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We aim to study the effects of CYP2D6 variants and drug-drug interaction on the metabolism of dacomitinib. CYP2D6 variants were incubated with 25-1000 μM dacomitinib for 40 min at 37 °C, and the reaction was terminated by cooling to -80 °C immediately. For an in vivo experiment, 18 male Sprague-Dawley rats were randomly divided into three groups ( n = 6): a single dose of 5 mg/kg dacomitinib (group A), a single dose of 6 mg/kg trazodone (group B), and a combined group (group C). Processed samples were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS.) The relative clearance of dacomitinib was reduced for most of the variants. Moreover, the inhibitory potency of classic CYP inhibitors on dacomitinib metabolism was significantly different among the main subtypes of CYP2D6. Interestingly, compared with gefitinib, even the same CYP2D6 variants showed significant differences in metabolic activity, suggesting that the activity of CYP2D6 has strong variability. In addition, the interaction between trazodone and dacomitinib was determined both in vitro and in vivo. When dacomitinib was given in combination with trazodone, the blood exposure to these two drugs increased remarkably. The mechanistic study revealed that the interaction followed the noncompetitive inhibition. We demonstrated that the activity of CYP2D6 variants to metabolize dacomitinib was significantly reduced. In combination with the CYP2D6 inhibitor, the degree of activity inhibition of different variants obviously differed. When trazodone and dacomitinib were used in combination, the body exposure to the two drugs increased significantly. This study provides data for the precise use of dacomitinib in clinical settings.

Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C9*1/*1, 8 subjects with CYP2C9*1/*3, and 5 subjects with CYP2C9*1/*13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C9*3 and *13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C9*1/*3 and CYP2C9*1/*13 genotypes, the mean AUC 0-∞ were increased by 44.8% and 58.2%, respectively (both P < 0.001), compared to those of subjects with CYP2C9*1/*1 genotype, while effects of glipizide on plasma glucose and insulin levels were not significantly different between CYP2C9 genotype groups. In conclusion, individuals carrying the defective CYP2C9*3 and CYP2C9*13 alleles have markedly elevated plasma concentrations of glipizide compared with CYP2C9*1/*1 wild-type., (© 2021. The Pharmaceutical Society of Korea.)

Cytochrome P450 2D6 (CYP2D6) is primarily expressed in the liver and in the central nervous system. It is known to be highly polymorphic in nature. It metabolizes several endogenous substrates such as anandamide (AEA). Concomitantly, it is involved in phase 1 metabolism of several antidepressants, antipsychotics, and other drugs. Research in the field of phytocannabinoids (pCBs) has recently accelerated owing to their legalization and increasing medicinal use for pain and inflammation. The primary component of cannabis is THC, which is well-known for its psychotropic effects. Since CYP2D6 is an important brain and liver P450 and is known to be inhibited by CBD, we investigated the interactions of four important highly prevalent CYP2D6 polymorphisms with selected phytocannabinoids (CBD, THC, CBDV, THCV, CBN, CBG, CBC, β-carophyllene) that are rapidly gaining popularity. We show that there is differential binding of CYP2D6*17 to pCBs as compared to WT CYP2D6. We also perform a more detailed comparison of WT and *17 CYP2D6, which reveals the possible regulation of AEA metabolism by CBD. Furthermore, we use molecular dynamics to delineate the mechanism of this binding, inhibition, and regulation. Taken together, we have found that the interactions of CYP2D6 with pCBs vary by polymorphism and by specific pCB class.

Purpose: Isoniazid (INH) is prescribed both for the prophylaxis as well as the treatment of tuberculosis. It is primarily metabolized through acetylation by a highly polymorphic enzyme, N-acetyl transferase 2 (NAT2), owing to which significant variable systemic drug levels have been reported among slow and rapid acetylators. Furthermore, many drugs, like phenytoin, diazepam, triazolam, etc., are known to show toxic manifestation when co-administered with INH and it happens prominently among slow acetylators. Additionally, it is revealed in in vitro inhibition studies that INH carries noteworthy potential to inhibit CYP2C19 and CYP3A4 enzymes. However, CYP inhibitory effect of INH gets masked by opposite enzyme-inducing effect of rifampicin, when used in combination. Thus, distinct objective of this study was to fill the knowledge gaps related to gene-drug-drug interactions (DDI) potential of INH when given alone for prophylactic purpose., Methods: Whole body-PBPK models of INH were developed and verified for both slow and fast acetylators. The same were then utilized to carry out prospective DDI studies with CYP2C19 and CYP3A4 substrates in both acetylator types., Results: The results highlighted likelihood of significant higher blood levels of CYP2C19 and CYP3A4 substrate drugs in subjects receiving INH pre-treatment. It was also re-established that interaction was more likely in slow acetylators, as compared to rapid acetylators., Conclusion: The novel outcome of the present study is the indication that prescribers should give careful consideration while advising CYP2C19 and CYP3A4 substrate drugs to subjects who are on prophylaxis INH therapy, and are slow to metabolic acetylation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer immunotherapy is an evolving field of research. Cytokines have been conceptualized as an anticancer therapy for longer than most other cancer immunotherapy modalities. Yet, to date, only two cytokines are FDA-approved: IFN-α and IL-2. Despite the initial breakthrough, both agents have been superseded by other, more efficacious agents such as immune checkpoint inhibitors. Several issues persist with cytokine-based cancer therapies; these are broadly categorised into a) high toxicity and b) low efficacy. Despite the only moderate benefits with early cytokine-based cancer therapies, advances in molecular engineering, genomics, and molecular analysis hold promise to optimise and reinstate cytokine-based therapies in future clinical practice. This review considers five important concepts for the successful clinical application of cytokine-based cancer therapies including: (i) improving pharmacokinetics and pharmacodynamics, (ii) improving local administration strategies, (iii) understanding context-dependent interactions in the tumour-microenvironment, (iv) elucidating the role of genetic polymorphisms, and (v) optimising combination therapies. IL-10 has been the focus of attention in recent years and is discussed herein as an example., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Phenytoin is metabolized through CYP2C9 and CYP2C19 . Polymorphisms of CYP2C9 and CYP2C19 may increase plasma concentration and side effects. Materials & methods: Systematic review and meta-analysis were performed to evaluate the effects of CYP2C9 and CYP2C19 polymorphism on pharmacokinetic parameters. PubMed, Science Direct, Cochrane library, and Thai databases were systematically searched. Results: Eight observational studies, comprising a total of 633 patients were included. Michaelis-Menten constant was significantly higher in the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups as compared with the control groups (CYP2C9EM/CYP2C19EM) at 2.16 and 1.55 mg/l (p < 0.00001, p < 0.0001). The maximum rate of action was significantly lower in the control groups as compared with the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups at 3.10 and 3.53 mg/kg/day (p = 0.00001, <0.0001). Conclusion: The dosage regimen for patients in the CYP2C9IM group to achieve phenytoin therapeutic levels was 2.1-3.4 mg/kg/day.

