Circular economyeast: Saccharomyces cerevisiae as a sustainable source of glucans and its safety for skincare application.

Glucans, a polysaccharide naturally present in the yeast cell wall that can be obtained from side streams generated during the fermentation process, have gained increasing attention for their potential as a skin ingredient. Therefore, this study focused on the extraction method to isolate and purify water-insoluble glucans from two different Saccharomyces cerevisiae strains: an engineered strain obtained from spent yeast in an industrial fermentation process and a wild strain produced through lab-scale fermentation. Two water-insoluble extracts with a high glucose content (> 90 %) were achieved and further subjected to a chemical modification using carboxymethylation to improve their water solubility. All the glucans' extracts, water-insoluble and carboxymethylated, were structurally and chemically characterized, showing almost no differences between both yeast-type strains. To ensure their safety for skin application, a broad safety assessment was undertaken, and no cytotoxic effect, immunomodulatory capacity (IL-6 and IL-8 regulation), genotoxicity, skin sensitization, and impact on the skin microbiota were observed. These findings highlight the potential of glucans derived from spent yeast as a sustainable and safe ingredient for cosmetic and skincare formulations, contributing to the sustainability and circular economy.

ß-Glucan extracts as high-value multifunctional ingredients for skin health: A review.

ß-Glucans, which are naturally present in cereals, yeast, and mushrooms, have gained attention as a potential natural source for functional foods and pharmaceuticals. Due to the availability of ß-glucans from several sources, different extraction methods can be employed to obtain high purity extracts that can be further modified to enhance their solubility or other biological properties. Apart from their known ability to interact with the immune system, ß-glucans possess specific properties that could benefit overall skin health and prevent age-related signs, including soothing and antioxidant activities. As a result, the use of ß-glucans to mitigate damage caused by environmental stressors or skin-related issues that accelerate skin aging or trigger chronic inflammation may represent a promising, natural, eco-friendly, and cost-effective approach to maintaining skin homeostasis balance. This review outlines ß-glucan extraction methodologies, molecular structure, functionalization approaches, and explores skin-related benefits of ß-glucans, along with an overview of related products in the market.

Preoperative assessment for vascular access: Vascular mapping and handgrip strength.

BACKGROUND: Reliable vascular access (VA) is required for patients receiving chronic hemodialysis (HD) treatment. Vascular mapping using duplex doppler ultrasonography (DUS) can aid in planning VA construction. Greater handgrip strength (HGS) was found to be associated with more developed distal vessels both in chronic kidney disease (CKD) patients and healthy individuals, and patients with lower HGS had worse morphologic vessel characteristics and were, therefore, less likely to construct distal VA. OBJECTIVES: This study aims to describe and analyze clinical, anthropometric, and laboratory characteristics of patients who underwent vascular mapping prior to VA creation. RESEARCH DESIGN: Prospective analysis. SUBJECTS: Adult patients with CKD referred for vascular mapping, at a tertiary center, between March 2021 and August 2021. MEASURES: Preoperative DUS by a single experienced nephrologist was carried out. HGS was measured using a hand dynamometer, and PAD was defined as ABI < 0.9. Sub-groups were analyzed according to distal vasculature size (<2 mm). RESULTS: A total of 80 patients were included, with a mean age of 65.7 ± 14.7 years; 67.5% were male, and 51.3% were on renal replacement therapy (RRT). Twelve (15%) participants had PAD. HGS was higher in the dominant arm (20.5 ± 12.0 vs 18.8 ± 11.2 kg). Fifty-eight (72.5%) patients had vessels smaller than 2 mm in diameter. There were no significant differences between groups concerning demographics or comorbidities (diabetes, HTN, PAD). HGS was significantly higher in patients with distal vasculature greater than or equal to 2 mm in diameter (dominant arm: 26.1 ± 15.5 vs 18.4 ± 9.7 kg, p = 0.010; non-dominant arm: 24.1 ± 15.3 vs 16.8 ± 8.6, p = 0.008). CONCLUSIONS: Higher HGS was associated with more developed distal cephalic vein and radial artery. Low HGS might be an indirect sign of suboptimal vascular characteristics, which might help predict the outcomes of VA creation and maturation.

Biogenic silica microparticles as a new and sustainable cosmetic ingredient: Assessment of performance and quality parameters.

