Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population.

Bioconjug Chem. 2017 Nov 01;:

Authors: Benasutti H, Wang G, Vu VP, Scheinman R, Groman E, Saba L, Simberg D

Abstract
Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15-30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical difference between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual's response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.

PMID: 29090582 [PubMed - as supplied by publisher]

Pharmacogenomics of sickle cell disease: steps toward personalized medicine.

Pharmgenomics Pers Med. 2017;10:261-265

Authors: Husain M, Hartman AD, Desai P

Abstract
Sickle cell disease (SCD) is a monogenetic disease but has a wide range of phenotypic expressions. Some of these differences in phenotype can be explained by genetic polymorphisms in the human globin gene. These polymorphisms can result in different responses to typical treatment, sometimes leading to inadequate therapeutics. Research is revealing more polymorphisms, and therefore, new targets for intervention to improve outcomes in SCD. This area of pharmacogenomics is continuing to develop. We provide a brief review of the current literature on pharmacogenomics in SCD and possible targets for intervention.

PMID: 29089781 [PubMed]

Mitochondrial fission/fusion and cardiomyopathy.

Curr Opin Genet Dev. 2016 06;38:38-44

Authors: Dorn G

Abstract
Mitochondria are highly abundant in and essential to the beat-to-beat contractile performance of hearts. However, relatively few cardiac diseases have been attributed to primary mitochondrial dysfunction. The paucity of evidence for 'primary mitochondrial cardiac diseases' may be because such an entity does not exist. Alternately, the consequences of mitochondrial dysfunction on hearts may be so severe that long-term viability is severely impaired and affected individuals are therefore not included in standard genetic screens of adult heart disease subjects. Here, I review accumulating experimental evidence that impairing mitochondrial fission or fusion causes cardiomyopathy in otherwise normal mice, and consider how these data could motivate screening of perinatal cardiomyopathy subjects for damaging mutations of mitochondrial fission and fusion factors.

PMID: 27061490 [PubMed - indexed for MEDLINE]

Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia.

Pharmacogenet Genomics. 2017 Oct 27;:

Authors: Rajagopal VM, Rajkumar AP, Jacob KS, Jacob M

Abstract
Clozapine is the drug of choice for treatment-resistant schizophrenia. However, its use is associated with variable clinical responses and serious adverse effects. Polymorphisms in genes encoding proteins involved in synaptic neurotransmission may account for such variability. Here, we studied independent and epistatic genetic associations of polymorphisms in DRD4 (120-bp duplication) and COMT (Val158Met) with clinical response to clozapine in people with treatment-resistant schizophrenia. We studied 93 participants who were on stable doses of clozapine for at least 12 weeks. A total score of less than or equal to 35 on the Brief Psychiatric Rating Scale was defined as a clinical response. The genetic associations were tested using logistic regression analyses. Neither polymorphism studied was found to be independently associated with response to clozapine. However, a statistically significant gene-gene interaction was observed between the polymorphisms. Participants with the COMT Val/Met or Met/Met genotype, who also had one or two DRD4 120-bp alleles (120/240 and 120/120), showed significantly better clinical response to clozapine. Our results highlight the importance of investigating gene-gene interactions, while studying the pharmacogenetics of clozapine.

PMID: 29087970 [PubMed - as supplied by publisher]

Strategies for Avoiding Benzopyrone Hepatotoxicity in Lymphedema Management-The Role of Pharmacogenetics, Metabolic Enzyme Gene Identification, and Patient Selection.

