Res Pharm Sci. 2023 Jan 19;18(2):121-137. doi: 10.4103/1735-5362.367792. eCollection 2023 Apr.

ABSTRACT

BACKGROUND AND PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer in which three hormone receptors are negative. This work aimed at identifying customized potential molecules inhibiting epidermal growth factor receptor (EGFR) by exploring variants using the pharmacogenomics approaches.

EXPERIMENTAL APPROACH: The pharmacogenomics approach has been followed to identify the genetic variants across the 1000 genomes continental population. Model proteins for the populations have been designed by including genetic variants in the reported positions. The 3D structures of the mutated proteins have been generated through homology modeling. The kinase domain present in the parent and the model protein molecules has been investigated. The docking study has been performed with the protein molecules against the kinase inhibitors evaluated by the molecular dynamic simulation studies. Molecular evolution has been performed to generate the potential derivatives of these kinase inhibitors suitable for the conserved region of the kinase domain. This study considered variants within the kinase domain as the sensitive region and remaining residues as the conserved region.

FINDINGS/RESULTS: The results reveal that few kinase inhibitors interact with the sensitive region. Among the derivatives of these kinase inhibitors molecules, the potential kinase inhibitor that interacts with the different population models has been identified.

CONCLUSIONS AND IMPLICATIONS: This study encompasses the importance of genetic variants in drug action as well as in the design of customized drugs. This research gives way to designing customized potential molecules inhibiting EGFR by exploring variants using the pharmacogenomics approaches.

PMID:36873279 | PMC:PMC9976054 | DOI:10.4103/1735-5362.367792

Front Psychiatry. 2023 Feb 16;14:1124796. doi: 10.3389/fpsyt.2023.1124796. eCollection 2023.

ABSTRACT

Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i.e., cariprazine, brexpiprazole, aripiprazole, lumateperone, and pimavanserin. Based on the analysis of 25 primary and secondary sources and the review of these agents' summaries of product characteristics, aripiprazole benefits from the most relevant data about the impact of gene variability on its pharmacokinetics and pharmacodynamics, with significant consequences on this antipsychotic's efficacy and tolerability. The determination of the CYP2D6 metabolizer status is important when administering aripiprazole, either as monotherapy or associated with other pharmacological agents. Allelic variability in genes encoding dopamine D2, D3, and serotonin, 5HT2A, 5HT2C receptors, COMT, BDNF, and dopamine transporter DAT1 was also associated with different adverse events or variations in the clinical efficacy of aripiprazole. Brexpiprazole also benefits from specific recommendations regarding the CYP2D6 metabolizer status and the risks of associating this antipsychotic with strong/moderate CYP2D6 or CYP3A4 inhibitors. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations about cariprazine refer to possible pharmacokinetic interactions with strong CYP3A4 inhibitors or inducers. Pharmacogenetic data about cariprazine is sparse, and relevant information regarding gene-drug interactions for lumateperone and pimavanserin is yet lacking. In conclusion, more studies are needed to detect the influence of gene variations on the pharmacokinetics and pharmacodynamics of new-generation antipsychotics. This type of research could increase the ability of clinicians to predict favorable responses to specific antipsychotics and to improve the tolerability of the treatment regimen in patients with SPD.

PMID:36873203 | PMC:PMC9978195 | DOI:10.3389/fpsyt.2023.1124796

Chem Biol Interact. 2023 Mar 1:110430. doi: 10.1016/j.cbi.2023.110430. Online ahead of print.

