Differential gene expression in growth factors, epithelial mesenchymal transition and chemotaxis in the diffuse type compared with the intestinal type of gastric cancer.

Oncol Lett. 2019 Jul;18(1):674-686

Authors: Perrot-Applanat M, Vacher S, Pimpie C, Chemlali W, Derieux S, Pocard M, Bieche I

Abstract
Gastric cancer (GC) is a highly heterogeneous disease and one of the major causes of cancer-related mortality worldwide. Diffuse-type gastric adenocarcinoma (or poorly cohesive- with independent cells) is characterized by aggressive behavior (rapid invasion, chemoresistance and peritoneal metastasis), as compared with intestinal-subtype adenocarcinoma. Diffuse subtype GC additionally has a substantially increasing incidence rate in Europe and the USA, and was often associated with younger age. Our objective was to analyze the expression and clinical significance of genes involved in several signaling pathways in diffuse-type GC. Tumors samples and non-malignant gastric tissues were obtained from patients with GC (diffuse-type and intestinal-subtype adenocarcinoma). The expression of 33 genes coding for proteins involved in four categories, growth factors and receptors, epithelial-mesenchymal transition, cell proliferation and migration, and angiogenesis was determined by reverse transcription-quantitative polymerase chain reaction. The expression of 22 genes was significantly upregulated in diffuse-type GC and two were downregulated (including CDH1) compared with normal tissues. Among these genes, acompared with intestinal-subtype adenocarcinoma, diffuse-type GC revealed elevated levels of IGF1 and IGF1R, FGF7 and FGFR1, ZEB2, CXCR4, CXCL12 and RHOA, and decreased levels of CDH1, MMP9 and MKI67. The expression of selected genes was compared with other genes and according to clinical parameters. Furthermore, TGF-β expression was significantly increased in linitis, a sub-population of diffusely infiltrating type associated with extensive fibrosis and tumor invasion. Our study identified new target genes (IGF1, FGF7, CXCR4, TG-β and ZEB2) whose expression is associated with aggressive phenotype of diffuse-type GC.

PMID: 31289541 [PubMed]

Anticoagulation Management With Coumarinic Drugs in Chilean Patients.

Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619834342

Authors: Nieto E, Suarez M, Roco Á, Rubilar JC, Tamayo F, Rojo M, Verón G, Sepúlveda J, Mejías F, Salas P, Góngora M, Andrade P, Canales A, Carabantes J, Cruz D, Contreras E, Pavez D, Charo P, Bravo G, Calderón J, Gallardo C, Vega P, Quiñones LA

Abstract
Warfarin and acenocoumarol are used in various cardiovascular disorders to improve the prognosis of patients with thromboembolic disease. However, there is a lack of substantial efficacy and safety data on antithrombotic prophylaxis in several countries, particularly in Latin America. The aim of this study was to provide information about the efficacy of anticoagulants in Chilean patients. Data were collected from databases of the Western Metropolitan Health Service, Santiago, Chile. We identified 6280 records of patients receiving anticoagulant treatment. The three most common diagnoses were rhythm disorder (43.7%), venous thrombosis (22%), and valvular prosthesis (10.7%). The majority of patients (98.5%) received acenocoumarol while 1.5% of patients received warfarin, at weekly therapeutic doses of 13.6 mg and 30.4 mg, respectively. For total diagnoses, the median time in the therapeutic range was 50%. However, better results, 66.7%, were observed when a telemedicine strategy was used only in Santiago Province. Our findings emphasize that in Chile, where the number of patients receiving anticoagulant treatment increases every year, telemedicine, by committed teams, improves the use of oral anticoagulants and is able to increase quality indicators of anticoagulant treatment care.

PMID: 30880431 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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Comparison of BCR-ABL Transcript Variants Between Patients With Chronic Myeloid Leukaemia and Leukaemia Cell Lines.

In Vivo. 2019 Jul-Aug;33(4):1119-1124

Authors: DE Oliveira Sales L, Mesquita FP, DE Sousa Portilho AJ, DE Moraes Filho MO, DE Moraes MEA, Montenegro RC, Moreira-Nunes CA

Abstract
BACKGROUND/AIM: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of breakpoint cluster region-Abelson murine leukemia (BCR-ABL1) gene fusion as a hallmark that is expressed as two major transcripts b2a2 and b3a2. The aim of this study was to compare the BCR-ABL transcripts in the blood cells of patients with CML, and in chemoresistant and chemosensitive CML cell lines to validate their use as a good method to elucidate CML biology.
MATERIALS AND METHODS: Twelve patients with CML and CML cell lines (K562, K562-LUCENA and FEPS) were analyzed by real-time polymerase chain reaction to evaluate gene expression of BCR-ABL transcripts.
RESULTS: All patients had the same expression levels of b2a2 and b3a3 transcripts, however, CML cell lines presented only b3a2 expression. There were no significant differences in absolute b3a2 expression between patients and CML cell lines.
CONCLUSION: CML cell lines provide a good in vitro alternative in that they have the same BCR-ABL expression as patients.

