Racial variations in lacosamide serum concentrations in adult patients with epilepsy.

J Neurol Sci. 2020 Feb 19;412:116742

Authors: Zutshi D, Yarraguntla K, Mahulikar A, Seraji-Bozorgzad N, Shah AK, Basha MM

Abstract
Lacosamide (LCM) is a third-generation anti-epileptic drug (AED) for partial-onset epilepsy with minimal hepatic metabolism and drug-drug interactions. The impact of individual patient variables such as race on drug metabolism have been under-reported in AEDs and LCM has not been specifically investigated. Our aim was to assess the role race plays on serum LCM levels in the management of epilepsy. Thus, we retrospectively reviewed patients with focal seizures who received LCM and had LCM levels as part of their routine clinical care in our Level IV Epilepsy Center. Variables including age, race, gender, LCM serum levels, LCM daily dose, and concomitant AEDs were collected and analyzed. A total of 93 patients with 1-3 clinic visits yielded 122 LCM serum levels. African Americans (AA) comprised 62.3% of our serum samples. Daily LCM doses averaged 350 mg/day (range 50-1000 mg/day). Eighty-nine percent of patients took 1-2 other AEDs. Overall, AA patients had lower LCM levels (mean 6.8 μg/mL) compared to White patients (mean of 7.1 μg/mL) (p = .017) even when considering for the daily dose effect (p = .007). Analysis of co-variables did not have significant effect on LCM levels. Overall, AA patients had a weaker relationship between LCM daily dose (adjusted for weight) and serum levels as compared to White patients and require a higher LCM dose per weight to achieve similar levels. Differences in pharmacogenetics may play an important role in these findings and focus on how these variations impact seizure burden.

PMID: 32126366 [PubMed - as supplied by publisher]

A review of clinical pharmacogenetics Studies in African populations.

Per Med. 2020 Mar 03;:

Authors: Radouani F, Zass L, Hamdi Y, Rocha JD, Sallam R, Abdelhak S, Ahmed S, Azzouzi M, Benamri I, Benkahla A, Bouhaouala-Zahar B, Chaouch M, Jmel H, Kefi R, Ksouri A, Kumuthini J, Masilela P, Masimirembwa C, Othman H, Panji S, Romdhane L, Samtal C, Sibira R, Ghedira K, Fadlelmola F, Kassim SK, Mulder N

Abstract
Effective interventions and treatments for complex diseases have been implemented globally, however, coverage in Africa has been comparatively lower due to lack of capacity, clinical applicability and knowledge on the genetic contribution to disease and treatment. Currently, there is a scarcity of genetic data on African populations, which have enormous genetic diversity. Pharmacogenomics studies have the potential to revolutionise treatment of diseases, therefore, African populations are likely to benefit from these approaches to identify likely responders, reduce adverse side effects and optimise drug dosing. This review discusses clinical pharmacogenetics studies conducted in African populations, focusing on studies that examined drug response in complex diseases relevant to healthcare. Several pharmacogenetics associations have emerged from African studies, as have gaps in knowledge.

PMID: 32125935 [PubMed - as supplied by publisher]

Clinical application of thiopurine pharmacogenomics in pediatrics.

Curr Drug Metab. 2020 Mar 02;:

Authors: Pavlovic S, Kotur N, Stankovic B, Gasic V, Lucafo M, Decorti G, Zukic B

Abstract
BACKGROUND: Thiopurine drugs are used for treatment of pediatric diseases. Inter-individual differences in metabolism of these drugs greatly influence the risk of thiopurine induced toxicity and therapy failure. These differences are the consequence of genomic, epigenomic and transcriptomic variability among patients. Pharmacogenomics aims to individualize therapy according to specific genetic signature of a patient. Treatment protocols based on thiopurine drugs have already been improved by applying pharmacogenomics in pediatric clinical practice.
OBJECTIVE: The aim of this review is to summarize the application of thiopurine pharmacogenomics in pediatric patients suffering from acute leukemias, different types of autoimmune and inflammatory diseases, as well as in post-transplant care.
METHOD: We searched PubMed/Medline database to identify thiopurine pharmacogenomic markers clinically relevant in pediatric diseases.
RESULTS: TPMT and NUDT15 pharmacogenomic testing is already in place in pediatric care, contributing to the reduction of thiopurine induced toxicity. Data on numerous novel potential pharmacogenomic markers relevant for optimization of thiopurine treatment are still controversial (ITPA, ABCC4, NT5C2, PRPS1, GSTM1, FTO gene variants). Majority of evidences regarding thiopurine pharmacogenomics in pediatrics have been acquired by studying acute lymphoblastic leukemia and inflammatory bowel disease. For other pediatric diseases, namely acute myeloid leukemia, non-Hodgkin lymphoma, juvenile idiopathic arthritis, atopic dermatitis, juvenile autoimmune hepatitis and renal allograft transplantation, data are still scarce.
CONCLUSION: Thiopurine pharmacogenomics has shown to be one of the best examples of successful application of pharmacogenomics in pediatrics.

