Effects of Sodium Nitroprusside on Lipopolysaccharide-Induced Inflammation and Disruption of Blood-Brain Barrier.

In various neurodegenerative conditions, inflammation plays a significant role in disrupting the blood-brain barrier (BBB), contributing to disease progression. Nitric oxide (NO) emerges as a central regulator of vascular function, with a dual role in inflammation, acting as both a pro- and anti-inflammatory molecule. This study investigates the effects of the NO donor sodium nitroprusside (SNP) in protecting the BBB from lipopolysaccharide (LPS)-induced inflammation, using bEnd.3 endothelial cells as a model system. Additionally, Raw 264.7 macrophages were employed to assess the effects of LPS and SNP on their adhesion to a bEnd.3 cell monolayer. Our results show that LPS treatment induces oxidative stress, activates the JAK2/STAT3 pathway, and increases pro-inflammatory markers. SNP administration effectively mitigates ROS production and IL-6 expression, suggesting a potential anti-inflammatory role. However, SNP did not significantly alter the adhesion of Raw 264.7 cells to bEnd.3 cells induced by LPS, probably because it did not have any effect on ICAM-1 expression, although it reduced VCAM expression. Moreover, SNP did not prevent BBB disruption. This research provides new insights into the role of NO in BBB disruption induced by inflammation.

Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints.

Coronavirus disease (COVID-19) causes various vascular and blood-related reactions, including exacerbated responses. The role of endothelial cells in this acute response is remarkable and may remain important beyond the acute phase. As we move into a post-COVID-19 era (where most people have been or will be infected by the SARS-CoV-2 virus), it is crucial to define the vascular consequences of COVID-19, including the long-term effects on the cardiovascular system. Research is needed to determine whether chronic endothelial dysfunction following COVID-19 could lead to an increased risk of cardiovascular and thrombotic events. Endothelial dysfunction could also serve as a diagnostic and therapeutic target for post-COVID-19. This review covers these topics and examines the potential of emerging vessel-on-a-chip technology to address these needs. Vessel-on-a-chip would allow for the study of COVID-19 pathophysiology in endothelial cells, including the analysis of SARS-CoV-2 interactions with endothelial function, leukocyte recruitment, and platelet activation. "Personalization" could be implemented in the models through induced pluripotent stem cells, patient-specific characteristics, or genetic modified cells. Adaptation for massive testing under standardized protocols is now possible, so the chips could be incorporated for the personalized follow-up of the disease or its sequalae (long COVID) and for the research of new drugs against COVID-19.

The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats.

The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach. We found that empagliflozin increases the content of diglycerides and oxidized fatty acids (FA) in VAT, while in SAT, it decreases the levels of several lysophospholipids and increases 2 phosphatidylcholines. Empagliflozin also reduces the expression of the cytokines interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNFα), monocyte-chemotactic protein-1 (MCP-1) and IL-10, and of Cd86 and Cd163 M1 and M2 macrophage markers in VAT, with no changes in SAT, except for a decrease in IL-1ß. Empagliflozin treatment also shows an effect on lipolysis increasing the expression of hormone-sensitive lipase (HSL) in SAT and VAT and of adipose triglyceride lipase (ATGL) in VAT, together with a decrease in the adipose content of the FA transporter cluster of differentiation 36 (CD36). In conclusion, our data highlighted differences in the VAT and SAT lipidomes, inflammatory profiles and lipolytic function, which suggest a distinct metabolism of these two white adipose tissue depots after the empagliflozin treatment.

Development and Evaluation of Virola oleifera Formulation for Cutaneous Wound Healing.

