Genetic Variation and Autism: A Field Synopsis and Systematic Meta-Analysis.

Brain Sci. 2020 Sep 30;10(10):

Authors: Lee J, Son MJ, Son CY, Jeong GH, Lee KH, Lee KS, Ko Y, Kim JY, Lee JY, Radua J, Eisenhut M, Gressier F, Koyanagi A, Stubbs B, Solmi M, Rais TB, Kronbichler A, Dragioti E, Vasconcelos DFP, Silva FRPD, Tizaoui K, Brunoni AR, Carvalho AF, Cargnin S, Terrazzino S, Stickley A, Smith L, Thompson T, Shin JI, Fusar-Poli P

Abstract
This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.

PMID: 33007889 [PubMed - as supplied by publisher]

Significant Decreased Expressions of CaN, VEGF, SLC39A6 and SFRP1 in MDA-MB-231 Xenograft Breast Tumor Mice Treated with Moringa oleifera Leaves and Seed Residue (MOLSr) Extracts.

Nutrients. 2020 Sep 30;12(10):

Authors: Lim WF, Mohamad Yusof MI, Teh LK, Salleh MZ

Abstract
Moringa oleifera is a miracle plant with many nutritional and medicinal properties. Chemopreventive values of the combined mixture of moringa leaves and seed residue (MOLSr) at different ratios (M1S9, M1S1 and M9S1) were investigated. MOLSr extracts were subjected to phytochemical screening, antioxidant assays, metabolite profiling and cytotoxic activity on the primary mammary epithelial cells (PMECs), non-malignant Chang's liver cells and various human cancer cell lines (including breast, cervical, colon and liver cancer cell lines). The MOLSr ratio with the most potent cytotoxic activity was used in xenograft mice injected with MDA-MB-231 cells for in vivo tumorigenicity study as well as further protein and gene expression studies. M1S9, specifically composed of saponin and amino acid, retained the lowest antioxidant activity but the highest glucosinolate content as compared to other ratios. Cell viability decreased significantly in MCF-7 breast cancer cells and PMECs after treatment with M1S9. Solid tumor from MDA-MB-231 xenograft mice was inhibited by up to 64.5% at third week after treatment with high-dose M1S9. High-dose M1S9 significantly decreased the expression of calcineurin (CaN) and vascular endothelial cell growth factor (VEGF) proteins as well as the secreted frizzled-related protein 1 (SFRP1) and solute carrier family 39 member 6 (SLC39A6) genes. This study provides new scientific evidence for the chemoprevention potential of MOLSr extracts in a breast cancer model; however, the precise mechanism warrants further investigation.

PMID: 33007803 [PubMed - as supplied by publisher]

Incorporating preemptive pharmacogenomic testing into the clinical setting.

Clin Adv Hematol Oncol. 2020 Sep;18(9):526-529

Authors: O'Donnell PH

PMID: 33006581 [PubMed - as supplied by publisher]

Copy number variations in BOLA-DQA2, BOLA-DQB, and BOLA-DQA5 reveal the genomic architecture and haplotype frequency of MHC class II genes in Holstein cows.

HLA. 2020 Oct 02;:

Authors: Fukunaga K, Yamashita Y, Yagisawa T

Abstract
Bovine major histocompatibility complex (MHC) class II region contains many genes. The bovine leukocyte antigen (BoLA)-DRB3 was reportedly associated with susceptibility of various phenotypes of infections including bovine leukemia virus-induced lymphoma. However, the association of the remaining genes with various phenotypes has not been clarified due to the complicated genomic structure of the MHC class II region. Thus, in this study, we elucidated the MHC class II genomic structure, including the novel alleles and copy number variations (CNVs). We determined the copy numbers of BOLA-DQA2 (DQA2), BOLA-DQB (DQB2), BOLA-DQA5 (DQA5), BLA-DQB (DQB1), LOC100848815 (DQA1), BOLA-DRB3 (DRB3) in 127 unrelated Holstein cows by TaqMan Copy Number Assay. The genomes were sequenced using target next generation sequencing (NGS) based on multiplex polymerase chain reaction. Combining the results of the copy numbers and alleles, we identified the BoLA alleles directly without haplotype estimation. Pairwise linkage disequilibrium (LD) analysis between alleles and genes were performed. The CNVs of DQA2, DQB2, and DQA5 in Holstein cows were detected. The frequency of the whole gene deletion in DQA2, DQB2, and DQA5 was 35.4%, 93.7%, and 93.7%, respectively. After target NGS, we identified 37 alleles in the six genes. Fifteen novel alleles (40.5%) were not registered in the IPD-MHC Database. LD analysis revealed strong LD among the DQB2*deletion, DQA5*deletion, and DRB3*27:03 alleles. Our findings will provide important insights into the identification of the BoLA genes associated with various infection-related phenotypes. This article is protected by copyright. All rights reserved.

PMID: 33006253 [PubMed - as supplied by publisher]

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids.

World J Gastrointest Oncol. 2020 Sep 15;12(9):942-956

Authors: Sabeti Aghabozorgi A, Moradi Sarabi M, Jafarzadeh-Esfehani R, Koochakkhani S, Hassanzadeh M, Kavousipour S, Eftekhar E

Abstract
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.

PMID: 33005290 [PubMed]

Pharmacogenomics, concepts for the future of perioperative medicine and pain management: A review.

Best Pract Res Clin Anaesthesiol. 2020 Sep;34(3):651-662

Authors: Kaye AD, Koress CM, Novitch MB, Jung JW, Urits I, Viswanath O, Renschler JS, Alpaugh ES, Cornett EM

Abstract
Pharmacogenomics is the study of how genetic differences between individuals affect pharmacokinetics and pharmacodynamics. These differences are apparent to clinicians when taking into account the wide range of responses to medications given in clinical practice. A review of literature involving pharmacogenomics and pain management was performed. The implementation of preoperative pharmacogenomics will allow us to better care for our patients by delivering personalized, safer medicine. This review describes the current state of pharmacogenomics as it relates to many aspects of clinical practice and how clinicians can use these tools to improve patient outcomes.

PMID: 33004174 [PubMed - in process]

Efficacy of active compounds of Chanqin granules on airway neurogenic inflammation induced by PM2.5 in vivo.

J Tradit Chin Med. 2020 Oct;40(5):792-802

Authors: Ju Y, Shen R, Yu X

Abstract
OBJECTIVE: To investigate the efficacy of active compounds of Chanqin (CQ) granules on PM2.5-induced airway neurogenic inflammation in vivo, and to elucidate the underlying mechanisms of action.
METHODS: The Traditional Chinese Medicine systems pharmacology (TCMSP) database was searched, and the results were combined with oral bioavailability and drug analysis to identify the compounds in CQ granules. The pharmacophore modeling approach was used to predict the compound targets, and the diseases corresponding to the targets were obtained by searching the therapeutic target database (TTD), pharmacogenomics knowledgebase (PharmGKB) and DrugBank databases. Cytoscape software was used to construct the network pharmacological charts for Component-Target and Target-Disease interactions of the CQ granules. Then, the mechanisms of action and effectiveness of CQ granules for the treatment of PM2.5-induced airway neurogenic inflammation were analyzed.
RESULTS: A total of 195 compounds and 171 targets were obtained from the analyses. A total of 569 corresponding diseases were identified for these targets. Component-target and target-disease networks were constructed. The possible mechanisms and effective components in CQ granules for treating airway neurogenic inflammation were analyzed. Quercetin, kaempferol and isorhamnetin, beta-sitosterol and sitosterol, which are typically found in the formulation, have extensive pharmacological activities, including anti-inflammatory, antioxidant and antiviral actions and neuroprotective properties. Among these targets, androgen receptor, estrogen receptor, prostaglandin G/H synthase 2, and inducible nitric oxide synthase play important pathological roles, including the induction of neurogenic inflammation. CQ granules may have therapeutic effectiveness for numerous diseases in addition to respiratory diseases, including neoplasms, digestive system diseases, cardiovascular diseases, respiratory tract diseases and nervous system diseases. In vivo, CQ granules are effective in treating pulmonary inflammation and downregulate neuropeptides in the bronchoalveolar lavage fluid after PM2.5 exposure. CQ granules significantly decreased the levels of neurokinin A, neurokinin B and calcitonin gene-related peptide in the lung and dorsal root ganglia. CQ also significantly suppressed the upregulation of p-extracellular regulated protein kinase 1/2 and p-methyl ethyl ketone 1/2 induced by PM2.5 exposure.
CONCLUSION: CQ granules have potential for the treatment of neurogenic inflammation induced by PM2.5 in vivo, and the mechanism might involve downregulation of neuropeptides in the BALF, lung and dorsal root ganglia.

