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The potential of antioxidants as tools for lowering the incidence of diseases, including cardiovascular events, is of growing interest. Some antioxidants (e.g. vitamin E and acetyl-salicylic acid) have been described as effective on cardiovascular diseases with mechanisms that differ from other scavenging agents. Currently, vitamin C is used to open occluded long-term central venous catheters, which avoids the process of reinserting a new one and injuring the patient. In this work, we investigated the vitamin C antihemostatic profile by evaluating its effects on the coagulation process. We used different assays, including prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT) and ancrod time tests. We also examined the overall pH disturbance caused by vitamin C at different concentrations and its effect on the thrombin-initiated fibrin polymerization assay. Our results revealed a significant anticoagulant activity of vitamin C at high plasma concentrations (surpassing the normal 100 μmol/L ratio) in a cell-independent mechanism. Our results suggest that vitamin C may affect blood coagulation by a direct impairment of fibrin assembly and further formation of a cohesive clot microstructure. This study supports the literature that points to the antihemostatic ability of antioxidant agents, and clarifies the mechanism of vitamin C in opening occluded long-term central venous catheters.

Aims: To develop paediatric physiologically based pharmacokinetic modelling (PBPK) models of semaglutide to estimate the pharmacokinetic profile for subcutaneous injections in children and adolescents with healthy and obese body weights. Methods: Pharmacokinetic modelling and simulations of semaglutide subcutaneous injections were performed using the Transdermal Compartmental Absorption & Transit model implemented in GastroPlus v.9.5 modules. A PBPK model of semaglutide was developed and verified in the adult population, by comparing the simulated plasma exposure with the observed data, and further scaled to the paediatric populations with normal and obese body weight. Results: The semaglutide PBPK model was successfully developed in adults and scaled to the paediatric population. Our paediatric PBPK simulations indicated a significant increase in maximum plasma concentrations for the 10–14 years' paediatric population with healthy body weights, which was higher than the observed values in adults at the reference dose. Since gastrointestinal adverse events are related to increased semaglutide concentrations, peak concentrations outside the target range may represent a safety risk for this paediatric age group. Besides, paediatric PBPK models indicated that body weight was inversely related to semaglutide maximum plasma concentration, corroborating the consensus on the influence of body weight on semaglutide PK in adults. Conclusion: Paediatric PBPK was successfully achieved using a top‐down approach and drug‐related parameters. The development of unprecedented PBPK models will support paediatric clinical therapy for applying aid‐safe dosing regimens for the paediatric population in diabetes treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Vancomycin is an antibiotic of growing importance in the treatment of hospital infections, with particular emphasis on its value in the fight against methicillin-resistant Staphylococcus aureus. However its usage profile must be evaluated to assure maximum benefit and minimum risk. Findings A cross-sectional retrospective study was carried out among inpatients that received vancomycin in a Brazilian quaternary hospital. The occurrence of adverse reactions reported was evaluated in medical records relating to patients taking vancomycin during a one year period. Males comprised 52% (95% CI: 41.7-60.2%) of the sample population, with a mean age of 50.6 (95% CI: 47.2-54.0) years and mean treatment period of 9.7 (95% CI: 8.0-11.5) Days. It was verified that nephrotoxicity occurred in 18.4% (95% CI: 11.3-27.5) of patients, Red man syndrome occurred in 2% (95% CI 0.2-7.2), while the occurrence of thrombocytopenia was 7.1% (95% CI: 2.9-14.2). Conclusions It may be noted that even after 50 years of use, adverse reactions associated with vancomycin continue with high frequency, presenting a public health problem, especially considering its current use in cases of multidrug resistant infections. In this context, we emphasize the importance of intensive pharmacovigilance in hospital as a surveillance tool after drug approval by the sanitary authority.

Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the inhibition of Herpes Virus type 1 are still not fully understood. Studies have shown that several viruses encode one or more proteases required for the production new infectious virions. This study presents an analysis of the interactions between HSV-1 protease and benzoxazinone derivatives through a combination of structure-activity relationships, comparative modeling and molecular docking studies. The structure activity relationship results showed an important contribution of hydrophobic and polarizable groups and limitations for bulky groups in specific positions. Two Herpes Virus type 1 protease models were constructed and compared to achieve the best model which was obtained by MODELLER. Molecular docking results pointed to an important interaction between the most potent benzoxazinone derivative and Ser129, consistent with previous mechanistic data. Moreover, we also observed hydrophobic interactions that may play an important role in the stabilization of inhibitors in the active site. Finally, we performed druglikeness and drugscore studies of the most potent derivatives and the drugs currently used against Herpes virus. [ABSTRACT FROM AUTHOR]

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO-EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a neglected disease responsible for about 56,000 deaths every year. Despite its importance, there are no effective, safe and proper treatments for leishmaniasis due to strain resistance and/or drug side-effects. In this work we report the synthesis, molecular modeling, cytotoxicity and the antileishmanial profile of a series of 4-(1H-pyrazol-1-yl)benzenesulfonamides. Our experimental data showed an active profile for some compounds against Leishmania infantum and Leishmania amazonensis. The profile of two compounds against L. infantum was similar to that of pentamidine, but with lower cytotoxicity. Molecular modeling evaluation indicated that changes in electronic regions, orientation as well as lipophilicity of the derivatives were areas to improve the interaction with the parasitic target. Overall the compounds represent feasible prototypes for designing new molecules against L. infantum and L. amazonensis [ABSTRACT FROM AUTHOR]

Bacterial infections involving multidrug-resistant strains are one of the ten leading causes of death and an important health problem in need for new antibacterial sources and agents. Herein, we tested and compared four snake venoms (Agkistrodon rhodostoma, Bothrops jararaca, B. atrox and Lachesis muta) against 10 Gram-positive and Gram-negative drug-resistant clinical bacteria strains to identify them as new sources of potential antibacterial molecules. Our data revealed that, as efficient as some antibiotics currently on the market (minimal inhibitory concentration (MIC) = 1-32 μg mL(-1)), A. rhodostoma and B. atrox venoms were active against Staphylococcus epidermidis and Enterococcus faecalis (MIC = 4.5 μg mL(-1)), while B. jararaca inhibited S. aureus growth (MIC = 13 μg ml(-1)). As genomic and proteomic technologies are improving and developing rapidly, our results suggested that A. rhodostoma, B. atrox and B. jararaca venoms and glands are feasible sources for searching antimicrobial prototypes for future design new antibiotics against drug-resistant clinical bacteria. They also point to an additional perspective to fully identify the pharmacological potential of these venoms by using different techniques.