Associations between genetic polymorphisms of membrane transporter genes and prognosis after chemotherapy: meta-analysis and finding from Seoul Breast Cancer Study (SEBCS).

Pharmacogenomics J. 2018 Apr 04;:

Authors: Kim JE, Choi J, Park J, Park C, Lee SM, Park SE, Song N, Chung S, Sung H, Han W, Lee JW, Park SK, Kim MK, Noh DY, Yoo KY, Kang D, Choi JY

Abstract
Membrane transporters can be major determinants of the pharmacokinetic profiles of anticancer drugs. The associations between genetic variations of ATP-binding cassette (ABC) and solute carrier (SLC) genes and cancer survival were investigated through a meta-analysis and an association study in the Seoul Breast Cancer Study (SEBCS). Including the SEBCS, the meta-analysis was conducted among 38 studies of genetic variations of transporters on various cancer survivors. The population of SEBCS consisted of 1338 breast cancer patients who had been treated with adjuvant chemotherapy. A total of 7750 SNPs were selected from 453 ABC and/or SLC genes typed by an Affymetrix 6.0 chip. ABCB1 rs1045642 was associated with poor progression-free survival in a meta-analysis (HR = 1.33, 95% CI: 1.07-1.64). ABCB1, SLC8A1, and SLC12A8 were associated with breast cancer survival in SEBCS (Pgene < 0.05). ABCB1 rs1202172 was differentially associated with survival depending on the chemotherapy (Pinteraction = 0.035). Our finding provides suggestive associations of membrane transporters on cancer survival.

PMID: 29618765 [PubMed - as supplied by publisher]

[The laboratory diagnostic of patients with tuberculosis with medicinal resistance of agent].

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2016 Sep-Oct;24(5):272-6

Authors: Popov SA, Sabgaiida TP, Mojokina GN

Abstract
The article considers possibilities and means of transition to personalized treatment of patients with tuberculosis conditioned by fast development and spreading of medicinal resistance of tuberculosis agent. The technical possibilities are demonstrated for realization of this approach and also necessity of information possessing in the field of evaluation of treatment effectiveness. Also, attention was paid to relationship ofpharmacogenetics and pharmacokinetics of wide spectrum of anti-tuberculosis medications, medicinal resistance of agent and genetic conditioning of development of side-effect negative reactions to chemotherapy.

PMID: 29558087 [PubMed - indexed for MEDLINE]

Relationships Between Self-Injurious Behaviors, Pain Reactivity, and β-Endorphin in Children and Adolescents With Autism.

J Clin Psychiatry. 2018 Mar 13;79(2):

Authors: Tordjman S, Anderson GM, Charrier A, Oriol C, Kermarrec S, Canitano R, Botbol M, Coulon N, Antoine C, Brailly-Tabard S, Cohen D, Haidar H, Trabado S, Carlier M, Bronsard G, Mottron L

Abstract
OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and β-endorphin levels in autism.
METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma β-endorphin concentrations were measured in 57 participants using 2 different immunoassay methods.
RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between β-endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations.
CONCLUSIONS: The absence of any observed relationships between β-endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain.

PMID: 29617065 [PubMed - as supplied by publisher]

Assessment of telomerase activity in leukocytes of type 2 diabetes mellitus patients having or not foot ulcer: Possible correlation with other clinical parameters.

Exp Ther Med. 2018 Apr;15(4):3420-3424

Authors: Baltzis D, Meimeti E, Grammatikopoulou MG, Roustit M, Mavrogonatou E, Kletsas D, Efraimidou S, Manes C, Nikolouzakis TK, Tsiaoussis J, Tsatsakis AM, Spandidos DA, Trakatelli CM, Drakoulis N

Abstract
Telomerase is the enzyme that maintains telomere length by adding telomeric repeats after each cell division. Numerous metabolic factors such as obesity, insulin resistance or physical inactivity have been associated with shortened telomeres. In the present study, we assessed telomerase activity in diabetic patients having or not foot ulcer. A total of 90 adult patients with type 2 diabetes mellitus (T2DM) were studied. Patients were allocated into two groups according to the absence or presence of active foot ulcers as follows: Νon-ulcer group (N=58) and ulcer group (N=32). Our data revealed that the patients with diabetic ulcers had significantly greater waist circumference and neuropathy disability score, while exhibiting lower telomerase activity, indicating the possible existence of a common clinical profile among ulcer-bearing diabetic patients. Validation of our findings by extending the study in larger patient groups may contribute to the understanding of T2DM pathophysiology and its main clinical implications.

PMID: 29616085 [PubMed]

Prediction of Glucose Tolerance without an Oral Glucose Tolerance Test.

