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Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 ( Pf NF54 IC 50 = 0.012 μM; Pf K1 IC 50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CL int < 11.6 μL·min -1 ·mg -1 ) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei -infected mice at 4 × 50 mg·kg -1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.

The need for new immunomodulatory drugs is due to the side effects associated with the prolonged use of the currently used immunomodulatory drugs. In this context, the present work aimed to investigate the immunomodulatory effect of an ethanolic concentrated extract from Physalis angulata. The cytotoxicity of samples was determined using peritoneal macrophages though the Alamar Blue assay. The immunomodulatory activity of the ethanolic extract from P. angulata on activated macrophages was determined by measurement of nitrite and cytokine production. The immunosuppressive effects of the ethanolic extract from P. angulata was evaluated on lymphocyte proliferation and cytokine production. The effects of the extract on cell cycle progression and cell death on lymphocytes were evaluated by flow cytometry. Lastly, the ethanolic extract from P. angulata was tested in vivo in toxicological tests and in models of peritonitis and delayed-type hypersensitivity response. The ethanolic extract from P. angulata decreased nitrite, interleukin-6, interleukin-12, and TNF- α production by activated macrophages without affecting the cell viability. In addition, the ethanolic extract from P. angulata inhibited lymphoproliferation and the secretion of interleukin-2, interleukin-6, and IFN- γ , and increased interleukin-4 secretion by activated splenocytes. Flow cytometry analysis in lymphocyte cultures showed that treatment with the ethanolic extract from P. angulata induces cell cycle arrest in the G1 phase followed by cell death by apoptosis. Moreover, mice treated with the extract from P. angulata at 100 or 200 mg/kg did not show signs of toxicity or alterations in serum components. Finally, the ethanolic extract from P. angulata significantly reduced neutrophil migration and reduced paw edema in bovine serum albumin-induced the delayed-type hypersensitivity response model. Our results demonstrate the potential of the ethanolic extract of P. angulata as an alternative for the treatment of immune-inflammatory diseases., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer's, Parkinson's, and Huntington's diseases, has also been addressed.

Objective: Venous thromboembolism (VTE) is particularly prevalent in neurosurgical patients. A major dilemma arises when a patient needs to be treated with therapeutic anticoagulation during the early days after brain surgery due to the concern of intracranial hemorrhage (ICH). There is still a lack of studies regarding the optimal time to start therapeutic anticoagulation and risk assessment of ICH in this setting. This study aims to assess the risk of ICH for patients with venous thromboembolism treated with therapeutic anticoagulation started within the first 30 days after intracranial neurosurgical procedure., Patients and Methods: This study was an analytical observational research based on a retrospective record review of VTE patients submitted to therapeutic anticoagulation started within the first 30 days after intracranial neurosurgical procedure at Paulo Niemeyer State Brain Institute, from September 2013 to February 2020. Patients' clinical and surgical data, anticoagulation drug therapy, time interval between surgery and start of therapeutic anticoagulation, bleeding complications and hemorrhage-related deaths were some of variables evaluated. A p value < 0.05 was considered statistically significant., Results: A series of 53 consecutive patients and 54 intracranial neurosurgical procedures met the criteria. Twenty-nine (53.7 %) patients were treated with warfarin, 21 (38.9 %) with new oral anticoagulant (NOAC) and 4 (7.4 %) only with enoxaparin. VTE diagnosis between the postoperative days 0 and 4 was statistically associated with a delay in starting therapeutic anticoagulation of more than two days (p < 0.001). The frequency of bleeding complication was statistically significant higher in patients treated with warfarin (p = 0.03). Although with no statistical significance, there were a higher rate of ICH in patients receiving warfarin (13.8 % vs. 0% in NOAC group, p = 0.13). There was no statistical difference about ICH incidence between the postoperative intervals from 2nd to 7th, 8th to 14th, 15th to 21 st and 22th to 29th days (p = 0.35). Hemorrhage-related mortality rate was 3.7 %., Conclusion: ICH was not statistically associated with the timing of therapeutic anticoagulation after brain surgery between the 2nd and 29th postoperative days, which may encourage the strategy of early treatment considering the life-threatening potential of VTE. However, the risk of ICH should not be ignored in the setting of warfarin use, which had a remarkable incidence of 13.8 %. Warfarin must be used cautiously, especially in high-grade gliomas., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This was a comparative cross-sectional study among public prenatal care users in conventional outpatient health services and family health services, aimed at assessing perception and quality differences between the two models of health services organization according to Ministry of Health guidelines. A total of 203 pregnant women from 22 municipalities in five regions of the country were interviewed while waiting for prenatal consultation. Besides soliciting the women's opinions, we checked for possible advantages in innovative family care services in issues like access and commitment. Data revealed approval by users for key aspects related to care and consultation in both types of public facilities and suggest consistent primary care policies. Low coverage in dentistry (18.9%), gynecological preventive tests (39.6%), and HIV tests (52.6%) indicates policy obstacles. Comparatively, family health services received significantly greater approval by women on issues like quality of the last visit (p = 0.0432), maternity hospital access (p = 0.0106), vaccination schedules (p = 0.0023), drug delivery (p = 0.0053), blood glucose tests (p = 0.0309), nursing visit (p = 0.0469), and home visits (p < 0.0001).