ABSTRACT

The mechanism of indomethacin toxicity at the systemic level is largely unknown. In this study, multi-specimen molecular characterization was conducted in rats treated with three doses of indomethacin (2.5, 5, and 10 mg/kg) for 1 week. Kidney, liver, urine, and serum samples were collected and analyzed using untargeted metabolomics. The kidney and liver transcriptomics data (10 mg indomethacin/kg and control) were subjected to a comprehensive omics-based analysis. Indomethacin exposure at 2.5 and 5 mg/kg doses did not cause significant metabolome changes, whereas considerable alterations in the metabolic profile compared to the control were induced by a dose of 10 mg/kg. Decreased levels of metabolites and an increase creatine level in the urine metabolome indicated injury to the kidney. The integrated omics analysis in both liver and kidney revealed an oxidant-antioxidant imbalance due to an excess of reactive oxygen species, likely originating from dysfunctional mitochondria. Specifically, indomethacin exposure induced changes in metabolites related to the citrate cycle, cell membrane composition, and DNA synthesis in the kidney. The dysregulation of genes related to ferroptosis and suppression of amino acid and fatty acid metabolism were evidence of indomethacin-induced nephrotoxicity. In conclusion, a multi-specimen omics investigation provided important insights into the mechanism of indomethacin toxicity. The identification of targets that ameliorate indomethacin toxicity will enhance the therapeutic utility of this drug.

PMID:36868495 | DOI:10.1016/j.cbi.2023.110430

Acta Neurol Belg. 2023 Mar 3. doi: 10.1007/s13760-023-02190-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Migraine usually ameliorates after menopause. However, 10-29% of women still experience migraine attacks after menopause, especially if menopause is surgical. The use of monoclonal antibodies against the calcitonin gene-related peptide (CGRP) is changing the landscape of migraine treatment. This study aims to explore the effectiveness and safety of anti-CGRP monoclonal antibodies in women in menopause.

METHODS: Women affected by either migraine or chronic migraine and treated with an anti-CGRP monoclonal antibody for up to 1 year. Visits were scheduled every 3 months.

RESULTS: Women in menopause displayed a similar response compared to women of childbearing age. Among women in menopause, the women experiencing surgical menopause seemed to exhibit a similar response compared to the ones experiencing physiological menopause. Erenumab and galcanezumab displayed similar effectiveness in women in menopause. No serious adverse events were registered.

DISCUSSION: The effectiveness of anti-CGRP monoclonal antibodies is almost the same between women in menopause and women of childbearing age, without appreciable differences between the different antibodies.

PMID:36867346 | DOI:10.1007/s13760-023-02190-5

Clin Transl Sci. 2023 Mar 2. doi: 10.1111/cts.13497. Online ahead of print.

ABSTRACT

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

PMID:36864560 | DOI:10.1111/cts.13497

Haematologica. 2023 Mar 2. doi: 10.3324/haematol.2022.282399. Online ahead of print.

ABSTRACT

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatmentdependent. In pre-clinical models of MM, synergy was observed in anti-tumor activity when poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.

PMID:36861411 | DOI:10.3324/haematol.2022.282399

Biol Pharm Bull. 2023;46(3):511-516. doi: 10.1248/bpb.b22-00810.

ABSTRACT

Pharmacogenetics (PGx) enhances personalized care, often reducing medical costs, and improving patients' QOL. Unlike single variant analysis, multiplex PGx panel tests can result in applying comprehensive PGx-guided medication to maximize drug efficacy and minimize adverse reactions. Among PGx genes, drug-metabolizing enzymes and drug transporters have significant roles in the efficacy and safety of various pharmacotherapies. In this study, a genotyping panel has been developed for the Japanese population called PGx_JPN panel comprising 36 variants in 14 genes for drug-metabolizing enzymes and drug transporters using a mass spectrometry-based genotyping method, in which all the variants could be analyzed in two wells for multiplex analysis. The verification test exhibited good concordance with the results analyzed using the other standard genotyping methods (microarray, TaqMan assay, or another mass spectrometry-based commercial kit). However, copy number variations such as CYP2D6*5 could not apply to this system. In this study, we demonstrated that the mass spectrometry-based multiplex method could be useful for in the simultaneous genotyping of more than 30 variants, which are essential among the Japanese population in two wells, except for copy number variations. Further study is needed to assess our panel to demonstrate the clinical use of pharmacogenomics for precision medicine in the Japanese population.

PMID:36858581 | DOI:10.1248/bpb.b22-00810

Biol Pharm Bull. 2023;46(3):412-418. doi: 10.1248/bpb.b22-00686.

