J Dev Behav Pediatr. 2023 Oct 6. doi: 10.1097/DBP.0000000000001215. Online ahead of print.

ABSTRACT

OBJECTIVE: This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results.

METHODS: Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories.

RESULTS: Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status.

CONCLUSION: In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

PMID:37807195 | DOI:10.1097/DBP.0000000000001215

Drug Discov Today. 2023 Oct 6:103797. doi: 10.1016/j.drudis.2023.103797. Online ahead of print.

ABSTRACT

Our understanding of drug-microbe relationships has evolved from viewing microbes as mere drug producers to a dynamic, modifiable system where they can serve as drugs or targets of precision pharmacology. This review highlights recent findings on the gut microbiome, particularly focusing on four aspects of research: (i) drugs for bugs, covering recent strategies for targeting gut pathogens; (ii) bugs as drugs, including probiotics; (iii) drugs from bugs, including postbiotics; and (iv) bugs and drugs, discussing additional types of drug-microbe interactions. This review provides a perspective on future translational research, including efficient companion diagnostics in pharmaceutical interventions. Teaser This review highlights the dynamic relationship between drugs and bugs in the human gut microbiome, providing insights into potential strategies for novel therapies and companion diagnostics for precision pharmacology.

PMID:37806386 | DOI:10.1016/j.drudis.2023.103797

Signal Transduct Target Ther. 2023 Oct 9;8(1):386. doi: 10.1038/s41392-023-01619-w.

ABSTRACT

Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.

PMID:37806986 | DOI:10.1038/s41392-023-01619-w

Clin Exp Allergy. 2023 Oct 7. doi: 10.1111/cea.14410. Online ahead of print.

NO ABSTRACT

PMID:37804101 | DOI:10.1111/cea.14410

J Clin Pharmacol. 2023 Oct 6. doi: 10.1002/jcph.2366. Online ahead of print.

ABSTRACT

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in African healthy volunteers to understand the effect of allelic variants of the human cytochrome-P450(CYP)2D6 enzyme namely, CYP2D6*1/*2 diplotypes, CYP2D6*17*17 and CYP2D6*29*29 genotypes. Overall, 28 adults were included through genotype screening into the three cohorts: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30-mg syrup on Day 1 and desipramine 50-mg tablet on Day 8. The PK parameters, area under plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf), and maximum plasma concentration (Cmax) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts as compared with those reported in the CYP2D6*1/*2 diplotype cohort, and for normal metabolizers in literature. All PK parameters including AUCinf, Cmax, and elimination half-life followed a similar trend: CYP2D6*17*17 >CYP2D6*29*29 >CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts when compared with those in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except for one subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicated that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings. This article is protected by copyright. All rights reserved.

PMID:37803948 | DOI:10.1002/jcph.2366

Anaesth Intensive Care. 2023 Oct 6:310057X231194833. doi: 10.1177/0310057X231194833. Online ahead of print.

ABSTRACT

Perioperative lidocaine (lignocaine) infusions are being employed with increasing frequency. The determinants of systemic lidocaine concentrations during prolonged administration are unclear. In the Long-term Outcomes after Lidocaine Infusions for PostOperative Pain (LOLIPOP) pilot trial, the impact of infusion duration and body size metrics on serum lidocaine concentrations was examined with regression models in 48 women undergoing breast cancer surgery. Lidocaine was delivered as an intravenous bolus (1.5 mg/kg) and infusion (2 mg/kg per h) intraoperatively, followed by a 12-h subcutaneous infusion (1.33 mg/kg per h) postoperatively. Dosing was based on total body weight. Wound infiltration with other long-acting local anaesthetics was permitted. Protein binding and pharmacogenomic data were also collected. Lidocaine concentrations (median (interquartile range) (range)) during prolonged administration were in the safe and potentially therapeutic range: post-anaesthesia care unit 2.16 (1.73-2.82) (1.12-6.06) µg/ml; ward 1.41 (1.22-1.75) (0.64-2.81) µg/ml. Concentrations increased non-linearly during the early intravenous phase of administration (mean rise 1.21 µg/ml per hour of infusion, P = 0.007) but reached a pseudo steady-state during the later subcutaneous phase. Higher dose rates received per kilogram of lean (P = 0.004), adjusted (P = 0.006) and ideal body weight (P = 0.009) were associated with higher steady-state concentrations. The lidocaine free fraction was unaffected by the presence of ropivacaine, and phenotypes linked to slow metabolism were infrequent. Serum lidocaine concentrations reached a pseudo steady-state during a 12-h postoperative infusion. Greater precision in steady-state concentrations can be achieved by dosing on lean body weight versus adjusted or ideal body weight (equivalent lean body weight doses: intravenous bolus 2.5 mg/kg; intravenous infusion 3.33 mg/kg per h; subcutaneous infusion 2.22 mg/kg per h.

