Population Pharmacokinetics and dosing optimisation of Imipenem in Children with haematological malignancies.

Antimicrob Agents Chemother. 2019 Apr 08;:

Authors: Dong L, Zhai XY, Yang YL, Wang L, Zhou Y, Shi HY, Tang BH, Wu YE, Yang F, Wen L, Kong HX, Zhi LJ, Jacqz-Aigrain E, Zhao W

Abstract
Objectives: Imipenem is widely used for the treatment of children with serious infections. Currently, there is lack of pharmacokinetic studies of imipenem in children with hematological malignancies. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population based pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population.Methods: After treated with imipenem/cilastatin (IMP/CS), blood samples of children were collected and the concentration of imipenem were quantified using HPLC-UV. Then, population level pharmacokinetic analysis was conducted using NONMEM software.Results: Data from 56 children (age range: 2.03-11.82 years) with haematological malignancies were collected to conduct a population based pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be best suitable. The parameters of current weight, age and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1% and 67.1% of children reached the pharmacodynamic target (70% fT>MIC) against sensitive pathogens with an MIC of 0.5 mg/L at 15, 20 and 25 mg/kg q6h of imipenem, respectively. However, only 11.1% of children achieved the pharmacodynamic target against Pseudomonas aeruginosa with an MIC of 2 mg/L at a dose of 25 mg/kg q6h.Conclusion: Population pharmacokinetics of imipenem was assessed in children. The current dosage regimens of imipenem are underdose for resistant pathogens including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h.

PMID: 30962334 [PubMed - as supplied by publisher]

Implementation of genotype-guided dosing of warfarin with point-of-care genetic testing in three UK clinics: a matched cohort study.

BMC Med. 2019 Apr 08;17(1):76

Authors: Jorgensen AL, Prince C, Fitzgerald G, Hanson A, Downing J, Reynolds J, Zhang JE, Alfirevic A, Pirmohamed M

Abstract
BACKGROUND: Warfarin is a widely used oral anticoagulant. Determining the correct dose required to maintain the international normalised ratio (INR) within a therapeutic range can be challenging. In a previous trial, we showed that a dosing algorithm incorporating point-of-care genotyping information ('POCT-GGD' approach) led to improved anticoagulation control. To determine whether this approach could translate into clinical practice, we undertook an implementation project using a matched cohort design.
METHODS: At three clinics (implementation group; n = 119), initial doses were calculated using the POCT-GGD approach; at another three matched clinics (control group; n = 93), patients were dosed according to the clinic's routine practice. We also utilised data on 640 patients obtained from routinely collected data at comparable clinics. Primary outcome was percentage time in target INR range. Patients and staff from the implementation group also provided questionnaire feedback on POCT-GGD.
RESULTS: Mean percentage time in INR target range was 55.25% in the control group and 62.74% in the implementation group; therefore, 7.49% (95% CI 3.41-11.57%) higher in the implementation group (p = 0.0004). Overall, patients and staff viewed POCT-GGD positively, suggesting minor adjustments to allow smooth implementation into practice.
CONCLUSIONS: In the first demonstration of the implementation of genotype-guided dosing, we show that warfarin dosing determined using an algorithm incorporating genetic and clinical factors can be implemented smoothly into clinic, to ensure target INR range is reached sooner and maintained. The findings are like our previous randomised controlled trial, providing an alternative method for improving the risk-benefit of warfarin use in daily practice.

PMID: 30961588 [PubMed - in process]

Usefulness of COMT gene polymorphisms in North African populations.

Gene. 2019 May 15;696:186-196

Authors: Boussetta S, Cherni L, Pakstis AJ, Ben Salem N, Elkamel S, Khodjet-El-Khil H, Kidd KK, Elgaaied ABA