PMID: 31280200 [PubMed - in process]

Pharmacogenetic Implications of eNOS Polymorphisms (Glu298Asp, T786C, 4b/4a) in Cardiovascular Drug Therapy.

In Vivo. 2019 Jul-Aug;33(4):1051-1058

Authors: Cozma A, Fodor A, Orasan OH, Vulturar R, Samplelean D, Negrean V, Muresan C, Suharoschi R, Sitar-Taut A

Abstract
Endothelial nitric oxide synthase (NOS3 or eNOS) is the enzyme responsible for the highest production of nitric oxide, with the greatest impact on the cardiovascular system, encoded by the eNOS gene, which presents various polymorphisms. ENOS gene polymorphisms play an important role in the response to drugs affecting nitric oxide (NO) signaling. This review discusses the pharmacogenetic impact of eNOS polymorphisms on the response to drugs affecting NO activity: angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium blockers, beta-blockers, diuretics, phosphodiesterase inhibitors, and statins. The identification of biomarkers that accurately predict particular phenotypes is a challenge that needs additional large studies, in different populations. Efforts should be oriented towards a more accurate evaluation of the effects of eNOS genetic variants on biochemical parameters reflecting eNOS gene expression and enzymatic activity, in different diseases, as well as following drug treatment. This approach will allow for a better understanding of the role of eNOS genetic variants in cardiovascular disease progression and for cardiovascular drug therapy optimization.

PMID: 31280192 [PubMed - in process]

Prediction Models for Voriconazole Pharmacokinetics Based on Pharmacogenetics: An Exploratory Study in Spanish population.

Int J Antimicrob Agents. 2019 Jul 04;:

Authors: Dapía I, García I, Martinez JC, Arias P, Guerra P, Díaz L, García A, Ochoa D, Tenorio J, Ramírez E, Román M, Gordo G, Saiz-Rodríguez M, Frías J, Abad-Santos F, Lapunzina P, Carcas AJ, Borobia AM

Abstract
Individualization of the therapeutic strategy for the oral antifungal voriconazole (VCZ) is extremely important for treatment optimization. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetics (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics (PK). We first designed a "Clinical Practice VCZ-AUC prediction model" based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction.

PMID: 31279853 [PubMed - as supplied by publisher]

Precision medicine and health disparities: The case of pediatric acute lymphoblastic leukemia.

Nurs Outlook. 2019 May 14;:

Authors: Burke W, Thummel K

Abstract
BACKGROUND: Precision medicine has uncertain potential to address population health disparities.
PURPOSE: Case study of disparities in pediatric acute lymphoblastic leukemia (ALL).
METHOD: Literature-based evaluation of ALL in African American (AA) and European American (EA) children.
FINDINGS: AA children have a lower incidence of ALL than EA children, experience higher relapse rates, and are more likely to be diagnosed with poor prognostic indicators. Environmental risk exposures for ALL have small effect sizes; data are insufficient to determine their contribution to differences in incidence and prognosis. Differences in prevalence of gene variants associated with treatment response contribute to higher relapse rates in AA children. However, higher relapse rates were not seen in a care setting that eliminated out of pocket costs, used risk-directed therapy, and included rigorous case management.
DISCUSSION: Unequal access to effective treatment contributes to ALL disparities. Precision medicine can help to define effective treatment for diverse patient populations.

PMID: 31279488 [PubMed - as supplied by publisher]

Challenges in the diagnosis of primary cutaneous CD30+ anaplastic large-cell lymphoma.

