Abstract In this study, we investigated the cerebroprotective effects of fenchone (FEN) against brain ischemia through in silico and in vivo approaches, focusing on the inhibition of nitric oxide synthase (NOS) and the modulation of oxidative stress markers. Molecular docking revealed the potential binding affinity of FEN for the NOS active site, with a binding energy of -6.6 kcal/mol. This was validated through molecular dynamics simulations over a 100 ns time frame, demonstrating stability and favorable interaction profiles. Wistar albino rats underwent bilateral common carotid artery occlusion/reperfusion (BCCAO/R) followed by FEN administration at doses of 100 and 200 mg/kg. Our results indicated a significant reduction in cerebral infarction size and improvements in electroencephalography (EEG) signal magnitude with FEN treatment. Additionally, FEN restored the activity of antioxidant enzymes (catalase and superoxide dismutase) and decreased malondialdehyde (MDA) and nitric oxide (NO) levels and infarct size compared to those in untreated ischemic rats. Histological analysis further corroborated the neuroprotective effects of FEN, demonstrating the structural preservation of neurons in the hippocampal CA1 region. Overall, the results suggest that FEN plays a neuroprotective role in brain ischemia, potentially through the inhibition of NOS, reduction of oxidative stress, and modulation of antioxidants, highlighting the potential of FEN as a therapeutic candidate for ischemic stroke management.

Abstract This research aims to create dabrafenib (DBF)-loaded nanosponges (NSPs) using β-cyclodextrin (β-CD) and diphenyl carbonate (DPC) as linker to improve oral bioavailability. DBF-loaded β-CD NSPs were synthesized by finely adjusting the molar ratio of β-CD to DPC and optimizing the stirring rate and duration using design methodology. After being loaded with DBF, the produced β-CD NSPs were characterized in terms of particle size, zeta potential (Z.P), polydispersity index (PdI), and drug entrapment efficiency (E.E). Studies on compatibility were carried out with FTIR (Fourier Transform Infrared Spectroscopy) and DSC (Differential Scanning Calorimetry). Permeability, in vivo, and in vitro experiments were performed on the improved NSPs and the pure medication. After optimizing DBF-loaded β-CD NSPs, a formulation with a mean size of 158.0 ± 7.2 nm, PdI of 0.282 ± 0.0044, and E.E of 86.23 ± 2.45% was obtained, based on the assessments indicated earlier. Zeta sizer, SEM, spectrum analysis, in vitro release, and pharmacokinetic tests were among the other analyses that further validated the optimization. An area under the curve (AUC0-t) of 7.95-fold greater and a Cmax 7.356 times higher than those of the free drug was demonstrated by the optimized β-CD NSPs, which showed a notable boost. The use of DBF-loaded NSPs holds promise as an effective strategy for enhancing release and bioavailability in the treatment of melanoma.

Abstract The study aimed to assess the prevalence and characteristics of potential drug-drug interactions (pDDIs) that increase the risk of QT prolongation, in a population of cardiovascular disease patients. An observational retrospective study was conducted at a cardiology ward. A total of 351 patients were included in the analysis, with almost equal gender distribution (female 48.4%) and mean age 70±10 years. In the total set of tested drug pairs (5620), QT-prolonging pDDIs were identified in 13 drug pairs on admission. The highest frequency was observed for ciprofloxacin (involved in 5 pDDIs), followed by propafenone (4 pDDIs) and beta2-agonists (4 pDDIs). The pharmacodynamic mechanism was involved in all pDDIs. The study revealed a low prevalence of QT-prolonging pDDIs on admission to the cardiology ward, about 3% in the studied population. However, given that underlying heart disease is a significant risk factor for the occurrence of QTc prolongation, the additional risk for acquired QT prolongation should not be neglected. Due to serious consequences caused by QT prolongation and TdP, the key role of health professionals is to identify predisposed patients and to recognize pDDIs involving QT-prolonging agents. Hence, patients’ modifiable risk factors for QT prolongation should be minimized, if not eliminated.

