Acciones cardiovasculares directas del paracetamol / Direct cardiovascular actions of paracetamol

Introducción: El paracetamol es uno de los antiinflamatorios no esteroideos con efecto analgésico y antipirético más utilizados a nivel mundial. Pocos estudios se enfocan en esclarecer los mecanismos de acción a nivel cardiovascular. Objetivos: Evaluar la acción del paracetamol sobre la fuerza de contracción de anillos de aorta torácica y sobre la actividad eléctrica y contráctil de corazones aislados y perfundidos de ratas Wistar. Métodos: Se midieron los efectos del paracetamol sobre anillos de aorta de rata denudados de su endotelio vascular. Se estudiaron las acciones del fármaco sobre los corazones aislados y perfundidos de las ratas por el método de Langendorff. Se evaluó la amplitud de la fuerza de contracción cardiaca y los intervalos QT, QTc, QRS y RR del electrocardiograma. Las condiciones (control y presencia de paracetamol) fueron comparadas con una prueba t de Student para muestras pareadas (p < 0,05), previa comprobación de la normalidad de los datos. Resultados: El paracetamol no tuvo efectos sobre el músculo liso vascular de los anillos aórticos ni sobre los intervalos QT, QTc, QRS y RR del electrocardiograma bajo ninguna de las concentraciones empleadas. Por otra parte, mostró efecto inotrópico negativo estadísticamente significativo en los corazones aislados, de forma dependiente de la concentración del fármaco. La IC50 estimada para la inhibición de la fuerza de contracción cardiaca fue de 17,15 ± 5,33 µmol/L. Conclusiones: Las acciones cardiovasculares directas del paracetamol son modestas, lo cual contribuye al buen margen de seguridad para su uso en clínica, en pacientes sin enfermedad cardiovascular(AU)

Introduction: Paracetamol is among the non-steroidal anti-inflammatory, analgesic and antipyretic drugs most commonly used worldwide. Few studies have focused on clarifying its mechanisms of action on a cardiovascular level. Objectives: Evaluate the action of paracetamol on the force of contraction of thoracic aortic rings and on the electrical and contractile activity of isolated perfused Wistar rat hearts. Methods: Measurements were taken of the effects of paracetamol on rat aortic rings denuded of their vascular endothelium. Analysis was performed of the actions of the drug on the isolated perfused rat hearts using the Langendorff method. Evaluation was conducted of the amplitude of the force of cardiac contraction and of intervals QT, QTc, QRS and RR of the electrocardiogram. The conditions (control and presence of paracetamol) were compared with a paired samples Student's t-test (p < 0.05) upon verification of the normality of the data. Results: Paracetamol had no effects on the vascular smooth muscle of aortic rings or on intervals QT, QTc, QRS and RR of the electrocardiogram at none of the concentrations used. On the other hand, it displayed a statistically significant negative inotropic effect on the isolated hearts dependent on drug concentration. The IC50 estimated for inhibition of the force of cardiac contraction was 17.15 ± 5.33 µmol/L. Conclusions: The direct cardiovascular actions of paracetamol are modest, which contributes to a good safety margin for its clinical use in patients without cardiovascular disease(AU)

Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable

Measurement uncertainty of dissolution test of acetaminophen immediate release tablets using Monte Carlo simulations

ABSTRACT Analytical results are widely used to assess batch-by-batch conformity, pharmaceutical equivalence, as well as in the development of drug products. Despite this, few papers describing the measurement uncertainty estimation associated with these results were found in the literature. Here, we described a simple procedure used for estimating measurement uncertainty associated with the dissolution test of acetaminophen tablets. A fractionate factorial design was used to define a mathematical model that explains the amount of acetaminophen dissolved (%) as a function of time of dissolution (from 20 to 40 minutes), volume of dissolution media (from 800 to 1000 mL), pH of dissolution media (from 2.0 to 6.8), and rotation speed (from 40 to 60 rpm). Using Monte Carlo simulations, we estimated measurement uncertainty for dissolution test of acetaminophen tablets (95.2 ± 1.0%), with a 95% confidence level. Rotation speed was the most important source of uncertainty, contributing about 96.2% of overall uncertainty. Finally, it is important to note that the uncertainty calculated in this paper reflects the expected uncertainty to the dissolution test, and does not consider variations in the content of acetaminophen.

Simultaneous Determination of Hyoscine N- Butyl Bromide and Paracetamol by RP-TLC Spectrodensitometric Method.

