Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents.

J Control Release. 2018 Sep 14;:

Authors: Xu J, Zhao W, Sun J, Huang Y, Wang P, Venkataramanan R, Yang D, Ma X, Rana A, Li S

Abstract
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM ≥ Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.

PMID: 30223045 [PubMed - as supplied by publisher]

Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study.

J Am Geriatr Soc. 2018 Sep 17;:

Authors: Heath L, Gray SL, Boudreau DM, Thummel K, Edwards KL, Fullerton SM, Crane PK, Larson EB

Abstract
OBJECTIVES: To determine whether antidepressant use is associated with dementia risk.
DESIGN: Prospective cohort study.
SETTING: Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system.
PARTICIPANTS: Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059).
MEASUREMENTS: Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models.
RESULTS: During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46).
CONCLUSION: Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

PMID: 30221747 [PubMed - as supplied by publisher]

Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

Molecules. 2018 Apr 17;23(4):

Authors: Dzobo K, Hassen N, Senthebane DA, Thomford NE, Rowe A, Shipanga H, Wonkam A, Parker MI, Mowla S, Dandara C

Abstract
Background: Environmental pollution such as exposure to pro-carcinogens including benzo-α-pyrene is becoming a major problem globally. Moreover, the effects of benzo-α-pyrene (BaP) on drug pharmacokinetics, pharmacodynamics, and drug resistance warrant further investigation, especially in cancer outpatient chemotherapy where exposure to environmental pollutants might occur. Method: We report here on the effects of benzo-α-pyrene on esophageal cancer cells in vitro, alone, or in combination with chemotherapeutic drugs cisplatin, 5-flurouracil, or paclitaxel. As the study endpoints, we employed expression of proteins involved in cell proliferation, drug metabolism, apoptosis, cell cycle analysis, colony formation, migration, and signaling cascades in the WHCO1 esophageal cancer cell line after 24 h of treatment. Results: Benzo-α-pyrene had no significant effect on WHCO1 cancer cell proliferation but reversed the effect of chemotherapeutic drugs by reducing drug-induced cell death and apoptosis by 30–40% compared to drug-treated cells. The three drugs significantly reduced WHCO1 cell migration by 40–50% compared to control and BaP-treated cells. Combined exposure to drugs was associated with significantly increased apoptosis and reduced colony formation. Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs. Conclusion: The present study suggest that BaP can reverse the effects of drugs on cancer cells via the activation of survival signaling pathways and upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Our data show that BaP contribute to the development of chemoresistant cancer cells.

PMID: 29673198 [PubMed - indexed for MEDLINE]

Qualitative user evaluation of a revised pharmacogenetic educational toolkit.

Pharmgenomics Pers Med. 2018;11:139-146

Authors: Mills R, Haga SB

Abstract
Introduction: Pharmacogenetic (PGx) testing is a leading application for personalized and precision medicine; however, there are barriers, including limited provider and patient understanding, which affect its uptake. There is a need for tools that can enhance the patient and provider experience with testing and promoting the shared and informed decision-making.
Materials and methods: In this study, we sought to gather additional feedback on a PGx toolkit comprised of four educational tools that had been previously evaluated through an online survey by pharmacists. Specifically, we conducted semi-structured interviews with pharmacists and members of the public regarding their understanding and utility of the toolkit and its individual components.
Results: Participants found three of the four toolkit components, a test information sheet, flipbook, and results sheet, to be useful and important. The fourth component, results card, was viewed less favorably. Participants differed in their preference for medical jargon and detailed results nomenclature (namely star * alleles).
Conclusion: User input during the development of educational materials is essential for optimizing utilization, effectiveness, and comprehension.

PMID: 30214267 [PubMed]

Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis.

Nephrol Dial Transplant. 2018 Sep 11;:

Authors: Yap DYH, Tam CH, Yung S, Wong S, Tang CSO, Mok TMY, Yuen CKY, Ma MKM, Lau CS, Chan TM

Abstract
Background: There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance.
Methods: We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated.
Results: C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level.
Conclusion: MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.

PMID: 30215770 [PubMed - as supplied by publisher]

Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes.

Pharmacogenomics J. 2018 Sep 14;:

Authors: Choi J, Tantisira KG, Duan QL

Abstract
More than 1100 genetic loci have been correlated with drug response outcomes but disproportionately few have been translated into clinical practice. One explanation for the low rate of clinical implementation is that the majority of associated variants may be in linkage disequilibrium (LD) with the causal variants, which are often elusive. This study aims to identify and characterize likely causal variants within well-established pharmacogenomic genes using next-generation sequencing data from the 1000 Genomes Project. We identified 69,319 genetic variations within 160 pharmacogenomic genes, of which 8207 variants are in strong LD (r2>0.8) with known pharmacogenomic variants. Of the latter, eight are coding or structural variants predicted to have high impact, with 19 additional missense variants that are predicted to have moderate impact. In conclusion, we identified putatively functional variants within known pharmacogenomics loci that could account for the association signals and represent the missing causative variants underlying drug response phenotypes.

PMID: 30214008 [PubMed - as supplied by publisher]

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.

