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

Pharmacogenomics. 2021 Sep 21. doi: 10.2217/pgs-2021-0088. Online ahead of print.

ABSTRACT

Tweetable abstract Sex-related pharmacogenetics is emerging area of research to better explain sex discrepancies in drug response. Sex pharmacogenetics should be considered an essential step for personalized medicine.

PMID:34545749 | DOI:10.2217/pgs-2021-0088

Pharmacogenet Genomics. 2021 Sep 20. doi: 10.1097/FPC.0000000000000457. Online ahead of print.

ABSTRACT

OBJECTIVE: To estimate prescribing rates of psychotropic drugs to individuals with autism and the proportion of these individuals who could benefit from pharmacogenetic testing.

METHODS: Prescribing data for 92 psychotropic drugs, including 31 antidepressants, 22 antipsychotics, 14 mood stabilizer/antiepileptics, 17 anxiolytic/hypnotics and eight antiadrenergic/psychostimulant were retrieved from medical records of 787 (613 males) autistic individuals who sought treatment from a primary care office enrolled in the Canadian Primary Care Sentinel Surveillance Network between 2012 and 2014. Each prescribed drug was cross-referenced with pharmacogenomic-based prescribing guidelines published by the Clinical Pharmacogenetics Implementation Consortium, the Dutch Pharmacogenetics Working Group, and the Canadian Pharmacogenomics Network for Drug Safety.

RESULTS: More than half (58%) of the participants were prescribed a psychotropic drug and 37% were prescribed two or more psychotropic drugs concurrently. Among the 83 psychotropic drugs examined, 54 (65%) were prescribed to one or more participants during the study's observation period. The ten most frequently prescribed psychotropics were methylphenidate (16.3%), risperidone (12.8%), lorazepam (12.1%), fluoxetine (7.9%), sertraline (7.1%), quetiapine (6.9%), aripiprazole (6.1%), lisdexamfetamine (5.8%), citalopram (5.6%) and clonazepam (4.8%). Seventeen (32%) of the 54 psychotropic drugs prescribed were linked to a pharmacogenomic-based prescribing guideline, including risperidone, sertraline, aripiprazole and citalopram.

CONCLUSIONS: Our findings suggest primary care providers in Canada prescribe a wide range of psychotropics to their patients with autism, some of which may benefit from the integration of pharmacogenomic information into their treatment planning.

PMID:34545026 | DOI:10.1097/FPC.0000000000000457

Cell Biosci. 2021 Sep 20;11(1):174. doi: 10.1186/s13578-021-00687-1.

ABSTRACT

BACKGROUND: Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the antitumor efficacy of T1012G virus in gastric cancer models.

METHODS: The proliferation of gastric cancer cells treated with monotherapy or combination treatment was detected by CCK8 cell proliferation assay. The effect of propranolol was further evaluated by in vitro viral replication assays. In vivo tumor xenograft experiments were used to observe the effect of combination therapy on gastric cancer growth in mice. The expression levels of viral proteins and interferon responsive genes were detected in the gastric cancer cell lines treated with combined treatment by western blot. The impact of propranolol on IFN-α/β-mediated inhibition of viral propagation and the expression of antiviral gene PKR was detected by viral replication assays and western blot.

RESULTS: Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a sevenfold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3 ± 36.92 mm3 vs. 1118 ± 210.0 mm3, P < 0.01) and enhanced the viral propagation (fourfold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P < 0.05) and suppressed p-PKR (65.94% ± 10.11%, P < 0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P < 0.001; IFNβ: 4.6-fold, P < 0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P < 0.001, IFNβ: 99.34% ± 0.13% decrease, P < 0.001).

CONCLUSIONS: In summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs. These data support new strategies of improving the efficacy of OVs in gastric cancer.

PMID:34544479 | DOI:10.1186/s13578-021-00687-1

Life Sci. 2021 Sep 17:119949. doi: 10.1016/j.lfs.2021.119949. Online ahead of print.

ABSTRACT

AIMS: Swietenia macrophylla have been considered for the treatment of various diseases, including anticancer activity. This study aimed to investigate the anticancer activity of S. macrophylla leaves extract and its isolated compound towards human colorectal cancer cell line.

MAIN METHODS: Hexanic extract of S. macrophylla leaves demonstrated relevant cytotoxicity only against colon cancer cell line HCT116.

