Front Neurosci. 2022 Jul 6;16:886709. doi: 10.3389/fnins.2022.886709. eCollection 2022.

ABSTRACT

Awake rodent fMRI is becoming a promising non-invasive brain imaging module when investigating large-scale brain function given behavioral tasks. Previous studies have either applied sedatives during scanning or pre-treatment of anesthetics, e.g., isoflurane, to reduce the motion of animals, which could confound the brain function of "awake" states in rodents. Here, we have established a long training awake mouse fMRI-pupillometry paradigm/setup without the initial use of anesthesia. To validate the awake mouse fMRI platform, evoked BOLD-fMRI was performed to identify brain activation in the visual cortex, dorsal lateral geniculate nuclei, and superior colliculus. Furthermore, pupil signal fluctuation was investigated during scanning, showing a less dilated pupil after 5-8 weeks of intermittent training. Thus, using the awake mouse fMRI with real-time pupillometry provides a longitudinal functional mapping tool to study fully conscious mice.

PMID:35903811 | PMC:PMC9318598 | DOI:10.3389/fnins.2022.886709

Cancer Cell Int. 2022 Jul 28;22(1):239. doi: 10.1186/s12935-022-02663-2.

ABSTRACT

The gaps between the complex nature of cancer and therapeutics have been narrowed down due to extensive research in molecular oncology. Despite gathering massive insight into the mysteries of tumor heterogeneity and the molecular framework of tumor cells, therapy resistance and adverse side effects of current therapeutic remain the major challenge. This has shifted the attention towards therapeutics with less toxicity and high efficacy. Myricetin a natural flavonoid has been under the spotlight for its anti-cancer, anti-oxidant, and anti-inflammatory properties. The cutting-edge molecular techniques have shed light on the interplay between myricetin and dysregulated signaling cascades in cancer progression, invasion, and metastasis. However, there are limited data available regarding the nano-delivery platforms composed of myricetin in cancer. In this review, we have provided a comprehensive detail of myricetin-mediated regulation of different cellular pathways, its implications in cancer prevention, preclinical and clinical trials, and its current available nano-formulations for the treatment of various cancers.

PMID:35902860 | DOI:10.1186/s12935-022-02663-2

Gut. 2022 Jul 28:gutjnl-2022-327570. doi: 10.1136/gutjnl-2022-327570. Online ahead of print.

ABSTRACT

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.

DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.

RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and were predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.

CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.

TRIAL REGISTRATION NUMBER: ISRCTN45176516.

PMID:35902214 | DOI:10.1136/gutjnl-2022-327570

PLoS One. 2022 Jul 28;17(7):e0272129. doi: 10.1371/journal.pone.0272129. eCollection 2022.

ABSTRACT

The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments.

PMID:35901010 | DOI:10.1371/journal.pone.0272129

J Genet Couns. 2022 Jul 28. doi: 10.1002/jgc4.1612. Online ahead of print.

ABSTRACT

Pharmacogenomic (PGx) testing is an increasingly utilized technology that offers the potential for precision drug selection to treat depression. Though PGx-guided therapy is associated with increased rates of remission of depression symptoms, for many patients, treatment will not change based on PGx testing results. Lack of consensus guidelines for pre-test counseling may hinder the communication of PGx testing limitations, and patients often have high expectations for test outcomes. To explore this issue, we created and evaluated the impact of a pre-test education video for patients with depression. Individuals in the education group (n = 198) viewed this brief video about PGx testing prior to completing a survey that explored knowledge, perception, and expectations of PGx testing developed using a theoretical framework to measure intention to test. Individuals in the survey-only group (n = 189) completed the same survey but were not provided with any PGx educational materials. Analyses demonstrate efficacy of the video in improving knowledge of PGx. The education group also reported more positive attitudes and greater perceived control over pursuing PGx testing compared to the survey-only group. Further analyses identified significant differences in expectations, attitudes, and intention to pursue PGx testing based on number of previous medication trials. Path analyses identified the best model for predicting PGx testing intention, specifically that social norms and ease of testing have a strong positive association, and knowledge has a strong negative association with patients' intentions to test across the full sample, the education group, and the survey-only group. The findings of this study serve as a foundation for future tailored educational initiatives in the PGx testing space.

