Multi-microdialysis analytical system to monitor acetaminophen and its pharmacokinetic interaction with A. bidentata in rat blood, forelimb extensor muscle, brain striatum, and the knee joint cavity.

Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60 mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3 g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUCorgan/AUCblood) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60 mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC50) in all sampled organs for close to 3 hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect.

Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.

AIMS: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. BACKGROUND: Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. OBJECTIVES: The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. METHODS: Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. RESULTS: Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. CONCLUSION: We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Biodistribution of samarium-153-EDTMP in rats treated with docetaxel / Biodistribuição de EDTMP-153-samário em ratos tratados com docetaxel

PURPOSE: Many patients with metastatic bone disease have to use radiopharmaceuticals associated with chemotherapy to relieve bone pain. The aim of this study was to assess the influence of docetaxel on the biodistribution of samarium-153-EDTMP in bones and other organs of rats. METHODS: Wistar male rats were randomly allocated into 2 groups of 6 rats each. The DS (docetaxel/samarium) group received docetaxel (15 mg/kg) intraperitoneally in two cycles 11 days apart. The S (samarium/control) group rats were not treated with docetaxel. Nine days after chemotherapy, all the rats were injected with 0.1ml of samarium-153-EDTMP via orbital plexus (25µCi). After 2 hours, the animals were killed and samples of the brain, thyroid, lung, heart, stomach, colon, liver, kidney and both femurs were removed. The percentage radioactivity of each sample ( percent ATI/g) was determined in an automatic gamma-counter (Wizard-1470, Perkin-Elmer, Finland). RESULTS: On the 9th day after the administration of the 2nd chemotherapy cycle, the rats had a significant weight loss (314.50±22.09g) compared (p<0.5) to pre-treatment weight (353.66± 22.8). The percent ATI/g in the samples of rats treated with samarium-153-EDTMP had a significant reduction in the right femur, left femur, kidney, liver and lungs of animals treated with docetaxel, compared to the control rats. CONCLUSION: The combination of docetaxel and samarium-153-EDTMP was associated with a lower response rate in the biodistribution of the radiopharmaceutical to targeted tissues. Further investigation into the impact of docetaxel on biodistribution of samarium-153-EDTMP would complement the findings of this study.

OBJETIVO: Muitos pacientes com metástases ósseas são tratados com radiofármacos associados com quimioterapia para alívio da dor óssea. O objetivo do trabalho foi estudar a influência do docetaxel na biodistribuição do EDTMP-153-samário nos ossos e outros órgãos de ratos. MÉTODOS: Ratos Wistar foram aleatoriamente alocados em 2 grupos de 6 animais cada. O grupo DS (docetaxel/samário) recebeu docetaxel (15 mg/kg) intraperitoneal em dois ciclos com 11 dias de intervalo. Os ratos do grupo S (samário/controle) não foram tratados com docetaxel. Nove dias após a quimioterapia, todos os animais receberam 0,1ml de EDTMP-153-samário via plexo orbital (25µCi). Após 2 horas, os animais foram mortos e feitas biópsias de cérebro, tireóide, pulmão, coração, estômago, cólon, fígado, rim e fêmures. O percentual de radioatividade por grama ( por centoATI/g) de tecido de cada biópsia foi determinado em contador gama automático (Wizard-1470, Perkin-Elmer, Finland). RESULTADOS: No 9º após 2º ciclo de docetaxel os ratos tiveram perda de peso significante, passando de 353,66± 22,8g (controle/pré-tratamento) para 314,50±22,09g (p<0,5). Os por cento ATI/g nos órgãos dos ratos tratados com EDTMP-153-samário e docataxel tiveram redução significante nos fêmures direito e esquerdo, rim, fígado e pulmão, quando comparados com os não tratados com docetaxel. CONCLUSÃO: A combinação de docetaxel com EDTMP-153-samário foi associada com resposta mais baixa na biodistribuição do radiofármaco em órgãos alvo. Futuras investigações sobre o impacto do docetaxel na biodistribuição do EDTMP-153-samário poderão complementar os achados teste estudo.