ABSTRACT

While nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphism Arg139Cys (rs116855232) is known to be a risk factor for thiopurine-induced severe leukopenia, association with the NUDT15 gene polymorphism Arg139His (rs147390019) has not yet been clarified. In addition, the accuracy of TaqMan PCR to assess these two polymorphisms has not been investigated. In this study, we evaluated TaqMan PCR for detection of the NUDT15 single-nucleotide polymorphisms (SNPs) and examined the clinical impact of Arg139His on thiopurine-induced leukopenia. First, we demonstrated that a TaqMan PCR assay successfully detected the Arg139His polymorphism of NUDT15 in clinical samples. Next, the NUDT15 gene polymorphisms (Arg139Cys and Arg139His) were separately analyzed by TaqMan Real-Time PCR in 189 patients from August 2018 to July 2019. The incidences of leukopenia within 2 years were 16.2, 57.9, and 100% for arginine (Arg)/Arg, Arg/cysteine (Cys), and Arg/histidine (His), respectively. The leukopenia was significantly increased in Arg/Cys and Arg/His compared with Arg/Arg. This retrospective clinical study indicated that, in addition to Arg139Cys, Arg139His may be clinically associated with a high risk of leukopenia. Pharmacogenomics will help in selecting drugs and determining the individualized dosage of thiopurine drugs.

PMID:36858569 | DOI:10.1248/bpb.b22-00686

Korean J Med Educ. 2023 Mar;35(1):103-107. doi: 10.3946/kjme.2023.253. Epub 2023 Feb 28.

NO ABSTRACT

PMID:36858381 | DOI:10.3946/kjme.2023.253

Database (Oxford). 2023 Feb 28;2023:baad006. doi: 10.1093/database/baad006.

ABSTRACT

The development of high-throughput molecular testing techniques has enabled the large-scale exploration of the underlying molecular causes of diseases and the development of targeted treatment for specific genetic alterations. However, knowledge to interpret the impact of genetic variants on disease or treatment is distributed in different databases, scientific literature studies and clinical guidelines. AIMedGraph was designed to comprehensively collect and interrogate standardized information about genes, genetic alterations and their therapeutic and diagnostic relevance and build a multi-relational, evidence-based knowledge graph. Graph database Neo4j was used to represent precision medicine knowledge as nodes and edges in AIMedGraph. Entities in the current release include 30 340 diseases/phenotypes, 26 140 genes, 187 541 genetic variants, 2821 drugs, 15 125 clinical trials and 797 911 supporting literature studies. Edges in this release cover 621 731 drug interactions, 9279 drug susceptibility impacts, 6330 pharmacogenomics effects, 30 339 variant pathogenicity and 1485 drug adverse reactions. The knowledge graph technique enables hidden knowledge inference and provides insight into potential disease or drug molecular mechanisms. Database URL: http://aimedgraph.tongshugene.net:8201.

PMID:36856726 | DOI:10.1093/database/baad006

Hum Genomics. 2023 Feb 28;17(1):15. doi: 10.1186/s40246-023-00461-z.

ABSTRACT

BACKGROUND: Genetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking.

RESULTS: Frequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs.

CONCLUSIONS: This study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

PMID:36855170 | DOI:10.1186/s40246-023-00461-z

Pharmacogenet Genomics. 2023 Apr 1;33(3):51-58. doi: 10.1097/FPC.0000000000000493. Epub 2023 Feb 9.

ABSTRACT

OBJECTIVES: Type 2 diabetes (T2D) imposes an enormous burden all over the world in both developed and developing countries. Inter-individual differences are attributed to polymorphisms in candidate genes resulting in altered absorption, transportation, distribution, and metabolism of oral antidiabetic drugs (OADs). Hence, the present study was undertaken to evaluate the pharmacogenetic impact of SLC22A1 gene variant rs628031 (G/A) on metformin monotherapy in newly diagnosed untreated T2D patients.