PMID:35900228 | DOI:10.1002/jgc4.1612

Clin Transl Sci. 2022 Jul 28. doi: 10.1111/cts.13376. Online ahead of print.

ABSTRACT

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of post-operative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2018 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided post-operative pain management (intervention arm) or delayed testing without CDS (control arm). Clinical decision support is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and one, three, and six months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days post-surgery, will be compared in the subgroup of IMs and PMs in the intervention (n=152) versus control (n=152) arm. Secondary endpoints include prescription pain medication misuse scores and opioid persistence at six months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

PMID:35899435 | DOI:10.1111/cts.13376

Front Med (Lausanne). 2022 Jul 11;9:854280. doi: 10.3389/fmed.2022.854280. eCollection 2022.

ABSTRACT

To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.

PMID:35899207 | PMC:PMC9309431 | DOI:10.3389/fmed.2022.854280

Health Sci Rep. 2022 Jul 25;5(4):e728. doi: 10.1002/hsr2.728. eCollection 2022 Jul.

ABSTRACT

BACKGROUND AND AIMS: Abnormalities in hematological and biochemical markers are assumed to be associated with the progression of COVID-19 disease. This meta-analysis was performed to assess the consequences of abnormalities of biomarkers (D-dimers, C-reactive protein [CRP], serum ferritin, lactate dehydrogenase [LDH], random blood sugar [RBS], absolute neutrophil count [ANC], neutrophil to lymphocyte ratio (NLR), serum creatinine, and hemoglobin) in the Bangladeshi COVID-19 patients.

METHODS: The data of biomarker levels in Bangladeshi COVID-19 patients were gathered from five databases: PubMed, ScienceDirect, Web of Science, Google Scholar and Bangladesh Journals Online between January 2020 to March 2022. Review Manager 5.4 was used for the meta-analysis, and Egger's test and Begg-Mazumdar's rank correlation were used to investigate publication bias.

RESULTS: This study included 1542 patients with 567 severe and 975 nonsevere statuses. Based on the accumulated data synthesis, there is a strong correlation between disease severity and different biomarkers, including D-dimer, CRP, ferritin, LDH, RBS, NLR, and serum creatinine (MD = 1.16, p = 0.0004; MD = 22.97, p = 0.003; MD = 419.26, p < 0.00001; MD = 118.37, p = 0.004; MD = 1.96, p = 0.02; MD = 1.26, p = 0.02; and MD = 0.31, p = 0.008, respectively). A significantly decreased correlation was observed for hemoglobin levels in severe COVID-19 patients (MD = -0.73, p = 0.10).

CONCLUSION: The elevated biomarkers level was noticed in severe cases compared to nonsevere patients, revealing that D-dimer, CRP, ferritin, LDH, RBS, NLR, and serum creatinine are significantly correlated to COVID-19 severity. Only lower hemoglobin level was found to be associated with COVID-19 severity.

PMID:35899180 | PMC:PMC9309618 | DOI:10.1002/hsr2.728

Front Pharmacol. 2022 Jul 11;13:915822. doi: 10.3389/fphar.2022.915822. eCollection 2022.

ABSTRACT

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

PMID:35899106 | PMC:PMC9309806 | DOI:10.3389/fphar.2022.915822

Front Endocrinol (Lausanne). 2022 Jul 11;13:915309. doi: 10.3389/fendo.2022.915309. eCollection 2022.

ABSTRACT

CONTEXT: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy.

OBJECTIVE: The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl.

METHODS: This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA).

RESULTS: Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed.

CONCLUSION: T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

PMID:35898448 | PMC:PMC9309506 | DOI:10.3389/fendo.2022.915309

Int J Tuberc Lung Dis. 2022 Aug 1;26(8):766-774. doi: 10.5588/ijtld.21.0702.

