Curr Cardiol Rep. 2021 May 7;23(6):62. doi: 10.1007/s11886-021-01484-5.

ABSTRACT

PURPOSE OF REVIEW: Drug development has evolved over the years from being one-at-a-time to be massive screens in an industrial manner. Bringing a new therapeutic agent from concept to bedside can take a decade and cost billions of dollars-with most concepts failing along the way. Of the few compounds that make it to clinical testing, less than one out of eight make it to approval. This traditional drug development pipeline is challenging for prevalent diseases and makes the development of new therapeutics for rare diseases financially intractable.

RECENT FINDINGS: Repurposing of drugs is an alternative to identify new applications for the thousands of compounds that have already been approved for clinical use. There is now a range of strategies for such efforts that leverage clinical data, pharmacologic data, and/or genomic or transcriptomic data. These strategies, together with examples, are detailed in this review. Drug repurposing bypasses the pre-clinical work and thereby opens up the opportunity to provide targeted treatment at a fraction of the cost that is accompanied with the development from ideation to full approval. Such an approach makes drug discovery for any disease process more efficient but holds particular promise for rare diseases for which there is little to no other viable drug development channel.

PMID:33961142 | DOI:10.1007/s11886-021-01484-5

Front Pharmacol. 2021 Apr 16;12:658734. doi: 10.3389/fphar.2021.658734. eCollection 2021.

ABSTRACT

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

PMID:33959025 | PMC:PMC8094024 | DOI:10.3389/fphar.2021.658734

Br J Dermatol. 2021 May 6. doi: 10.1111/bjd.20440. Online ahead of print.

ABSTRACT

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs), probably the most consumed medicines, are the main triggers of drug hypersensitivity, being NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID-hypersensitivity is bred by cyclooxygenase (COX)-1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl-leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID-hypersensitivity, genetic factors are believed to participate; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID-hypersensitivity.

OBJECTIVES: We aimed to simultaneously evaluate genetic variants in main genes involved in PG and CysLT biosynthesis in NIUA.

METHODS: Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort only included NIUA patients; the replication one also included NSAID-exacerbated respiratory disease (NERD) patients. A set of tagging single nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX-5 and LTC4S was genotyped using mass spectrometry coupled with end point PCR.

RESULTS: The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, being three significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1, and rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 marginally with NERD. Effect sizes in the combined analysis (discovery and replication NIUA populations) were: rs10306194 (OR=1.7, 95%CI=1.34-2.14; corrected p-value=2.44E-5) and rs28395868 (OR=2.19, 95%CI=1.43-3.36, corrected p-value=2.17E-4).

CONCLUSIONS: PTGS1 and ALOX5 gene variants may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light into their genetic basis.

PMID:33955560 | DOI:10.1111/bjd.20440

Oncologist. 2021 May 5. doi: 10.1002/onco.13811. Online ahead of print.

ABSTRACT

BACKGROUND: The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (ie, end of Week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.

MATERIALS AND METHODS: ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n=584) and PALOMA-3 (n=442). SNP, race, and Cycle 1 Day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n=122) and non-Asian (n=530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed.

RESULTS: ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR]=6.033, 95% CI=2.615-13.922, P<0.0001; Non-Asians: OR=6.884, 95% CI=4.138-11.451, P<0.0001). ABCB1_rs1128503 (C/C vs T/T: OR=0.57, 95% CI=0.311-1.047, P=0.070) and ERCC1_rs11615 (A/A vs G/G: OR=1.75, 95% CI=0.901-3.397, P=0.098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype.

CONCLUSION: This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135).

IMPLICATIONS FOR PRACTICE: Palbociclib plus endocrine therapy improves HR+/HER2- advanced breast cancer (ABC) outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (P<0.0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (P<0.10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.

PMID:33955129 | DOI:10.1002/onco.13811

Front Pharmacol. 2021 Apr 19;12:650039. doi: 10.3389/fphar.2021.650039. eCollection 2021.