Abstract
The COMT gene encodes for catechol-O-methyl-transferase, an enzyme playing a major role in regulation of synaptic catecholamine neurotransmitters. Investigating 4 markers of the COMT gene (rs2020917, rs4818, rs4680, rs9332377) in 6 Tunisian populations and a pool of Libyans. Our objective was to determine the distribution of allelic, genotypic and haplotypic frequencies by comparison to other populations of the 1000 genomes project and 59 populations from the Kidd Lab dataset. The allelic frequencies established for these SNPs in the North African populations are similar to those of Europeans and South Asians. Linkage disequilibrium between these SNPs and haplotypes frequencies are different between populations whose clustering in principal components analysis (PCA) according to their geographic origin was more significant using haplotypic frequencies. COMT activity prediction by haplotypes genotyping could be limited to rs4818-rs4680 micro-haplotypes. The Low activity haplotype (CG) displays the highest frequency in African populations (55%), in the 59 Kidd Lab populations we found also that Sub-Saharan Africans, Native Americans, and some East Asian and Pacific Island populations all have frequencies in the 50-81% range for (CG) where as its lowest frequency was found in Europeans (10%), this results have been also confirmed for Southwest Asians. North Africans and South Asians with intermediate frequencies have approximately similar values (20% and 25%). Europeans show the highest frequencies of haplotypes with predicted High and Medium activity in contrast to Africans. North Africans and South Asians present similar results for all the category of the COMT activity prediction by haplotypes genotyping. The high level of genetic diversity of COMT haplotypes, not only allows distinction between populations according to their history settlement, origin and ethnicity, it constitutes a basis for studies of association of the COMT gene polymorphism with pathologies, drugs response and for forensic investigation in North African populations.

PMID: 30790653 [PubMed - indexed for MEDLINE]

Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients.

Am J Psychiatry. 2018 05 01;175(5):463-470

Authors: Jukić MM, Haslemo T, Molden E, Ingelman-Sundberg M

Abstract
OBJECTIVE: The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population.
METHOD: A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively.
RESULTS: Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively.
CONCLUSIONS: The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.

PMID: 29325448 [PubMed - indexed for MEDLINE]

3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism and toxicity: Emerging culture paradigms and applications.

Biotechnol J. 2019 Apr 08;:e1800347

Authors: Lauschke VM, Shafagh RZ, Hendriks DFG, Ingelman-Sundberg M

Abstract
Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo-like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips and plate-based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity and liver functionality have increased tremendously as compared to conventional in vitro models in which cells were cultured as two-dimensional monolayers. Here, we highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology and disease. This article is protected by copyright. All rights reserved.

PMID: 30957976 [PubMed - as supplied by publisher]

Risk of myocardial infarction associated with non-steroidal anti-inflammatory drugs: Impact of additional confounding control for variables collected from self-reported data.

J Clin Pharm Ther. 2019 Apr 07;:

Authors: Bakhriansyah M, Souverein PC, de Boer A, Klungel OH

Abstract
WHAT IS KNOWN AND OBJECTIVE: Important risk factors and over-the-counter (OTC) dispensing of non-steroidal anti-inflammatory drugs (NSAIDs) are often not routinely recorded in electronic health records. This study aimed to assess the impact of patient's reports on these factors on the risk of acute myocardial infarction (AMI) for NSAID use.
METHODS: A nested case-control study was conducted among adults in the Utrecht Cardiovascular Pharmacogenetics study. Cases were patients with a first diagnosis of AMI as a hospital discharge diagnosis and controls were those without AMI. NSAID exposure was either current use of selective COX-2 inhibitors or conventional NSAIDs. Information was collected from The Dutch PHARMO Database Network (pharmacy records of drug dispensing linked to hospitalization records) and the patient's questionnaire (lifestyle factors, body mass index and history of cardiovascular diseases). Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and to control for confounding factors.
RESULTS: We identified 970 AMI cases and 2974 controls. Among cases, 11 (1.1%) and 185 (19.1%) were exposed to selective COX-2 inhibitors and conventional NSAIDs, respectively. Compared to non-use, none of these drug classes were associated with an increased risk of AMI (adjusted OR 1.07, 95% CI: 0.52-2.18 and 0.93, 95% CI: 0.77-1.12, respectively). Additional adjustment for potential confounders from patient's reports did not change the risk estimates (adjusted OR 1.08, 95% CI: 0.53-2.22 and 0.89, 95% CI: 0.73-1.09, respectively).
WHAT IS NEW AND CONCLUSION: Additional confounding control for variables from self-reported data or considering self-reported OTC NSAID use did not change the risk estimates for the association between NSAIDs and AMI.