Human NAT2 is a polymorphic pharmacogene encoding for N-acetyltransferase 2, a hepatic enzyme active towards arylamine and arylhydrazine drugs, including the anti-tubercular antibiotic isoniazid. The isoenzyme also modulates susceptibility to chemical carcinogenesis, particularly of the bladder. Human NAT2 represents an ideal model for anthropological investigations into the demographic adaptation of worldwide populations to their xenobiotic environment. Its sequence appears to be subject to positive selection pressures that are population-specific and may be attributed to gene-environment interactions directly associated with exogenous chemical challenges. However, recent evidence suggests that the same evolutionary pattern may not be observed in other primates. Here, we report NAT2 polymorphism in 25 rhesus macaques (Macaca mulatta) and compare the frequencies and functional characteristics of 12 variants. Seven non-synonymous single nucleotide variations (SNVs) were identified, including one nonsense mutation. The missense SNVs were demonstrated to affect enzymatic function in a substrate-dependent manner, albeit more moderately than certain NAT1 SNVs recently characterised in the same cohort. Haplotypic and functional variability of NAT2 was comparable to that previously observed for NAT1 in the same population sample, suggesting that the two paralogues may have evolved under similar selective pressures in the rhesus macaque. This is different to the population variability distribution pattern reported for humans and chimpanzees. Recorded SNVs were also different from those found in other primates. The study contributes to further understanding of NAT2 functional polymorphism in the rhesus macaque, a non-human primate model used in biomedicine and pharmacology, indicating variability in xenobiotic acetylation that could affect drug metabolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031., Subjects and Methods: A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMET TM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG)., Results: The plasma DA-8031 concentration reached the maximum concentration (C max ) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild., Conclusion: After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031., Competing Interests: All authors report no conflicts of interest regarding the publication of this manuscript., (© 2021 Hwang et al.)

A decrease in the clinical efficacy of a 3-day artesunate-mefloquine combination treatment was reported in the areas of multidrug-resistant Plasmodium falciparum along the Thailand-Myanmar border. The current study investigated the possible contribution of genetic polymorphisms of the three major genes encoding drug efflux transporters, ABCB1, ABCG2, and ABCC1, to responses to the aforementioned treatment in 91 patients with acute uncomplicated falciparum malaria residing along the Thailand-Myanmar border. Patients carrying homozygous mutant genotype ABCB1 c.1236C>T (TT) were found to have a three-times higher chance of successful treatment with this combination compared with other genotypes (CC and CT). Furthermore, whole blood mefloquine concentrations in these patients with the TT genotype were significantly lower than those of patients carrying the CC genotype. Patients with heterozygous mutant genotype (CT), however, were three-times more likely to experience treatment failure. No significant association was found with the ABCG2 and ABCC1 gene polymorphisms. The results suggest that ABCB1 c.1236C>T polymorphisms could be useful genetic markers for predicting responses to the 3-day artesunate-mefloquine treatment; however, studies using larger sample sizes in different malaria-endemic areas are necessary to confirm this finding. This study highlights the impact of pharmacogenetic factors on antimalarial treatment responses and the basis for the application of control policies in various malaria-endemic areas.

Background: Maturation inhibitors (MIs) potently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Bevirimat (BVM), a highly efficacious first-in-class MI against HIV-1 subtype B isolates, elicited sub-optimal efficacy in clinical trials due to polymorphisms in the CA-SP1 region of the Gag protein (SP1:V7A). HIV-1 subtype C inherently contains this polymorphism thus conferring BVM resistance, however it displayed sensitivity to second generation BVM analogs., Results: In this study, we have assessed the efficacy of three novel second-generation MIs (BVM analogs: CV-8611, CV-8612, CV-8613) against HIV-1 subtype B and C isolates. The BVM analogs were potent inhibitors of both HIV-1 subtype B (NL4-3) and subtype C (K3016) viruses. Serial passaging of the subtype C, K3016 virus strain in the presence of BVM analogs led to identification of two mutant viruses-Gag SP1:A1V and CA:I201V. While the SP1:A1V mutant was resistant to the MIs, the CA:I120V mutant displayed partial resistance and a MI-dependent phenotype. Further analysis of the activity of the BVM analogs against two additional HIV-1 subtype C strains, IndieC1 and ZM247 revealed that they had reduced sensitivity as compared to K3016. Sequence analysis of the three viruses identified two polymorphisms at SP1 residues 9 and 10 (K3016: N9, G10; IndieC1/ZM247: S9, T10). The N9S and S9N mutants had no change in MI-sensitivity. On the other hand, replacing glycine at residue 10 with threonine in K3016 reduced its MI sensitivity whereas introducing glycine at SP1 10 in place of threonine in IndieC1 and ZM247 significantly enhanced their MI sensitivity. Thus, the specific glycine residue 10 of SP1 in the HIV-1 subtype C viruses determined sensitivity towards BVM analogs., Conclusions: We have identified an association of a specific glycine at position 10 of Gag-SP1 with an MI susceptible phenotype of HIV-1 subtype C viruses. Our findings have highlighted that HIV-1 subtype C viruses, which were inherently resistant to BVM, may also be similarly predisposed to exhibit a significant degree of resistance to second-generation BVM analogs. Our work has strongly suggested that genetic differences between HIV-1 subtypes may produce variable MI sensitivity that needs to be considered in the development of novel, potent, broadly-active MIs.

Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated ( r = 0.87, P < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of AADAC on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other four substrates of AADAC; that is, p -nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response. SIGNIFICANCE STATEMENT: This is the first study to clarify that arylacetamide deacetylase (AADAC) is responsible for the activation of eslicarbazepine acetate, an antiepileptic prodrug, to eslicarbazepine, an active form, in the human liver and intestines. In addition, we found that several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Graft acceptance against immunity is one of the major challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome however, it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events., Objective: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients., Methods: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3 ABCB1 1236 T>C ABCB1 2677 G>A/T ABCB1 3435 T>C) and mycophenolate (UGT1A8*3 UGT1A9 IMPDH I IMPDH II c.787C>T ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing., Results: Acute rejection (AR) was observed in 5.88% of the transplant recipients whereas acute tubular necrosis (ATNs) was observed in 7.45% of the patients within early stage of the maintenance phase. Infections such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T c.3972C>T polymorphisms and ABCB1 3435 C-allele were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk and ABCC 3972C>T CC-genotype showed protection against adverse events., Conclusion: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Platelet Endothelial Aggregation Receptor (PEAR1), as a platelet receptor, plays a vital role in hemostasis. This receptor, by its extracellular part, causes platelet adhesion and consequently initiates platelet aggregation. Dysfunction of PEAR1 can disrupt platelet aggregation in patients with cardiovascular diseases (CVDs). The content used in this paper has been taken from English language articles (2005-2020) retrieved from Pubmed database and Google scholar search engine using "Cardiovascular Disease", "PEAR1", "Polymorphism", and "Platelet Aggregation" keywords. Some PEAR1 polymorphisms can disrupt homeostasis and interfere with the function mechanism of cardiac drugs. Since polymorphisms in this gene affect platelet function and the platelet aggregation process, PEAR1 could be further studied in the future as an essential factor in controlling the treatment process of patients with cardiovascular diseases. PEAR1 polymorphisms through disruption of the platelet aggregation process can be a risk factor in patients with CVDs. Therefore, controlling patients through genetic testing and the evaluation of PEAR1 polymorphisms can help improve the treatment process of patients. According to the studies on the PEAR1 gene and the effect of different polymorphisms on some crucial issues in CVDs patients (changes in platelet activity), it is clear that if there is a significant relationship between polymorphisms and CVDs, they can be used as prognostic and diagnostic markers. This study aims to evaluate the prognosis and drug treatment of the PEAR1 gene in CVDs patients.

Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of Plasmodium falciparum genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%;  P  < 0.001), PfMDR1 Y184F (73.0% versus 53.0%; P < 0.001), and PfCRT K76T (46.4% versus 24.0%; P < 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; P = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; P = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility., (Copyright © 2020 American Society for Microbiology.)

Objective: The study aims to test the effect of influenza vaccination on phenytoin, CYP2C9, and IFNγ levels in epileptic patients receiving phenytoin monotherapy METHODS: Thirty-one epileptic patients receiving stable-dose phenytoin monotherapy were enrolled onto the study. Serum concentrations of phenytoin, CYP2C9, and IFNγ were compared before and after influenza immunization. The participants were given 0.5 mL of quadrivalent influenza vaccine types A and B subvirion. Blood samples were drawn at baseline, and days 3, 7, 14 post-immunization. The outcomes were levels of phenytoin, CYP2C9, IFNγ, and the incidence of adverse events., Results: No significant changes in serum phenytoin, IFNγ, and CYP2C9 levels between baseline and days 3, 7, and 14 after immunization were found. The mean levels of phenytoin, IFNγ, and CYP2C9, respectively, were 11.94 ± 7.43, 1.14 ± 0.98, and 47.69 ± 37.53 pg/mL (baseline); 12.15 ± 6.57, 2.13 ± 3.41, and 49.44 ± 39.83 pg/mL (day 3); 12.19 ± 7.69, 1.15 ± 0.94, and 49.48 ± 33.83 pg/mL (day 7); 12.79 ± 7.94, 2.15 ± 3.11, and 53.65 ± 40.91 pg/mL (day 14). The incidence of vaccine-related adverse events, which were generally mild and resolved without clinical consequences, was 58.1 %. No seizure or changes in seizure frequency were observed during the study. One patient experienced dizziness and ataxia which were symptoms attributed to phenytoin toxicity (34.57 μg/mL) by day 14., Conclusions: Influenza vaccine has no significant effect on the serum phenytoin and CYP2C9 levels in epileptic patients receiving chronic phenytoin monotherapy. The administration of influenza vaccine to epileptic patients receiving phenytoin monotherapy appears to be safe. Therefore, it is not necessary to routinely measure the serum phenytoin level after influenza immunization., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The current study was conducted to determine the distribution of genetic polymorphisms in CYP2C19 in Iraqi patients and their role in inter-individual variability of clopidogrel efficacy., Patients and Methods: A prospective controlled study was done on 100 patients under high risk of cardiovascular diseases who started clopidogrel prophylactic therapy. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine the existence of the CYP2C19 gene mutation. Vasodilator-stimulated phosphoprotein (VASP) index baseline besides one-month post-therapy was analyzed by dual-color flow cytometry analysis., Results: Eight gene mutations of CYP2C19 were found (*1/*1), (*1/*2), (*1/*3), (*1/*8), (*1/*17), (*2/*2), (*2/*4), and (*3/*3) with higher prevalent CYP2C19*1 gene. Homozygous CYP2C19*1 allele was shown to be the rapid metabolizer comparing to the heterozygous CYP2C19*1 allele, whereas, CYP2C19*2 and CYP2C19*3 were resistant alleles and were present in 28% of patients. The analysis of VASP phosphorylation produces accurate inter-individual response variability in platelets inhibition by antiplatelet drugs., Conclusions: In vitro gene analysis and VASP index improve the clinical outcome of a patient candidate to clopidogrel as prophylaxis in cardiovascular events.

Background: Since 2014, seasonal malaria chemoprevention (SMC) with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) has been implemented on a large scale during the high malaria transmission season in Burkina Faso. This paper reports the prevalence of microscopic and submicroscopic malaria infection at the outset and after the first round of SMC in children under 5 years old in Bama, Burkina Faso, as well as host and parasite factors involved in mediating the efficacy and tolerability of SMC., Methods: Two sequential cross-sectional surveys were conducted in late July and August 2017 during the first month of SMC in a rural area in southwest Burkina Faso. Blood smears and dried blood spots were collected from 106 to 93 children under five, respectively, at the start of SMC and again 3 weeks later. Malaria infection was detected by microscopy and by PCR from dried blood spots. For all children, day 7 plasma concentrations of desethylamodiaquine (DEAQ) were measured and CYP2C8 genetic variants influencing AQ metabolism were genotyped. Samples were additionally genotyped for pfcrt K76T and pfmdr1 N86Y, molecular markers associated with reduced amodiaquine susceptibility., Results: 2.8% (3/106) of children were positive for Plasmodium falciparum infection by microscopy and 13.2% (14/106) by nested PCR within 2 days of SMC administration. Three weeks after SMC administration, in the same households, 4.3% (4/93) of samples were positive by microscopy and 14.0% (13/93) by PCR (p = 0.0007). CYP2C8*2, associated with impaired amodiaquine metabolism, was common with an allelic frequency of 17.1% (95% CI  10.0-24.2). Day 7 concentration of DEAQ ranged from 0.48 to 362.80 ng/mL with a median concentration of 56.34 ng/mL. Pfmdr1 N86 predominated at both time points, whilst a non-significant trend towards a higher prevalence of pfcrt 76T was seen at week 3., Conclusion: This study showed a moderate prevalence of low-level malaria parasitaemia in children 3 weeks following SMC during the first month of administration. Day 7 concentrations of the active DEAQ metabolite varied widely, likely reflecting variability in adherence and possibly metabolism. These findings highlight factors that may contribute to the effectiveness of SMC in children in a high transmission setting.