PMID: 33000580 [PubMed - in process]

Impact of vitamin D receptor gene polymorphisms on vitiligo susceptibility and clinical features in a Southeastern European Caucasian population.

Int J Mol Med. 2020 Nov;46(5):1899-1907

Authors: Katsarou MS, Sidiropoulou P, Ieronymaki D, Mastraftsi S, Sifaki M, Xenos K, Nosyrev A, Kovatsi L, Spandidos DA, Lagiou M, Dagklis C, Gregoriou S, Tagka A, Rigopoulos D, Drakoulis N, Nicolaidou E

Abstract
An association of vitamin D receptor (VDR) polymorphisms and vitiligo has been suggested. However, previous studies have reported contradictory results while including limited data among Caucasians. The aim of this single‑center study was to evaluate the effect of three common VDR gene polymorphisms (FokI, TaqI and BsmI) on susceptibility and clinical aspects of vitiligo in a Southeastern European Caucasian population. A total of 110 unrelated vitiligo cases and 509 general population controls were enrolled from October 2018 to November 2019. Genomic DNA was extracted from whole blood after de‑identification and anonymization of the samples and genotyped for the selected VDR polymorphisms by the qPCR (melting curve analysis). Subgroup analysis by clinical features among subsets of patients indicated that, compared to subjects with the FokI TT genotype or T allele, carriers of the FokI CC genotype or C allele exhibited significantly decreased risk of developing vitiligo before the age of 30 [TT vs. CC: odds ratio (OR)=0.286, 95% confidence interval (CI): 0.083‑0.984, P=0.041; T vs. C: OR=0.545, 95% CI: 0.313‑0.948, P=0.031]. Intra‑patient analysis also revealed that, compared to T allele, the presence of TaqI C allele was adversely associated with the incidence of concurrent leukotrichia (T vs. C: OR=1.874, 95% CI: 1.018‑3.451, P=0.042). Comparisons between the case and control groups showed no evidence to support an association between susceptibility to vitiligo and the VDR BsmI, TaqI, and FokI polymorphisms in this cohort. Thus, the studied VDR polymorphisms might indirectly impact the clinical course and treatment decision‑making despite their lack of association with vitiligo per se. Further research with larger sample sizes, especially across Caucasian individuals, should be performed to confirm these findings.

PMID: 33000207 [PubMed - in process]

Efficacy and safety of a single switch from etanercept originator to etanercept biosimilar in a cohort of inflammatory arthritis.