METHODS: Newly diagnosed T2D patients ( n = 500) were enrolled according to inclusion/exclusion criteria. Initially, enrolled subjects were prescribed metformin monotherapy and followed up for at least 12 weeks. Response to metformin was evaluated in 478 patients who revisited for follow-up by measuring HbA1c.

RESULT: Out of 478 patients, 373 were responders to metformin monotherapy while 105 were non-responders. The pharmacogenetic impact was evaluated by genotype, haplotype, and pharmacogenetic analyses. 'GG' genotype and 'G' allele of SLC22A1 rs628031 G/A were observed in 48.8% and 67.7% of Met responders, respectively, while 20.9% and 49.1 % were in non-responders. Therefore, there was a 2.18-fold increase in the success rate of Met therapeutics.

CONCLUSION: Individuals carrying the 'GG' genotype or 'G' allele for SLC22A1 gene variant rs628031 G/A are better responders for Metformin monotherapy.

PMID:36853844 | DOI:10.1097/FPC.0000000000000493

Drug Metab Pers Ther. 2023 Mar 1. doi: 10.1515/dmpt-2022-0194. Online ahead of print.

ABSTRACT

Pharmacogenetics (PGx)-guided prescribing is an evidence-based precision medicine strategy. Although the past two decades have reported significant advancements in both the quality and quantity of PGx research studies, they are seldom done in developing countries like Bangladesh. This review identified and summarized PGx studies conducted in the Bangladeshi population by searching PubMed and Google Scholar. Additionally, a quality evaluation of the identified studies was also carried out. Eleven PGx studies were identified that looked at the effects of genetic variants on blood thinners (CYP2C9, VKORC1, and ITGB3), cancer drugs (TPMT, MTHFR, DPYD, ERCC1, GSTP1, XPC, XRCC1, TP53, XPD, and ABCC4), statins (COQ2, CYP2D6, and CYP3A5), and prednisolone (ABCB1, CYP3A5, and NR3C1) in the Bangladeshi population. Most studies were of low to moderate quality. Although the identified studies demonstrated the potential for PGx testing, the limited PGx literature in the Bangladeshi population poses a significant challenge in the widespread implementation of PGx testing in Bangladesh.

PMID:36854045 | DOI:10.1515/dmpt-2022-0194

Minerva Anestesiol. 2023 Feb 27. doi: 10.23736/S0375-9393.22.16983-X. Online ahead of print.

ABSTRACT

INTRODUCTION: Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients who might benefit from specific prophylactic and therapeutic antiemetic treatment. The aim of the present review was to investigate gene polymorphisms that influence 5-hydroxytryptamine (serotonin) type 3 receptor antagonists (5HT3RA) efficacy in PONV.

EVIDENCE AQUISITION: We included articles published from 2005 to 2022, utilizing the electronic databases PUBMED, EMBASE, COHRANE Library and ScienceDirect. To explore the relationship between genetic variations and 5HT3 receptor antagonist efficacy in PONV we focused on three different gene polymorphisms: the cytochrome P450 mono-oxygenase system gene (CYP2D6), the adenosine triphosphate (ATP)-binding cassette subfamily B gene (ABCB1) as well as the 5HT3 receptor gene (5HT3R). We also explored the relationship between the above genetic variations and their impact on 5HT3RA efficacy in the context of chemotherapy induced nausea and vomiting.

EVIDENCE SYNTHESIS: Our search retrieved a total of 70 articles; 29 of them were included in the present review. Regarding polymorphisms of the CYP2D6 gene and the efficacy of serotonin antagonists in PONV, the ultra-rapid metabolizer genotype was associated with reduced efficacy of ondansetron, dolasetron and tropisetron, with the latter presenting more pronounced failure in these patients, while granisetron's efficacy remained unaffected. Regarding variations in the ABCB1 gene, three polymorphisms ("2677G>T/A" in exon 21; "3435C>T" in exon 27; "C1236T" in exon 12) were associated with a better response to ondansetron and ramosetron, while they did not affect palonosetron's efficacy. Additionally, polymporphisms of the 5-HT3B receptor gene were associated with ondancetron's postoperative efficacy; the "100_-102AAG" deletion variant was associated with reduced efficacy, while the Y129S variant did not show any effect on the drug's antiemetic effect.