The demand for sustainable products is increasing worldwide and cosmetic industry is not an exception. Besides exploring nature as source of new ingredients, their production must be sustainable and should use environmentally friendly processes. In this work, biogenic silica microparticles were synthesized from sugarcane ash, and their potential application as cosmetic and skincare ingredient was evaluated. For such application, several properties were validated, including cytotoxicity in skin keratinocytes, potential sensitization effect on skin peptides, stimulation of pro-collagen I alpha 1, wound healing capacity, as well as the ingredient stability along a storage period. Biogenic silica showed to be non-cytotoxic on skin keratinocytes, at concentrations up to 5 wt%, and non-skin sensitizer. A positive effect on the stimulation of pro-collagen I alpha 1 suggests a potential anti-ageing activity, while the migration of fibroblasts to a wounded area suggests a regenerative capacity. Under an accelerated stability study, biogenic silica showed an increase on the loss on drying, but no changes were observed on its functional properties, mainly oil absorption capacity, as well the microbiological quality, which was maintained. Overall, novel biogenic silica microparticles produced from a sustainable source are safe, stable over time and have potential to be used as a cosmetic and skincare ingredient.

Postoperative myocardial fibrosis assessment in aortic valvular heart diseases-a cardiovascular magnetic resonance study.

AIMS: Left ventricular remodelling occurs during the chronic course of aortic regurgitation (AR) and aortic stenosis (AS), leading to myocardial hypertrophy and fibrosis. Several studies have shown that extracellular volume fraction (ECV) and indexed extracellular volume (iECV) are important surrogate markers of diffuse myocardial fibrosis (MF). Postoperative data on these cardiovascular magnetic resonance (CMR) extracellular expansion parameters for either AS or AR are scarce. This study aimed to demonstrate the postoperative changes that occur in diffuse MF, and the influence of preoperative MF on the reversal of LV remodelling, in patients with AR or AS. METHODS AND RESULTS: Patients with severe AR or AS and indications for surgery were prospectively enrolled. Patients underwent pre- and postoperative CMR, and ECV and iECV were quantified. Data from 99 patients were analysed (32 with AR and 67 with AS). After surgery, the left ventricle mass index decreased in both groups (AR: 110 vs. 91 g/m2; AS: 86 vs. 68 g/m2, both P < 0.001). The late gadolinium enhancement fraction (AR: preoperative 1.9% vs. postoperative 1.7%, P = 0.575; AS: preoperative 2.4% vs. postoperative 2.4%, P = 0.615) and late gadolinium enhancement mass (AR: preoperative 3.8 g vs. postoperative 2.5 g, P = 0.635; AS: preoperative 3.4 g vs. postoperative 3.5 g, P = 0.575) remained stable in both groups. Preoperative iECV and ECV were greater in the AR group (iECV: 30 mL/m2 vs. 22 mL/m2, P = 0.001; ECV: 28.4% vs. 27.2%, P = 0.048). Indexed extracellular volume decreased after surgery in both groups (AR: 30-26.5 mL/m2, AS: 22-18.2 mL/m2, both P < 0.001); it was still greater in the AR group (AR: 26.5 mL/m2 vs. AS: 18.2 mL/m2, P < 0.001). Postoperative ECV remained stable in the AR group (preoperative 28.4% vs. postoperative 29.9%; P = 0.617) and increased in the AS group (preoperative 27.2% vs. postoperative 28.6%; P = 0.033). CONCLUSION: Patients with both AR or AS presented reduction in iECV after surgery, unfolding the reversible nature of diffuse MF. In contrast to patients with AS, those with AR developed postoperative iECV regression with stable ECV, suggesting a balanced reduction in both intracellular and extracellular myocardial components.

Non-invasive cardiovascular magnetic resonance assessment of pressure recovery distance after aortic valve stenosis.

