Pharmacogenomics. 2021 Sep 27. doi: 10.2217/pgs-2021-0093. Online ahead of print.

ABSTRACT

Genetic variation in the gene encoding CYP2D6 is used to guide drug prescribing in clinical practice. However, genetic variants in CYP2D6 show substrate-specific effects that are currently not accounted for. With a systematic literature, we retrieved 22 original studies describing in vitro experiments focusing on CYP2D6 alleles (CYP2D6*1, *2, *10 and *17) and substrates. Allele activity (clearance of the allele of interest divided by the clearance of the wildtype) was extracted. The results support the hypothesis of the existence of substrate specificity of the CYP2D6*17-allele (higher debrisoquine clearance), a subtle effect of the CYP2D6*10-allele (lower dextromethorphan clearance) but no substrate-specific effect of the CYP2D6*2-allele. Although our results support substrate specificity, for most substrates data are too sparse and require further studies.

PMID:34569808 | DOI:10.2217/pgs-2021-0093

Pharmacotherapy. 2021 Sep 27. doi: 10.1002/phar.2626. Online ahead of print.

ABSTRACT

BACKGROUND: Spironolactone improved diastolic function (decreased E/e') compared to placebo in the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial. However, there was significant interpatient variability in spironolactone response.

OBJECTIVES: This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldo-DHF participants.

METHODS: Aldo-DHF participants treated with spironolactone (n=184) or placebo (n=178) were genotyped for NR3C2 rs5522, NR3C2 rs2070951, and CYP11B2 rs1799998 via pyrosequencing. In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area.

RESULTS: Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to non-carriers (β=1.10; 95% confidence interval [CI]: 0.05-2.16; p = 0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to non-carriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17-1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = -3.56; 95% CI: -6.73 to -0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes.

CONCLUSION: Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

PMID:34569641 | DOI:10.1002/phar.2626

Pan Afr Med J. 2021 Jan 7;38:17. doi: 10.11604/pamj.2021.38.17.27507. eCollection 2021.

ABSTRACT

Methotrexate (MTX) is an effective, economical and safe drug used in the treatment of ectopic pregnancy. Complications are very rare. Herein, we reported a case of febrile neutropenia following single low-dose methotrexate for the treatment of ectopic pregnancy. Febrile neutropenia developed on day 4 of single-dose methotrexate administered intramuscularly. Although methotrexate single-dose regimen is quite effective and safe in ectopic pregnancy, febrile neutropenia can occur very rarely.

PMID:34567344 | PMC:PMC8444121 | DOI:10.11604/pamj.2021.38.17.27507

Front Neurol. 2021 Sep 10;12:700616. doi: 10.3389/fneur.2021.700616. eCollection 2021.

ABSTRACT

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.

PMID:34566844 | PMC:PMC8461233 | DOI:10.3389/fneur.2021.700616

Eur J Hum Genet. 2021 Sep 27. doi: 10.1038/s41431-021-00969-9. Online ahead of print.

NO ABSTRACT

PMID:34565798 | DOI:10.1038/s41431-021-00969-9

Int J Obes (Lond). 2021 Sep 25. doi: 10.1038/s41366-021-00972-6. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVES: Evidence regarding the influence of coffee on appetite and weight control is equivocal and the influence of covariates, such as genetic variation in caffeine metabolism, remains unknown. Herein, we addressed the novel hypothesis that genetic variation in CYP1A2, a gene responsible for more than 95% of caffeine metabolism, differentially impacts the association of coffee consumption with appetite and BMI among individuals with different genetic predispositions to obesity.

SUBJECTS/METHODS: A cross-over randomized intervention study involving 18 volunteers assessed the effects of coffee consumption on dietary intake, appetite, and levels of the appetite-controlling hormones asprosin and leptin. Data on habitual coffee intake, BMI, and perceived appetite were obtained from an observational cohort of 284 volunteers using validated questionnaires. Participants were stratified according to a validated genetic risk score (GRS) for obesity and to the -163C > A (rs762551) polymorphism of CYP1A2 as rapid (AA), intermediate (AC), or slow (CC) caffeine metabolizers.

RESULTS: Coffee consumption led to lower energy and dietary fat intake and circulating asprosin levels (P for interaction of rs762551 genotype*coffee consumption=0.056, 0.039, and 0.043, respectively) as compared to slow/intermediate metabolizers. High coffee consumption was more prevalent in rapid compared to slow metabolizers (P = 0.008 after adjustment for age, sex, and BMI) and was associated with lower appetite perception and lower BMI only in rapid metabolizers (P for interaction of rs762551 genotype*coffee consumption = 0.002 and 0.048, respectively). This differential association of rs762551 genotype and coffee consumption with BMI was more evident in individuals at higher genetic risk of obesity (mean adjusted difference in BMI = -5.82 kg/m2 for rapid versus slow/intermediate metabolizers who consumed more than 14 cups of coffee per week).

