Nephrol Dial Transplant. 2021 Dec 9:gfab353. doi: 10.1093/ndt/gfab353. Online ahead of print.

NO ABSTRACT

PMID:34888693 | DOI:10.1093/ndt/gfab353

Future Healthc J. 2021 Nov;8(3):e703-e708. doi: 10.7861/fhj.2021-0063.

ABSTRACT

Personalised medicine (PM) is becoming increasingly integrated into standard clinical practice for treating numerous diseases, including cancer. Implementing PM into healthcare systems will only be successful with the acceptance and input of both patients' and public opinion. This review, therefore, aimed to identify both patients' and public understanding, and perceived benefits and concerns of PM in cancer treatment. A literature search was conducted using MEDLINE, EMBASE, PsycINFO and CINAHL databases. The eligibility criteria specified that papers must explore the public or patients' understanding of PM or pharmacogenomic (PGx) testing in relation to cancer treatment. Patients have a greater understanding of, and trust in, PM compared with members of the public, but often misunderstand how genomic testing in PM works. Key areas that can be targeted to inform future health literacy interventions include genetic literacy for the public and understanding of how PM testing and treatment works for patients.

PMID:34888471 | PMC:PMC8651337 | DOI:10.7861/fhj.2021-0063

Psychopharmacol Bull. 2021 Nov 3;51(4):87-104.

ABSTRACT

INTRODUCTION: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder.

MATERIAL AND METHODS: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS.

RESULTS: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468.

CONCLUSION: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.

PMID:34887601 | PMC:PMC8601761

Sci Rep. 2021 Dec 9;11(1):23757. doi: 10.1038/s41598-021-03208-9.

ABSTRACT

Chemotherapy related toxicities have been the major factor limiting the success of acute lymphoblastic leukemia (ALL) induction therapy. Several factors, including the pharmacogenetics of asparaginase and anthracyclines, could contribute to difference in treatment outcome in ALL. We investigated the significance of variations in genes involved in hepatic and cardiac toxicity in acute lymphoblastic leukemia (ALL). Genotyping of SOD2 (rs4880), PNPL3 (rs738409) and ABCC1 (rs4148350), CBR1 (rs9024) and ABCG2 (rs2231142) was performed by Tetra-ARMS PCR-based technique to evaluate the genotype-phenotype correlation. Our results showed only minor allele G of SOD2 rs4880 increase the risk of hepatic toxicity [OR 2.63 (1.42-4.84), P = < 0.05] while minor alleles of other SNPs showed protective impact. However, the genetic contrast analysis showed a recessive form of SOD2 rs4880 [OR 7.82 (3.86-15.85), P = < 0.05] and PNPLA3 I148M [OR 5.82 (3.43-9.87), P = < 0.05] variants whereas dominant genotype of ABCC1 rs4148350 [OR 2.52 (1.55-4.10), P = < 0.05] significantly predisposes hepatotoxicity. Furthermore, heterozygous form of ABCG2 rs2231142 [OR 5.25 (1.84-14.95), P = < 0.05] and recessive genotype of 3'UTR variant CBR1 rs9024 [OR 2.31 (1.31-4.07), P = < 0.05] were strongly associated with cardiotoxicity. The information obtained from these genetic variations could offer biomarkers for individualization of therapeutic intervention in ALL.

PMID:34887513 | DOI:10.1038/s41598-021-03208-9

Int J Mol Sci. 2021 Nov 24;22(23):12670. doi: 10.3390/ijms222312670.

ABSTRACT

The authors wish to make the following corrections to this paper [...].

PMID:34884979 | DOI:10.3390/ijms222312670

Int J Mol Sci. 2021 Dec 2;22(23):13061. doi: 10.3390/ijms222313061.

ABSTRACT

The ability of NQO2 to increase the production of free radicals under enhanced generation of quinone derivatives of catecholamines is considered to be a component of neurodegenerative disease pathogenesis. The present study aimed to investigate the neuroprotective mechanisms of original NQO2 inhibitor M-11 (2-[2-(3-oxomorpholin-4-il)-ethylthio]-5-ethoxybenzimidazole hydrochloride) in a cellular damage model using NQO2 endogenous substrate adrenochrome (125 µM) and co-substrate BNAH (100 µM). The effects of M-11 (10-100 µM) on the reactive oxygen species (ROS) generation, apoptosis and lesion of nuclear DNA were evaluated using flow cytometry and single-cell gel electrophoresis assay (comet assay). Results were compared with S29434, the reference inhibitor of NQO2. It was found that treatment of HT-22 cells with M-11 results in a decline of ROS production triggered by incubation of cells with NQO2 substrate and co-substrate. Pre-incubation of HT-22 cells with compounds M-11 or S29434 results in a decrease of DNA damage and late apoptotic cell percentage reduction. The obtained results provide a rationale for further development of the M-11 compound as a potential neuroprotective agent.

