioisótopos de Carbono , Cristalización , Análisis Diferencial Térmico , Espectroscopía de Resonancia Magnética , Peso Molecular , Procainamida/síntesis química , Procaína/síntesis química , Solubilidad , Soluciones , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Agua/análisisRESUMEN
BACKGROUND: Ischemia-reperfusion injury during open heart surgery related to unsuccessful myocardial protection may increase morbidity or mortality. We analyze the clinical outcome after cardiac surgery with a cardioplegic solution based on intracellular components added with histidine-ketoglutarate-tryptophan. METHODS: Thirty patients programmed for elective open heart surgery were randomized into two groups. In group I (n = 15), myocardial protection was carried out with Bretschenider solution (HTK), and in group II (n = 15) with conventional crystalloid cardioplegia. The incidence of arrhythmias, inotropic support requirement, and length-of-stay in the intensive care unit were evaluated. RESULTS: During reperfusion, there was no difference in incidence of arrhythmias; however, in the postoperative period group I had a lower incidence of arrhythmias (p = 0.001). Inotropic support (p = 0.003) and length-of-stay in the intensive care unit (p = 0.037) were lower in group I. There were no deaths in either group. CONCLUSIONS: It was concluded that myocardial protection with Bretschneider solution effectively decreases incidence of arrhythmias, inotropic support, and length-of-stay in the intensive care unit.
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Soluciones Cardiopléjicas/uso terapéutico , Glucosa/uso terapéutico , Paro Cardíaco Inducido , Manitol/uso terapéutico , Soluciones Preservantes de Órganos , Cloruro de Potasio/uso terapéutico , Procaína/uso terapéutico , Adenosina/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/química , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/prevención & control , Bicarbonatos/química , Cloruro de Calcio/química , Soluciones Cardiopléjicas/efectos adversos , Soluciones Cardiopléjicas/química , Cardiotónicos/administración & dosificación , Cardiotónicos/uso terapéutico , Niño , Preescolar , Puente de Arteria Coronaria , Procedimientos Quirúrgicos Electivos , Femenino , Glucosa/efectos adversos , Glucosa/química , Glutatión/química , Paro Cardíaco Inducido/efectos adversos , Cardiopatías Congénitas/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Insulina/química , Tiempo de Internación , Magnesio/química , Masculino , Manitol/efectos adversos , Manitol/química , Persona de Mediana Edad , Daño por Reperfusión Miocárdica/prevención & control , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Cloruro de Potasio/efectos adversos , Cloruro de Potasio/química , Procaína/efectos adversos , Procaína/química , Estudios Prospectivos , Rafinosa/química , Riesgo , Cloruro de Sodio/químicaRESUMEN
The use of differential scanning potentiometry (DSP) to assay pure drugs and mixtures is illustrated through a set of model cases. The profiles obtained by scanning glycine (0.3 mmol), sulfanilamide (0.3 mmol), epinephrine (0.06 mmol), and norfloxacin (0.05 mmol) are reported, as well as the areas (A+, A-, and At) obtained in each scan. Such information is useful to assess identity and/or chemical purity and to get the pKa of the ionizing groups of the drugs. The degree of hydrolysis of a parenteral solution of procaine hydrochloride is also determined through DSP as an example of mixture assay. Comparison with conventional aqueous acid-based potentiometry shows that the new technique exhibits much better performance to assay small samples or samples carrying weak acidic and/or basic groups.