Objective: To investigate the drug-resistant gene polymorphisms in Plasmodium falciparum imported from Equatorial Guinea to Shandong Province., Methods: From 2015 to 2016, blood samples were collected from imported P. falciparum malaria patients returning from Equatorial Guinea to Shandong Province, and genome DNA of the malaria parasite was extracted. The drug-resistant Pfcrt , Pfmdr1 , Pfdhfr , Pfdhps , and K13 genes of P. falciparum were amplified using a PCR assay, followed by DNA sequencing, and the sequences were aligned., Results: The target fragments of all 5 drug-resistant genes of P. falciparum were successfully amplified and sequenced. There were 72.8%, 18.6%, and 8.6% of P. falciparum parasites carrying the wild-, mutant-, and mixed-type Pfcrt gene, respectively, and all mutant haplotypes were CVI ET (the underline indicates the mutation site). There were 20.0%, 61.4% and 18.6% of P. falciparum parasites carrying the wild-, mutant-, and mixed-type Pfmdr1 gene, respectively, and the mutant haplotypes mainly included YF and NF (the underlines indicate the mutation sites). There were 1.4%, 98.6%, and 0 of P. falciparum parasites carrying the wild-, mutant-, and mixed-type Pfdhfr gene, respectively, and A IRN I was the predominant mutant haplotype (the underline indicates the mutation site). There were 1.4%, 94.3%, and 4.3% of P. falci parum parasites carrying the wild-, mutant-, and mixed-type Pfdhps gene, respectively, and S G KAA was the predominant mutant haplotype (the underline indicates the mutation site). The complete drug-resistant IRNGE genotype consisted of 8.6% of the Pfdhfr and Pfdhps genes, and the K13 gene A578S mutation occurred in 1.4% of the parasite samples., Conclusions: There are mutations in the Pfcrt , Pfmdr1 , Pfdhfr , Pfdhps , and K13 genes of P. falciparum imported from Equatorial Guinea to Shandong Province, with a low frequency in the Pfcrt gene mutation and a high frequency in the Pfmdr1 , Pfdhfr , and Pfdhps gene mutations, and the K13 gene A578S mutation is detected in the parasite samples.

Background: The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients., Methods: Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed., Results: Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration-time curves (AUC) 0-12 on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC 0-12 (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy., Conclusions: Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.

Retrotransposon activity and genomic template stability (GTS) are one of the most significant rearranging mechanisms in environmental stress. Therefore, in this study, it is aimed to elucidate effecting of Cobalt (Co) on the instability of genomes and Long Terminal Repeat retrotransposon polymorphism in Zea mays and whether humic acid (HA) has any role on these parameters. For this purpose, Retrotransposon-microsatellite amplified polymorphism (REMAP) and Inter-Retrotransposon Amplified Polymorphism (IRAP) markers were applied to evaluate retrotransposon polymorphism and the GTS levels. It was found that IRAP and REMAP primers generate unique polymorphic band structures on maize plants treated with various doses of Co. Retrotransposon polymorphism increased and GTS decreased while increasing Co concentration. On the other hand, there was a reduction in negative effects of Co on retrotransposon GTS and polymorphism after treatment with HA. The results indicate that HA may be used effectively for the protection of maize seedlings from the destructive effects of Co toxicity., (© 2020. Akadémiai Kiadó Zrt.)

We examined possible early-effect biomarkers and polymorphisms of susceptibility in primary school children living near the Atoyac River in central México, which receives waste from multiple industries. We observed a significant increase in micronucleated reticulocytes associated with the oxidative stress index (OSI) and the OGG1 GG (S326C) genotype, and a significant decrease of reticulocytes carrying the transferrin receptor, inversely correlated with OSI., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: This retrospective cohort study is to analyze the impacts of CYP2C19 polymorphism and clopidogrel dosing on in-stent restenosis (ISR) after coronary stenting., Methods: Totally, 111 patients were included, who underwent percutaneous coronary intervention (PCI) with drug-eluting stent. Patients received clopidogrel treatment after the intervention on the background treatment with aspirin, based on the genotypes: 75 mg clopidogrel once each day for subjects without CYP2C19 loss-of-function (LOF) alleles (n=51; EM), 75 mg clopidogrel once each day (n=27; IM75) or twice each day (n=33; IM150) for subjects with one CYP2C19 LOF allele. ISR at 3-18 months after coronary stenting was assessed., Results: ISR rate was significantly higher in the IM75 group (40.7%) than the EM group (11.8%). ISR rate in the IM150 group was lower than the IM75 group (6.1% vs 40.7%), and comparable to that in the EM group. Multivariate logistic regression showed that both CYP2C19 genotype and clopidogrel dosing were associated with the risk of ISR after adjusting the relevant confounding factors. ISR risk was higher in the IM patients than the EM patients. Patients with clopidogrel dose of 75 mg once each day had significantly higher risk of ISR than those with the dose of 75 mg twice each day., Conclusion: Increased dose of clopidogrel may reduce the risk of ISR after PCI in CYP2C19 LOF allele(s) carriers. The presence of CYP2C19 LOF allele(s) increases the risk of ISR after stenting, which could be counteracted by the increased dose of clopidogrel., Competing Interests: All authors declare no conflicts of interest in this work., (© 2020 Zhang et al.)

Personalized medicine has been a booming area in clinical research for the past decade, in which the detailed information about the patient genotype and clinical conditions were collected and considered to optimize the therapy to prevent adverse reactions. However, the utility of commercially available personalized medicine has not yet been maximized due to the lack of a structured protocol for implementation. In this narrative review, we explain the role of pharmacogenetics in personalized medicine, next-generation personalized medicine, i.e., patient-centric personalized medicine, in which the patient's comfort is considered along with pharmacogenomics to be a primary factor. We extensively discuss the classifications, strategies, tools, and drug delivery systems that can support the implementation of patient-centric personalized medicine from an industrial perspective.

Introduction and Aims: Choline-metabolizing genetic variation may interact with choline intake on fetal programming and pregnancy outcome. This case-control study aims to explore the association of maternal choline consumption and phosphatidylethanolamine N-methyltransferase (PEMT) gene polymorphism rs7946 with preterm birth risk., Methods: 145 Han Chinese women with preterm delivery and 157 Han Chinese women with term delivery were recruited in Shanghai. Dietary choline intake during pregnancy was assessed using a validated food frequency questionnaire. Additionally, DNA samples were genotyped for PEMT rs7946 (G5465A) with plasma homocysteine (Hcy) levels measured., Results: Compared with the lowest quartile of choline intake, women within the highest consumption quartile had adjusted odds ratio (aOR) for preterm birth of 0.48 (95% confidence interval, CI [0.24, 0.95]). There was a significant interaction between maternal choline intake and PEMT rs7946 (p for interaction = 0.04), where the AA genotype carriers who consumed the energy-adjusted choline <255.01 mg/day had aOR for preterm birth of 3.75 (95% CI [1.24, 11.35]), compared to those with GG genotype and choline intake >255.01 mg/day during pregnancy. Additionally, the greatest elevated plasma Hcy was found in the cases with AA genotype and choline consumption <255.01 mg/day (p < 0.001)., Conclusion: The AA genotype of PEMT rs7946 may be associated with increased preterm birth in these Han Chinese women with low choline intake during pregnancy., (© 2021 S. Karger AG, Basel.)

In total, 77 rhizobial strains isolated from the root nodules of T. repens, inhabiting heavy metal-contaminated waste heap (36 isolates) and control grassland (41 ones) in southern Poland, were analyzed for genome polymorphism and strength of the heavy metals' (mainly Zn, Pb, Cd) selective pressure on bacterial genome polymorphism using two PCR-based techniques, ERIC- (enterobacterial repetitive intergenic consensus) and REP-PCR (repetitive extragenic palindromic) sequences. Both methods of different discriminatory power index (D) (ERIC-PCR D = 0.9737; REP-PCR D = 0.9826) allowed to distinguish 47 and 44 rhizobial strains, respectively. Combined analysis of ERIC-PCR and REP-PCR DNA amplicons differentiated all tested isolates. Both ERIC- and REP-PCR DNA fingerprinting techniques showed significant decline of the genome polymorphism (h) in rhizobial population from metalliferous waste heap (h = 0.89 ± 0.03; h = 0.90 ± 0.02, respectively) compared to rhizobia from control non-metalliferous area (h = 0.99 ± 0.01; h = 0.98 ± 0.02, respectively) as well as substantial differences in the genomic polymorphism between both these populations (F ST  = 0.162, p = 0.008; F ST  = 0.170, p = 0.000, respectively).