PMID:34884863 | DOI:10.3390/ijms222313061

Int J Mol Sci. 2021 Nov 25;22(23):12765. doi: 10.3390/ijms222312765.

ABSTRACT

The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.

PMID:34884570 | DOI:10.3390/ijms222312765

Clin Infect Dis. 2021 Nov 19:ciab961. doi: 10.1093/cid/ciab961. Online ahead of print.

ABSTRACT

BACKGROUND: The late-onset efavirenz neurotoxicity syndrome (LENS) presents as ataxia and/or encephalopathy with supratherapeutic efavirenz plasma concentrations (>4 µg/mL). Efavirenz is primarily metabolized by cytochrome P450 2B6 (CYP2B6), with CYP2A6 as an accessory pathway. We hypothesized that participants with LENS would predominantly be CYP2B6 slow metabolizers. The aim of our study was to determine the frequency of CYP2B6 slow metabolizers in participants with LENS.

METHODS: Adult HIV-positive participants on efavirenz-based antiretroviral therapy presenting with LENS were prospectively enrolled. Genetic polymorphisms known to be associated with increased efavirenz plasma concentrations in CYP2B6 (rs3745274, rs28399499, rs4803419) and CYP2A6 (rs28399433) were selected and used to determine proportions of slow metabolizers. Pharmacokinetic analyses were performed using liquid chromatography-tandem mass spectrometry. Median (IQR) plasma efavirenz and 8-hydroxyefavirenz were described.

RESULTS: Fifteen participants were enrolled. Thirteen (13/15) were Black-African and 13 were female. Median weight was 49.9kg with a median duration on efavirenz of 2.2 years. All 15 participants were successfully genotyped as slow CYP2B6 metabolizers, with 6 participants additionally having CYP2A6 heterozygous genotype. Thirteen were receiving the CYP2A6 enzyme inhibitor isoniazid, and all 15 were genotypic NAT2 slow or intermediate acetylators. Efavirenz plasma concentration was markedly increased at 50.5 (47.0-65.4) µg/mL; 8-hydroxyefavirenz concentration was markedly decreased at 0.10 (0.07-0.15) µg/mL.

CONCLUSIONS: Our cohort provides definitive evidence that LENS is associated with the CYP2B6 slow metabolizer genotype, with a median efavirenz plasma concentration >12-fold higher than the defined upper limit of the therapeutic range. Isoniazid and low body weight are important contributors to LENS development.

PMID:34882770 | DOI:10.1093/cid/ciab961

Per Med. 2021 Dec 9. doi: 10.2217/pme-2021-0088. Online ahead of print.

ABSTRACT

Aim: To determine if interventional cardiologists' knowledge and attitudes toward pharmacogenetic (PGx) testing influenced their antiplatelet prescribing decisions in response to CYP2C19 results. Materials & methods: Surveys were administered prior to participating in a randomized trial of CYP2C19 testing. Associations between baseline knowledge/attitudes and agreement with the genotype-guided antiplatelet recommendations were determined using multivariable logistic regression. Results: 50% believed that PGx testing would be valuable to predict medication toxicity or efficacy. 64% felt well informed about PGx testing and its therapeutic application. However, PGx experience, knowledge, nor attitudes were significantly associated with agreement to genotype-guided antiplatelet recommendations. Conclusion: Cardiologists' knowledge and attitudes were not associated with CYP2C19-guided antiplatelet prescribing, but larger studies should be done to confirm this finding.

PMID:34881641 | DOI:10.2217/pme-2021-0088

Per Med. 2021 Dec 9. doi: 10.2217/pme-2021-0061. Online ahead of print.

