Fresh Carrier for an Old Topical Local Anesthetic: Benzocaine in Nanostructured Lipid Carriers.

Nanostructured lipid carriers (NLC) have emerged as innovative drug delivery systems, offering distinct advantages over other lipid-based carriers, such as liposomes and solid lipid nanoparticles. Benzocaine (BZC), the oldest topical local anesthetic in use, undergoes metabolism by pseudocholinesterase, leading to the formation of p-aminobenzoic acid, a causative agent for allergic reactions associated with prolonged BZC usage. In order to mitigate adverse effects and enhance bioavailability, BZC was encapsulated within NLC. Utilizing a 23 factorial design, formulations comprising cetyl palmitate (solid lipid), propylene glycol monocaprylate (liquid lipid), and Pluronic F68 as surfactants were systematically prepared, with variations in the solid/liquid lipid mass ratios (60:40-80:20%), total lipid contents (15-25%), and BZC concentrations (1-3%). The optimized formulation underwent characterization by dynamic light scattering, differential scanning calorimetry, Raman imaging, X-ray diffraction, small-angle neutron scattering, nanotracking analysis, and transmission electron microscopy (TEM)/cryo-TEM, providing insights into the nanoparticle structure and the incorporation of BZC into its lipid matrix. NLCBZC exhibited a noteworthy encapsulation efficiency (%EE = 96%) and a 1 year stability when stored at 25 °C. In vitro kinetic studies and in vivo antinociceptive tests conducted in mice revealed that NLCBZC effectively sustained drug release for over 20 h and prolonged the anesthetic effect of BZC for up to 18 h. We therefore propose the use of NLCBZC to diminish the effective anesthetic concentration of benzocaine (from 20 to 3% or less), thus minimizing allergic reactions that follow the topical administration of this anesthetic and, potentially, paving the way for new routes of BZC administration in pain management.

Hematological and biochemical characteristics during the transport of dog snapper Lutjanus jocu (Perciformes: Lutjanidae)

The objective of this study was to evaluate stress responses in dog snapper (Lutjanus jocu) during transport by evaluating their hematological and biochemical responses. Twenty-five wild dog snapper specimens were used in the experiment (220 ± 68 g and 24.5 ± 2.5 cm total length). Blood samples were collected prior to transport (control), and fish were placed in two transport boxes, one with anesthetic and one without anesthetic. Immediately after transport and after 24 h, blood was collected from the fish that underwent each treatment (with anesthetic and without anesthetic). Biochemical and hematological results demonstrated the inefficiency of benzocaine as a stress reliever during handling and transport. Biochemical parameters revealed the effects of stress during transport, and after 24 h, glucose levels and hematological parameters (hemoglobin, erythrocytes, leukocytes, neutrophils and MCH) showed a tendency to return to control levels. This study is the first to report stress response measurements of hematological and biochemical indicators in dog snapper, representing an important basis for the planning of future experiments involving the transport and handling of this fish species.(AU)

O objetivo desde estudo foi avaliar as repostas de estresse em dentão (Lutjanus jocu) durante o procedimento de transporte, através de respostas hematológicas e bioquímicas. Vinte e cinco exemplares selvagens de dentão foram utilizados no experimento (220 ± 68 g e 24.5 ± 2.5 cm de comprimento total). Foram realizadas coletas de sangue previamente ao transporte (controle), e os demais peixes foram acondicionados em duas caixas de transporte, uma com anestésico e outra sem anestésico. Imediatamente após o transporte e após 24 h, houve coleta de sangue para cada tratamento (com anestésico e sem anestésico). Os resultados bioquímicos e hematológicos apontam a ineficiência da benzocaína como mitigador do estresse durante o manuseio e transporte. Os parâmetros bioquímicos foram capazes de detectar o efeito do estresse durante o transporte, e após 24 h os níveis de glicose e alguns parâmetros hematológicos (hemoglobina, eritrócitos, leucócitos, neutrófilos e MCH) demonstraram uma tendência de retorno aos níveis do controle. Este trabalho é o primeiro a informar os níveis de resposta basal e de estresse para indicadores hematológicos e bioquímicos em dentão, representando uma base importante para o planejamento de futuras experiências com transporte e manejo dessa espécie.(AU)

Hematological and biochemical characteristics during the transport of dog snapper Lutjanus jocu (Perciformes: Lutjanidae)