PMID: 32124692 [PubMed - as supplied by publisher]

PHARMIP: An insilico method to predict genetics that underpin adverse drug reactions.

MethodsX. 2020;7:100775

Authors: Zidan AM, Saad EA, Ibrahim NE, Mahmoud A, Hashem MH, Hemeida AA

Abstract
Pharmacovigilance is the pharmacological science that focuses on the safe and appropriate use of drugs.Variability in response to drug therapy in both terms of safety and efficacy is highly related to patient's personal genomics. Hence, pharmacovigilance considers pharmacogenomics methodologies in the evaluation of medicinal products. The aim of this work is to introduce the pharmacovigilance/ pharmacogenomics insilico pipeline (PHARMIP) that uses the drug (or drug candidate) digital structure and the advances in bioinformatics tools and databases to figure-out the genetic factors underlying the drug reported adverse reactions (ADRs).PHARMIP uses user-friendly freely available bioinformatics resources to help pharmacovigilance and pharmacogenomics scientists with minimal bioinformatics experience to retrieve helpful information for their daily basis activities. Also, PHARMIP could help the advances in precision medicine in a drug-centric approach as it can be used to reveal genetic risk factors for certain drug ADRs. Domperidone was used as an example to the application of PHARMIP as the pipeline was initially developed during the insilico exploration of domperidone cardiotoxic ADRs. Method is composed of 3 main steps: •Preparing the drug off-label targets (OLT) list.•Retrieving the related diseases/ adverse reactions (DA) list.•Analysis of DA list to get answers.

PMID: 32123669 [PubMed]

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury.

Acta Pharmacol Sin. 2020 Mar 02;:

Authors: Rao T, Liu YT, Zeng XC, Li CP, Ou-Yang DS

Abstract
Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.

PMID: 32123300 [PubMed - as supplied by publisher]

Association of MICA-129Met/Val polymorphism with clinical outcome of anti-TNF therapy and MICA serum levels in patients with rheumatoid arthritis.

Pharmacogenomics J. 2020 Mar 03;:

Authors: Iwaszko M, Świerkot J, Dratwa M, Wysoczańska B, Korman L, Bugaj B, Kolossa K, Jeka S, Wiland P, Bogunia-Kubik K

Abstract
MHC class I polypeptide-related sequence A (MICA) is a stress-induced protein involved in activation of NK and T cells through interaction with NKG2D receptor. These molecules are atypically expressed in synovium of patients diagnosed with rheumatoid arthritis (RA). A total of 279 patients with RA, qualified to TNF-blockade therapy, were genotyped for MICA rs1051792 SNP. The effectiveness of anti-TNF agents was assessed with European League Against Rheumatism criteria. Significant relationship between MICA rs1051792 and outcome of TNF-blockade therapy has been found. The MICA rs1051792 GG genotype was overrepresented in patients non-responsive to anti-TNF drugs in comparison with other genotypes (p = 0.010). On the other hand, beneficial therapeutic response was more frequently detected among RA subjects possessing heterozygous genotype than those with homozygous genotypes (p = 0.003). Furthermore, increased MICA concentrations in serum were observed in patients possessing MICA rs1051792 GG genotype as compared with those with GA or AA genotypes (p = 1.8 × 10-5). The results from this study indicate the potential influence of MICA rs1051792 polymorphism on modulation of therapeutic response to TNF-blockade treatment in RA.

PMID: 32123296 [PubMed - as supplied by publisher]

Pharmacogenetic Implications for Antidepressant Pharmacotherapy in Late-Life Depression: A Systematic Review of the Literature for Response, Pharmacokinetics and Adverse Drug Reactions.