The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K 1 through a drug interaction study with ketoconazole, a CYP4F2 inhibitor, and a pharmacogenetic study with CYP4F2*3. Twenty-one participants with different CYP4F2*3 polymorphisms were enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3). All participants were treated twice daily for 5 days with 200 mg of ketoconazole or placebo. Finally, a single dose of 10 mg vitamin K 1 was administered, plasma levels of vitamin K 1 were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K 1 and increased the average area under the concentration-time curve (AUC inf ) and peak concentration by 41% and 40%, respectively. CYP4F2*3 polymorphism also affected plasma levels of vitamin K 1 and its pharmacokinetics in a gene dose-dependent manner. The average AUC inf value was 659.8 ng·h/mL for CYP4F2*1/*1, 878.1 ng·h/mL for CYP4F2*1/*3, and 1125.2 ng·h/mL for CYP4F2*3/*3 (P = .010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K 1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K 1 exposure due to CYP4F2-related drug interactions and genetic polymorphisms., (© 2019, The American College of Clinical Pharmacology.)

There is a relationship between the life cycle of the hepatitis C virus (HCV) and the synthesis and hemostasis of lipids as well as lipid metabolism and interferon (IFN) regulatory system. This study was aimed to examine the effect of fluvastatin and IFN-ƛ in the expression of mediators involved in lipid metabolism and HCV proliferation in patients with rs12979860 CC polymorphism. Thirteen patients with HCV and five controls with rs1297986CC polymorphism were included in this study. Peripheral blood mononuclear cells (PBMCs) of patients and controls were treated by fluvastatin, IFN-λ or fluvastatin+IFN-λ. Assessment of IL-28B polymorphism, RNA extraction, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed. The mRNA expression of sterol regulatory element-binding protein 1 c (SREBP1c), ATP-binding cassette transporter A1 (ABCA1), diacylglycerol acyltransferase 1 (DGAT1), and HCV core as well as measurement of ABCA1 protein level were evaluated before and after treatment. The results indicated that IFN-λ +fluvastatin acted as an inhibitor in mRNA expression of SREBP1c; while acting as an inducer in the expression of ABCA-1. The results of ABCA1 assay showed a significant increase of this protein after treatment with fluvastatin and IFN-λ compared with untreated cells (p=0.02). Moreover, the mRNA expression of HCV core was suppressed in all experimental groups treated with fluvastatin, IFN-λ or their combination which was more significant after treatment with fluvastatin+IFN-λ (p<0.001). The results of this study demonstrated the significant effect of treatment with fluvastatin+IFN-λ in PBMCs of HCV patients with rs12979860 CC polymorphism. According to the drug resistance of viruses and prevention of virus-induced steatosis in patients with HCV, using regulatory agents of lipid mediators in parallel with current medications could be considered as an effective therapeutic strategy.

Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.

Viral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or expanded into new patient populations. We developed an evolutionary model-based counting method to quickly quantify the population genetic potential to resistance and assess population differences. We demonstrate its applicability to HIV-1 integrase inhibitors, as their increasing use globally contrasts with limited availability of non-B subtype resistant sequence data and corresponding knowledge gap. A large sequence data set encompassing most prevailing HIV-1 subtypes and resistance-associated mutations of currently approved integrase inhibitors was investigated. A complex interplay between codon predominance, polymorphisms, and associated evolutionary costs resulted in a subtype-dependent varied genetic potential for 15 resistance mutations against integrase inhibitors. While we confirm the lower genetic barrier of subtype B for G140S, we convincingly discard a similar effect previously suggested for G140C. A supplementary analysis for HIV-1 reverse transcriptase inhibitors identified a lower genetic barrier for K65R in subtype C through differential codon usage not reported before. To aid evolutionary interpretations of genomic differences for antiviral strategies, we advanced existing counting methods with increased sensitivity to identify subtype dependencies of resistance emergence. Future applications include novel HIV-1 drug classes or vaccines, as well as other viral pathogens., (Copyright © 2019 American Society for Microbiology.)

Introduction: Candidiasis is the most frequent opportunistic mycosis in humans and can cause mortality, particularly in immunodeficient patients. One major concern is the increasing number of infections caused by drug-resistant Candidas trains, as these cannot be efficiently treated with standard therapeutics. The most common mechanism of fluconazole resistance in Candida is mutation of ERG11, a gene involved in the biosynthesis of ergosterol, a compound essential for cell integrity and membrane function., Methods: Based on this knowledge, we investigated polymorphisms in the ERG11 gene of 3 Candida species isolated from immunocompromised and immunocompetent patients. In addition, we correlated the genetic data with the fluconazole susceptibility profile of the Candida isolates., Results: A total of 80 Candida albicans, 8 Candida tropicalis and 6 Candida glabrata isolates were obtained from the saliva of diabetic, kidney transplant and immunocompetent patients. Isolates were considered susceptible to fluconazole if the minimum inhibitory concentration was lower than 8 μg/mL. The amino acid mutations F105L, D116E, K119N, S137L, and K128T were observed in C. albicans isolates, and T224C and G263A were found in C. tropicalis isolates., Conclusions: Despite the high number of polymorphisms observed, the mutations occurred in regions that are not predicted to interfere with ergosterol synthesis, and therefore are not related to fluconazole resistance.

Oxidative stress and DNA damage are considered as possible mechanisms involved in lead toxicity. To test this hypothesis, DNA damage and expression variations of aminolevulinic acid dehydratase (ALAD), superoxide dismutase 2 (SOD2), and 8-oxoguanine DNA glycosylase 2a (OGG1-2a) genes was studied in a cohort of 100 exposed workers and 100 controls with comet assay and real-time polymerse chain reaction (PCR). Results indicated that increased number of comets was observed in exposed workers versus controls ( p < 0.001). After qPCR analysis, significant down-regulation in ALAD ( p < 0.0001), SOD2 ( p < 0.0001), and OGG1-2a ( p < 0.0001) level was observed in exposed workers versus controls. Additionally, a positive spearmen correlation was observed between ALAD versus SOD2 ( r = 0.402**, p < 0.001), ALAD versus OGG1-2a ( r = 0.235*, p < 0.05), and SOD2 versus OGG1-2a ( r = 0.292*, p < 0.05). This study showed that lead exposure induces DNA damage, which is accompanied by an elevated intensity of oxidative stress and expression variation of lead-related gene.