In regions adjacent to the Brazilian Atlantic Forest, Virola oleifera (VO) resin extract has been popularly used for decades as a skin and mucosal healing agent. However, this antioxidant-rich resin has not yet been investigated in wound healing, whose physiological process might also be aggravated by oxidative stress-related diseases (e.g., hypertension/diabetes). Our aim, therefore, was to investigate whether VO resin presents healing effects through an innovative cream for topical applications. For this, adult male Wistar rats were divided into four groups. Then, four 15 mm excisions were performed on the shaved skin. All treatments were applied topically to the wound area daily. At the end of experiments (0, 3rd, and 10th days) macroscopic analysis of wound tissue contraction and histological analysis of inflammatory cell parameters were performed. The group treated with VO cream showed the best wound contraction (15%, p < 0.05) and reduced levels of lipid peroxidation and protein oxidation (118% and 110%, p < 0.05, respectively) compared to the control group. Our results demonstrated the healing capacity of a new formulation prepared with VO, which could be, at least in part, justified by antioxidant mechanisms that contribute to re-epithelialization, becoming a promising dermo-cosmetic for the treatment of wound healing.

Synthesis and Vasorelaxant Activity of Nitrate-Coumarin Derivatives.

Due to the need for new chemical entities for cardiovascular diseases, we have synthesized a new series of nitrate-coumarins and evaluated their vasorelaxant activity in contraction-relaxation studies using rat aorta rings precontracted with phenylephrine or by depolarization with a high concentration of potassium chloride. Four of the new compounds were able to relax smooth vascular muscle with a similar profile and potency to glyceryl trinitrate (IC50 =12.73 nM) and sodium nitroprusside (IC50 =4.32 nM). Coumarin-7-yl-methyl nitrate (4), the best compound within the series, was able to relax smooth vascular muscle in the low nanomolar range (IC50 =1.92 nM). The mechanisms of action have been explored, being the activation of sGC and the opening of K+ channels involved. Our studies indicate that the new nitrate derivatives are reversible and not deleterious for aortic rings, suggesting that these compounds have a potential interest for the development of new and highly efficient vasodilator drugs.

The Gut Microbiota-Brain Axis: A New Frontier on Neuropsychiatric Disorders.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder of integrative areas of the brain, characterized by cognitive decline and disability resulting in negative impacts on the family of the patients and the health care services worldwide. AD involves oxidative stress, neuroinflammation and accelerated apoptosis, accompanied by deposition of amyloid-ß peptide plaques and tau protein-based neurofibrillary tangles in the central nervous system. Among the multiple factors that contribute to the onset and evolution of this disease, aging stands out. That is why the prevalence of this disease has increased due to the constant increase in life expectancy. In the hope of finding new, more effective methods to slow the progression of this disease, over the last two decades, researchers have promoted "omics"-based approaches that include the gut microbiota and their reciprocal interactions with different targets in the body. This scientific advance has also led to a better understanding of brain compartments and the mechanisms that affect the integrity of the blood-brain barrier. This review aims to discuss recent advances related to the gut-brain-microbiota axis in AD. Furthermore, considering that AD involves psychiatric symptoms, this review also focuses on the psychiatric factors that interact with this axis (an issue that has not yet been sufficiently addressed in the literature).

A Review of Population Pharmacokinetic Analyses of Linezolid.

In recent years, many studies on population pharmacokinetics of linezolid have been conducted. This comprehensive review aimed to summarize population pharmacokinetic models of linezolid, by focusing on dosage optimization to maximize the probability of attaining a certain pharmacokinetic-pharmacodynamic parameter in special populations. We searched the PubMed and EMBASE databases for population pharmacokinetic analyses of linezolid using a parametric non-linear mixed-effect approach, including both observational and prospective trials. Of the 32 studies, 26 were performed in adults, four in children, and one in both adults and children. High between-subject variability was determined in the majority of the models, which was in line with the variability of linezolid concentrations previously detected in observational studies. Some studies found that patients with renal impairment, hepatic failure, advanced age, or low body weight had higher exposure and adverse reactions rates. In contrast, lower concentrations and therapeutic failure were associated with obese patients, young patients, and patients who had undergone renal replacement techniques. In critically ill patients, the inter-individual and intra-individual variability was even greater, suggesting that this population is at an even higher risk of underexposure and overexposure. Therapeutic drug monitoring may be warranted in a large proportion of patients given that the Monte Carlo simulations demonstrated that the one-size-fits-all labeled dosing of 600 mg every 12 h could lead to toxicity or therapeutic failure for high values of the minimum inhibitory concentration of the target pathogen. Further research on covariates, including renal function, hepatic function, and drug-drug interactions related to P-glycoprotein could help to explain variability and improve linezolid dosing regimens.