Am J Geriatr Psychiatry. 2020 Feb 03;:

Authors: Marshe VS, Islam F, Maciukiewicz M, Bousman C, Eyre HA, Lavretsky H, Mulsant BH, Reynolds CF, Lenze EJ, Müller DJ

Abstract
Affecting up to 15% of older adults, late-life depression (LLD) is characterized by the occurrence of depressive symptoms after the age of 50-65 years and maybe pathophysiologically distinct from depression in younger adults. Therefore, LLD is challenging to treat, and predictive genetic testing might be essential to improve treatment in this vulnerable population. The current review aims to provide a summary of the literature exploring genetic associations with antidepressant treatment outcomes in late-life. We conducted a systematic search of three integrated electronic databases. We identified 29 articles investigating genetic associations with antidepressant treatment outcomes, pharmacokinetic parameters, and adverse drug reactions in older adults. Given the small number of investigations conducted in older adults, it is difficult to conclude the presence or absence of genetic associations with the outcomes of interest. In sum, the most substantial amount of evidence exists for the CYP2D6 metabolizer status, SLC6A4 5-HTTLPR, and BDNF rs6265. These findings are consistent in the literature when not restricting to older adults, suggesting that similar treatment recommendations may be provided for older adults regarding genetic variation, such as those outlined for CYP2D6 by the Clinical Pharmacogenetics Implementation Consortium. Nonetheless, further studies are required in well-characterized samples, including genome-wide data, to validate if similar treatment adjustments are appropriate in older adults, given that there appear to be significant effects of genetic variation on antidepressant treatment factors.

PMID: 32122803 [PubMed - as supplied by publisher]

Methods to assess anticancer immune responses in orthotopic bladder carcinomas.

Methods Enzymol. 2020;635:127-137

Authors: Sweis RF

Abstract
Urothelial bladder cancer is the most common malignancy of the urinary tract resulting in over 165,000 deaths worldwide. Immunotherapies targeting the programmed cell death protein-1 (PD-1) checkpoint pathway were recently approved for the treatment of bladder cancer, but favorable responses to this treatment are still limited to a minority of patients. This resistance to therapy has driven a need to optimize syngeneic models of bladder cancer that enable evaluation of the tumor immune microenvironment under varying conditions. Several models have been in place for many years, and we discuss in this chapter the optimization of an orthotopic model of bladder cancer that can be employed to study the anti-tumor immune response.

PMID: 32122541 [PubMed - in process]

