Front Neurol. 2023 Jan 9;13:1042888. doi: 10.3389/fneur.2022.1042888. eCollection 2022.

ABSTRACT

OBJECTIVE: Tumor-treating fields (TTFields) are a new therapeutic modality for patients with glioblastoma (GBM). However, studies on survival outcomes of TTFields are rarely reported in China. This study aimed to examine the clinical efficacy and safety of TTFields therapy for GBM in China.

METHODS: A total of 93 patients with newly diagnosed GBM (ndGBM) and recurrent GBM (rGBM) were included in our study retrospectively. They were divided into two groups based on whether they used TTFields. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed.

RESULTS: Among the patients with ndGBM, there were 13 cases with TTFields and 39 cases with no TTFields. The median PFS was 15.3 [95% confidence interval (CI): 6.5-24.1] months and 10.6 (95% CI: 5.4-15.8) months in the two groups, respectively, with P = 0.041. The median OS was 24.8 (95% CI: 6.8-42.8) months and 18.6 (95% CI: 11.4-25.8) months, respectively, with P = 0.368. Patients with subtotal resection (STR) who used TTFields had a better PFS than those who did not (P = 0.003). Among the patients with rGBM, there were 13 cases with TTFields and 28 cases with no TTFields. The median PFS in the two groups was 8.4 (95% CI: 1.7-15.2) months and 8.0 (95% CI: 5.8-10.2) months in the two groups, respectively, with P = 0.265. The median OS was 10.6 (95% CI: 4.8-16.4) months and 13.3 (95% CI: 11.0-15.6) months, respectively, with P = 0.655. A total of 21 patients (21/26, 80.8%) with TTFields developed dermatological adverse events (dAEs). All the dAEs could be resolved or controlled.

CONCLUSION: TTFields therapy is a safe and effective treatment for ndGBM, especially in patients with STR. However, it may not improve survival in patients with rGBM.

PMID:36698900 | PMC:PMC9869119 | DOI:10.3389/fneur.2022.1042888

Front Neurol. 2023 Jan 9;13:1054333. doi: 10.3389/fneur.2022.1054333. eCollection 2022.

ABSTRACT

INTRODUCTION: Migraine is a complex disorder with genetic and environmental inputs. Cumulative evidence implicates oxidative stress (OS) in migraine pathophysiology while genetic variability may influence an individuals' oxidative/antioxidant capacity. Aim of the current study was to investigate the impact of eight common OS-related genetic variants [rs4880 (SOD2), rs1001179 (CAT), rs1050450 (GPX1), rs1695 (GSTP1), rs1138272 (GSTP1), rs1799983 (NOS3), rs6721961 (NFE2L2), rs660339 (UCP2)] in migraine susceptibility and clinical features in a South-eastern European Caucasian population.

METHODS: Genomic DNA samples from 221 unrelated migraineurs and 265 headache-free controls were genotyped for the selected genetic variants using real-time PCR (melting curve analysis).

RESULTS: Although allelic and genotypic frequency distribution analysis did not support an association between migraine susceptibility and the examined variants in the overall population, subgroup analysis indicated significant correlation between NOS3 rs1799983 and migraine susceptibility in males. Furthermore, significant associations of CAT rs1001179 and GPX1 rs1050450 with disease age-at-onset and migraine attack duration, respectively, were revealed. Lastly, variability in the CAT, GSTP1 and UCP2 genes were associated with sleep/weather changes, alcohol consumption and physical exercise, respectively, as migraine triggers.

DISCUSSION: Hence, the current findings possibly indicate an association of OS-related genetic variants with migraine susceptibility and clinical features, further supporting the involvement of OS and genetic susceptibility in migraine.

PMID:36698892 | PMC:PMC9868718 | DOI:10.3389/fneur.2022.1054333

Front Oncol. 2023 Jan 9;12:966527. doi: 10.3389/fonc.2022.966527. eCollection 2022.

