Search

Background: Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression. Aim: To investigate the mechanistic pathways of high dose atorvastatin in MDD. Patients and methods: This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of ≤7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as ≥ 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-richcontaining family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured. Results: The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine (p = 0.03, and p = 0.005), respectively. Conclusion: These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/ NLRP3 and IL-6/STAT-3. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression. Aim: To investigate the mechanistic pathways of high dose atorvastatin in MDD. Patients and methods: This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of =7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as = 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-richcontaining family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured. Results: The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine (p = 0.03, and p = 0.005), respectively. Conclusion: These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/NLRP3 and IL-6/STAT-3. [ABSTRACT FROM AUTHOR]

Objectives To investigate the effect of high-dose methotrexate (HDMTX) on P-glycoprotein (P-gp) serum levels in pediatric patients with acute lymphocytic leukemia (ALL). Methods This controlled parallel clinical study was conducted between April 2020 and February 2022. Thirty-three pediatric patients with a confirmed diagnosis of ALL were included in this study (ALL group). Patients were enrolled before receiving the HDMTX protocol and after completion of the induction phase. Age, body mass index (BMI), and sex ratio matched healthy pediatric subjects were also included in this study and were selected from a primary care center (control group). Blood samples were collected from the healthy control group at baseline, and patients with ALL at baseline and after MTX therapy, for biochemical analysis of P-glycoprotein. MTX concentration was also determined in ALL samples after treatment to correlate with P-gp serum level. Results No statistically significant difference was observed in P-gp serum levels between the healthy pediatric subjects and patients with ALL before receiving MTX treatment. P-gp serum levels were significantly lower (P <0.05) in pediatric patients with ALL after MTX treatment in all age segments as compared to its levels before MTX treatment (baseline data). Moreover, there was no statistically significant difference in P-gp serum levels between the healthy pediatric subjects and pediatric patients with ALL after MTX treatment in the first age segments (4--7 years old). However, P-gp serum levels were significantly lower in pediatric patients with ALL who received MTX in both the 8--10 and the 11--14 years old segments compared to the healthy group. In addition, there was no significant correlation between MTX concentration and P-gp serum level in patients with ALL after MTX treatment. Conclusion High-dose methotrexate may exert a down-regulatory effect on P-gp serum level in pediatric patients with ALL. However, this needs further investigation. (ClinicalTrials.gov Identifier: NCT05021159, September 2021). [ABSTRACT FROM AUTHOR]

This document is a corrigendum for an article titled "Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study." The corrigendum addresses an error in the affiliation of one of the authors, Manal A. Hamouda. The correct affiliation should be "Department of Clinical Pharmacy, Faculty of Pharmacy, Menoufia University, Shebin El-Kom, Menoufia, Egypt." The authors apologize for the error and state that it does not affect the scientific conclusions of the article. [Extracted from the article]

ABC transporters (ATP‐binding cassette transporter) traffic drugs and their metabolites across membranes, making ABC transporter expression levels a key factor regulating local drug concentrations in different tissues and individuals. Yet, quantification of ABC transporters remains challenging because they are large and low‐abundance transmembrane proteins. Here, we analysed 200 samples of crude and membrane‐enriched fractions from human liver, kidney, intestine, brain microvessels and skin, by label‐free quantitative mass spectrometry. We identified 32 (out of 48) ABC transporters: ABCD3 was the most abundant in liver, whereas ABCA8, ABCB2/TAP1 and ABCE1 were detected in all tissues. Interestingly, this atlas unveiled that ABCB2/TAP1 may have TAP2‐independent functions in the brain and that biliary atresia (BA) and control livers have quite different ABC transporter profiles. We propose that meaningful biological information can be derived from a direct comparison of these data sets. [ABSTRACT FROM AUTHOR]

Liver enzymes and transporters play an essential role in xenobiotic metabolism, distribution and elimination. Pre-clinical safety assessment relies on studies on animal models, including the (mini)pig. The pig shares many anatomical and physiological characteristics with humans, and there is currently a gap in information about porcine metabolism and disposition pathways and their similarities and differences from human ones. Three different sample preparation methods (filter-aided sample preparation (FASP), enhanced FASP (eFASP) and in-solution sample preparation) were used to prepare porcine liver tissue (two samples) for proteomic analysis. The analysis relied on rapid-separation liquid chromatography coupled to Orbitrap mass spectrometry in data-dependent acquisition mode. MASCOT was used for identification and relative label-free quantification was based on spectral counting. The three sample preparation methods provided complementary results, allowing characterisation of approximately 70 pharmacologically relevant proteins. The main quantified proteins included 16 cytochrome P450 (CYP) enzymes, 5 UGT enzymes, and 11 transporters. In addition, 20 Phase I and 14 Phase II enzymes were also characterised. Inter-operator differences were negligible and the pig liver pies for CYP, UGT and efflux transporter proteins were established. Human homologues of the quantified CYP, UGT and transporter proteins were identified. [ABSTRACT FROM AUTHOR]