Whocely Victor de Castro

Stimulating follicle growth could have utility for fertility preservation before follicular culture or as part of ovarian stimulation protocol therapies for women with a limited ovarian reserve. Propranolol is a clinically approved beta-blocker. Beyond its beta-adrenergic receptors, recent investigations have suggested an alternative role in activating Mammalian target of rapamycin (mTOR). Therefore, this study aimed to evaluate the efficacy of propranolol treatment on early follicle growth, both in vitro and in vivo. For in vitro studies, neonatal mouse ovaries were cultured for up to 3 days in the presence or absence of propranolol and then processed for histological analysis, quantitative PCR (qPCR), RNA in situ hybridization, and western blot (WB). For in vivo experiments, mice were treated with a low or a high dose of propranolol or no drug for 15 days. Then, analyses were performed, including body and ovarian weight measurements, histological analyses, WB, and qPCR. In vitro experiments demonstrated that treatment decreased primordial follicles and increased transitional, primary, and secondary follicles. Consistent with this, propranolol treatment resulted in the downregulation of Pten and an increased presence of Cpeb1, a novel biomarker of follicle activation, in primordial follicles. In our in vivo studies, propranolol promoted follicle activation, increased PI3K-p110 levels, and decreased Pten expression. In summary, propranolol increases the transition of primordial follicles to more advanced stages of development. These findings highlight propranolol as a potential drug to induce, in vivo and in vitro, early preantral follicle growth, potentially improving fertility preservation techniques and studies.

Diarrhea is a common adverse event at the beginning of metformin hydrochloride use. Extended-release (XR) tablets are an alternative for patients intolerant to the immediate-release formulation. This study evaluated the perception of gastrointestinal adverse events (GAE), quality, and dissolution behavior between reference (R) and generic (G) XR formulations. A prospective cohort study recorded diarrhea, abdominal discomfort, and impact on daily activities using a perception form. R and G were analyzed for quality and dissolution behavior. Among 29 patients, 16 used R (55.2%) and 13 G (44.8%). Both groups presented GAE (diarrhea: R= 8, G= 8; abdominal discomfort: R= 9, G= 7). BMI was significantly associated with the occurrence of GAE regardless of the medications studied. All samples met pharmacopoeial quality standards. The Higuchi model best described the dissolution kinetics of R, and Peppas-Sahlin for G. The dissolution profiles were similar (F2= 67), although the dissolution efficiency differed by more than 10%. Our findings reinforce the interchangeability between reference and generic medicines, providing an effective option for patients with type II diabetes mellitus. This strengthens the principles of the National Generic Medicines Policy in Brazil, contributing to the sustainability of the healthcare system and the democratization of access to essential medicines.

Maytenus ilicifolia Mart. ex Reiss is a plant native to South America, popularly used in the treatment of gastric disorders. The increase in the consumption of herbal products associated with conventional medications demands attention for the potential risks of interactions. The aim of the study was to evaluate potential pharmacokinetic interactions due to coadministration of M. ilicifolia extracts with drug substrates of P-glycoprotein (P-gp) and cytochrome P450 3A4 isoform (CYP3A4). Five extracts of M. ilicifolia were prepared, and the contents of the main secondary metabolites were determined. A high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of midazolam, nifedipine, and their respective metabolites and applied to assess the potential of M. ilicifolia extracts on hepatic metabolism mediated by the CYP3A4 enzyme. The influence of the extracts on the intestinal permeability of fexofenadine was evaluated by determining P-gp activity, using a Caco-2 cell model. The extracts were characterized in terms of total phenolic (1.77–11.46%), tannin (1.67–3.36%), and flavonoid (0.21–2.64%). The hydroacetonic extract (HAE1) exhibited a remaining activity (%RA) of 50.1% for the 1-hydroxylation of midazolam and 40.1% for the oxidation of nifedipine, indicating moderate inhibition of CYP3A4. HAE1 reduced the fexofenadine efflux ratio to an extent similar to that of verapamil (IC₅₀ = 20.42 μg/mL), suggesting an inhibitory effect on the P-gp activity. The extracts demonstrated the potential to inhibit both CYP3A4 and P-gp. Therefore, coadministration of M. ilicifolia-based preparations may potentially alter the pharmacokinetics of drugs that are substrates of these systems.