ABSTRACT

In a phase II trial of nivolumab in advanced thymic carcinoma (UMIN000022007), long SD (SD for more than 24 weeks) was seen in three patients and irAE (Gr2 or higher) was seen in four patients among 15 patients. Here, we report preplanned comprehensive biomarker analyses. We obtained tumor samples for immunohistochemistry, peripheral blood mononuclear cells (PBMCs), plasma and serum for pharmacokinetic analysis of nivolumab and cytokine evaluations, and whole blood for immuno pharmacogenomic (PGx) analysis. PD-L1 expression on tumor cells were not associated with therapeutic efficacy, but FOXP3 expression in tumor area and stroma, CD204 expression in stroma, and MHC class I in tumor area were all low among long SD patients. PBMC of long SD patients presented with larger number of naïve/memory cells prior to treatment, suggesting priming after nivolumab administration. Immuno-PGx analysis showed non-synonymous SNVs in ITGAX and PDCD1 had some correlation with PFS. Concentration of nivolumab in blood during the treatment was not related to PFS, with their overall trend towards decreased nivolumab concentration in patients with irAEs. Low immunogenicity of thymic carcinoma demonstrated in our study may require the activation of immune systems via a combination of immune checkpoint blockades.

PMID:36698400 | PMC:PMC9869613 | DOI:10.3389/fonc.2022.966527

Lancet Psychiatry. 2023 Feb;10(2):80. doi: 10.1016/S2215-0366(22)00432-1.

NO ABSTRACT

PMID:36697125 | DOI:10.1016/S2215-0366(22)00432-1

Genes Chromosomes Cancer. 2023 Jan 25. doi: 10.1002/gcc.23127. Online ahead of print.

ABSTRACT

Renal cell carcinoma with rearrangement of TFE3 (Transcription Factor for Immunoglobulin Heavy-Chain Enhancer 3) (TFE3-rearranged RCC) at Xp11.2 is a rare tumor entity but the most frequent among the MiT (Microphthalmia Transcription Factor) family translocation renal cell carcinomas. Here, we report the identification of a new VCP::TFE3 fusion gene as the result of a t(X;9)(p11.23;p13.3) translocation identified by Whole Transcriptome Sequencing. No other relevant molecular alteration was identified by Whole Exome Sequencing. This case showed typical morphological features of TFE3-rearranged RCC with positive TFE3 immunostaining and positive TFE3 break-apart FISH. MET was also overexpressed on immunohistochemistry. The patient had metastatic disease and was treated by surgery and five lines of therapy, including 24 months of stable disease on the MET inhibitor cabozantinib, with an overall survival of 7 years. In addition to expanding the spectrum of TFE3 rearrangement partners, this report highlights the complexity of these tumors and supports the development of translational programs in renal cancer. This article is protected by copyright. All rights reserved.

PMID:36695651 | DOI:10.1002/gcc.23127

J Vet Pharmacol Ther. 2023 Jan 23. doi: 10.1111/jvp.13113. Online ahead of print.

ABSTRACT

CYP2D15 is a major drug metabolizing P450 in canine liver. Like the human orthologue (CYP2D6), this enzyme is highly polymorphic with at least five common nonsynonymous variants reported that result in amino acid changes, including p.Ile109Val, p.Leu115Phe, p.Gly186Ser, p.Ile250Phe and p.Ile307Val. Furthermore, a mRNA splice variant of CYP2D15 has been found in canine liver that lacks the exon 3 gene region resulting in an inactive enzyme. The objective of this study was to evaluate whether any of these amino acid variants or the exon 3 deletion mRNA variant (exon3-delta) was associated with differences in CYP2D15-selective activities or protein content in a bank of canine livers. Livers were obtained from 25 Beagles and 34 dogs of various other breeds. CYP2D15-selective activities measured included dextromethorphan o-demethylation and tramadol o-demethylation. Reverse transcription PCR showed that 76% of livers (44/58) expressed both exon3-delta and normally spliced CYP2D15 RNA, while the remaining 24% (14/58) expressed only normally spliced RNA. The presence of exon3-delta was not correlated with CYP2D15 activities or protein content. Compared with wild-type livers, Beagle dog livers heterozygous for the p.Ile109Val and p.Gly186Ser variants showed from 40 to 50% reductions in median enzyme activities, while heterozygous p.Gly186Ser livers were associated with a 41% reduction in median CYP2D15 protein content (p < .05; Dunn's test). In the entire liver bank, livers homozygous for p.Ile109Val were also associated with a 40% reduction in median dextromethorphan O-demethylation activities versus wild-type livers (p < .05). These results identify several nonsynonymous CYP2D15 gene variants associated with variable CYP2D15 metabolism in canine liver.