Omethoate is an organophosphorus pesticide that poses a major health hazard, especially DNA damage. The purpose of this study was to investigate the factors affecting telomere length in workers exposed to omethoate by analyzing the interaction between cell cycle gene polymorphism and environmental factors. The exposure group consisted of 118 workers exposed to omethoate for 8-10 years, the control group comprised 115 healthy people without occupational toxicant exposure history. The telomere length of genomic DNA from peripheral blood leucocyte was determined with real-time PCR. Polymerase chain reaction and restriction fragment length polymorphism was used to detect the polymorphisms in p 53, p 21 and MDM 2 gene. The telomere length in the (CA + AA) genotypes for p 21 rs1801270 polymorphism was longer than that in the CC genotype in control group ( P  = 0.015). The generalized linear model analysis indicated the interaction of the p 21 rs1801270 polymorphic (CA + AA) genotypes and smoking has a significant effect on telomere length (β = -0.258, P  = 0.085). The prolongation of telomere length in omethoate-exposed workers was associated with genotypes (CA + AA) of p 21 rs1801270, and interactions of (CA + AA) genotypes and smoking factor.

Background: Irinotecan (CPT-11) can be used as a first-line therapeutic drug against extensive-stage small cell lung cancer (SCLC); it can also be used in second-line treatment for SCLC. CPT-11-induced delayed diarrhea restricts its clinical application. This study aimed to confirm whether Banxia Xiexin decoction was effective in preventing and controlling CPT-11-induced delayed diarrhea., Methods: A total of 27 patients with recurrent SCLC undergoing chemotherapy regimens including CPT-11 were enrolled for the study. UGT1A1*28, UGTlAl*6, ABCB1*2, and SLCO1B1*15 gene polymorphisms were detected. If delayed diarrhea occurred in the first cycle of chemotherapy, Banxia Xiexin decoction was orally administered for 5 consecutive days starting 1 day before the second cycle of chemotherapy to prevent and control the delayed diarrhea. The objective response, overall survival, and toxicity were recorded., Results: Complete response, partial response, and stable disease were observed in none, 6, and 10 patients, respectively. Delayed diarrhea occurred in 6 patients, and 4 of 5 patients were relieved or controlled using Banxia Xiexin decoction. The median overall survival was 6 months., Conclusion: Banxia Xiexin decoction appeared to prevent and control delayed diarrhea induced by CPT-11 in this small observational study, and further study with a larger sample size, including potentially randomized trials, is suggested.

Background: Anticoagulant rodenticides have been widely used in rodent control in China for >30 years and resistant Norway rats have been reported. Mutations in the vitamin K epoxide reductase complex, subunit 1 (Vkorc1) gene can cause anticoagulant resistance in rodents. In this study, we analyzed the Vkorc1 polymorphisms of 681 Norway rats collected in Zhanjiang and Harbin Cities in China from 2008 to 2015 and evaluated the warfarin resistance frequency., Results: Analysis revealed four mutations, including three not previously reported. Two new synonymous mutations, His68His and Leu105Leu, are not associated with warfarin resistance. One new nonsynonymous mutation, Ala140Thr, was found in Zhanjiang rat samples collected in 3 years with low frequencies (3.3-4.0%) and is probably associated with warfarin resistance. Laboratory resistance tests suggested low warfarin resistance frequencies in rats from Zhanjiang (4.9-17.1%) and Harbin (0-2.5%) Cities., Conclusions: Both genetic analysis and laboratory resistance tests suggested low warfarin resistance frequencies in rats from Zhanjiang and Harbin Cities. The alternate usage of first-generation anticoagulant rodenticides (FGARs) and second-generation anticoagulant rodenticides (SGARs) might represent an effective strategy against the development of warfarin resistance in Norway rats in China. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

Ambient air pollution is a major global health problem and commercial drivers are particularly exposed to it. As no systematic assessment of the health risks associated with occupational exposure to ambient air pollution in this population had yet been carried out, we conducted a systematic review using a protocol-driven strategy. Papers published from inception to April 20, 2018 in MEDLINE, EMBASE, CINAHL, African journals online, the Cochrane library, ISRCTN WHO ICTRP, and the Web of Science and Scopus databases were screened for inclusion by two independent reviewers. Original articles with at least an available abstract in English or French were included. The initial search retrieved 1454 published articles of which 20 articles were included. Three studies reported a significant difference in white blood cells (10⁶/L) among commercial motorcyclists compared to rural inhabitants (5.041 ± 1.209 vs. 5.900 ± 1.213, p = 0.001), an increased risk of lung cancer (RR = 1.6, 95%CI 1.5⁻1.8) in bus drivers and an increased standardized mortality ratio (SMR) in bus drivers from Hodgkin's lymphoma (SMR 2.17, 95%CI 1.19⁻3.87) compared to white-collar workers. Other studies also found that drivers had more oxidative DNA damage and chromosome breaks. Four papers failed to demonstrate that the drivers were more exposed to air pollution than the controls. Three other studies also reported no significant difference in lung function parameters and respiratory symptoms. The genetic polymorphisms of detoxifying enzymes were also not homogeneously distributed compared to the controls. There is some evidence that occupational exposure to ambient air pollution among commercial drivers is associated with adverse health outcomes, but the existing literature is limited, with few studies on small sample size, methodological weaknesses, and contradictory findings-thus, further research is recommended.

Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus , has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC 90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC 90 and 25-fold lower than the linezolid and vancomycin MIC 90 We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log 10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential., (Copyright © 2018 Roch et al.)

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A , DPYD*13 , c.2846A>T, and c.1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU; however, none of these DPYD polymorphisms has been identified in the Asian population. Recently, 21 DPYD allelic variants, including some novel single-nucleotide variants (SNVs), were identified in 1070 healthy Japanese individuals by analyzing their whole-genome sequences (WGSs), but the functional alterations caused by these variants remain unknown. In this study, in vitro analysis was performed on 22 DPD allelic variants by transiently expressing wild-type DPD and 21 DPD variants in 293FT cells and characterizing their enzymatic activities using 5-FU as a substrate. DPD expression levels and dimeric forms were determined using immunoblotting and blue-native PAGE, respectively. Additionally, the values of three kinetic parameters-the Michaelis constant ( K m ), maximum velocity ( V max ), and intrinsic clearance ( CL int = V max /K m )-were determined for the reduction of 5-FU. Eleven variants exhibited significantly decreased intrinsic clearance compared with wild-type DPD. Moreover, the band patterns observed in the immunoblots of blue-native gels indicated that DPD dimerization is required for enzymatic activity in DPD. Thus, the detection of rare DPYD variants might facilitate severe adverse effect prediction of 5-FU-based chemotherapy in the Japanese population., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Objectives: This study aimed to describe correlations between glucose, insulin and adipokine levels and the homeostasis model assessment (HOMA) index with regards to the presence/absence of fat mass and obesity-associated ( FTO ) rs9939609 and peroxisome proliferator-activated receptor ( PPAR ) -y rs1801282 single nucleotide polymorphisms (SNPs) as indicators of body mass index in adolescents., Methods: This cross-sectional study was conducted between September and December 2016 in Toluca, Mexico. A total of 71 students between 14-18 years old were included. Various anthropometric and laboratory measurements were collected, including lipid profile, glucose, insulin and adipokine levels and HOMA index. The degree of association between variables was evaluated with regards to the presence/absence of the SNPs., Results: Leptin levels were significantly higher among female students ( P = 0.001), although adiponectin levels did not differ significantly ( P = 0.060). There were significant positive correlations between insulin levels and HOMA index with FTO (r = 0.391; P = 0.007 and r = 0.413; P = 0.005, respectively) and PPARγ (r = 0.529; P = 0.007 and r = 0.537; P = 0.007, respectively) SNPs. Leptin showed a significant positive correlation in the presence of PPARγ (r = 0.483; P = 0.007) or in the absence of both SNPs (r = 0.627; P = 0.039). However, adiponectin was significantly negatively correlated in the presence of FTO , either alone (r = -0.333; P = 0.024) or in combination with PPARγ (r = -0.616; P = 0.043)., Conclusion: The presence of FTO and/or PPARγ SNPs might be related to a genetic predisposition to metabolic syndrome., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest.