PMID: 30957267 [PubMed - as supplied by publisher]

Variability in analgesic response to non-steroidal anti-inflammatory drugs.

Prostaglandins Other Lipid Mediat. 2018 11;139:63-70

Authors: Theken KN

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used agents for the treatment of acute and chronic pain. However, it has long been recognized that there is substantial inter-individual variability in the analgesic response to NSAIDs, reflecting the complex interplay between mechanisms of pain, differences between distinct NSAIDs, and patient-specific factors such as genetic variation. This review summarizes the current knowledge regarding how these factors contribute to variability in the analgesic response to NSAIDs.

PMID: 30393163 [PubMed - indexed for MEDLINE]

Mitochondrial fission promotes cell migration by Ca2+ /CaMKII/ERK/FAK pathway in hepatocellular carcinoma.

Liver Int. 2018 07;38(7):1263-1272

Authors: Sun X, Cao H, Zhan L, Yin C, Wang G, Liang P, Li J, Wang Z, Liu B, Huang Q, Xing J

Abstract
BACKGROUND & AIMS: Mitochondrial dynamics of fission and fusion plays critical roles in a diverse range of important cellular functions, and its deregulation has been increasingly implicated in human diseases. Previous studies have shown that increased mitochondrial fission significantly promoted the proliferation of hepatocellular carcinoma (HCC) cells. However, how they influence the migration of tumour cells remained largely unknown.
METHODS: In the present study, we further investigated the effect of mitochondrial fission on the migration and metastasis of hepatocellular carcinoma cells. Moreover, the underlying molecular mechanisms and therapeutic application were explored.
RESULTS: Our data showed that dynamin-1-like protein expression was strongly increased in distant metastasis of hepatocellular carcinoma when compared to primary hepatocellular carcinoma. In contrast, the mitochondrial fusion protein mitofusin 1 showed an opposite trend. Moreover, the expression of dynamin-1-like protein and mitofusin 1 was significantly associated with the disease-free survival of hepatocellular carcinoma patients. In addition, our data further showed that mitochondrial fission significantly promoted the reprogramming of focal-adhesion dynamics and lamellipodia formation in hepatocellular carcinoma cells mainly by activating typical Ca2+ /CaMKII/ERK/FAK pathway. Importantly, treatment with mitochondrial division inhibitor-1 significantly decreased calcium signalling in hepatocellular carcinoma cells and had a potential treatment effect for hepatocellular carcinoma metastasis in vivo.
CONCLUSIONS: Taken together, our findings demonstrate that mitochondrial fission plays a critical role in the regulation of hepatocellular carcinoma cell migration, which provides strong evidence for this process as a drug target in hepatocellular carcinoma metastasis treatment.

PMID: 29210177 [PubMed - indexed for MEDLINE]

Genetic analysis of pharmacogenomic VIP variants in the Blang population from Yunnan Province of China.

Mol Genet Genomic Med. 2019 Apr 05;:e574

Authors: Zhang C, Guo W, Cheng Y, Li Q, Yang X, Dai R, Zhu L, Chen W

Abstract
BACKGROUND: Genetic polymorphisms in numerous pharmacogenetics studies were regarded as the essential factors involved in the response to or metabolism of drugs. These genetic variants called very important pharmacogenetic (VIP) variants played a role in drugs metabolism, which have been summarized in the PharmGKB database. In this study, we genotyped 80 VIP variants from the PharmGKB in 100 members of Blang volunteers from Yunnan province.
METHODS: Based on the PharmGKB database, we genotyped 80 VIP variants loci located in 47 genes. We used χ2 tests to evaluate the significant loci between Blang and the other populations, including ASW, CEU, CHB, CHD, GIH, JPT, LWK, MEX, MKK, TSI, and YRI. The global variation distribution of the significant variants was observed from the ALlele FREquency Database. And then, we used F-statistics (Fst), genetic structure, and phylogenetic tree analyses to ascertain the genetic affinity among 12 populations.
RESULTS: Comparing the Blang with the other 11 populations from the HapMap Project, the statistical results revealed that rs3814055 (NC_000003.12:g.119781188C>T) of nuclear receptor subfamily 1 group I member 2 (NR1I2, OMIM# 603,065) was the most significant variant, followed by rs1540339 (NC_000012.12:g.47863543C>T) of vitamin D receptor (VDR, OMIM#601,769). Furthermore, we found that genotype frequency of rs3814055 in the Blang was closer to the populations distributed in Miao. And genetic structure and F-statistics indicated that the Blangs had a relatively closer affinity with CHD, CHB, and JPT populations. In addition, the Han nationality in Shaanxi was closer to it.
CONCLUSIONS: Our results will complement the pharmacogenomics information of the Blang ethnic group and provide a theoretical basis for safer drug administration for Blang.