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun. 2019 10 31;10(1):4957

Authors: Clark DW, Okada Y, Moore KHS, Mason D, Pirastu N, Gandin I, Mattsson H, Barnes CLK, Lin K, Zhao JH, Deelen P, Rohde R, Schurmann C, Guo X, Giulianini F, Zhang W, Medina-Gomez C, Karlsson R, Bao Y, Bartz TM, Baumbach C, Biino G, Bixley MJ, Brumat M, Chai JF, Corre T, Cousminer DL, Dekker AM, Eccles DA, van Eijk KR, Fuchsberger C, Gao H, Germain M, Gordon SD, de Haan HG, Harris SE, Hofer E, Huerta-Chagoya A, Igartua C, Jansen IE, Jia Y, Kacprowski T, Karlsson T, Kleber ME, Li SA, Li-Gao R, Mahajan A, Matsuda K, Meidtner K, Meng W, Montasser ME, van der Most PJ, Munz M, Nutile T, Palviainen T, Prasad G, Prasad RB, Priyanka TDS, Rizzi F, Salvi E, Sapkota BR, Shriner D, Skotte L, Smart MC, Smith AV, van der Spek A, Spracklen CN, Strawbridge RJ, Tajuddin SM, Trompet S, Turman C, Verweij N, Viberti C, Wang L, Warren HR, Wootton RE, Yanek LR, Yao J, Yousri NA, Zhao W, Adeyemo AA, Afaq S, Aguilar-Salinas CA, Akiyama M, Albert ML, Allison MA, Alver M, Aung T, Azizi F, Bentley AR, Boeing H, Boerwinkle E, Borja JB, de Borst GJ, Bottinger EP, Broer L, Campbell H, Chanock S, Chee ML, Chen G, Chen YI, Chen Z, Chiu YF, Cocca M, Collins FS, Concas MP, Corley J, Cugliari G, van Dam RM, Damulina A, Daneshpour MS, Day FR, Delgado GE, Dhana K, Doney ASF, Dörr M, Doumatey AP, Dzimiri N, Ebenesersdóttir SS, Elliott J, Elliott P, Ewert R, Felix JF, Fischer K, Freedman BI, Girotto G, Goel A, Gögele M, Goodarzi MO, Graff M, Granot-Hershkovitz E, Grodstein F, Guarrera S, Gudbjartsson DF, Guity K, Gunnarsson B, Guo Y, Hagenaars SP, Haiman CA, Halevy A, Harris TB, Hedayati M, van Heel DA, Hirata M, Höfer I, Hsiung CA, Huang J, Hung YJ, Ikram MA, Jagadeesan A, Jousilahti P, Kamatani Y, Kanai M, Kerrison ND, Kessler T, Khaw KT, Khor CC, de Kleijn DPV, Koh WP, Kolcic I, Kraft P, Krämer BK, Kutalik Z, Kuusisto J, Langenberg C, Launer LJ, Lawlor DA, Lee IT, Lee WJ, Lerch MM, Li L, Liu J, Loh M, London SJ, Loomis S, Lu Y, Luan J, Mägi R, Manichaikul AW, Manunta P, Másson G, Matoba N, Mei XW, Meisinger C, Meitinger T, Mezzavilla M, Milani L, Millwood IY, Momozawa Y, Moore A, Morange PE, Moreno-Macías H, Mori TA, Morrison AC, Muka T, Murakami Y, Murray AD, de Mutsert R, Mychaleckyj JC, Nalls MA, Nauck M, Neville MJ, Nolte IM, Ong KK, Orozco L, Padmanabhan S, Pálsson G, Pankow JS, Pattaro C, Pattie A, Polasek O, Poulter N, Pramstaller PP, Quintana-Murci L, Räikkönen K, Ralhan S, Rao DC, van Rheenen W, Rich SS, Ridker PM, Rietveld CA, Robino A, van Rooij FJA, Ruggiero D, Saba Y, Sabanayagam C, Sabater-Lleal M, Sala CF, Salomaa V, Sandow K, Schmidt H, Scott LJ, Scott WR, Sedaghati-Khayat B, Sennblad B, van Setten J, Sever PJ, Sheu WH, Shi Y, Shrestha S, Shukla SR, Sigurdsson JK, Sikka TT, Singh JR, Smith BH, Stančáková A, Stanton A, Starr JM, Stefansdottir L, Straker L, Sulem P, Sveinbjornsson G, Swertz MA, Taylor AM, Taylor KD, Terzikhan N, Tham YC, Thorleifsson G, Thorsteinsdottir U, Tillander A, Tracy RP, Tusié-Luna T, Tzoulaki I, Vaccargiu S, Vangipurapu J, Veldink JH, Vitart V, Völker U, Vuoksimaa E, Wakil SM, Waldenberger M, Wander GS, Wang YX, Wareham NJ, Wild S, Yajnik CS, Yuan JM, Zeng L, Zhang L, Zhou J, Amin N, Asselbergs FW, Bakker SJL, Becker DM, Lehne B, Bennett DA, van den Berg LH, Berndt SI, Bharadwaj D, Bielak LF, Bochud M, Boehnke M, Bouchard C, Bradfield JP, Brody JA, Campbell A, Carmi S, Caulfield MJ, Cesarini D, Chambers JC, Chandak GR, Cheng CY, Ciullo M, Cornelis M, Cusi D, Smith GD, Deary IJ, Dorajoo R, van Duijn CM, Ellinghaus D, Erdmann J, Eriksson JG, Evangelou E, Evans MK, Faul JD, Feenstra B, Feitosa M, Foisy S, Franke A, Friedlander Y, Gasparini P, Gieger C, Gonzalez C, Goyette P, Grant SFA, Griffiths LR, Groop L, Gudnason V, Gyllensten U, Hakonarson H, Hamsten A, van der Harst P, Heng CK, Hicks AA, Hochner H, Huikuri H, Hunt SC, Jaddoe VWV, De Jager PL, Johannesson M, Johansson Å, Jonas JB, Jukema JW, Junttila J, Kaprio J, Kardia SLR, Karpe F, Kumari M, Laakso M, van der Laan SW, Lahti J, Laudes M, Lea RA, Lieb W, Lumley T, Martin NG, März W, Matullo G, McCarthy MI, Medland SE, Merriman TR, Metspalu A, Meyer BF, Mohlke KL, Montgomery GW, Mook-Kanamori D, Munroe PB, North KE, Nyholt DR, O'connell JR, Ober C, Oldehinkel AJ, Palmas W, Palmer C, Pasterkamp GG, Patin E, Pennell CE, Perusse L, Peyser PA, Pirastu M, Polderman TJC, Porteous DJ, Posthuma D, Psaty BM, Rioux JD, Rivadeneira F, Rotimi C, Rotter JI, Rudan I, Den Ruijter HM, Sanghera DK, Sattar N, Schmidt R, Schulze MB, Schunkert H, Scott RA, Shuldiner AR, Sim X, Small N, Smith JA, Sotoodehnia N, Tai ES, Teumer A, Timpson NJ, Toniolo D, Tregouet DA, Tuomi T, Vollenweider P, Wang CA, Weir DR, Whitfield JB, Wijmenga C, Wong TY, Wright J, Yang J, Yu L, Zemel BS, Zonderman AB, Perola M, Magnusson PKE, Uitterlinden AG, Kooner JS, Chasman DI, Loos RJF, Franceschini N, Franke L, Haley CS, Hayward C, Walters RG, Perry JRB, Esko T, Helgason A, Stefansson K, Joshi PK, Kubo M, Wilson JF