PMID:37802488 | DOI:10.1177/0310057X231194833

Pharmacol Res. 2023 Oct 4:106949. doi: 10.1016/j.phrs.2023.106949. Online ahead of print.

ABSTRACT

OBJECTIVES: A cost-utility analysis was conducted to evaluate pharmacogenomic (PGx)-guided treatment compared to the standard-of-care intervention among patients diagnosed with colorectal cancer (CRC) in Italy.

METHODS: Data derived from a prospective, open-label, block randomized clinical trial, as a part of the largest PGx study worldwide (355 patients in both arms) were used. Mortality was used as the primary health outcome to estimate life years (LYs) gained in treatment arms within a survival analysis context. PGx-guided treatment was based on established drug-gene interactions between capecitabine, 5-fluorouracil and irinotecan with DPYD and/or UGT1A1 genomic variants. Utility values for the calculation of Quality Adjusted Life Year (QALY) was based on Visual Analog Scale (VAS) score. Missing data were imputed via the Multiple Imputation method and linear interpolation, when possible, while censored cost data were corrected via the Replace-From-The-Right algorithm. The Incremental Cost-Effectiveness Ratio (ICER) was calculated for QALYs. Raw data were bootstrapped 5,000 times in order to produce 95% Confidence Intervals based on non-parametric percentile method and to construct a cost-effectiveness acceptability curve. Cost differences for study groups were investigated via a generalized linear regression model analysis. Total therapy cost per patient reflected all resources expended in the management of any adverse events, including medications, diagnostics tests, devices, surgeries, the utilization of intensive care units, and wards.

RESULTS: The total cost of the study arm was estimated at €380 (~ US$416; 95%CI: 195-596) compared to €565 (~ US$655; 95%CI: 340-724) of control arm while the mean survival in study arm was estimated at 1.58 (+0.25) LYs vs 1.50 (+0.26) (Log Rank test, X2=4.219, df=1, p-value=0.04). No statistically significant difference was found in QALYs. ICER was estimated at €13418 (~ US$14695) per QALY, while the acceptability curve indicated that when the willingness-to-pay was under €5000 (~ US$5476), the probability of PGx being cost-effective overcame 70%. The most frequent adverse drug event in both groups was neutropenia of severity grade 3 and 4, accounting for 82.6% of total events in the study arm and 65.0% in the control arm. Apart from study arm, smoking status, Body-Mass-Index and Cumulative Actionability were also significant predictors of total cost. Subgroup analysis conducted in actionable patients (7.9% of total patients) indicated that PGx-guided treatment was a dominant option over its comparator with a probability greater than 92%. In addition, a critical literature review was conducted, and these findings are in line with those reported in other European countries.

CONCLUSION: PGx-guided treatment strategy may represent a cost-saving option compared to the existing conventional therapeutic approach for colorectal cancer patient management in the National Health Service of Italy.

PMID:37802427 | DOI:10.1016/j.phrs.2023.106949

Sci Rep. 2023 Oct 6;13(1):16893. doi: 10.1038/s41598-023-44124-4.

ABSTRACT

Parkinson's disease (PD) is a common neurodegenerative disease with aggregation of α-synuclein (α-syn) in substantia nigra (SN). The association between the α-syn and ferroptosis in PD remains unclear. GSE49036 was obtained from the Gene Expression Omnibus (GEO) database and intersected with ferroptosis genes. Bioinformatics analysis was used to identify the potential differentially expressed genes (DEGs) included the development of Gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network. We screened 8 key genes were modulated and crosslinked by 238 miRNAs. Additionally, 5 hub genes were predicted and 38 lncRNAs targeting 3 key miRNAs were revealed. Finally, 3 hub genes (PIK3CA, BRD4, ATM) and the key lncRNA (NEAT1) were verified in neurotoxic PD models. The in vitro experiments showed that PIK3CA and ATM were significantly upregulated or the BRD4 was downregulated in the rotenone treatment and they could be rescued by the specific ferroptosis inhibitor, liproxstatin-1. The expression of the key lncRNA NEAT1 were consistent with the hub genes in same models. This study identified the proposed NEAT1-PIK3CA/ATM ceRNA network may be a specific biomarker in α-syn driving ferroptosis as well as to predict clinical outcomes and therapeutic targets in PD patients.