ABSTRACT

Aim: Characterize current perceptions, practices, preferences and barriers to integrating pharmacogenomics into patient care at an institution with an established pharmacogenomics clinic. Materials & methods: A 16-item anonymous survey was sent to healthcare professionals practicing at Tampa General Hospital and the University of South Florida Health. Results: Survey participants consisted of nine advanced practice providers, 41 pharmacists and 64 physicians. Majority of survey participants did not feel confident in their ability to interpret and apply pharmacogenomic results. In the past 12 months, 27% of physicians reported ordering a pharmacogenomic test. The greatest reported barrier to integrating pharmacogenomics was the absence of established guidelines or protocols. Conclusion: Most clinicians believed pharmacogenomics would be useful in their clinical practice but do not feel prepared to interpret pharmacogenomic results.

PMID:34881640 | DOI:10.2217/pme-2021-0061

J Basic Clin Physiol Pharmacol. 2021 Dec 8. doi: 10.1515/jbcpp-2021-0312. Online ahead of print.

ABSTRACT

For many years, the medical community has relied in clinical practice on historic data about the physiological changes that occur during pregnancy. However, some newer studies have disputed a number of assumptions in these data for not being evidence-based or derived from large prospective cohort-studies. Accurate knowledge of these physiological changes is important for three reasons: Firstly, it facilitates correct diagnosis of diseases during pregnancy; secondly, it enables us to answer questions about the effects of medication during pregnancy and the ways in which pregnancy alters pharmacokinetic and drug-effects; and thirdly, it allows for proper modeling of physiologically-based pharmacokinetic models, which are increasingly used to predict gestation-specific changes and drug-drug interactions, as well as develop new knowledge on the mode-of-action of drugs, the mechanisms underlying their interactions, and any adverse effects following drug exposure. This paper reviews new evidence regarding the physiologic changes during pregnancy in relation to existing knowledge.

PMID:34881531 | DOI:10.1515/jbcpp-2021-0312

Pharmgenomics Pers Med. 2021 Dec 2;14:1575-1582. doi: 10.2147/PGPM.S324612. eCollection 2021.

ABSTRACT

AIM: The aim of this study is to assess 6 micro-RNAs: miR-126, miR-223, miR-150, miR-29, miR-34, miR-142 as potential biomarkers for P2Y12- inhibitors resistance prediction.

METHODS: Eighty patients with an acute coronary syndrome undergoing percutaneous coronary intervention treated in a multidisciplinary hospital in Moscow with DAPT (either with ticagrelor, n=45, or clopidogrel, n=35) were enrolled. The carriership of 6 clinically relevant polymorphisms for ticagrelor and 17 for clopidogrel was detected. Expression levels of six prospective miRNAs were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of cortisol and 6β-hydroxycortisol.

RESULTS: The polymorphisms of the P2Y12-inhibitors ADME genes that demonstrated statistically significant connection with miRNA expression levels are as follows: P2Y12R (A>G, rs3732759) and miR-29 (p=0.017), miR-34 (p=0.003); CYP2C19*17 (C-806T, rs1224856) and miR-142 (p=0.012); PON1 (Q192R, rs662) and miR-29 (p=0.004), ABCG2 (G>T, rs2231142) and miR-34 (p=0.007). MiRNAs expression levels showed connection with the results of the platelet reactivity assessment by utilizing VerifyNow assay ("Instrumentation laboratory", MA, US). MiR-126 (β coefficient=-0.076, SE=0.032, p=0.021), miR-223 (β coefficient=-0.089, SE=0.041, p=0.032), miR-29 (β coefficient=-0.042, SE=0.018, p=0.026), miR-142 (β coefficient=-0.072, SE=0.026, p=0.008) have the potential to be used as biomarkers and may substitute platelet reactivity testing.

CONCLUSION: This study has revealed new biomarkers for P2Y12-inhibitors resistance testing: miR-29, miR-34, miR-126, miR-142, miR-223.

PMID:34880651 | PMC:PMC8648096 | DOI:10.2147/PGPM.S324612

Nature. 2021 Dec 8. doi: 10.1038/s41586-021-04175-x. Online ahead of print.

ABSTRACT

The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3-5 and other areas of biology6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

PMID:34880501 | DOI:10.1038/s41586-021-04175-x

Sci Rep. 2021 Dec 8;11(1):23670. doi: 10.1038/s41598-021-03244-5.