CONCLUSIONS: This review highlights that inefficacy of a specific drug in managing PONV could be attributed to specific genetic profiles and patients would possibly benefit from a drug switch.

PMID:36852569 | DOI:10.23736/S0375-9393.22.16983-X

Mol Biol Rep. 2023 Feb 27. doi: 10.1007/s11033-023-08304-9. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) plays a central role in the selection of targeted therapies that underpins precision-medicine. We investigated the prevalence of three important pharmacogenetic variants of VKORC1, CYP2C9, and CYP3A5 genes among Pakistani populations.

METHODS: A total of 1104 individuals were included representing thirteen major ethnicities. Samples were genotyped by using PCR-RFLP analysis. The allelic and genotypic frequencies of the three SNV's were calculated and were compared with the world's population data (ALFA, gnomAD, and 1000Genome, 1 K databases), using the chi-square test.

RESULTS: We found overall frequencies of functional-alleles of VKORC1 0.43, CYP2C9 0.94, and CYP3A5 0.14 in our population. Data showed a low prevalence of homozygous functional genotypes of VKORC1 (0.18; 0.0-0.45) and CYP3A5 (0.04; 0.0-0.22), and a high frequency of CYP2C9 (0.885; 0.80-1.0) across ethnicities. Genotyping distribution of VKCOR1 functional genotype was varied across ethnic groups such as 0.0-0.10 in Brahuis and Mohanas, Sindhis, Rajputs, and Gujjars populations, 0.11-0.20 in Makranis, Parsis, and Burusho populations, and 0.20-0.30 in Kalash, Kashmiris and Baloch populations. The highest VKORC1 (CC) was found in Pathans (0.45) and Hazaras (0.39) populations. Interestingly, we found a high prevalence of functional genotype CYP2C9 (rs1799853; C) and non-functional genotype of CYP3A5 (rs776746; T) across various ethnic groups of Pakistan.

CONCLUSION: Data regarding prevalence of clinically important pharmacogenomics SNVs could be useful in drug adjustment and avoiding adverse drug reactions in a specific ethnic population. This could help in moving current medical practices toward precision medicine in our part of the world.

PMID:36849858 | DOI:10.1007/s11033-023-08304-9

Int J Pharm. 2023 Feb 25:122785. doi: 10.1016/j.ijpharm.2023.122785. Online ahead of print.

ABSTRACT

The current healthcare dynamic has shifted from one-size-fits-all to patient-centred care, with our increased understanding of pharmacokinetics and pharmacogenomics demanding a switch to more individualised therapies. As the pharmaceutical industry remains yet to succumb to the push of a technological paradigm shift, pharmacists lack the means to provide completely personalised medicine (PM) to their patients in a safe, affordable, and widely accessible manner. As additive manufacturing technology has already established its strength in producing pharmaceutical formulations, it is necessary to next consider methods by which this technology can create PM accessible from pharmacies. In this article, we reviewed the limitations of current pharmaceutical manufacturing methods for PMs, three-dimensional (3D) printing techniques that are most beneficial for PMs, implications of bringing this technology into pharmacy practice, and implications for policy surrounding 3D printing techniques in the manufacturing of PMs.

PMID:36849040 | DOI:10.1016/j.ijpharm.2023.122785

Front Oncol. 2023 Feb 9;13:1107307. doi: 10.3389/fonc.2023.1107307. eCollection 2023.

ABSTRACT

BACKGROUND: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma.

METHODS: The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks).

DISCUSSION: Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival.

CLINICAL TRIAL REGISTRATION: eudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.

PMID:36845751 | PMC:PMC9949553 | DOI:10.3389/fonc.2023.1107307

Front Cell Infect Microbiol. 2023 Feb 10;13:1108155. doi: 10.3389/fcimb.2023.1108155. eCollection 2023.

