Janett Flores-Pérez

A reliable method of liquid chromatography for the quantification of acetaminophen and identification of its toxic metabolite N-acetyl-p-benzoquinoneimine for application in pediatric studies

The aim of the present study was to develop a simple, selective and reliable method to quantify acetaminophen and its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) for pediatric studies using 100 µL plasma samples, by reverse-phase HPLC and UV detection. The assay was performed using a C₁₈ column and an isocratic elution with water-methanol-formic acid (70:30:0.15; v/v/v) as mobile phase. Linearity of the method was assayed in the range of 1-30 µg/mL for acetaminophen and 10-200 µg/mL for NAPQI, with a correlation coefficient r = 0.999 for both compounds, and inter- and intra-day coefficients of variation of less than 13%. Several commonly co-administered drugs were analyzed for selectivity and no interference with the determinations was observed. The detection and quantification limits for acetaminophen and NAPQI were 0.1 and 1 µg/mL, and 0.1 and 10 µg/mL respectively. The present method can be used to monitor acetaminophen levels using 100 µL plasma samples, which may be helpful when very small samples need to be analyzed, as in pharmacokinetics determination or drug monitoring in plasma in children. This assay is also able to detect the NAPQI for drug monitoring in patients diagnosed with acetaminophen intoxication.

Pharmacovigilance and pharmacoepidemiology of drugs in a Mexican pediatric hospital. A proposed guide.

We describe the procedures of pharmacovigilance (PV) and pharmacoepidemiology (PE) of drugs in a pediatric hospital. These activities contribute to the detection and registration of adverse drug reactions and to determine the patterns of drug prescription among children attended at the hospital. The PV activities show that there is a relation between an increase in incidence of adverse drug reactions and the prescription of a larger number of drugs. The PE activities reveal that antibiotics are the most frequently prescribed drugs and next are drugs used for gastrointestinal diseases. Since PV and PE activities were initiated at our hospital, they have contributed to a more adequate use of drugs in children. As a conclusion of these activities, it could be that if the PE of a hospital is known, drug consumption can be optimally planned. PV and PE demonstrate that, if polytherapy is not necessary, it must be avoided. Finally, the present guide can be adopted to initiate PV and PE at a hospital.

Adverse Effects of Imipramine are Increased by Interaction with ASA in Depressed Patients

Because protein binding is a process that can be changed by the presence of other drugs with similar or greater affinity for proteins than the original compound, this causes a greater concentration of the free drug, while potentializing adverse effects, the most important factor responsible for noncompliance (Demyttenaere 1997; Fincke et al. 1998). The purpose of this study was to measure the binding of imipramine to plasma proteins when administered simultaneously with acetyl salicylic acid (ASA). Such interaction would be more clearly defined using clinical assessment parameters in patients treated with imipramine, who additionally need the second drug. The study was carried out in 20 clinically diagnosed depressed patients (16 F, 4 M, average age 38.3 6 13.3 years and weight 63.8 6 9.0 kg) to which imipramine (Tofranil) was administered at doses of 75 mg every 12 h. Informed consent was obtained for all patients before the study. After the first 3 days, while fasting, 6-ml blood samples were taken from the patients and processed. The following were measured: (1) total concentration of the drug in plasma; (2) fraction of imipramine bound to plasma proteins as reported in Juárez and Jung (1986), and protein levels, as indicators of the protein state in the patients studied. Before taking the sample, each patient’s clinical state was assessed using a questionnaire on the possible effects a patient reported, recording the time when the effect arose, its duration, and its severity. This questionnaire was previously validated by the Mental Health Division, Department of the Faculty of Medicine (UNAM). After this first phase, patients took 500 mg of ASA every 12 h for 2 days. At this time, a second sample was taken. The samples were processed, and the parameters as above were assessed. Patients were asked to answer the questionnaire again. The adverse effects were registered and investigation proceedings were carried out by the psychiatry service medical staff at INNN, who had no information about the patients’ treatment. These professionals were well qualified to evaluate the described adverse effects. The degree of binding in patients before the coadministration was 84.4 6 7.07%, and after its administration with the second drug, it was 72.18 6 6.5% ( p , .05, Student’s t -test). The protein levels in all patients were normal. The study confirms that imipramine has a high degree of binding to plasma proteins (Kristensen 1983). When patients were treated with imipramine only, they reported 18 different adverse effects; whereas, after adding the salicylate, the number of adverse effects increased to 28. A parameter confirming the presence of a greater amount of free drug, after the interaction process, was the change in the severity of adverse effects. When patients were treated with imipramine only, 39 effects were expressed as mild, 30 as moderate, and 12 as severe. After the administration of the salicylate, 62 effects were recorded as mild, 31 moderate, and 30 as severe, as shown in Figure 1. No significant increments were seen in the effects classified as moderate. However, in those cases of mild and severe adverse effects, there was a significant increment ( p , .05, Student’s t -test) after administrating the combined drugs. During the analysis of the adverse effects, we found 15 adverse effects that may be common to the levels of imipramine (Petit et al. 1977). However, these effects were found to increase in severity when the amount of free drug increased. The imipramine binding process to plasma proteins may be affected, as in this case, by salicylates as precedent, and studies seem to confirm this process.