BACKGROUND: Decisions in the management of aortic stenosis are based on the peak pressure drop, captured by Doppler echocardiography, whereas gold standard catheterization measurements assess the net pressure drop but are limited by associated risks. The relationship between these two measurements, peak and net pressure drop, is dictated by the pressure recovery along the ascending aorta which is mainly caused by turbulence energy dissipation. Currently, pressure recovery is considered to occur within the first 40-50 mm distally from the aortic valve, albeit there is inconsistency across interventionist centers on where/how to position the catheter to capture the net pressure drop. METHODS: We developed a non-invasive method to assess the pressure recovery distance based on blood flow momentum via 4D Flow cardiovascular magnetic resonance (CMR). Multi-center acquisitions included physical flow phantoms with different stenotic valve configurations to validate this method, first against reference measurements and then against turbulent energy dissipation (respectively n = 8 and n = 28 acquisitions) and to investigate the relationship between peak and net pressure drops. Finally, we explored the potential errors of cardiac catheterisation pressure recordings as a result of neglecting the pressure recovery distance in a clinical bicuspid aortic valve (BAV) cohort of n = 32 patients. RESULTS: In-vitro assessment of pressure recovery distance based on flow momentum achieved an average error of 1.8 ± 8.4 mm when compared to reference pressure sensors in the first phantom workbench. The momentum pressure recovery distance and the turbulent energy dissipation distance showed no statistical difference (mean difference of 2.8 ± 5.4 mm, R2 = 0.93) in the second phantom workbench. A linear correlation was observed between peak and net pressure drops, however, with strong dependences on the valvular morphology. Finally, in the BAV cohort the pressure recovery distance was 78.8 ± 34.3 mm from vena contracta, which is significantly longer than currently accepted in clinical practise (40-50 mm), and 37.5% of patients displayed a pressure recovery distance beyond the end of the ascending aorta. CONCLUSION: The non-invasive assessment of the distance to pressure recovery is possible by tracking momentum via 4D Flow CMR. Recovery is not always complete at the ascending aorta, and catheterised recordings will overestimate the net pressure drop in those situations. There is a need to re-evaluate the methods that characterise the haemodynamic burden caused by aortic stenosis as currently clinically accepted pressure recovery distance is an underestimation.

Microgap and bacterial microleakage during the osseointegration period: An in vitro assessment of the cover screw and healing abutment in a platform-switched implant system.

STATEMENT OF PROBLEM: Microgap and bacterial microleakage at the implant-prosthetic abutment interface are recognized concerns for implant-supported restorations, leading to inflammation of the peri-implant tissues, with deleterious consequences for crestal bone levels. However, little is known regarding the interface established between the implant and the healing abutment or cover screw placed for the osseointegration phase. PURPOSE: The purpose of this in vitro study was to characterize the implant-cover screw and implant-healing abutment interfaces of a platform-switched implant system to determine the microgap and bacterial microleakage of the system and evaluate the biological response and functionality of an interface sealing agent. MATERIAL AND METHODS: The interfacial microgaps of the implant-healing abutment and implant-cover screw interfaces were characterized by scanning electron microscopy (n=10), and bacterial microleakage was evaluated after colonization with Enterococcus faecalis in a 30-day follow-up (n=10). The sealing efficacy and irritation potential of a silicone-based sealer were determined by using the hen's egg test on chorioallantoic membrane assay. The 2-sample t test was performed to compare means between groups, and data presented with the Kaplan-Meier method were compared statistically by using the log-rank test (α=.05). RESULTS: The interfacial microgap was less than 2.5 µm for both systems. Bacterial microleakage was noted in approximately 50% of the specimens, particularly at early time points, at both the healing abutment and cover screw interfaces. The silicone-based sealer prevented bacterial leakage in the experimental setting. CONCLUSIONS: The implant-healing abutment and implant-cover screw interfaces of the tested system, despite the low microgap, allowed for bacterial microleakage after internal colonization. The use of a nonirritating silicone-based sealing agent effectively sealed the system.

Orofacial myofunctional assessment and quality of life of individuals with Parkinson's disease.