Abstract
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

PMID: 31673082 [PubMed - indexed for MEDLINE]

A Survey of Precision Diagnosis and Management Capacity of Pulmonary Embolism in 90 Hospitals of China.

Clin Respir J. 2020 Mar 02;:

Authors: Wang D, Shao X, Lei J, Zhai Z

Abstract
OBJECTIVE: To conduct a survey of diagnostic facility and therapeutic capability of PE in 90 hospitals throughout China.
METHOD: It was a cross-sectional study among the participating hospitals of the National Key Research & Development Program of China -- the Precision Research of Standardized Management and Application of Pulmonary Thromboembolism to obtain the equipment and application of radiological facility to diagnose PE, laboratory tests for thrombophilia, coagulation function and the availability of anticoagulants and thrombolysis agents.
RESULTS: CTPA is capable in all 90 hospitals, 71.11% of the hospitals could perform V/Q scintigraphy, 24.44% of the hospitals do not routinely perform right heart evaluation by echocardiography. Protein C and protein S activity can be detected in half of the hospitals and warfarin pharmacogenomics test can be conducted in 40 hospitals. Immune turbidimetry was used as the detection method of D-dimer in 72.37% hospitals. 81.11% participating hospitals were equipped with new NOACs, all of which were equipped with Rivaroxaban.
CONCLUSION: The hospitals are capable for standardized diagnosis and management PE, while the capability of precise stratification, coagulation function tests, thrombophilia screening and pharmacogenomics requires further improvement.

PMID: 32119187 [PubMed - as supplied by publisher]

Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for The Early Assessment of Drug Safety Liabilities.

Toxicol Sci. 2020 Mar 02;:

Authors: Podtelezhnikov AA, Monroe JJ, Aslamkhan AG, Pearson K, Qin C, Tamburino AM, Loboda AP, Glaab WE, Sistare FD, Tanis KQ

Abstract
The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 120 different compounds, many of which are known to be associated with clinical risk for drug induced liver injury (DILI) by diverse mechanisms. Clustering, correlation and linear modeling analyses were used to identify and optimize co-expressed gene signatures modulated by drug treatment. Here, we specifically focused on prioritizing 9 key signatures for their pragmatic utility for routine monitoring in initial rat tolerability studies just prior to entering drug development. These signatures are associated with 5 canonical xenobiotic nuclear receptors (AHR, CAR, PXR, PPARα, ER), 3 mediators of reactive metabolite mediated stress responses (NRF2, NRF1, P53), and 1 liver response following activation of the innate immune response (IIR). Comparing paradigm chemical inducers of each receptor to the other compounds surveyed enabled us to identify sets of optimized gene expression panels and associated scoring algorithms proposed as quantitative mechanistic biomarkers with high sensitivity, specificity and quantitative accuracy. These findings were further qualified using public datasets, Open TG-GATEs and DrugMatrix, and internal development compounds. With broader collaboration and additional qualification, the quantitative toxicogenomic framework described here could inform candidate selection prior to committing to drug development, as well as complement and provide a deeper understanding of the conventional toxicology study endpoints used later in drug development.