CONCLUSIONS: CYP1A2 rs762551 polymorphism modifies the association of habitual coffee consumption with BMI, in part by influencing appetite, energy intake and circulating levels of the orexigenic hormone asprosin. This association is more evident in subjects with high genetic predisposition to obesity. ClinicalTrials.gov: registered Clinical Trial NCT04514588.

PMID:34564706 | DOI:10.1038/s41366-021-00972-6

Pharmacy (Basel). 2021 Sep 6;9(3):152. doi: 10.3390/pharmacy9030152.

ABSTRACT

To enable application-oriented training of Swiss pharmacists on pharmacogenetic (PGx) testing, an advanced, digital training program was conceptualized based on the Miller's Pyramid framework, using a blended learning approach. The PGx advanced training program included an asynchronous self-study online module, synchronous virtual classroom sessions with lectures and workshops, and a follow-up case study for in-depth applied learning including the analysis of the participants' PGx profile. The evaluation of the training program consisted of (a) an assessment of the participants' development of knowledge, competencies and attitudes towards PGx testing in the pharmacy setting; (b) a satisfaction survey including; (c) questions about their future plans for implementing a PGx service. Twenty-one pharmacists participated in this pilot program. The evaluation showed: (a) a significant improvement of their PGx knowledge (mean score in the knowledge test 75.3% before to 90.3% after training completion) and a significant increase of their self-perceived competencies in applying PGx counselling; (b) a high level of satisfaction with the training program content and the format (at least 79% expressed high/very high agreement with the statements in the questionnaire); (c) a mixed view on whether participants will implement PGx testing as a pharmacy service (indecisive 8; agreed/completely agreed to implement 7/1; disagreed 3 (n = 19)). We consider ongoing education as an important driver for the implementation of PGx in pharmacy practice.

PMID:34564559 | DOI:10.3390/pharmacy9030152

Metabolites. 2021 Sep 21;11(9):645. doi: 10.3390/metabo11090645.

ABSTRACT

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European-American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European-American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European-American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = -1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.

PMID:34564461 | DOI:10.3390/metabo11090645

Biomed Pharmacother. 2021 Sep 22;143:112195. doi: 10.1016/j.biopha.2021.112195. Online ahead of print.

ABSTRACT

BACKGROUND: The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia.

METHODS: We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants.

RESULTS: We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04-0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P = 0.0437).

CONCLUSIONS: GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.

PMID:34562771 | DOI:10.1016/j.biopha.2021.112195

Clin Transl Sci. 2021 Sep 25. doi: 10.1111/cts.13154. Online ahead of print.

ABSTRACT

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.

PMID:34562070 | DOI:10.1111/cts.13154

Curr Opin Pediatr. 2021 Sep 24. doi: 10.1097/MOP.0000000000001065. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future.

RECENT FINDINGS: The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while 'poor metabolizer' haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform.

SUMMARY: The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.

PMID:34561358 | DOI:10.1097/MOP.0000000000001065

Mol Pharmacol. 2021 Sep 24:MOLPHARM-AR-2021-000348. doi: 10.1124/molpharm.121.000348. Online ahead of print.

ABSTRACT

Tenofovir (TFV) is a key component of HIV pre-exposure prophylaxis (PrEP). TFV is a nucleotide analog reverse transcriptase inhibitor prodrug that requires two separate phosphorylation reactions by intracellular kinases in order to form the active metabolite, tenofovir-diphosphate (TFV-DP). Muscle-type creatine kinase (CKM) has previously been demonstrated to be the kinase most responsible for the phosphorylation of tenofovir-monophosphate (TFV-MP) to the active metabolite in colon tissue. Due to the importance of CKM in TFV activation, genetic variation in CKM may contribute to inter-individual variability in TFV-DP levels. In the present study, we report ten naturally-occurring CKM mutations that reduced TFV-MP phosphorylation in vitro: T35I, R43Q, I92M, H97Y, R130H, R132C, F169L, Y173C, W211R, and N286I. Interestingly, of these ten, only four - R130H, R132C, W211R, and N286I - reduced both canonical CKM activities: ADP phosphorylation and ATP dephosphorylation. While positions 130, 132, and 286 are located in the active site, the other mutations that resulted in decreased TFV-MP phosphorylation occur elsewhere in the protein structure. Four of these eight mutations - T35I, R43Q, I92M, and W211R - were found to decrease the thermal stability of the protein. Additionally, the W211R mutation was found to impact protein structure both locally and at a distance. These data suggest a substrate-specific effect such that certain mutations are tolerated for canonical activities while being deleterious toward the pharmacological activity of TFV activation, which could influence PrEP outcomes. Significance Statement Muscle-type creatine kinase (CKM) is important to the activation of tenofovir, a key component of HIV prophylaxis. This study demonstrates that naturally-occurring CKM mutations impact enzyme function in a substrate-dependent manner such that some mutations that do not reduce canonical activities lead to reductions in the pharmacologically-relevant activity. This finding at the intersection of drug metabolism and energy metabolism is important to the perspective on pharmacology of other drugs acted on by atypical drug metabolizing enzymes.

