Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00218-8. Online ahead of print.

ABSTRACT

Reduced clopidogrel effectiveness in preventing recurrent myocardial ischemia following percutaneous coronary intervention has been demonstrated in CYP2C19 loss-of-function carriers. Less is known about the effect of CYP2C19 genotype on the effectiveness of clopidogrel for stroke prevention, particularly in Caucasians. This is a retrospective cohort study, in which we used the Clalit clinical database to follow genotyped clopidogrel initiators, for up to 3 years. Endpoint was a new primary discharge diagnosis of ischemic stroke; secondary endpoints were new primary discharge diagnoses of coronary angioplasty, myocardial infarction (MI), or a composite endpoint of: stroke, MI, or coronary angioplasty. After 3 years of follow up over 628 clopidogrel initiators, 2 out of 12 (16.7%) poor metabolizers, 9 out of 144 intermediate metabolizers (6.3%), and 29 out of 472 (6.1%) normal/rapid/ultrarapid metabolizers have been newly diagnosed with ischemic stroke. Poor metabolizer status was associated with higher risk for ischemic stroke, marginally significant in univariate analysis and in multivariable models; and higher risk for the composite outcome of stroke, myocardial infarction and coronary angioplasty, HR = 3.32 (1.35-8.17) p = 0.009, 2.86 (1.16-7.06) p = 0.02 (univariate and multivariate analyses, respectively). Poor metabolizer status was associated with higher risk for stroke HR = 5.80 (1.33-25.24) p = 0.019, HR = 4.13 (0.94-18.13) p = 0.06 (univariate and multivariate analyses, respectively) in patients who "survived" the first year, and were in the cohort 1-3 years. Caucasian treated with clopidogrel who are homozygote for the CYP2C19 loss-of function allele might be at increased risk for ischemic stroke, and for the composite outcome of ischemic stroke, myocardial infarction and coronary angioplasty.

PMID:33649514 | DOI:10.1038/s41397-021-00218-8

Rev Colomb Psiquiatr. 2021 Jan-Mar;50(1):57-63. doi: 10.1016/j.rcp.2018.10.005. Epub 2018 Dec 17.

ABSTRACT

This paper is the result of research, from the bioethics and bio-legal perspectives, on the existing guidelines in Colombia for the handling of pharmacogenomic and pharmacogenetic tests in clinical trials. Colombian legislation on this kind of research was reviewed and then compared with international and supranational standards. It was found that Colombia lacks specific legislation in this area, a situation that puts both participants and researchers at risk, from bioethical and legal perspectives. These risks should not be underestimated, as they compromise the ethical viability of clinical and basic research in our setting. In the end, a proposal, based on principles of ethics is made, proposing a series of actions for the creation and promotion nationwide of guidelines which can be used to shape legislation to be applied to protect the genetic data and the rights of subjects participating in these types of research studies in Colombia.

PMID:33648699 | DOI:10.1016/j.rcp.2018.10.005

OMICS. 2021 Mar 1. doi: 10.1089/omi.2020.0230. Online ahead of print.

ABSTRACT

The increasing incorporation of genomics in clinical practice underscores the need to improve genomics knowledge and familiarity among future health care providers. To this end, it is important to consider both the "push" and the "pull" factors that shape or determine the transition of new personalized medicine (PM) discoveries to clinical practice. One of the pull factors involves the attitudes, values, and education of the user communities such as patients, physicians, and scientists who are poised to use the PM diagnostics. Among the push factors are often health scientists who contribute to PM science and development efforts. Seen in this light, health sciences trainees represent both the push and pull factors, not to mention the next generation of stakeholders and innovation actors who will make PM a reality in mainstream medical practice in the future. Τhis study aimed at investigating and comparing awareness and attitudes (ethical and other) on pharmacogenomics (PGx) and PM adoption among undergraduate students from the school of health sciences and other students. A convenience sample was used in this survey in two groups of students: 205 students from the School of Health Sciences and 141 students from other schools (e.g., biology, computer engineering, and business administration) of the University of Patras, Greece, and mostly at undergraduate education level. We observed that despite the relatively low level of awareness about genetics, PGx, and relevant notions, both groups of students were very optimistic about the genetic testing usefulness and professed their positive anticipations about PGx on disease management. Thus, health sciences students and those in other faculties appeared to be avid proponents of genetics testing and in favor of public endorsement of the concepts of individually tailored medicine. This case study in Greece is one of the first studies on perceptions and attitudes toward PGx testing and PM in Southern Europe. Of importance, the study informs the prospects and challenges on the push and pull factors of PM innovation while offering potential lessons for future PM curriculum needs in health sciences in other countries in Europe.