ABSTRACT

Anticancer chemotherapies have been shown to produce severe side effects, with cardiotoxicity from anthracycline being the most notable. Identifying risk factors for anticancer therapy-induced cardiotoxicity in cancer patients as well as understanding its underlying mechanism is essential to improving clinical outcomes of chemotherapy treatment regimens. Moreover, cardioprotective agents against anticancer therapy-induced cardiotoxicity are scarce. Human induced pluripotent stem cell technology offers an attractive platform for validation of potential single nucleotide polymorphism with increased risk for cardiotoxicity. Successful validation of risk factors and mechanism of cardiotoxicity would aid the development of such platform for novel drug discovery and facilitate the practice of personalized medicine.

PMID:33953683 | PMC:PMC8090862 | DOI:10.3389/fphar.2021.650039

Pharmgenomics Pers Med. 2021 Apr 29;14:509-520. doi: 10.2147/PGPM.S285144. eCollection 2021.

ABSTRACT

BACKGROUND: CYP2C19 is a highly polymorphic gene that encodes an enzyme with the same name and whose function is associated with the metabolism of many important drugs, such as proton pump inhibitors (such as esomeprazole, which is used for the treatment of acid peptic disease). Genetic variants in CYP2C19 alter protein function and affect drug metabolism. This study aims to genotypically and phenotypically characterize the genetic variants in the CYP2C19 gene in 12 patients with acid peptic disorders and different therapeutic profiles to proton pump inhibitor (PPI) drugs. The patients were randomly selected from a controlled, randomized and blinded clinical pilot trial of 33 patients. We determined the presence and frequency of single nucleotide polymorphisms (SNPs) within exons 1-5 and 9, the intron-exon junctions, and a fragment in the 3' UTR region of the CYP2C19 gene using Sanger sequencing. Undescribed polymorphisms were analyzed by free online bioinformatics tools to evaluate the potential molecular effects of these genetic variants.

RESULTS: We identified nine polymorphisms, six of which had no reported functions. One of these genetic variants, with a functional impact, not yet reported (p.Arg132Trp) was predicted by bioinformatic tools as potentially pathogenic. This finding suggests that p.Arg132Trp could be related to poor metabolizers of drugs metabolized by CYP2C19.

CONCLUSION: We identified the genotype spectrum of variants in CYP2C19. The genotype spectrum of variants in CYP2C19 could predict the treatment response and could support to evaluate clinical efficacy in patients treated with esomeprazole.

PMID:33953602 | PMC:PMC8092628 | DOI:10.2147/PGPM.S285144

Nat Rev Cardiol. 2021 May 5. doi: 10.1038/s41569-021-00549-w. Online ahead of print.

ABSTRACT

Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.

PMID:33953382 | DOI:10.1038/s41569-021-00549-w

BMJ Open. 2021 May 5;11(5):e042887. doi: 10.1136/bmjopen-2020-042887.

ABSTRACT

PURPOSE: Neuropathic pain is a common disorder of the somatosensory system that affects 7%-10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.

PARTICIPANTS: DOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised 'core' study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later).

FINDINGS TO DATE: At baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain.

FUTURE PLANS: The cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank.

PMID:33952538 | DOI:10.1136/bmjopen-2020-042887

Anticancer Res. 2021 May;41(5):2397-2402. doi: 10.21873/anticanres.15014.

ABSTRACT

BACKGROUND/AIM: Experimental oncology commonly uses cells as oncological models, providing a framework for the testing of drugs, and investigation of cytotoxicity, mutagenesis and carcinogenesis. Investigations into poly-ADP-ribose polymerase 1 (PARP1) inhibition have become ever more relevant due to its approval as a therapeutic option for tumors with BRCA1/2 DNA repair-associated mutation and the seemingly high PARP expression levels in some tumor subtypes. In this study, we aimed to determine PARP1 gene expression of different hematological cancer-derived cell lineages and compare them to that of normal cell lines.

MATERIALS AND METHODS: PARP1 gene expression in seven different neoplastic lineages, representing three different hematological disorders (chronic myeloid leukemia, Burkitt lymphoma and acute lymphoblastic leukemia), was quantified by quantitative real-time polymerase chain reaction.