The objective of this study was to evaluate stress responses in dog snapper (Lutjanus jocu) during transport by evaluating their hematological and biochemical responses. Twenty-five wild dog snapper specimens were used in the experiment (220 ± 68 g and 24.5 ± 2.5 cm total length). Blood samples were collected prior to transport (control), and fish were placed in two transport boxes, one with anesthetic and one without anesthetic. Immediately after transport and after 24 h, blood was collected from the fish that underwent each treatment (with anesthetic and without anesthetic). Biochemical and hematological results demonstrated the inefficiency of benzocaine as a stress reliever during handling and transport. Biochemical parameters revealed the effects of stress during transport, and after 24 h, glucose levels and hematological parameters (hemoglobin, erythrocytes, leukocytes, neutrophils and MCH) showed a tendency to return to control levels. This study is the first to report stress response measurements of hematological and biochemical indicators in dog snapper, representing an important basis for the planning of future experiments involving the transport and handling of this fish species.(AU)

O objetivo desde estudo foi avaliar as repostas de estresse em dentão (Lutjanus jocu) durante o procedimento de transporte, através de respostas hematológicas e bioquímicas. Vinte e cinco exemplares selvagens de dentão foram utilizados no experimento (220 ± 68 g e 24.5 ± 2.5 cm de comprimento total). Foram realizadas coletas de sangue previamente ao transporte (controle), e os demais peixes foram acondicionados em duas caixas de transporte, uma com anestésico e outra sem anestésico. Imediatamente após o transporte e após 24 h, houve coleta de sangue para cada tratamento (com anestésico e sem anestésico). Os resultados bioquímicos e hematológicos apontam a ineficiência da benzocaína como mitigador do estresse durante o manuseio e transporte. Os parâmetros bioquímicos foram capazes de detectar o efeito do estresse durante o transporte, e após 24 h os níveis de glicose e alguns parâmetros hematológicos (hemoglobina, eritrócitos, leucócitos, neutrófilos e MCH) demonstraram uma tendência de retorno aos níveis do controle. Este trabalho é o primeiro a informar os níveis de resposta basal e de estresse para indicadores hematológicos e bioquímicos em dentão, representando uma base importante para o planejamento de futuras experiências com transporte e manejo dessa espécie.(AU)

Metahemoglobinemia adquirida en el recién nacido asociada con benzocaína y paracetamol / Association of benzocaine and paracetamol with neonatal-acquired methemoglobinemia

ResumenIntroducción:La metahemoglobinemia adquirida inducida por medicamentos es un trastorno raro en el recién nacido que, de no diagnosticarse y tratarse oportuna y adecuadamente, puede ser particularmente grave y determinar daño cerebral permanente o la muerte del paciente.Caso clínico: Se reporta un caso metahemoglobinemia clínica severa que desarrolló un recién nacido después de la aplicación de una cantidad mínima de crema con benzocaína en una herida quirúrgica anal cuando al mismo tiempo recibía paracetamol. Además de considerar la benzocaína como agente causal primario de la metahemoglobinemia, se analiza y sustenta la posibilidad de que el paracetamol haya aumentado la susceptibilidad del paciente a las caínas debido a la inmadurez enzimática de los sistemas involucrados en la depuración de los agentes oxidantes, en particular de caínas y de paracetamol.Conclusiones: Se alerta sobre la posibilidad de metahemoglobinemia en el recién nacido al emplear caínas solas o junto con otros medicamentos oxidantes en esta época del desarrollo humano, cuando es más susceptible a los efectos oxidantes de químicos incluyendo medicamentos. Se revisa el tratamiento y se propone etiquetar debidamente los productos farmacológicos que contienen caínas, prohibiendo su empleo en recién nacidos para evitar la metahemoglobinemia iatrogénica.

