Validated analytical study of the effect of Lycopene on the pharmacokinetics of Paracetamol and Chlorzoxazone in rats

Lycopene was reported to influence some cytochrome P450 enzymes activity. The present study investigates the effect of lycopene on the pharmacokinetics of paracetamol and chlorzoxazone. Lycopene (20 mg/kg) was intra-peritoneally administered to two groups of rats for eight consecutive days and two other groups were given vehicle. On the eighth day, chlorzoxazone and paracetamol were separately intravenously administered to a lycopene group and a control group. Blood samples were collected at different time intervals, treated and analyzed using HPLC. The HPLC method used for paracetamol analysis was based on isocratic elution using a mobile phase consisting of water: methanol, (77:23 v/v) at a flow rate 1 mL min−1, Kromasil C18 column, and UV detection at 254 nm using caffeine as internal standard. About chlorzoxazone, separation was carried out using water: acetonitrile (60: 40, v/v) as the mobile phase at a flow rate 1 mL min−1, Inertsil ODS-3 C18 column, UV detection at 283 nm and esomeprazole as internal standard. Statistical analysis of the pharmacokinetic data using student t test showed a significant increase in AUC 0-t , AUC 0-Inf and t1/2 of paracetamol (P<0.05) and of chlorzoxazone (P<0.05) in the groups pretreated with lycopene (20 mg/kg), significant increase in the volume of distribution of paracetamol (P < 0.05), but no significant difference in that of chlorzoxazone. In other words, paracetamol and chlorzoxazone showed significant decrease (P < 0.05), respectively. These results demonstrate that treatment of rats with Lycopene (20mg/kg, ip) has a significant effect on the metabolic clearance and the pharmacokinetics of both drugs

Equivalência farmacêutica e estudo comparativo dos perfis de dissolução de medicamentos genéricos contendo paracetamol / Pharmaceutical equivalence and comparative study of dissolution profiles of generic drugs containing acetaminophen

Este trabalho teve como objetivo principal comparar, através do estudo de equivalência farmacêutica e do perfil de dissolução in vitro, oito medicamentos genéricos contendo paracetamol 750 mg, comercializados na região central do Rio Grande do Sul. As análises foram realizadas em conformidade com a monografia do paracetamol comprimidos, descrita na Farmacopeia Brasileira (2010). Os genéricos A, B, D, E, F, G e H são equivalentes farmacêuticos do medicamento referência, pois foram aprovados em todos os testes a que foram submetidos. O Genérico C, no entanto, foi reprovado no doseamento. Quando avaliados em relação ao perfil de dissolução, pelos critérios descritos na RDC 31/2010, somente o genérico E não possui o mesmo perfil de dissolução que o medicamento referência, porém quando comparados pela eficiência de dissolução (ED) podemos verificar que somente os Genéricos G, H, F e A possuem a mesma ED que o medicamento referência.

The aim of this study was to compare, by testing their pharmaceutical equivalence and dissolution profiles in vitro, eight generic medicines containing 750 mg paracetamol, marketed in the central region of Rio Grande do Sul (Brazil). Analyses were carried out in accordance with the monograph on paracetamol tablets in the Brazilian Pharmacopoeia (2010). The generic medicines A, B, D, E, F, G and H are pharmaceutically equivalent to the drug reference, since they passed all the tests they underwent. Of all the samples analyzed, only drug E did not have the same dissolution profile as the reference drug, a fact that may interfere with the interchangeability of these products, which is required of a drug being marketed as a generic. Regarding dissolution efficiency (DE), the ANOVA showed a significant difference between the products, so the Tukey test was applied, showing that only the generics A, F, G and H have the same DE as the reference drug.

Pharmacokinetic-interaction of Vitex negundo Linn. & paracetamol.

Background & objectives: Currently, herbal preparations are clinically used as functional food, food supplements or as add on therapy, which affects the bioavailability and also the net therapeutic potential of co-administered allopathic drugs. Therefore, it is important to assess the interaction among these two classes of drugs. Here we studied the interaction between orally-administered ethanolic extract of leaves of Vitex negundo Linn. (Verbenaceae) (VN extract) and paracetamol in albino rats. Method: Solvent free dried extract of VN leaves was orally given to experimental rats in different doses (62.5-1000 mg/kg/b.wt.), daily for six consecutive days. On days 3 and 6, paracetamol (100 mg/kg/b.wt.) was orally administered to these extract treated rats and control rats (drug vector). At various time intervals (5 min - 120 min), blood was collected from each animal and paracetamol concentration was determined in plasma by using HPLC with UV detector at 249 nm. Various pharmacokinetic parameters were calculated by non compartmental model. Results: A significant decline in plasma concentration of paracetamol with time-gap was recorded with the increasing dose of VN extract, without affecting its Tmax (maximum time to achieve peak plasma concentration). There was a significant decrease in the extent of absorption and decline in intensity of therapeutic response (as evidenced by reduced AUC value and decline in Cmax). Further, compared to control, the relative bioavailability of paracetamol, in presence of VN extract, decreased significantly. Interpretation & conclusions: VN extract or its ayurvedic formulation if co-administered with allopathic drug like paracetamol, the dose of allopathic drug needs to be adjusted in order to achieve desired therapeutic response of paracetamol.