ABSTRACT

Among cases of SARS-CoV-2 infections that result in serious conditions or death, many have pre-existing conditions such as hypertension and are on renin-angiotensin-aldosterone system (RAAS) inhibitors. The angiotensin-converting-enzyme-2 (ACE2), a key protein of the RAAS pathway, also mediates cellular entry of SARS-CoV-2. RAAS inhibitors might affect the expression levels of ace2, which could impact patient susceptibility to SARS-CoV-2. However, multi-organ-specific information is currently lacking and no species other than rodents have been examined. To address this knowledge gap, we treated adult zebrafish with the RAAS inhibitors aliskiren, olmesartan, and captopril for 7 consecutive days and performed qRT-PCR analysis of major RAAS pathway genes in the brain, gill, heart, intestine, kidney, and liver. Both olmesartan and captopril significantly increased ace2 expression in the heart, gill, and kidney. Olmesartan also increased ace2 expression in the intestine. Conversely, aliskiren significantly decreased ace2 expression in the heart. Discontinuation of compound treatments for 7 days did not return ace2 expression to baseline levels. While potential risks or benefits of antihypertensive RAAS inhibitors to SARS-CoV-2 infections in humans remain uncertain, this study provides new insights regarding the impact of RAAS inhibitors on organ-specific ace2 expression in another vertebrate model, thereby providing comparative data and laying scientific groundwork for future clinical decisions of RAAS inhibitor use in the context of COVID-19.

PMID:34880395 | DOI:10.1038/s41598-021-03244-5

Br J Dermatol. 2021 Dec 8. doi: 10.1111/bjd.20940. Online ahead of print.

ABSTRACT

Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK's population and is associated with extra-cutaneous morbidities and a reduced quality of life. A complex cross-talk between innate and adaptive immunity, the epithelia and the vasculature maintains the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient's goals. Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF-A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF-A in in vivo models of psoriasis-like inflammation resulted in disease clearance. Anti-angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF-A inhibitors, who have experienced PASI improvement. Existing psoriasis treatments downregulate VEGF-A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF-A, who may be most likely to benefit from anti-VEGF-A therapy, offering an opportunity to personalise treatment in psoriasis. Anti-VEGF-A therapies may offer an alternative to existing anti-cytokine strategies or be complementary to standard treatments for the management of psoriasis.

PMID:34878645 | DOI:10.1111/bjd.20940

Clin Pharmacokinet. 2021 Dec 8. doi: 10.1007/s40262-021-01096-w. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids.

METHODS: Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach.

RESULTS: Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids.

CONCLUSIONS: Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).

PMID:34878624 | DOI:10.1007/s40262-021-01096-w

J Chemother. 2021 Dec 8:1-11. doi: 10.1080/1120009X.2021.2009989. Online ahead of print.

ABSTRACT

We conducted a meta-analysis to determine if MTHFR polymorphisms are effective biomarkers for non-small cell lung cancer (NSCLC) patient survival and pemetrexed (PEM) treatment toxicity. Because of data heterogeneity, fixed or random effects models were chosen, and pooled HRs and 95% confidence intervals (CIs) were calculated. No correlation between MTHFR 677 C > T polymorphism and progression-free survival (PFS) or overall survival (OS) was detected in NSCLC patients; however, patients with the T allele benefited more than those with the wild-type allele. Two papers reported hematologic toxicity of single-agent PEM treatment in patients with the MTHFR 677 C > T polymorphism. However, data on MTHFR polymorphisms and toxicity could not be combined, even though publication bias and sensitivity analysis results were stable and reliable. We conclude that the MTHFR 677 C > T polymorphism could not predict PEM efficacy in NSCLC patients; however, the T allele may increase the risk of haematological toxicity. A large-scale clinical trial is recommended.

PMID:34877924 | DOI:10.1080/1120009X.2021.2009989

Clin Pharmacol Ther. 2021 Dec 7. doi: 10.1002/cpt.2506. Online ahead of print.

ABSTRACT

Fentanyl is an anesthetic/analgesic commonly used in surgical and recovery settings. CYP3A4 and CYP3A5 encode enzymes which metabolize fentanyl; genetic variants in these genes impact fentanyl pharmacokinetics in adults. Pharmacokinetic (PK) studies are difficult to replicate in children due to the burden of additional blood taken solely for research purposes. The aim of this study is to test the effect of CYP3A5 and CYP3A4 genetic variants on fentanyl PK in children using opportunistically collected samples. Fentanyl concentrations were measured from remnant blood specimens and dosing data were extracted from electronic health records. Variant data defining CYP3A4*1G and CYP3A5*3 and *6 alleles were available from prior genotyping; alleles with no variant were defined as *1. The study cohort included 434 individuals (median age 9 months, 52% male) and 1937 fentanyl concentrations were available. A two-compartment model was selected as the base model, and the final covariate model included age, weight, and surgical severity score. Clearance was significantly associated with either CYP3A5*3 or CYP3A5*6 alleles, but not the CYP3A4*1G allele. A genotype of CYP3A5*1/*3 or CYP3A5*1/*6 (i.e., intermediate metabolizer status) was associated with a 0.84-fold (95% confidence interval [CI]: 0.71 to 1.00) reduction in clearance vs. CYP3A5*1/*1 (i.e., normal metabolizer status). CYP3A5*3/*3, CYP3A5*3/*6, or CYP3A5*6/*6 (i.e., poor metabolizer status) was associated with a 0.76-fold (95% CI: 0.58 to 0.99) reduction in clearance. In the final model, expected clearance was 8.9 and 6.8 L/hr for a normal and poor metabolizer, respectively, with median population covariates (9 months old, 7.7 kg, low surgical severity).