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile.

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.

Listado de medicamentos a evitar en atención primaria y su aplicación en pacientes polimedicados / List of medicines to avoid in Primary Care Health and their application in polymedicated patients

Introduction: The high prevalence of inappropriate medication use andits important health consequences for health require specific and agiletools to detect and avoid it.The objective of this work was to elaborate a list of medications toavoid in Primary Care and to apply it on the polymedicated patients ofa Primary Care assistance service.Methods: In the Database of the Spanish General Council of OfficialAssociations of Pharmacists (BOT-Plus) the status and availability ofeach of the 93 MAE of the Prescrire 2019 List was checked. The list ofmedications to be avoided in Primary Care was drawn up with thosethat were marketed in Spain and excluded those that were not financedand those for exclusive hospital use.With the list of medicines to avoid in Primary Care, a retrospectiveanalysis was made of all the prescription reports of polimedicated >10medications for 2017 in a Primary Care services (N=262) in 5 healthcenters. Frequency analysis, central tendency measures and dispersionwere carried out; they were estimated [CI: 95%] and X or Fisher’s exactwas used to determine the association between variables and logisticregression analysis.Results: A prevalence of polymedicated drugs of 1.2% was observed,with a mean age of 71.7 years (DT± 12.4) and a mean prescription of12 drugs (DT±1.7).The list of medications to be avoided in PC included 45 active ingredients. The 50.4% of the polymedicated had at least one drug to avoidand an average age of 68.5 years (DT±11.8). Sex was a risk factor forinappropriate prescription, the fact of being a woman increases withan OR=1.8 (IC95%=1, 3-3.0) the probability of having some medicinesto avoid. The most commonly used drugs to avoid were: duloxetine,sitagliptin and olmesartan. ...

Introduction: La alta prevalencia del uso de medicación inadecuada ysus importantes consecuencias para la salud requieren herramientasespecíficas y ágiles que ayuden a detectarla y evitarla.Objetivo de este trabajo fue elaborar un listado de medicamentos aevitar en AP y aplicarlo en pacientes polimedicados de un servicio asistencial de Atención Primaria (AP).Métodos: En la Base de datos del Consejo General de Colegios Oficialesde Farmacéuticos español (BOT-Plus) se comprobó el estado y disponibilidad de cada uno de los 93 medicamentos del Listado Prescrire2019. Se elaboró el Listado de medicamentos a evitar en AP con aquellos que estaban comercializados en España y se excluyeron los que noestaban financiados y los de uso exclusivo hospitalario.Con el listado de medicamentos a evitar en AP se hizo un análisis retrospectivo de todos (N=262) los informes de prescripción de polimedicados >10 medicamentos del año 2017 en un servicio asistencial deAP (5 centros de salud). Se realizó análisis de frecuencias, medidasde tendencia central y dispersión; se estimaron (IC 95%) y se utilizóX o exacta de Fisher para determinar la asociación entre variables yanálisis de regresión logística.Resultados: Se observó una prevalencia de polimedicados de 1,2%, conuna media de edad de 71,7 ± 12,4 años y una media de prescripcionesde 12 ±1,7 medicamentos.El listado de medicamentos a evitar en AP incluyó 45 principios activos.Los fármacos a evitar más usados han sido: duloxetina, sitagliptina yolmesartán. El 50,4% de los polimedicados tenían al menos un medicamento a evitar y una edad media de 68,5±11,8 años. El sexo fue unfactor de riesgo de prescripción inadecuada, el hecho de ser mujerincrementa con un OR=1,8 (IC 95%=1,3-3,0) la probabilidad de medicamentos a evitar. ...

