Risperidone-Induced Obesity in Children and Adolescents With Autism Spectrum Disorder: Genetic and Clinical Risk Factors.

Front Pharmacol. 2020;11:565074

Authors: Vanwong N, Ngamsamut N, Nuntamool N, Hongkaew Y, Sukprasong R, Puangpetch A, Limsila P, Sukasem C

Abstract
Aims: Obesity is a significant problem for patients taking atypical antipsychotics. There were two aims of our study. The first aim was to compare the prevalence of overweight and obesity between children and adolescents with autism spectrum disorder (ASD) treated with risperidone with the general pediatric population. The second aim was to investigate the association of the HTR2C -759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T polymorphisms with risperidone-induced overweight and obesity in children and adolescents with ASD. Methods: Body weight and height were measured in 134 subjects. Overweight and obesity in children and adolescents were classified using the International Obesity Task Force (IOTF) criteria. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR). Results: Our study found that the prevalence of overweight and obesity was significantly higher in children and adolescents with ASD treated with risperidone compared with healthy individuals (p = 0.01 and p = 0.002). The genetic polymorphisms of HTR2C -759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T were not associated with overweight/obesity in children and adolescents with ASD treated with risperidone after adjustment for multiple comparisons by the method of Bonferroni. Additionally, haplotype analysis revealed that there was no significant association between ABCB1 3435T-2677T/A-1236T haplotype and overweight/obesity. In multivariate logistic regression, after adjustment by the Bonferroni correction, there was only the duration of risperidone treatment that was significantly associated with overweight/obesity in children and adolescents with ASD. Conclusions: The findings suggest that children and adolescents with ASD treated with risperidone are at a higher risk of obesity, especially patients with extended treatment with risperidone. For the pharmacogenetic factors, -759C>T polymorphism of HTR2C gene and 1236C>T, 2677G>T/A, and 3435C>T polymorphisms of ABCB1 gene were not likely to be associated with the susceptibility to overweight/obesity in children and adolescents treated with risperidone. Due to the small sample size, further studies with a larger independent group are needed to confirm these findings.

PMID: 33240086 [PubMed]

VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

Pharmaceuticals (Basel). 2020 Nov 23;13(11):

Authors: Gal J, Milano G, Brest P, Ebran N, Gilhodes J, Llorca L, Dubot C, Romieu G, Desmoulins I, Brain E, Goncalves A, Ferrero JM, Cottu PH, Debled M, Tredan O, Chamorey E, Merlano MC, Lemonnier J, Etienne-Grimaldi MC, Pierga JY

Abstract
The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33-4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.

PMID: 33238394 [PubMed]

Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice.

Eur J Clin Pharmacol. 2020 Nov 26;:

Authors: Russmann S, Rahmany A, Niedrig D, Hatz KD, Ludin K, Burden AM, Englberger L, Backhaus R, Serra A, Béchir M

Abstract
PURPOSE: The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes.
METHODS: We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis.
RESULTS: Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3-14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies.
CONCLUSION: PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.

PMID: 33242107 [PubMed - as supplied by publisher]

Impact of previous abdominal surgery on robotic-assisted rectal surgery in patients with locally advanced rectal adenocarcinoma: a propensity score matching study.

World J Surg Oncol. 2020 Nov 25;18(1):308

Authors: Huang CW, Su WC, Chang TK, Ma CJ, Yin TC, Tsai HL, Chen PJ, Chen YC, Li CC, Hsieh YC, Wang JY