ABSTRACT

While early and precise diagnosis is the key to eliminating tuberculosis (TB), conventional methods using culture conversion or sputum smear microscopy have failed to meet demand. This is especially true in high-epidemic developing countries and during pandemic-associated social restrictions. Suboptimal biomarkers have restricted the improvement of TB management and eradication strategies. Therefore, the research and development of new affordable and accessible methods are required. Following the emergence of many high-throughput quantification TB studies, immunomics has the advantages of directly targeting responsive immune molecules and significantly simplifying workloads. In particular, immune profiling has been demonstrated to be a versatile tool that potentially unlocks many options for application in TB management. Herein, we review the current approaches for TB control with regard to the potentials and limitations of immunomics. Multiple directions are also proposed to hopefully unleash immunomics' potential in TB research, not least in revealing representative immune biomarkers to correctly diagnose TB. The immune profiles of patients can be valuable covariates for model-informed precision dosing-based treatment monitoring, prediction of outcome, and the optimal dose prediction of anti-TB drugs.

PMID:36844400 | PMC:PMC9950414 | DOI:10.3389/fcimb.2023.1108155

Front Pharmacol. 2023 Feb 9;14:1111115. doi: 10.3389/fphar.2023.1111115. eCollection 2023.

ABSTRACT

Introduction: Although pharmacogenetics and pharmacogenomics have been at the forefront of research aimed at finding novel personalized therapies, the focus of research has recently extended to the potential of intestinal microbiota to affect drug efficacy. Complex interplay of gut microbiota with bile acids may have significant repercussions on drug pharmacokinetics. However, far too little attention has been paid to the potential implication of gut microbiota and bile acids in simvastatin response which is characterized by large interindividual variations. The Aim: In order to gain more insight into the underlying mechanism and its contribution in assessing the clinical outcome, the aim of our study was to examine simvastatin bioaccumulation and biotransformation in probiotic bacteria and the effect of bile acids on simvastatin bioaccumulation in in vitro conditions. Materials and methods: Samples with simvastatin, probiotic bacteria and three different bile acids were incubated at anaerobic conditions at 37°C for 24 h. Extracellular and intracellular medium samples were collected and prepared for the LC-MS analysis at predetermined time points (0 min, 15 min, 1 h, 2 h, 4 h, 6 h, 24 h). The concentrations of simvastatin were analyzed by LC-MS/MS. Potential biotransformation pathways were analyzed using a bioinformatics approach in correlation with experimental assay. Results: During the incubation, simvastatin was transported into bacteria cells leading to a drug bioaccumulation over the time, which was augmented upon addition of bile acids after 24 h. A decrease of total drug level during the incubation indicates that the drug is partly biotransformed by bacterial enzymes. According to the results of bioinformatics analysis, the lactone ring is the most susceptible to metabolic changes and the most likely reactions include ester hydrolysis followed by hydroxylation. Conclusion: Results of our study reveal that bioaccumulation and biotransformation of simvastatin by intestinal bacteria might be the underlying mechanisms of altered simvastatin bioavailability and therapeutic effect. Since this study is based only on selected bacterial strains in vitro, further more in-depth research is needed in order to elicit completely the contribution of complex drug-microbiota-bile acids interactions to overall clinical response of simvastatin which could ultimately lead to novel approaches for the personalized lipid-lowering therapy.

PMID:36843926 | PMC:PMC9946981 | DOI:10.3389/fphar.2023.1111115

Schizophr Bull. 2023 Feb 26:sbad009. doi: 10.1093/schbul/sbad009. Online ahead of print.

ABSTRACT

BACKGROUND: Antipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels.

STUDY DESIGN: Linear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed.

STUDY RESULTS: Each 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs >3 months (+0.84% and +0.47% per month, respectively, P < .001), with a significant association with the dose for durations >3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P < .001) and +1.32% among men (P < .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses >300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found.

CONCLUSIONS: This study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months.

PMID:36841954 | DOI:10.1093/schbul/sbad009