PMID:36691326 | DOI:10.1111/jvp.13113

Am Fam Physician. 2023 Jan;107(1):97-98.

NO ABSTRACT

PMID:36689984

Blood Adv. 2023 Jan 23:bloodadvances.2022009088. doi: 10.1182/bloodadvances.2022009088. Online ahead of print.

ABSTRACT

Cytarabine arabinoside (Ara-C) has been the cornerstone of AML chemotherapy for decades. Following cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway have been shown to impact intracellular abundance of Ara-CTP and thus its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance and consequently, clinical response in AML. Despite this the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within SAMHD1 gene for association with clinical outcome in 400 newly diagnosed pediatric AML patients from two clinical trials- AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least one clinical outcome endpoint: minimal residual disease (MRD) after induction I, event free survival (EFS), or overall survival (OS) in the two cohorts. In an independent cohort of patients from COG-AAML1031 trial (n=854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, adjusting for other prognostic factors such as race, age, risk group, and white blood cell count, all the SNPs remained independent predictors of clinical outcome endpoints. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

PMID:36689724 | DOI:10.1182/bloodadvances.2022009088

Front Behav Neurosci. 2023 Jan 5;16:1068736. doi: 10.3389/fnbeh.2022.1068736. eCollection 2022.

ABSTRACT

Stimulation of remyelination is critical for the treatment of multiple sclerosis (MS) to alleviate symptoms and protect the myelin sheath from further damage. The current study aimed to investigate the possible therapeutic effects of combining vitamin D3 (Vit D3) and siponimod (Sipo) on enhancing remyelination and modulating microglia phenotypes in the cuprizone (CPZ) demyelination mouse model. The study was divided into two stages; demyelination (first 5 weeks) and remyelination (last 4 weeks). In the first 5 weeks, 85 mice were randomly divided into two groups, control (n = 20, standard rodent chow) and CPZ (n = 65, 0.3% CPZ mixed with chow for 6 weeks, followed by 3 weeks of standard rodent chow). At week 5, the CPZ group was re-divided into four groups (n = 14) for remyelination stages; untreated CPZ (0.2 ml of CMC orally), CPZ+Vit D3 (800 IU/kg Vit D3 orally), CPZ+Sipo (1.5 mg/kg Sipo orally), and CPZ+Vit D3 (800 IU/kg Vit D3) + Sipo (1.5 mg/kg Sipo orally). Various behavioral tasks were performed to evaluate motor performance. Luxol Fast Blue (LFB) staining, the expression level of myelin basic protein (MBP), and M1/M2 microglia phenotype genes were assessed in the corpus callosum (CC). The results showed that the combination of Vit D3 and Sipo improved behavioral deficits, significantly promoted remyelination, and modulated expression levels of microglia phenotype genes in the CC at early and late remyelination stages. These results demonstrate for the first time that a combination of Vit D3 and Sipo can improve the remyelination process in the cuprizone (CPZ) mouse model by attenuating the M1 microglia phenotype. This may help to improve the treatment of MS patients.

PMID:36688131 | PMC:PMC9849768 | DOI:10.3389/fnbeh.2022.1068736

Front Genet. 2023 Jan 4;13:1088189. doi: 10.3389/fgene.2022.1088189. eCollection 2022.

