A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

Acta Ophthalmol. 2018 Sep 04;:

Authors: Meng W, Shah KP, Pollack S, Toppila I, Hebert HL, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Daniell M, Kaidonis G, Craig JE, Mitchell P, Liew G, Kifley A, Wang JJ, Christiansen MW, Jensen RA, Penman A, Hancock HA, Chen CJ, Correa A, Kuo JZ, Li X, Chen YI, Rotter JI, Klein R, Klein B, Wong TY, Morris AD, Doney ASF, Colhoun HM, Price AL, Burdon KP, Groop PH, Sandholm N, Grassi MA, Sobrin L, Palmer CNA, Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group

Abstract
PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.
METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.
RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).
CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

PMID: 30178632 [PubMed - as supplied by publisher]

In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics.

Eur J Clin Pharmacol. 2018 Apr;74(4):455-464

Authors: Jin Y, Borell H, Gardin A, Ufer M, Huth F, Camenisch G

Abstract
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism.
METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software.
RESULTS: Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0-2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype.
CONCLUSION: .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.

PMID: 29273968 [PubMed - indexed for MEDLINE]

Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China.

Eur J Clin Pharmacol. 2018 Apr;74(4):423-431

Authors: Zhong Z, Hou J, Zhang Q, Li B, Li C, Liu Z, Yang M, Zhong W, He X, Wu H, Zhong M, Zhao P

Abstract
BACKGROUND AND OBJECTIVES: The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China.
METHODS: Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke.
RESULTS: The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044).
CONCLUSIONS: Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.

PMID: 29243114 [PubMed - indexed for MEDLINE]

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

Eur J Clin Pharmacol. 2018 Apr;74(4):433-442

Authors: Wang P, Lin XQ, Cai WK, Xu GL, Zhou MD, Yang M, He GH

Abstract
PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA.
METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship.
RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA.
CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

PMID: 29243113 [PubMed - indexed for MEDLINE]

[Use of Pharmacogenetic Information for Therapeutic Drug Monitoring of an Antiarrhythmic Drug].

Yakugaku Zasshi. 2018;138(9):1145-1150

Authors: Doki K

Abstract
　Antiarrhythmic drugs require therapeutic drug monitoring (TDM) to avoid adverse effects such as proarrhythmia. However, TDM is not necessarily used to adjust the dosage of antiarrhythmic drugs because there is a lack of information regarding the therapeutic range of the serum concentration and the selection of patients who require TDM. The aim of this review was to provide an overview of the pharmacogenetic information on the pharmacokinetics and drug response of flecainide, a class Ic antiarrhythmic drug with a sodium channel-blocking effect. A population pharmacokinetic analysis revealed that the CYP2D6 genotype was a determining factor of the age-related decline in flecainide clearance. Elderly patients show large interindividual variability of flecainide clearance because they have a more pronounced effect of the CYP2D6 genotype and require more frequent monitoring of serum flecainide concentrations. Carriers of an Asian-specific promoter haplotype B of the cardiac sodium channel gene (SCN5A) more frequently achieve clinically relevant flecainide efficacy even at lower concentrations. This suggests that the therapeutic range of serum flecainide concentrations is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes. The β1-adrenergic receptor Gly389 polymorphism decreases the antiarrhythmic efficacy of flecainide when co-administered with β-blockers. Carriers of Gly389 with co-administration of β-blockers may not achieve clinically relevant flecainide efficacy even when the serum flecainide concentrations are within the therapeutic range. These findings provide pharmacogenetic information for the effective utilization of TDM in antiarrhythmic drug therapy.

PMID: 30175758 [PubMed - in process]

Pharmacogenetic Labeling of FDA-Approved Drugs: A Regulatory Retrospective.

JACC Basic Transl Sci. 2018 Aug;3(4):545-549

Authors: Drozda K, Pacanowski MA, Grimstein C, Zineh I

Abstract
The U.S. Food and Drug Administration recently marked 10 years since first updating the labeling for warfarin (often referred to as the "poster child" of pharmacogenomics) to include information regarding the potential impact of CYP2C9 and VKORC1 genetic variation on warfarin dosing requirements and risks. Herein, we opine on the experience updating the warfarin labeling, highlighting more generally the enabling factors and challenges encountered when considering incorporation of pharmacogenomic information into the prescribing recommendations for already approved drugs. We also provide a historical perspective of implemented changes in regulatory policies related to personalized medicine.