Ziconotide: una alternativa innovadora en el dolor crónico neuropático intenso / Ziconide: An innovative alternative for intense chronic neuropathic pain

El dolor crónico intenso es un problema de salud de primer orden, ya que presenta un prevalenciaelevada (5-10%), una etiología multifactorial y un abordaje en muchas ocasiones realmente complejo. El tratamiento en los casos graves precisa, en ocasiones, abordajes intervencionistas, como los opioides vía intratecal en infusión continua. Casoclínico. Mujer de 38 años de edad, con dolor neuropático intenso en la zona lumbar y los miembros inferiores secundario a tres intervenciones en el segmento lumbar L5-S1. Tras diversos esquemas farmacológicos orales y mediante sistemas implantados(estimulador de cordones posteriores y bomba de infusión subaracnoidea con diferentes combinaciones farmacológicas) sin obtener mejoría clínica, se incluyó en el protocolo de infusión intratecal con ziconotide. Conclusiones. El ziconotide es el primer bloqueador neuronal específico que actúa sobre el canal de calcio, bloqueando los canales tipo N del calcio dependientesde voltaje. Es un nuevo analgésico no opioide con indicación aprobada en el tratamiento del dolor crónico intenso, en aquellos pacientes que requieren de analgesia intratecal, refractario a otros tratamientos analgésicos. Por lo tanto, deberemosconsiderar este fármaco como una alternativa de terapia en aquellos pacientes que con la farmacopea y los mediosdisponibles actualmente no encuentran alivio suficiente

Intense chronic pain is a very important health problem, as it has a high prevalence (5-10%), amultifactorial aetiology and its management is very often a very complex affair. Treatment of severe cases sometimes requires interventional approaches, such as continuous intrathecal infusion of opioids. Case report.We report the case of a 38-year-oldfemale with intense neuropathic pain in the lower back and the lower limbs secondary to three operations on the L5-S1 lumbar segment. After implementing several different pharmacological regimes involving both oral and implanted systems (spinal cord stimulation and subarachnoid infusion pump with different pharmacological combinations) with no clinicalimprovement, intrathecal infusion with ziconotide was included in the protocol. Conclusions. Ziconotide is the first specific neuronal blocker that acts on the calcium channel by blocking the N-type voltage-dependent calcium channels. It is a new nonopioidanalgesic with approved indication in the treatment of intense chronic pain, in patients who require intrathecalanalgesics and are refractory to other analgesic treatments. Therefore, we shall have to consider this drug as a therapeutic alternative in patients do not experience sufficient relief with the pharmacological agents and means currently available to treat them

Evaluación de la eficacia y la seguridad del tolmetín sódico como antipirético jen niños con infecciones de las vías respiratorias superiores / Evaluation of efficacy and safety of sodium tolmetin as an antipiretic in children with upper respiratory tract infections

Se evaluó la eficacia y la seguridad del tolmetín sódico como antipirético en niños con una de las siguientes afecciones de las vías respiratorias superiores: faringoamigdalitits, faringitis, sinusitis, otitis o amigdalitis. La muestra estuvo formada por 83 niños a los que se administró el fármaco en dosis de 20-30 mg/kg/día, fraccionados en tres a cuatro dosis por vía oral. Se interrogó a los padres para seguir la evolución del tratamiento. Se obtuvo mejoría de toda la sintomatología a los cinco días de tratamiento

Efectividad del fenobarbital, diazepam y antipirético para prevenir recurrencias en niños con una primera convulsión febril

El propósito de este estudio fue comparar la efectividad de estos tres tipos de tratamiento para prevenir las recurrencias de las convulsiones febriles durante el primer año posterior a la primera convulsión febril. Se trata de un trabajo prospectivo, tipo ensayo clínico controlado, abierto, no aleatorio. Se incluyeron finalmente 87 niños que consultaron al servicio de urgencias del Hospital Militar Central, por presentar una primera convulsión febril durante el período comprendido entre marzo de 1990 a junio de 1992. Los tres grupos de tratamiento se recomendaron así: fenobarbital como profilaxis continua 5 mg/Kg/día; diazepam 0,5 mg/Kg sublingual o rectal cada 12 horas en caso de presentar fiebre y acetaminofen 10 mg/Kg cada seis horas también en caso de fiebre. Presentaron recurrencias 2/29 pacientes tratados con diazepam, 9/28 niños tratados con fenobarbital y 12/30 casos que recibieron acetaminofen. Encontrándose una diferencia estadísticamente significativa (p<0.025) a favor del tratamiento con diazepam. En este trabajo no se encontró ninguna justificación para continuar recomendando la administración continua de fenobarbital en niños sanos con convulsiones febriles.