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Erendira Vicencio-Rosas,1 María Gabriela Pérez-Guillé,2 Carmen Flores-Pérez,2 Janett Flores-Pérez,2 Francisca Trujillo-Jiménez,2 Juan Luis Chávez-Pacheco2 1Anesthesiology Department, Hospital Regional de Alta Especialidad “Bicentenario de la Independencia”, ISSSTE, Tultitlán de Mariano Escobedo, México; 2Pharmacology Laboratory, Instituto Nacional de Pediatría, Ciudad de México, México 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. Keywords: buprenorphine, opioid, analgesia, child, adverse effects, pharmacokinetics

Background: Buprenorphine (BPN) is a widely used analgesic in the pediatric population, although there are few studies on the pharmacokinetics and pharmacodynamics of this drug., Objective: The objective was to characterize the pharmacokinetics of BPN after intravenous administration and analyze the effect of age, gender, weight, height, body mass index (BMI), and drug-drug interactions as covariates., Methods: Ninety-nine children (2-10 years), who underwent orthopedic surgery under regional, general, or combined anesthesia were included. Patients evaluated according to the American Society of Anesthesiologists Physical Status Classification, who received intravenous BPN 2 μg/kg were enrolled. Blood was collected from 1-240 min. Drug plasma concentrations were determined by LC-MS/MS. Population pharmacokinetic parameters were obtained with Monolix 2021R1 software. Pearson's correlation and/or ANOVA were used for statistical analysis., Results: Age was associated with changes in clearance and central compartment volume and the female gender was associated with lower intercompartmental clearance, while BMI modified clearance, central and peripheral compartment volume. Concomitant administration of BPN with fentanyl and dexamethasone produced decreases in clearance., Conclusions: The covariates of sex, age, and BMI are directly related to the increase or decrease in BPN pharmacokinetic parameters., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.

Whether age and sex influence the depth of sedation and the pharmacokinetics of midazolam is currently unknown. The influence of age and sex was investigated in 117 children (2 to 17 years) who required intravenous sedation for minor surgery (0.05 mg/kg). Plasma concentrations and sedation effects were simultaneously measured. The measured concentrations were analyzed using a two-compartment model with first-order elimination. Among the age ranges, significant differences were found ( p < 0.05) between the volume of distribution (Vd) of the first compartment (V1) and that of the second (V2). With respect to sex, differences in V2 were found between age groups. At the administered dose, in patients younger than 6 years, a profound sedative effect (40-60 BIS) was observed for up to 120 min, while in older children, the effect lasted only half as long. The differences found in the Vd and bispectral index (BIS) in patients younger than 6 years compared to older patients may be due to immature CYP3A activity and body fat content; furthermore, the Vd varies with age due to changes in body composition and protein binding. Patients younger than 6 years require intravenous (IV) doses <0.05 mg/kg of midazolam for deep sedation. Dosage adjustments according to age group are suggested.

Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The present study aimed to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children. Seventy-two DNA samples were genotyped by real-time PCR. Children ≤ five years of age who carry the rs776746 (T) allele in CYP3A5 gene were associated with lower plasma midazolam levels. The concentration median in patients was 0.0 ng/mL, while in patients with the normal (C) allele, it was 438.17 ng/mL (Q 25 135.75-Q 75 580.24), p = 0.005. The midazolam plasmatic concentration in female patients with the minor (T) allele was 0.0 ng/mL (Q 25 0.00-Q 75 204.3), while in patients with the normal (C) allele median it was 459.0 ng/mL (Q 25 296.9-Q 75 789.7), p = 0.002. Analysis of the dominant model for the rs2740574 variant in CYP3A4 revealed a median of 0.38 L/kg (Q 25 0.02-Q 75 1.5) for the volume of distribution parameter in female patients with the normal T allele, while female patients with the minor C allele showed a median of 18.1 L/kg (Q 25 7.5-Q 75 28.7) p = 0.02. Our results suggest an altered midazolam metabolism due to the presence the allelic rs2740574 variants of CYP3A4 and rs776746 of CYP3A5 , and also the strong influence of age and sex.