ABSTRACT

A microRNA is a small, single-stranded, non-coding ribonucleic acid that plays a crucial role in RNA silencing and can regulate gene expression. With the in-depth study of miRNA in development and disease, miRNA has become an attractive target for novel therapeutic strategies. Exploring miRNA targeting therapy only through experiments is expensive and laborious, so it is essential to develop novel and efficient computational methods to narrow down the search. Recent advances in machine learning applied in biomedical informatics provide opportunities to explore miRNA-targeting drugs, thus promoting miRNA therapeutics. This review provides an overview of recent advancements in miRNA targeting therapeutic using machine learning. First, we mainly describe the basics of predicting miRNA targeting drugs, including pharmacogenomic data resources and data preprocessing. Then we present primary machine learning algorithms and elaborate their application in discovering relationships among miRNAs, drugs, and diseases. Along with the progress of miRNA targeting therapeutics, we finally analyze and discuss the current challenges and opportunities that machine learning confronts.

PMID:36685965 | PMC:PMC9845262 | DOI:10.3389/fgene.2022.1088189

Front Genet. 2023 Jan 4;13:1070236. doi: 10.3389/fgene.2022.1070236. eCollection 2022.

ABSTRACT

Underrepresentation of subpopulations within geo-ancestral groups engaged in research can exacerbate health disparities and impair progress toward personalized medicine. This is particularly important when implementing pharmacogenomics which uses genomic-based sources of variability to guide medication selection and dosing. This mini-review focuses on pharmacogenomic findings with Hmong in the United States and their potential clinical implications. By actively engaging Hmong community in pharmacogenomic-based research, several clinically relevant differences in allele frequencies were observed within key pharmacogenes such as CYP2C9 and CYP2C19 in Hmong compared to those in either East Asians or Europeans. Additionally, using state-of-the-art genome sequencing approaches, Hmong appear to possess novel genetic variants within CYP2D6, a critical pharmacogene affecting pharmacokinetics of a broad range of medications. The allele frequency differences and novel alleles in Hmong have translational impact and real-world clinical consequences. For example, Hmong patients exhibited a lower warfarin stable dose requirement compared to East Asian patients. This was predicted based on Hmong's unique genetic and non-genetic factors and confirmed using real-world data from clinical practice settings. By presenting evidence of the genetic uniqueness and its translational impact within subpopulations, such as the Hmong, we hope to inspire greater inclusion of other geo-ancestrally underrepresented subpopulations in pharmacogenomic-based research.

PMID:36685861 | PMC:PMC9845584 | DOI:10.3389/fgene.2022.1070236

Saudi Pharm J. 2023 Jan;31(1):180-183. doi: 10.1016/j.jsps.2022.11.016. Epub 2022 Dec 1.

ABSTRACT

OBJECTIVES: Studies have proved that UGT1A1 (*6, *28 and *93) gene polymorphism was closely related to the side effects of irinotecan. This study intends to perform a correlation analysis on the relationship between pharmacogenomic studies and ADRs based on time series.

METHODS: The ADRs related to irinotecan were derived through the FAERS; searched all pharmacogenomic studies in PubMed and Web of Science; then analyzed the sequence of correlation coefficients between total ADRs, fatal ADRs and pharmacogenomic studies under different time offset.

RESULTS: There is a positive correlation between the number of total ADRs and pharmacogenomic studies, of which the maximum correlation coefficient was 0.78 (95 % CI: 0.58-0.90), with a lag of 1 year. There is also a positive correlation between the number of fatal ADRs and pharmacogenomic studies, with the maximum correlation coefficient of 0.87 (95 % CI: 0.73-0.94) and a offset of - 4 years.

CONCLUSION: It was found that both the total ADRs and fatal ADRs were significantly positively correlated with change trend of published pharmacogenomic literatures, which confirmed the role of pharmacogenomic research in promoting the safe use of irinotecan, and have a faster response time in reducing fatal ADRs during clinical application.

PMID:36685299 | PMC:PMC9845122 | DOI:10.1016/j.jsps.2022.11.016

Clin Ther. 2023 Jan 20:S0149-2918(22)00418-0. doi: 10.1016/j.clinthera.2022.12.012. Online ahead of print.