PMID:37803093 | DOI:10.1038/s41598-023-44124-4

JAMA Netw Open. 2023 Oct 2;6(10):e2335518. doi: 10.1001/jamanetworkopen.2023.35518.

ABSTRACT

IMPORTANCE: Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia.

OBJECTIVE: To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).

DESIGN, SETTING, AND PARTICIPANTS: This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.

INTERVENTIONS: Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.

RESULTS: A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.

CONCLUSIONS AND RELEVANCE: In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.

TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.

PMID:37801319 | DOI:10.1001/jamanetworkopen.2023.35518

J Genet Eng Biotechnol. 2023 Oct 6;21(1):94. doi: 10.1186/s43141-023-00554-1.

ABSTRACT

BACKGROUND: Vibrio species are among the autochthonous bacterial populations found in surface waters and associated with various life-threatening extraintestinal diseases, especially in human populations with underlying illnesses and wound infections. Presently, very diminutive information exists regarding these species' mutational diversity of virulence and resistance genes. This study evaluated variations in endonucleases and mutational diversity of the virulence and resistance genes of Vibrio isolates, harboring virulence-correlated gene (vcgCPI), dihydropteroate synthase type 1 and type II genes (Sul 1 and 11), (aadA) aminoglycoside (3'') (9) adenylyltransferase gene, (aac(3)-IIa, (aacC2)a, aminoglycoside N(3)-acetyltransferase III, and (strA) aminoglycoside 3'-phosphotransferase resistance genes.

METHODS: Using combinations of molecular biology techniques, bioinformatics tools, and sequence analysis.

RESULTS: Our result revealed various nucleotide variations in virulence determinants of V. vulnificus (vcgCPI) at nucleotide positions (codon) 73-75 (A → G) and 300-302 (N → S). The aminoglycosides resistance gene (aadA) of Vibrio species depicts a nucleotide difference at position 482 (A → G), while the aminoglycosides resistance gene (sul 1 and 11) showed two variable regions of nucleotide polymorphism (102 and 140). The amino acid differences exist with the nucleotide polymorphism at position 140 (A → E). The banding patterns produced by the restriction enzymes HinP1I, MwoI, and StyD4I showed significant variations. Also, the restriction enzyme digestion of protein dihydropteroate synthase type 1 and type II genes (Sul 1 and 11) differed significantly, while enzymes DpnI and Hinf1 indicate no significant differences. The restriction enzyme NlaIV showed no band compared to reference isolates from the GenBank. However, the resistant determinants show significant point nucleotide mutation, which does not produce any amino acid change with diverse polymorphic regions, as revealed in the restriction digest profile.

CONCLUSION: The described virulence and resistance determinants possess specific polymorphic locus relevant to pathogenomics studies, pharmacogenomic, and control of such water-associated strains.

PMID:37801152 | DOI:10.1186/s43141-023-00554-1

J Am Pharm Assoc (2003). 2023 Oct 3:S1544-3191(23)00307-2. doi: 10.1016/j.japh.2023.09.012. Online ahead of print.

ABSTRACT

PURPOSE: Patients of Asian descent are under-represented in the United States healthcare system and provider cultural competence is inadequate in addressing Asian health disparities. The purpose of this study was to evaluate the impact of the pharmacist-led cultural competence training on provider self-perceived preparedness and diabetes-related health outcomes in patients of Asian descent.

METHODS: This study is a cross-sectional followed by a quasi-experimental design conducted in two phases in a primary care clinic. Phase one evaluated the association of providers' cross-cultural competency survey (CCCS) scores with patients' diabetic health indices: HbA1C, systolic blood pressure (SBP), diastolic blood pressure (DBP) and body mass index (BMI). Phase two examined the impact of pharmacist led cultural competence training on providers' cross-cultural competency using survey analysis as well as, pre- and post-training diabetic health indices in patients of Asian descent.