Lymphat Res Biol. 2017 Oct 31;:

Authors: Hu M, Piller NB

Abstract
INTRODUCTION: Benzopyrones are plant-derived chemicals which have an evidenced degree of clinical efficacy in lymphedema management indicated in past trials. Unfortunately, in some of these cases idiosyncratic hepatotoxicity have been documented in a minority of patients. This review aims to tackle the problem of benzopyrone (particularly coumarin) toxicity by considering their metabolic pathways and identifying relevant alleles needed to take a targeted pharmacogenetic approach in its future use.
METHODS AND RESULTS: The nontoxic 7-hydroxylation and the toxic heterocyclic "ring-splitting" epoxidation pathways are the two main detoxification pathways in the hepatometabolism of coumarin, the former catalyzed by CYP2A6 and the latter by possibly CYP1A and CYP2E. Acetaldehyde dehydrogenase (ALDH) clears toxic aldehyde intermediates. CYP2A6 polymorphism screening methods, including genotyping, by real-time polymerase chain reaction and chromatography-mass spectroscopy functional metabolite assays; efficiency of these techniques are continually improving. ALDH polymorphisms have also been implicated, with clinically viable screening tests, rapid genotyping, and sensitive questionnaires already available for ALDH2*1/ALDH2*2. Dysfunctional polymorphisms of the above genes and others are significantly more prevalent in Eastern Asian populations, uncommon in Caucasian populations. The role of other enzymes/genes in the pathway is yet to be clarified.
CONCLUSION: Although screening techniques are becoming increasingly clinically feasible, uncertainty remains on the link between the genotype, metabolic phenotype, and the exact gene products involved. These must be elucidated further before a targeted pharmacogenomic approach is fully viable. In the meantime, treatment should be avoided in those with vulnerable familial and ethnic descents if used.

PMID: 29087786 [PubMed - as supplied by publisher]

Synthesis, molecular docking and biological evaluation of bis-pyrimidine Schiff base derivatives.

Chem Cent J. 2017 Sep 18;11(1):89

Authors: Kumar S, Lim SM, Ramasamy K, Vasudevan M, Shah SAA, Selvaraj M, Narasimhan B

Abstract
BACKGROUND: Heterocyclic pyrimidine nucleus, which is an essential base component of the genetic material of deoxyribonucleic acid, demonstrated various biological activities. A series of bis-pyrimidine Schiff bases were synthesized and screened for its antimicrobial and anticancer potentials. The molecular docking study was carried to find the interaction between active molecules with receptor.
RESULTS: The structures of synthesized bis-pyrimidine Schiff bases were confirmed by spectral studies. The synthesized bis-pyrimidine derivatives were evaluated for their antimicrobial activity (MIC = µmol/mL) against selected Gram positive; Gram negative bacterial and fungal strains by tube dilution method. The anticancer activity (IC50 = µmol/mL) of the synthesized compounds was determined against human colorectal carcinoma (HCT116) cancer cell line by Sulforhodamine B (SRB) assay. Molecular docking studies provided information regarding the binding mode of active bis-pyrimidine Schiff bases with the cyclin-dependent kinase 8 (CDK8) receptor.
CONCLUSIONS: The antimicrobial screening results indicated that compounds, q1 (MICbs = 0.83 µmol/mL), q16 (MICan = 1.54 µmol/mL and MICec = 0.77 µmol/mL), q1 and q19 (MICca = 0.41 µmol/mL) and q20 (MIC = 0.36 µmol/mL) are the most active ones. Compounds q1 (IC50 = 0.18 µmol/mL) have emerged as potent anticancer molecule against human colorectal carcinoma cancer cell line than the reference drug, 5-fluorouracil. Molecular docking studies indicated that compound q1 (the most active molecule) has the maximum hydrogen bond interaction (four) and π-π stacking (three) network among the bis-pyrimidine Schiff bases. Graphical abstract Graphical illustration of predicted binding mode of bis-pyrimidine Schiff bases in the active site of CDK8. a. Compound 1 (magenta color), b. Compound 5 (green color), c. Compound 8 (red color), d. Compound 13 (split pea color).

PMID: 29086867 [PubMed]

Polymorphism of 11 Y Chromosome Short Tandem Repeat Markers among Malaysian Aborigines.