Aims: A simple RP-TLC Spectrodensitometric method was developed for determination of Hyoscine N-Butyl Bromide (HBB) and Paracetamol (PAR) either in bulk powder or in their pharmaceutical preparation. Study Design: Validation study. Methodology: In this method, HBB and PAR were separated on RP-18 W/ UV254 TLC plates using developing mobile phase consisting of methanol: citrate buffer (pH=1.5): triflouroacetic acid (70:30:0.1, by volume) at room temperature. Experimental conditions such as band size, slit width, different developing systems and scanning wavelength were carefully studied and the optimum conditions were selected. The obtained bands were then scanned at 210 nm. The two drugs were satisfactorily resolved with RF 0.60 ± 0.02 for HBB and 0.81 ± 0.02 for PAR. The validation of spectrodensitometric method was done regarding linearity, accuracy, precision, and specificity. Results: Linearity of the proposed methods was evaluated and it was found to lie within the concentration range of 2.0-12.0 μg.band-1 for HBB and 2.0-14.0 μg.band-1 for PAR. Conclusion: The proposed method was successfully applied for determination of HBB and PAR in pure form and in their different pharmaceutical formulations. The method proved to be specific, accurate and selective.

Control de la calidad y estudio de estabilidad del paracetamol gotas orales 100 mg/ml / Quality control and stability study of 100 mg/ml paracetamol oral drops

Introducción: las gotas orales de Paracetamol, están indicadas a la población infantil hasta los 5 años para el alivio de la fiebre, dolor de cabeza, dolores dentales y proporciona alivio sintomático del resfriado común. Objetivo: validar dos métodos analíticos, para el control de la calidad y el estudio de estabilidad y estudiar la estabilidad de las gotas orales de producción nacional. Métodos: para cuantificar el principio activo para el estudio de estabilidad, la separación se realizó a través de una columna cromatográfica Lichrosorb RP - 18 (5µm) (250 x 4 mm), con detección ultravioleta a 243 nm, empleando una fase móvil compuesta por Agua destilada: Metanol (3:1). Mientras que el método para el control de la calidad se utilizó un Espectrofotómetro SPECTRONIC GENESYS 2.Para el estudio de estabilidad, se emplearon los métodos de vida de estante (a temperatura inferior a 30 º C) y de estabilidad acelerada (40 ± 2ºC) mediante cromatografía líquida de alta eficiencia. Resultados: los resultados obtenidos de los parámetros evaluados en las validaciones se encontraron dentro de los límites establecidos. Los resultados del estudio de estabilidad realizado, demuestran que el producto terminado cumplió con las especificaciones de calidad durante el estudio. Conclusiones: los métodos analíticos por espectrofotometría UV y cromatografía líquida de alta resolución, son válidos para el control de la calidad y estudio de estabilidad de las gotas orales de Paracetamol 100 mg/mL, ya que resultaron lineales, precisos, exactos y específicos. Se demostró la estabilidad física, química y microbiológica del producto por espacio de 12 meses a temperatura inferior a 30 ºC, envasados en frascos de vidrio ámbar por 15 mL, boca 18 mm, calidad hidrolítica III. Además se evidenció que el producto es estable durante 30 días después de abierto el frasco

Introduction: paracetamol is an effective analgesic and antipyretic drug of the non-steroidal anti-inflammatory drug group. Paracetamol oral drops are indicated for use in infant population aged up to 5 years to relieve fever, headache, toothache and symptomatic relief of common cold. Objective: to validate two analytical methods for the quality control and the stability study and to study the stability of 100 mg/ml Paracetamol oral drops made in Cuba. Methods: for quantification of the active principle in the final product in order to study stability, a chromatographic column equipment called Lichrosorb RP-18 was used for separation (5µm) (250 x 4 mm), with ultraviolet ray detection at 243 nm and a mobile phase made up of distilled water: methanol (3:1) and the quantification of this principle against a reference sample by using the external standard method. For the quality control, the spectrophotometry used the spectrophotometer SPECTRONIC GENESYS 2, the ideal wavelength was 245 nm since it matches the maximum absorption rate and there is no interference with the excipients. As to the stability study of the drops, the on- shelf life method (temperature below 30 C) was used, and for the accelerated stability analysis (40 ± 2ºC) through high performance liquid chromatography. Results: the results of the evaluated parameters in the validation of the methods for the quality control and the stability study were within the set limits. The results of the stability study, both accelerated and on- shelf life and reservoir use, showed that the final product met the quality specifications during the study. Conclusions: the analytical methods based on UV spectrophotometry and high performance liquid chromatography are valid for the quality control and the stability study of 100 mg/ml Paracetamol...