ABSTRACT

BACKGROUND: Pharmacokinetic variability arising from drug-drug interactions and pharmacogenetics may influence the effectiveness of treatment regimens for TB. The Improving Treatment Success Trial compared the WHO-recommended standard treatment in TB patients with an experimental regimen substituting ethambutol with moxifloxacin (MFX) in Durban, South Africa.METHODS: Non-linear mixed-effects modelling was used to investigate the population pharmacokinetics of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA). A total of 25 single-nucleotide polymorphisms, including pregnane-X-receptor, were selected for analysis.RESULTS: TB drug concentrations were available in a subset of 101 patients: 58 in the MFX arm and 43 in the control arm. Baseline characteristics were well-balanced between study arms: median age and weight were respectively 36 years and 57.7 kg; 75.2% of the patients were living with HIV. Although weight-based drug dosing was the same in the two arms, we found that RIF exposure was increased by 19.3%, INH decreased by 19% and PZA decreased by 19.2% when administered as part of the MFX-containing regimen. Genetic variation in pregnane-X-receptor (rs2472677) was associated with a 25.3% reduction in RIF exposure.CONCLUSION: Optimised weight-based TB treatment dosing is essential when RIF, INH and PZA are co-administered with fluoroquinolones. The reduction in RIF exposure associated with pharmacogenetic variation is worrying.

PMID:35898135 | DOI:10.5588/ijtld.21.0702

Int J Mol Sci. 2022 Jul 26;23(15):8212. doi: 10.3390/ijms23158212.

ABSTRACT

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC's interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.

PMID:35897788 | DOI:10.3390/ijms23158212

Int J Mol Sci. 2022 Jul 23;23(15):8105. doi: 10.3390/ijms23158105.

ABSTRACT

The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor®&amp;nbsp;488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.

PMID:35897681 | DOI:10.3390/ijms23158105

Nature. 2022 Jul 27. doi: 10.1038/s41586-022-04984-8. Online ahead of print.

ABSTRACT

In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.

PMID:35896750 | DOI:10.1038/s41586-022-04984-8

Haemophilia. 2022 Jul 27. doi: 10.1111/hae.14632. Online ahead of print.

NO ABSTRACT

PMID:35895993 | DOI:10.1111/hae.14632

Cardiovasc Res. 2022 Jul 27:cvac110. doi: 10.1093/cvr/cvac110. Online ahead of print.

ABSTRACT

A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette's syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.

PMID:35895876 | DOI:10.1093/cvr/cvac110

Biomed Chromatogr. 2022 Jul 27:e5463. doi: 10.1002/bmc.5463. Online ahead of print.

ABSTRACT

Salvianolic acids for injection (SAI) is developed from traditional Chinese medicine and approved for the treatment of cardiovascular and cerebrovascular diseases. Clopidogrel is an inhibitor of platelet aggregation, which is often prescribed to patients in combination with SAI. This present study is aiming to assess the influences of SAI on the pharmacogenomics, pharmacokinetics and pharmacodynamics of clopidogrel, thereby ensuring the safety and efficacy of the co-administration. In vitro Cytochrome P450 isoenzymes assays were performed in human liver microsomes by LC-MS/MS method to assess the metabolites of CYPs substrates. The influences of SAI on the pharmacokinetics and pharmacodynamics behavior of clopidogrel were investigated in rats. The main pharmacokinetic parameters were analyzed by LC-MS/MS. Prothrombin time, activated partial thromboplastin time, bleeding time and inhibition of platelet aggregation were measured to evaluate the effects of pharmacodynamics. In our study, SAI at the clinical dose has no significant inhibitory effect on clopidogrel-related liver microsomes metabolic CYP450 isoenzymes. Moreover, SAI didn't affect the pharmacokinetics of clopidogrel both single dose and multiple dose in rats. In pharmacodynamics study, SAI has no effect on the platelet aggregation rate, PT and APTT time of clopidogrel, but could significantly prevent the risk of bleeding caused by clopidogrel.