Front Endocrinol (Lausanne). 2018;9:82

Authors: Babbar R, Heni M, Peter A, Hrabě de Angelis M, Häring HU, Fritsche A, Preissl H, Schölkopf B, Wagner R

Abstract
Introduction: Impaired glucose tolerance (IGT) is diagnosed by a standardized oral glucose tolerance test (OGTT). However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state.
Methods: Given a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA), proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year.
Results: The most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78). For all classifiers, mean accuracy was 0.73 ± 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77.
Conclusion: Machine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a subsequent OGTT.

PMID: 29615972 [PubMed]

Implementation of Genotype-Guided Antiplatelet Therapy: Feasible but Not Without Obstacles.

Circ Genom Precis Med. 2018 Apr;11(4):e002118

Authors: Lewis JP

PMID: 29615455 [PubMed - in process]

Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Circ Genom Precis Med. 2018 Apr;11(4):e002069

Authors: Lee CR, Sriramoju VB, Cervantes A, Howell LA, Varunok N, Madan S, Hamrick K, Polasek MJ, Lee JA, Clarke M, Cicci JD, Weck KE, Stouffer GA

Abstract
BACKGROUND: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear.
METHODS: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression.
RESULTS: CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72-2.85; P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816).
CONCLUSIONS: Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.

PMID: 29615454 [PubMed - in process]

Identification of HLA-DRB1 association to adalimumab immunogenicity.

PLoS One. 2018;13(4):e0195325

Authors: Liu M, Degner J, Davis JW, Idler KB, Nader A, Mostafa NM, Waring JF

Abstract
Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA-subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and HLA-DRB1*011) that were more abundant in AAA+ than AAA-subjects (ORs: 2.52, and 2.64, respectively; and P values: 0.006 and 0.019). Similar to the finding of Billiet et al. who found that carriage of the HLA-DRB1*03 allele was more prevalent in those with anti-infliximab antibodies (OR = 3.6, p = 0.002, 95% CI: [1.5,8.6]).), we found HLA-DRB1*03 allele was also more prevalent in anti-adalimumab positive (OR = 2.52, p = 0.006, 95% CI: [1.37,4.63]). The results suggest that specific HLA alleles may play a key role in developing AAAs in RA and HS patients treated with adalimumab.

PMID: 29614084 [PubMed - in process]

Synthesis, Structural Studies and Biological Evaluation of Connections of Thiosemicarbazide, 1,2,4-Triazole and 1,3,4-Thiadiazole with Palmitic Acid.

Molecules. 2018 Apr 03;23(4):

Authors: Jóźwiak M, Stępień K, Wrzosek M, Olejarz W, Kubiak-Tomaszewska G, Filipowska A, Filipowski W, Struga M

Abstract
Thirty new derivatives of palmitic acid were efficiently synthesized. All obtained compounds can be divided into three groups of derivatives: Thiosemicarbazides (compounds 1-10), 1,2,4-triazoles (compounds 1a-10a) and 1,3,4-thiadiazoles (compounds 1b-10b) moieties. ¹H-NMR, 13C-NMR and MS methods were used to confirm the structure of derivatives. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. Compounds 4, 5, 6, 8 showed significant inhibition against C. albicans. The range of MIC values was 50-1.56 μg/mL. The halogen atom, especially at the 3rd position of the phenyl group was significantly important for antifungal activity. The biological activity against Candida albicans and selected molecular descriptors were used as a basis for QSAR models, that have been determined by means of multiple linear regression. The models have been validated by means of the Leave-One-Out Cross Validation. The obtained QSAR models were characterized by high determination coefficients and good prediction power.

PMID: 29614061 [PubMed - in process]

HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion.

Pediatrics. 2018 Apr;141(Suppl 5):S434-S438

Authors: Kim H, Chadwick L, Alzaidi Y, Picker J, Poduri A, Manzi S

Abstract
Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The Food and Drug Administration-approved label for oxcarbazepine currently presents information regarding a pharmacogenomic association with the HLA antigen allele HLA-B*15:02 and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the presence of this allele is not routinely recommended before administration of oxcarbazepine. In practice, even with carbamazepine, HLA antigen testing is not always performed before initiating treatment because of lack of physician awareness of the recommendations and because of the desire to initiate treatment without delay. We present the clinical course of a pediatric patient with focal epilepsy refractory to several AEDs who developed drug reaction with eosinophilia and systemic symptoms after oxcarbazepine administration. The pharmacogenomic testing for various HLA antigen alleles was performed post hoc, and results were evaluated for structural similarities between AEDs and their molecular associations with HLA antigen proteins. In addition, we review the population-wide prevalence of various hypersensitivity reactions to AEDs and associated HLA antigen alleles. Finally, we discuss the potential utility of preemptive pharmacogenomic screening of patients before pharmacological treatment of epilepsy to assess the risk of developing hypersensitivity reactions.

