Annu Rev Pharmacol Toxicol. 2022 Aug 1. doi: 10.1146/annurev-pharmtox-051921-092701. Online ahead of print.

ABSTRACT

Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in CYP2C19 may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function CYP2C19 alleles and thus have reduced active clopidogrel metabolites, have high on-treatment platelet reactivity and increased ischemic risk. Prospective studies have examined the utility of CYP2C19 genetic testing to guide antiplatelet therapy, and more recently published metanalyses suggest that pharmacogenetics represents a key treatment strategy to individualize antiplatelet therapy. Rapid genetic tests, including bedside genotyping platforms that are validated and have high reproducibility, are available to guide selection of P2Y12 inhibitors in clinical practice. The aim of this review is to provide an overview of the background and rationale for the role of a guided antiplatelet approach to enhance patient care. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:35914768 | DOI:10.1146/annurev-pharmtox-051921-092701

Expert Rev Clin Pharmacol. 2022 Aug 1. doi: 10.1080/17512433.2022.2108401. Online ahead of print.

ABSTRACT

INTRODUCTION: Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke.

AREAS COVERED: A systematic literature review retrieved articles which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes.

EXPERT OPINION: There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

PMID:35912831 | DOI:10.1080/17512433.2022.2108401

Front Oncol. 2022 Jul 15;12:916650. doi: 10.3389/fonc.2022.916650. eCollection 2022.

ABSTRACT

BACKGROUND: The two common methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677G>A and 1298A>C may have been affecting 5-FU toxicity in cancer patients for decades. Drug efficacy has also been shown by previous studies to be affected. In this study, we investigated the effects of these polymorphisms on 5-FU hematological toxicity and treatment efficacy, to provide enhanced pharmacological treatment for cancer patients.

METHODS: This is a retrospective study involving 52 Thai colorectal cancer patients who were treated with 5-FU based therapy, using TaqMAN real-time PCR to genotype the MTHFR polymorphisms (677G>A and 1298A>C). The toxicity and response rate were assessed using standardized measures.

RESULTS: Neutropenia was significantly more likely to be experienced (P=0.049, OR=7.286, 95% CI=0.697-76.181) by patients with the MTHFR 677G>A polymorphism, in the same way as leukopenia (P =0.036, OR=3.333, 95%CI=2.183-5.090) and thrombocytopenia (P<0.001, OR=3.917, 95%CI=2.404-6.382). The MTHFR 1298A>C polymorphism had no statistical association with hematological toxicity in 5-FU treatment. The response rate to 5-FU was not significantly affected by these two polymorphisms.

CONCLUSION: The MTHFR polymorphism 677G>A is a significant risk factor for developing leukopenia, neutropenia and thrombocytopenia as toxic effects of 5-FU therapy in cancer patients. Therefore, patients receiving 5-FU-based therapy should be aware of their polymorphisms as one risk factor for experiencing severe toxicity.

PMID:35912215 | PMC:PMC9335196 | DOI:10.3389/fonc.2022.916650

Front Psychiatry. 2022 Jul 15;13:942268. doi: 10.3389/fpsyt.2022.942268. eCollection 2022.

ABSTRACT

We report the case of a 50-year-old male with major depressive disorder (MDD) to illustrate the challenge of finding effective antidepressant pharmacotherapy and the role that the patient's genetic makeup may play. Recent treatment attempts before clinic admission included venlafaxine and fluoxetine. Venlafaxine was discontinued due to lack of response, and subsequently switched to fluoxetine based on pharmacogenotyping of the P-glycoprotein transporter (P-gp, encoded by ABCB1) by the outpatient psychiatrist. Despite steady state serum levels within the therapeutic range, the patient did not benefit from fluoxetine either, necessitating admission to our clinic. Here a clinical pharmacist-led medication review including additional pharmacogenetic (PGx) analysis resulted in the change of the antidepressant therapy to bupropion. Under the new regimen, established in the in-patient-setting, the patient remitted. However, based on the assessed pharmacokinetics-related gene variants, including CYPs and ABCB1, non-response to fluoxetine could not be conclusively explained. Therefore, we retrospectively selected the serotonin transporter (SERT1, encoded by SLC6A4) for further genetic analysis of pharmacodynamic variability. The patient presented to be a homozygous carrier of the short allele variant in the 5-HTTLPR (S/S) located within the SLC6A4 promoter region, which has been associated with a reduced expression of the SERT1. This case points out the potential relevance of panel PGx testing considering polymorphisms in genes of pharmacokinetic as well as pharmacodynamic relevance.