Validação de metodologia analítica e estudo de estabilidade para quantificação sérica de paracetamol / Analytical methodology validation and stability study for serum quantification of acetaminophen

INTRODUÇÃO E OBJETIVO: Paracetamol ou acetaminofeno é atualmente um dos analgésicos-antipiréticos mais utilizados, principalmente em crianças. Porém o fácil acesso ao medicamento e o desconhecimento da população sobre seus efeitos nocivos têm aumentado muito o número de intoxicações por esse medicamento. A análise da concentração sérica de paracetamol confirma o diagnóstico. O resultado não só tem valor de certeza diagnóstica como também avalia o risco de hepatotoxicidade, indicando uso ou não do antídoto específico n-acetilcisteína. O objetivo deste trabalho foi propor um método analítico para quantificação sérica do paracetamol por espectrofotometria visível em 430 nm. MATERIAIS E MÉTODOS: Após desproteinização da amostra, acetaminofeno (n-acetil-p-aminofenol) reage com nitrito de sódio, formando 2,4-nitro-4-acetaminofenol, que assume coloração amarela em meio alcalino. As figuras de mérito linearidade, precisão, exatidão, robustez, recuperação, limites de detecção e qualificação foram avaliadas segundo critérios preconizados pelo International Conference on Harmonisation (ICH) e pela Agência Nacional de Vigilância Sanitária (ANVISA). O estudo de estabilidade foi realizado após ciclos de congelamento/descongelamento, curta duração, longa duração sob refrigeração e em freezer. RESULTADOS: O método se mostrou linear de 20 a 300 mg/l. Os limites de detecção e quantificação foram de respectivamente 3,6 mg/l e 20 mg/l. CONCLUSÃO: O método se mostrou preciso, exato e robusto e apresentou boa recuperação. As amostras-controle foram estáveis nas condições testadas. O método desenvolvido demonstrou possuir todos os parâmetros necessários para ser aplicado na quantificação de paracetamol em amostras de plasma ou soro humano para análise de emergência. Além disso, é uma técnica simples, de rápida execução e baixo custo.

INTRODUCTION AND OBJECTIVE: Acetaminophen or paracetamol is currently one of the most used analgesic-antipyretic agents, mainly with children. However, both the easy access to this medicine and the population's unawareness of its toxic effects have contributed to a rise in the number of intoxications caused by this drug. Assessment of serum acetaminophen confirms the diagnosis. Not only does the result have diagnostic reliability but it also evaluates the risk of hepatotoxicity, indicating or not the administration of the specific antidote n-acetylcysteine. The aim of this study is to present an analytical method to the assessment of serum acetaminophen by spectrophotometric detection at 430 nm. MATERIALS AND METHODS: After sample deproteinization, acetaminophen (n-acetyl-p-aminophenol) reacts with sodium nitrite forming 2.4-nitro-4-acetaminophenol, which becomes yellowish in alkaline medium. For method validation, linearity, precision, accuracy, robustness, recovery and detection limits were evaluated according to ICH and ANVISA criteria. The stability study was carried out after freezing/defreezing cycles, short-time duration, long-time duration under refrigeration and long-time duration under freezing. RESULTS: The method showed to be linear from 20 to 300 mg/l. The detection and quantification limits were 3.6 mg/l and 20 mg/l, respectively. CONCLUSION: The method was precise, accurate and robust and showed good recovery. The control-samples were stable in all tested conditions. The method developed presented all the necessary parameters to be applied in acetaminophen quantification in plasma samples or human serum for emergency analyzes. Furthermore, it is a simple, time and cost-effective technique.