OBJECTIVES: To characterize orofacial myofunctional structures of elders with Parkinson's disease (PD) and examine the relationship with the stages of PD, pharmacotherapy, and quality of life. METHODS: PD Group with 45 elders and a control group (CG) of 10 healthy elders of both sexes were included (60-86 years). Structured interviews, medical records, and clinical examination gathered information on health aspects such as the use of drugs, Hoehn & Yahr stages 1-4, and oral health status. The Mini-Mental State Examination, Parkinson's Disease Questionnaire, and Orofacial Myofunctional Evaluation with Scores for Elders were applied. RESULTS: Better oral health status was found in participants diagnosed as Hoehn & Yahr stage 1 compared to the later stages. OMES-Elders scores for appearance/posture, mobility, breathing, and speech functions were different between groups, and decreased overall OMES-Elders was observed across the Hoehn & Yahr stages. A higher number of masticatory cycles was required for chewing and ingestion of the test food in the PD group compared to CG (p < .05). Significant differences were found in the mobility and daily living activities domains and an overall score of QoL between the Hoehn & Yahr stages 1 and 4, and worst orofacial functioning was accompanied by the worst self-perception of QoL in the communication domain (rho = -0.32; p = .034). The use of xerogenic drugs did not affect the OMES-Elders swallowing domain. CONCLUSION: Worse dental condition and performance of orofacial functions was observed in the elders with PD as the disease progresses, and poorer orofacial performance negatively affects their perception of communication skills.

Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors.

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Neurotoxicity Assessment of 1-[(2,3-Dihydro-1-Benzofuran-2-yl)Methyl]Piperazine (LINS01 Series) Derivatives and their Protective Effect on Cocaine-Induced Neurotoxicity Model in SH-SY5Y Cell Culture.

Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly D1R, D2R, and D3R subtypes, contributing to neurotoxic effects. New synthetic 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine derivatives (the LINS01 compounds), designed as histaminergic receptor (H3R) ligands, are also dopaminergic receptor ligands, mainly D2R and D3R. This study aims to evaluate the neurotoxicity of these new synthetic LINS01 compounds (LINS01003, LINS01004, LINS01011, and LINS01018), as well as to investigate their protective potential on a cocaine model of dopamine-induced neurotoxicity using SH-SY5Y cell line culture. Neurotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and automated cell counting with fluorescent dyes (acridyl orange and propidium iodide) assays. Concentration-response curves (CRCs) were performed for all LINS compounds and cocaine using MTT assay. The results show that LINS series did not decrease cell viability after 48h of exposure-except for 100 µM LINS01018, which was discontinued from the study. Likewise, MTT, LDH, and fluorescent dyes staining showed no difference is cell viability for LINS compounds at 10 µM. When incubated with 2.5 mM cocaine (lethal concentration 50) for 48h, 10 µM of each LINS compound, metoclopramide (D2R antagonist) and haloperidol (D2R/D3R antagonist), ameliorated cocaine-induced neurotoxicity. However, only metoclopramide, haloperidol, and LINS01011 compound significantly decreased LDH released in the culture medium, suggesting that this new synthetic compound presents a more robust effect. This preliminary in vitro neurotoxicity study suggests that LINS01 compounds are not neurotoxic, and that they play a promising role in preventing cocaine-induced neurotoxicity.

The Economic Burden of Non-Alcoholic Steatohepatitis: A Systematic Review.

BACKGROUND: The global prevalence of non-alcoholic steatohepatitis (NASH) is increasing, such that NASH is predicted to become the leading cause of liver transplantation (LT) in the US by 2025. Despite this, data on the economic burden of NASH are limited. OBJECTIVES: This systematic literature review aimed to summarise and critically evaluate studies reporting on the economic burden of NASH and identify evidence gaps for subsequent research. METHODS: Medline, EMBASE, the Cochrane Library and EconLit were searched up to 6 January 2021 for English language articles published from January 2010 to January 2021 inclusive that reported economic outcomes of a NASH population or subpopulation. Evidence was presented and synthesised using narrative data analysis, and quality was assessed by two reviewers using an 11-item checklist developed for economic evaluations and adapted to cost of illness. RESULTS: Fourteen studies were included, of which five presented data on costs and resource use, four on costs only and five on resource use only. Overall, NASH is associated with a significant and increasing economic burden in terms of healthcare resource utilisation (HCRU) and direct and indirect costs. This burden was higher among NASH patients with advanced (fibrosis stage 3-4) versus early (fibrosis stage 0-2) disease, symptomatic versus asymptomatic disease and for patients with complications or comorbidities versus those without. In LT patients, those with NASH as the primary indication had greater HCRU and higher costs compared with non-NASH indications such as hepatitis B and C viruses. Considerable variability in HCRU and costs was seen across the US and Europe, with the highest costs seen in the US. The quality of the included studies was variable, and the studies themselves were heterogeneous in terms of study methodology, patient populations, comorbidities, follow-up time and outcomes measured. CONCLUSIONS: This review highlights a general scarcity of NASH-specific economic outcomes data. Despite this, the identified studies show that NASH is associated with a significant economic burden in terms of increased HCRU, and high direct medical and non-medical costs and societal burden that increases with disease severity or when patients have complications or comorbidity. More national-level NASH prevalence data are needed to generate accurate forecasts of HCRU and costs in the coming decades. FUNDING: Novo Nordisk A/S, Søborg, Denmark.