PMID:33646050 | DOI:10.1089/omi.2020.0230

Gen Psychiatr. 2021 Feb 8;34(1):e100289. doi: 10.1136/gpsych-2020-100289. eCollection 2021.

ABSTRACT

BACKGROUND: Atypical antipsychotics as first-line drugs have been used in patients with schizophrenia in China and abroad. However, its safety still needs to be evaluated in a large population, especially in Chinese patients.

OBJECTIVE: The main objective of this study is to evaluate the safety and related factors of long-term atypical antipsychotic use in patients with schizophrenia in China. The secondary objective includes the long-term efficacy of atypical antipsychotics in these patients, as well as pharmacoeconomic evaluation, population pharmacokinetic studies and pharmacogenomics studies.

METHODS: This study has an observational design. The atypical antipsychotics include quetiapine, olanzapine, risperidone, aripiprazole, ziprasidone, paliperidone, amisulpride, perospirone and clozapine. Visits occur at 0, 4, 8, 13, 26, 52, 78, 104, 130 and 156 weeks. The efficacy evaluations include symptoms, social function, recurrence rate and hospitalisation. The safety measures include physical examination, vital signs, abdominal circumference, laboratory tests (such as blood cell analysis, blood biochemical tests and serum prolactin/thyroxine levels), 12-lead ECG, extrapyramidal syndrome assessment, sexual function evaluation, medication and other adverse events. The secondary measures include the Positive and Negative Syndrome Scale, Clinical Global Impression-Severity of Illness Scale, Calgary Depression Scale for Schizophrenia, Personal and Social Performance Scale, relapse rate, drug consolidation, medical-related expenses, income, drug plasma concentration and genetic information.

RESULTS: This is a large sample, non-interventional and long-term prospective clinical study designed to truly reflect the specific details of clinical practice, fully respect patients' needs, and understand patients' treatment intentions and actual treatment details.

CONCLUSIONS: This research method details the aims, methods, study design, strengths and limitations of the study.

PMID:33644688 | PMC:PMC7871676 | DOI:10.1136/gpsych-2020-100289

ACS Omega. 2021 Feb 10;6(7):4551-4561. doi: 10.1021/acsomega.0c04394. eCollection 2021 Feb 23.

ABSTRACT

Ferulic acid, a hydroxycinnamic acid, is abundant in vegetables, grains, and medicinal plants. Emerging evidence suggests that ferulic acid may exert beneficial effects against colorectal cancer. However, the anticancer activity of ferulic acid is relatively low, and its metabolism after oral administration is largely unknown. In this study, mimicking the enteric environment, human intestinal microflora and commercial probiotics were used to metabolize ferulic acid to its metabolites, and their anticancer activities were evaluated. Ferulic acid can be biotransformed to 4-vinylguaiacol (2-methoxy-4-vinylphenol), and the contents of ferulic acid and 4-vinylguaiacol in bio-transformed extracts were determined by high-performance liquid chromatography (HPLC). Using the chemotherapy-sensitive cell line HCT-116 and the chemo-resistant cell line HT-29, the cell proliferation was determined by the modified trichrome stain assay. The cell cycle and induction of apoptosis were assayed using flow cytometry. HPLC data showed that there was a marked transformation from ferulic acid to 4-vinylguaiacol, and the conversion rates of intestinal microflora and four probiotics were from 1.3 to 36.8%. Both ferulic acid and 4-vinylguaiacol possessed dose- and time-related anticancer activities on the two cell lines, while 4-vinylguaiacol showed more potent effects than ferulic acid. Interestingly, 4-vinylguaiacol exhibited significantly higher antiproliferative effects on the HT-29 cell line than that on HCT-116. The IC50 of the metabolite 4-vinylguaiacol on HT-29 cells was 350 μM, 3.7-fold higher than its parent compound. The potential of cancer cell growth inhibition of 4-vinylguaiacol was mediated by cell cycle arrest at the G1 phase and induction of apoptosis. Data from this study indicate that the oral administration of ferulic acid offers a promising approach to increase its anticancer activity through gut microbial conversion to 4-vinylguaiacol, and the biotransformation could also be achieved by selected commercial probiotics. 4-Vinylguaiacol is a potential anticancer metabolite from ferulic acid for chemotherapy-resistant colon cancer cells.

PMID:33644563 | PMC:PMC7905800 | DOI:10.1021/acsomega.0c04394

Data Brief. 2021 Feb 3;35:106832. doi: 10.1016/j.dib.2021.106832. eCollection 2021 Apr.

