Biol Pharm Bull. 2023;46(11):1498-1505. doi: 10.1248/bpb.b23-00213.

ABSTRACT

Adiponectin is an abundant adipocytokine secreted by adipocytes. It exists in the plasma in its trimeric, hexameric, high-molecular-weight (HMW), and globular (a proteolytic product) isoforms. Adiponectin's anti-inflammatory effects on macrophages remain controversial. We have previously reported a simple and effective method for purifying native HMW adiponectin from human plasma. Here, we investigated whether native HMW adiponectin from human plasma has anti-inflammatory effects on macrophages. Pretreatment with human native HMW adiponectin inhibited lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) gene expression, but not tumor necrosis factor (TNF)-α expression. However, simultaneous treatment with HMW adiponectin and LPS did not inhibit IL-1β expression. Further, HMW adiponectin pretreatment decreases glycogen synthase kinase-3β (GSK-3β) inactivation by abrogating LPS-induced Akt (Ser473) phosphorylation, which subsequently suppresses LPS-induced CCAAT/enhancer binding protein β (C/EBPβ) protein translation and nuclear translocation. However, HMW adiponectin pretreatment did not affect LPS-induced nuclear factor-kappaB (NF-κB) activation. These results suggest that HMW adiponectin mediates potent anti-inflammatory activities in macrophages by inhibiting its Akt-C/EBPβ signaling pathway, thereby suppressing IL-1β gene expression.

PMID:37914352 | DOI:10.1248/bpb.b23-00213

J Invest Dermatol. 2023 Oct 21:S0022-202X(23)02972-X. doi: 10.1016/j.jid.2023.09.282. Online ahead of print.

ABSTRACT

HLA-B*15:11 and HLA-A*31:01 would be used as biomarkers in predicting the risk of CBZ-induced cADRs in the populations where allele frequency of HLA-B*15:02 is extremely rare.

PMID:37914023 | DOI:10.1016/j.jid.2023.09.282

Curr Probl Cardiol. 2023 Oct 30:102182. doi: 10.1016/j.cpcardiol.2023.102182. Online ahead of print.

ABSTRACT

Cardiovascular diseases (CVDs) are considered as the leading cause of death worldwide. CVD continues to be a major cause of death and morbidity despite significant improvements in its detection and treatment. Therefore, it is strategically important to be able to precisely characterize an individual's sensitivity to certain illnesses. The discovery of genes linked to cardiovascular illnesses has benefited from linkage analysis and genome-wide association research. The last 20 years have seen significant advancements in the field of molecular genetics, particularly with the development of new tools like genome-wide association studies. In this article we explore the profound impact of genetic variations on disease development, prognosis, and therapeutic responses. And the significance of genetics in cardiovascular risk assessment and the ever-evolving realm of genetic testing, offering insights into the potential for personalized medicine in this domain. Embracing the future of cardiovascular care, the article explores the implications of pharmacogenomics for tailored treatments, the promise of emerging technologies in cardiovascular genetics and therapies, including the transformative influence of nanotechnology. Furthermore, it delves into the exciting frontiers of gene editing, such as CRISPR/Cas9, as a novel approach to combat cardiovascular diseases. And also explore the potential of stem cell therapy and regenerative medicine, providing a holistic view of the dynamic landscape of cardiovascular genomics and its transformative potential for the field of cardiovascular medicine.

PMID:37913933 | DOI:10.1016/j.cpcardiol.2023.102182

Pharmacogenet Genomics. 2023 Nov 1. doi: 10.1097/FPC.0000000000000515. Online ahead of print.

ABSTRACT

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants.

METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change.

RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant (P < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain.

CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

PMID:37910437 | DOI:10.1097/FPC.0000000000000515

Elife. 2023 Nov 1;12:e84235. doi: 10.7554/eLife.84235.

ABSTRACT

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.