It is important to know the cost of treating different diseases because this helps to guide how healthcare resources and funds are used. Non-alcoholic steatohepatitis (NASH) is a serious liver disease that can lead to liver scarring (cirrhosis), liver transplantation and early death, and the number of people with NASH is growing around the world. Fourteen studies published over the past 10 years have investigated the costs of treating patients with NASH. Patients with NASH generally use more healthcare services with a higher cost than the general population or patients with type 2 diabetes. In people with more serious liver disease, such as liver transplant patients, NASH tends to be more expensive and use more healthcare services than other serious liver diseases such as hepatitis. Costs and use of health services are particularly high in patients with more severe NASH, or those who have other diseases or complications in addition to NASH (such as type 2 diabetes or kidney failure).

Unlocking the Non-invasive Assessment of Conduit and Reservoir Function in the Aorta : The Obstructive Descending Aorta in HLHS.

Aortic surgeries in congenital conditions, such as hypoplastic left heart syndrome (HLHS), aim to restore and maintain the conduit and reservoir functions of the aorta. We proposed a method to assess these two functions based on 4D flow MRI, and we applied it to study the aorta in pre-Fontan HLHS. Ten pre-Fontan HLHS patients and six age-matched controls were studied to derive the advective pressure difference and viscous dissipation for conduit function, and pulse wave velocity and elastic modulus for reservoir function. The reconstructed neo-aorta in HLHS subjects achieved a good conduit function at a cost of an impaired reservoir function (69.7% increase of elastic modulus). The native descending HLHS aorta displayed enhanced reservoir (elastic modulus being 18.4% smaller) but impaired conduit function (three-fold increase in peak advection). A non-invasive and comprehensive assessment of aortic conduit and reservoir functions is feasible and has potentially clinical relevance in congenital vascular conditions.

Adherence to and persistence with antidiabetic medications and associations with clinical and economic outcomes in people with type 2 diabetes mellitus: A systematic literature review.

We designed a systematic literature review to identify available evidence on adherence to and persistence with antidiabetic medication in people with type 2 diabetes (T2D). Electronic screening and congress searches identified real-world noninterventional studies (published between 2010 and October 2020) reporting estimates of adherence to and persistence with antidiabetic medication in adults with T2D, and associations with glycaemic control, microvascular and/or macrovascular complications, hospitalizations and healthcare costs. Ninety-two relevant studies were identified, the majority of which were retrospective and reported US data. The proportions of patients considered adherent (median [range] 51.2% [9.4%-84.3%]) or persistent (median [range] 47.7% [16.9%-94.0%]) varied widely across studies. Multiple studies reported an association between greater adherence/persistence and greater reductions in glycated haemoglobin levels. Better adherence/persistence was associated with fewer microvascular and/or macrovascular outcomes, although there was little consistency across studies in terms of which outcomes were improved. More adherent and more persistent patients were typically less likely to be hospitalized or to have emergency department visits/admissions and spent fewer days in hospital annually than less adherent/persistent patients. Greater adherence and persistence were generally associated with lower hospitalization costs, higher pharmacy costs and lower or budget-neutral total healthcare costs compared with lower adherence/persistence. In conclusion, better adherence and persistence in people with T2D is associated with lower rates of microvascular and/or macrovascular outcomes and inpatient hospitalization, and lower or budget-neutral total healthcare expenditure. Education and treatment strategies to address suboptimal adherence and persistence are needed to improve clinical and economic outcomes.

Looking Ahead: Health Impact Assessment of Front-Of-Pack Nutrition Labelling Schema as a Public Health Measure.