RESULTS: Phase 1 CCCS results showed baseline cross-cultural competence of the providers is inadequate (N=9 providers). Furthermore, a significant negative correlation was found between providers' CCCS score and patients' HbA1C (N=49, p=0.04). Phase 2 showed that cultural competence training significantly reduced providers' self-perceived "un-preparedness" to care for patients of alternative cultures (N=30 providers). Average diabetic health indices for all patients (N=95) pre- and post-training were not significantly different. In the subset of patients with uncontrolled diabetes (HbA1C ≥ 7), SBP and HbA1C were significantly reduced post training (p=0.032 and p=0.039, respectively).

CONCLUSIONS: Pharmacist-led cultural competence training had a positive impact on provider self-assessment and diabetic clinical outcomes in uncontrolled patients.

PMID:37797919 | DOI:10.1016/j.japh.2023.09.012

Bioorg Chem. 2023 Sep 20;141:106869. doi: 10.1016/j.bioorg.2023.106869. Online ahead of print.

ABSTRACT

The opioids have been used for more than a thousand years and are not only the most widely prescribed drugs for moderate to severe pain and acute pain, but also the preferred drugs. However, their non-analgesic effects, especially respiratory depression and potential addiction, are important factors that plague the safety of clinical use and are an urgent problem for pharmacological researchers to address. Current research on analgesic drugs has evolved into different directions: de-opioidization; application of pharmacogenomics to individualize the use of opioids; development of new opioids with less adverse effects. The development of new opioid drugs remains a hot research topic, and with the in-depth study of opioid receptors and intracellular signal transduction mechanisms, new research ideas have been provided for the development of new opioid analgesics with less side effects and stronger analgesic effects. The development of novel opioid drugs in turn includes selective opioid receptor ligands, biased opioid receptor ligands, and multi-target opioid receptor ligands and positive allosteric modulators (PAMs) or antagonists and the single compound as multi-targeted agnoists/antagonists for different receptors. PAMs strategies are also getting newer and are the current research hotspots, including the BMS series of compounds and others, which are extensive and beyond the scope of this review. This review mainly focuses on the selective/biased/multi-targeted MOR/DOR/KOR (mu opioid receptor/delta opioid receptor/kappa opioid receptor) small molecule ligands and involves some cryo-electron microscopy (cryoEM) and structure-based approaches as well as the single compound as multi-targeted agnoists/antagonists for different receptors from 2019 to 2022, including discovery history, activities in vitro and vivo, and clinical studies, in an attempt to provide ideas for the development of novel opioid analgesics with fewer side effects.

PMID:37797454 | DOI:10.1016/j.bioorg.2023.106869

Brief Bioinform. 2023 Sep 22;24(6):bbad338. doi: 10.1093/bib/bbad338.

ABSTRACT

Spatial cellular authors heterogeneity contributes to differential drug responses in a tumor lesion and potential therapeutic resistance. Recent emerging spatial technologies such as CosMx, MERSCOPE and Xenium delineate the spatial gene expression patterns at the single cell resolution. This provides unprecedented opportunities to identify spatially localized cellular resistance and to optimize the treatment for individual patients. In this work, we present a graph-based domain adaptation model, SpaRx, to reveal the heterogeneity of spatial cellular response to drugs. SpaRx transfers the knowledge from pharmacogenomics profiles to single-cell spatial transcriptomics data, through hybrid learning with dynamic adversarial adaption. Comprehensive benchmarking demonstrates the superior and robust performance of SpaRx at different dropout rates, noise levels and transcriptomics coverage. Further application of SpaRx to the state-of-the-art single-cell spatial transcriptomics data reveals that tumor cells in different locations of a tumor lesion present heterogenous sensitivity or resistance to drugs. Moreover, resistant tumor cells interact with themselves or the surrounding constituents to form an ecosystem for drug resistance. Collectively, SpaRx characterizes the spatial therapeutic variability, unveils the molecular mechanisms underpinning drug resistance and identifies personalized drug targets and effective drug combinations.

PMID:37798249 | DOI:10.1093/bib/bbad338

Transl Oncol. 2023 Oct 3;38:101795. doi: 10.1016/j.tranon.2023.101795. Online ahead of print.

ABSTRACT

EWSR1 fusions are highly promiscuous and are associated with unique malignancies, clinical phenotypes, and molecular subtypes. However, rare fusion partners (RFP) of EWSR1 has not been well described. Here, we conducted a cross-sectional, retrospective study of 1,140 unique tumors harboring EWSR1 fusions. We identified 64 unique fusion partners. RFPs were identified more often in adults than children. Alterations in cell cycle control and DNA damage response genes as driving the differences between fusion partners. Potentially clinically actionable genomic variants were more prevalent in tumors harboring RFP than common fusions. While the data presented here is limited, tumors harboring RFP of EWSR1 may represent molecularly distinct entities and may benefit from further molecular testing to identify targeted therapeutic options.

