Evaluation of hepatic and renal effects in rat dams and their offspring after exposure to paracetamol during gestation and lactation.

Paracetamol (PAR) is the analgesic and antipyretic of choice for pregnant and nursing women. PAR may reach the fetus and/or neonate through the placenta and/or milk and effect development. This study evaluated possible hepatic and renal effects in rat dams and their offspring exposed to PAR using a human-relevant route of administration and doses from Gestational Day 6 to Postnatal Day (PND) 21. Dams were gavaged daily with PAR (35 or 350mg kg-1) or water (CON). Dams and pups were killed on PND21 and 22 respectively, and blood was collected for biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine). The kidneys and liver were isolated and processed for histopathological assessment and evaluation of oxidative stress markers. Compared with the CON groups, pups exposed to 350mg kg-1 PAR had increased renal reduced glutathione (GSH), whereas dams exposed to both doses of PAR increased serum AST. PAR administration did not affect parameters of general toxicity or renal and hepatic oxidative stress. In conclusion, maternal exposure to human-relevant doses of PAR by gavage was not associated with hepatic or renal toxicity in the pups or dams, but PAR was not devoid of effects. Exposure to PAR increased renal GSH in pups, which could suggest an adaptive antioxidant response, and affected maternal serum AST activity.

Perinatal exposure to paracetamol: Dose and sex-dependent effects in behaviour and brain's oxidative stress markers in progeny.

Paracetamol (PAR) has been employed worldwide for pain and fever treatment during pregnancy and lactation. Epidemiologic studies have shown that exposure to PAR can increase the risk for developmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. This study aimed to investigate if gestational and lactational exposure to human-relevant doses of PAR could alter behavioural and brain oxidative stress parameters in the rat`s offspring. Wistar dams were gavaged daily with water or PAR (35 mg/kg/ or 350 mg/kg) during gestational day 6 to weaning (postnatal day 21). Behavioural assessments occurred at post-natal days 10 (nest seeking test), 27 (behavioural stereotypy) and 28 (three chamber sociability test and open field). Concentration of advanced oxidation protein products (AOPP), reduced glutathione (GSH), lipid hydroperoxides (LOOH) and activity of superoxide dismutase (SOD) were estimate in prefrontal cortex, hippocampus, striatum and cerebellum of 22-day-old rats. Compared to CON animals, males exposed to PAR during pregnancy and lactation augmented apomorphine-induced stereotyped behaviour (350 mg/kg) and ambulation in open-field test (35 mg/kg). Reduced exploratory behaviour in three chamber sociability test was observed in pups exposed to PAR at 350 mg/kg in both sexes. PAR treatment decreased hippocampal GSH level and striatal SOD activity in males exposed to 35 mg/kg, suggesting the vulnerability of these areas in PAR-induced developmental neurotoxicity. Findings suggest PAR use during pregnancy and lactation as a potential risk factor for neurodevelopmental disorders with males being more susceptible.

Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny.

Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders.

Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?

BACKGROUND: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms. OBJECTIVES: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities. METHODS: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity. RESULTS: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity. CONCLUSION: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.

Development and validation of the discriminating method of prasugrel dissolution in tablets using ultraviolet detection / Desenvolvimento e validação de método discriminativo de dissolução em comprimidos de Prasugrel utilizando detecção ultravioleta

Current study develops and validates a dissolution test for Prasugrel hydrochloride 10 mg in coated tablets. After sink condition, filters and drug stability were evaluated, the discriminatory dissolution conditions were achieved with a USP apparatus 1 (basket) at 50 rpm stirring speed and 900 mL of 0.01 M HCl as dissolution medium. The UV spectrometric method at 220 nm was performed and validated for the determination of Prasugrel. The parameters specificity, linearity, accuracy, precision and robustness were evaluated according to international protocols. UV method and dissolution test proposed in current analysis may be applied for quality control of coated tablets containing Prasugrel since there is no official monograph for this drug.

O objetivo do presente estudo foi desenvolver e validar um teste de dissolução para cloridrato de Prasugrel 10 mg presente em comprimidos revestidos. Após avaliação da condição sink, filtros e estabilidade da droga, condições discriminatórias foram alcançadas utilizando equipamento USP 1 (cesta) em velocidade de 50 rpm e meio de dissolução composto por HCL 0,01 M . Foi desenvolvido e validado método de espectrofotometria na região do ultravioleta (UV) a 220 nm para a determinação de Prasugrel. Foram avaliados os parâmetros como especificidade, linearidade, exatidão, precisão e robustez de acordo com os guias internacionais. O método UV e o teste de dissolução propostos neste estudo podem ser aplicados para o controle de qualidade de comprimidos revestidos contendo Prasugrel, uma vez que não há monografia oficial para este fármaco.

Avaliação da qualidade e perfil de dissolução de comprimidos de cloridrato de propranolol / Assessment of quality and dissolution profile of propranolol hydrochloride tablets

O presente trabalho objetivou avaliar a equivalência farmacêutica de comprimidos de cloridrato de propranolol 40,00 mg, por meio de testes físicos e físico-químicos de qualidade, tais como: variação de peso, friabilidade, teor, uniformidade de conteúdo, dissolução e perfil de dissolução. Realizou-se estudo comparativo de comprimidos provenientes de três laboratórios, denominados de A (referência), B (genérico) e C (similar), sendo dois lotes distintos e aleatórios de cada. Todos os produtos apresentaram resultados satisfatórios nos testes farmacopeicos de qualidade a que foram submetidos, entretanto os resultados dos perfis de dissolução do cloridrato de propranolol das amostras B1, B2, C1 e C2 demonstraram que, se comparados ao perfil do medicamento referência Lote 1 (A1), os medicamentos similares não são equivalentes farmacêuticos, porém quando comparados ao medicamento referência Lote 2 (A2) somente o medicamento genérico, amostra B2, não foi considerado equivalente farmacêutico. A falta de homogeneidade entre lotes do medicamento referência pode gerar equívocos na análise comparativa a outras marcas.

The present study aimed to evaluate the pharmaceutical equivalence of propranolol hydrochloride tablets, through physical and physical- chemical quality tests such as weight variation, friability, assay, uniformity of dosage units, dissolution test and dissolution profile. A comparative study was carried out with tablets from three laboratories, designated as A (reference), B (generic) and C (similar), with two different and random batches. All products showed satisfactory results in pharmacopoeial quality tests, however, the results of the propranolol hydrochloride dissolution profiles of the samples B1, B2, C1 and C2 evidenced that, when compared to the reference A1, the similar medicines are not pharmaceutically equivalent, but when compared to the reference A2 only the generic medicine B2 was not considered pharmaceutically equivalent. The homogeneity lack between reference medicines batches can lead to mistakes in comparison to other brands.