PMID: 32119089 [PubMed - as supplied by publisher]

Impact of Population and Pharmacogenetics Variations on Efavirenz Pharmacokinetics and Immunologic Outcomes During Anti-Tuberculosis Co-Therapy: A Parallel Prospective Cohort Study in Two Sub-Sahara African Populations.

Front Pharmacol. 2020;11:26

Authors: Mugusi S, Habtewold A, Ngaimisi E, Amogne W, Yimer G, Minzi O, Makonnen E, Sudfeld C, Burhenne J, Aklillu E

Abstract
Efavirenz-based combination antiretroviral-therapy (cART) is the recommended regimen during tuberculosis (TB) therapy. In a multi-national parallel prospective-cohort study, we investigated the impact of population and pharmacogenetic variations for efavirenz pharmacokinetics, auto-induction, and immunologic outcome during antituberculosis treatment. A total of 921 treatment-naïve HIV patients with (196 Ethiopians and 231 Tanzanians) or without TB co-infection (285 Ethiopians and 209 Tanzanians) were enrolled and treated with efavirenz-based cART. TB-HIV patients started rifampicin-based anti-TB therapy 4 weeks before cART. Efavirenz plasma concentrations were measured on the 4th and 16th weeks of cART. Genotyping for CYP2B6, CYP3A5, ABCB1, UGT2B7, and SLCO1B1 was done. CD4 cells-count was measured at baseline, 12th, 24th, and 48th weeks of cART. Among HIV-only cohort, plasma efavirenz concentration and median CD4 cell count were significantly higher in Tanzanians than Ethiopians, and both CYP2B6 genotype and population-variation were significant predictors of efavirenz plasma concentration. Within-population analyses indicated a pronounced efavirenz autoinduction in Tanzanians as reflected by a significant decrease of plasma efavirenz concentration over time (p = 0.0001), but not in Ethiopians. Among TB-HIV cohort, there were no significant between-population differences in plasma efavirenz concentrations or CD4 cell-recovery, and CYP2B6 genotype but not population-variation was a significant predictor of efavirenz plasma exposure. In Tanzanian patients, short-term anti-TB co-treatment significantly reduced the mean plasma efavirenz concentration in CYP2B6*1/*1 genotype at week-4 (p = 0.005), but not at week-16 of cART. In Ethiopian patients, anti-TB cotreatment increased the mean plasma efavirenz concentration among CYP2B6*6 carriers at week-4 (p = 0.003) and week-16 (p = 0.035) of cART. In general, long-term anti-TB co-treatment increased plasma efavirenz concentration at week 16 of cART in both Ethiopians and Tanzanians being higher in CYP2B6*6/*6 > *1/*6 > *1/*1 genotypes. In TB-HIV patients, baseline body mass index (BMI), viral load, and WHO clinical-stage but not genotype, population-variation, or efavirenz concentration were significant predictors of immunologic outcome at week-48. In summary efavirenz auto-induction, pharmacokinetics, and the immunologic outcome are influenced by population-variation, anti-TB co-medication, and CYP2B6 genotype. CYP2B6 genotype is a significant predictor of efavirenz plasma exposure regardless of population-variation or antituberculosis co-treatment, but population-variation is insignificant during antituberculosis treatment. CYP2B6 genotype, population, and geographic differences need to be considered for efavirenz dosage-optimization.

PMID: 32116703 [PubMed]

Progress in Genetic Polymorphisms Related to Lipid Disturbances Induced by Atypical Antipsychotic Drugs.

Front Pharmacol. 2019;10:1669

Authors: Li N, Cao T, Wu X, Tang M, Xiang D, Cai H

Abstract
Metabolic side effects such as weight gain and disturbed lipid metabolism are often observed in the treatment of atypical antipsychotic drugs (AAPDs), which contribute to an excessive prevalence of metabolic syndrome among schizophrenic patients. Great individual differences are observed but the underlying mechanisms are still uncertain. Research on pharmacogenomics indicates that gene polymorphisms involved in the pathways controlling food intake and lipid metabolism may play a significant role. In this review, relevant genes (HTR2C, DRD2, LEP, NPY, MC4R, BDNF, MC4R, CNR1, INSIG2, ADRA2A) and genetic polymorphisms related to metabolic side effects of AAPDs especially dyslipidemia were summarized. Apart from clinical studies, in vitro and in vivo evidence is also analyzed to support related theories. The association of central and peripheral mechanisms is emphasized, enabling the possibility of using peripheral gene expression to predict the central status. Novel methodological development of pharmacogenomics is in urgent need, so as to provide references for individualized medication and further to shed some light on the mechanisms underlying AAPD-induced lipid disturbances.