Evol Bioinform Online. 2017;13:1176934317735318

Authors: Mohd Yussup SS, Marzukhi M, Md-Zain BM, Mamat K, Mohd Yusof FZ

Abstract
The conventional technique such as patrilocality suggests some substantial effects on population diversity. With that, this particular study investigated the paternal line, specifically Scientific Working Group on DNA Analysis Methods (SWGDAM)-recommended Y-STR markers, namely, DYS19, DYS385, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS438, and DYS439. These markers were tested to compare 184 Orang Asli individuals from 3 tribes found in Peninsular Malaysia. As a result, the haplotype diversity and the discrimination capacity obtained were 0.9987 and 0.9076, respectively. Besides, the most diverse marker was DYS385b, whereas the least was DYS391. Furthermore, the Senoi and Proto-Malay tribes were found to be the most distant, whereas the Senoi and Negrito clans were almost similar to each other. In addition, the analysis of molecular variance analysis revealed 82% of variance within the population, but only 18% of difference between the tribes. Finally, the phylogenetic trees constructed using Neighbour Joining and UPGMA (Unweighted Pair Group Method with Arithmetic Mean) displayed several clusters that were tribe specific. With that, future studies are projected to analyse individuals based on more specific sub-tribes.

PMID: 29085238 [PubMed]

Psoriasis pharmacogenetics: HLA-Cw*0602 as a marker of therapeutic response to ustekinumab.

Eur J Dermatol. 2017 Oct 01;27(5):528-530

Authors: Raposo I, Carvalho C, Bettencourt A, Da Silva BM, Leite L, Selores M, Torres T

PMID: 29084639 [PubMed - in process]

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients.

Expert Opin Drug Metab Toxicol. 2017 Oct 30;:1-12

Authors: Andrews LM, Li Y, De Winter BCM, Shi YY, Baan CC, Van Gelder T, Hesselink DA

Abstract
INTRODUCTION: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure - research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.

PMID: 29084469 [PubMed - as supplied by publisher]

Insight gained from genome-wide interaction and enrichment analysis on weight gain during citalopram treatment.

Neurosci Lett. 2017 Jan 10;637:38-43

Authors: Corfitsen HT, Drago A

Abstract
Weight gain is a possible side effect of the pharmacological antidepressant treatments. Defining antidepressant prescriptions based on personal genetic makeups would decrease the risk of weight gain and increase the quality of the current antidepressant pharmacological treatments. 643 depressed, citalopram treated individuals with available clinical and genome-wide genetic information were investigated to identify the molecular pathways associated with weight gain. 111 individuals experienced weight gain during citalopram treatment. The axon guidance (p.adjust=0.005) and the developmental biology pathway (p.adjust=0.01) were enriched in variations associated with weight gain. The developmental biology pathway includes molecular cascades involved in the regulation of beta-cell development, and the transcriptional regulation of white adipocyte differentiation. A number of variations were harbored by genes whose products are involved in the synthesis of collagen (COL4A3, COL5A1 and ITGA1), activity of the thyroid-hormones (NCOR1 and NCOR2), energy metabolism (ADIPOQ, PPARGC1A) and myogenic differentiation (CDON). A molecular pathway analysis conducted in a sample of depressed patients identified new candidate genes whose future investigation may provide insights in the molecular events that drive weight gain during antidepressant treatment.

PMID: 27899308 [PubMed - indexed for MEDLINE]

Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.

Mol Diagn Ther. 2017 Feb;21(1):75-83

Authors: Shaul C, Blotnick S, Muszkat M, Bialer M, Caraco Y

Abstract
BACKGROUND: Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions.
OBJECTIVE: The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes.
METHODS: Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period.
RESULTS: Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CLS was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001).
CONCLUSIONS: The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision.
TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT00162474.

PMID: 27878474 [PubMed - indexed for MEDLINE]

Stop the Spam! Conference Ethics and Decoding the Subtext in Post-Truth Science. What Would Denis Diderot Say?