This study aimed to describe the underlying process, used methods and major recommendations emerging from a comprehensive and prospective health impact assessment of the endorsement of a front-of-pack nutrition labelling (FOP-NL) system by the Portuguese health authorities. A mixed-methods approach was used to gather information on the impact of four FOP-NL schemes on consumers' selection of food products according to the perception of their nutritional quality, combining a systematic literature review, focus groups (FG), in-depth individual interviews, and an open-label crossover randomized controlled study. The relevance of FOP-NL as a public health promotion policy has emerged as a consensual idea among either FGs' participants (i.e., consumers and experts), or interviewed stakeholders. Although all of the evaluated FOP-NLs result better than no system on promoting the choice of the healthiest product, the effectiveness of easy-to-interpret FOP-NL among vulnerable groups raised concerns related to the need of integrating specific nutritional information to promote a better self-management of chronic diseases, and related to the level of literacy of consumers, which could impair the usage of FOP-NL. Educational campaigns addressing skills to use FOP-NL is recommended. Furthermore, a monitoring strategy should be considered to evaluate the long-term effectiveness of this policy in promoting healthier food choices, and in reducing diet-related non-communicable diseases burden.

Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses.

EtOH extracts from the leaves and twigs of Nectandra oppositifolia Nees & Mart. shown activity against amastigote forms of Trypanosoma cruzi. These extracts were subjected to successive liquid-liquid partitioning to afford bioactive CH2Cl2 fractions. UHPLC-TOF-HRMS/MS and molecular networking were used to obtain an overview of the phytochemical composition of these active fractions. Aiming to isolate the active compounds, both CH2Cl2 fractions were subjected to fractionation using medium pressure chromatography combined with semi-preparative HPLC-UV. Using this approach, twelve compounds (1-12) were isolated and identified by NMR and HRMS analysis. Several isolated compounds displayed activity against the amastigote forms of T. cruzi, especially ethyl protocatechuate (7) with EC50 value of 18.1 µM, similar to positive control benznidazole (18.7 µM). Considering the potential of compound 7, protocatechuic acid and its respective methyl (7a), n-propyl (7b), n-butyl (7c), n-pentyl (7d), and n-hexyl (7e) esters were tested. Regarding antitrypanosomal activity, protocatechuic acid and compound 7a were inactive, while 7b-7e exhibited EC50 values from 20.4 to 11.7 µM, without cytotoxicity to mammalian cells. These results suggest that lipophilicity and molecular complexity play an important role in the activity while efficiency analysis indicates that the natural compound 7 is a promising prototype for further modifications to obtain compounds effective against the intracellular forms of T. cruzi.

Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives.

BACKGROUND: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. In addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite. In a previous study, the compounds were evaluated and showed moderate antimycobacterial activity and no important cytotoxic profile; however, information about their pharmacokinetic profile is lacking. OBJECTIVE: The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters. METHOD: The compounds were analyzed for their chemical stability, n-octanol:water partition coefficient (logP) and apparent permeability (Papp) in monolayer of Caco-2 cells. The stability of the compounds in rat and human microsomes and in rat plasma was also evaluated. RESULTS: The compounds I, II and IV were found to be hydrophilic, while compound III was the most lipophilic (logP 1.59) compound. All compounds showed stability at the three evaluated pHs (1.2, 7.4 and 8.8). The apparent permeability measured suggests good intestinal absorption of the compounds. Additionally, the compounds showed metabolic stability under action of human and rat microsomal enzymes and stability in rat plasma for at least 6 hours. CONCLUSION: The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives.

Real-world cost-effectiveness of insulin degludec in type 1 and type 2 diabetes mellitus from a Swedish 1-year and long-term perspective.