PMID: 30175278 [PubMed]

Association between polymorphisms in SLC15A1 and PLA2G16 genes and development of obesity in Chinese subjects.

Diabetes Metab Syndr Obes. 2018;11:439-446

Authors: Wang CY, Liu S, Xie XN, Luo ZY, Yang L, Tan ZR

Abstract
Introduction: The small peptide transporter 1 (PepT-1) and adipose phospholipase A2 (AdPLA) play a key role in the development of obesity. However, there are no data assessing the impact of PepT-1 (SLC15A1) and AdPLA (PLA2G16) variants on obesity susceptibility. Therefore, we assessed the contribution of 9 single-nucleotide polymorphisms (SNPs) between these two genes on obesity susceptibility in Chinese subjects.
Materials and methods: A total of 611 participants were enrolled in the study, and 9 SNPs in the SLC15A1 and PLA2G16 genes were selected. Blood samples were collected for genotyping. Overweight and obesity were established by body mass index. Regression analyses were performed to test for any association of genetic polymorphisms with weight abnormality.
Results: The genotype frequencies (P=0.04 for rs9557029, P=0.027 for rs1289389) were significantly different between obese or overweight subjects and healthy controls. However, no significant difference in allele was found between these three groups (P>0.05). Further logistic regression analyses adjusted for age and sex also failed to reveal significant associations between overweight, obesity, and the selected SNPs (P>0.05).
Conclusion: Data indicate that the selected 9 SNPs in SLC15A1 and PLA2G16 genes were not related to obesity susceptibility in the Han Chinese population.

PMID: 30174451 [PubMed]

A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

Nat Commun. 2016 08 09;7:12342

Authors: Rivas MA, Graham D, Sulem P, Stevens C, Desch AN, Goyette P, Gudbjartsson D, Jonsdottir I, Thorsteinsdottir U, Degenhardt F, Mucha S, Kurki MI, Li D, D'Amato M, Annese V, Vermeire S, Weersma RK, Halfvarson J, Paavola-Sakki P, Lappalainen M, Lek M, Cummings B, Tukiainen T, Haritunians T, Halme L, Koskinen LL, Ananthakrishnan AN, Luo Y, Heap GA, Visschedijk MC, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, MacArthur DG, Neale BM, Ahmad T, Anderson CA, Brant SR, Duerr RH, Silverberg MS, Cho JH, Palotie A, Saavalainen P, Kontula K, Färkkilä M, McGovern DP, Franke A, Stefansson K, Rioux JD, Xavier RJ, Daly MJ, Barrett J, de Lane K, Edwards C, Hart A, Hawkey C, Jostins L, Kennedy N, Lamb C, Lee J, Lees C, Mansfield J, Mathew C, Mowatt C, Newman B, Nimmo E, Parkes M, Pollard M, Prescott N, Randall J, Rice D, Satsangi J, Simmons A, Tremelling M, Uhlig H, Wilson D, Abraham C, Achkar JP, Bitton A, Boucher G, Croitoru K, Fleshner P, Glas J, Kugathasan S, Limbergen JV, Milgrom R, Proctor D, Regueiro M, Schumm PL, Sharma Y, Stempak JM, Targan SR, Wang MH

Abstract
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

PMID: 27503255 [PubMed - indexed for MEDLINE]

Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.

Nat Commun. 2016 06 08;7:11762

Authors: Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, Belt BA, Alspach E, Leahy K, Luo J, Schaffer A, Edwards JR, Longmore G, Faccio R, DeNardo DG, Stewart SA

Abstract
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.

PMID: 27272654 [PubMed - indexed for MEDLINE]

The ABCB1, CYP2C19, CYP3A5 and CYP4F2 genetic polymorphisms and platelet reactivity in the early phases of acute coronary syndromes.

