Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0052. Online ahead of print.

ABSTRACT

Aim: To investigate whether the TNIK gene affects risperidone treatment outcomes in the Chinese population. Methods: A total of 148 unrelated inpatients who received risperidone for six weeks were enrolled. The selected single nucleotide polymorphisms (SNPs; rs2088885, rs7627954 and rs13065441) were genotyped using the MassARRAY® SNP IPLEX platform. Results: The analysis showed that one novel SNP of TNIK, rs7627954, had a significant association with the response to risperidone (χ2 = 4.472; p = 0.034). This work also identified rs2088885 as significantly associated with risperidone response (χ2 = 5.257; p = 0.022). The result revealed that the rs2088885-rs7627954 C-T haplotype was more prevalent in good responders than in poor responders (p = 0.0278). Conclusion: This study revealed that the rs2088885 and rs7627954 SNPs of TNIK are associated with risperidone treatment response.

PMID:35698907 | DOI:10.2217/pgs-2022-0052

Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0062. Online ahead of print.

ABSTRACT

Tweetable abstract Pharmacogenomics cascade testing in a digital health solution can improve medication adherence in dementia care for disadvantaged populations.

PMID:35698906 | DOI:10.2217/pgs-2022-0062

Pharmacogenomics. 2022 Jun 14. doi: 10.2217/pgs-2022-0027. Online ahead of print.

ABSTRACT

Drug-induced long QT syndrome (diLQTS) is an adverse effect of many commonly prescribed drugs, and it can increase the risk for lethal ventricular arrhythmias. Genetic variants in pharmacodynamic genes have been associated with diLQTS, but the strength of the evidence for each of those variants has not yet been evaluated. Therefore, the purpose of this review was to evaluate the strength of the evidence for pharmacodynamic genetic variants associated with diLQTS using a novel, semiquantitative scoring system modified from the approach used for congenital LQTS. KCNE1-D85N and KCNE2-T8A had definitive and strong evidence for diLQTS, respectively. The high level of evidence for these variants supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.

PMID:35698903 | DOI:10.2217/pgs-2022-0027

J Gene Med. 2022 Jun 13:e3436. doi: 10.1002/jgm.3436. Online ahead of print.

ABSTRACT

Previous studies in nephrotic syndrome have shown that three common variants in the ABCB1 gene including, rs1128503, rs2032582, and rs1045642, change the expression and activity of ABCB1 that may be responsible for drug resistance. However, due to inconclusive outcomes of these studies, we performed a meta-analysis to validate the association between ABCB1 polymorphisms and the susceptibility of steroid-resistant nephrotic syndrome (SRNS). The association was evaluated by calculating the odds ratio (OR) and 95% confidence interval. All analyses were performed with Review Manager v5.4. A total of 12 studies containing 1,463 subjects (514 steroid-resistant and 949 steroid-sensitive) were included. SNP rs1128503 showed significant association with SRNS (p<0.05) only in the allele model (OR=1.40) in Africans. A statistically significant association was found for rs2032582 in codominant 2, dominant, recessive, and allele models (OR=1.85, 1.52, 1.38, and 1.34, respectively). Subgroup analysis revealed that rs2032582 showed a significant correlation with SRNS in codominant 1, 2, dominant, over-dominant, and allele model in Africans (OR=3.22, 3.52, 3.29, 1.74, and 1.83, respectively). In the case of rs1045642, codominant 1 (OR=0.72) and recessive model (OR=1.34) revealed a significant correlation with SRNS. Again, codominant 1 (OR=0.58), dominant (OR=0.69), and over-dominant model (OR=0.62) showed a protective effect in Asians. Haplotype analysis showed that TGC haplotype is associated with 1.83, 1.77, and 2.17 time significant correlation in overall, Asian, and African population, respectively. In contrast, CGC haplotype showed 0.69 and 0.57 time lower association in the overall and African populations, respectively. CTC haplotype also showed 1.79 time enhanced susceptibility for SRNS in the overall population. Our study suggests that ABCB1 polymorphisms are associated with SRNS development, especially in Africans and Asians.

PMID:35697639 | DOI:10.1002/jgm.3436

Child Adolesc Psychiatr Clin N Am. 2022 Jul;31(3):393-416. doi: 10.1016/j.chc.2022.03.003. Epub 2022 May 11.