PMID: 29610167 [PubMed - in process]

Genotype vs Clinically Guided Dosing of Warfarin to Prevent Adverse Events-Reply.

JAMA. 2018 03 27;319(12):1279-1280

Authors: Gage BF, Bass AR, Eby CS

PMID: 29584836 [PubMed - indexed for MEDLINE]

Genotype vs Clinically Guided Dosing of Warfarin to Prevent Adverse Events.

JAMA. 2018 03 27;319(12):1278-1279

Authors: Han-You X

PMID: 29584834 [PubMed - indexed for MEDLINE]

Improving adherence to asthma medications: current knowledge and future perspectives.

Curr Opin Pulm Med. 2017 01;23(1):62-70

Authors: Blake KV

Abstract
PURPOSE OF REVIEW: Poor adherence to asthma controller medications, particularly inhaled corticosteroids, has been well known for decades and is a major cause of uncontrolled asthma and increased healthcare utilization. This review presents recent evidence on factors leading to nonadherence in specific age groups, parents of young children, adolescents and young adults, adults, and the elderly. Novel management strategies including electronic sensors with associated smart phone applications for adherence improvement are discussed.
RECENT FINDINGS: Interventions to promote adherence must include a focus on issues important to the patient. Parents are concerned about adverse effects and the difficulty of medication administration in their child; adolescents and young adults need help with organizational skills and social barriers; adults may be more receptive to the need for daily medication after an acute exacerbation and acceptance of their disease; the elderly may have medication misuse issues associated with cognitive decline and other comorbidities related to aging. In all age groups, a trusting relationship with the provider is the key. New digital devices to track adherence may provide feedback to the patient and provider to evaluate and to promote adherence.
SUMMARY: Personalized approaches are required to address adherence barriers in target populations. Research on specific needs and barriers in target populations and development of appropriate strategies for use of new digital technology for adherence monitoring is needed.

PMID: 27755160 [PubMed - indexed for MEDLINE]

Telomere length in bipolar disorder and lithium response.

Eur Neuropsychopharmacol. 2017 06;27(6):560-567

Authors: Squassina A, Pisanu C, Corbett N, Alda M

Abstract
Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.

PMID: 26621262 [PubMed - indexed for MEDLINE]

Have there been improvements in Alzheimer's disease drug discovery over the past 5 years?

Expert Opin Drug Discov. 2018 Apr 01;:1-16

Authors: Cacabelos R

Abstract
INTRODUCTION: Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013-2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (<1% each). Expert opinion: Unsuccessful outcomes in AD therapeutics are attributed to pathogenic misconceptions, erratic procedures in drug development and inappropriate regulations. Recommendations for the future are as follows: (i) the reconsideration of dominant pathogenic theories, (ii) the identification of reliable biomarkers, (iii) the redefinition of diagnostic criteria, (iv) new guidelines for disease management, (v) the reorientation of drug discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.

PMID: 29607687 [PubMed - as supplied by publisher]

Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

Pharmgenomics Pers Med. 2018;11:43-49

Authors: Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV, Loskutnikov MA, Smirnov VV, Konova OD, Matsneva IA, Bochkov PO

Abstract
Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke.
Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-β-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent.
Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A.
Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.

PMID: 29606886 [PubMed]

Molecular epidemiology of blastocystosis in Malaysia: does seasonal variation play an important role in determining the distribution and risk factors of Blastocystis subtype infections in the Aboriginal community?

Parasit Vectors. 2017 Jul 31;10(1):360

Authors: Noradilah SA, Moktar N, Anuar TS, Lee IL, Salleh FM, Manap SNAA, Mohtar NSHM, Azrul SM, Abdullah WO, Nordin A, Abdullah SR