RESULTS: All hematological malignant lineages in this study overexpressed PARP1 when compared to the normal cell line MRC-5, with Burkitt's lymphoma cells having the highest expression values (fold change: 93).

CONCLUSION: Overexpression of PARP1 in hematological malignant lineages is a finding of crucial importance to future studies exploring possible cellular oncogenic pathways and supports investigations into the effectiveness of PARP1 inhibitors against hematological disorders.

PMID:33952464 | DOI:10.21873/anticanres.15014

Medicine (Baltimore). 2021 May 7;100(18):e25781. doi: 10.1097/MD.0000000000025781.

ABSTRACT

INTRODUCTION: Azathioprine (AZA) has been widely used for the treatment of various immune-related diseases and has become a mainstay in the treatment of inflammatory bowel disease. However, patients with genetic mutations may experience severe adverse events when treated with azathioprine. Most of the previous literature focused on the TPMP gene-related adverse reactions, herein, we report a case of Crohn's disease patient with nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) variation and wild-type TPMP gene who developed toxoplasma gondii infection after azathioprine treatment.

PATIENT CONCERNS: A 56-year-old Crohn's disease patient developed toxoplasma gondii infection within 2 months after the administration of azathioprine; however, he had no relevant high-risk factors.

DIAGNOSIS: Subsequent genetic testing revealed that the patient was heterozygous for NUDT15. Therefore, it was reasonable to consider that the patient's genetic mutation resulted in reduced tolerance to azathioprine, leading to low immunity and eventually toxoplasma infection.

INTERVENTIONS: AZA was then discontinued; after anti-infection, antipyretic and other supportive treatments were administered, the patient's condition gradually improved.

OUTCOMES: The patient was followed up at 1, 3, and 6 months after discharge; fortunately, he was in good health.

CONCLUSION: We report a case of Crohn's disease in a patient who developed severe pneumonia caused by toxoplasma gondii infection due to the administration of AZA, with normal TPMP gene but NUDT15 gene mutation. This indicates that NUDT15 variation may contribute to severe adverse events in patients treated with azathioprine, and we suggest that NUDT15 genotype be detected before the use of azathioprine in order to provide personalized therapy and reduce side effects.

PMID:33950972 | PMC:PMC8104275 | DOI:10.1097/MD.0000000000025781

J Clin Immunol. 2021 May 5. doi: 10.1007/s10875-021-01045-z. Online ahead of print.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.

PMID:33950324 | DOI:10.1007/s10875-021-01045-z

Cell Death Dis. 2021 May 4;12(5):441. doi: 10.1038/s41419-021-03727-3.

ABSTRACT

There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

PMID:33947843 | DOI:10.1038/s41419-021-03727-3

Clin Cancer Res. 2021 May 4:clincanres.4050.2020. doi: 10.1158/1078-0432.CCR-20-4050. Online ahead of print.

ABSTRACT

PURPOSE: In BRAFV600MUT metastatic melanoma, cyclin-D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of CDK4 inhibitors. In this phase I-II study, we aimed to establish the maximum tolerated dose (MTD) of palbociclib when added to vemurafenib.

PATIENTS AND METHODS: BRAFV600E/KMUT metastatic melanoma patients harboring CDKN2A loss and RB1 expression were included and stratified into 2 groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics and tumor molecular profiling.

RESULTS: Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were AJCC stage IVM1c (N=16; 88.9%), high LDH (N=9; 50.0%), and median number of previous treatments of 2. One and five patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25mg and vemurafenib 960mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median PFS was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib.

CONCLUSIONS: Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25mg, a significant clinical benefit was achieved in pretreated melanoma patients. An association between the transcriptomic data and clinical response was highlighted.

PMID:33947696 | DOI:10.1158/1078-0432.CCR-20-4050

Cells. 2021 Apr 29;10(5):1051. doi: 10.3390/cells10051051.

ABSTRACT

The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific.