Drug Metab Pers Ther. 2018 Sep 25;33(3):109-118

Authors: Mirzaev KB, Rytkin E, Ryzhikova KA, Grishina EA, Sozaeva ZA, Fedorinov DS, Konova OD, Giliarov MI, Belyakova GA, Andreev DA, Sychev DA

PMID: 30171809 [PubMed - in process]

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pharmacogenomics

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11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A simple UHPLC-PDA method with a fast dilute-and-shot sample preparation for the quantification of canrenone and its prodrug spironolactone in human urine samples.

J Pharmacol Toxicol Methods. 2018 Aug 27;:

Authors: Avataneo V, De Nicolò A, Rabbia F, Sciandra M, Tosello F, Cusato J, Perlo E, Fatiguso G, Allegra S, Favata F, Mulatero P, Veglio F, Di Perri G, D'Avolio A

Abstract
INTRODUCTION: Nowadays, the treatment of hypertension represents an important issue, particularly in developed countries. While in most cases the standard therapeutic approaches, consisting in the administration of 1 to 3 drugs, are adequate to reach adequate blood pressure levels, in some cases more drugs are needed: this condition is called "resistant hypertension". In this context, the administration of a diuretic, such as spironolactone or canrenoate salts, represents a standard practice. Since a reliable discrimination of real cases of resistant hypertension from cases of poor therapeutic adherence is currently difficult to obtain, the adoption of therapeutic drug monitoring has been suggested as a useful tool for this purpose. In this work, the authors developed and validated a simple, cheap and fast dilute-and-shot method with UHPLC-PDA analysis for the quantification of spironolactone and its metabolite canrenone in human urine samples.
METHODS: Standards and quality controls were prepared in urine. Only 100 μL of sample were added with 80 μL of internal standard (6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline) working solution and 820 μL of phosphate buffer 10 mM pH 3.2 (phase A):acetonitrile (phase B) 90:10 v:v solution. Chromatographic separation was performed on an Acquity® UPLC HSS T3 1.8 μm 2.1 × 150 mm column, with a binary gradient for 11 min at 40 °C.
RESULTS: Accuracy, intra-day and inter-day precision, selectivity and sensitivity fitted FDA guidelines for all analytes (LLOQ and LOD were 156.25 ng/mL and 78.12 ng/mL, respectively, for both analytes) and recovery resulted high and reproducible. Method performances were tested on urine samples from hypertensive patients with good results.
DISCUSSION: This simple analytical method could represent a useful tool for the management of antihypertensive therapy.

PMID: 30165207 [PubMed - as supplied by publisher]

Clinical verification of Lou type warfarin pharmacokinetic dosing algorithms equation.

Mol Med Rep. 2018 Apr;17(4):6144-6149

Authors: Jiang J, Ji N, Lan J, Ge X, Du X

Abstract
Warfarin is the most commonly used oral anti-coagulant in clinic practice. However, it is difficult to recommend the correct dosage due to its narrow therapeutic window. The aim of the present study was to verify the clinical value of the Lou type equation, using pharmacogenetics‑based warfarin dosing algorithms to appropriately predict the actual maintenance dose. A total of 87 Chinese Han patients who required treatment with warfarin were enrolled and randomly divided into the experimental and control groups. In the experimental group, the first 3 doses of warfarin were calculated according to the Lou type equation. While in the control group, these 3 treatments were performed following the doctors' recommendations. Then the dose of warfarin was gradually adjusted to the stable dose according to the changes in the international standardized ratio. At the end of the 50 day experimental period, there were a greater number of patients in the experimental group who exhibited a stable blood concentration of warfarin than those in the control group (83.35 and 64.4%, respectively). In addition, the mean and median times for patients to obtain a stable dose in the experimental group were significantly shorter than those in the control group (mean, 18.2±1.7 and 27.3±2.0 days; and median, 11.7±1.1 and 20.5±1.8 days, respectively). The adverse reaction rate of the experimental group (9.5%) was markedly lower than that of the control group (26.7%). The occurrence of adverse reactions in the experimental group was also significantly later when compared with the control group (43.9±1.6 and 38.6±1.5 days, respectively). Furthermore, there was no significant difference between the average predicted dose (3.4±1.1 mg/day) and the average actual dose (3.5±1.4 mg/day; P=0.313). In conclusion, using the Lou type warfarin pharmacokinetic dosing algorithm equation to administer warfarin markedly shortened the adjustment time of warfarin to reach a stable dose and reduced the adverse reactions rate, thus supporting clinical feasibility.