PMID: 30955239 [PubMed - as supplied by publisher]

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis. 2019 Apr 03;:

Authors: Guerreiro R, Escott-Price V, Hernandez DG, Kun-Rodrigues C, Ross OA, Orme T, Neto JL, Carmona S, Dehghani N, Eicher JD, Shepherd C, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Dawson T, Rosenthal L, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, International Parkinson's Disease Genomics Consortium, Stone DJ, Bras J

Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

PMID: 30953760 [PubMed - as supplied by publisher]

In vivo pharmacodynamic and pharmacokinetic effects of metformin mediated by the gut microbiota in rats.

Life Sci. 2019 Apr 03;:

Authors: Wu B, Chen M, Gao Y, Hu J, Liu M, Zhang W, Huang W

Abstract
AIMS: The gut microbiota plays a crucial role in the efficacy of metformin in T2DM treatment. We evaluated whether the pharmacodynamics and pharmacokinetics of metformin are mediated by gut microbiota.
MAIN METHODS: We used conventional diabetic and pseudo-germ-free rats. After 6 weeks of metformin treatment, pharmacodynamic indexes were determined. Metformin concentrations were measured with a validated HPLC-MS/MS method after the first oral administration.
KEY FINDINGS: Most endpoints were similar between vehicle-treated diabetic and vehicle-treated pseudo-germ-free diabetic rats. However, after 6 weeks of metformin treatment, compared with conventional diabetic rats, pseudo-germ-free diabetic rats exhibited significantly increased FBG, decreased oral glucose, reduced GSP, worsened insulin resistance, increased hyperlipidemia, and increased hepatic steatosis severity. Moreover, the Cmax of pseudo-germ-free rats increased significantly, while the t1/2α decreased significantly. These pharmacodynamic and pharmacokinetic changes were probably due to a decrease in Oct1 expression in the liver, resulting in altered hepatic uptake of metformin in vivo.
SIGNIFICANCE: These results implied that the gut microbiota may play an important role in the pharmacodynamics and pharmacokinetics of metformin and that the changes in these properties are probably due to Oct1 downregulation in the livers of pseudo-germ-free rats.

PMID: 30953641 [PubMed - as supplied by publisher]

Molecular typing of Bluetongue virus using the nCounter® Analysis System platform.

J Virol Methods. 2019 Apr 02;:

Authors: Curini V, Marcacci M, Tonelli A, Di Teodoro G, Di Domenico M, D'Alterio N, Portanti O, Ancora M, Savini G, Panfili M, Camma' C, Lorusso A

Abstract
Bluetongue virus (BTV) is a segmented double-stranded RNA virus, existing in multiple serotypes, belonging to the genus Orbivirus of the family Reoviridae. BTV causes Bluetongue (BT), a major OIE-listed disease of ruminants. Identification of BTV serotype is accomplished using multiple typing assays and tends to be executed based on the known epidemiological situation within a given country. Samples containing multiple serotypes, particularly those containing novel introductions, may therefore be missed. The aim of this work was to optimize the nCounter® Analysis System Microarray platform (NanoString technologies), that would simultaneously identify all BTV serotypes and co-infections in analyzed samples. Probes were designed according to all Seg-2 sequences, coding for VP2 proteins which determine serotype specificity, available on line. A specific BTV CodeSet of probes was optimized. Experiments were performed with 30 BTV isolates and with 46 field samples previously shown to be infected with BTV by classical molecular assays. All BTV isolates were correctly identified and the expected BTV serotype was recognized in 35 field samples with CT values between 22.0-33.0. In turn, it was unable to identify 11 samples with CT values between 29.0-38.0. Although specificity of the assay needs to be further investigated against a larger panel of BTV collected worldwide, RNA loads, which are normally detected in blood samples during the acute phase of infection, are within the range of CT values detectable by the BTV CodeSet. We propose the NanoString RNA microarray as a first-line molecular diagnostic tool for identification and typing of BTV. Once identification of the index cases is performed, diagnosis of the following samples may be performed by specific, more sensitive and cheaper PCR-based tools.