ABSTRACT

Here we describe the dataset of the first report of pharmacogenomics profiling in an outpatient spine setting with the primary aims to catalog: 1) the genes, alleles, and associated rs Numbers (accession numbers for specific single-nucleotide polymorphisms) analysed and 2) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications. The present description applies to analgesic medication-metabolizing enzymes and may be especially valuable to investigators who are exploring strategies to optimize pharmacologic pain management (e.g., by tailoring analgesic regimens to the genetically identified sensitivities of the patient). Buccal swabs were used to acquire tissue samples of 30 adult patients who presented to an outpatient spine clinic with the chief concern of axial neck and/or back pain. Array-based assays were then used to detect the alleles of genes involved in the metabolism of pain medications, including all common (wild type) and most rare variant alleles with known clinical significance. Both CYP450 isozymes - including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 - and the phase II enzyme UDP-glucuronosyltransferase-2B7 (UGT2B7) were examined. Genotypes/phenotypes were then used to evaluate each patient's relative ability to metabolize 37 commonly used analgesic medications. These medications included both non-opioid analgesics (i.e., aspirin, diclofenac, nabumetone, indomethacin, meloxicam, piroxicam, tenoxicam, lornoxicam, celecoxib, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, naproxen, and mefenamic acid) and opioid analgesics (i.e., morphine, codeine, dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, alfentanil, fentanyl, sufentanil, meperidine, ketobemidone, dextropropoxyphene, levacetylmethadol, loperamide, methadone, buprenorphine, dextromethorphan, tramadol, tapentadol, and tilidine). The genes, alleles, and associated rs Numbers that were analysed are provided. Also provided are: 1) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications and 2) the mechanisms of metabolism of the analgesic medications by primary and ancillary pathways. In supplemental spreadsheets, the raw and analysed pharmacogenomics data for all 30 patients evaluated in the primary research article are additionally provided. Collectively, the presented data offer significant reuse potential in future investigations of pharmacogenomics for pain management.

PMID:33644270 | PMC:PMC7893444 | DOI:10.1016/j.dib.2021.106832

Acta Pharm Sin B. 2021 Feb;11(2):434-441. doi: 10.1016/j.apsb.2020.08.015. Epub 2020 Sep 3.

ABSTRACT

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.

PMID:33643822 | PMC:PMC7893119 | DOI:10.1016/j.apsb.2020.08.015

Front Pharmacol. 2021 Feb 11;12:619339. doi: 10.3389/fphar.2021.619339. eCollection 2021.

ABSTRACT

Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes among 120 patients taking warfarin. A new coding variant was identified by sequencing CYP2C9. The novel A > G mutation at nucleotide position 14,277 led to an amino acid substitution of isoleucine with valine at position 213 (I213V). The functional consequence of the variant was subsequently evaluated in vitro. cDNA of the novel variant was constructed by site-directed mutagenesis and the recombinant protein was expressed in vitro using a baculovirus-insect cell expression system. The recombinant protein expression was quantified at apoprotein and holoprotein levels. Its enzymatic activities toward tolbutamide, warfarin and losartan were then assessed. It exhibited changed apparent Km values and increases of 148%, 84% and 67% in the intrinsic clearance of tolbutamide, warfarin and losartan, respectively, compared to wild-type CYP2C9*1, indicating dramatically enhanced in vitro enzymatic activity. Our study suggests that the amino acid at position 213 in wild-type CYP2C9*1 may be important for the enzymatic activity of CYP2C9 toward tolbutamide, warfarin and losartan. In summary, a patient taking high-dose warfarin (6.0 mg/day) in order to achieve the target international normalized ratio was found to have a mutation in the CYP2C9 gene.

PMID:33643050 | PMC:PMC7905303 | DOI:10.3389/fphar.2021.619339

Pharmgenomics Pers Med. 2021 Feb 19;14:279-286. doi: 10.2147/PGPM.S285807. eCollection 2021.

ABSTRACT

Pharmacogenotyping is applied to determine the hereditable component of a patient's susceptibility to experience therapy failure and/or adverse drug reactions (ADRs). We present the case of a female patient diagnosed with breast cancer and treated with tamoxifen as recurrence therapy who experienced various ADRs. Pharmacogenotyping revealed variants in the cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, and CYP2C19. The observed genotype was associated with a risk for lower tamoxifen efficacy. Aside from the tamoxifen therapy, the comedication was reviewed for the influence of the patient's pharmacogenetic profile. As a result of this pharmacist-led medication review with pharmacogenetic analyses, concrete genotype-driven recommendations for the treating gynecologist were compiled. This case revealed the added value of a large pharmacogenetic panel and the complexity of integrating a pharmacogenetic profile into a recommendation.