PMID:35911243 | PMC:PMC9334565 | DOI:10.3389/fpsyt.2022.942268

Biol Pharm Bull. 2022;45(8):1198-1202. doi: 10.1248/bpb.b22-00136.

ABSTRACT

Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (Pcombined = 4.92 × 10-5 and 5.50 × 10-5, respectively). These data suggest that rs8032978 and rs7406710 could be predictive markers of trastuzumab-induced cardiotoxicity in Japanese and Singaporean populations, and support their potential use in clinical risk assessment. These findings offer a first step toward the development of clinically available markers for the potential risk of trastuzumab-induced cardiotoxicity as well as an improved understanding of the pathogenesis of this complication.

PMID:35908902 | DOI:10.1248/bpb.b22-00136

Pharmacol Rep. 2022 Jul 30. doi: 10.1007/s43440-022-00396-7. Online ahead of print.

ABSTRACT

BACKGROUND: The lack of drug targets is an obstacle to the treatment of patients with triple-negative breast cancer (TNBC). At present, non-specific cytotoxic drugs are first-line agents, but the development of resistance is a major problem with these agents. The epidermal growth factor receptor (EGFR) is a potential target in some TNBCs, because its tyrosine kinase activity drives tumorigenesis. Thus, small molecule inhibitors of the EGFR in combination with cytotoxic agents could be important for the treatment of TNBCs.

METHODS: The present study evaluated the efficacies of clinically approved EGFR inhibitors in combination with the cytotoxic agent ixabepilone in parental and docetaxel-resistant MDA-MB-231 cells (231C and TXT cells, respectively). Cell viability was assessed using MTT reduction assays, cell death pathways were evaluated using annexin V/7-aminoactinomycin D staining and flow cytometry and Western immunoblotting was used to assess the expression of pro- and anti-apoptotic proteins in cells.

RESULTS: Ixabepilone and the EGFR inhibitors gefitinib and vandetanib inhibited 231C and TXT cell proliferation, but the alternate EGFR inhibitors erlotinib and lapatinib were poorly active. Using combination analysis, ixabepilone/vandetanib was synergistic in both cell types, whereas the ixabepilone/gefitinib combination exhibited antagonism. By flow cytometry, ixabepilone/vandetanib enhanced 231C and TXT cell death over that produced by the single agents and also enhanced caspase-3 cleavage and the pro/anti-apoptotic Bcl-2 protein ratios over ixabepilone alone.

CONCLUSIONS: These findings suggest that the ixabepilone/vandetanib combination may have promise for the treatment of patients with drug-resistant TNBC.

PMID:35908023 | DOI:10.1007/s43440-022-00396-7

Neuropsychopharmacology. 2022 Jul 29. doi: 10.1038/s41386-022-01384-4. Online ahead of print.

ABSTRACT

Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108-2114; Biol. Psychiatry 88 (9), 727-735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen's f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen's f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.

PMID:35906490 | DOI:10.1038/s41386-022-01384-4

Prog Biomater. 2022 Jul 29. doi: 10.1007/s40204-022-00198-3. Online ahead of print.

ABSTRACT

Medicinal applications of turmeric-derived curcumin have been known to mankind for long ages. Its potential in managing "cystic fibrosis" has also been evaluated. This autosomal recessive genetic disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which involves an impaired secretion of chloride ions and leads to hypersecretion of thick and sticky mucus and serious complications including airway obstruction, chronic lung infection, and inflammatory reactions. This narrative review aims to highlight the available evidence for the efficacy of curcumin nanoformulations in its potential treatment of cystic fibrosis. Recent research has shown that curcumin acts on the localized mutant CFTR ion channel at the plasma membrane. Preclinical studies have also shown that curcumin nanoformulations have promising effects in the treatment of cystic fibrosis. In this context, the purpose of this narrative review is to highlight the general bioactivity of curcumin, the types of formulations and related studies, thus opening new therapeutic perspectives for CF.

PMID:35904711 | DOI:10.1007/s40204-022-00198-3

Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221106563. doi: 10.1177/15330338221106563.

ABSTRACT

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.

PMID:35903924 | DOI:10.1177/15330338221106563

Front Neurosci. 2022 Jul 6;16:886709. doi: 10.3389/fnins.2022.886709. eCollection 2022.