PMID:37910431 | DOI:10.7554/eLife.84235

Front Genet. 2023 Oct 16;14:1289015. doi: 10.3389/fgene.2023.1289015. eCollection 2023.

ABSTRACT

Introduction: Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions. Methods: A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01, and HLA-B*58:01 were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient's medical records. Carrier frequencies found were compared to a LUMC blood donor population. Results: A total of 13.1% of transplant cohort patients carried at least one of the five HLA risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No HLA-B*15:11 carrier was found. In total nine HLA-B*57:01 carriers received flucloxacillin and seven HLA-B*58:01 carriers within our cohort received allopurinol. Discussion: Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele.

PMID:37908589 | PMC:PMC10613976 | DOI:10.3389/fgene.2023.1289015

Pharmacogenomics J. 2023 Nov 1. doi: 10.1038/s41397-023-00317-8. Online ahead of print.

ABSTRACT

BACKGROUND: South Asian ancestry populations are underrepresented in genomic studies and therapeutics trials. British South Asians suffer from multi-morbidity leading to polypharmacy. Our objective was to elucidate British South Asian ancestry community perspectives on pharmacogenomic implementation and sharing pharmacogenomic clinical data for research.

METHODS: Four focus groups were conducted (9-12 participants in each). Two groups were mixed gender, while one group was male only and one was female only. Simultaneous interpretation was available to participants in Urdu and Bengali. Focus groups were recorded and abridged transcription and thematic analysis were undertaken.

RESULTS: There were 42 participants, 64% female. 26% were born in the UK or Europe. 52% were born in Bangladesh and 17% in Pakistan. 36% reported university level education. Implementation of pharmacogenomics was perceived to be beneficial to individuals but pose a risk of overburdening resource limited systems. Pharmacogenomic research was perceived to be beneficial to the community, with concerns about data privacy and misuse. Data sharing was desirable if the researchers did not have a financial stake, and benefits would be shared. Trust was the key condition for the acceptability of both clinical implementation and research. Trust was linked with medication compliance. Education, outreach, and communication facilitate trust.

CONCLUSIONS (SIGNIFICANCE AND IMPACT OF THE STUDY): Pharmacogenomics implementation with appropriate education and communication has the potential to enhance trust and contribute to increased medication compliance. Trust drives data sharing, which would enable enhanced representation in research. Representation in scientific evidence base could cyclically enhance trust and compliance.

PMID:37907686 | DOI:10.1038/s41397-023-00317-8

Stud Hist Philos Sci. 2023 Oct 29;102:72-83. doi: 10.1016/j.shpsa.2023.10.006. Online ahead of print.

ABSTRACT

Research in pharmacogenomics and precision medicine has recently introduced the concept of Polygenic Scores (PGSs), namely, indexes that aggregate the effects that many genetic variants are predicted to have on individual disease risk. The popularity of PGSs is increasing rapidly, but surprisingly little attention has been paid to the idealisations they make about phenotypic development. Indeed, PGSs rely on quantitative genetics models and methods, which involve considerable theoretical assumptions that have been questioned on various grounds. This comes with epistemological and ethical concerns about the use of PGSs in clinical decision-making. In this paper, I investigate to what extent idealisations in genetics models can impact the data gathering and clinical interpretation of genomics findings, particularly the calculation and predictive accuracy of PGSs. Although idealisations are considered ineliminable components of scientific models, they may be legitimate or not depending on the epistemic aims of a model. I thus analyse how various idealisations have been introduced in classical models and progressively readapted throughout the history of genetic theorising. Notably, this process involved important changes in the epistemic purpose of such idealisations, which raises the question of whether they are legitimate in the context of contemporary genomics.

PMID:37907020 | DOI:10.1016/j.shpsa.2023.10.006

Pharmacogenet Genomics. 2023 Nov 1. doi: 10.1097/FPC.0000000000000514. Online ahead of print.