PMID:35895507 | DOI:10.1002/bmc.5463

J Mol Med (Berl). 2022 Jul 27. doi: 10.1007/s00109-022-02238-8. Online ahead of print.

ABSTRACT

Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (β-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects. Intertumoral studies were performed using propranolol, a β1-AR selective agent (atenolol), and a β2-AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8+ immunological effects on anticancer activity. We found that repression of β2-AR but not β1-AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were significantly decreased following the inhibition of β2-AR. Furthermore, propranolol was found to activate the tumor microenvironment by inducing an increased intratumoral frequency of CD8+ T cells, whereas neither selective β1 nor β2-AR blockers had a significant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of tumor cell signaling, rather than the accumulation of CD8+ T cells, as the basis for propranolol antitumor activity. KEY MESSAGES : Molecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control. CD8+ T cells in tumor microenvironment were activated upon propranolol exposure. The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8+ T cells.

PMID:35895125 | DOI:10.1007/s00109-022-02238-8

Obesity (Silver Spring). 2022 Aug;30(8):1608-1620. doi: 10.1002/oby.23481.

ABSTRACT

OBJECTIVE: This study aimed to determine the effects of a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on weight and gastric functions and to evaluate associations of single-nucleotide polymorphisms in GLP1R (rs6923761) and TCF7L2 (rs7903146) with effects of liraglutide.

METHODS: The study conducted a randomized, parallel-group, placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg subcutaneously daily in 136 otherwise healthy adults with obesity. Weight, gastric emptying of solids (GES), gastric volumes, satiation, and body composition measured at baseline and after treatment were compared in two treatment groups using analysis of covariance.

RESULTS: Liraglutide (n = 59) and placebo (n = 65) groups completed treatment. Relative to placebo, liraglutide increased weight loss at 5 and 16 weeks (both p < 0.05), slowed time to half GES (T1/2 ) at 5 and 16 weeks (both p < 0.001), and increased fasting gastric volume (p = 0.01) and satiation (p < 0.01) at 16 weeks. GES T1/2 was positively correlated with weight loss on liraglutide (both p < 0.001). After 16 weeks of liraglutide, GLP1R rs6923761 (AG/AA vs. GG) was associated with reduced percent body fat (p = 0.062), and TCF7L2 rs7903146 (CC vs. CT/TT) was associated with lower body weight (p = 0.015).

CONCLUSIONS: Liraglutide, 3 mg, induces weight loss with delay in GES T1/2 and reduces calorie intake. Slowing GES and variations in GLP1R and TCF7L2 are associated with liraglutide effects in obesity.

PMID:35894080 | DOI:10.1002/oby.23481

Pharmaceutics. 2022 Jul 26;14(8):1555. doi: 10.3390/pharmaceutics14081555.

ABSTRACT

A severe form of myopia defined as pathologic/high myopia is the main cause of visual impairment and one of the most frequent causes of blindness worldwide. It is characterized by at least 6 diopters or axial length (AL) of eyeball &gt;26 mm and choroidal neovascularization (CNV) in 5 to 10% of cases. Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A) used in the treatment of CNV. It acts by preventing VEGF-A from interacting with its receptors (VEGFR-1 and -2) encoded by the FLT1 and KDR genes. Several studies found that the KDR and FLT1 genotypes may represent predictive determinants of efficacy in ranibizumab-treated neovascular age-related macular degeneration (nAMD) patients. We performed a retrospective study to evaluate the association of single nucleotide polymorphisms (SNPs) in VEGFR coding genes with the response rate to ranibizumab in patients with high myopia and CNV. In the association study of genotypes in FLT1 with the response to ranibizumab, we found a significant association between two FLT1 variants (rs9582036, rs7993418) with ranibizumab efficacy at the 12-month follow-up. About the KDR gene, we found that two KDR variants (rs2305948, rs2071559) are associated with best-corrected visual acuity (BCVA) improvement and KDR (rs2239702) is associated with lower rates of BCVA worsening considering a 12-month follow-up period.

PMID:35893809 | DOI:10.3390/pharmaceutics14081555