ABSTRACT

A nonoptimized medication therapy (NOMT) event is an iatrogenic hazard or incident associated with medications and is a leading cause of death, serious injury, and illness. NOMT events are often related to multidrug interactions in patients with polypharmacy. In these patients, NOMT events can be avoided by using advanced clinical decision support systems and clinical interventions such as separating the time of administration of certain drugs during the day. At the individual level, medication reconciliation is a first logical step for reducing adverse side effects. Then, intersubject variability in drug response should be considered to optimize patient drug regimens. Furthermore, patient pharmacogenomic status information can help ensure appropriateness of drug therapy. However, in patients with polypharmacy, such information is most valuable when combined with phenoconversion probability. At a population level, the virtual addition of drugs to various drug regimens and the use of a medication risk score can help predict the risk of NOMT events. This review outlines some of the mechanisms behind multidrug interactions and their association with drug safety and NOMTs, polypharmacy and its impact on patient outcomes, the value of pharmacogenomics, and an assessment of simulation studies and the virtual addition of drugs to a drug regimen using real-world data. (Clin Ther. 2023;45:XXX-XXX) © 2023 Elsevier HS Journals, Inc.

PMID:36682993 | DOI:10.1016/j.clinthera.2022.12.012

Am J Hum Genet. 2023 Jan 13:S0002-9297(23)00003-4. doi: 10.1016/j.ajhg.2023.01.003. Online ahead of print.

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.

PMID:36681081 | DOI:10.1016/j.ajhg.2023.01.003

Pharmacotherapy. 2023 Jan 20. doi: 10.1002/phar.2768. Online ahead of print.

ABSTRACT

Precision medicine is a growing field in critical care. Research increasingly demonstrated pharmacogenomic variability to be an important determinant of analgesic and sedative drug response in the intensive care unit (ICU). Genome-wide association and candidate gene finding studies suggest analgesic and sedatives tailored to an individual's genetic makeup, environmental adaptations, in addition to several other patient- and drug-related factors, will maximize effectiveness and help mitigate harm. However, the number of pharmacogenetic studies in ICU patients remains small and no prospective studies have been published using pharmacogenomic data to optimize analgesic or sedative therapy in critically ill patients. Current recommendations for treating ICU pain and agitation are based on controlled studies having low external validity, including the failure to consider pharmacogenomic factors affecting response. Use of a precision medicine approach to individualize pharmacotherapy focused on optimizing ICU patient comfort and safety may improve the outcomes of critically ill adults. Additionally, benefits and risks of analgesic and/or sedative therapy in an individual may be informed with large, standardized datasets. The purpose of this review is to describe a precision medicine approach focused on optimizing analgesic and sedative therapy in individual ICU patients to optimize clinical outcomes and reduce safety concerns.

PMID:36680385 | DOI:10.1002/phar.2768

Pharmaceutics. 2022 Dec 29;15(1):113. doi: 10.3390/pharmaceutics15010113.

ABSTRACT

In recent times, the progress of Clinical Pharmacogenetics has been remarkable [...].

PMID:36678742 | DOI:10.3390/pharmaceutics15010113

Pharmaceutics. 2022 Dec 21;15(1):23. doi: 10.3390/pharmaceutics15010023.