PMID:34877660 | DOI:10.1002/cpt.2506

Pharmgenomics Pers Med. 2021 Nov 30;14:1537-1547. doi: 10.2147/PGPM.S339854. eCollection 2021.

ABSTRACT

INTRODUCTION: Genetic variability in genes encoding drug-metabolizing enzymes may contribute to the heterogeneity of drug responses in different populations. Extensive research in pharmacogenomics in major populations around the world provides us with a great deal of information about drug-related genetic polymorphisms.

OBJECTIVE: The purpose of this study was to detect the genetic variation of drug-metabolism-related genes in the five ethnic minorities Daur, Hezhen, Ewenki, Mongolian and Manchu in China, and to analyze the distribution differences among ethnic groups.

METHODS: We genotyped 32 SNPs of drug metabolism genes in 882 healthy Chinese volunteers from five ethnic groups. The genotype frequency and allele frequency of the five ethnic groups were calculated, and the different variants among the five ethnic groups were compared by chi-square test. Genetic parameters were analyzed using Popgene software. The genetic structure of five ethnic minorities was analyzed by principal component analysis, and compared with 26 populations.

RESULTS: We found that SNPs of genes related to drug metabolism existed diversity in different populations. Among them, rs8192766 and rs9419082 in CYP2E1 showed statistical differences between Daur and Manchu, and NAT2 rs1801280 showed statistical differences between Hezhen and Mongolian. In addition, the five populations we studied had the smallest differences with EAS populations. There was haplotype diversity in CHST3, VKORC1, CYP1A2 and CYP2E1 genes in the five ethnic minorities, and these haplotype polymorphisms were related to the use of corresponding drug doses. Cluster analysis shows that the five ethnic minorities in Heilongjiang Province are clustered together with the EAS populations.

CONCLUSION: These results suggest that understanding the diversity of drug-related genetic markers is critical for individualized drug gene therapy programs in ethnic minorities in China as well as in populations highly mixed with these ethnic groups.

PMID:34876832 | PMC:PMC8643223 | DOI:10.2147/PGPM.S339854

Chin Med. 2021 Dec 7;16(1):133. doi: 10.1186/s13020-021-00547-7.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is one of the common gastrointestinal malignancies, tumor heterogeneity is the main cause of refractory CRC. Syndrome differentiation is the premise of individualized treatment of traditional Chinese medicine (TCM), but TCM syndrome lacks objective identification in CRC. This study is to investigate the correlation and significance of tumor heterogeneity and TCM syndromes classification in CRC.

METHODS: In this study, we using scRNA-seq technology, investigate the significance of tumor heterogeneity in TCM syndromes classification on CRC.

RESULTS: The results showed that 662 cells isolated from 11 primary CRC tumors are divided into 14 different cell clusters, and each cell subtype and its genes have different functions and signal transduction pathways, indicating significant heterogeneity. CRC tumor cell clusters have different proportions in Excess, Deficiency and Deficiency-Excess syndromes, and have their own characteristic genes, gene co-expression networks, gene functional interpretations as well as monocle functional evolution. Moreover, there were significant differences between the high expressions of MUC2, REG4, COL1A2, POSTN, SDPR, GPX1, ELF3, KRT8, KRT18, KRT19, FN1, SERPINE1, TCF4 and ZEB1 genes in Excess and Deficiency syndrome classification in CRC (P < 0.01).

CONCLUSIONS: The Excess and Deficiency syndromes classification may be related to tumor heterogeneity and its microenvironment in CRC.

PMID:34876190 | DOI:10.1186/s13020-021-00547-7