Pharmacol Res. 2018 Sep 10;:

Authors: Salvador-Martín S, García-González X, García MI, Blanco C, García-Alfonso P, Robles L, Grávalos C, Pachón V, Longo F, Martínez V, Sanjurjo M, López-Fernández LA

Abstract
Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.

PMID: 30213564 [PubMed - as supplied by publisher]

Reducing anthracycline-induced cardiotoxicity through pharmacogenetics.

Pharmacogenomics. 2018 Sep 14;:

Authors: Scott E, Hasbullah JS, Ross CJ, Carleton BC

PMID: 30213233 [PubMed - as supplied by publisher]

[Personalized medicine in psychiatry: nightmare of the industry?]

Neuropsychopharmacol Hung. 2016 09;18(3):137-142

Authors: Lazary J, Elemery M, Csala I, Faludi G

Abstract
Personalized medicine is a hot topic in the literature of the psychiatric field but it seems that regular clinical application of valid tests are awaited. Urgent requirement of objective tools for screening high-risk patients is postulated by prominent authors because long-term set up time, serious side effects or ineffectiveness of psychiatric agents mean a great challenge for clinicians to find optimal therapy on time. Unwanted suffering from inaccurate medicine, progression of the disorder and mistrust or in adherence of the patients are dramatic consequences of the delay of adequate therapy which is linked with irreversible health and mental damages and financial loss. On the other hand, a growing body of data are published on pharmacogenomic studies in association with psychiatric conditions. Although several pharmacogenetic tests are commercially available, accurate use of these tools are absent from clinical protocols. Here we give a short review on the most important pharmacogenomic results and a discussion on possible conflict of interests around pharmacogenetic tests. We conclude that all participants of the health care system could benefit from personalized medicine in psychiatry.

PMID: 27824309 [PubMed - indexed for MEDLINE]

Hypertension genomics and cardiovascular prevention.

Ann Transl Med. 2018 Aug;6(15):291

Authors: Ng FL, Warren HR, Caulfield MJ

Abstract
Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions.

PMID: 30211179 [PubMed]

The Mouse Hospital and Its Integration in Ultra-Precision Approaches to Cancer Care.

Front Oncol. 2018;8:340

Authors: Clohessy JG, Pandolfi PP

Abstract
Precision medicine holds real promise for the treatment of cancer. Adapting therapeutic strategies so patients receive individualized treatment protocols, will transform how diseases like cancer are managed. Already, molecular profiling technologies have provided unprecedented capacity to characterize tumors, yet the ability to translate this to actionable outcome in the clinic is limited. To enable real time translation of personalized therapeutic approaches to patient care in a co-clinical manner will require the adoption and integration of approaches that facilitate modeling of patient disease. The Mouse Hospital represents an approach that is ideally suited to pre- and co-clinical evaluation of novel therapeutic strategies for clinical care. Patient derived xenograft (PDX) technologies and in situ tumor modeling approaches using genetically engineered mouse models (GEMMs) already have a proven capacity to mimic human tumor responses, and their application can deliver invaluable insights into appropriate clinical approaches for individual patients by mirroring human clinical trials using a Co-Clinical Trial project and Mouse Hospital infrastructure. Additionally, the integration of the Mouse Hospital with other emerging technologies for the application of precision medicines, including organoid technologies, provides a platform that enables medical centers to truly reap the benefits that precision medicine has to offer.

PMID: 30211119 [PubMed]

User considerations in assessing pharmacogenomic tests and their clinical support tools.

NPJ Genom Med. 2018;3:26

Authors: Mukerjee G, Huston A, Kabakchiev B, Piquette-Miller M, van Schaik R, Dorfman R

Abstract
Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support. Demystifying an often confusing and variable PGx marketplace can lead to greater acceptance of PGx as a standard-of-care practice that improves drug outcomes and provides a lifetime value for patients. Here, we highlight the key underlying factors of a PGx test that should be considered, and discuss the current progress of PGx implementation.

PMID: 30210808 [PubMed]

American ginseng microbial metabolites attenuate DSS-induced colitis and abdominal pain.

Int Immunopharmacol. 2018 Sep 10;64:246-251

Authors: Wang CZ, Yao H, Zhang CF, Chen L, Wan JY, Huang WH, Zeng J, Zhang QH, Liu Z, Yuan J, Bi Y, Sava-Segal C, Du W, Xu M, Yuan CS