ABSTRACT

Tenatoprazole, a newly developed proton pump inhibitor candidate, was developed as an acid inhibitor for gastric acid hypersecretion disorders such as gastric ulcer and reflux esophagitis. It is known that tenatoprazole is metabolized to three major metabolites of 5'-hydroxy tenatoprazole, tenatoprazole sulfide, and tenatoprazole sulfone in human liver, primarily catalyzed by CYPs 2C19 and 3A4. While CYP2C19 prefers the hydroxylation of tenatoprazole at C-5' position, CYP3A4 is mainly involved in sulfoxidation reaction to make tenatoprazole sulfone. Tenatoprazole sulfide is a major human metabolite of tenatoprazole and is formed spontaneously and non-enzymatically from tenatoprazole. However, its metabolic fate in the human liver is not fully known. Furthermore, no systematic metabolic study has been performed to study tenatoprazole or tenatoprazole sulfide. Here, we studied the functions of human cytochromes P450 in the metabolic pathway of tenatoprazole and tenatoprazole sulfide by using recombinant human P450s and human liver microsomes. Both CYP 2C19 and CYP3A4 showed distinct regioselective and stereospecific monooxygenation activities toward tenatoprazole and tenatoprazole sulfide. Furthermore, a new major metabolite of tenatoprazole sulfide was found, 1'-N-oxy-5'-hydroxytenatoprzole sulfide, which has never been reported. In conclusion, the metabolic fates of tenatoprazole and tenatoprazole sulfide should be considered in the clinical use of tenatoprazole.

PMID:36678652 | DOI:10.3390/pharmaceutics15010023

Nutrients. 2023 Jan 4;15(2):255. doi: 10.3390/nu15020255.

ABSTRACT

Early intervention in rheumatoid arthritis (RA) is critical for optimal treatment, but initiation of pharmacotherapy to prevent damage remains unsatisfactory currently. Manipulation of the gut microbiome and microbial metabolites can be effective in protecting against RA. Thus, probiotics can be utilized to explore new strategies for preventing joint damage. The aim of this study was to explore the metabolites and mechanisms by which Bifidobacterium pseudocatenulatum affects RA. Based on 16S rRNA sequencing and UPLC-MS/MS assays, we focused on bile acid (BA) metabolism. In a collagen-induced arthritis (CIA) mouse model, B. pseudocatenulatum prevented joint damage by protecting the intestinal barrier and reshaped gut microbial composition, thereby elevating bile salt hydrolase (BSH) enzyme activity and increasing the levels of unconjugated secondary BAs to suppress aberrant T-helper 1/17-type immune responses; however, these benefits were eliminated by the Takeda G protein-coupled receptor 5 (TGR5) antagonist SBI-115. The results suggested that a single bacterium, B. pseudocatenulatum, can prevent RA, indicating that prophylactic administration of probiotics may be an effective therapy.

PMID:36678126 | DOI:10.3390/nu15020255

Metabolites. 2023 Jan 16;13(1):134. doi: 10.3390/metabo13010134.

ABSTRACT

Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington's disease, Parkinson's disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient's pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine).

PMID:36677060 | DOI:10.3390/metabo13010134

Medicina (Kaunas). 2023 Jan 6;59(1):118. doi: 10.3390/medicina59010118.

ABSTRACT

Pharmacotherapy for major depressive disorder (MDD) typically consists of trial-and-error and clinician preference approaches, where patients often fail one or more antidepressants before finding an optimal regimen. Pharmacogenomics (PGx) can assist in prescribing appropriate antidepressants, thereby reducing the time to MDD remission and occurrence of adverse drug events. Since many antidepressants are metabolized by and/or inhibit cytochrome P450 enzymes (e.g., CYP2C19 or CYP2D6), drug-induced phenoconversion is common in patients on antidepressant combinations. This condition influences the interpretation of a patient's PGx results, overall risk of ineffective/adverse medication response due to multi-drug interactions, and the recommendations. This complex case describes a patient with MDD, generalized anxiety disorder, and chronic pain who experienced a fall due to excessive sedation following a prescribing cascade of fluoxetine, bupropion, and doxepin. These antidepressants delivered a significant additive sedative effect and interacted with the patient's hydrocodone, potentially contributing to uncontrolled pain, upward dose titration of hydrocodone, and a higher overall sedative burden. The PGx results and drug-induced phenoconversion described in this case report explain the patient's excessive sedation and possibly ineffective/toxic antidepressant and opioid treatment. This case report also illustrates how a more timely multi-drug interaction assessment (preferably in conjunction with preemptive PGx testing) may have informed a different prescribing pattern, reduced/avoided a prescribing cascade, and potentially prevented a drug-related fall.

PMID:36676742 | DOI:10.3390/medicina59010118