PMID: 30951789 [PubMed - as supplied by publisher]

Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants used in Atrial Fibrillation.

Expert Opin Drug Metab Toxicol. 2019 Apr 05;:

Authors: Fawzy AM, Lip GY

Abstract
INTRODUCTION: The availability of non-vitamin K antagonist oral anti-coagulants alongside vitamin K antagonists has offered a variety of options for anti-coagulation, but has also necessitated a good understanding of the pharmacological properties of each of these drugs prior to their use, to maximise the therapeutic benefit and minimise patient harm Areas covered: This review article outlines the pharmacokinetic and pharmacodynamic profiles of the currently licensed NOACs and VKAs that are most commonly used in clinical practice, with the aim of demonstrating how variations in these processes contribute to their use in clinical practice. A literature search was conducted on PubMed using keywords and relevant articles published by the 31st of December 2018 were included. Expert opinion: The effect of a drug is determined by a combination of elements which include patient characteristics and external influences, in addition to its pharmacokinetic and pharmacodynamic properties. A good understanding of this is essential. Despite the wealth of information available, particularly on VKAs, our knowledge on the pharmacology responsible for certain drug effects and inter-individual variations is still limited. Increasing efforts are being made to uncover these and includes focus on pharmacogenomics and drug transporter proteins.

PMID: 30951640 [PubMed - as supplied by publisher]

Pharmacogenomics of inhalational anesthetic agents.

Med Gas Res. 2019 Jan-Mar;9(1):52-53

Authors: Nair AS

PMID: 30950419 [PubMed - in process]

Different Underlying Mechanism Might Explain the Absence of a Significant Difference in Area Under the Concentration-Time Curve of Linezolid for Different ABCB1 Genotypes.

Ther Drug Monit. 2019 04;41(2):254-255

Authors: Allegra S, Di Paolo A, Cusato J, Fatiguso G, Arrigoni E, Danesi R, Corcione S, DʼAvolio A

PMID: 30883522 [PubMed - indexed for MEDLINE]

Zebrafish: A Pharmacogenetic Model for Anesthesia.

Methods Enzymol. 2018;602:189-209

Authors: Bedell V, Buglo E, Marcato D, Pylatiuk C, Mikut R, Stegmaier J, Scudder W, Wray M, Züchner S, Strähle U, Peravali R, Dallman JE

Abstract
General anesthetics are small molecules that interact with and effect the function of many different proteins to promote loss of consciousness, amnesia, and sometimes, analgesia. Owing to the complexity of this state transition and the transient nature of these drug/protein interactions, anesthetics can be difficult to study. The zebrafish is an emerging model for the discovery of both new genes required for the response to and side effects of anesthesia. Here we discuss the tools available to manipulate the zebrafish genome, including both genetic screens and genome engineering approaches. Additionally, there are various robust behavior assays available to study anesthetic and other drug responses. These assays are available for single-gene study or high throughput for genetic or drug discovery. Finally, we present a case study of using propofol as an anesthetic in the zebrafish. These techniques and protocols make the zebrafish a powerful model to study anesthetic mechanisms and drug discovery.

PMID: 29588029 [PubMed - indexed for MEDLINE]

Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned.