Effect of cardiopulmonary bypass on the pharmacokinetics of intravenous paracetamol [Propacetmol hydrochloride]

Recently, intravenous paracetamol [propacetamol] is commonly in use as analgesic and antipyretic after surgery. To our knowledge, the pharmacokinetic of intravenous paracetamol in patients undergoing cardiac surgery with cardiopulmonary bypass were not previously described. This study was designed to investigate the effect of cardiopulmonary bypass on the pharmacokinetics of single intravenous dose of paracetamol in adult patients undergoing coronary artery bypass surgery with hypothermic cardiopulmonary bypass. Nine patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass using mild hypothermia 30°C were selected. Intravenous paracetamol [2g single dose of Propacetamol hydrochloride [Pro-Daflgan UPSA, Fr]] was infused over 10 min and arterial samples were taken starting from 20 min after infusion and afterwards over 8 hours from infusion. Plasma paracetamol concentrations were measured by high-pressure liquid chromatography. The pharmacokinetics of paracetamol was calculated assuming a linear one compartment model with instantaneous input and first order output. The pharmacokinetic data were reported as mean [SD]. ANOVA was used to compare between the pharmacokinetic parameters before and after CPB. C[max] 10.19 [0.9545] mg.litre[-1] appeared 20 min after the end of infusion [experimentally]. Mean clearance [CL] was significantly reduced by about 40% in post CPB [prebypass 0.589 [0.1069] L.h[-1].kg[-1] vs. 0.357 [0.0394] L.h[-1].kg[-1] after CPB, P < 0.05]. The elimination rate constant [Ke] was significantly reduced by about 43% after CPB compared to pre-bypass values. However, the elimination half-life [t[1/2]] was significantly increased from 1.380 h before bypass to 2.431h in post bypass period. It appears from this study that hypotuermic cardiopulmonary bypass can affect the kinetic profile of IV paracetamol in patients undergoing coronary artery bypass graft surgery, and these changes should be considered while using this drug in such situations

Analgésicos no opioides en dolor postoperatorio pediátrico / Analgesic not opioids in pediatric postoperative pain

El dolor postoperatorio es todavía subvalorado en la población pediátrica. Por otro lado, entre las publicaciones que abordan el tema del dolor postoperatorio solo un 10 por ciento de ellas incluye a la población menor de 15 años. Las alternativas terapéuticas en base a analgésicos no opiaceos es restringida en niños, ya que sólo un 20 por ciento del total de las drogas disponibles en el mercado ha probado su eficacia y seguridad en esta población. un analgésico antiguo es el acetaminofeno, acumulando la mayor cantidad de estudios. Los antinflamatorios no esteriodales (AINEs) han ganado popularidad en el manejo del dolor postoperatorio pediátrico. El objetivo de esta revision es determinar cuáles son las indicaciones y las dosis mas racionales y seguras para el tratamiento del dolor agudo en niños.

Postoperatory pain is still subvaluated in pediatric population. On the other hand, only 10 percent of publications discussing postoperatory pain subjects includes a population under age 15. Therapeutic alternatives based on nonopiate analgesics are restrained for children as only 20 percent of the total available drugs in the market has proven their efficacy and safety in children. An old analgesic is acetaminophen, which accumulates most part of studies. Nonsteroidal antinflammarory drugs (NSAI) are gaining popularity to manage postoperatory pain in children. The objective of this revision is to determine the most rational and safest indications and dosages when treating acute pain in children.

effects of acetaminophen on human serum albumin [HSA]

Thermal conformational changes in human serum albumin [HSA] in present with a 10 mM phosphate buffer, at pH=7 have been investigated via circular dichroism [CD] and UV spectroscopic methods. The results indicate that temperature in a range of 25oC to 55oC could induce a reversible conformational change in the structure of HSA. The HSA phase transition corresponds to the physiological and pathological conditions of the body, especially fever. The conformational change observed in HSA is accompanied by a mild conversion of its secondary structures. Acetaminophen is a papular pain killer, and HSA is used as a drug carrier. Hence, acetaminophen could it interact with HSA. The study of HSA - acetaminophen interaction reveals the effects of acetaminophen on HSA structure, preventing it's phase transition. HSA - acetaminophen interaction leads to the stabilization of HAS. This interaction is accompanied with 8 kJ/mol of free energy change. The structural changes within HSA due to it's interaction with acetaminophen could be considered as a drug side effect and it may affect the protein functions

Comparative bioavailability of paracetamol.