Abstract
BACKGROUND: The application of minimally invasive surgery in patients with colorectal cancer (CRC) and a history of previous abdominal surgery (PAS) remains controversial. This retrospective study with propensity score matching (PSM) investigated the impact of PAS on robotic-assisted rectal surgery outcomes in patients with locally advanced rectal adenocarcinoma undergoing preoperative concurrent chemoradiotherapy (CCRT).
METHODS: In total, 203 patients with locally advanced rectal adenocarcinoma who underwent preoperative CCRT and robotic-assisted rectal surgery between May 2013 and December 2019 were enrolled. Patients were categorized into PAS and non-PAS groups based on the PAS history. The PSM caliper matching method with 1-to-3 matches was used to match PAS patients with non-PAS.
RESULTS: Of the 203 enrolled patients, 35 were PAS patients and 168 were non-PAS patients. After PSM, 32 PAS patients and 96 non-PAS patients were included for analysis. No significant between-group differences were noted in the perioperative outcomes, including median console time (165 min (PAS) vs. 175 min (non-PAS), P = 0.4542) and median operation time (275 min (PAS) vs. 290 min (non-PAS), P = 0.5943) after PSM. Postoperative recovery and overall complication rates were also similar (all P > 0.05). Moreover, the between-group differences in pathological or short-term oncological outcomes were also nonsignificant (all P > 0.05). No 30-day postoperative deaths were observed in either group.
CONCLUSION: The current results indicate that robotic-assisted surgery is safe and feasible for PAS patients with locally advanced rectal adenocarcinoma undergoing preoperative CCRT. However, future prospective randomized clinical trials are required to verify these findings.

PMID: 33239020 [PubMed - in process]

[Pharmacogenomics : a toolbox to improve drug prescription].

Rev Med Suisse. 2020 Nov 25;16(716):2259-2263

Authors: Jaccard E, Redin C, Girardin F, Waeber G, Fellay J, Vollenweider P

Abstract
As a result of advances in pharmacogenomics (PGx), the paradigm that a single dose of a drug is extrapolated to an entire population is set to change. Personalising drug prescriptions according to individual genomic determinants would make it possible to increase the effectiveness and tolerance of treatments. In Switzerland, any doctor can prescribe validated PGx tests for five actionable drugs : abacavir, carbamazepine, thiopurines [azathioprine], fluoropyrimidines [5-FU, capecitabine] and irinotecan. Such an approach presupposes that PGx data are shared with trained clinicians and that prescribing aids can guide them.

PMID: 33237643 [PubMed - as supplied by publisher]

Pharmacogenetics at Scale: An Analysis of the UK Biobank.

Clin Pharmacol Ther. 2020 Nov 25;:

Authors: McInnes G, Lavertu A, Sangkuhl K, Klein TE, Whirl-Carrillo M, Altman RB

Abstract
Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well-understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the U.K. Biobank, the largest PGx study to date. For fourteen CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least one drug; on average they may have an atypical response to 10.3 drugs. Nearly 24% of participants have been prescribed a drug for which they are predicted to have an atypical response. Non-European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.

PMID: 33237584 [PubMed - as supplied by publisher]

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis.

JAMA Psychiatry. 2020 Nov 25;:

Authors: Milosavljevic F, Bukvic N, Pavlovic Z, Miljevic C, Pešic V, Molden E, Ingelman-Sundberg M, Leucht S, Jukic MM

Abstract
Importance: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization.
Objective: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers.
Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions.
Study Selection: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available.
Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies.
Main Outcomes and Measures: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category.
Results: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies.
Conclusions and Relevance: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.

PMID: 33237321 [PubMed - as supplied by publisher]

Influence of PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease.

Pharmgenomics Pers Med. 2020;13:619-632

Authors: Al-Eitan LN, Elsaqa BZ, Almasri AY, Aman HA, Khasawneh RH, Alghamdi MA

Abstract
Background: Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. Several cardiovascular diseases require therapy with warfarin, an anticoagulant with large interindividual variability resulting in dosing difficulties. The selected genes and their polymorphisms have been implicated in several Genome-Wide Association Study (GWAS) to be associated with cardiovascular disease.
Objective: The goal of this study is to discover if there are any associations between rs646776 of PSRC1, rs660240 and rs12740374 of CELSR2, and rs602633 of SORT1 to coronary heart disease (CHD) and warfarin dose variability in patients diagnosed with cardiovascular disease undergoing warfarin therapy.
Methods: The study was directed at the Queen Alia Hospital Anticoagulation Clinic in Amman, Jordan. DNA was extracted and genotyped using the Mass ARRAY™ system, statistical analysis was done using SPSS.
Results: The study found several associations between the selected SNPs with warfarin, but none with cardiovascular disease. All 4 studied SNPs were found to be correlated to warfarin sensitivity during the stabilization phase except rs602633 and with warfarin dose variability at the initiation phase. CELSR2 SNPs also showed association with dose variability during the stabilization phase. Also, rs646776 and rs12740374 were linked to warfarin sensitivity over the initiation phase. Only rs602633 was associated with INR treatment outcomes.
Conclusion: The findings presented in this study found new pharmacogenomic associations for warfarin, that warrant further research in the field of genotype-guided warfarin dosing.