Clin Transl Sci. 2018 03;11(2):175-181

Authors: Weitzel KW, Smith DM, Elsey AR, Duong BQ, Burkley B, Clare-Salzler M, Gong Y, Higgins TA, Kong B, Langaee T, McDonough CW, Staley BJ, Vo TT, Wake DT, Cavallari LH, Johnson JA

Abstract
Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme). TPMT tests were most commonly ordered for gastroenterology, rheumatology, dermatology, and hematology/oncology patients (661 of 834 patients (79.2%); 580 outpatient vs. 293 inpatient; P < 0.0001). Thirty-nine patients had both genotype and enzyme tests (n = 2 discordant results). We observed significant differences between TPMT test use and characteristics in a diverse, multispecialty environment vs. a pediatric cancer setting, which led to unique implementation needs. As pharmacogenetic implementations expand, disseminating lessons learned in diverse, real-world environments will be important to support routine adoption.

PMID: 29351371 [PubMed - indexed for MEDLINE]

Genome-wide and Phenome-wide Approaches to Understand Variable Drug Actions in Electronic Health Records.

Clin Transl Sci. 2018 03;11(2):112-122

Authors: Robinson JR, Denny JC, Roden DM, Van Driest SL

PMID: 29148204 [PubMed - indexed for MEDLINE]

The safety of treating newly diagnosed epilepsy.

Expert Opin Drug Saf. 2019 Apr 04;:

Authors: Sharma S, Kwan P

Abstract
INTRODUCTION: Epilepsy is a serious chronic neurological disorder manifested by an enduring symptomatic predisposition to seizures. Newly diagnosed individuals face increased morbidity, mortality and socio-economic costs. Anti-epileptic drug therapy is the treatment usually prescribed, which has efficacy in seizure control and mitigating long-term mortality. Areas covered: Safety of anti-epileptic drug therapy in adults with focus in newly diagnosed patients. Areas covered include the most commonly experienced adverse drug effects, as well as those with the highest impacts on drug tolerability, quality of life, morbidity and mortality. Evidence was also reviewed to identify clinical strategies to improve the safety of anti-epileptic drug therapy. Expert opinion: Anti-epileptic drugs (AEDs) are mostly effective and well tolerated. However, a lack of standardised reporting of adverse drug effects in trials and in clinical practice provides an obstacle for evaluation of which adverse drug effects need to be prioritised in management. Improvement in the reporting of cognitive and other effects, as well as improved precision medicine and pharmacogenomics to target the incidence of high-mortality idiosyncratic reactions, will help to reduce the harm of AEDs in people newly diagnosed with epilepsy.

PMID: 30943798 [PubMed - as supplied by publisher]

Ensemble of machine learning algorithms using the stacked generalization approach to estimate the warfarin dose.

PLoS One. 2018;13(10):e0205872

Authors: Ma Z, Wang P, Gao Z, Wang R, Khalighi K

Abstract
Warfarin dosing remains challenging due to narrow therapeutic index and highly individual variability. Incorrect warfarin dosing is associated with devastating adverse events. Remarkable efforts have been made to develop the machine learning based warfarin dosing algorithms incorporating clinical factors and genetic variants such as polymorphisms in CYP2C9 and VKORC1. The most widely validated pharmacogenetic algorithm is the IWPC algorithm based on multivariate linear regression (MLR). However, with only a single algorithm, the prediction performance may reach an upper limit even with optimal parameters. Here, we present novel algorithms using stacked generalization frameworks to estimate the warfarin dose, within which different types of machine learning algorithms function together through a meta-machine learning model to maximize the prediction accuracy. Compared to the IWPC-derived MLR algorithm, Stack 1 and 2 based on stacked generalization frameworks performed significantly better overall. Subgroup analysis revealed that the mean of the percentage of patients whose predicted dose of warfarin within 20% of the actual stable therapeutic dose (mean percentage within 20%) for Stack 1 was improved by 12.7% (from 42.47% to 47.86%) in Asians and by 13.5% (from 22.08% to 25.05%) in the low-dose group compared to that for MLR, respectively. These data suggest that our algorithms would especially benefit patients requiring low warfarin maintenance dose, as subtle changes in warfarin dose could lead to adverse clinical events (thrombosis or bleeding) in patients with low dose. Our study offers novel pharmacogenetic algorithms for clinical trials and practice.

PMID: 30339708 [PubMed - indexed for MEDLINE]