Abstract
BACKGROUND: Alternating wet and dry seasons may play an important role in the acquisition and distribution of Blastocystis subtype infection in the tropics. This cross-sectional study was therefore conducted to provide the prevalence of Blastocystis and to determine the potential risk factors associated with each subtype during the wet and dry seasons in the Aboriginal community, Pahang, Malaysia.
METHODS: A total of 473 faecal samples were collected: 256 (54.1%) and 217 (45.9%) samples were obtained during the wet (October-November 2014) and the dry season (June 2015), respectively. All fresh faecal samples were subjected to molecular analysis for subtype and allele identification.
RESULTS: Of the 473 samples, 42.6% and 37.8% were positive for Blastocystis ST1, ST2, ST3 and ST4 during wet and dry seasons, respectively. Prevalence of Blastocystis ST1 was significantly higher during the wet season compared to the dry season (Z = 2.146, P < 0.05). Analysis of the association of each Blastocystis subtype with socioeconomic characteristics showed the presence of other family members infected with Blastocystis ST3 and the use of stored river water for domestic activities were the significant risk factors for Blastocystis ST3 infections during both seasons. Untreated water supply and low monthly household income (less or equal to RM 500) were the other significant risk factors for Blastocystis ST3 infections during wet and dry season, respectively. The presence of other family members with Blastocystis ST1 and ST2 was the only significant risk factor associated with ST1 and ST2 infections during both seasons. We hypothesise that transmission of Blastocystis ST1, ST2 and ST3 occurred from person to person during both seasons. The waterborne transmission was also identified as a mode of transmission of Blastocystis ST3.
CONCLUSION: The significant risk factors identified in this study were important in the dynamic transmission of Blastocystis infections during both seasons. Provision of treated water supply and health education are affirmative actions to be taken to control Blastocystis infections in this community.

PMID: 28760145 [PubMed - indexed for MEDLINE]

Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatment in rheumatoid arthritis patients: evidence from a systematic review and meta-analysis.

Int J Rheum Dis. 2017 May;20(5):526-540

Authors: Fan H, Li Y, Zhang L, Li Y, Li W

Abstract
OBJECTIVES: The aim of this study was to evaluate the association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism A1298C and methotrexate (MTX) outcome in rheumatoid arthritis (RA) patients.
METHODS: We conducted a meta-analysis of the relevant published literature through to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models.
RESULTS: A total of 1325 cases (10 studies) of MTX efficacy and 2777 cases (18 studies) of MTX toxicity in RA patients were analyzed. Pooled results showed that MTHFR gene A1298C polymorphism was not significantly related to MTX toxicity or efficacy in RA patients. However, subgroup analysis indicated a significant association between MTHFR gene A1298C polymorphism and decreased MTX efficacy in the South Asian population (CCvs. CA + AA: OR = 0.45, 95% CI = 0.23-0.89, P = 0.021). Also, MTHFR gene A1298C polymorphism in the partial folate supplementation group showed a relationship with decreased MTX efficacy (CCvs. CA + AA: OR = 0.43, 95% CI = 0.20-0.92, P = 0.029) and toxicity (CCvs. CA + AA: OR = 0.40, 95% CI = 0.17-0.96, P = 0.04; CCvs. AA: OR = 0.38, 95% CI = 0.16-0.94, P = 0.035).
CONCLUSIONS: Overall, our meta-analysis suggested no significant effect of MTHFR gene A1298C polymorphism on MTX outcome in RA patients. However, due to several limitations of our meta-analysis, the results should be interpreted cautiously and require further confirmation using high-quality studies.

PMID: 28544525 [PubMed - indexed for MEDLINE]

A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach.

Clin Pharmacokinet. 2017 Aug;56(8):963-975

Authors: Andreu F, Colom H, Elens L, van Gelder T, van Schaik RHN, Hesselink DA, Bestard O, Torras J, Cruzado JM, Grinyó JM, Lloberas N

Abstract
BACKGROUND: Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients.
METHODS: Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEM® version 7.2.
RESULTS: The tacrolimus whole-blood concentration versus time data were best described by a two-open-compartment model with inter-occasion variability assigned to plasma clearance. The following factors led to the final model, which significantly decreased the minimum objective function value (p < 0.001): a new genotype cluster variable combining the CYP3A5*3 and CYP3A4*22 SNPs defined as extensive, intermediate, and poor metabolizers; the standardization of tacrolimus whole blood concentrations to a hematocrit value of 45%; and age included as patients <63 years versus patients ≥63 years. External validation confirmed the prediction ability of the model with median bias and precision values of 1.17 ng/mL (95% confidence interval [CI] -3.68 to 4.50) and 1.64 ng/mL (95% CI 0.11-5.50), respectively. Simulations showed that, for a given age and hematocrit at the same fixed dose, extensive metabolizers required the highest doses followed by intermediate metabolizers and then poor metabolizers.
CONCLUSIONS: Tacrolimus disposition in renal transplant recipients was described using a new population pharmacokinetic model that included the CYP3A5*3 and CYP3A4*22 genotype, age, and hematocrit.

PMID: 28050888 [PubMed - indexed for MEDLINE]

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients.

Clin Pharmacokinet. 2017 Aug;56(8):977-985

Authors: Barratt DT, Cox HK, Menelaou A, Yeung DT, White DL, Hughes TP, Somogyi AA

Abstract
OBJECTIVE: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients.
METHODS: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc).
RESULTS: CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively).
CONCLUSIONS: CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

PMID: 27995529 [PubMed - indexed for MEDLINE]