PMID: 33235484 [PubMed]

Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

Pharmgenomics Pers Med. 2020;13:601-617

Authors: Bruera G, Ricevuto E, Oncology Network ASL1 Abruzzo

Abstract
Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

PMID: 33235483 [PubMed]

Evolving Role of Pharmacogenetic Biomarkers to Predict Drug-Induced Hematological Disorders.

Ther Drug Monit. 2020 Nov 20;:

Authors: Pattanaik S, Ahluwalia J, Jain A

Abstract
Drug induced haematological disorders constitute up to 30% of all blood dyscrasias seen in the clinic. Hematologic toxicity from drugs may range from life threatening marrow aplasia, agranulocytosis, haemolysis, thrombosis to mild leukopenia and thrombocytopenia. Pathophysiologic mechanisms underlying these disorders vary from an extension of the pharmacological effect of the drug to idiosyncratic and immune mediated reactions. Predicting these reactions is often difficult and this makes clinical decision making challenging. Evidence supporting the role of pharmacogenomics in the management of these disorders in clinical practise is rapidly evolving. Despite the Clinical Pharmacology Implementation Consortium and Pharmacogenomics Knowledge Base recommendations, few tests have been incorporated into routine practice. This review aims to provide a comprehensive summary of the various drugs which are implicated for the haematological adverse events, their underlying mechanisms and the current evidence and practical recommendations to incorporate pharmacogenomic testing in clinical care for predicting these disorders.

PMID: 33235023 [PubMed - as supplied by publisher]

Pharmacogenetics to Predict Adverse Events Associated With Antidepressants.

Pediatrics. 2020 Nov 24;:

Authors: Rossow KM, Aka IT, Maxwell-Horn AC, Roden DM, Van Driest SL

Abstract
OBJECTIVES: To determine the association between cytochrome P450 2C19 (CYP2C19) metabolizer status and risk for escitalopram and citalopram, collectively termed (es)citalopram, and sertraline adverse events (AEs) in children.
METHODS: In this retrospective cohort study, we used deidentified electronic health records linked to DNA. The cohort included children ≤18 years with ≥2 days of (es)citalopram or ≥7 days of sertraline exposure. The primary outcome was AEs assessed by manual chart review. CYP2C19 was genotyped for functional variants (*2, *3, *4, *6, *8, and *17), and individuals were assigned metabolizer status. Association between AEs and metabolizer status was determined by using Cox regression adjusting for age, race, ethnicity, dose, and concomitant CYP2C19-inhibiting medications.
RESULTS: The cohort included 249 sertraline-exposed and 458 (es)citalopram-exposed children, with a median age of 14.2 years (interquartile range 11.2-16.2) and 13.4 years (interquartile range 10.1-15.9), respectively. Sertraline AEs were more common in normal metabolizers (NMs) compared to poor metabolizers (PMs) or intermediate metabolizers (IMs) (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.01-3.2; P = .047) in unadjusted analysis and after adjustment (HR 1.9; CI 1.04-3.4; P = .04). For (es)citalopram, more AEs were observed in NMs than PMs and IMs without statistically significant differences (unadjusted HR 1.6; CI 0.95-2.6; P = .08; adjusted HR 1.6; CI 0.95-2.6; P = .08).
CONCLUSIONS: In contrast to adults, in our pediatric cohort, CYP2C19 NMs experienced increased sertraline AEs than PMs and IMs. (Es)citalopram AEs were not associated with CYP2C19 status in the primary analysis. The mechanism underlying this pediatric-specific finding is unknown but may be related to physiologic differences of adolescence. Further research is required to inform genotype-guided prescribing for these drugs in children.