PMID:34561299 | DOI:10.1124/molpharm.121.000348

Rev Esp Cardiol (Engl Ed). 2021 Sep 21:S1885-5857(21)00248-6. doi: 10.1016/j.rec.2021.08.003. Online ahead of print.

ABSTRACT

INTRODUCTION Y OBJECTIVES: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Most patients are empirically treated with beta-blockers and antiplatelet drugs. The Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection (BA-SCAD) is an academic, pragmatic, prospective, randomized, open-label, blinded-endpoint clinical trial, performed under the auspices of the Spanish Society of Cardiology, to assess the efficacy of pharmacological therapy in patients with SCAD.

METHODS: Using a 2 x 2 factorial design, 600 patients will be randomized (1:1/1:1) to: a) beta-blockers (yes/no) and b) "short" (1 month) vs "prolonged" (12 months) antiplatelet therapy. Only patients with preserved left ventricular ejection fraction will be randomized to beta-blockers (yes/no) because patients with reduced left ventricular ejection fraction will receive beta-blockers according to current guidelines. Similarly, only conservatively managed patients (ie, no coronary intervention) will be randomized to the antiplatelet stratum, as patients requiring coronary interventions will receive 1-year dual antiplatelet therapy. The primary efficacy endpoint includes a composite of death, myocardial infarction, stroke, coronary revascularization, recurrent SCAD, and unplanned hospitalization for acute coronary syndrome or heart failure at 1 year. The primary safety endpoint will be bleeding. All patients will be clinically followed up yearly. A comprehensive set of additional substudies (clinical, imaging, revascularization, biomarkers, inflammatory, immunologic, pharmacogenetics, and genetic) will be conducted to ensure a holistic view of this unique and challenging clinical entity.

CONCLUSIONS: The results of the BA-SCAD randomized clinical trial will advance our knowledge in the treatment of patients with SCAD. The study was registered at ClinicalTrials.gov (Identifier: NCT04850417).

PMID:34561195 | DOI:10.1016/j.rec.2021.08.003

Biomedica. 2021 Sep 22;41(3):403-408. doi: 10.7705/biomedica.5840.

ABSTRACT

We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2),a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient’s genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

PMID:34559488 | DOI:10.7705/biomedica.5840

Front Pharmacol. 2021 Sep 6;12:735260. doi: 10.3389/fphar.2021.735260. eCollection 2021.

ABSTRACT

Background: Drug-induced liver injury (DILI) is a common and serious adverse drug reaction with insufficient clinical diagnostic strategies and treatment methods. The only clinically well-received method is the Roussel UCLAF Causality Assessment Method scale, which can be applied to both individuals and prospective or retrospective studies. However, in severe cases, patients with DILI still would develop acute liver failure or even death. Pharmacogenomics, a powerful tool to achieve precision medicine, has been used to study the polymorphism of DILI related genes. Summary: We summarized the pathogenesis of DILI and findings on associated genes and variations with DILI, including but not limited to HLA genes, drug metabolizing enzymes, and transporters genes, and pointed out further fields for DILI related pharmacogenomics study to provide references for DILI clinical diagnosis and treatment. Key Messages: At present, most of the studies are mainly limited to CGS and GWAS, and there is still a long way to achieve clinical transformation. DNA methylation could be a new consideration, and ethnic differences and special populations also deserve attention.

PMID:34552491 | PMC:PMC8450320 | DOI:10.3389/fphar.2021.735260

Nature. 2021 Sep;597(7877):522-526. doi: 10.1038/s41586-021-03902-8. Epub 2021 Sep 22.