OMICS. 2017 Oct 30;:

Authors: Özdemir V, Dandara C, Hekim N, Birch K, Springer S, Kunej T, Endrenyi L

Abstract
Science and its practice always had a subtext, subject to influence by scientists', funders', and other innovation actors' values and assumptions. The recent emergence of post-truth, authoritarian and populist penchants, in both developed and developing countries, has further blurred the already fluid boundaries between material scientific facts and their social construction/shaping by scientific subtext, human values, powers, and hegemony. While there are certain checks, balances, and oversight mechanisms for publication ethics, other pillars of science communication, most notably, scientific conferences and their governance, are ill prepared for post-truth science. Worrisomely, the proliferation of spam conferences is a major cause for concern for integrative biology and postgenomic science. The current gaps in conference ethics are important beyond science communication because conferences help build legitimacy of emerging technologies and frontiers of science and, thus, bestows upon the organizers, funders, enlisted scientific advisors, speakers, among others, power, which in turn needs to be checked. Denis Diderot (1713-1784), a prominent intellectual during the Enlightenment period, has aptly observed that the very act of organizing brings about power, influence, and control. If the subtext of conference practices is left unchecked, it can pave the way for hegemony, and yet more volatile and violent authoritarian governance systems in science and society. This begs for innovative solutions to increase accountability, resilience, and capacity of technology experts and scientists to discern and decode the subtext in science and its communication in the current post-truth world. We propose that the existing undergraduate and graduate programs in life and physical sciences and medicine could be redesigned to include a rotation for exposure to and training in political science. Such innovative PhD+ programs straddling technical and political science scholarship would best equip future students and citizens to grasp and respond to subtext and embedded opaque value and power systems in scientific practices in an increasingly post-truth world. Political science scholarship unpacks the inner workings, subtext, and power dynamics in science and society. Thus, knowledge of political science competency is akin to molecular biology in life sciences. Both make the invisible (e.g., cell biology versus subtext of knowledge) visible. The ability to read subtext in science and claims of post-truth knowledge is a new and essential form of societal literacy in 21(st) century science and integrative biology.

PMID: 29083982 [PubMed - as supplied by publisher]

Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet. 2017 Oct 30;:

Authors: Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, Amouyel P, Di Angelantonio E, Arveiler D, Assimes TL, Auer PL, Baber U, Ballantyne CM, Bang LE, Benn M, Bis JC, Boehnke M, Boerwinkle E, Bork-Jensen J, Bottinger EP, Brandslund I, Brown M, Busonero F, Caulfield MJ, Chambers JC, Chasman DI, Chen YE, Chen YI, Chowdhury R, Christensen C, Chu AY, Connell JM, Cucca F, Cupples LA, Damrauer SM, Davies G, Deary IJ, Dedoussis G, Denny JC, Dominiczak A, Dubé MP, Ebeling T, Eiriksdottir G, Esko T, Farmaki AE, Feitosa MF, Ferrario M, Ferrieres J, Ford I, Fornage M, Franks PW, Frayling TM, Frikke-Schmidt R, Fritsche LG, Frossard P, Fuster V, Ganesh SK, Gao W, Garcia ME, Gieger C, Giulianini F, Goodarzi MO, Grallert H, Grarup N, Groop L, Grove ML, Gudnason V, Hansen T, Harris TB, Hayward C, Hirschhorn JN, Holmen OL, Huffman J, Huo Y, Hveem K, Jabeen S, Jackson AU, Jakobsdottir J, Jarvelin MR, Jensen GB, Jørgensen ME, Jukema JW, Justesen JM, Kamstrup PR, Kanoni S, Karpe F, Kee F, Khera AV, Klarin D, Koistinen HA, Kooner JS, Kooperberg C, Kuulasmaa K, Kuusisto J, Laakso M, Lakka T, Langenberg C, Langsted A, Launer LJ, Lauritzen T, Liewald DCM, Lin LA, Linneberg A, Loos RJF, Lu Y, Lu X, Mägi R, Malarstig A, Manichaikul A, Manning AK, Mäntyselkä P, Marouli E, Masca NGD, Maschio A, Meigs JB, Melander O, Metspalu A, Morris AP, Morrison AC, Mulas A, Müller-Nurasyid M, Munroe PB, Neville MJ, Nielsen JB, Nielsen SF, Nordestgaard BG, Ordovas JM, Mehran R, O'Donnell CJ, Orho-Melander M, Molony CM, Muntendam P, Padmanabhan S, Palmer CNA, Pasko D, Patel AP, Pedersen O, Perola M, Peters A, Pisinger C, Pistis G, Polasek O, Poulter N, Psaty BM, Rader DJ, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Rich SS, Ridker PM, Rioux JD, Robertson NR, Roden DM, Rotter JI, Rudan I, Salomaa V, Samani NJ, Sanna S, Sattar N, Schmidt EM, Scott RA, Sever P, Sevilla RS, Shaffer CM, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith BH, Somayajula S, Southam L, Spector TD, Speliotes EK, Starr JM, Stirrups KE, Stitziel N, Strauch K, Stringham HM, Surendran P, Tada H, Tall AR, Tang H, Tardif JC, Taylor KD, Trompet S, Tsao PS, Tuomilehto J, Tybjaerg-Hansen A, van Zuydam NR, Varbo A, Varga TV, Virtamo J, Waldenberger M, Wang N, Wareham NJ, Warren HR, Weeke PE, Weinstock J, Wessel J, Wilson JG, Wilson PWF, Xu M, Yaghootkar H, Young R, Zeggini E, Zhang H, Zheng NS, Zhang W, Zhang Y, Zhou W, Zhou Y, Zoledziewska M, Charge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program, Howson JMM, Danesh J, McCarthy MI, Cowan CA, Abecasis G, Deloukas P, Musunuru K, Willer CJ, Kathiresan S

Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

PMID: 29083408 [PubMed - as supplied by publisher]

The role of depression pharmacogenetic decision support tools in shared decision making.

J Neural Transm (Vienna). 2017 Oct 29;:

Authors: Arandjelovic K, Eyre HA, Lenze E, Singh AB, Berk M, Bousman C

Abstract
Patients discontinue antidepressant medications due to lack of knowledge, unrealistic expectations, and/or unacceptable side effects. Shared decision making (SDM) invites patients to play an active role in their treatment and may indirectly improve outcomes through enhanced engagement in care, adherence to treatment, and positive expectancy of medication outcomes. We believe decisional aids, such as pharmacogenetic decision support tools (PDSTs), facilitate SDM in the clinical setting. PDSTs may likewise predict drug tolerance and efficacy, and therefore adherence and effectiveness on an individual-patient level. There are several important ethical considerations to be navigated when integrating PDSTs into clinical practice. The field requires greater empirical research to demonstrate clinical utility, and the mechanisms thereof, as well as exploration of the ethical use of these technologies.

PMID: 29082439 [PubMed - as supplied by publisher]

Optimization of Antidepressant use with Pharmacogenetic Strategies.