Prescribing brand name versus generic drugs continues to be a controversial issue. The harmful effects of nonequivalence result from either too little or too much drug reaching the patient which will cause either failure of treatment or adverse drug reactions. On the other hand, if physicians prescribe higher priced original drugs instead of therapeutically equivalent lower cost generic drugs to their patients, the patients then have to pay for the added cost. This study was designed to compare the bioavailability of paracetamol of a generic versus original drug. The original brand (Tylenol, Cilag) which was assigned as the reference standard against another generic formulation (Sara, Thai Nakorn Patana). Ten healthy male volunteers aged 20 to 45 years participated in this study. The study was conducted as a cross-over experimental design. The dose was 2 tablets of 500 mg. In conclusion, based on the concentration-time curve and pharmacokinetic analysis there were no statistically significant differences between T1/2 absorption and Cmax. Although AUC of Sara was marginally statistically greater than Tylenol, this magnitude of difference probably has no clinical significance. All these parameters are within the accepted 20 per cent difference, indicating these products are bioequivalent.

Excretion of free and conjugated acetaminophen; assessment in urine of female volunteers

Acetaminophen [Paracetamol] was given orally to 08 normal female volunteers of 20-22 years age and 48-62: kg body weight and the excretion of free/unchanged and conjugated drug was determined in urine by a spectrophotometric method. Normal urine pH ranged from 4.03 to 6.16 and the rate of urine flow was 0.007 to 0.036 ml/min.kg body weight. The mean +/- SD values for the cumulative% age of the dose excreted in 24 hours urine as total drug was 54.1 +/- 15.5, free or unchanged 28.7 +/- 9.10 and the conjugated metabolites were 27.3 +/- 13.7%. The excretion rate of the drug did not show any relationship with the rate of urine flow [diuresis] and pH of the urine. The observed values for the urinary excretion of the drug and metabolites are different than the values recorded in literature

Comparison between sprague-dawley and wistar rats as an experimental model of pharmacokinetic alterations induced by spinal cord injury

Two strains of rats, Sprague-Dawley and Wistar, were assayed in order to determine which strain is the more suitable experimental model for the study of pharmacokinetic alterations inuced by spinal cord injury. Animals were submitted to spinal cord contusion at the T8-T9 level by the weight drop method. A single acetaminophen oral dose (100 mg/kg) was administered 24 h after injury and blood samples were drawn for a period of 4 h. Acetaminophen concentration in whole blood was determined by high performance liquid chromatography and pharmacokinetic parameters were estimated. For both strains, Cmax and AUC were significantly lower, whereas tmax remained uchanged, in injured animals compared to sham-injured controls. Circulating acetaminophen concentrations were higher; therefore, pharmacokinetic alterations were more easily discerned, in Sprague-Dawley than in Wistar rats. It is concluded that the Sprague-Dawley strain is a more suitable model for the study of pharmacokinetic alternations induced by spinal cord injury

Inhibition of paracetamol induced reduction in hepatic glutathione level by INH of rifampin coadministration in mice

Repated administration of paracetamol induces hepatotoxicity due to depletion of the liver tissue from its glutathione contents. As paracetamol may be currently used in combination with INH and rifampin it was notworthy to explore the effect of these drugs on hepatic glutathione contents. Paracetamol, INH and rifampin were given either alone or in combination. After certain period of drug treatment, the animals were sacrificed and their livers were homogenized to determine its glutathione contents. It was observed that paracetamol significantly decreased while either INH or rifampin significantly increased the glutathione contents of the liver. When given in combination, both INH and rifampin could prevent the decrease in glutathione level when paracetamol was given with either of them for 2 days and only partially when it was given for 7 days. How much this effect can be benificial ? this needs thorough clinical investigation

Uma análise crítica sobre benefícios e riscos da dipirona / A critical analysis of the benefits and risks of dipyrone