PMID:33946771 | DOI:10.3390/cells10051051

Pharmacogenomics. 2021 May 4. doi: 10.2217/pgs-2021-0006. Online ahead of print.

ABSTRACT

Aim: We examined the relationships between visfatin/NAMPT and nitrite concentrations (a marker of nitric oxide [NO] formation) or sFlt-1 levels in 205 patients with preeclampsia (PE) responsive or nonresponsive to antihypertensive therapy, and whether NAMPT SNPs rs1319501 and rs3801266 affect nitrite concentrations in PE and 206 healthy pregnant women. Patients & methods: Circulating visfatin/NAMPT and sFlt-1 levels were measured by ELISA, and nitrite concentrations by using an ozone-based chemiluminescence assay. Results: In nonresponsive PE patients, visfatin/NAMPT levels were inversely related to nitrite concentrations and positively related to sFlt-1 levels. NAMPT SNP rs1319501 affected nitrite concentrations in nonresponsive PE patients and was tightly linked with NAMPT functional SNPs in Europeans. Conclusion: NAMPT SNP rs1319501 and visfatin/NAMPT affect NO formation, sFlt-1 levels and antihypertensive therapy response in PE.

PMID:33944612 | DOI:10.2217/pgs-2021-0006

Pharmacotherapy. 2021 May 4. doi: 10.1002/phar.2532. Online ahead of print.

ABSTRACT

INTRODUCTION: Levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) influence recombinant tissue plasminogen activator (rtPA) therapy response in patients with acute ischemic stroke (AIS). Serum levels of MMPs and TIMPs along with the expression of genes coding these proteins are related to the recovery and appearance of adverse effects (AE) after AIS. Consequently, it is important to explore whether polymorphisms in regulatory sequences of MMPs and TIMPs are associated with rtPA response in AIS patients.

OBJECTIVES: To determine whether selected polymorphic variants within MMP-2, MMP-9, and TIMP-2 genes may influence rtPA therapy response with regards to outcomes in patients with AIS and the occurrence of AE.

METHODS: Our study included 166 patients suffering AIS, treated with rtPA. Patients' recovery was estimated using the Modified Rankin Scale (mRS) 3 months after the AIS occurred. Favorable outcome was defined with scores 0-1, and poor outcome with scores 2-6. Genotyping was performed using Real-Time PCR (rs243866, rs243865, rs243864, rs2277698, and rs8179090) and PCR-RFLP (rs2285053, rs3918242) methods. Additionally, rtPA AE were followed during the hospitalization.

RESULTS: There was no significant association between genotypes and alleles of selected polymorphisms and rtPA therapy response measured through the decrease of the mRS score in patients with AIS. Intracranial hemorrhage, as well as parenchymal hematoma type 2, were significantly more frequent in patients with TT genotype of the MMP-9-1562C/T polymorphism (p=0.047, p=0.011, respectively). Patients with intracranial hemorrhages after rtPA were significantly more likely to have the TT genotype of TIMP-2-303C/T polymorphism and the TT genotype of MMP-9-1562C/T polymorphism (p<0.001).

CONCLUSION: TT genotype of the MMP-9-1562C/T polymorphism may be a risk factor for rtPA-induced hemorrhagic complications after AIS.

PMID:33942334 | DOI:10.1002/phar.2532

J Clin Endocrinol Metab. 2021 May 4:dgab290. doi: 10.1210/clinem/dgab290. Online ahead of print.

ABSTRACT

PURPOSE: We aimed to evaluate the effect of mineralocorticoid receptor antagonists on aldosterone-to-renin ratio in patients with primary aldosteronism.

METHODS: We prospectively enrolled 121 patients with confirmed primary aldosteronism who started a mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) composed the short-term study cohort and underwent aldosterone, renin and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy.

RESULTS: Renin and potassium levels showed a significant increase, and aldosterone-to-renin ratio displayed a significant reduction compared with baseline after both a short and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests raised to 16.7%, 38.9%, 54.5% and 72.5% after 2 weeks, 8 weeks, 2-6 months and 7-12 months of mineralocorticoid receptor antagonist treatment, respectively.