PMID: 33234666 [PubMed - as supplied by publisher]

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

BMC Med. 2020 Nov 25;18(1):367

Authors: Turner RM, de Koning EM, Fontana V, Thompson A, Pirmohamed M

Abstract
BACKGROUND: The number of patients living with co-existing diseases is growing. This study aimed to assess the extent of multimorbidity, medication use, and drug- and gene-based interactions in patients following a non-ST elevation acute coronary syndrome (NSTE-ACS).
METHODS: In 1456 patients discharged from hospital for a NSTE-ACS, comorbidities and multimorbidity (≥ 2 chronic conditions) were assessed. Of these, 698 had complete drug use recorded at discharge, and 652 (the 'interaction' cohort) had drug use and actionable genotypes available for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, SLCO1B1, TPMT, UGT1A1, and VKORC1. The following drug interactions were investigated: pharmacokinetic drug-drug (DDIs) involving CYPs (CYPs above, plus CYP1A2, CYP2C8, CYP3A4), SLCO1B1, and P-glycoprotein; drug-gene (DGIs); drug-drug-gene (DDGIs); and drug-gene-gene (DGGIs). Interactions predicted to be 'substantial' were defined as follows: DDIs due to strong inhibitors/inducers, DGIs due to variant homozygous/compound heterozygous genotypes, and DDGIs/DGGIs where the constituent DDI/DGI(s) both influenced the victim drug in the same direction.
RESULTS: In the whole cohort, 727 (49.9%) patients had multimorbidity. Non-linear relationships between age and increasing comorbidities and decreasing coronary intervention were observed. There were 98.1% and 39.8% patients on ≥ 5 and ≥ 10 drugs, respectively (from n = 698); women received more non-cardiovascular drugs than men (median (IQR) 3 (1-5) vs 2 (1-4), p = 0.014). Overall, 98.7% patients had at least one actionable genotype. Within the interaction cohort, 882 interactions were identified in 503 patients (77.1%), of which 346 in 252 patients (38.7%) were substantial: 59.2%, 11.6%, 26.3%, and 2.9% substantial interactions were DDIs, DGIs, DDGIs, and DGGIs, respectively. CYP2C19 (49.5% of all interactions) and SLCO1B1 (18.4%) were involved in the largest number of interactions. Multimorbidity (p = 0.019) and number of drugs (p = 9.8 × 10-10) were both associated with patients having ≥ 1 substantial interaction. Multimorbidity (HR 1.76, 95% CI 1.10-2.82, p = 0.019), number of drugs (HR 1.10, 95% CI 1.04-1.16, p = 1.2 × 10-3), and age (HR 1.05, 95% CI 1.03-1.07, p = 8.9 × 10-7), but not drug interactions, were associated with increased subsequent major adverse cardiovascular events.
CONCLUSIONS: Multimorbidity, polypharmacy, and drug interactions are common after a NSTE-ACS. Replication of results is required; however, the high prevalence of DDGIs suggests integrating co-medications with genetic data will improve medicines optimisation.

PMID: 33234119 [PubMed - in process]

Ethnopharmacology, Phytochemistry and Biological Activities of Native Chilean Plants.

Curr Pharm Des. 2020 Nov 23;:

Authors: Salehi B, Sharifi-Rad J, Herrera-Bravo J, Salazar LA, Delporte C, Barra GV, Cazar Ramirez ME, López MD, Ramírez Alarcón K, Martins N, Martorell M