KEY FINDINGS: Our results showed significant DNA damage and apoptosis after treatment with the hexanic extract of S. macrophylla. Moreover, no toxicity was noticed for the animal model. The isolated compound limonoid L1 showed potent cytotoxicity against cancer cell lines with IC50 at 55.87 μg mL-1. Limonoid L1 did not trigger any cell membrane rupture in the mice erythrocytes suggesting no toxicity. The antiproliferative effect of L1 was confirmed in colorectal cancer cells by clonogenic assay, inducing G2/M arrest, apoptosis, and DNA damage in cancer-type cells.

SIGNIFICANCE: L1 reduced BCL2 and increased ATM, CHK2, TP53, ARF, CDK1, CDKN1A, and CASP3 in the colorectal cancer cell line. These findings suggest that limonoid L1 isolated from S. macrophylla can be a promising anticancer agent in managing colorectal cancer.

PMID:34543640 | DOI:10.1016/j.lfs.2021.119949

Oxid Med Cell Longev. 2021 Sep 9;2021:6331630. doi: 10.1155/2021/6331630. eCollection 2021.

ABSTRACT

Daidzein is a phytoestrogen isoflavone found in soybeans and other legumes. The chemical composition of daidzein is analogous to mammalian estrogens, and it could be useful with a dual-directional purpose by substituting/hindering with estrogen and estrogen receptor (ER) complex. Hence, daidzein puts forth shielding effects against a great number of diseases, especially those associated with the control of estrogen, such as breast cancer, diabetes, osteoporosis, and cardiovascular disease. However, daidzein also has other ER-independent biological activities, such as oxidative damage reduction acting as an antioxidant, immune regulator as an anti-inflammatory agent, and apoptosis regulation, directly linked to its potential anticancer effects. In this sense, the present review is aimed at providing a deepen analysis of daidzein pharmacodynamics and its implications in human health, from its best-known effects alleviating postmenopausal symptoms to its potential anticancer and antiaging properties.

PMID:34539970 | PMC:PMC8448605 | DOI:10.1155/2021/6331630

Oxid Med Cell Longev. 2021 Sep 7;2021:4014867. doi: 10.1155/2021/4014867. eCollection 2021.

ABSTRACT

Cyperaceae are a plant family of grass-like monocots, comprising 5600 species with a cosmopolitan distribution in temperate and tropical regions. Phytochemically, Cyperus is one of the most promising health supplementing genera of the Cyperaceae family, housing ≈950 species, with Cyperus rotundus L. being the most reported species in pharmacological studies. The traditional uses of Cyperus spp. have been reported against various diseases, viz., gastrointestinal and respiratory affections, blood disorders, menstrual irregularities, and inflammatory diseases. Cyperus spp. are known to contain a plethora of bioactive compounds such as α-cyperone, α-corymbolol, α-pinene, caryophyllene oxide, cyperotundone, germacrene D, mustakone, and zierone, which impart pharmacological properties to its extract. Therefore, Cyperus sp. extracts were preclinically studied and reported to possess antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, antidepressive, antiarthritic, antiobesity, vasodilator, spasmolytic, bronchodilator, and estrogenic biofunctionalities. Nonetheless, conclusive evidence is still sparse regarding its clinical applications on human diseases. Further studies focused on toxicity data and risk assessment are needed to elucidate its safe and effective application. Moreover, detailed structure-activity studies also need time to explore the candidature of Cyperus-derived phytochemicals as upcoming drugs in pharmaceuticals.

PMID:34539969 | PMC:PMC8443348 | DOI:10.1155/2021/4014867

Front Genet. 2021 Sep 3;12:693952. doi: 10.3389/fgene.2021.693952. eCollection 2021.

ABSTRACT

The European Society of Human Genetics (ESHG) was founded in 1967 as a professional organisation for members working in genetics in clinical practice, research and education. The Society seeks the integration of scientific research and its implementation into clinical practice and the education of specialists and the public in all areas of medical and human genetics. The Society works to do this through many approaches, including educational sessions at the annual conference; training courses in general and specialist areas of genetics; an online resource of educational materials (EuroGEMS); and a mentorship scheme. The ESHG Education Committee is implementing new approaches to expand the reach of its educational activities and portfolio. With changes in technology, appreciation of the utility of genomics in healthcare and the public's and patients' increased awareness of the role of genomics, this review will summarise how the ESHG is adapting to deliver innovative educational activity.