Br J Dermatol. 2019 Jul 06;:

Authors: Dobos G, Battistella M, Jouenne F, Mourah S, Vignon-Pennamen MD, Ram-Wolff C, Herms F, Dauendorffer JN, Rivet J, Cayuela JM, Bouaziz JD, Brice P, Lebbé C, Bagot M, de Masson A

Abstract
To the Editor: Primary cutaneous anaplastic large-cell lymphoma (pcALCL) is a cutaneous Tcell lymphoma (CTCL) generally associated with a good prognosis, composed of large cells, with >75% expressing CD301 . The rare cases of extensive disease can be efficiently treated with chemotherapy and/or brentuximab vedotin, an anti-CD30 antibody-drug conjugate. 2 Primary cutaneous peripheral T-cell lymphomas, not otherwise specified (pcPTCL-NOS) include all CTCL cases that cannot be assigned to any specific lymphoma category, and display usually an aggressive behaviour. 1,3 We report two patients who presented with cutaneous lesions without extracutaneous disease and a first diagnosis of pcPTCL-NOS with low or absent CD30 expression, and who experienced a relapse that was consistent with CD30+ ALCL with disseminated systemic involvement. A 79-year-old male patient presented with a rapidly growing ulcerated tumour of the foreskin (fig. 1A). This article is protected by copyright. All rights reserved.

PMID: 31278742 [PubMed - as supplied by publisher]

Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study.

Cancers (Basel). 2019 Jul 04;11(7):

Authors: Argentiero A, De Summa S, Di Fonte R, Iacobazzi RM, Porcelli L, Da Vià M, Brunetti O, Azzariti A, Silvestris N, Solimando AG

Abstract
Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window. To this end, we provide an original bioinformatic dissection of the gene expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient's derived samples indicated that WNT increased activation and a peculiar immune microenvironment identify subjects with nodal involvement. In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939-a specific WNT pathway inhibitor-has in re-educating a tumor-permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in node-positive disease.

PMID: 31277479 [PubMed]

Differential effects of rapamycin on glucose metabolism in 9 inbred strains.

J Gerontol A Biol Sci Med Sci. 2019 Jul 04;:

Authors: Reifsnyder PC, Te A, Harrison DE

Abstract
Studies in mice suggest that rapamycin has a negative impact on glucose homeostasis by inducing insulin resistance. However, results have been inconsistent and difficult to assess because the strains, methods of treatment, and analysis vary among studies. Using a consistent protocol, we surveyed 9 inbred strains of mice for the effect of rapamycin on various aspects of glucose metabolism. Across all strains, rapamycin significantly delayed glucose clearance after challenge. However, rapamycin showed no main effect on systemic insulin sensitivity. Analysis of individual strains shows that rapamycin induced higher glucose values at 15 minutes post challenge in 7/9 strains. However, only 3 strains show rapamycin-induced reduction in glucose clearance from 15 to 120 minutes. While pancreatic insulin content was reduced by rapamycin in 7 strains, none showed reduced serum insulin values. While one strain showed no effects of rapamycin on glucose metabolism (129), another showed increased systemic insulin sensitivity (B6). We suggest that rapamycin likely inhibits insulin production/secretion in most strains while having strain-specific effects on glucose clearance without altering systemic insulin sensitivity. This strain survey indicates that genetic differences greatly influence the metabolic response to rapamycin.

PMID: 31276577 [PubMed - as supplied by publisher]

miR-3188 (rs7247237-C>T) Single-Nucleotide Polymorphism Is Associated With the Incidence of Vascular Complications in Chinese Patients With Type 2 Diabetes.

J Cardiovasc Pharmacol. 2019 Jul;74(1):62-70

Authors: Wu B, Liu G, He F, Liu R, Wang Z, Wang Y, Zhou H, Zhang W

Abstract
miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055-2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433-1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression.

PMID: 31274844 [PubMed - in process]

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib.

J Clin Pharmacol. 2019 Jul 05;:

Authors: Ramírez J, House LK, Karrison TG, Janisch LA, Turcich M, Salgia R, Ratain MJ, Sharma MR

Abstract
This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug-drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady-state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04-1.49), 1.30 (1.11-1.53) and 1.28 (1.11-1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration-time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16-1.66), minimum plasma concentration (1.53; 1.10-2.12) and area under the concentration-time curve from time zero to 8 hours (1.41; 1.19-1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients.

PMID: 31274208 [PubMed - as supplied by publisher]

Association of blood cell counts with the risk of olanzapine- or clozapine-induced dyslipidemia in Chinese schizophrenia patients.