Abstract The transdermal pathway serves as a significant route for achieving localized or systemic effects. Within this context, the stratum corneum is a crucial barrier limiting the permeation of many drugs. To surmount this barrier, carriers, and nanocarriers have been utilised, notably ‘invasome’ being one such example. In our study, we formulated invasomes loaded with simvastatin using the conventional thin-layer evaporation technique. This formulation involved the use of soy phosphatidylcholine, terpene (Limonene), chloroform, and ethanol. Simvastatin-loadedinvasomes were incorporated into a carbopol 934 solution to create a gel. We prepared and assessed different formulationsfor various parameters, including zeta potential, scanning electron microscopy, entrapment efficiency, viscosity, and drug content, and conducted in vitro studies. The entrapment efficiency was as high as 83.17±0.61%. The maximum in vitro drug permeation (45.44±0.4%) was found in the gel with 0.5% soy phosphatidylcholine and 0.25% terpene. Upon evaluating these parameters, our findings suggest that the simvastatin invasomal gel effectively enhances drug permeability across membranes and successfully achieves prolonged drug release.

Abstract Rifampicin (RFP) is used for the treatment of chronic bone tuberculosis owing to its powerful and wide spectrum antibacterial activities. However, effective concentrations of RFP required to treat bone tuberculosis are maintained for a short time in vivo, and adverse reactions and bone defects may occur after surgery. Therefore, the construction of a new drug delivery system to overcome these problems is required. In this study, we designed, constructed, and demonstrated the applicability of a calcium phosphate cement scaffold loaded with RFP liposomes for the treatment of bone tuberculosis. RFP liposomes were prepared using a film dispersion method. The preparation method was optimized using the encapsulation rate as an indicator and the morphology, mean particle size, zeta potential, encapsulation rate, and drug loading of RFP liposomes were characterized. Calcium phosphate cement scaffolds were constructed using 3D printing technology and used as RFP liposome carriers for sustained-release drug delivery. Finally, some of the properties were verified in vivo through experiments in rabbits. The results indicated that composite scaffolds can provide sustained drug release and are a promising treatment option for bone tuberculosis.

Abstract This study aimed to analyze the effectiveness of using an antivenom serum (AVS) premedication protocol to prevent early adverse reactions (EAR). This is a cohort study conducted with data from the Londrina Information and Toxicological Assistance Center (CIATox-Londrina) at the University Hospital of the State University of Londrina (HU-UEL), which included patients treated with AVS between January/2017 and December/2021. The independent variable was performing the premedication protocol and the dependent variable was the occurrence of EAR after AVS administration. Patients were followed until hospital discharge. The association analysis was performed with calculation of the Relative Risk (RR) and 95% Confidence Interval (95% CI). A total of 806 cases of accidents with venomous animals were analyzed. The minority (8.1%; n=65) had EAR, and the most frequent symptoms were related to dermatological and respiratory manifestations. The AVS premedication protocol was performed in 96.6% (n=734) of the cases. There was no statistically significant difference in the unadjusted (RR: 1.487; 95% CI: 0.530-4.174) and adjusted (RR: 1.482; 95% CI: 0.522-4.210) models regarding the performance of the AVS premedication protocol and the occurrence of EAR. It is recommended against AVS premedication given the lack of effectiveness in preventing EAR.

Abstract Traditionally, raw cow milk has been employed to treat acid and thermal burns due to its antibacterial, antibiotic, and antifungal properties. It also aids in preventing scarring and alleviating burn-related skin discomfort. This study focuses on evaluating a nanoemulsion cream made from casein extracted from raw cow milk for managing acid and thermal burns. Casein was isolated and used to create 2%, 5%, and 10% w/w nanoemulsion creams. Wistar albino rats were used to induce acid and thermal burns, and the healing progress was monitored by measuring wound contraction and epithelialization period. The results demonstrated significant wound healing effects of the casein creams (p<0.001) in acid burns, with the 10% w/w cream showing the highest epithelization rate in thermal burns. Raw milk also exhibited notable healing properties in acid burns. However, its effectiveness was relatively lower in thermal burns. This study suggests that raw milk and its casein-derived creams could be utilized as first-aid treatments for acid burns, though they may be less effective for thermal burns.