Os analgésicos-antipiréticos säo drogas maciçamente consumidas em nível mundial e, por serem fármacos relativamente antigos, pouco se tem publicado a esse respeito. Este estudo visa fazer uma análise crítica e objetiva sobre os riscos e benefícios na utilizaçäo de analgésicos, bem como sobre a coerência de alternativas terapêuticas. Foi realizada extensa e profunda análise da literatura científica internacional sobre o assunto, com particular atençäo ao notável "Estudo de Boston". Conclui-se que o uso de analgésicos é bastante seguro, sendo que a dipirona é o fármaco mais bem avaliado quanto ao seu perfil de segurança

Effect of s-adenosyl-l-methionine on acetaminophen pharmacokinetics in the rabbit

The effect of SAMe on acetaminophen pharmacokinetics has been studied in rabbits. SAMe administration [IM] resulted in a decrease in acetaminophen half-life from 0.85 +/- 0.12 [control group] to 0.68 +/- 0.10 h in the treated group. Acetaminophen total body clearance increased from 1.98 +/- 0.08 L/h, [control group] to 2.38 +/- 0.46 L/h in the treated group. It was not possible to determine which of the acetaminophen metabolic pathways is affected by SAMe administration because acetaminophen metabolities were not determined. To investigate the mechanism of SAMe protective effect against acetaminophen intoxication, acetaminophen was administered in the form of suspension either alone or after pretreatment with SAMe administered intramuscularly. The activity of the serum transaminase enzymes, liver glutathione level as well as histopathological examination were measured to assess liver function. SAMe administration resulted in reduction of the serum activity of alanine aminotransferase [ALT] and aspartate aminotransferase [AST] enzymes. The pathological changes in the liver produced by acetaminophen also decreased SAMe pretreatment prevented liver glutathione [GSH] depletion in acetaminophen intoxicated animals

In-vitro and in vivo availability of paracetamol from different commercial tablets in Egypt

Four brands of paracetamol tablets manufactured in Egypt, an imported brand [Panadol tablets] and an expertimental tablet were evaluated for in vitro dissolution and in vivo availability of the drug. The results of the study demonstrated that the different tablets appear to follow first order dissolution kinetics. Three dissolution media were used in this study. The highest dissolution rate constant was obtained in 0.1N hydrochloric acid for all the products. The dissolution of the drug from the different tablets was a function of their disintegration. The cumulative amounts of paracetamol excreted in urine after 24 hours were above 84% of the administrated dose in all cases. Brand V was shown to give the best in vitro and in vivo availability. Comparable data were given by brand I. A good linear correlation was obtained between the maximum amount of the drug dissoluted and the percentage of the dose excreted in urine after 24 hours

Placental transfer of paracetamol.

Paracetamol (1 g orally) was given to each of 10 healthy pregnant women undergoing normal vaginal delivery at the onset of second stage of labour. Following delivery, there was no significant difference in the serum concentration of paracetamol in the mother and the foetus (p less than 0.1), the mean value being 5.925 +/- 2.15 mg/ml and 7.875 +/- 2.22 mg/ml respectively. Paracetamol may be recommended as a safe analgesic-antipyretic during pregnancy and labour.

Influência da constante dielétrica do solvente na solubilidade do paracetamol / Influence of dielectric constant in the solubility of paracetamol

Foram realizados estudos de solubilidade do paracetamol em solventes puros e sistemas solventes binários, com diferentes valores de constante dielétrica. A solubilidade do paracetamol variou consideravelmente frente aos diferentes valores de constante dielétrica, bem como aos diferentes sistemas solventes com o mesmo valor de constante dielétrica, ficando, portanto, demonstrado que a constante dielétrica näo é o fator determinante na solubilizaçäo do paracetamol

Paracetamol: estudo cromatográfico (CCD) de soluçöes semi-aquosas e demonstraçäo da interferência do P-Aminofenol sobre as análises quantitativas realizadas por espectrofotometria U.V / Paracetamol: chromatographic (TLC) studies of the semi-aqueous solutions and p-aminophenol interfering on spectrophotometric quantitative analysis

Soluçöes de paracetamol 100mg/ml, constituídas por misturas binárias água/polietilenoglicol 400 e água/álcool etílico absoluto, submetidas e näo submetidas a tratamento térmico, foram analisadas através de cromatografia em camada delgada. Tais estudos, acrescidos de varredura do espectro de absorçäo U.V., confirmaram a interferência exercida pelo p-aminofenol sobre as análises quantitativas, realizadas através de espectrofotometria U.V. a 244nm