ABSTRACT

BACKGROUND: Many factors affect the survival rate after kidney transplantation, including laboratory tests, medicine therapy and pharmacogenomics. Tacrolimus, mycophenolate mofetil and methylprednisolone were used as an immunosuppressive regimen after kidney transplantation. The primary goal of this study was to investigate the factors affecting the tacrolimus concentrations and mycophenolate mofetil area under the curve of mycophenolic acid AUC-MPA. Secondary goals were to study the association between perioperative period laboratory tests, medicine therapy, CYP3A5 genetic polymorphisms, and survival rate in kidney renal transplant patients.

METHODS: A total of 303 patients aged above 18 years were enrolled in this study. Their clinical characteristics, laboratory tests, and medicine therapy regimens were collected. We followed the patients for survival for 1 year after kidney transplantation.

RESULTS: Multivariable logistic analyses reveal that age greater than 50 years, and the CY3A5 *3*3 genotype were independently, positively, and significantly related to tacrolimus C/D ratio at 7 days. At 1 month of follow-up, only CYP3A5 *3*3 was associated with tacrolimus C/D ratio. Basiliximab, Imipenem and cilastatin sodium, sex were associated with mycophenolate mofetil AUC-MPA at 7 days. In the COX regression analysis, a high-density lipoprotein cholesterol level≥1 mmol/L was identified as a positive independent risk factors for the survival rate, while a creatinine level ≥200 μmol/L was a negatively independent risk factors for survival rate.

CONCLUSION: These results suggest that age, genes, and drug-drug interaction can affect the concentration of tacrolimus.

PMID:37906625 | DOI:10.1097/FPC.0000000000000514

J Med Chem. 2023 Oct 30. doi: 10.1021/acs.jmedchem.3c01516. Online ahead of print.

ABSTRACT

Healthcare systems heavily rely on antibiotics to treat bacterial infections, but the widespread presence of multidrug-resistant bacteria puts this strategy in danger. Novel drugs capable of overcoming current resistances are needed if our ability to treat bacterial infections is to be maintained. Boron clusters offer a valuable possibility to create a new class of antibiotics and expand the chemical space of antibiotics beyond conventional carbon-based molecules. In this work, we identified two promising structural patterns providing cobalta bis(dicarbollide)(COSAN)-based compounds with potent and selective activity toward Staphylococcus aureus (including clinical strains): introduction of the α-amino acid amide and addition of iodine directly to the metallacarborane cage. Furthermore, we found that proper hydrophilic-lipophilic balance is crucial for the selective activity of the tested compounds toward S. aureus over mammalian cells. The patterns proposed in this paper can be useful in the development of metallacarborane-based antibiotics with potent antibacterial properties and low cytotoxicity.

PMID:37903296 | DOI:10.1021/acs.jmedchem.3c01516

Cell Oncol (Dordr). 2023 Oct 30. doi: 10.1007/s13402-023-00894-7. Online ahead of print.

ABSTRACT

PURPOSE: TRPV1 is a nonselective Ca2+ channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly.

METHOD: The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry.

RESULTS: In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca2+-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4+ T cells, CD8+ T cells, GZMB+CD8+ T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC.

CONCLUSION: Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.

PMID:37902941 | DOI:10.1007/s13402-023-00894-7

Front Med (Lausanne). 2023 Oct 11;10:1213889. doi: 10.3389/fmed.2023.1213889. eCollection 2023.

ABSTRACT

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

PMID:37901413 | PMC:PMC10600400 | DOI:10.3389/fmed.2023.1213889

Front Immunol. 2023 Oct 13;14:1227897. doi: 10.3389/fimmu.2023.1227897. eCollection 2023.