Rhus coriaria L., a new candidate for controlling metabolic syndrome: a systematic review.

OBJECTIVES: Rhus coriaria L. (RC) is a deciduous shrub with several pharmacological activities. Evidence of the effects of RC on weight, hyperlipidaemia, hypertension and diabetes mellitus have been presented in this study. Books, thesis and internet-based resources such as PubMed, Web of Science, Scopus, EMBASE, Cochrane, Ovid and Google Scholar were searched for the English, Arabic and Persian literature from 1966 to 2020 (December). The keywords were Rhus coriaria L., Sumac, metabolic syndrome and all its medical conditions (hyperlipidaemia, hypertension, obesity and diabetes mellitus). The inclusion criteria were full-text animal and human studies conducted on RC to evaluate its efficacy on any components of metabolic syndrome (MetS). Jadad scale was used to assess the quality of evidence. KEY FINDINGS: Reviewing 23 relevant studies demonstrated that RC is able to decrease the level of blood glucose, glycated haemoglobin, serum insulin and insulin resistance. Studies on hyperlipidaemia and obesity have very contradicting results, and there is no definite conclusion on the effect of RC on lipid profile. However, the hypotensive and effect of RC was confirmed in the existing studies. SUMMARY: According to the literature, RC can be considered as a promising curative candidate for MetS. However, further studies with larger sample size and higher methodological quality are needed.

The Emerging Scenario of the Gut-Brain Axis: The Therapeutic Actions of the New Actor Kefir against Neurodegenerative Diseases.

The fact that millions of people worldwide suffer from Alzheimer's disease (AD) or Parkinson's disease (PD), the two most prevalent neurodegenerative diseases (NDs), has been a permanent challenge to science. New tools were developed over the past two decades and were immediately incorporated into routines in many laboratories, but the most valuable scientific contribution was the "waking up" of the gut microbiota. Disturbances in the gut microbiota, such as an imbalance in the beneficial/pathogenic effects and a decrease in diversity, can result in the passage of undesired chemicals and cells to the systemic circulation. Recently, the potential effect of probiotics on restoring/preserving the microbiota was also evaluated regarding important metabolite and vitamin production, pathogen exclusion, immune system maturation, and intestinal mucosal barrier integrity. Therefore, the focus of the present review is to discuss the available data and conclude what has been accomplished over the past two decades. This perspective fosters program development of the next steps that are necessary to obtain confirmation through clinical trials on the magnitude of the effects of kefir in large samples.

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer's Disease.

The vascular hypothesis used to explain the pathophysiology of Alzheimer's disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood-brain barrier (BBB) permeability plays a prominent role in this process. It is generally accepted that, in physiological conditions, cyclic AMP (cAMP) plays a key role in maintaining BBB permeability by regulating the formation of tight junctions between endothelial cells of the brain microvasculature. It is also known that intracellular cAMP signaling is highly compartmentalized into small nanodomains and localized cAMP changes are sufficient at modifying the permeability of the endothelial barrier. This spatial and temporal distribution is maintained by the enzymes involved in cAMP synthesis and degradation, by the location of its effectors, and by the existence of anchor proteins, as well as by buffers or different cytoplasm viscosities and intracellular structures limiting its diffusion. This review compiles current knowledge on the influence of cAMP compartmentalization on the endothelial barrier and, more specifically, on the BBB, laying the foundation for a new therapeutic approach in the treatment of AD.

Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect.

Crambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro, in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.

Evaluation of Virola oleifera activity in musculoskeletal pathologies: Inhibition of human multiple myeloma cells proliferation and combination therapy with dexamethasone or bortezomib.