Curr Genomics. 2017 Oct;18(5):442-449

Authors: Torrellas C, Carril JC, Cacabelos R

Abstract
BACKGROUND: The response rate in the pharmacological treatment of depression has been estimated to be around 50%, achieving a remission in symptomatology in only one third of the patients. Suboptimal prescription of antidepressants has been proposed as a significant explanatory factor for this therapeutic inefficacy. The use of pharmacogenetic testing might favor the optimization of pharmacotherapy in emotional disorders. However, its implementation in the clinical routine requires studies which prove its efficacy.
OBJECTIVE: The aim is to explore the clinical effects obtained by means of the personalization of antidepressant treatment derived from the pharmacogenetic profile of the individual.
METHOD: A sample of 291 patients under antidepressant treatment was selected, and these patients were genotyped for the most common polymorphisms of the CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5 genes using RT-PCR and TaqMan® technology. 30 of them were subjected to psycho-affective assessment using the HDRS scale before and after a process of individualization of their psychopharmacological treatment in accordance with the genotype obtained.
RESULTS: 70% of the individuals treated using the traditional criterion of trial-and-error were not taking the active ingredient most suited to their pharmacogenetic profile. The inclusion of this genetic information in the choice of drug and its dosage entailed a significant, progressive reduction in depressive symptomatology, with an efficacy ratio of 80% and a remission of the pathology in almost 30% of the cases.
CONCLUSION: These results suggest that the prescription of pharmacogenetic profile-based strategies has a positive effect on the therapeutic response to antidepressants.

PMID: 29081699 [PubMed]

[Pharmacogenetic approaches to predicting the efficiency and safety of amlodipine in patients with arterial hypertension].

Biomed Khim. 2017 Oct;63(5):432-439

Authors: Sychev DA, Shih NV, Kalle EG, Ryzhikova KA, Morozova TE

Abstract
An open, non-comparative, prospective clinical study was conducted to evaluate the antihypertensive efficacy and tolerability of amlodipine, a calcium antagonist, in patients with arterial hypertension (AH) I-II stages, depending on the genotype for the polymorphic marker C3435T of the ABCB1 gene. The study included 100 patients with AH I-II stages, aged from 45 to 58 years. The initial dose of amlodipine was 5 mg, duration of treatment was 12 weeks. General clinical examination methods, office measurement and daily blood pressure monitoring, tolerance evaluation, and genotyping using the ABCB1 polymorphic marker C3435T by the PCR-RFLP method (polymerase chain reaction and restriction fragment length polymorphism) were used. The statistical analysis of results was carried out using the Mann-Whitney U test for quantitative variables, Kruskal-Wallis one-way analysis of variance (ANOVA) for three independent groups of quantitative data. Excellent antihypertensive efficacy with the CC genotype was found in 11.8% patients, with CT - 33.9%, with TT - 43.3%; good - 35.3%, 32.1%, and 33.3% respectively, satisfactory - 52.9%, 34,0% and 23.4% respectively. Six patients with the CT genotype and nine patients with the CC genotype required the increase in the dose to 10 mg. The number of patients with Adverse drug reactions (ADR) were found in 35.3% of patients with the CC genotype, 6.7% with the TT genotype and 11.3% with the CT genotype. The Kruskal-Wallis test revealed significant differences between CC and TT genotypes in the degree of decrease in SBP (p=0.02), antihypertensive efficacy parameter (p=0.02), an increase in dose requirements (p = 0.04) and the incidence of ADR(p=0.05). In AH patients (I-II stage) with the TT genotype of the C3435T gene polymorphism one can expect higher rates of antihypertensive efficacy of amlodipine in combination with a good safety profile and the lowest ADR percentage, while patients with the CC genotype more likely to develop ADR and lower antihypertensive responsiveness.

PMID: 29080877 [PubMed - in process]

Occult hepatitis B virus infection: clinical implications in tuberculosis treatment.