Sci Rep. 2020 Sep 30;10(1):16178

Authors: Ditto MC, Parisi S, Priora M, Sanna S, Peroni CL, Laganà A, D'Avolio A, Fusaro E

Abstract
AntiTNF-α biosimilars are broadly available for the treatment of inflammatory arthritis. There are a lot of data concerning the maintenance of clinical efficacy after switching from originators to biosimilars; therefore, such a transition is increasingly encouraged both in the US and Europe. However, there are reports about flares and adverse events (AE) as a non-medical switch remains controversial due to ethical and clinical implications (efficacy, safety, tolerability). The aim of our work was to evaluate the disease activity trend after switching from etanercept originator (oETA-Enbrel) to its biosimilar (bETA-SP4/Benepali) in a cohort of patients in Turin, Piedmont, Italy. In this area, the switch to biosimilars is stalwartly encouraged. We switched 87 patients who were in a clinical state of stability from oETA to bETA: 48 patients were affected by Rheumatoid Arthritis (RA),26 by Psoriatic Arthritis (PsA) and 13 by Ankylosing Spondylitis (AS).We evaluated VAS-pain, Global-Health, CRP, number of swollen and tender joints, Disease Activity Score on 28 joints (DAS28) for RA, Disease Activity in Psoriatic Arthritis (DAPSA) for PsA, Health Assessment Questionnaire (HAQ) and Health Assessment Questionnaire for the spondyloarthropathies (HAQ-S),Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. 11/85 patients (12.6%) stopped treatment after switching to biosimilar etanercept. No difference was found between oETA and bETA in terms of efficacy. However, some arthritis flare and AE were reported. Our data regarding maintenance of efficacy and percentage of discontinuation were in line with the existing literature.

PMID: 32999362 [PubMed - in process]

The HLA-Cw6 Dilemma: Is It Really an Outcome Predictor in Psoriasis Patients under Biologic Therapy? A Monocentric Retrospective Analysis.

J Clin Med. 2020 Sep 28;9(10):

Authors: Burlando M, Russo R, Clapasson A, Carmisciano L, Stecca A, Cozzani E, Parodi A

Abstract
HLA-Cw6 is one of the most strongly associated psoriasis susceptibility alleles. Data regarding correlation between HLA-Cw6 status and biologic treatment outcomes are divergent. The aim of our study in our cohort of psoriatic patients was to explore if the HLA-Cw6 status influences the response rate to biologic therapies at 16 and 48 weeks. One hundred and one psoriatic patients eligible for biologic therapies were enrolled. HLA-C*06 alleles were detected from their blood samples. The effectiveness of antipsoriatic treatments was reported as 90% Psoriasis Area and Severity Index reduction (PASI90). All biologics showed efficacy at week 16, without significant differences between one another. HLA-Cw6 status did not seem to affect baseline characteristics, or treatment response at week 16. At week 48, IL-12/23 and IL-17 targeting drugs were more effective on Cw6-positive patients than on Cw6-negative patients. Conversely, TNF-targeting drugs seemed to be more effective on Cw6- negative patients than on Cw6-positive patients. The HLA-Cw6 test could well deserve to be integrated into the clinical laboratory work-up supporting the choice of the correct biologic.

PMID: 32998429 [PubMed]

Pharmacogenomics with red cells: a model to study protein variants of drug transporter genes.

Vox Sang. 2020 Sep 30;:

Authors: Flegel WA, Srivastava K, Sissung TM, Goldspiel BR, Figg WD

Abstract
The PharmacoScan pharmacogenomics platform screens for variation in genes that affect drug absorption, distribution, metabolism, elimination, immune adverse reactions and targets. Among the 1,191 genes tested on the platform, 12 genes are expressed in the red cell membrane: ABCC1, ABCC4, ABCC5, ABCG2, CFTR, SLC16A1, SLC19A1, SLC29A1, ATP7A, CYP4F3, EPHX1 and FLOT1. These genes represent 5 ATP-binding cassette proteins, 3 solute carrier proteins, 1 ATP transport protein and 3 genes associated with drug metabolism and adverse drug reactions. Only ABCG2 and SLC29A1 encode blood group systems, JR and AUG, respectively. We propose red cells as an ex vivo model system to study the effect of heritable variants in genes encoding the transport proteins on the pharmacokinetics of drugs. Altered pharmacodynamics in red cells could also cause adverse reactions, such as haemolysis, hitherto unexplained by other mechanisms.