ETHNOPHARMACOLOGICAL RELEVANCE: Virola oleifera (Schott) A.C. Smith, Myristicaceae, has been widely used in traditional medicine in Brazil to treat rheumatic pain, joint tumours, skin diseases, halitosis, bronchial asthma, haemorrhoids, and intestinal worms. Recently, research data showed the antioxidant properties in several oxidative stress-related models. However, there is no experimental evidence supporting its potential use in managing rheumatic diseases and bone malignancies. AIMS OF THE STUDY: To evaluate the therapeutic potential of the resin from Virola oleifera in joint and bone diseases, namely arthritis, osteosarcoma, chondrosarcoma, and multiple myeloma. MATERIALS AND METHODS: To determine Virola oleifera resin (VO) effects on arthritis-associated inflammation and cartilage degradation, the LPS-induced NO production, and mRNA and protein expression of ADAMTS5, MMP13, COL2, and ACAN, were evaluated in chondrocytes (ATDC5 and TC28 cell lines). The cytotoxic effects of VO (0.05-50 µg/ml) on multiple myeloma (ARH-77), osteosarcoma (SAOS-2), and chondrosarcoma (SW-1353) cell lines were analysed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The VO effects, combined with dexamethasone or bortezomib, were evaluated in a multiple myeloma cell line. The mechanisms of VO, alone or in combination with bortezomib, were determined by cell cycle analysis through flow cytometry, while expression levels of p-Akt/Akt, p-ERK/ERK, p-p38/p38 MAPK, Bax, Bcl-2, and cleaved-caspase-3/caspase-3 proteins by Western blot. RESULTS: VO had no significant effect on LPS-induced NO production in chondrocytes at non-cytotoxic concentrations. VO treatment diminished the mRNA levels of metalloproteinases and ECM components; however, any significant effect was observed on the protein expression levels. The cell viability of a multiple myeloma cell line was strongly reduced by VO treatment in a dose- and time-dependent manner, while osteosarcoma and chondrosarcoma cell lines viability was significantly affected only by the highest dose assessed. In multiple myeloma cells, VO leads to G2/M cell cycle arrest. Furthermore, it synergizes with dexamethasone by increasing cell toxicity. Finally, VO reverts bortezomib activity by counteracting ERK1/2, Bax, and caspase-3 activation. CONCLUSIONS: The current work supports the ethnopharmacological use of Virola oleifera (Schott) A.C. Smith in bone and joint diseases, but there is no evidence for the amelioration of arthritis-associated inflammatory or catabolic processes. Our data also supports the potential use of Virola oleifera as adjuvant therapy to optimize the pharmacologic effects of current chemotherapeutic drugs. However, possible herb-drug interactions should be considered before clinical application.

Pharmacological Extracts and Molecules from Virola Species: Traditional Uses, Phytochemistry, and Biological Activity.

Virola is the largest genus of Myristicaceae in America, comprising about 60 species of medium-sized trees geographically spread from Mexico to southern Brazil. The plant species of this genus have been widely used in folk medicine for the treatment of several ailments, such as rheumatic pain, bronchial asthma, tumors in the joints, intestinal worms, halitosis, ulcers, and multiple infections, due to their pharmacological activity. This review presents an updated and comprehensive summary of Virola species, particularly their ethnomedicinal uses, phytochemistry, and biological activity, to support the safe medicinal use of plant extracts and provide guidance for future research. The Virola spp.'s ethnopharmacology, including in the treatment of stomach pain and gastric ulcers, as well as antimicrobial and tryponosomicidal activities, is attributable to the presence of a myriad of phytoconstituents, such as flavonoids, tannins, phenolic acids, lignans, arylalkanones, and sitosterol. Hence, such species yield potential leads or molecular scaffolds for the development of new pharmaceutical formulations, encouraging the elucidation of not-yet-understood action mechanisms and ascertaining their safety for humans.

Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: Limits and improvements.