AbstractBackground: Drug-induced acquired methemoglobinemia in the newborn is a rare event; however, when it develops, early diagnosis and proper treatment become paramount because it can evolve rapidly into a particularly serious disease causing permanent brain damage or death.Case report: We report a unique case of severe methemoglobinemia that developed in a newborn associated with a minimal application of a benzocaine healing cream to an anal surgical wound while on acetaminophen. In addition to benzocaine as the primary cause in this case, we raise the possibility that acetaminophen-a mild oxidant-increased the susceptibility of the patient to benzocaine, leading to severe clinical methemoglobinemia based on the known immaturity of the enzymatic systems involved in caines and acetaminophen clearance in the newborn. Treatment of methemoglobinemia is reviewed.Conclusions: Methemoglobinemia is a serious condition that can be easily induced by the use of oxidant medications in the newborn like local anesthetics. The possibility of unexpected drug to drug interactions, particularly between commonly used medications such as acetaminophen with other methemoglobin-causing agents, must always be kept in mind. Because of the possible deleterious consequences, mandatory labelling of caine-containing local anesthetic creams, gels and sprays with a warning for the likelihood of causing severe methemoglobinemia in children is recommended. Also, prohibiting their use in the newborn becomes mandatory.

Efectividad de la benzocaina en gel al 20% y la lidocaina en solución al 10% en pacientes que requieren punción en la mucosa oral: un ensayo clínico controlado aleatorizado cruzado a triple ciego / Effectiveness of benzocaine gel at 20% and lidocaine solution at 10% in patients requiring puncture in the oral mucosa: a randomized controlled crossover triple blind clinical trial

El objetivo del presente estudio fue determinar y comparar la efectividad de la Benzocaína en gel al 20% y la Lidocaína en solución al 10% en pacientes que requerían punción en la mucosa oral. El presente es un ensayo clínico controlado aleatorizado a triple ciego y de diseño cross-over. Se llevó a cabo en la clínica dental de la Unidad de Segunda Especialización en Estomatología (USEE) de la Universidad Nacional de Trujillo, durante los meses de Noviembre y Diciembre del 2010 y de Enero a Marzo del 2011. La muestra estuvo conformada por 60 pacientes, cada paciente firmó un consentimiento informado y se le realizó un análisis de su estado de ansiedad mediante la escala de ansiedad estado-rasgo (IDARE). Antes de realizar la punción en la mucosa oral se aplicó 4 preparados (2 anestésicos tópicos y 2 placebos) para después determinar y comparar la efectividad de los preparados en la reducción del dolor usando la escala visual análoga (EVA). Para la recolección de los datos se usó una ficha especial para tal fin. Para la comparación de la efectividad de los preparados se empleó el Análisis de Varianza (ANOVA). La efectividad de los anestésicos en gel y en solución fue evaluada empleando el test de Tuckey para comparaciones múltiples y el T de students. La significación estadística fue del 5%. Se encontró que la Benzocaína en gel al 20% y la Lidocaína en solución al 10% son efectivos para reducir el dolor a la punción y que no existe una relación estadísticamente significativa (p= 0,0575) entre la efectividad de cada uno de ellos. La administración de Benzocaína en gel al 20% o de la Lidocaína en solución al 10% reduce el dolor a la punción en igual magnitud y pueden ser usados indistintamente en la práctica odontológica diaria.

The objective of this study was to determine the effectiveness of benzocaine 20% gel and lidocaine in 10% solution in patients requiring puncture in the oral mucosa. This is a randomized controlled clinical trial to triple-blind, cross-over design. It was held at the dental clinic of the Unit of Second Specialization in Dentistry (usee) of the National University of Trujillo, in the months of November and December 2010 and January to March 2011. The sample consisted of 60 patients, each patient signed an informed consent and underwent a review of their status by anxiety scale state-trait anxiety (STAI). Before the puncture in the oral mucosa four preparations (2 topical anesthetics and 2 placebo) and then determine and compare the effectiveness of preparations in reducing pain using a visual analogue scale (VAS) was applied. For data collection a special token was used for that purpose. For comparison of the effectiveness of preparations Analysis of Variance (ANOVA). The effectiveness of the gel and anesthetic solution was evaluated using Tukey's test for multiple comparisons and students T. Statistical significance was 5%. We found that benzocaine 20% gel and lidocaine in 10% solution are effective at reducing pain at the puncture and that there is no statistically significant relationship (p= 0.0575) between the effectiveness of each. The administration of benzocaine 20% gel or lidocaine in 10% solution to reduce pain puncture equal and can be used interchangeably in everyday dental practice.

Drug action of benzocaine on the sarcoplasmic reticulum Ca-ATPase from fast-twitch skeletal muscle.