PMID: 32996603 [PubMed - as supplied by publisher]

Zebrafish as an emerging model to study gonad development.

Comput Struct Biotechnol J. 2020;18:2373-2380

Authors: Ye M, Chen Y

Abstract
The zebrafish (Danio rerio) has emerged as a popular model organism in developmental biology and pharmacogenetics due to its attribute of pathway conservation. Coupled with the availability of robust genetic and transgenic tools, transparent embryos and rapid larval development, studies of zebrafish allow detailed cellular analysis of many dynamic processes. In recent decades, the cellular and molecular mechanisms involved in the process of gonad development have been the subject of intense research using zebrafish models. In this mini-review, we give a brief overview of these studies, and highlight the essential genes involved in sex determination and gonad development in zebrafish.

PMID: 32994895 [PubMed]

Clinical and Laboratory Associations with Methotrexate Metabolism Gene Polymorphisms in Rheumatoid Arthritis.

J Pers Med. 2020 Sep 26;10(4):

Authors: D'Cruz LG, McEleney KG, Tan KBC, Shukla P, Gardiner PV, Connolly P, Conway C, Cobice D, Gibson DS

Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients. DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (ABCC1), rs1476413 (MTHFR), rs2231142 (ABCG2), rs3740065 (ABCC2), rs4149081 (SLCO1B1), rs4846051 (MTHFR), rs10280623 (ABCB1), rs16853826 (ATIC), rs17421511 (MTHFR) and rs717620 (ABCC2). Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher (p < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher (p < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores. Patients with the rs17421511 SNP AA allele reported significantly lower pain scores (p < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity.

PMID: 32993083 [PubMed]

Chaperone Sigma1R and Antidepressant Effect.

Int J Mol Sci. 2020 Sep 25;21(19):

Authors: Voronin MV, Vakhitova YV, Seredenin SB

Abstract
This review analyzes the current scientific literature on the role of the Sigma1R chaperone in the pathogenesis of depressive disorders and pharmacodynamics of antidepressants. As a result of ligand activation, Sigma1R is capable of intracellular translocation from the endoplasmic reticulum (ER) into the region of nuclear and cellular membranes, where it interacts with resident proteins. This unique property of Sigma1R provides regulation of various receptors, ion channels, enzymes, and transcriptional factors. The current review demonstrates the contribution of the Sigma1R chaperone to the regulation of molecular mechanisms involved in the antidepressant effect.

PMID: 32992988 [PubMed - in process]

Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region.

Genes (Basel). 2020 Sep 25;11(10):

Authors: Cardoso de Carvalho D, Pereira Colares Leitão L, Mello Junior FAR, Vieira Wanderley A, Souza TP, Borges Andrade de Sá R, Cohen-Paes A, Rodrigues Fernandes M, Santos S, Salim Khayat A, Pimentel de Assumpção P, Pereira Carneiro Dos Santos N

Abstract
Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient's genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

PMID: 32992962 [PubMed - in process]

Improving the Care of Older Patients by Decreasing Potentially Inappropriate Medications, Potential Medication Omissions, and Serious Drug Events Using Pharmacogenomic Data about Variability in Metabolizing Many Medications by Seniors.

Geriatrics (Basel). 2020 Sep 27;5(4):