Constant exposure of the living ecosystems to heavy metals, like cadmium (Cd), induces a detectable change at the biochemical and genetic level. Repeated application of phosphate fertilizers in paddy fields, leads to increase in Cd content of soil. Cd being highly mobile is transported to shoot and grain, thereby entering into the food chain of animal system. In the present study, treatment of 7-day old rice seedlings with 10 μM cadmium chloride resulted in Cd toxicity across the seven non-aromatic and six aromatic rice cultivars and landraces used for the study. Free proline and malondialdehyde content of treated samples were higher in comparison to the untreated samples, which indicated Cd induced tissue damage in plants. Photosynthetic pigment content of treated samples was also found to be much lower in comparison to the untreated samples, which is probably due to peroxidation of membrane, leading to compromised and lower photosynthetic efficiency of treated plants. At the genetic level, Randomly Amplified Polymorphic DNA assay was found to efficiently detect the genetic polymorphisms (caused by alterations in DNA bases) induced by Cd. Production of unique polymorphic bands in Cd-treated plants helps in assessment of the degree of damage Cd imparts on the plant system. Cluster analysis was performed and the rice genotypes were grouped into five distinct clusters, with IR64 and Tulsibhog in two distinct groups. Based on the variability in responses, the 13 rice genotypes were grouped into sensitive and tolerant ones.

Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non-human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Atropa belladonna, commonly known as belladonna or deadly nightshade, ranks among one of the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more cohesive paradigm for future research. This review offers an integrated view of the homeopathy and neurotoxicity of Atropa belladonna in children, adults, and animal models as well as its implications to neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics, pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for treatment of neurological disorders., (Copyright © 2018. Published by Elsevier Ltd.)

1 alpha,25-dihydroxyvitamin D 3 (1,23(OH) 2 D 3 ) is known to play a dual role in cancer, by promoting or inhibiting carcinogenesis via 1,23(OH) 2 D 3 receptor (VDR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Fok I polymorphism of VDR may indirectly influence the receptor levels through autoregulation. The involvement of neutral sphingomyelinase in the non-classic VDR-mediated genomic pathway response to 1,23(OH) 2 D 3 treatment has been reported. Until now no information were reported about Fok I polymorphism of VDR in NCI-N87 human gastric cancer cells and the relation between acid sphingomyelinase and 1,23(OH) 2 D 3 . Herein, we showed that NCI-N87 human gastric cancer cells are homozygous for the Fok I 'C' allele; resulting in a three amino acid-truncated protein form of the VDR. Surprisingly 1,23(OH) 2 D 3 treatments strongly down-regulated the expression of VDR whereas acid sphingomyelinase and PTEN expression were upregulated. No changes of neutral sphingomyelinase expression were observed after 1,23(OH) 2 D 3 treatment, whereas acid sphingomyelinase activity increased. Furthermore 1,23(OH) 2 D 3 induced over-expression of caspase 8, CDKN2B, MAP3K5, cytochrome C apoptotic genes. Morphological analysis highlighted some very large round or oval cells and small cells with angular or fusiform extensions, confirmed by MIB-1 immunodetection and Hercep test. Taken together our results indicated that the action of 1,23(OH) 2 D 3 in gastric cancer cells was independent on 1,23(OH) 2 D 3 receptor and suggested the acid sphingomyelinase as a possible target to induce molecular events., (Copyright © 2017. Published by Elsevier B.V.)

Tramadol is a centrally acting synthetic opioid analgesic and has received special attention due to its abuse potential and unexpected responses induced by CYP2D6 polymorphism. Oral fluid is an advantageous biofluid for drug analysis due to non-invasive sampling and high correlation of drug concentrations with plasma. However, few studies have been performed on distribution of tramadol and its metabolites in oral fluid. In the present study, a linear dual column HPLC-MS/MS method was developed and fully validated for the simultaneous determination of tramadol and its phase I [O-desmethyltramadol (ODMT), N-desmethyltramadol (NDMT) and N,O-didesmethyltramadol (NODMT)] and II metabolites in oral fluid. Furthermore, the distribution of tramadol and its metabolites, in relation to CYP2D6 genetic variations, in oral fluid was investigated following a clinical study including 23 subjects with CYP2D6*wt/*wt, CYP2D6*10/*10 or CYP2D6*5/*5. The validation results of selectivity, matrix effect, linearity, precision and accuracy were satisfactory. Pharmacokinetic parameters, such as C ss,max and AUC 0-τ of tramadol, NDMT and NODMT, in the CYP2D6*10/*10 group were significantly higher than those in the CYP2D6*wt/*wt group. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT correlated well with the CYP2D6 genotypes. We demonstrated that oral fluid is a promising biofluid for pharmacokinetic evaluation in relation to genetic variations.