PMID: 29436624 [PubMed - indexed for MEDLINE]

The N-recognin UBR4 of the N-end rule pathway is required for neurogenesis and homeostasis of cell surface proteins.

PLoS One. 2018;13(8):e0202260

Authors: Kim ST, Lee YJ, Tasaki T, Hwang J, Kang MJ, Yi EC, Kim BY, Kwon YT

Abstract
The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of proteins act as a class of degrons (N-degrons) that determine the half-lives of proteins. We have previously identified a family of mammals N-recognins (termed UBR1, UBR2, UBR4/p600, and UBR5/EDD) whose conserved UBR boxes bind N-degrons to facilitate substrate ubiquitination and proteasomal degradation via the ubiquitin-proteasome system (UPS). Amongst these N-recognins, UBR1 and UBR2 mediate ubiquitination and proteolysis of short-lived regulators and misfolded proteins. Here, we characterized the null phenotypes of UBR4-deficient mice in which the UBR box of UBR4 was deleted. We show that the mutant mice die around embryonic days 9.5-10.5 (E9.5-E10.5) associated with abnormalities in various developmental processes such as neurogenesis and cardiovascular development. These developmental defects are significantly attributed to the inability to maintain cell integrity and adhesion, which significantly correlates to the severity of null phenotypes. UBR4-loss induces the depletion of many, but not all, proteins from the plasma membrane, suggesting that UBR4 is involved in proteome-wide turnover of cell surface proteins. Indeed, UBR4 is associated with and required to generate the multivesicular body (MVB) which transiently store endocytosed cell surface proteins before their targeting to autophagosomes and subsequently lysosomes. Our results suggest that the N-recognin UBR4 plays a role in the homeostasis of cell surface proteins and, thus, cell adhesion and integrity.

PMID: 30157281 [PubMed - in process]

Validation of A Nomogram for Achieving Target Trough Concentration of Vancomycin: Accuracy in Patients with Augmented Renal Function.

Ther Drug Monit. 2018 Aug 27;:

Authors: Ishii H, Hirai K, Sugiyama K, Nakatani E, Kimura M, Itoh K

Abstract
BACKGROUND: Adjustment of initial vancomycin (VCM) dosage has been recommended on the basis of the renal function nomogram in therapeutic drug monitoring guidelines in Japan. However, this nomogram has not been clinically validated, and few studies have focused on its usefulness in patients with risk of augmented renal function. Therefore, this study aimed to evaluate the validity of the VCM nomogram and the association between patient conditions related to augmented renal function and its accuracy.
METHODS: In this retrospective study, we screened data of 398 patients who received VCM and had estimated glomerular filtration rates (eGFRs) ≥ 30 mL·min·1.73 m. Patients who met nomogram dosing criteria were categorized into a nomogram group, and the associations of age, renal function, and individual conditions such as febrile neutropenia (FN), solid tumor, blood cancer, and brain injury with subtherapeutic concentrations (< 10.0 μg/mL) of VCM were evaluated.
RESULTS: In total, 177 patients were categorized into the nomogram group, and 83 (47%), 81 (46%), and 13 patients (7%) had VCM trough concentrations of 10-20, < 10, and > 20 μg/mL, respectively. Age < 50 years was only significantly associated with subtherapeutic trough concentrations. Specific conditions of patients such as FN, solid tumor, and blood cancer were associated with elevated VCM clearance; however, there was no decline in trough VCM concentrations regardless of the presence of the specific conditions.
CONCLUSIONS: The Japanese VCM dosing nomogram was effective in minimizing the number of instances of supra-therapeutic VCM serum concentrations; however, it lacked accuracy in achieving target trough concentrations. The accuracy of the nomogram could be enhanced by categorizing patients according to age. Nevertheless, this study provides novel evidence of the usefulness of this nomogram in avoiding subtherapeutic concentrations of VCM in patients with risk factors for augmented renal clearance.

PMID: 30157096 [PubMed - as supplied by publisher]

Individualized Tacrolimus Therapy for Pediatric Nephrotic Syndrome: Considerations for Ontogeny and Pharmacogenetics of CYP3A.