ABSTRACT

Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants - recipients carried the C allele more often than their donors (0.975 vs 0.865, p<0.0001). Increased soluble HLA-E (sHLA-E) levels detected in recipients' serum 30 days after transplantation seemed to play a prognostic and protective role. It was observed that recipients with higher sHLA-E levels were less prone to chronic GvHD (11.65 vs 6.33 pg/mL, p=0.033) or more severe acute GvHD grades II-IV (11.07 vs 8.04 pg/mL, p=0.081). Our results also showed an unfavourable role of HLA-E donor-recipient genetic incompatibility in CMV infection development after transplantation (OR=5.92, p=0.014). Frequencies of NK cells (both CD56dim and CD56bright) expressing NKG2C were elevated in recipients who developed CMV, especially 30 and 90 days post-transplantation (p<0.03). Percentages of NKG2C+ NK cells lacking NKG2A expression were also increased in these patients. Moreover, recipients carrying a NKG2C deletion characterized with decreased frequency of NKG2C+ NK cells (p<0.05). Our study confirms the importance of NK cells in the development of post-transplant complications and highlights the effect of HLA-E and NKG2C genetic variants, sHLA-E serum concentration, as well as NKG2C surface expression on transplant outcome.

PMID:37901227 | PMC:PMC10611459 | DOI:10.3389/fimmu.2023.1227897

Front Genet. 2023 Oct 13;14:1230998. doi: 10.3389/fgene.2023.1230998. eCollection 2023.

ABSTRACT

Objective: Estrogen receptor breast cancer (BC) is characterized by the expression of estrogen receptors. It is the most common cancer among women, with an incidence rate of 2.26 million cases worldwide. The aim of this study was to identify differentially expressed genes and isoform switching between estrogen receptor positive and triple negative BC samples. Methods: The data were collected from ArrayExpress, followed by preprocessing and subsequent mapping from HISAT2. Read quantification was performed by StringTie, and then R package ballgown was used to perform differential expression analysis. Functional enrichment analysis was conducted using Enrichr, and then immune genes were shortlisted based on the ScType marker database. Isoform switch analysis was also performed using the IsoformSwitchAnalyzeR package. Results: A total of 9,771 differentially expressed genes were identified, of which 86 were upregulated and 117 were downregulated. Six genes were identified as mainly associated with estrogen receptor positive BC, while a novel set of ten genes were found which have not previously been reported in estrogen receptor positive BC. Furthermore, alternative splicing and subsequent isoform usage in the immune system related genes were determined. Conclusion: This study identified the differential usage of isoforms in the immune system related genes in cancer cells that suggest immunosuppression due to the dysregulation of CXCR chemokine receptor binding, iron ion binding, and cytokine activity.

PMID:37900178 | PMC:PMC10611502 | DOI:10.3389/fgene.2023.1230998

Front Genet. 2023 Oct 13;14:1281075. doi: 10.3389/fgene.2023.1281075. eCollection 2023.

ABSTRACT

Psychotropic medications are typically prescribed in a trial-and-error fashion, and some providers are beginning to utilize pharmacogenetic testing (PGx) as a supplemental prescribing tool in treatment decision making. PGx testing shows potential in enhancing provider insights into personalized prescribing for patients by examining genetic information related to drug metabolism. Literature points to providers' lack of knowledge in PGx interpretation as a main barrier, including psychiatric mental health nurse practitioners (PMHNPs). The aim of this study was to measure a difference, if any, in the knowledge and perceptions of PGx after implementation using a pre-post design. This study implemented an educational intervention on graduate nursing students (n = 15). Data were collected by using a pre- and post-interventional questionnaire. Results demonstrated a significant difference in findings related to students' knowledge (p < 0.001), students' skills related to pharmacogenetics, (p < 0.001), as well as students' perceived ability to implement pharmacogenetics into their practice, (p = 0.028). The authors propose that the knowledge gained from the study demonstrates the importance of introducing PGx education into the PMHNP curricula and to prepare future PMHNPs to confidently utilize PGx in their clinical practice.