ABSTRACT

The psychostimulants-amphetamine and methylphenidate-have been in clinical use for well more than 60 years. In general, both stimulants are rapidly absorbed with relatively poor bioavailability and short half-lives. The pharmacokinetics of both stimulants are generally linear and dose proportional although substantial interindividual variability in pharmacokinetics is in evidence. Amphetamine (AMP) is highly metabolized by several oxidative enzymes forming multiple metabolites while methylphenidate (MPH) is primarily metabolized by hydrolysis to the inactive metabolite ritalinic acid. At present, pharmacogenomic testing as an aid to guide dosing and personalized treatment cannot be recommended for either agent. Few pharmacokinetically based drug-drug interactions (DDIs) have been documented for either stimulant.

PMID:35697392 | DOI:10.1016/j.chc.2022.03.003

Front Pharmacol. 2022 May 20;13:928527. doi: 10.3389/fphar.2022.928527. eCollection 2022.

NO ABSTRACT

PMID:35694262 | PMC:PMC9175562 | DOI:10.3389/fphar.2022.928527

Pharmgenomics Pers Med. 2022 Jun 4;15:561-571. doi: 10.2147/PGPM.S363058. eCollection 2022.

ABSTRACT

BACKGROUND: Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics.

METHOD: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction.

RESULTS: The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.

CONCLUSION: The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

PMID:35693129 | PMC:PMC9176238 | DOI:10.2147/PGPM.S363058

Curr Med Chem. 2022 Jun 10. doi: 10.2174/0929867329666220610090405. Online ahead of print.

ABSTRACT

Background- Even though the battle against cancer has advanced remarkably in last few decades and the survival rate has improved very significantly, an ultimate cure for cancer treatment stills remains an undeterred problem. In such scenario, nanoinformatics, which is bioinformatics coupled with nanotechnology, endows with many novel research opportunities in the preclinical and clinical development of specially personalized nanosized drugs and carriers bestowing newer dimensions in anticancer research and therapy. Personalized nanomedicines tends to serve as a promising treatment option for cancer owing to their noninvasiveness and their novel approach. Explicitly, the field of personalized medicine is expected to have an enormous impact in clinical research owing to its diverse advantages and its versatility to adapt a drug to a cohort of patients. Objective- The current review attempts to explain the implications of nanoinformatics as a new emerging field in the field of pharmacogenomics and precision medicine. This review also recapitulates how nanoinformatics could accelerate the developments of personalized nanomedicine in anticancer research, which is undoubtedly the need of the hour. Conclusion- The approach and concept of personalized nanomedicine has been facilitated by humongous impending field of Nanoinformatics. The breakthrough progressions made through nanoinformatics have prominently changed the insight of the future personalized medicinal drug in cancer research. Nanoparticle based medicine has been developing and has created a center of attention in recent years, with a prime focus on proficient delivery mechanisms for various chemotherapy drugs. Nanoinformatics has allowed merging of all recent advances from creating nanosized particles that contain drugs targeting cell surface receptors to other potent molecules designed to kill cancerous cells and its subsequent application to personalize medicine.

PMID:35692148 | DOI:10.2174/0929867329666220610090405

Vascul Pharmacol. 2022 Jun 8:107021. doi: 10.1016/j.vph.2022.107021. Online ahead of print.

ABSTRACT

OBJECTIVE: We examined quantitative (in terms of mtDNA/nuclear DNA) and structural (in terms of common deletions in the MT-ND4 gene region) characteristics of mitochondrial DNA (mtDNA) in varicose veins (VVs) and venous wall layers by comparing mitochondrial genome parameters, as well as mitochondrial function (in terms of mitochondrial membrane potential (MtMP) differences), in varicose vein (VV) vs. non-varicose vein (NV) tissue samples.

METHODS: We analyzed paired great saphenous vein samples (VV vs. NV segments from each patient left after venous surgery) harvested from patients with VVs. Relative mtDNA level and the proportion of no-deletion mtDNA were determined by a multiplex quantitative PCR (qPCR), confirming the later with a more sensitive method - droplet digital PCR (ddPCR). Mitochondria's functional state in VVs was assessed using fluorescent (dependent on MtMP) live-staining of mitochondria in venous tissues.

RESULTS: Total mtDNA level was lower in VV than in NV samples (predominantly in the t. media layer). ddPCR analysis showed lower proportion of no-deletion mtDNA in VVs. Because of the decrease in relative MtMP in VVs, our results suggest a possible reduction of mitochondrial function in VVs.