J Viral Hepat. 2016 Dec;23(12):1027-1035

Authors: Trigo C, do Brasil PE, Costa MJ, de Castro L

Abstract
Occult hepatitis B virus infection (OBI) is characterized by the absence of HBsAg and persistence of the virus genome (HBV-DNA) in liver tissue and/or blood. OBI has been reported in several clinical contexts. However, the clinical significance of OBI in tuberculosis (TB) treatment is unknown. We investigated the OBI prevalence and its impact on the risk of drug-induced liver injury (DILI) during TB treatment. This was a prospective cohort study with one hundred patients who were treated for TB from 2008 to 2015. Laboratory, clinical and demographic data of TB patients were extracted from medical records. Based on HBV-DNA testing of serum samples, an OBI prevalence of 12% was established; almost half of these patients had both anti-HBc and anti-HBs serological markers. Low CD4(+) cell counts have been shown to be a risk factor for OBI among TB patients co-infected with HIV (P=.036). High DILI incidence was observed in this study. A multivariable Cox proportional hazard model was conducted and identified OBI (HR 2.98, 95% CI 1.30-6.86) as the strongest predictor for DILI when adjusted to CD4(+) cell count (HR 0.38, 95% CI 0.17-0.90), ALT before TB treatment (HR 1.37, 95% CI 0.81-2.32) and TB extrapulmonary clinical form (HR 2.91, 95% CI 1.75-7.21). The main aim of this study was to highlight DILI as a clinical outcome during treatment of TB patients with OBI. Therefore, HBV-DNA testing should be considered routinely in monitoring DILI, and also in other clinical implications associated with OBI, reduce morbidity and mortality.

PMID: 27624908 [PubMed - indexed for MEDLINE]

A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel.

Acta Biomater. 2016 Oct 01;43:282-291

Authors: Sun J, Chen Y, Li K, Huang Y, Fu X, Zhang X, Zhao W, Wei Y, Xu L, Zhang P, Venkataramanan R, Li S

Abstract
UNLABELLED: In order to achieve enhanced and synergistic delivery of paclitaxel (PTX), a hydrophobic anticancer agent, two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks, were synthesized. Both POEG-b-PFTS polymers were able to form micelles with intrinsic antitumor activity in vitro and in vivo. Employing these micelles as a carrier to load PTX, their drug loading capacity, stability, in vivo biodistribution and tumor inhibition effect were evaluated. PTX/POEG15-b-PFTS16 mixed micelles exhibited an excellent stability of 9days at 4°C with a PTX loading capacity of 8.2%, which was more effective than PTX/POEG15-b-PFTS6 mixed micelles. In vivo biodistribution data showed that DiR-loaded POEG-b-PFTS micelles were more effectively localized in the tumor than in other organs. Moreover, both PTX/POEG-b-PFTS micelles showed significantly higher antitumor activity than Taxol in a 4T1.2 murine breast tumor model, and the tumor inhibition and animal survival followed the order of PTX/POEG15-b-PFTS16>PTX/POEG15-b-PFTS6>POEG15-b-PFTS16>Taxol≈POEG15-b-PFTS6. Our data suggest that POEG-b-PFTS micelles are a promising anticancer drug carrier that warrants more studies in the future.
STATEMENT OF SIGNIFICANCE: Polymerization of drug-based monomer represents a facile and precise method to obtain well-defined polymeric prodrug amphiphiles. Currently, most reports largely focus on the synthesis methods and the biophysical properties. There is limited information about their anti-tumor activity and delivery function as prodrug carriers in vitro and in vivo. In this manuscript, we report the development of two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks. Both POEG-b-PFTS polymers were able to self-assemble into nano-sized micelles with intrinsic antitumor activity in vitro and in vivo. More importantly, POEG-b-PFTS polymers were effective in forming stable mixed micelles with various anticancer agents including PTX, DOX, docetaxel, gefitinib, and imatinib. Delivery of PTX via our new carrier led to significantly improved antitumor activity, suggesting effective PTX/FTS combination therapy. We believe that our study shall be of broad interest to the readers in the fields of biomaterials and drug delivery.

PMID: 27422196 [PubMed - indexed for MEDLINE]

The expression of G protein-coupled receptor kinase 5 and its interaction with dendritic marker microtubule-associated protein-2 after status epilepticus.