PMID:34539735 | PMC:PMC8446627 | DOI:10.3389/fgene.2021.693952

Front Physiol. 2021 Sep 1;12:712787. doi: 10.3389/fphys.2021.712787. eCollection 2021.

ABSTRACT

Background: Polymorphisms in lipid metabolism-related genes have been associated with obesity and body composition, but these have been scarcely described concerning the magnitude of the response to exercise interventions in the overweight/obese population. Objective: To evaluate the association of perilipin 1 (PLIN1; rs1052700 and rs2304795), lipoprotein lipase (rs283), and adrenoceptor beta 3 (rs4994) polymorphisms with high and low responders (LoRes) to fat mass reduction after 12 weeks of high-intensity interval training (HIIT) and dietary energy restriction in overweight/obese adult women. In addition, we examined the effect of these genetic variants on body composition changes. Methods: Forty-three unrelated overweight/obese adult women were incorporated and genotyped, of which 30 women (age = 27.4 ± 7.9 years; BMI = 29.9 ± 3.3 kg/m2) successfully completed the 12-week supervised HIIT program plus an individually prescribed home hypocaloric diet. Results: An association was observed between the PLIN1 rs1052700 polymorphism with high and LoRes (χ 2 = 8.138; 2 df; p = 0.01). Moreover, after the intervention, the carriers of TT genotype of PLIN1 rs1052700 as compared to AA and AT showed a greater reduction in absolute fat mass (Δ: -5.1 ± 1.8 vs. - 1.8 ± 1.4 vs. - 2.1 ± 2.3 kg; p = 0.04). The effect size of this fat mass reduction between TT and AT genotypes was a mean difference of -3.01 kg [95%IC - 4.88- - 1.1], and between TT and AA genotypes was -3.29 kg [95%IC - 4.86- - 1.65]. No differences were observed for other polymorphisms investigated. Conclusion: These results suggest that the rs1052700 (14995A>T) polymorphism of the PLIN1 gene is associated with a differential response to fat mass reduction after a 12-week intervention in overweight/obese adult women. In addition, women with the TT genotype of this genetic variant showed greater changes in fat mass than AA and AT genotypes. However, further studies are needed to confirm these findings.

PMID:34539437 | PMC:PMC8440869 | DOI:10.3389/fphys.2021.712787

Nucleic Acids Res. 2021 Sep 17:gkab810. doi: 10.1093/nar/gkab810. Online ahead of print.

ABSTRACT

Altered A-to-I RNA editing has been widely observed in many human cancers and some editing sites are associated with drug sensitivity, implicating its therapeutic potential. Increasing evidence has demonstrated that a quantitative trait loci mapping approach is effective to understanding the genetic basis of RNA editing. We systematically performed RNA editing quantitative trait loci (edQTL) analysis in 33 human cancer types for >10 000 cancer samples and identified 320 029 edQTLs. We also identified 1688 ed-QTLs associated with patient overall survival and 4672 ed-QTLs associated with GWAS risk loci. Furthermore, we demonstrated the associations between RNA editing and >1000 anti-cancer drug response with ∼3.5 million significant associations. We developed GPEdit (https://hanlab.uth.edu/GPEdit/) to facilitate a global map of the genetic and pharmacogenomic landscape of RNA editing. GPEdit is a user-friendly and comprehensive database that provides an opportunity for a better understanding of the genetic impact and the effects on drug response of RNA editing in cancers.

PMID:34534336 | DOI:10.1093/nar/gkab810

Front Pharmacol. 2021 Aug 31;12:712084. doi: 10.3389/fphar.2021.712084. eCollection 2021.