Abstract This study aims to analyze the existence of information about deprescription in the leaflets of proton pump inhibitor (PPI) medications. The leaflets available on the Brazilian Health Regulatory Agency (ANVISA) and Food and Drug Administration (FDA) websites for the following medications were analyzed: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. The variables collected in each leaflet were the existence: a) about deprescribing; b) of guidance on the deprescription process; c) maximum recommended time for use; and d) risk of prolonged use. This information was analyzed in accordance with the PPI deprescription guideline, from Canada. Regarding the medication leaflets, 83.33 % from ANVISA and 100 % from the FDA did not present explicit and systematic guidance on deprescribing. Regarding the maximum time of use, 100 % of the leaflets from both agencies contained this information. Regarding the risks of prolonged use of the medication, 33.33 % of the ANVISA leaflets and 33.3 % of the FDA leaflets did not report the increased risks described in the guideline. The results highlight a large gap in information about deprescribing in PPI leaflets; this highlighting is necessary to contribute to the promotion of the rational use of medicines.

Abstract Entecavir is an inhibitor of hepatitis B virus (HBV) DNA synthesis that has been widely prescribed in the treatment of chronic infections caused by the virus. Production of generic ETV drugs is an ongoing global endeavor, with particular significance for developing countries that rely on importing the expensive reference drug. ETV-excipient compatibility studies were conducted with the declared inputs in solid pharmaceutical formulations on the market through thermal analysis and HPLC techniques. Thermal analyses by TGA and DTA indicated compatibility of entecavir with the excipients microcrystalline cellulose, crospovidone, titanium dioxide, magnesium stearate, hypromellose, polyethylene glycol and povidone; this was confirmed via HPLC. Lactose monohydrate proved to be incompatible with ETV in thermal and chromatographic assays. The thermal analysis of marketed solid dosage forms revealed a predominance of the lactose monohydrate profile at the expense of ETV and other inputs in the TGA and DTA curves, due to its high content in the formulations; this makes the evidence of ETV-lactose chemical interaction even more important. Compatibility tests by HPLC showed no chemical interaction of ETV with the excipient mannitol, a soluble diluent proposed as a replacement for lactose monohydrate, with the same function in the formulation.

Abstract Hydroxychloroquine (HCQ) is a chiral drug used to treat malaria and inflammatory diseases, available as a racemic mixture of R-and S-HCQ. This work aimed to build physiologically-based pharmacokinetic (PBPK) models to predict the pharmacokinetics (PK) of R-and S-HCQ and assess the impact of major genetic polymorphisms on PK. Whole-body PBPK models accounting for first-order absorption, Rodgers and Rowland distribution method, and enzyme kinetics data were built for R-and S-HCQ. The models were verified by comparing predicted PK parameters with observed ones, with a mean error within the acceptable range (0.5-2 fold). Simulations covered CYP2D6 normal metabolizer (NM), poor metabolizer (PM), and ultra-rapid metabolizer (UM) phenotypes, as well as CYP2C8 NM and PM phenotypes. The results revealed a 1.1-fold increase in area under the curve blood concentration versus time (AUC) for CYP2D6 PM individuals and a 0.9-fold reduction for UM individuals compared to NM individuals. In addition, simulations with CYP2D6 and CYP2C8 PM phenotype individuals combined with the CYP3A4 inhibitor clarithromycin showed increased AUC for R-and S-HCQ of 2.34 and 2.68, respectively. These PBPK models offer reliable predictions for R-and S-HCQ enantioselective kinetics and shed light on previously unexplored scenarios.

Abstract Depression has substantially increased in the last 10 years in Brazil, and mental health became a concerning issue for the public health globally, especially considering the COVID-19 pandemic. The therapeutic conduct in depression mainly relies on medication and psychotherapy. However, more than one attempt in the treatment can be considered a common procedure before finding out the right medication. This conduct leads many patients to give up following pharmacological treatment. In this scenario, pharmacogenomics emerges as a possible supporting tool of the medical treatment. This paper aims to analyze the scenario of depression in Brazil and the viability of pharmacogenomic tests implementation as a part of the medical procedure. Official data bank from the Brazilian government was used to analyze the prevalence of depressive disorder, as well as Pharmacogenomic data bases and relevant articles around this topic. Additionally, pharmacogenomic tests typically take into consideration the genes CYP2D6 and CYP2C19, which are relevant for antidepressant treatment. Data shows that these tests could help patients achieve remission of symptoms, and they could also be economically advantageous. Thus, pharmacogenomic tests present as an interesting approach for the therapeutic conduct of depression and can significantly improve the health quality of this affected population.