BACKGROUND AND AIMS: The ReFLeCT study demonstrated that switching to insulin degludec from other basal insulins was associated with reductions in glycated hemoglobin and hypoglycemic events in type 1 (T1D) and type 2 diabetes (T2D), and reductions in insulin doses in T1D. The aim of the present analysis was to assess the short- and long-term cost-effectiveness of switching to insulin degludec in Sweden. METHODS: Short-term outcomes were evaluated over 1 year in a Microsoft Excel model, while long-term outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Cohort characteristics and treatment effects were sourced from the ReFLeCT study. Costs (in 2018 Swedish krona [SEK]) encompassed direct medical expenditure and indirect costs from loss of workplace productivity. In the long-term analyses, patients were assumed to receive insulin degludec or continue prior insulin therapy (primarily insulin glargine U100) for 5 years, before all patients intensified to once-daily degludec and mealtime aspart. RESULTS: Switching to insulin degludec was associated with improved quality-adjusted life expectancy of 0.04 and 0.02 quality-adjusted life years (QALYs) over 1 year, and 0.16 and 0.08 QALYs over patient lifetimes, in T1D and T2D. Combined costs in T1D and T2D were estimated to be SEK 1,249 lower and SEK 1,181 higher over the short-term, and SEK 157,258 and SEK 2,114 lower over the long-term. Benefits were due to lower insulin doses in T1D, reduced rates of hypoglycemia, and lower incidences of diabetes-related complications. Insulin degludec was associated with an incremental cost-effectiveness ratio of SEK 64,298 per QALY gained for T2D over 1 year and considered dominant for T1D and T2D in all other comparisons. CONCLUSIONS: Insulin degludec was projected to be cost-effective or dominant versus other basal insulins for the treatment of T1D and T2D in Sweden.

Biochemical and genotoxic biomarkers and cell cycle assessment in the zebrafish liver (ZF-L) cell line exposed to the novel metal-insecticide magnesium-hespiridin complex.

The flavonoid metal-insecticide magnesium-hesperidin complex (MgHP) has recently been considered as a novel insecticide to replace some persistent pesticides. However, it is important to evaluate its action on non-target species, mainly those living in an aquatic environment, as these ecosystems are the final receptors of most chemicals. Reactive oxygen species, antioxidant and oxidative stress biomarkers, genotoxicity as well as cell cycle was evaluated in the liver cell line from zebrafish (Danio rerio; ZF-L) exposed to 0, 0.1, 1, 10, 100 and 1000 ng mL-1 MgHP. MgHP affected cell stability by increasing reactive oxygen species (ROS) in both exposure times (24 and 96 h) at high concentrations. Catalase (CAT) activity decreased after 24 h exposure, and glutathione and metallothionein values increased, avoiding the lipid peroxidation. Genotoxicity increased as MgHP concentration increased, after 24 h exposure, exhibiting nuclear abnormalities; it was recovered after 96 h exposure, evidencing possible stimulation of DNA repair mechanisms. The alteration in the cell cycle (increasing in the Sub-G1 phase and decreasing in the S-phase) was associated with chromosomal instability. In conclusion, the responses of ROS and the antioxidant defense system depended on MgHP concentration and time exposure, while DNA exhibited some instability after 24 h exposure, which was recovered after 96 h.

A survey of physician experience and treatment satisfaction using fast-acting insulin aspart in people with type 1 or type 2 diabetes.

AIMS: This survey aimed to explore real-world physician experiences and treatment satisfaction with fast-acting insulin aspart (faster aspart) in clinical practice across Europe and Canada. MATERIALS AND METHODS: An online web-based survey was used for physicians treating people with type 1 or type 2 diabetes. General practitioners and specialists, with experience using faster aspart, were interviewed. RESULTS: A total of 191 physicians participated in the survey. Most of their patients (68% of those with T1D and 63% of those with T2D) were previously treated with another mealtime insulin before switching to faster aspart. At the time of initiating faster aspart, nearly half of patients had an HbA1c level between 7.5% (59 mmol/mol) and 8.5% (69 mmol/mol). The main prescription drivers for faster aspart, versus other mealtime insulins, were faster onset of action, improved postprandial glucose (PPG) control, and dosing flexibility. Most physicians were more satisfied with faster aspart than other mealtime insulins regarding at-meal (66%) and post-meal (71%) dosing flexibility, improved PPG levels (66%), and onset of action (61%). Main reasons for not prescribing faster aspart included a good response to current treatment (76%) or patient reluctance to switch (57%). Overall, 12% of patients discontinued faster aspart, for reasons including concerns of hypoglycemia (17%), poor adherence (17%), and level of patient co-pay (17%). More than half of physicians had fewer concerns regarding postprandial hyperglycemia, and were more confident in their patients reaching their HbA1c target with faster aspart than with other mealtime insulins. LIMITATIONS: The findings of this survey are based heavily on physicians' experiences, and could therefore be subject to recall bias. CONCLUSIONS: Reported physician and patient experiences of using faster aspart have been positive, and better PPG control and increased dosing flexibility are expected to improve glycemic management.