PMID:33642872 | PMC:PMC7903951 | DOI:10.2147/PGPM.S285807

Clin Transl Sci. 2021 Feb 28. doi: 10.1111/cts.12986. Online ahead of print.

ABSTRACT

The literature on pharmacogenomics as a tool to support antidepressant precision is burgeoning. Recently, a more active role has been argued for pharmacists in pharmacogenomic testing, with both pharmacists and family physicians perceiving pharmacist-led testing as a valuable method by which to scale this innovation for depression treatment. In this prospective, single-blind randomized controlled design, we evaluated the impact of pharmacogenomics guided versus standard antidepressant treatment of depression and anxiety, implemented in three large community pharmacies. Participants were 213 outpatients diagnosed with major depressive disorder and/or generalized anxiety disorder, randomized to receive pharmacogenomics guided (n = 105) or standard antidepressant treatment (n = 108); participants were blinded to the study. Patient reported outcomes of depression, anxiety, disability, and treatment satisfaction were assessed at months 0, 1, 3, and 6. Hypotheses were investigated using mixed effect models on the full data. All clinical outcomes improved significantly. The primary outcome (depression) and two secondary outcomes (generalized anxiety and disability) exhibited significant time by group interactions indicating that they improved for participants who received pharmacogenomics guided treatment more so than they did for participants who received standard treatment. Treatment satisfaction improved similarly for both groups. Results contribute to a growing body of work evaluating the impact of pharmacogenomics testing to inform antidepressant medication treatment for depression and anxiety, and provides important initial evidence for the role of pharmacists in care delivery. Pharmacogenomic testing may be a valuable tool to allow pharmacists to more effectively collaborate in facilitating clinical treatment decisions. ClinicalTrials.gov registration: (NCT03591224).

PMID:33641259 | DOI:10.1111/cts.12986

Eur Heart J Cardiovasc Pharmacother. 2021 Feb 26:pvab018. doi: 10.1093/ehjcvp/pvab018. Online ahead of print.

ABSTRACT

There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level.

PMID:33638977 | DOI:10.1093/ehjcvp/pvab018

Drug Metab Dispos. 2021 Feb 25:DMD-AR-2020-000301. doi: 10.1124/dmd.120.000301. Online ahead of print.

ABSTRACT

Alaska Native people are under-represented in genetic research, but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9M1L (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and, thus, can contribute to the risk of an adverse drug response from narrow therapeutic index CYP2C9 substrates, such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity phenotyped human liver microsomes and selective CYP inhibitors, then developed and validated a novel LC/MS method for simultaneous quantification of (S)-naproxen, (S)-O-desmethyl naproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethyl naproxen to unchanged (S)-naproxen in urine was 18.0 {plus minus} 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 {plus minus} 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. Significance Statement Our group recently identified the novel CYP2C9 Met1Leu variant in Alaska Native people. Here, we validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of our pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow therapeutic index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.

PMID:33632714 | DOI:10.1124/dmd.120.000301

J Pain Symptom Manage. 2021 Feb 22:S0885-3924(21)00205-0. doi: 10.1016/j.jpainsymman.2021.02.022. Online ahead of print.

ABSTRACT

CONTEXT: Despite being among the most reported concerns in breast cancer patients, sleep disturbances are still poorly assessed and managed in routine clinical practice. Correctly evaluating these symptoms and understanding the underlying clinical and genetic factors would help medical teams develop an adequate treatment strategy for each patient.

OBJECTIVES: i. To explore the severity of insomnia as well as sleep quality in a sample of Lebanese women with breast cancer undergoing chemotherapy; ii. To examine the correlation between sociodemographic, clinical, psychiatric (anxiety and depression), genetic factors, and alterations in sleep patterns.

METHODS: A cross-sectional study was carried out using the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) (December 2017-June 2019; Ethical reference number: CEHDF1016). All patients gave their written consent and were genotyped for several polymorphisms in CLOCK, CRY2, PER2, COMT, DRD2, OPRM1, and ABCB1 genes using Lightcycler®(Roche).

RESULTS: Our sample included a total of 112 women. Almost half of the patients reported insomnia problems (with 20.5% moderate insomnia and 7.1% severe insomnia). Multivariable analyses taking the PSQI score as the dependent variable, showed that higher depression score and dyslipidemia (yes versus no) were significantly associated with higher PSQI scores (worse sleep quality), whereas having the DRD2 CT genotype versus CC and a higher chemotherapy cycle number were significantly associated with lower PSQI scores (better sleep quality). Depression was also significantly associated with higher ISI scores. When forcing all the genes in each model, the results remained the same except for depression that has been replaced by anxiety in the multivariable analysis.