Abstract
The native flora of Chile has unique characteristics due to the geographical situation of the country, with the vast desert in the North, Patagonia in the South, the Andean Mountains on the east and the Pacific Ocean on the west. This exclusivity is reflected in high concentrations of phytochemicals in the fruits and leaves of its native plants. Some examples are Aristotelia chilensis (Molina) Stuntz (maqui), Berberis microphylla G. Forst. (calafate), Peumus boldus Molina (boldo), Ribes magellanicum Poir. (Magellan currant), Ugni molinae Turcz. (murtilla), Rubus geoides Sm. (miñe miñe), Drimys winteri J.R.Forst. & G.Forst. (canelo), Luma apiculata (DC.) Burret (arrayán) distributed throughout the entire Chilean territory. Some of these Chilean plants have been used for centuries in the country's traditional medicine. The most recent studies of phytochemical characterization of parts of Chilean plants show a wide spectrum of antioxidant compounds, phenolic components, terpenoids and alkaloids, which have shown biological activity in both in vitro and in vivo studies. This manuscript covers the entire Chilean territory characterizing the phytochemical profile and reporting some of its biological properties, focusing mainly on antioxidant, anti-inflammatory, antimicrobial, chemopreventive and cytotoxic activity, and potential against diabetes, metabolic syndrome and gastrointestinal disorders.

PMID: 33234091 [PubMed - as supplied by publisher]

Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies.

Eur J Clin Pharmacol. 2020 Dec;76(12):1623-1630

Authors: Ragia G, Manolopoulos VG

Abstract
AIM: The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells.
METHOD: We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin.
RESULTS: Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil).
CONCLUSION: Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.

PMID: 32696234 [PubMed - indexed for MEDLINE]

Polypharmacy, potentially inappropriate medication, and pharmacogenomics drug exposure in the Rhineland Study.

Br J Clin Pharmacol. 2020 Nov 24;:

Authors: de Vries FM, Stingl JC, Breteler MMB

Abstract
AIM: High medication use may contribute to the efficiency of drug therapy in general, however, it could also increase the burden of adverse drug reactions. We aimed to assess medication use and the prevalence of three risk factors for adverse drug reactions: the use of polypharmacy, potentially inappropriate medication in elderly, and pharmacogenomic polymorphisms affecting the metabolism of drugs.
METHODS: Cross-sectional interview-based medication data (including over-the-counter drugs) collected in a large population-based cohort (≥30 years of age) in Bonn, Germany.
RESULTS: Analyses were based on the first 5,000 participants of the Rhineland Study (mean age 55 years; 57% women). Of our participants, 66.0% reported the use of a drug regularly, which increased to 87.4% in participants aged ≥65 years (n=1,301). The use of polypharmacy, potentially inappropriate medication, and pharmacogenomic drugs was 15.9%, 6.4%, and 20.5%, respectively. In participants <65 years, 16.0% (95%CI 14.8;17.3) had at least one risk factor. In participants aged ≥65 years, 54.1% (95%CI 51.4;56.8) had at least one, and 27.4% (95%CI 25.0;29.9) had at least two risk factors. Extrapolating these numbers to the German population implies, that around 9 of the 17 million individuals aged 65 years or older are potentially at an elevated risk for adverse drug reactions, of which 4.6 million are at a potentially highly elevated risk for adverse drug reactions.
CONCLUSION: Our study shows that drug use is common and the individual risk for an adverse drug reaction in our population is high. This suggests room for improvement in general medication use.

PMID: 33232531 [PubMed - as supplied by publisher]

Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy.

Swiss Med Wkly. 2020 Nov 16;150:w20375

Authors: Hamzic S, Aebi S, Joerger M, Montemurro M, Ansari M, Amstutz U, Largiadèr C

Abstract
Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10&ndash;40% of patients experience severe, and in rare cases (0.2&ndash;0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotype-guided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy. We recommend preemptive testing of four DPYD variants (c.1905+1G&gt;A (rs3918290), c.1679T&gt;G (rs55886062), c.2846A&gt;T (rs67376798) and c.1129-5923C&gt;G (rs75017182, c.1236G&gt;A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40&ndash;50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy&rsquo;s safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.

PMID: 33232506 [PubMed - as supplied by publisher]

Analysis of expression of vitamin E-binding proteins in H2O2 induced SK-N-SH neuronal cells supplemented with α-tocopherol and tocotrienol-rich fraction.