ABSTRACT

Awake rodent fMRI is becoming a promising non-invasive brain imaging module when investigating large-scale brain function given behavioral tasks. Previous studies have either applied sedatives during scanning or pre-treatment of anesthetics, e.g., isoflurane, to reduce the motion of animals, which could confound the brain function of "awake" states in rodents. Here, we have established a long training awake mouse fMRI-pupillometry paradigm/setup without the initial use of anesthesia. To validate the awake mouse fMRI platform, evoked BOLD-fMRI was performed to identify brain activation in the visual cortex, dorsal lateral geniculate nuclei, and superior colliculus. Furthermore, pupil signal fluctuation was investigated during scanning, showing a less dilated pupil after 5-8 weeks of intermittent training. Thus, using the awake mouse fMRI with real-time pupillometry provides a longitudinal functional mapping tool to study fully conscious mice.

PMID:35903811 | PMC:PMC9318598 | DOI:10.3389/fnins.2022.886709

Cancer Cell Int. 2022 Jul 28;22(1):239. doi: 10.1186/s12935-022-02663-2.

ABSTRACT

The gaps between the complex nature of cancer and therapeutics have been narrowed down due to extensive research in molecular oncology. Despite gathering massive insight into the mysteries of tumor heterogeneity and the molecular framework of tumor cells, therapy resistance and adverse side effects of current therapeutic remain the major challenge. This has shifted the attention towards therapeutics with less toxicity and high efficacy. Myricetin a natural flavonoid has been under the spotlight for its anti-cancer, anti-oxidant, and anti-inflammatory properties. The cutting-edge molecular techniques have shed light on the interplay between myricetin and dysregulated signaling cascades in cancer progression, invasion, and metastasis. However, there are limited data available regarding the nano-delivery platforms composed of myricetin in cancer. In this review, we have provided a comprehensive detail of myricetin-mediated regulation of different cellular pathways, its implications in cancer prevention, preclinical and clinical trials, and its current available nano-formulations for the treatment of various cancers.

PMID:35902860 | DOI:10.1186/s12935-022-02663-2

Gut. 2022 Jul 28:gutjnl-2022-327570. doi: 10.1136/gutjnl-2022-327570. Online ahead of print.

ABSTRACT

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.

DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.

RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and were predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.

CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.

TRIAL REGISTRATION NUMBER: ISRCTN45176516.

PMID:35902214 | DOI:10.1136/gutjnl-2022-327570

PLoS One. 2022 Jul 28;17(7):e0272129. doi: 10.1371/journal.pone.0272129. eCollection 2022.

ABSTRACT

The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments.

PMID:35901010 | DOI:10.1371/journal.pone.0272129

J Genet Couns. 2022 Jul 28. doi: 10.1002/jgc4.1612. Online ahead of print.

ABSTRACT

Pharmacogenomic (PGx) testing is an increasingly utilized technology that offers the potential for precision drug selection to treat depression. Though PGx-guided therapy is associated with increased rates of remission of depression symptoms, for many patients, treatment will not change based on PGx testing results. Lack of consensus guidelines for pre-test counseling may hinder the communication of PGx testing limitations, and patients often have high expectations for test outcomes. To explore this issue, we created and evaluated the impact of a pre-test education video for patients with depression. Individuals in the education group (n = 198) viewed this brief video about PGx testing prior to completing a survey that explored knowledge, perception, and expectations of PGx testing developed using a theoretical framework to measure intention to test. Individuals in the survey-only group (n = 189) completed the same survey but were not provided with any PGx educational materials. Analyses demonstrate efficacy of the video in improving knowledge of PGx. The education group also reported more positive attitudes and greater perceived control over pursuing PGx testing compared to the survey-only group. Further analyses identified significant differences in expectations, attitudes, and intention to pursue PGx testing based on number of previous medication trials. Path analyses identified the best model for predicting PGx testing intention, specifically that social norms and ease of testing have a strong positive association, and knowledge has a strong negative association with patients' intentions to test across the full sample, the education group, and the survey-only group. The findings of this study serve as a foundation for future tailored educational initiatives in the PGx testing space.

PMID:35900228 | DOI:10.1002/jgc4.1612

Clin Transl Sci. 2022 Jul 28. doi: 10.1111/cts.13376. Online ahead of print.

ABSTRACT

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of post-operative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2018 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided post-operative pain management (intervention arm) or delayed testing without CDS (control arm). Clinical decision support is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and one, three, and six months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days post-surgery, will be compared in the subgroup of IMs and PMs in the intervention (n=152) versus control (n=152) arm. Secondary endpoints include prescription pain medication misuse scores and opioid persistence at six months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

PMID:35899435 | DOI:10.1111/cts.13376

Front Med (Lausanne). 2022 Jul 11;9:854280. doi: 10.3389/fmed.2022.854280. eCollection 2022.