Abstract
Inflammatory bowel disease (IBD) is a significant public health problem in the United States. Abdominal pain is a major complaint among individuals with IBD. Successful IBD management not only controls enteric inflammation, but also reduces abdominal discomfort. Recently, increased attention has been focused on alternative strategies for IBD management. HPLC/Q-TOF-MS analysis was employed to evaluate the intestinal microbiome's biotransformation of parent American ginseng compounds into their metabolites. Using a DSS mouse model, the effects of American ginseng microbial metabolites on chemically induced colitis was investigated with disease activity index and histological assessment. Expressions of inflammatory cytokines were determined using real-time PCR and ELISA. Abdominal pain was evaluated using the von Frey filament test. After the gut microbiome's biotransformation, the major metabolites were found to be the compound K and ginsenoside Rg3. Compared with the DSS animal group, American ginseng treatment significantly attenuated experimental colitis, as supported by the histological assessment. The enteric microbiome-derived metabolites of ginseng significantly attenuated the abdominal pain. American ginseng treatment significantly reduced gut inflammation, consistent with pro-inflammatory cytokine level changes. The gut microbial metabolite compound K showed significant anti-inflammatory effects even at low concentrations, compared to its parent ginsenoside Rb1. American ginseng intestinal microbial metabolites significantly reduced chemically-induced colitis and abdominal pain, as mediated by the inhibition of pro-inflammatory cytokine expression. Intestinal microbial metabolism plays a critical role in American ginseng mediated colitis management.

PMID: 30212750 [PubMed - as supplied by publisher]

Optimization of the Cohesion Index in the SeDeM Diagram Expert System and application of SeDeM Diagram: An improved methodology to determine the Cohesion Index.

PLoS One. 2018;13(9):e0203846

Authors: Nofrerias I, Nardi A, Suñé-Pou M, Boeckmans J, Suñé-Negre JM, García-Montoya E, Pérez-Lozano P, Ticó-Grau JR, Miñarro-Carmona M

Abstract
In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density. Therefore, the resulting tablet will have a height within a defined range of heights where it has no critical effects on its hardness. Then, the impact of this optimization is shown in a formula development, one of the main SeDeM's applications. A mathematical equation was used to calculate the theoretical amount of excipient to formulate the API according to both methodologies. The compression results demonstrate that the characterization with the NM-Icd is more accurate than the previous one while preserving its simplicity.

PMID: 30212557 [PubMed - in process]

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia.

Radiol Oncol. 2018 Sep 11;52(3):296-306

Authors: Gasic V, Zukic B, Stankovic B, Janic D, Dokmanovic L, Lazic J, Krstovski N, Dolzan V, Jazbec J, Pavlovic S, Kotur N

Abstract
Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.

PMID: 30210047 [PubMed - in process]

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Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.

Psychol Med. 2018 Sep 12;:1-9

Authors: Sadeh N, Spielberg JM, Logue MW, Hayes JP, Wolf EJ, McGlinchey RE, Milberg WP, Schichman SA, Stone A, Miller MW

Abstract
BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.
METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.
RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.
CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

PMID: 30207258 [PubMed - as supplied by publisher]

Pharmacogenetic profile and major depressive and/or bipolar disorder treatment: a retrospective, cross-sectional study.

Pharmacogenomics. 2018 Sep 12;:

Authors: Tonozzi TR, Braunstein GD, Kammesheidt A, Curran C, Golshan S, Kelsoe J

Abstract
AIM: To compare pharmacogenetic test predictions with self-reported treatment experience and side effect tolerability among patients with depression taking psychotherapeutic medications.
METHODS: Subjects completed a survey recalling medication effectiveness and side effects and then underwent pharmacogenetic testing.
RESULTS: Our 15 gene pharmacogenetic panel predicted efficacy (p < 0.001) but did not predict side effect tolerability (p = 0.70) in a group of 352 patients. The pharmacogenetic panel and reported efficacy corresponded 60% of the time and medication tolerability agreed 71% of the time.
CONCLUSION: Pharmacogenetic testing may be a useful adjunct to predict efficacy of medications used to treat depression.

PMID: 30207201 [PubMed - as supplied by publisher]

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients.

Pharmacogenomics. 2018 Sep 12;:

Authors: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJ, Appel IM, Tamminga RY, Cessie SL, Swen JJ, der Straaten TV, Boer A, Maitland-van der Zee AH

Abstract
AIM: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm.
METHODS: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement.
RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement.
CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

PMID: 30207196 [PubMed - as supplied by publisher]

Weekly versus 3-weekly paclitaxel in combination with carboplatin in advanced ovarian cancer: which is the optimal adjuvant chemotherapy regimen?

J Gynecol Oncol. 2018 Nov;29(6):e96

Authors: Lee MX, Tan DS

Abstract
The 3-weekly regimen of carboplatin and paclitaxel is the backbone of first line adjuvant chemotherapy for advanced ovarian cancer. The landmark Japanese Gynaecologic Oncology Group (JGOG) 3016 study demonstrated significant improvements in progression-free survival and overall survival with dose dense weekly administration of paclitaxel in combination with 3-weekly carboplatin. However, efforts to replicate these benefits have failed in subsequent phase III trials. Weekly paclitaxel is purported to have enhanced antitumor activity, with stronger anti-angiogenic effects, and yet is better tolerated. In this review, we explore the rationale for dose dense weekly paclitaxel, and compare the relevant trials as well as quality of life considerations. Possible reasons for the difference in outcomes between the JGOG 3016 and other studies are reviewed, with a focus on how the addition of bevacizumab, the variations between histological and molecular subtypes of epithelial ovarian cancers, and ethnic pharmacogenetic differences may potentially affect the efficacy of dose dense paclitaxel.

PMID: 30207104 [PubMed - in process]