Three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, PPARγ, and PPARβ/δ, have been investigated widely over the past few decades. Although the roles of these PPARs and their agonists/antagonists were defined in clinical and basic studies, the conflicting results from these studies indicate that more analysis is needed to understand the roles of PPARs. PPARα is a ligand-activated transcription factor that contributes to the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. In this review, we focus on the function and mechanisms of PPARα in the cardiovascular system under various pathological conditions, including vascular and heart injury, blood pressure regulation, and lipid disorder-related cardiovascular injury, as well as its polymorphisms and pharmacogenetic associations with cardiovascular diseases. The anti-inflammatory effect of PPARα in cardiovascular injury is mainly through inhibition of pro-inflammatory signaling pathways and improvement of the lipid profile. Moreover, PPARα also modulates the activity of endothelial nitric oxide synthase and resets the renin-angiotensin system to regulate vascular tone. PPARα gene variants appear to be associated with some cardiovascular risk factors, such as higher plasma lipid levels, cardiac growth, and increased risk of coronary artery disease. Nowadays, novel PPARα drugs with broad safety margins and therapeutic potential for metabolic syndrome and cardiovascular diseases are being developed and applied in the clinical setting. The insights from the current review shed new light on areas of further study and provide a better understanding of the role of PPARα in cardiovascular diseases., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background: Zinc is an essential component for all living organisms, representing the second most abundant trace element, after iron. This element is widely distributed in the tissues of a human body where it is involved in normal growth, reproduction and several biological functions including immunity, energy metabolism and antioxidant processes. Because of its essential role, zinc levels in the human body must remain constant, independently of dietary intake fluctuations. The homeostasis of zinc is a well-regulated cellular process and has been reported to be chiefly mediated by the expression and activity of zinc-binding proteins such as metallothioneins and zinc transporters. Genes encoding for these proteins are subjected to genetic variants., Methods: We performed a multi-database electronic search to provide an overview on the relationship between specific polymorphisms (SNP) of genes encoding for metallothioneins and zinc transporters and their relationship with zinc status, immune function and some non-communicable diseases., Results: A number of SNP are implicated in a range of metabolic disease. Some SNP may affect the impact of zinc supplementation on immune function, diabetes, and obesity., Conclusion: New studies are needed to clarify the interaction between individual genetic profile and zinc status. Moreover, there is a need for a better interaction between the scientific bodies and health professionals to allow better dietary and behavioural recommendations to promote human health, with particular concern to elderly people., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The purpose of this study was to determine the relationship between Kinesin like protein 6 (KIF6) gene Trp719Arg and major cardiovascular events (MACEs) risk in subjects who received statin therapy., Methods: PubMed, EmBase, and the Cochrane Library were searched from inception through September 2017. The selected studies evaluated the association of Trp719Arg with MACEs in individuals who received statins. Relative risk (RR) and 95% confidence interval (CI) were used to evaluate the effect of statin therapy on MACEs in subjects carrying polymorphisms, and the odds ratio (OR) and 95% CI were used to evaluate the relationship between Trp719Arg and MACE risk in individuals who received statins, using the random-effects model., Results: Seven studies were included (N=48,885). Overall, we found that statin therapy significantly reduced the risk for MACEs in subjects carrying ArgArg (RR: 0.79; 95% CI: 0.69-0.90; P=0.001), ArgTrp (RR: 0.71; 95% CI: 0.60 -0.83; P<0.001), ArgArg+ArgTrp (RR: 0.71; 95% CI: 0.63 -0.81; P<0.001), and TrpTrp (RR: 0.79; 95% CI: 0.73-0.85; P<0.001). Furthermore, there was no significant difference between subjects carrying ArgArg and those carrying TrpTrp (OR: 1.11; 95% CI: 0.92-1.34; P=0.265). However, ArgTrp (OR: 1.29; 95% CI: 1.07-1.55; P=0.007) and ArgArg+ArgTrp (OR: 1.26; 95% CI: 1.05-1.51; P=0.012) were associated with an increased risk for MACEs when compared with TrpTrp., Conclusions: Statin therapy significantly reduced the risk for MACEs in subjects carrier specific KIF6 gene Trp719Arg polymorphisms. Further, subjects carrying ArgTrp or ArgArg+ArgTrp had a greater incidence of MACEs as compared with TrpTrp when they received statins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Candida albicans, a common fungal pathogen that can cause opportunistic infections, is regarded as an apparently asexual, diploid fungus. A parasexual cycle was previously found between homozygotes with opposite mating type-like loci (MTLa/α). Fluconazole-resistant strains had a higher proportion of MTL homozygotes, whereas MTL homozygous C. albicans was found in only about 3.2% of clinical strains. MTL heterozygotes had a low frequency (1.4 × 10 -4 ) of white-opaque switching to MTL homozygotes in nature., Methods: Here, a reference C. albicans strain (SC5314) was used in a fluconazole-induced assay to obtain standard opaque MTL homozygous strains and first-generation daughter strains from the fluconazole inhibition zone. Further separation methods were employed to produce second- and third-generation daughter strains. Polymerase chain reaction analysis based on MTL genes was used to define MTL genotypes, and microscopic observations, a flow-cytometric assay, and an antifungal E-test were used to compare microbiological characteristics., Results: MTL homozygotes were found at a high frequency (17 of 35; 48.6%) in fluconazole-induced first-generation daughter strains, as were morphological polymorphisms, decreased DNA content, and modified antifungal drug susceptibility. High-frequency MTL homozygosity was identified inside the fluconazole inhibition zone within 24 hours. The DNA content of fluconazole-induced daughter strains was reduced compared with their progenitor SC5314 and standard MTL homozygous strains., Conclusion: Treatment with fluconazole, commonly used to treat invasive candidiasis, inhibited the growth of C. albicans and altered its microbiological characteristics. Our results suggest that fluconazole treatment induces the high frequency of loss of heterozygosity and microbiological polymorphism in C. albicans., (Copyright © 2016. Published by Elsevier B.V.)

Objectives: To determine natural phenotypic susceptibility of non-group M HIV-1 to integrase strand transfer inhibitors (INSTIs) in a large panel of 39 clinical strains from groups O, N and P and to identify genotypic polymorphisms according to susceptibility levels., Methods: Susceptibility to raltegravir, elvitegravir and dolutegravir was evaluated in 36 HIV-1/O, 2 HIV-1/N and 1 HIV-1/P strains plus an HIV-1/M reference strain. IC50 values were determined after 3 days, and fold changes (FCs) were calculated relative to the HIV-1/M strain. Genotypic polymorphism was determined by amplification of codons 19-263 of the integrase; the natural occurrence of resistance-associated mutations was analysed using the main resistance algorithms and the IAS-USA list. VESPA analysis of the strain sequences was used to determine a signature pattern associated with higher FC., Results: Similar IC50 results were observed for the three drugs. Based on the value for the HIV-1/M reference strain, the data showed FC values <2.5 for raltegravir and dolutegravir, whereas the distribution for elvitegravir was heterogeneous, with FC > 10 for six strains (15%). Analysis of the non-M integrase sequences showed a high level of polymorphism without a major genotypic impact; it also revealed mutations that may be associated with the highest FC values obtained for elvitegravir., Conclusions: Our phenotypic data showed that non-M strains are globally susceptible to the three currently used INSTIs, but the impact of the high FC values observed for some strains with elvitegravir needs to be explored. Clinical data are now needed to confirm these phenotypic results., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Arsenic methylation, the primary biotransformation in the human body, is catalyzed by the enzyme As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT). This process is thought to be protective from acute high-level arsenic exposure. However, with long-term low-level exposure, hAS3MT produces intracellular methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)), which are considerably more toxic than inorganic As(III) and may contribute to arsenic-related diseases. Several single nucleotide polymorphisms (SNPs) in putative regulatory elements of the hAS3MT gene have been shown to be protective. In contrast, three previously identified exonic SNPs (R173W, M287T, and T306I) may be deleterious. The goal of this study was to examine the effect of single amino acid substitutions in hAS3MT on the activity of the enzyme that might explain their contributions to adverse health effects of environmental arsenic. We identified five additional intragenic variants in hAS3MT (H51R, C61W, I136T, W203C, and R251H). We purified the eight polymorphic hAS3MT proteins and characterized their enzymatic properties. Each enzyme had low methylation activity through decreased affinity for substrate, lower overall rates of catalysis, or lower stability. We propose that amino acid substitutions in hAS3MT with decreased catalytic activity lead to detrimental responses to environmental arsenic and may increase the risk of arsenic-related diseases.