ABSTRACT

To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.

PMID:35899207 | PMC:PMC9309431 | DOI:10.3389/fmed.2022.854280

Health Sci Rep. 2022 Jul 25;5(4):e728. doi: 10.1002/hsr2.728. eCollection 2022 Jul.

ABSTRACT

BACKGROUND AND AIMS: Abnormalities in hematological and biochemical markers are assumed to be associated with the progression of COVID-19 disease. This meta-analysis was performed to assess the consequences of abnormalities of biomarkers (D-dimers, C-reactive protein [CRP], serum ferritin, lactate dehydrogenase [LDH], random blood sugar [RBS], absolute neutrophil count [ANC], neutrophil to lymphocyte ratio (NLR), serum creatinine, and hemoglobin) in the Bangladeshi COVID-19 patients.

METHODS: The data of biomarker levels in Bangladeshi COVID-19 patients were gathered from five databases: PubMed, ScienceDirect, Web of Science, Google Scholar and Bangladesh Journals Online between January 2020 to March 2022. Review Manager 5.4 was used for the meta-analysis, and Egger's test and Begg-Mazumdar's rank correlation were used to investigate publication bias.

RESULTS: This study included 1542 patients with 567 severe and 975 nonsevere statuses. Based on the accumulated data synthesis, there is a strong correlation between disease severity and different biomarkers, including D-dimer, CRP, ferritin, LDH, RBS, NLR, and serum creatinine (MD = 1.16, p = 0.0004; MD = 22.97, p = 0.003; MD = 419.26, p < 0.00001; MD = 118.37, p = 0.004; MD = 1.96, p = 0.02; MD = 1.26, p = 0.02; and MD = 0.31, p = 0.008, respectively). A significantly decreased correlation was observed for hemoglobin levels in severe COVID-19 patients (MD = -0.73, p = 0.10).

CONCLUSION: The elevated biomarkers level was noticed in severe cases compared to nonsevere patients, revealing that D-dimer, CRP, ferritin, LDH, RBS, NLR, and serum creatinine are significantly correlated to COVID-19 severity. Only lower hemoglobin level was found to be associated with COVID-19 severity.

PMID:35899180 | PMC:PMC9309618 | DOI:10.1002/hsr2.728

Front Pharmacol. 2022 Jul 11;13:915822. doi: 10.3389/fphar.2022.915822. eCollection 2022.

ABSTRACT

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

PMID:35899106 | PMC:PMC9309806 | DOI:10.3389/fphar.2022.915822

Front Endocrinol (Lausanne). 2022 Jul 11;13:915309. doi: 10.3389/fendo.2022.915309. eCollection 2022.

ABSTRACT

CONTEXT: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy.

OBJECTIVE: The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl.

METHODS: This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA).

RESULTS: Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed.

CONCLUSION: T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

PMID:35898448 | PMC:PMC9309506 | DOI:10.3389/fendo.2022.915309

Int J Tuberc Lung Dis. 2022 Aug 1;26(8):766-774. doi: 10.5588/ijtld.21.0702.

ABSTRACT

BACKGROUND: Pharmacokinetic variability arising from drug-drug interactions and pharmacogenetics may influence the effectiveness of treatment regimens for TB. The Improving Treatment Success Trial compared the WHO-recommended standard treatment in TB patients with an experimental regimen substituting ethambutol with moxifloxacin (MFX) in Durban, South Africa.METHODS: Non-linear mixed-effects modelling was used to investigate the population pharmacokinetics of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA). A total of 25 single-nucleotide polymorphisms, including pregnane-X-receptor, were selected for analysis.RESULTS: TB drug concentrations were available in a subset of 101 patients: 58 in the MFX arm and 43 in the control arm. Baseline characteristics were well-balanced between study arms: median age and weight were respectively 36 years and 57.7 kg; 75.2% of the patients were living with HIV. Although weight-based drug dosing was the same in the two arms, we found that RIF exposure was increased by 19.3%, INH decreased by 19% and PZA decreased by 19.2% when administered as part of the MFX-containing regimen. Genetic variation in pregnane-X-receptor (rs2472677) was associated with a 25.3% reduction in RIF exposure.CONCLUSION: Optimised weight-based TB treatment dosing is essential when RIF, INH and PZA are co-administered with fluoroquinolones. The reduction in RIF exposure associated with pharmacogenetic variation is worrying.

PMID:35898135 | DOI:10.5588/ijtld.21.0702