Abstract The Covid-19 pandemic, caused by SARS-CoV-2, was responsible for millions of deaths worldwide. The main protease (Mpro) of SARS-CoV-2 is considered one of the important drug targets for the treatment of Covid-19. Recent studies have shown that anisotine should be a potent Mpro inhibitor. In the present work, four oxoquinoline derivatives are proposed as candidates for Mpro inhibitors. The main functional group of these derivatives shows similarity to anisotine, and they are active against the HSV-1, as well as the latter. Molecular docking studies evaluated whether these compounds could be active against Mpro of SARS-CoV-2. Structural modifications were proposed on the oxoquinoline derivative which formed a more stable complex with Mpro and this proposal formed an even more stable complex besides exhibiting improvements in the toxicological profile. Molecular dynamics simulations indicated that derivatives proposed promote greater stabilization by complexing with Mpro than anisotine.

Abstract Pharmaceutical controlled-release formulations are systems developed by a set of unit operations to achieve a satisfactory combination between a drug and excipients to allow its gradual release. These devices must simultaneously meet criteria for stability, biocompatibility, safety, efficacy, scalability at industrial volumes, and technological efficiency for drug release. Controlled-release systems (CRSs) must release drugs in a way that maintains an adequate concentration in the organism, a requirement that is challenging to meet in practice. Even though novel CRSs may be designed with new materials as excipients, new drugs, or emerging manufacturing technologies, the mechanisms for drug release continue to be governed by a set of similar physicochemical phenomena such as diffusion, swelling, or erosion. These phenomena are too complex to be analyzed by numerical methods; however, they are relatively accessible by probabilistic models especially the Monte Carlo simulation. In this review, we discuss key findings related to the use of this probabilistic method for analyzing the drug-controlled release process in different pharmaceutical devices. Based on this evidence, we propose their potential application in the characterization of new drug-controlled release systems, synergy with other computational methods, and their capability to be adapted for in vivo or in vitro kinetic analysis.

Abstract Mikania glomerata (guaco) is included in Brazil’s National List of Essential Drugs (RENAME) with expectorant and bronchodilator indications. This research aims to describe the profile of patients and prescribers of guaco-based herbal medicines within the Unified Health System in the municipalities of Rio Grande do Sul (RS)/Brazil, quantify the consumption and cost of this product, and assess the prescriber’s experience with guaco and herbal medicine. A cross-sectional observational study was conducted based on questionnaires applied to prescribers and guaco usage data in primary care in RS municipalities (May 1, 2020 - April 30, 2021). 44 municipalities (40%) were identified dispensing guaco syrup in the sample. The results showed a prevalence of women users (57.4%) and patients between 19 and 59 years of age (58.2%). All participating prescribers were physicians, and 37% of the responses indicated daily doses of coumarin lower than recommended. The syrup consumption per 1,000 inhabitants ranged from 0.3 to 36.6 bottles, and the monthly cost per municipality varied from $0.50 to $247.78. Only five prescribers (21.7%) were familiar with the herbal medicines in RENAME, and only one had formal training for prescribing herbal medicines, highlighting the need for instruction and dissemination of programs for using herbal medicines.

Abstract The study investigates the potential of Morus alba L. (mulberry) young and ripe fruit extracts against lung cancer cells. Cancer ranking as the second leading cause of global mortality, it is essential to investigate natural compounds like phytochemicals for therapeutic benefits. The research investigates presence of phytochemicals and antioxidant activity of both young (MAF-Y) and ripe (MAF-R) mulberry fruit extracts. Results revealed presence of various secondary metabolites, particularly high phenolic content and antioxidant properties in MAF-R. Both extracts demonstrated significant cytotoxicity against lung adenocarcinoma cells (A549), with IC50 18.4 ± 3.01µg/ml (MAF-R) and 29.41 ±3.6 µg/ml (MAF-Y). Moreover, the extracts effectively inhibited cell migration. Treatment of extracts elevated reactive oxygen species (ROS) production which resulted in disruption of mitochondrial membrane potential, and induced the process of apoptosis in lung carcinoma cells. This was evidenced through various assays including differential staining and DNA fragmentation analysis. These findings underscore the potential of mulberry fruit extracts as promising candidates for cancer prevention and treatment due to their antioxidant properties, cytotoxic effects, and ability to induce apoptosis in lung cancer cells.