Hum Psychopharmacol. 2019 Jul 04;:e2699

Authors: Xiong Z, Cheng M, Zhu P, Huang S, Guo J, Zhang W, Zhou H, Shu Y, Li Q

Abstract
OBJECTIVE: The aim of this study was to investigate correlation of peripheral blood cell counts with the dyslipidemia induced by olanzapine or clozapine in Chinese schizophrenia patients.
METHODS: A total of 703 eligible schizophrenia patients were enrolled . The counts of red blood cell (RBC), platelet, white blood cell (WBC) and its subtypes, and serum lipids were determined for all participants before and after 2-4 weeks of olanzapine or clozapine treatment.
RESULTS: The two representative second-generation antipsychotics (SGAs), olanzapine and clozapine, markedly caused dyslipidemia in Chinese schizophrenia patients. The tertiles of total RBC counts were positively associated with the odds of having abnormal triglyceride (p < .01) and high-density lipoprotein cholesterol (HDL-C) levels (.05). The tertiles of platelet counts were also positively associated with the odds of having abnormal total cholesterol (.03), low-density lipoprotein cholesterol (p < .01), HDL-C (.01), and non-HDL-C (p < .01). However, the counts of WBC and its some subtypes were negatively correlated with the risk of dyslipidemia in these patients.
CONCLUSION: The profile of peripheral blood cells may be an early biomarker for predicting the risk of metabolic disorders and cardiovascular diseases in schizophrenia patients treated with SGAs.

PMID: 31273857 [PubMed - as supplied by publisher]

Acute Carotid Stent Thrombosis in an Ultrarapid Clopidogrel Metabolizer: Case Report and Literature Review.

Vasc Endovascular Surg. 2019 Jul 04;:1538574419857965

Authors: Toljan K, Jovanović I, Starčević K, Ljevak J, Blažević N, Radoš M, Poljaković Z

Abstract
INTRODUCTION: Carotid angioplasty and stenting (CAS) represents an effective procedure for treating carotid artery disease. The acute in-stent thrombosis is an extremely rare complication of CAS especially when it occurs postprocedurally during the first 24 hours. Improper antiplatelet therapy or poor response to antiplatelet medications is known to be associated with a higher risk of in-stent thrombosis during early postprocedural period following a successful intervention.
MATERIAL AND METHODS: A patient who experienced acute carotid in-stent thrombosis in early postprocedural period is described. He had been taking dual antiplatelet therapy for 2 weeks before undergoing a successful CAS. Moreover, pharmacogenetics studies showed the patient to be a clopidogrel ultrarapid metabolizer, which theoretically confers hyperresponsivity to medication. Alongside the report itself, a brief literature review of relevant sources pertinent to the case has been conducted.
RESULTS: According to the available literature, this is the first case report describing an ultrarapid clopidogrel metabolizer who underwent an uneventful CAS but experienced acute carotid in-stent thrombosis in early postprocedural period. A rescue procedure included an endovascular intervention consisting of thrombectomy and local alteplase application, followed by postprocedural administration of intravenous eptifibatide. At discharge, patient's dual antiplatelet therapy included ticagrelor instead of clopidogrel.
CONCLUSION: Acute carotid in-stent thrombosis is a highly unexpected complication of CAS and can occur despite ultrarapid clopidogrel metabolism trait.

PMID: 31272299 [PubMed - as supplied by publisher]

Capecitabine and Celecoxib as a Promising Therapy for Thymic Neoplasms.

Am J Clin Oncol. 2018 10;41(10):963-966

Authors: Wood K, Byron E, Janisch L, Salgia R, Sharma MR

Abstract
OBJECTIVES: For patients with unresectable or metastatic thymic epithelial neoplasms, few therapy options are available and outcomes are poor. This case series demonstrates that the combination of capecitabine and celecoxib may be a promising therapeutic option for these patients.
MATERIALS AND METHODS: The current report describes the outcomes of 5 patients with thymic neoplasms treated on a drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies (NCT01705106) conducted at the University of Chicago, plus a sixth patient treated with the same regimen outside of the protocol.
RESULTS: Six patients with thymic neoplasms were treated with capecitabine 1000 mg/m twice daily and celecoxib 200 mg twice daily, day 1 to day 14 on a 21-day cycle. This included 3 patients with thymic carcinoma, 1 with thymic neuroendocrine tumor, and 2 with thymomas. Objective response rates were noted in 3 of 6 patients. Two of the 3 thymic carcinoma patients had complete responses, and the third had a partial response. Best response for the other patients included stable disease for both thymoma patients and progressive disease for the thymic neuroendocrine patient. Other than grade 3 palmar-plantar erythrodysesthesia, which developed in 4 of 6 patients and required dose reductions, the regimen was well tolerated.
CONCLUSIONS: This case series suggests that capecitabine plus celecoxib may be an effective and well-tolerated treatment option for patients with thymic carcinoma. Further studies should be carried out to establish the efficacy of capecitabine plus celecoxib in thymic carcinoma, and to determine whether monotherapy with capecitabine would be similarly effective.