Epilepsy Res. 2017 Oct 13;138:62-70

Authors: Zeng X, Chen S, Gao Q, Zong W, Jiang D, Zeng G, Zhou L, Chen L, Luo W, Xiao J, Xiao B, Ouyang D, Hu K

Abstract
OBJECTIVE: Acute seizures induced dendritic formation and synaptogenesis promotes aberrant circuitry development and further aggravates underlying conditions towards chronic epilepsy. The G protein-coupled receptor kinase-5 (GRK5) served as a key modulator in neurogenesis and the establishment of functional neuronal circuitry. This included dendritic development, as its dysfunction could cause different central nervous system disorders, including Alzheimer's disease. However, the involvement of GRK5 in the progression of epilepsy remains unclear. The purpose of this study is to investigate the involvement of GRK5 in epilepsy, as well as its potential correlation with dendritic formation after status epilepticus.
METHODS: 120 rats were divided into control and model groups. The rats in the model group were injected intraperitoneally with lithium chloride-pilocarpine hydrochloride to establish the rat model of status epilepticus (SE). The brain and hippocampus were collected at 1, 3, 7, 14 and 28days post SE induction. The expression and distribution of GRK5 and the dendritic marker microtubule-associated protein-2 (MAP-2) were detected in the hippocampus via western blot or immunohistochemistry. The co-localization of GRK5 with MAP-2 was examined via laser confocal double immunofluorescence staining. The interactions between GRK5 and MAP-2 during epileptogenesis were evaluated via immunoprecipitation.
RESULTS: GRK5 was distributed in all areas of the hippocampus. Its expression was significantly up-regulated in the hippocampal CA1, DG, and H areas at 7d and 14d after SE. After 14d it began to reduce. and then reduced. MAP-2 primarily existed in the neuronal dendrites of the hippocampal subregion. Its expression was enhanced at 3d. It reached its maximum level at 14d after SE, where it then began to fall. The confocal microscope analysis revealed that GRK5 was co-located well within MAP-2 positive cells. The interaction between GRK5 and MAP-2 became enhanced at 7d and 14d after SE.
CONCLUSIONS: GRK5 was involved in the development of epilepsy. It was associated with dendritic formation in epilepsy. This study provides a new perspective for elucidating the epilepsy pathogenesis. The concrete mechanisms of the GRK5 within epileptogenesis require further research.

PMID: 29080472 [PubMed - as supplied by publisher]

A clinical pharmacy pilot within a Precision Medicine Program for cancer patients and review of related pharmacist clinical practice.

J Oncol Pharm Pract. 2017 Jan 01;:1078155217738324

Authors: Arnall JR, Petro R, Patel JN, Kennedy L

Abstract
Purpose The implementation, benefits, and challenges of clinical pharmacist services within a Precision Medicine Program for cancer patients are described. By relating the practice model that was developed, this report may further encourage pharmacists at cancer centers nationally to be involved and lead precision-based care in the oncology setting. Summary A clinical pharmacist was integrated into a Precision Medicine Program for oncology patients using somatic testing to identify actionable mutations and apply targeted therapy to malignancies. This pharmacist served as a drug resource for the program's molecular tumor board and oncologists seeking precision-based oncologic strategies. The pharmacist was a facilitator of drug assistance and dispensing in collaboration with the specialty pharmacy and provided care to 14 oncology patients receiving precision-based therapies. The clinical pharmacist was readily accepted as an addition to the team by both oncologists and patients and the experience served as an important learning opportunity. Conclusion The success of integrating this precision medicine pharmacist into a newly formed Precision Medicine Program and the model it can serve as may be considered for other cancer centers that may or may not have easily accessible pharmacogenomic experts and resources. This service highlights the importance of pharmacist care in such a program and the various opportunities for integration. Oncology clinical pharmacists should seek to integrate into Precision Medicine Programs and systems directing this care and develop their knowledge and understanding of genomics to continue providing the highest level of cancer care as a pivotal member of the cancer care team.

PMID: 29078708 [PubMed - as supplied by publisher]