Authors: Thomas RE

Abstract
Polypharmacy, potentially inappropriate medications (PIMs) identified by the American Geriatrics Society and Screening Tool of Older People's Prescriptions (STOPP), potential prescribing omissions (PPOs) identified by Screening Tool to Alert to Right Treatment (START) and serious drug events (SDEs), are major problems for seniors. They correlate with increased risks of rehospitalization and death within six months of hospital discharge. About 75% of commonly prescribed medications are metabolized by P450 cytochrome enzymes. Electronic medical records (EMRs) providing integrated comprehensive pharmacogenomic advice are available only in very large health organizations. The study design of this article is a cross-sectional analysis of the American Geriatrics Society (AGS) and STOPP PIM and START PPO databases integrated with three P450 cytochrome enzyme databases (Flockhart Tables, DrugBank, and Rx Files) and the data are reported using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. To enable optimally prudent prescribing this article presents for primary care physicians and physicians in remote or rural areas without access to such services a comprehensive integration of the data on PIM and PPO medications with the data on the P450 cytochrome isoforms that metabolize these medications. Additionally presented are the medications metabolized by multiple isoforms and medications that inhibit or induce individual or multiple isoforms. The most extensive metabolic activities involve the central nervous system, anxiolytic, antidepressive, antipsychotic, musculoskeletal, and cardiovascular drugs. The P450 cytochrome isoforms that metabolize the most medications are 3A457, 2C9, 2D6, and 2C19 and nearly all central nervous systems medications compete to be metabolized by 3A457. Medications with the largest inducer or inhibitor activity are highlighted and also a list of commonly prescribed medications that are neither PIMs nor PPOs but compete for metabolism by the same isoforms.

PMID: 32992638 [PubMed]

Medical Genetics Summaries

Book. 2012

Authors: Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ

Abstract
Rasburicase (brand name Elitek) is a uric oxidase used to treat the high levels of uric acid that are associated with tumor lysis syndrome (TLS). Tumor lysis syndrome is a potentially life-threatening condition caused by rapid break down of tumor cells during chemotherapy. Tumor lysis syndrome is associated with the treatment of aggressive lymphoma and leukemia, but it may also occur with other tumors including solid tumors. Massive cell breakdown results in the release of potassium, phosphate, and uric acid into the circulation. Urate crystals can precipitate in the kidneys, causing acute kidney damage. Prophylaxis and treatment of TLS involve aggressive intravenous (IV) hydration and the use of drugs to lower uric acid levels. Rasburicase breaks down uric acid to a more soluble metabolite (allantoin), which is then eliminated by the kidneys. A by-product of this reaction is hydrogen peroxide, an oxidizing agent. Red blood cells that lack the enzyme glucose-6-phosphate dehydrogenase (G6PD) are sensitive to oxidative damage caused by agents like hydrogen peroxide due to a deficiency in nicotinamide adenine dinucleotide phosphate (NADPH). Once exposed, the red blood cells become rigid, trapped, and are rapidly broken down (hemolysis). This can lead to a deficiency of mature red blood cells (hemolytic anemia) and the production of red blood cells with abnormally high levels of methemoglobin (methemoglobinemia). Approximately 400 million people worldwide have G6PD deficiency. Most of these individuals are asymptomatic. However, they are at risk of life-threating hemolytic reactions and methemoglobinemia if given oxidizing drugs such as rasburicase. Rasburicase is contraindicated in individuals with G6PD deficiency. The FDA-approved drug label states that individuals at higher risk for G6PD deficiency should be screened before starting rasburicase therapy, for example, individuals of African or Mediterranean ancestry (Table 1) (1). Approximately 12% of African-Americans have G6PD deficiency. A rare cause of methemoglobinemia is a deficiency of antioxidant enzymes such as cytochrome b5 reductase 3 (CYB5R3). The drug label states it is not known whether individuals who have a deficiency of this enzyme, or another enzyme with antioxidant activity, are at increased risk of methemoglobinemia or hemolytic anemia during rasburicase therapy. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing recommendations for rasburicase based on G6PD phenotype (Table 2). The CPIC states for individuals with normal G6PD phenotype, there is no reason to withhold rasburicase based on G6PD status. For individuals who are G6PD deficient, with or without hemolytic anemia, rasburicase is contraindicated. For individuals who have a variable G6PD phenotype, G6PD enzyme activity must be measured to ascertain that G6PD status is normal. For cases where rasburicase is contraindicated, alternative drugs include allopurinol (2).

PMID: 32997466

Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial.