AIMS: Since the publication of the American Gastroenterological Association's recommendations in 2017, there have been no significant changes in the biological monitoring recommendations in inflammatory bowel disease. Possible limitations are the lack of evidence to recommend proactive therapeutic drug monitoring (pTDM) over reactive TDM (rTDM), and the limited information about individualized dosing methods. This article aims to review the TDM strategy updates and the use of individualized dosing methods. METHODS: For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In the TDM case, since August 2017. RESULTS: A total of 263 publications were found, but only 7 related to proactive TDM. Five of these publications directly compared pTDM vs rTDM and 2 were randomized clinical trials. Six studies found benefits of pTDM and 1 found no differences. Regarding the individualized dosing method, 229 distinct results were found. Population pharmacokinetics was the most widely used method to develop individual dosage models and to analyse the influence of factors on drug concentrations (albumin concentration, weight, presence of anti-drug antibodies etc). CONCLUSION: We have found no major changes in TDM strategies. There is a growing trend towards the use of pTDM because it has shown a longer duration of treatment response, lower rates of discontinuation and relapses. However, the available evidence is limited and of low quality. Despite the common use of population pharmacokinetic methods to analyse pharmacokinetic factors, they are not commonly used for personalized dosing.

Oxidative Stress and Dementia in Alzheimer's Patients: Effects of Synbiotic Supplementation.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in elderly patients. Recently, several studies have shown that inflammation and oxidative stress precede the cardinal neuropathological manifestations of AD. In view of the proven antioxidant effects of probiotics, we proposed that continuous dietary supplementation with milk fermented with kefir grains might improve cognitive and metabolic and/or cellular disorders in the AD patients. METHODS: This study was designed as an uncontrolled clinical investigation to test the effects of probiotic-fermented milk supplementation (2 mL/kg/daily) for 90 days in AD patients exhibiting cognitive deficit. Cognitive assessment, cytokine expression, systemic oxidative stress levels, and blood cell damage biomarkers were evaluated before (T0) and after (T90) kefir synbiotic supplementation. RESULTS: When the patients were challenged to solve 8 classical tests, the majority exhibit a marked improvement in memory, visual-spatial/abstraction abilities, and executive/language functions. At the end of the treatment, the cytometric analysis showed an absolute/relative decrease in several cytokine markers of inflammation and oxidative stress markers (·O2 -, H2O2, and ONOO-, ~30%) accompanied by an increase in NO bioavailability (100%). In agreement with the above findings by using the same technique, we observed in a similar magnitude an improvement of serum protein oxidation, mitochondrial dysfunction, DNA damage/repair, and apoptosis. CONCLUSION: In conclusion, we demonstrated that kefir improves cognitive deficits, which seems to be linked with three important factors of the AD-systemic inflammation, oxidative stress, and blood cell damage-and may be a promising adjuvant therapy against the AD progression.

A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.

Voriconazole is an antifungal metabolised by CYP2C19 enzyme, which can be inhibited by proton-pump inhibitors (PPIs). A prospective observational study was carried out to determine the influence of PPIs on voriconazole pharmacokinetic. The 78 patients included were divided into 4 groups: omeprazole (n = 32), pantoprazole (n = 25), esomeprazole (n = 3) and no PPI (n = 18). Patients with no PPI had no significant difference in plasma voriconazole concentration when compared with those with PPI (2.63 ± 2.13 µg/mL [95% confidence interval {CI} 1.57-3.69] vs 2.11 ± 1.73 µg/mL [95%CI 1.67-2.55], P > .05). However, voriconazole plasma concentration was significantly lower in patients treated with pantoprazole vs those treated with omeprazole (1.44 ± 1.22 µg/mL [95%CI 0.94-1.94) vs 2.67 ± 1.88 µg/mL [95%CI 2.02-3.32], P = .013) suggesting a greater CYP2C19 enzyme inhibitory effect of omeprazole. This study demonstrates the greater CYP inhibition capacity of omeprazole and should be helpful for the choice of PPIs for patients treated with voriconazole.

Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.

BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.