PMID: 32116676 [PubMed]

Drugs in pregnancy: Pharmacologic and physiologic changes that affect clinical care.

Semin Perinatol. 2020 Jan 25;:151221

Authors: Pinheiro EA, Stika CS

Abstract
Pharmacologic interventions play a major role in obstetrical care throughout pregnancy, labor and delivery and the postpartum. Traditionally, obstetrical providers have utilized standard dosing regimens developed for non-obstetrical indications based on pharmacokinetic knowledge from studies in men or non-pregnant women. With the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigators have begun to study drug disposition in this unique patient dyad. Many of the basic physiologic changes that occur during pregnancy have significant impact on drug absorption, distribution and clearance. Activity of Phase I and Phase II drug metabolizing enzymes are differentially altered by pregnancy, resulting in drug concentrations sufficiently different for some medications that efficacy or toxicity is affected. Placental transporters play a major dynamic role in determining fetal drug exposure. In the past two decades, we have begun to expand our understanding of obstetrical pharmacology; however, to truly optimize pharmacologic care of our pregnant patients and their developing fetus, additional research is critically needed.

PMID: 32115202 [PubMed - as supplied by publisher]

Predictors of blood pressure control in patients with resistant hypertension after intensive management in two expert centres: the Brussels-Torino experience.

Blood Press. 2019 10;28(5):336-344

Authors: Pappaccogli M, Di Monaco S, Coralie G, Petit G, Eula E, Ritscher S, Lengelé JP, Fanelli E, Severino F, Renkin J, Avataneo V, Wallemacq P, Toennes SW, de Timary P, Rabbia F, Persu A

Abstract
Background: Management of resistant hypertension (RHTN) is challenging and often implies the use of complex polypharmacy and interventional therapies. The main objectives of this study were (i) to describe the characteristics of patients with RHTN referred to two expert centres; (ii) to identify predictors of blood pressure (BP) control after intensive management. Methods: We reviewed electronic medical files of all patients referred for RHTN to the Brussels and Torino centres, and extracted detailed clinical data, informations on drug adherence and psychological profile. All patients with confirmed diagnosis of RHTN, according to office and ambulatory BP monitoring (ABPM) measurements, were considered eligible. Results: 313 patients (51% men; age: 56 ± 12 years; office BP 177/98 mmHg; 24-hour ABPM 153/90 mmHg) were included. At the end of follow-up (median: 2 years [1-4]), only 26% of patients (n = 81) reached BP control. When compared to patients remaining resistant, patients eventually controlled had lower pulse pressure (71 vs. 82 mmHg, p < 0.001), less often myocardial infarction (6% vs. 20%, p < 0.005) and showed a higher recourse to cognitive reappraisal as far as emotion regulation is concerned (4.8 ± 1.1 vs. 3.9 ± 1.2, p = 0.009; ERQ Questionnaire). In a multivariate analysis looking for predictors of controlled BP, only the psychological characteristic of cognitive reappraisal (i.e., changing one's thoughts about a potentially emotion-eliciting event) remained significant (OR 2.06 [1.10; 3.84], p = 0.02). Conclusions: Even in expert centres, only a minority of patients with RHTN reached BP control, irrespective of the centre involved or the interventions applied. Patients who eventually responded to therapy had lower arterial stiffness and less cardiac organ damage. Furthermore, besides vascular damage, the single predictor of BP control was the ability to modify the emotional impact of stressful situations.

PMID: 31257937 [PubMed - indexed for MEDLINE]

Genetic Variations and Precision Medicine.

Perspect Health Inf Manag. 2019;16(Spring):1a

Authors: Alzu'bi AA, Zhou L, Watzlaf VJM

Abstract
The time and costs associated with the sequencing of a human genome have decreased significantly in recent years. Many people have chosen to have their genomes sequenced to receive genomics-based personalized healthcare services. To reach the goal of genomics-based precision medicine, health information management (HIM) professionals need to manage and analyze patients' genomic data. Two important pieces of information from the genome sequence are the risk of genetic diseases and the specific medication or pharmacogenomic results for the individual patient, both of which are linked to a patient's genetic variations. In this review article, we introduce genetic variations, including their data types, relevant databases, and some currently available analysis methods and systems. HIM professionals can choose to use these databases, methods, and systems in the management and analysis of patients' genomic data.