PMID:37797367 | DOI:10.1016/j.tranon.2023.101795

Can J Psychiatry. 2023 Oct 5:7067437231203433. doi: 10.1177/07067437231203433. Online ahead of print.

ABSTRACT

OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample.

METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models.

RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052).

CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

PMID:37796764 | DOI:10.1177/07067437231203433

Adv Mater. 2023 Oct 5:e2306419. doi: 10.1002/adma.202306419. Online ahead of print.

ABSTRACT

Promoting innate immunity through pyroptosis induction or cGAS-STING pathway activation has emerged as a potent approach to counteract the immunosuppressive tumor microenvironment and elicit systemic antitumor immunity. However, current pyroptosis inducers and STING agonists often suffer from limitations including instability, unpredictable side effects, or inadequate intracellular expression of gasdermin and STING. Here, a tumor-specific nanotheranostic platform that combines photodynamic therapy (PDT) with epigenetic therapy to simultaneously activate pyroptosis and the cGAS-STING pathway in a light-controlled manner is constructed. This approach involves the development of oxidation-sensitive nanoparticles (NP1) loaded with the photosensitizer TBE, along with decitabine liposomes (NP2). NP2 enables the restoration of STING and GSDME expression, while NP1-mediated PDT facilitates the release of DNA fragments from damaged mitochondria to potentiate the cGAS-STING pathway, and promotes the activation of caspase-3 to cleave the upregulated GSDME into pore-forming GSDME-N terminal. Subsequently, the released inflammatory cytokines facilitate the maturation of antigen-presentation cells, triggering T cell-mediated antitumor immunity. Overall, this study presents an elaborate strategy for simultaneous photoactivation of pyroptosis and the cGAS-STING pathway, enabling targeted photoimmunotherapy in immunotolerant tumors. This innovative approach holds significant promise in overcoming the limitations associated with existing therapeutic modalities and represents a valuable avenue for future clinical applications. This article is protected by copyright. All rights reserved.

PMID:37796042 | DOI:10.1002/adma.202306419

Diabetes Obes Metab. 2023 Oct 5. doi: 10.1111/dom.15288. Online ahead of print.

ABSTRACT

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.

MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.

RESULTS: First, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics.

CONCLUSIONS: Completely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

PMID:37795639 | DOI:10.1111/dom.15288

Front Oncol. 2023 Sep 15;13:1225081. doi: 10.3389/fonc.2023.1225081. eCollection 2023.

ABSTRACT

Immune checkpoints limit the activation of the immune system and serve an important homeostatic function but can also restrict immune responses against tumors. Inhibition of specific immune checkpoint proteins such as the B7:CD28 family members programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has transformed the treatment of various cancers by promoting the anti-tumor activation of immune cells. In contrast to these effects, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) regulates the steady state of the resting immune system and promotes homeostasis by mechanisms distinct from PD-1 and CTLA-4. The effects of VISTA blockade have been shown to include a decrease in myeloid suppression coupled with proinflammatory changes by mechanisms that are separate and distinct from other immune checkpoint proteins; in some preclinical studies these immune effects appear synergistic. Given the potential benefits of VISTA blockade in the context of cancer therapy, the second Annual VISTA Symposium was convened virtually on September 23, 2022, to review new research from investigators and immuno-oncology experts. Discussions in the meeting extended the knowledge of VISTA biology and the effects of VISTA inhibition, particularly on cells of the myeloid lineage and resting T cells, as three candidate anti-VISTA antibodies are in, or nearing, clinical development.

PMID:37795437 | PMC:PMC10547146 | DOI:10.3389/fonc.2023.1225081

Front Endocrinol (Lausanne). 2023 Sep 18;14:1287807. doi: 10.3389/fendo.2023.1287807. eCollection 2023.

NO ABSTRACT

PMID:37795358 | PMC:PMC10545849 | DOI:10.3389/fendo.2023.1287807

Front Pharmacol. 2023 Sep 19;14:1267294. doi: 10.3389/fphar.2023.1267294. eCollection 2023.

ABSTRACT

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

PMID:37795032 | PMC:PMC10545970 | DOI:10.3389/fphar.2023.1267294