CONCLUSION: Quantitative and structural changes (copy number and integrity) of mtDNA are plausibly involved in VV pathogenesis. Future clinical studies implementing the mitochondrial targeting may be eventually fostered after auxiliary mechanistic studies.

PMID:35690235 | DOI:10.1016/j.vph.2022.107021

Med (N Y). 2022 Jun 10;3(6):388-405.e6. doi: 10.1016/j.medj.2022.04.007. Epub 2022 May 11.

ABSTRACT

BACKGROUND: Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with adverse effects for a subset of patients, including disrupted metabolic control and increased risk of type 2 diabetes.

METHODS: We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991). Microbiome composition was assessed in these cohorts using stool 16S rRNA amplicon and shotgun metagenomic sequencing, respectively. Microbiome associations with markers of statin on-target and adverse effects were tested via a covariate-adjusted interaction analysis framework, utilizing blood metabolomics, clinical laboratory tests, genomics, and demographics data.

FINDINGS: The hydrolyzed substrate for 3-hydroxy-3-methylglutarate-coenzyme-A (HMG-CoA) reductase, HMG, emerged as a promising marker for statin on-target effects in cross-sectional cohorts. Plasma HMG levels reflected both statin therapy intensity and known genetic markers for variable statin responses. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and adverse metabolic effects of statins, we find that heterogeneity in statin responses was consistently associated with variation in the gut microbiome across two independent cohorts. A Bacteroides-enriched and diversity-depleted gut microbiome was associated with more intense statin responses, both in terms of on-target and adverse effects.

CONCLUSIONS: With further study and refinement, gut microbiome monitoring may help inform precision statin treatment.

FUNDING: This research was supported by the M.J. Murdock Charitable Trust, WRF, NAM Catalyst Award, and NIH grant U19AG023122 awarded by the NIA.

PMID:35690059 | DOI:10.1016/j.medj.2022.04.007

Mol Oncol. 2022 Jun 10. doi: 10.1002/1878-0261.13270. Online ahead of print.

ABSTRACT

The oncogenic role of ephrin type-B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than in healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4-specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin-proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib-resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.

PMID:35689424 | DOI:10.1002/1878-0261.13270

Clin Transl Sci. 2022 Jun 10. doi: 10.1111/cts.13318. Online ahead of print.

ABSTRACT

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

PMID:35689378 | DOI:10.1111/cts.13318

Leukemia. 2022 Jun 10. doi: 10.1038/s41375-022-01622-0. Online ahead of print.

ABSTRACT

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.

PMID:35688939 | DOI:10.1038/s41375-022-01622-0

J Pharmacol Exp Ther. 2022 Jun 10:JPET-AR-2022-001217. doi: 10.1124/jpet.122.001217. Online ahead of print.

ABSTRACT

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared to the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared to BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of CYP enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. Significance Statement Our findings show genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite following oxycodone administration, and reinforces the need for sex as a biological factor in pharmacogenomic studies. The co-occurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.

PMID:35688478 | DOI:10.1124/jpet.122.001217

Apoptosis. 2022 Jun 10. doi: 10.1007/s10495-022-01729-w. Online ahead of print.

ABSTRACT

Pyroptosis defines a new type of GSDMs-mediated programmed cell death, distinguishes from the classical concepts of apoptosis and necrosis-mediated cell death and is prescribed by cell swelling and membrane denaturation, leading to the extensive secretion of cellular components and low-grade inflammatory response. However, NLRP3 inflammasome activation can trigger its downstream inflammatory cytokines, leading to the activation of pyroptosis-regulated cell death. Current studies reveal that activation of caspase-4/5/11-driven non-canonical inflammasome signaling pathways facilitates the pathogenesis and progression of acute pancreatitis (AP). In addition, a large number of studies have reported that NLRP3 inflammasome-dependent pyroptosis is a crucial player in driving the course of the pathogenesis of AP. Excessive uncontrolled GSDMD-mediated pyroptosis has been implicated in AP. Therefore, the pyroptosis-related molecule GSDMD may be an independent prognostic biomarker for AP. The present review paper summarizes the molecular mechanisms of pyroptotic signaling pathways and their pathophysiological impacts on the progress of AP. Moreover, we briefly present some experimental compounds targeting pyroptosis-regulated cell death for exploring novel therapeutic directions for the treatment and management of AP. Our review investigations strongly suggest that targeting pyroptosis could be an ideal therapeutic approach in AP.