Hum Psychopharmacol. 2020 Sep 29;:

Authors: Koller D, Almenara S, Mejía G, Saiz-Rodríguez M, Zubiaur P, Román M, Ochoa D, Wojnicz A, Martín S, Romero-Palacián D, Navares-Gómez M, Abad-Santos F

Abstract
OBJECTIVE: To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment.
METHODS: Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded.
RESULTS: ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs.
CONCLUSIONS: OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects.

PMID: 32991788 [PubMed - as supplied by publisher]

Extended-Release Dinalbuphine Sebacate Versus Intravenous Patient-Controlled Analgesia with Fentanyl for Postoperative Moderate-to-Severe Pain: A Randomized Controlled Trial.

Pain Ther. 2020 Sep 29;:

Authors: Chang TK, Huang CW, Su WC, Tsai HL, Ma CJ, Yeh YS, Chen YC, Li CC, Cheng KI, Su MP, Wang JY

Abstract
INTRODUCTION: Post-operative pain control remains unsatisfactory in patients after laparotomy. This study aimed to evaluate the efficacy, safety, and quality of life with a single dose of extended-release dinalbuphine sebacate (ERDS) pre-operatively to intravenous patient-controlled analgesia (PCA) with fentanyl in patients undergoing laparotomy.
METHODS: This was a prospective, open-label, randomized controlled study. Of 110 randomized patients, 107 completed all assessments. The area under the curve (AUC) of visual analogue scale (VAS) from baseline to 48 h after surgery, VAS throughout 7 days after surgery, post-operative analgesics use, quality of life, satisfaction, and safety were evaluated.
RESULTS: The AUC of VAS from baseline to 48 h after surgery were 118.6 [97.5% confidence interval (CI) 95.6-141.6] in ERDS group and 176.13 (97.5% CI 150.8-201.4) in PCA group, which showed the non-inferiority because the upper limit of the 97.5% CIs of ERDS group was lower than the lower limit of PCA group (P < 0.001), but also had superiority in favor of ERDS group (P < 0.001). ERDS group reported a significant reduction in VAS pain intensity at 4, 24, 32, 72, 120, and 144 h after surgery, and better quality of life (P < 0.05). The safety profile was comparable between ERDS and PCA groups.
CONCLUSIONS: In patients undergoing laparotomy, a single dose of dinalbuphine sebacate was superior to intravenous PCA with fentanyl on lower pain intensity and better quality of life.
TRIAL REGISTRATION: NCT03296488.

PMID: 32990938 [PubMed - as supplied by publisher]

Functional Correlations between CXCL10/IP10 Gene Polymorphisms and Risk of Kawasaki Disease.

Pediatr Allergy Immunol. 2020 Sep 29;:

Authors: Hsu YW, Lu HF, Chou WH, Kuo HC, Chang WC

Abstract
BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis syndrome with unknown pathogen. Immune system has been suggested to involve in the pathogenesis in KD. IP10 is a chemoattractant for initiating T cell activation. The aim of this study was to investigate the association between genetic polymorphisms of IP10 and KD.
METHODS: A total of 354 KD patients and 1,709 control subjects (709 subjects in cohort 1 and 1,000 subjects in cohort 2) were enrolled in this study. There are four tagging single nucleotide polymorphisms (rs3921, rs4256246, rs4508917, and rs4386624) were chosen for TaqMan SNP genotyping assay.
RESULTS: Our results indicated that CC genotype of rs3921 and GG genotype of rs4386624 had higher frequency in KD patients compared to control. In addition, higher plasma IP10 level was observed in CC genotype of rs3921 than CG genotype and GG genotype. C/G haplotype carriers of rs3921/rs4386624 had 5.48-fold risk for KD compared to G/C haplotype carriers. Two-locus analysis further showed the combinatorial effects of rs3921 and rs4386624 in KD susceptibility.
CONCLUSIONS: This study indicated the close correlation between IP10 and the risk of Kawasaki disease.

PMID: 32989803 [PubMed - as supplied by publisher]