Midazolam (MDZ) is a short-acting benzodiazepine that is widely used to induce and maintain general anesthesia during diagnostic and therapeutic procedures in pediatric patients due to its sedative properties. The aim of this study was to perform a systematic review without a meta-analysis to identify scientific articles and clinical assays concerning MDZ-induced sedation for a pediatric surgery approach. One hundred and twenty-eight results were obtained. After critical reading, 37 articles were eliminated, yielding 91 publications. Additional items were identified, and the final review was performed with a total of 106 publications. In conclusion, to use MDZ accurately, individual patient characteristics, the base disease state, comorbidities, the treatment burden and other drugs with possible pharmacological interactions or adverse reactions must be considered to avoid direct alterations in the pharmacokinetics and pharmacodynamics of MDZ to obtain the desired effects and avoid overdosing in the pediatric population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: C max 1503.2 ng/mL vs 1521.4, T max 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13-113.6), 98.08% (88.04-109.2), and 97.52% (84.9-112.01), for C max , AUC 0-t , and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

In yeast and higher eukaryotes, transcription factor TFIIIB is required for accurate initiation of transcription by RNA Polymerase III (Pol III), which synthesizes transfer RNAs (tRNAs), 5S ribosomal RNA (rRNA), and other essential RNA molecules. TFIIIB is composed of three subunits: B double prime 1 (Bdp1), TATA-binding protein (TBP), and TFIIB-related factor 1 (Brf1). Here, we report the molecular characterization of Brf1 in Leishmania major (LmBrf1), a parasitic protozoan that shows distinctive transcription characteristics, including the apparent absence of Pol III general transcription factors TFIIIA and TFIIIC. Although single-knockout parasites of LmBrf1 were obtained, attempts to generate LmBrf1-null mutants were unsuccessful, which suggests that LmBrf1 is essential in promastigotes of L. major . Notably, Northern blot analyses showed that the half-lives of the messenger RNAs (mRNAs) from LmBrf1 and other components of the Pol III transcription machinery (Bdp1 and Pol III subunit RPC1) are very similar (~40 min). Stabilization of these transcripts was observed in stationary-phase parasites. Chromatin immunoprecipitation (ChIP) experiments showed that LmBrf1 binds to tRNA, small nuclear RNA (snRNA), and 5S rRNA genes. Unexpectedly, the results also indicated that LmBrf1 associates to the promoter region of the 18S rRNA genes and to three Pol II-dependent regions here analyzed. Tandem affinity purification and mass spectrometry analyses allowed the identification of a putative TFIIIC subunit. Moreover, several proteins involved in transcription by all three RNA polymerases co-purified with the tagged version of LmBrf1.

Propafenone is an antiarrhythmic that has been used for the treatment of tachiarrytmias in both adults and children. The aim of this study was to analyze the pharmacologic effect of a magistral suspension of propafenone, due to lack of an adequate commercial formulation for use in children. In this study we present, a case of a 2-year-old boy that was diagnosed with Wolff-Parkinson White syndrome and treated with a magistral suspension of propafenone. He has now been one year with no symptoms, no tachycardia and no cyanosis. The clinical status of the patient under treatment with propafenone was improved through constant medical care in the Cardiological Health Care Unit. The use of a magistral formulation of propafenone developed in our laboratory offers a temporal solution due to lack of medicines for children.

Aim: The purpose of the present study is to determine the relationship between the anticonvulsant drug use during pregnancy and the presence of malformations in the newborns., Methods: The frequency of malformations in the neonates of epileptic mothers under anticonvulsant treatment was analyzed in two periods, one from 1988 to 1992, which included 76 epileptic mothers, and another from 1996 to 2003 with 170 patients., Results: In the first period, 51 (67.1%) of mothers received monotherapy and 25 (32.9%) received polytherapy of phenytoin with carbamazepine, valproic acid or phenobarbital. In this period, 4 newborns (16%) with congenital malformations were registered. In the second period, 159 (93.5%) of the epileptic mothers received monotherapy and 11 (6.5%) received polytherapy of valproic acid with carbamazepine or phenytoin. During this period only 3 newborns 27.3% with malformations were registered., Discussion: Clinical treatment should consider the risk of using polytherapy, mainly if phenytoin or valproic acid are combined with other anticonvulsants.