PMID:37900176 | PMC:PMC10611450 | DOI:10.3389/fgene.2023.1281075

J Mood Anxiety Disord. 2023 Oct;3:100026. doi: 10.1016/j.xjmad.2023.100026. Epub 2023 Sep 21.

ABSTRACT

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression. Results showed that PTSD (β = .199) and AUD (β = .186) were associated with a quickened pace of epigenetic aging over time (ps < .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology.

PMID:37900051 | PMC:PMC10602583 | DOI:10.1016/j.xjmad.2023.100026

Genes (Basel). 2023 Sep 24;14(10):1858. doi: 10.3390/genes14101858.

ABSTRACT

BACKGROUND: Genetic testing may provide information for diagnostic, prognostic and pharmacogenetic purposes. The PREPARE study recently showed that the number of clinically relevant adverse drug reactions could be reduced via genotype-guided treatment. The aim of this work was to assess the relevance of genetic testing and its actual use in consecutive rheumatic outpatients.

METHODS: A retrospective cross-sectional analysis was performed with data from a prospectively designed observational project with outpatients consecutively recruited from a university clinic of rheumatology.

RESULTS: In this cohort of 2490 patients, the potential need for genetic testing is immense, with 57.3% of patients having the potential to benefit from genetic testing according to their diagnosis and treatment and 53.3% of patients with actually performed genetic testing for diagnostic, prognostic or pharmacogenetic purposes. In detail, patients would potentially benefit from genetic testing especially for therapeutic (28.0%) and diagnostic (26.9%) purposes. Genetic testing was performed for diagnostic purposes in 51.6% of subjects, for pharmacogenetic purposes in 3.7% and for prognostic purposes in 0.1%. The ratio between the number of patients who had had tests performed to those with a potential need for genetic testing decreased with age, from 127.1% for 20 to <30-year-old patients to 46.1% for 80 to <90-year-old patients. Pharmacogenetic testing was only performed for disease-related medications.

CONCLUSIONS: Genetic testing is frequently needed in patients with rheumatic diseases. The value of pharmacogenetic testing is certainly underestimated, especially in case of medications for comorbidities.

PMID:37895207 | PMC:PMC10606470 | DOI:10.3390/genes14101858

Eur J Clin Pharmacol. 2023 Oct 28. doi: 10.1007/s00228-023-03587-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution model has been already proposed in the past to accurately describe this phenomenon. These previous population pharmacokinetics models (POPPK) have been developed using iterative two stage Bayesian (IT2B) or non-parametric adaptive grid (NPAG) methods. However, non-linear mixed effect (NLME) approaches based on stochastic approximation expectation-maximization (SAEM) algorithms have never been published so far for this particular model. The objectives of this study were (i) to implement the double absorption gamma model in Monolix, (ii) to compare different absorption models to describe the pharmacokinetics of MMF, and (iii) to develop a limited sampling strategy (LSS) to estimate AUC in pediatric SLE patients.

MATERIAL AND METHODS: A data splitting of full pharmacokinetic profiles sampled in 67 children extracted either from the expert system ISBA (n = 34) or the hospital Saint Louis (n = 33) was performed into train (75%) and test (25%) sets. A POPPK was developed for MPA in the train set using a NLME and the SAEM algorithm and different absorption models were implemented and compared (first order, transit, or simple and double gamma). The best limited sampling strategy was then determined in the test set using a maximum-a-posteriori Bayesian method to estimate individual PK parameters and AUC based on three blood samples compared to the reference AUC calculated using the trapezoidal rule applied on all samples and performances were assessed in the test set.

RESULTS: Mean patient age and dose was 13 years old (5-18) and 18.1 mg/kg (7.9-47.6), respectively. MPA concentrations (764) from 107 occasions were included in the analysis. A double gamma absorption with a first-order elimination from the central compartment best fitted the data. The optimal LSS with samples at 30 min, 2 h, and 3 h post-dose exhibited good performances in the test set (mean bias - 0.32% and RMSE 21.0%).