CONCLUSIONS: Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.

PMID:33942084 | DOI:10.1210/clinem/dgab290

Farm Hosp. 2021 Apr 15;45(3):155-159. doi: 10.7399/fh.11607.

ABSTRACT

OBJECTIVE: The main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive effect. One of the main secondary goals is to analyze allele frequencies and the association of polymorphisms rs895819 (miR27A) and rs1801160 (DPYD*6) with toxicity by conducting an observational study to determine their clinical relevance and standardize a dose adjustment recommendation.

METHOD: The study has an single-center ambispective, quasi-experimental design and is based on a multidisciplinary protocol involving implementation and standardization of DPYD*2A; DPYD*13; c.2846A&gt;T; and HapB3 measurements. Following these measurements, pharmacogenetic counseling will be carried out and its clinical impact will be evaluated. The primary endpoint of the study is severe toxicity and/or mortality. The toxicity observed in two groups with similar epidemiological characteristics will be compared: the intervention group (candidates for treatment with fluoropyrimidines who will be subjected to the protocol) and the control group (retrospective cohort). Additionally, rs895819 (MIR27A) and rs1801160 (DPYD*6) will be determined. Testing for these variants is not part of the hospital's daily practice, nor are they included in clinical guidelines. However, according to recently published studies, the activity of dihydropyrimidine dehydrogenase might be affected by these variants, as they may be associated with toxicity. The results of the measurements of these two variants will not be incorporated to pharmacogenetics counseling until their association with toxicity is determined by means of the observational study to be conducted. The project, as well as the patient information sheet and the informed consent form, were approved by the Ethics Committee of the participating center (code 20/006).

PMID:33941060 | DOI:10.7399/fh.11607

Biomed Pharmacother. 2021 Apr 30;139:111631. doi: 10.1016/j.biopha.2021.111631. Online ahead of print.

ABSTRACT

The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Genetic polymorphisms for ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and Cytochrome P450 Oxidoreductase (POR) were investigated. Age significantly correlated with drug exposure, and patients CYP3A5 expressers (GA and AA) were found at high risk to be underexposed to the drug when treated at standard dose. This association was confirmed even after correction with age. No association was found with ABCB1 polymorphism. Our data suggest that CYP3A5 polymorphisms might significantly affect linezolid disposition, putting patients at higher risk to be underexposed, while P-glycoprotein polymorphism seem not to play any role.

PMID:33940510 | DOI:10.1016/j.biopha.2021.111631

Pharmacol Res. 2021 Apr 30:105643. doi: 10.1016/j.phrs.2021.105643. Online ahead of print.

ABSTRACT

Lung cancer has become a paradigm for the future of precision medicine in oncology, and liquid biopsy (LB) and radiomics may have great potential in this scenario. They are both minimally invasive, easy to perform, and can be repeated during patient's follow-up. Also, increasing evidence suggests that LB and radiomics may provide an efficient way to screen and diagnose tumors at an early stage, including the monitoring of any change in the tumor molecular profile. This could allow treatment optimization, patient's quality of life improvement, and healthcare-related costs reduction. Latest reports on lung cancer patients suggest a combination of these two strategies, along with cutting-edge data analysis, to decode valuable information regarding tumor type, aggressiveness, progression, and response to treatment. The approach seems more compatible with clinical practice than the current standard, and provides new diagnostic companions being able to suggest the best treatment strategy compared to conventional methods. To implement radiomics and liquid biopsy research findings directly into clinical practice, an artificial intelligence (AI)-based system could help to coherently link patient clinical data together with respective of tumor molecular profile and imaging characteristics. AI could also solve problems and limitations related to LB and radiomics methodologies. Further work is needed, including new health policies and the access to large amounts of high-quality and well-organized data, allowing the complementary and synergistic combination of LB and imaging to provide an attractive choice to the traditional molecular profile in the personalized treatment of lung cancer.

PMID:33940185 | DOI:10.1016/j.phrs.2021.105643