This work investigated interactions ascribed to the administration of phytomedicines containing Valeriana officinalis and Piper methysticum with conventional drugs. The phytomedicines were characterized by HPLC and administered per os to male Wistar rats, either concomitantly or not with the CYP3A substrate midazolam. To distinguish between the presystemic or systemic effect, midazolam was given orally and intravenously. The effects on the P-gp substrate fexofenadine uptake by Caco-2 cells were examined. The valerenic acid content was 1.6 ± 0.1 mg per tablet, whereas kavain was 13.7 ± 0.3 mg/capsule. Valerian and kava-kava extracts increased the maximum plasma concentration (C_max) of midazolam 2- and 4-fold compared to the control, respectively. The area under the plasma concentrations versus time curve (AUC_(0-∞)) was enhanced from 994.3 ± 152.3 ng.h/mL (control) to 3041 ± 398 ng.h/mL (valerian) and 4139 ± 373 ng.h/mL (kava-kava). The half-life of midazolam was not affected. These changes were attributed to the inhibition of midazolam metabolism by the enteric CYP3A since the i. v. pharmacokinetic of midazolam remained unchanged. The kava-kava extract augmented the uptake of fexofenadine by 3.5-fold compared to the control. Although Valeriana increased the uptake of fexofenadine, it was not statistically significant to that of the control (12.5 ± 3.7 ng/mg protein vs. 5.4 ± 0.3 ng/mg protein, respectively). Therefore, phytomedicines containing V. officinalis or P. methysticum inhibited the intestinal metabolism of midazolam in rats. Conversely, the P-gp-mediated transport of fexofenadine was preferably affected by kava-kava. Received: 14 November 2023 Accepted after revision: 21 June 2024 Article published online: 16 July 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Background Several countries’ most incorrectly discarded medicines are acetaminophen (ACM), metamizole (MTZ), and nimesulide (NMS). These xenobiotics easily reach the aquatic environment; such contamination is very important for the health of humans and other species, yet little explored. Objectives To evaluate the cocktail effect of ACM, MTZ, and NMS during zebrafish’s initial development. Methods Zebrafish embryos 6–8 h post-fertilization (hpf) were exposed to different concentrations of ACM, MTZ, and NMS, separately, to obtain the 50% lethal concentrations (LC₅₀). Next, the embryos were exposed to distinct concentrations of the cocktail (LC₅₀/2, LC₅₀/5, LC₅₀/10, and LC₅₀/20) in a semi-static system. Samples were analyzed 0, 24, 48, and 96 h after exposure, and the drugs’ concentrations in E3 medium were assessed by high-performance liquid chromatography. For embryotoxicity evaluation, the mortality, hatching, and heart rates; total length; and pericardial and yolk sac areas were determined. In addition, body malformations, edemas, presence of pigmentation, and histopathological assessments were also recorded. Results The LC₅₀ values obtained for MTZ, ACM, and NMS were 4.69 mgmL⁻¹, 799.98 μgmL⁻¹, and 0.92 μgmL⁻¹, respectively. No difference was observed between the drugs’ nominal and observed concentrations at each time point. The cocktail significantly induced mortality and decreased hatching in the LC₅₀/10, LC₅₀/5, and LC₅₀/2 groups. Additionally, body malformations, pigmentation loss, and yolk sac and pericardial edemas were observed in the cocktail groups. The cocktail groups’ larvae had decreased total length and slower heart rates compared to the controls (p < 0.05). The histopathological assessment showed that yolk sac edema promoted severe histological changes in the esophageal-intestine junction and intestine in larvae treated with cocktails. Moreover, PAS-positive structures decreased in the esophageal-intestine junction, intestine, and liver in larvae exposed to pharmaceutical cocktails. Conclusion This study’s findings suggest the cocktail of ACM, MTZ, and NMS may be hazardous to aquatic organisms in case of environmental contamination. Graphical Abstract

Diabetes mellitus is defined by hyperglycemia resulting from impaired insulin action or distress, or both. Metformin is widely prescribed to control the disease and the most common adverse events caused by its use are diarrhea, nausea and/or abdominal discomfort. We evaluated the frequency profile of gastrointestinal adverse events associated with the use of metformin. This is a cross-sectional observational study, in which the occurrence of diarrhea in patients with type 2 diabetes mellitus who started treatment with metformin hydrochloride at a dose of 500 mg of prolonged release was reported. 12 (41.37%) participants were male and 17 (58.62%) were female. Diarrhea was present (n=16) in more than half of the patients (55.2%) who used the drug. Patients had an average of 12 episodes of diarrhea per month. There was also the presence of abdominal discomfort (n=7), in which 24.1% reported being very high. The study showed that the extended-release drug metformin hydrochloride 500 mg can cause gastrointestinal adverse events at the start of treatment and lasts for approximately twelve days.

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h⁻¹ and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.

The genus Duguetia encompasses 93 species, 63 of which are distributed in Brazil. However, only ten species had their chemical and biological profiles investigated so far. Although the alkaloids are the class of phytocompounds most studied, the interest in the phenylpropanoids is growing since distinct biological activities have been attributed to these derivatives lately. This review gathered studies describing the phytochemical distribution, methods of extraction, and biological activities of the phenylpropanoid from Duguetia species. It was evidenced that nonpolar solvents were able to provide the highest yield of 2,4,5-trimethoxystyrene, γ-asarone, and asaraldehyde which were mainly located at the ground stem barks. On the other hand, the α-asarone, elimicin, and (E)-methyl-isoeugenol were isolated from the polar extracts or the essential oils from the barks and leaves. The 2,4,5-trimethoxystyrene and asarone derivates were effective as crop protectors. The α- and γ-asarone, 2,4,5-trimethoxycinnamic acid, asaraldehyde, elemicin, and (E)-methyl-isoeugenol demonstrated anti-inflammatory, antidyslipidemic, antinociceptive, antibacterial, antidepressant, anxiolytic, insecticide, and larvicide activities. The Duguetia species can be a potential source of phenylpropanoids, therefore, future studies involving their extraction, identification, and application are still necessary and may culminate in the discovery of new drug candidates or natural agricultural defensives.