The effect of the local anesthetic benzocaine on sarcoplasmic reticulum membranes isolated from fast-twitch muscles was tested. The effects on Ca-ATPase activity, calcium binding and uptake, phosphoenzyme accumulation and decomposition were assessed using radioisotopic methods. The calcium binding to the Ca-ATPase was noncompetitively inhibited, and the enzymatic activity decreased in a concentration-dependent manner (IC50 47.1 mM). The inhibition of the activity depended on the presence of the calcium ionophore calcimycin and the membrane protein concentration. The pre-exposure of the membranes to benzocaine enhanced the enzymatic activity in the absence of calcimycin, supporting the benzocaine permeabilizing effect, which was prevented by calcium. Benzocaine also interfered with the calcium transport capability by decreasing the maximal uptake (IC50 40.3 mM) without modification of the calcium affinity for the ATPase. It inhibited the phosphorylation of the enzyme, and at high benzocaine concentration, the dephosphorylation step became rate-limiting as suggested by the biphasic profile of phosphoenzyme accumulation at different benzocaine concentrations. The data reported in this paper revealed a complex pattern of inhibition involving two sites for interaction with low and high benzocaine concentrations. It is concluded that benzocaine not only exerts an indirect action on the membrane permeability to calcium but also affects key steps of the Ca-ATPase enzymatic cycle.

[Association of benzocaine and paracetamol with neonatal-acquired methemoglobinemia]. / Metahemoglobinemia adquirida en el recién nacido asociada con benzocaína y paracetamol.

BACKGROUND: Drug-induced acquired methemoglobinemia in the newborn is a rare event; however, when it develops, early diagnosis and proper treatment become paramount because it can evolve rapidly into a particularly serious disease causing permanent brain damage or death. CASE REPORT: We report a unique case of severe methemoglobinemia that developed in a newborn associated with a minimal application of a benzocaine healing cream to an anal surgical wound while on acetaminophen. In addition to benzocaine as the primary cause in this case, we raise the possibility that acetaminophen-a mild oxidant-increased the susceptibility of the patient to benzocaine, leading to severe clinical methemoglobinemia based on the known immaturity of the enzymatic systems involved in caines and acetaminophen clearance in the newborn. Treatment of methemoglobinemia is reviewed. CONCLUSIONS: Methemoglobinemia is a serious condition that can be easily induced by the use of oxidant medications in the newborn like local anesthetics. The possibility of unexpected drug to drug interactions, particularly between commonly used medications such as acetaminophen with other methemoglobin-causing agents, must always be kept in mind. Because of the possible deleterious consequences, mandatory labelling of caine-containing local anesthetic creams, gels and sprays with a warning for the likelihood of causing severe methemoglobinemia in children is recommended. Also, prohibiting their use in the newborn becomes mandatory.

Benzocaine hydrochloride anesthesia in carp (Cyprinus carpio) / Cloridrato de benzocaína na anestesia de carpas (Cyprinus carpio)

Fish anesthesia is indicated to allow the accomplishment of several procedures such as biometry, tagging, transportation, physical examination, surgical procedures, and reproductive management. The doses of benzocaine in the carp anesthesia (Cyprinus carpio) were determined, carrying through six phases with 40 fish each. The average weight of carps in each phase was of 147.45±7.99g, 173.32±9.15g, 191.26±14.05g, 269.84±19.24g, 285.25±17.97g, and 300.91±16.45g. In each phase, fish had been captured and placed in four containers each one with different concentrations of benzocaine (100, 140, 180 and 220 mg/L respectively). The induction time (IT) was registered for each fish and after that the anesthetic induction biometry was performed. In each phase the minimal dose of benzocaine was calculated using the Linear Response Plateau (LRP), in a model that included dose and IT. The LRP was calculated for each phase: 125.79mg/L in 114.33s, 155.68mg/L in 115.75s, 145.33mg/L in 102.52s, 149.50mg/L in 140.53s, 166.42mg/L in 116.15s, and 158.34mg/L in 102.00s. The optimal dose was related with the weight, resulting in the equation: dose=114.230+0.158 x weight (r2=0.53). The equation shows that an increase in the weight in 1g corresponds to an increase of 0.158 mg/L in the dose of benzocaine hydrochloride for carps.