Curr Pharm Des. 2018 Aug 28;:

Authors: Sun JY, Xu ZJ, Sun F, Guo HL, Ding XS, Chen F, Xu J

Abstract
Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine therapeutic drug monitoring (TDM) is critical to keep tacrolimus blood levels within therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. Guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It's important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.

PMID: 30156148 [PubMed - as supplied by publisher]

Advances in Regenerative Medicine and Tissue Engineering: Innovation and Transformation of Medicine.

Stem Cells Int. 2018;2018:2495848

Authors: Dzobo K, Thomford NE, Senthebane DA, Shipanga H, Rowe A, Dandara C, Pillay M, Motaung KSCM

Abstract
Humans and animals lose tissues and organs due to congenital defects, trauma, and diseases. The human body has a low regenerative potential as opposed to the urodele amphibians commonly referred to as salamanders. Globally, millions of people would benefit immensely if tissues and organs can be replaced on demand. Traditionally, transplantation of intact tissues and organs has been the bedrock to replace damaged and diseased parts of the body. The sole reliance on transplantation has created a waiting list of people requiring donated tissues and organs, and generally, supply cannot meet the demand. The total cost to society in terms of caring for patients with failing organs and debilitating diseases is enormous. Scientists and clinicians, motivated by the need to develop safe and reliable sources of tissues and organs, have been improving therapies and technologies that can regenerate tissues and in some cases create new tissues altogether. Tissue engineering and/or regenerative medicine are fields of life science employing both engineering and biological principles to create new tissues and organs and to promote the regeneration of damaged or diseased tissues and organs. Major advances and innovations are being made in the fields of tissue engineering and regenerative medicine and have a huge impact on three-dimensional bioprinting (3D bioprinting) of tissues and organs. 3D bioprinting holds great promise for artificial tissue and organ bioprinting, thereby revolutionizing the field of regenerative medicine. This review discusses how recent advances in the field of regenerative medicine and tissue engineering can improve 3D bioprinting and vice versa. Several challenges must be overcome in the application of 3D bioprinting before this disruptive technology is widely used to create organotypic constructs for regenerative medicine.

PMID: 30154861 [PubMed]

A Nanomicellar Prodrug Carrier Based on Ibuprofen-Conjugated Polymer for Co-delivery of Doxorubicin.

Front Pharmacol. 2018;9:781

Authors: Li Z, Sun J, Huang Y, Liu Y, Xu J, Chen Y, Liang L, Li J, Liao Q, Li S, Zhou K

Abstract
Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID), which is widely used to reduce fever and treat inflammation and acute pain. Recently, its application in cancer treatment is also being explored. In this work, we synthesized a well-defined IBU-based amphiphilic diblock copolymer via reversible addition fragmentation transfer (RAFT) polymerization of IBU-based vinyl monomer. The amphiphilic copolymer POEG-b-PVBIBU (denoted as POVI) was composed of a hydrophilic poly(oligo(ethylene glycol)) block and a hydrophobic IBU-bearing prodrug block, which was able to self-assemble into prodrug nanomicelles. In addition, it could serve as a carrier to co-load other drugs including doxorubicin (DOX), paclitaxel (PTX), and docetaxel (DTX). By using DOX as a model anti-cancer drug, the delivery function of POVI carrier, including the drug release, in vitro cytotoxicity, cellular uptake, and in vivo antitumor activity, was evaluated. DOX-loaded POVI micelles exhibited sustained release of DOX. Besides, DOX/POVI micelles were effectively taken up by tumor cells with an efficiency comparable to that of free DOX. Moreover, in vivo studies showed that POVI carrier itself had modest antitumor activity. After loading DOX, the antitumor activity was significantly increased, which was significantly higher than that of free DOX. Our results suggest that POVI polymer represents a simple and effective dual-functional carrier for co-delivery of IBU and DOX to improve the anticancer activity.

PMID: 30154714 [PubMed]

Dyslipidaemia: The PCSK9 adventure - humanizing extreme LDL lowering.

Nat Rev Cardiol. 2017 06;14(6):319-320

Authors: Shapiro MD, Fazio S

PMID: 28470176 [PubMed - indexed for MEDLINE]