Development of a capillary electrophoresis method for the determination of orphenadrine citrate in tablets in the presence of paracetamol

A validated method using capillary electrophoresis was developed, for the determination of orphenadrine citrate in its tablet formulations, in the presence of paracetamol. The method employs a running buffer of 30 mM pentane sulfonate sodium, dissolved in 20mM MOPS buffer pH 7.7. Samples were injected using hydrodynamic sample injection mode [25 mbar, for 25s], using positive polarity of 25 kV, at a constant temperature of 30 [degree sign] C. Samples of orphenadrine citrate alone or in mixture solutions with paracetamol were exposed to various degradation conditions, and were electrophoresed using the recommended condition. The method was found to be specific, linear [r[2] =0.994], precise, accurate, and robust, with an LOQ of 0.02 mg/mL. The proposed method was successfully applied for measurement of the percentage per label of orphenadrine citrate in commercially available tablets

Normal-phase LC method for simultaneous analysis of pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol in tablet formulation

A simple, precise, and accurate method and validated for the analysis of pseudophedrin hydrochloride, dextromethrophan hydrobromide chlorpheniramine maleate, and paracetamol in tablet formulations. The method has shown adequate separation of the four ingredients from each other. Separation was achieved on a silica column [5 micro m, 125 X 4,6 mm inner diameter] using a mobile phase consisting of methanaol/ammonium dihyddrogen phosphate buffer [90:10, v/v] at a flow rate of 1.0 ml/min and UV detection at 220 nm. This new method is validated in accordance with USP requirements for new methods for assay determination, which include accuracy, precision, selectivity, linearity and range, probustness and ruggedness. The current method demonstrates good linearity over the range of 0.15-0.45 mg/ml of pseudophedrine hydrochloride with r[2] of 0.996, and in the range of 0.075-0.225 mg/ml of dextromethorphan hydrobromide with r[2] of 0.992, and in the range of 0.01-0.03 mg/ml of chlorpheniramine maleate with r[2] of 0.994, and in the range of 0.25-0.75 mg/ml of paracetamol with r[2] of 0.991. The average recovery of the method is 99.7%, 98.1%, and 99.2% for pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramien maleate, and paracetamol, respectively. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operator has proven that the method is robust and rugged

Simultaneous spectrophotometric determination of paracetamol, phenylephrine and chlorpheniramine in pharmaceuticals using chemometric approaches

The linear multivariate calibration models such as principal components regression [PCR] and partial least squares regressions [PLS1 and PLS2] due to the mathematical simplicity and physical or chemical interpretability are sufficient and generally preferred method for analysis of multicomponent drugs. In this study, simultaneous determination of paracetamol, phenylephrine and chlorpheniramine in pharmaceuticals using chemometric methods and UV spectrophotometry is reported as a simple alternative technique. Principal components regression [PCR] and partial least squares regressions [PLS 1 and PLS2] were used for chemometric analyses of data obtained from the spectra of paracetamol, phenylephrine and chlorpheniramine between wavelengths of 200 to 400 nm at several concentrations within their linear ranges. The analytical performance of these chemometric methods were characterized by relative prediction errors and recoveries [%] and compared with each other. PCR, PLS1 and PLS2 were successfully applied to a tablet formulation, with no interference from excipients as indicated by the recovery. However, the PLS1 shows better results due to its flexibility and mathematical principals. The proposed methods are simple and rapid requiring no separation step, and can be easily used as an alternative in the quality control of drugs

Estabilidade térmica do paracetamol em soluçäo: cromatografia em camada delgada (CCD) - Espectrofotometria ultravioleta / Thermic stabilitys of paracetamol solution: thin layer cromatography (TLC) - Ultraviolet spectrophotometrie

A interferência exercida pelos produtos de degradaçäo do paracetamol quando da aplicaçäo da espectrofotometria UV constitui-se no principal empecilho para a realizaçäo dos estudos de estabilidade térmica do paracetamol em soluçäo. A aplicaçäo da cromatografia em camada delgada para o isolamento do paracetamol, apesar de excessivamente trabalhosa, mostrou-se satisfatória aos propósitos desejados. O tipo e a extensäo da degradaçäo sofridos pelo paracetamol em soluçäo sugerem a conveniência da inclusäo, nas formulaçöes, de um sistema antioxidante. Esta prática possibilitou o bloqueio da oxidaçäo do p-aminofenol, produzido pela degradaçäo hidrolítica do paracetamol (fato este que propiciou a diminuiçäo do número de produtos de degradaçäo do medicamento), tornando-o mais seguro para o uso. Por outro lado, considerando especificamente as necessidades metodológicas do presente trabalho, a presença de um sistema antioxidante facilitou a separaçäo do paracetamol através de Cromatografia em Camada Delgada e, conseqüentemente, otimizou sua quantificaçäo por Expectrofotometria UV, durante o estudo da estabilidade térmica. A formulaçäo proposta revelou excelente estabilidade