PMID: 28654574 [PubMed - indexed for MEDLINE]

Discoidin Domain Receptors: A promising target in melanoma.

Pigment Cell Melanoma Res. 2019 Jul 04;:

Authors: Reger de Moura C, Battistella M, Sohail A, Caudron A, Feugeas JP, Podgorniak MP, Pages C, Mazouz Dorval S, Marco O, Menashi S, Fridman R, Lebbé C, Mourah S, Jouenne F

Abstract
The Discoidin Domain Receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small-interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1-IN-1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma. This article is protected by copyright. All rights reserved.

PMID: 31271515 [PubMed - as supplied by publisher]

Genetic contribution in low back pain: a prospective genetic association study.

Pain Pract. 2019 Jul 03;:

Authors: Margarit C, Roca R, Inda MD, Muriel J, Ballester P, Moreu R, Conte AL, Nuñez A, Morales D, Peiró A

Abstract
OBJECTIVES: Chronic pain is one of the commonest reasons individuals seek medical attention. It is a major issue because of the wide inter-individual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low-back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics.
METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63±14 years, 64% female, 29±6 Kg/m2 , VAS pain intensity 73±16 mm. Clinical data were collected at baseline, 3 months after opioid titration and after 2-4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities and drug prescription (opioid dose, rotations and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by RT-PCR genotyping.
RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low-back pain disability, anxiety and depression significantly decreased, while quality of life increased.
CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in CLBP patients. We encourage clinical trials for their clinical application in chronic pain management. This article is protected by copyright. All rights reserved.

PMID: 31269327 [PubMed - as supplied by publisher]

Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients.

Curr Drug Metab. 2019 Jun 30;:

Authors: Wang Z, Zhang N, Chen C, Chen S, Xu J, Zhou Y, Zhao X, Cui Y

Abstract
BACKGROUND: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant inter-subject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX.
OBJECTIVE: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1、OATP1B3 on MTX's pharmacokinetics.
METHOD: MTX concentration and Clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1、OATP1B1 and OATP1B3 genotyping was tested. Population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored.
RESULTS: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283 and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h-1)=1.69.
CONCLUSION: In our study, it was showed that OATP1B1-388 G＞A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

PMID: 31267867 [PubMed - as supplied by publisher]

Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction.

Diab Vasc Dis Res. 2019 Jul 03;:1479164119860215

Authors: Savina Y, Duflot T, Bounoure F, Kotzki S, Thiebaut PA, Serreau PA, Skiba M, Picquenot JM, Cornic M, Morisseau C, Hammock B, Imbert L, Cracowski JL, Richard V, Roustit M, Bellien J

Abstract
The impact of the local inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide hydrolase inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.

PMID: 31267765 [PubMed - as supplied by publisher]

Pharmacogenomics-based practice in North Cyprus: its adoption by pharmacists and their attitudes and knowledge.

Int J Clin Pharm. 2019 Jul 02;:

Authors: Alsaloumi L, Abdi A, Tosun Ö, Başgut B

Abstract
Background Pharmacogenomics is a branch of biotechnological science integrating medicine, pharmacology, and genomics techniques. Moreover, it focuses on creating drug therapies in order to analyze genetic differences in patients causing various responses to a single therapeutic regimen. Objective This cross sectional study aimed to examine the attitude, knowledge and adoption among pharmacists in North Cyprus and the most appropriate method to improve education among them. Setting Community pharmacy setting. Method A total of 103 out of 140 pharmacists responded to a pre-tested and validated questionnaire consisting of 25 items during July through September 2016. Main outcome measure Pharmacists attitude, knowledge and adoption towards pharmacogenomic tests. Result Data showed that most of the pharmacists in North Cyprus had positive attitude and knowledge scores with mean value of 28.3 ± 5.3 (out of 40) and 6.9 ± 0.8 (out of 10) respectively, further findings showed that there is a significant difference among age groups in their total attitude score (p < 0.05). Conclusion Even though pharmacogenomics is a field promising a variety of benefits, it is vital to implement it in clinical settings in order to improve outcomes. Our findings highlight the necessity for more education on the availability and interpretation of pharmacogenomics tests.

PMID: 31267362 [PubMed - as supplied by publisher]