PMID: 31019429 [PubMed - indexed for MEDLINE]

Progranulin Stimulates the In Vitro Maturation of Pro-Cathepsin D at Acidic pH.

J Mol Biol. 2019 03 01;431(5):1038-1047

Authors: Butler VJ, Cortopassi WA, Argouarch AR, Ivry SL, Craik CS, Jacobson MP, Kao AW

Abstract
Single-copy loss-of-function mutations in the progranulin gene (PGRN) underlie the neurodegenerative disease frontotemporal lobar degeneration, while homozygous loss-of-function of PGRN results in the lysosomal storage disorder neuronal ceroid lipofuscinosis. Despite evidence that normal PGRN levels are critical for neuronal health, the function of this protein is not yet understood. Here, we show that PGRN stimulates the in vitro maturation of the lysosomal aspartyl protease cathepsin D (CTSD). CTSD is delivered to the endolysosomal system as an inactive precursor (proCTSD) and requires sequential cleavage steps via intermediate forms to achieve the mature state (matCTSD). In co-immunoprecipitation experiments, PGRN interacts predominantly with immature pro- and intermediate forms of CTSD. PGRN enhances in vitro conversion of proCTSD to matCTSD in a concentration-dependent manner. Differential scanning fluorimetry shows a destabilizing effect induced by PGRN on proCTSD folding (∆Tm = -1.7 °C at a 3:1 molar ratio). We propose a mechanism whereby PGRN binds to proCTSD, destabilizing the propeptide from the enzyme catalytic core and favoring conversion to mature forms of the enzyme. Further understanding of the role of PGRN in CTSD maturation will assist in the development of targeted therapies for neurodegenerative disease.

PMID: 30690031 [PubMed - indexed for MEDLINE]

The potentiation of menadione on imatinib by down-regulation of ABCB1 expression.

Clin Exp Pharmacol Physiol. 2020 Feb 28;:

Authors: Xiao FY, Zhou FJ, Yuan F, Kuang W, Zhou G, Zhou HH, Shan C

Abstract
Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

PMID: 32112424 [PubMed - as supplied by publisher]

Calcaneal quantitative ultrasound and urine retinol binding protein in HIV-positive antiretroviral-treated patients in Uganda: a pilot study.

J Infect Dis. 2020 Feb 28;:

Authors: Costa C, Scabini S, Kaimal A, Kasozi W, Cusato J, Kafufu B, Borderi M, Mwaka E, Di Perri G, Lamorde M, Calcagno A, Castelnuovo B

Abstract
BACKGROUND: Data on bone health and renal impairment in people with HIV in resource-limited settings are limited. The primary aim was to investigate the potential role of calcaneal Quantitative Ultrasound in predicting bone mineral density (BMD) reduction in a population of Ugandan HIV+ individuals on long-term antiretroviral therapy (ART); the secondary endpoint was to assess the prevalence of proximal tubular dysfunction and the correlation among elevated urine retinol binding protein/creatinine ratio (uRBP/uCr) and reduced BMD.
METHODS: We conducted a cross-sectional study at the Infectious Diseases Institute, Kampala, Uganda. We included 101 HIV+ adults on continuous ART for ≥10 years that had undergone DXA scan during the previous 12 months. All patients underwent calcaneal quantitative ultrasound evaluation and urine samples collection.
RESULTS: DXA BMD measurements were significantly associated (p<0.01) with calcaneal speed of sound, broadband ultrasound attenuation, and quantitative ultrasound index. 47 individuals (47%) had abnormal uRBP/uCr values. A significant inverse correlation between uRBP/uCr and DXA T-scores [lumbar (p=0.031), femoral neck (p>0.001) and total hip (p=0.002)] was observed.
CONCLUSIONS: Calcaneal quantitative ultrasound results showed a moderate correlation with DXA scan outputs. Secondly, the identified high prevalence of subclinical tubular impairment highlights the importance of expanding access to TDF-sparing regimens in resource-limited settings.

PMID: 32112093 [PubMed - as supplied by publisher]

Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models.

Transl Psychiatry. 2019 08 05;9(1):187

Authors: Paul R, Andlauer TFM, Czamara D, Hoehn D, Lucae S, Pütz B, Lewis CM, Uher R, Müller-Myhsok B, Ising M, Sämann PG

Abstract
The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.

PMID: 31383853 [PubMed - indexed for MEDLINE]