CONCLUSION: Our study confirms the relationship between anxiety/depression, cycle number, dyslipidemia and DRD2 polymorphism with insomnia and highlights the importance of treating all associated factors to improve the overall QOL of patients.

PMID:33631331 | DOI:10.1016/j.jpainsymman.2021.02.022

Toxicol Sci. 2021 Feb 25:kfab023. doi: 10.1093/toxsci/kfab023. Online ahead of print.

ABSTRACT

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.

PMID:33629115 | DOI:10.1093/toxsci/kfab023

Front Pharmacol. 2021 Feb 8;11:610806. doi: 10.3389/fphar.2020.610806. eCollection 2020.

ABSTRACT

The pharmacotherapy of inflammatory bowel diseases (Crohn's disease and ulcerative colitis) has experienced significant progress with the advent of monoclonal antibodies (mABs). As therapeutic proteins, mABs display peculiar pharmacokinetic characteristics that differentiate them from chemical drugs, such as aminosalicylates, antimetabolites (i.e., azathioprine, 6-mercaptopurine, and methotrexate), and immunosuppressants (corticosteroids and cyclosporine). However, clinical trials have demonstrated that biologic agents may suffer from a pharmacokinetic variability that could influence the desired clinical outcome, beyond primary resistance phenomena. Therefore, therapeutic drug monitoring (TDM) protocols have been elaborated and applied to adaptation drug doses according to the desired plasma concentrations of mABs. This activity is aimed at maximizing the beneficial effects of mABs while sparing patients from toxicities. However, some aspects of TDM are still under discussion, including time-changing therapeutic ranges, proactive and reactive approaches, the performance and availability of instrumental platforms, the widely varying individual characteristics of patients, the severity of the disease, and the coadministration of immunomodulatory drugs. Facing these issues, personalized medicine in IBD may benefit from a combined approach, made by TDM protocols and pharmacogenetic analyses in a timeline that necessarily considers the frailty of patients, the chronic administration of drugs, and the possible worsening of the disease. Therefore, the present review presents and discusses the activities of TDM protocols using mABs in light of the most recent results, with special attention on the integration of other actions aimed at exploiting the most effective and safe therapeutic effects of drugs prescribed in IBD patients.

PMID:33628180 | PMC:PMC7898166 | DOI:10.3389/fphar.2020.610806

Genet Med. 2021 Feb 24. doi: 10.1038/s41436-021-01117-w. Online ahead of print.

NO ABSTRACT

PMID:33627827 | DOI:10.1038/s41436-021-01117-w

Sci Transl Med. 2021 Feb 24;13(582):eabb0130. doi: 10.1126/scitranslmed.abb0130.

ABSTRACT

Tumor-induced CD45-Ter119+CD71+ erythroid progenitor cells, termed "Ter cells," promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti-programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell-dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti-PD-L1 therapies by restoring Ter cell numbers and serum ARTN concentration. Blockade of ARTN or potential ARTN signaling partners, or depletion of Ter cells augmented the antitumor effects of both IR and anti-PD-L1 therapies in mice. Analysis of samples from patients who received radioimmunotherapy demonstrated that IR-mediated reduction of Ter cells, ARTN, and GFRα3, an ARTN signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or "abscopal," effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.

PMID:33627484 | DOI:10.1126/scitranslmed.abb0130

Expert Opin Drug Metab Toxicol. 2021 Feb 23:1-6. doi: 10.1080/17425255.2021.1890715. Online ahead of print.

NO ABSTRACT

PMID:33622115 | DOI:10.1080/17425255.2021.1890715

J Pharm Pract. 2021 Feb 24:897190021997000. doi: 10.1177/0897190021997000. Online ahead of print.

ABSTRACT

BACKGROUND: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy.

OBJECTIVE: The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS.

METHODS: The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions.

RESULTS: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 (rs35599367) genotypes: (CC) -9.0 [-13.0; -5.0], (CT+TT) -13.5 [-15.0; -10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 7.5 [6.0; 11.0], (CT+TT) 11.0 [8.0; 12.0], p = 0.003.

CONCLUSION: Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-β-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

PMID:33622083 | DOI:10.1177/0897190021997000

Pharmacogenomics. 2021 Feb 24. doi: 10.2217/pgs-2020-0172. Online ahead of print.

NO ABSTRACT

PMID:33622053 | DOI:10.2217/pgs-2020-0172