A anestesia em peixes é indicada para permitir a realização de diversos procedimentos como: biometria, marcação, transporte, exame físico, procedimentos cirúrgicos e manejo reprodutivo. Determinou-se a dose de benzocaína na anestesia de carpas (Cyprinus carpio), com a realização de seis etapas com 40 peixes cada. O peso médio das carpas em cada etapa foi de 147,45±7,99g, 173,32±9,15g, 191,26±14,05g, 269,84±19,24g, 285,25±17,97g, e 300,91±16,45g. Em cada etapa, os peixes foram capturados e colocados em quatro recipientes com benzocaína nas concentrações de 100, 140, 180 e 220 mg/L respectivamente. O tempo de indução (TI) foi registrado para cada peixe e após a indução anestésica foi realizada a biometria. Em cada etapa foi calculada a dose mínima de benzocaína através do Linear Response Plateau (LRP), em um modelo que incluiu dose e TI. O LRP foi calculado para cada fase, e os valores encontrados foram: 125,79mg/L em 114,33s, 155,68mg/L em 115,75s, 145,33mg/L em 102,52s, 149,50mg/L em 140,53s, 166,42mg/L em 116,15s e 158,34mg/L em 102,00s. A dose ótima foi relacionada com o peso, resultando na equação: dose=114,230+0,158 x peso (r2=0,53). A equação mostra que um aumento no peso em 1g, corresponde a um aumento de 0,158 mg/L na dose de cloridrato de benzocaína para carpas.

Benzocaine hydrochloride anesthesia in carp (Cyprinus carpio) / Cloridrato de benzocaína na anestesia de carpas (Cyprinus carpio)

Fish anesthesia is indicated to allow the accomplishment of several procedures such as biometry, tagging, transportation, physical examination, surgical procedures, and reproductive management. The doses of benzocaine in the carp anesthesia (Cyprinus carpio) were determined, carrying through six phases with 40 fish each. The average weight of carps in each phase was of 147.45±7.99g, 173.32±9.15g, 191.26±14.05g, 269.84±19.24g, 285.25±17.97g, and 300.91±16.45g. In each phase, fish had been captured and placed in four containers each one with different concentrations of benzocaine (100, 140, 180 and 220 mg/L respectively). The induction time (IT) was registered for each fish and after that the anesthetic induction biometry was performed. In each phase the minimal dose of benzocaine was calculated using the Linear Response Plateau (LRP), in a model that included dose and IT. The LRP was calculated for each phase: 125.79mg/L in 114.33s, 155.68mg/L in 115.75s, 145.33mg/L in 102.52s, 149.50mg/L in 140.53s, 166.42mg/L in 116.15s, and 158.34mg/L in 102.00s. The optimal dose was related with the weight, resulting in the equation: dose=114.230+0.158 x weight (r2=0.53). The equation shows that an increase in the weight in 1g corresponds to an increase of 0.158 mg/L in the dose of benzocaine hydrochloride for carps.

A anestesia em peixes é indicada para permitir a realização de diversos procedimentos como: biometria, marcação, transporte, exame físico, procedimentos cirúrgicos e manejo reprodutivo. Determinou-se a dose de benzocaína na anestesia de carpas (Cyprinus carpio), com a realização de seis etapas com 40 peixes cada. O peso médio das carpas em cada etapa foi de 147,45±7,99g, 173,32±9,15g, 191,26±14,05g, 269,84±19,24g, 285,25±17,97g, e 300,91±16,45g. Em cada etapa, os peixes foram capturados e colocados em quatro recipientes com benzocaína nas concentrações de 100, 140, 180 e 220 mg/L respectivamente. O tempo de indução (TI) foi registrado para cada peixe e após a indução anestésica foi realizada a biometria. Em cada etapa foi calculada a dose mínima de benzocaína através do Linear Response Plateau (LRP), em um modelo que incluiu dose e TI. O LRP foi calculado para cada fase, e os valores encontrados foram: 125,79mg/L em 114,33s, 155,68mg/L em 115,75s, 145,33mg/L em 102,52s, 149,50mg/L em 140,53s, 166,42mg/L em 116,15s e 158,34mg/L em 102,00s. A dose ótima foi relacionada com o peso, resultando na equação: dose=114,230+0,158 x peso (r2=0,53). A equação mostra que um aumento no peso em 1g, corresponde a um aumento de 0,158 mg/L na dose de cloridrato de benzocaína para carpas.