ABSTRACT

Studies on pharmacogenetics of praziquantel (PZQ) and its relevance on plasma drug concentrations and schistosomiasis treatment outcomes are lacking. We investigated the effect of pharmacogenetics variations of PZQ on plasma drug levels and schistosomiasis treatment outcomes among infected Tanzanian school-aged children. A total of 340 Schistosoma mansoni infected children were enrolled and treated with single-dose PZQ. Stool samples analysis was done by thick smear Kato-Katz technique, and treatment efficacy was assessed at 3-weeks post-treatment. Safety was assessed within 4 h after PZQ intake. Plasma samples were collected at 4 h post-dose, and PZQ and trans-4-OH-PZQ concentrations were quantified using UPLCMS/MS. Genotyping for CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), and CYP2C9 (*2, *3) were done by Real-Time PCR. The median age (range) of the study participants was 12 years (7-17). There was a significant association of CYP2C19 genotypes with PZQ concentrations and its metabolic ratio (trans-4-OH-PZQ/PZQ). PZQ concentration was significantly higher among CYP2C19 (*2, *3) carriers than CYP2C19 *1/*1 and CYP2C19 *17 carriers (ultra-rapid metabolizers) (p = 0.04). The metabolic ratio was significantly higher among CYP2C19*17 carriers than CYP2C19 (*2, *3) carriers (p = 0.01). No significant effect of CYP3A4, CYP3A5, CYP2C19, and CYP2C9 genotypes on treatment efficacy or adverse events were observed. Baseline infection intensity and CYP3A5 genotype were significant predictors of treatment associated-adverse events. In conclusion, CYP2C19 genotype significantly affects plasma PZQ concentration and its metabolic ratio. For the first time, we report the importance of pharmacogenetic variation for the treatment of schistosomiasis, a neglected tropical disease.

PMID:34531744 | PMC:PMC8438567 | DOI:10.3389/fphar.2021.712084

Ann Gen Psychiatry. 2021 Sep 16;20(1):43. doi: 10.1186/s12991-021-00365-z.

ABSTRACT

BACKGROUND: Major depressive disorder (MDD) patients not responding to two or more different antidepressant treatments are currently considered to suffer from treatment resistant depression (TRD). Recently, intranasal esketamine has been approved by both the American Food and Drug Administration and European Medicines Agency for TRD and, more recently, in moderate to severe episode of MDD, as acute short-term treatment for the rapid reduction of depressive symptoms, which, according to clinical judgement, constitute a psychiatric emergency. There is currently no indication for obsessive-compulsive disorder (OCD) although recently published studies have already shown a rapid and significant reduction of OCD-like symptoms following ketamine administration. The etiology of OCD has not yet been fully elucidated but there is a growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical circuitry plays an essential role. This case report exemplifies possible clinical effects of esketamine on both depressive and OCD symptoms.

CASE PRESENTATION: We present the case of a 39-year-old man suffering from TRD. During the first evaluation at our clinic, he also reported the presence of OCD spectrum symptoms, causing him to perform time-consuming mental rituals due to pathological doubts regarding the relationship with his wife as well as intrusive thoughts regarding his mental conditions. He underwent psychometric evaluations, therapeutic drug monitoring analysis, and pharmacogenomic tests. The overall results helped to explain patient's treatment-resistance. Moreover, we observed a significant reduction in both depressive and OCD symptoms after administration of esketamine.

CONCLUSION: This case underlines the importance of pharmacogenomic tests in profiling TRD patients and confirms the possible use of esketamine in the treatment of comorbid OCD.

PMID:34530843 | PMC:PMC8444432 | DOI:10.1186/s12991-021-00365-z

Clin Chim Acta. 2021 Sep 13:S0009-8981(21)00314-4. doi: 10.1016/j.cca.2021.09.003. Online ahead of print.

ABSTRACT

Diabetic nephropathy (DN), a sterile inflammatory disease, is a serious complication common to diabetes mellitus. Recent evidence indicates that pyroptosis, a new term for pro-inflammatory cell death featured by gasdermin D (GSDMD)-stimulated plasma membrane pore generation, cell expansion and rapid lysis with the extensive secretion of pro-inflammatory factors, including interleukin-1β (IL-1β) and -18 (IL-18) may be involved in DN. Caspase-1-induced canonical and caspase-4/5/11-induced non-canonical inflammasome-signaling pathways are mainly believed to participate in pyroptosis-mediated cell death. Further research has uncovered that activation of the caspase-3/8 signaling pathway may also activate pyroptosis. Accumulating evidence has shown that NLRP3 inflammasome activation plays a critical role in promoting DN pathogenesis. In addition, current studies have suggested that pyroptosis-induced cell death promoted several diabetic complications that include DN. Our present study briefs the cellular mechanisms of pyroptosis-related signaling pathways and their impact on the promotion of DN. In this review, several investigational compounds suppressing pyroptosis-mediated cell death are explored as promising therapeutics in DN.

PMID:34529985 | DOI:10.1016/j.cca.2021.09.003