PLoS One. 2020;15(11):e0241112

Authors: Chiroma AA, Khaza'ai H, Abd Hamid R, Chang SK, Zakaria ZA, Zainal Z

Abstract
Natural α-tocopherol (α-TCP), but not tocotrienol, is preferentially retained in the human body. α-Tocopherol transfer protein (α-TTP) is responsible for binding α-TCP for cellular uptake and has high affinity and specificity for α-TCP but not α-tocotrienol. The purpose of this study was to examine the modification of α-TTP together with other related vitamin E-binding genes (i.e., TTPA, SEC14L2, and PI-TPNA) in regulating vitamin E uptake in neuronal cells at rest and under oxidative stress. Oxidative stress was induced with H2O2 for an hour which was followed by supplementation with different ratios of α-TCP and tocotrienol-rich fraction (TRF) for four hours. The cellular levels of vitamin E were quantified to determine bioavailability at cellular levels. The expression levels of TTPA, SEC14L2, and PI-TPNA genes in 0% α-TCP were found to be positively correlated with the levels of vitamin E in resting neuronal cells. In addition, the regulation of all the above-mentioned genes affect the distribution of vitamin E in the neuronal cells. It was observed that, increased levels of α-TCP secretion occur under oxidative stress. Thus, our results showed that in conclusion vitamin E-binding proteins may be modified in the absence of α-TCP to produce tocotrienols (TCT), as a source of vitamin E. The current study suggests that the expression levels of vitamin E transport proteins may influence the cellular concentrations of vitamin E levels in the neuronal cells.

PMID: 33232330 [PubMed - as supplied by publisher]

The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?

J Pers Med. 2020 Nov 19;10(4):

Authors: Simões AR, Fernández-Rozadilla C, Maroñas O, Carracedo Á

Abstract
In recent decades, survival rates in colorectal cancer have improved greatly due to pharmacological treatment. However, many patients end up developing adverse drug reactions that can be severe or even life threatening, and that affect their quality of life. These remain a limitation, as they may force dose reduction or treatment discontinuation, diminishing treatment efficacy. From candidate gene approaches to genome-wide analysis, pharmacogenomic knowledge has advanced greatly, yet there is still huge and unexploited potential in the use of novel technologies such as next-generation sequencing strategies. This review summarises the road of colorectal cancer pharmacogenomics so far, presents considerations and directions to be taken for further works and discusses the path towards implementation into clinical practice.

PMID: 33228198 [PubMed]

Genetic basis of sleep bruxism and sleep apnea-response to a medical puzzle.

Sci Rep. 2020 05 04;10(1):7497

Authors: Wieckiewicz M, Bogunia-Kubik K, Mazur G, Danel D, Smardz J, Wojakowska A, Poreba R, Dratwa M, Chaszczewska-Markowska M, Winocur E, Emodi-Perlman A, Martynowicz H

Abstract
Sleep bruxism (SB) and obstructive sleep apnea (OSA) are co-occurring sleep conditions. The study aimed to evaluate the association of selected single-nucleotide polymorphisms (SNPs) occurring within the genes of the serotonin and dopamine pathways in SB and OSA and investigate the relationship between them. The study group included 100 Caucasian patients. SB and OSA were diagnosed in 74 and 28 patients, respectively. In addition, 125 unrelated Caucasian healthy blood donors served as randomly selected controls to enable comparison of polymorphisms. The following SNPs were analyzed: rs2770304 and rs6313 within the serotonin receptor encoding gene (HTR2A), rs4680 polymorphism of the catechol-O-methyltransferase (COMT) gene, and rs686 within the dopamine receptor (DRD1) encoding gene. The prevalence of the DRD1 rs686 G variant (GG homozygosity) was found to be high in the study group compared to the control group. Bruxism episode index (BEI) was found to be significantly increased in the HTR2A rs6313 TT homozygotes compared to the heterozygous patients. Moreover, within a group of the HTR2A rs2770304 TT homozygous cases, a statistically significant correlation was observed between BEI and apnea-hypopnea index. These results indicate that DRD1 rs686 may potentially affect predisposition to SB, that HTR2A rs6313 SNP may be involved in SB pathogenesis, and that HTR2A rs2770304 polymorphism might contribute to the association between SB and OSA. This suggests a possible genetic contribution to the etiology of primary SB.

PMID: 32367059 [PubMed - indexed for MEDLINE]

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