CONCLUSION: The POPPK developed in this study adequately estimated the MPA AUC in pediatric patients with SLE based on three samples. The double absorption gamma model developed with the SAEM algorithm showed very accurate fit and reduced computation time.

PMID:37897528 | DOI:10.1007/s00228-023-03587-0

J Biomol Struct Dyn. 2023 Oct 28:1-10. doi: 10.1080/07391102.2023.2275186. Online ahead of print.

ABSTRACT

The renin enzyme is considered a promising target for hypertension and renal diseases. Over the last three decades, several experimental and theoretical studies have been engaged in the discovery of potent renin inhibitors. The identified inhibitors that undergo clinical trials are still failing to meet the criteria of potency and safety. To date, there is no specific FDA-approved drug for renin inhibition. Our theoretical opinion describes that the most potent compounds identified in experimental studies but lacking safety and overdose issues could be solved by finding similar molecules that are stable, very active, and have no side effects, which will kick start the drug discovery process. Here, we utilized the most potent direct renin inhibitors reported earlier, followed further by our theoretical study reported in 2019. Ligand-based virtual screening, density functional theory, and dynamic simulation studies were employed to explore the identified compounds and co-crystallized molecule in the protein structure. From the diverse databases, we have identified several identical molecules based on their structural features, such as functional groups like hydrophobic (H), aromatic rings (R), hydrogen bond acceptor (A), and donor (D). The HHHPR five-point pharmacophore feature was identified as a template pharmacophore to search the potential compounds from the Enamine and LifeChemical databases and have a good fitness score with known renin inhibitors. Furthermore, theoretical validation was done through several studies that confirmed the activity of the identified molecules. Overall, we propose that these compounds might break the failure in adverse events and improve the potency of hypertension treatment.Communicated by Ramaswamy H. Sarma.

PMID:37897186 | DOI:10.1080/07391102.2023.2275186

Pharmaceuticals (Basel). 2023 Oct 20;16(10):1496. doi: 10.3390/ph16101496.

ABSTRACT

INTRODUCTION: Up to 73% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) currently have prescriptions for psychotropic drugs. This is explained by a higher prevalence of medical and psychiatric chronic comorbidities, which favors polypharmacy, increasing the probability of the appearance of adverse events (AEs). These could be a preventable cause of harm to patients with ASD and an unnecessary waste of healthcare resources.

OBJECTIVE: To study the impact of pharmacogenetic markers on the prevention of AE appearance in a population with ASD and ID.

METHODS: This is a cross-sectional, observational study (n = 118, 72 participants completed all information) in the ASD population. Sociodemographic and pharmacological data were gathered. The Udvalg for Kliniske Undersøgelser Scale (UKU Scale) was used to identify AEs related to the use of psychotropic medication. Polymorphisms of DOP2, ABCB1, and COMT were genotyped and correlated with the AE to find candidate genes. Furthermore, a review of all medications assessed in a clinical trial for adults with autism was performed to enrich the search for potential pharmacogenetic markers, keeping in mind the usual medications.

RESULTS: The majority of the study population were men (75%) with multiple comorbidities and polypharmacy, the most frequently prescribed drugs were antipsychotics (69%); 21% of the participants had four or more AEs related to psychotropic drugs. The most common were "Neurological" and" Psychiatric" (both 41%). Statistical analysis results suggested a significant correlation between the neurological symptoms and the DOP2 genotype, given that they are not equally distributed among its allelic variants. The final review considered 19 manuscripts of medications for adults with ASD, and the confirmed genetic markers for those medications were consulted in databases.

CONCLUSION: A possible correlation between neurologic AEs and polymorphisms of DOP2 was observed; therefore, studying this gene could contribute to the safety of this population's prescriptions. The following studies are underway to maximize statistical power and have a better representation of the population.

PMID:37895967 | DOI:10.3390/ph16101496