ABSTRACT

Polynesia was settled in a series of extraordinary voyages across an ocean spanning one third of the Earth1, but the sequences of islands settled remain unknown and their timings disputed. Currently, several centuries separate the dates suggested by different archaeological surveys2-4. Here, using genome-wide data from merely 430 modern individuals from 21 key Pacific island populations and novel ancestry-specific computational analyses, we unravel the detailed genetic history of this vast, dispersed island network. Our reconstruction of the branching Polynesian migration sequence reveals a serial founder expansion, characterized by directional loss of variants, that originated in Samoa and spread first through the Cook Islands (Rarotonga), then to the Society (Tōtaiete mā) Islands (11th century), the western Austral (Tuha'a Pae) Islands and Tuāmotu Archipelago (12th century), and finally to the widely separated, but genetically connected, megalithic statue-building cultures of the Marquesas (Te Henua 'Enana) Islands in the north, Raivavae in the south, and Easter Island (Rapa Nui), the easternmost of the Polynesian islands, settled in approximately AD 1200 via Mangareva.

PMID:34552258 | DOI:10.1038/s41586-021-03902-8

Korean J Anesthesiol. 2021 Sep 17. doi: 10.4097/kja.21327. Online ahead of print.

ABSTRACT

BACKGROUND: The depth of anesthesia is an important factor in surgical prognosis. The neurotoxic effect of chemotherapeutic drugs affects the sensitivity to anesthetics. The purpose of this study is to find out whether the effect-site concentration (Ce) of propofol for loss of consciousness (LOC) differs in patients with preoperative chemotherapy treatment.

METHODS: 60 patients scheduled for surgery for colorectal cancer under general anesthesia were included in this study. Those who had chemotherapy were the experimental (C) group, and those without prior history of chemotherapy were the control (N) group. Propofol was administered as an effect-site target-controlled infusion and the Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S) was evaluated. When the plasma concentration and the Ce became the same, if the MOAA/S score did not change, the target Ce was increased by 0.2 μg∙ml-1, otherwise Ce was maintained for 2 min and then increased.

RESULTS: The values of Ce of propofol for LVC in group C and N were 2.40 ± 0.39 and 2.29 ± 0.39 μg∙ml-1 (P = 0.286), and for LOC in group C and N were 2.69 ± 0.43 and 2.50 ± 0.36 μg∙ml-1 (P = 0.069), respectively. There was no significant difference in Ce values between the two groups.

CONCLUSIONS: Chemotherapy did not affect the Ce of propofol for LVC and LOC in colorectal cancer patients.

PMID:34551470 | DOI:10.4097/kja.21327

Pharmacol Res. 2021 Sep 19:105904. doi: 10.1016/j.phrs.2021.105904. Online ahead of print.

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency caused by genetic variants in the G6PD gene, constitutes the most common enzymopathy worldwide affecting approximately 5% of the global population. While carriers are mostly asymptomatic, they are at substantial risk of acute hemolytic anemia upon certain infections or exposure to various medications. As such, information about G6PD activity status in a given patient can constitute an important parameter to guide clinical decision-making. Here, we leveraged whole genome sequencing data from 142,069 unrelated individuals across seven human populations to provide a global comprehensive map of G6PD variability. By integrating established functional classifications with stringent computational predictions using 13 partly orthogonal algorithms for uncharacterized and novel variants, we reveal the large extent of ethnogeographic variability in G6PD deficiency and highlight its population-specific genetic composition. Overall, estimated disease prevalence in males ranged between 12.2% in Africans, 2.7-3.5% across Asia and 2.1% in Middle Easterners to <0.3% in Europeans, Finnish and Amish. In Africans, the major deficient alleles were A-202A/376G (minor allele frequency 11.6%) and A-968C/376G (0.5%). In contrast, G6PD deficiency in Middle Easterners was primarily due to the Mediterranean allele (1.3%) and the population-specific Cairo variant (0.4%). In South Asia, the most prevalent deficient alleles were Mediterranean (1.7%), Kerala (1.1%), Gond (0.9%) and Orissa (0.2%), whereas in East Asian populations the Canton (1.1%), Kaiping (0.7%) and Viangchan (0.3%) variants were predominant. Combined, our analyses provide a large dataset of G6PD variability across major ethnogeographic groups and can guide population-specific genotyping strategies to optimize genetically guided therapeutic interventions.

PMID:34551338 | DOI:10.1016/j.phrs.2021.105904

Elife. 2021 Sep 22;10:e69795. doi: 10.7554/eLife.69795.

ABSTRACT

Parkinson's disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.

PMID:34550070 | DOI:10.7554/eLife.69795

Support Care Cancer. 2021 Sep 21. doi: 10.1007/s00520-021-06519-9. Online ahead of print.

NO ABSTRACT

PMID:34546453 | DOI:10.1007/s00520-021-06519-9