Clinical evidence of an interaction between imipramine and acetylsalicylic acid on protein binding in depressed patients.

The binding of imipramine to plasma proteins was studied in 20 adult patients with endogenous depression, with the purpose of assessing the effect produced by its simultaneous administration with an analgesic. Patients were administered 150 mg/day imipramine for 5 days and the binding to plasma proteins was determined. This was repeated 2 days later, after simultaneous administration of imipramine with 1,000 mg/day acetylsalicylic acid (ASA). Adverse effects for each patient were registered during both phases and were classified as mild, moderate, or severe. Results showed 84.4 ± 7.07% of imipramine bound to plasma proteins and 72.18 ± 6.5% when imipramine was administered with ASA (p < 0.05). When imipramine was administered alone, 1.95 mild adverse events per patient were registered. When imipramine was administered with ASA, the mild adverse events increased to 3.1 (p < 0.01) and the severe adverse events increased from 0.6 to 1.5 (p < 0.01). The levels of free imipramine increased when ASA was administered, indicating a displacement on the binding to plasma proteins. When adverse events were compared for each treatment, the accumulation of the free fraction of imipramine caused an increase in adverse events as well as in their clinical severity.

Stability, content uniformity and therapeutic efficacy of sildenafil extemporaneous capsules

®, Maxifort ® and Apodefil ® ). The powder from crushed tablets was distributed into 32 gelatine capsules for each brand. Content uniformity and stability at 25 and 40°C were analysed by HPLC-UV ( μBondapack C 18 column, H 2KPO 4 35 mM (pH 6.0)/ acetonitrile (53:47 v/v), 0.8 ml/min). Therapeutic efficacy of unitary doses was assessed in 25 patients (14 boys and 11 girls), according to clinical improvement and systolic pulmonary arterial pressure (SPAP) decrease, before and after taking sildenafil. Unitary doses showed content uniformity (4.93 ± 0.327 ≈ 5 mg) and were stable for 30 days at 25 and 40°C. SPAP values decreased to normal in 64% of the patients. Dyspnoea disappeared in 85% (11/13) and cyanosis in 67% (6/9). Two children (8%) showed no therapeutic response. Individualised doses of sildenafil in gelatine capsules are stable, uniform in content, and therapeutically effective, being an alternative to treat PAH in hospitalised and ambulatory patients.

Buprenorphine and pain treatment in pediatric patients: an update

Introduction The usual management of moderate to severe pain is based on the use of opioids. Buprenorphine (BPN) is an opioid with an analgesic potency 50 times greater than that of morphine. It is widely used in various pain models and has demonstrated efficacy and safety in adult patients; however, there are insufficient clinical trials in pediatric populations. Purpose The aim of this study was to perform an updated meta-analysis on the implementation of BPN in the treatment of pain in the pediatric population. Methods A bibliographic search was carried out in different biomedical databases to identify scientific papers and clinical trials with evidence of BPN use in children and adolescents. Results A total of 89 articles were found, of which 66 were selected. Analysis of these items revealed additional sources, and the final review included a total of 112 publications. Conclusion Few studies were found regarding the efficacy and safety of BPN use in children. In recent years, the use of this drug in the pediatric population has become widespread, so it is imperative to perform clinical trials and pharmacological and pharmacovigilance studies, which will allow researchers to develop dosage schemes based on the evidence and minimize the risk of adverse effects.