PMID:35687256 | DOI:10.1007/s10495-022-01729-w

Front Genet. 2022 May 24;13:857120. doi: 10.3389/fgene.2022.857120. eCollection 2022.

ABSTRACT

As our understanding of genomics and genetic testing continues to advance, the personalization of medical decision making is progressing simultaneously. By carefully crafting medical care to fit the specific needs of the individual, patients can experience better long-term outcomes, reduced toxicities, and improved healthcare experiences. Genetic tests are frequently ordered to help diagnose a clinical presentation and even to guide surveillance. Through persistent investigation, studies have begun to delineate further therapeutic implications based upon unique relationships with genetic variants. In this review, a pre-emptive approach is taken to understand the existing evidence of relationships between specific genetic variants and available therapies. The review revealed an array of diverse relationships, ranging from well-documented clinical approaches to investigative findings with potential for future application. Therapeutic agents identified in the study ranged from highly specific targeted therapies to agents possessing similar risk factors as a genetic variant. Working in conjunction with national standardized treatment approaches, it is critical that physicians appropriately consider these relationships when developing personalized treatment plans for their patients.

PMID:35685436 | PMC:PMC9170921 | DOI:10.3389/fgene.2022.857120

Nutrients. 2022 May 30;14(11):2287. doi: 10.3390/nu14112287.

ABSTRACT

Targeting pancreatic lipase and α-amylase by digestion-derived fractions of ethanolic-aqueous (60%, v/v) extract from Cornus mas fruit (CM) in relation to the control and prevention of metabolic disorders, including diabetes, was the first purpose of the present study. Taking into consideration the significance of bio-accessibility of compounds, we attempted to identify metabolites of CM after gastrointestinal digestion in vitro, as well as their kinetic changes upon gut microbiota treatment. The digestion of extract was simulated with digestive enzymes in vitro and human gut microbiota ex vivo (1 h, 3 h, 6 h, 24 h), followed by chromatographic analysis using the UHPLC-DAD-MSn method. The effect of fractions from gastrointestinal digestion in vitro on the activity of pancreatic lipase and α-amylase was studied with fluorescence-based assays. The gastric and intestinal fractions obtained after in vitro digestion of CM inhibited pancreatic lipase and α-amylase. Loganic acid as the main constituent of the extract was digested in the experimental conditions in contrast to cornuside. It was found in most analytes such as salivary, gastric, intestinal, and even colon (fecal slurry, FS) fractions. In all fractions, kaempferol hexoside and reduced forms of kaempferol, such as aromadendrin, and benzoic acid were assigned. The signals of tannins were detected in all fractions. Cornusiin A was tentatively assigned in the gastric fraction. The metabolites originating from kinetic analytes have been classified mainly as phenolic acids, hydrolyzable tannins, and flavonoids. Phenolic acids (protocatechuic acid, gallic acid), tannins (digalloylglucose, tri-O-galloyl-β-D-glucose), and flavonoids (aromadendrin, dihydroquercetin) were detected in the late phases of digestion in fecal slurry suspension. Cornuside was found in FS analyte after 3 h incubation. It was not detected in the samples after 6 and 24 h incubation with FS. In conclusion, cornuside, aromadendrin, and phenolic acids may be potentially bio-accessible compounds of CM. The presence of plants' secondary metabolites in the intestinal fractions allows us to indicate them as responsible for decreasing glucose and lipid absorption.

PMID:35684087 | DOI:10.3390/nu14112287

J Clin Med. 2022 May 26;11(11):3009. doi: 10.3390/jcm11113009.

ABSTRACT

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

PMID:35683399 | DOI:10.3390/jcm11113009

Int J Mol Sci. 2022 Jun 2;23(11):6261. doi: 10.3390/ijms23116261.

ABSTRACT

Novel conjugates (CP) of moxifloxacin (MXF) with fatty acids (1m-16m) were synthesized with good yields utilizing amides chemistry. They exhibit a more pronounced cytotoxic potential than the parent drug. They were the most effective for prostate cancer cells with an IC50 below 5 µM for respective conjugates with sorbic (2m), oleic (4m), 6-heptenoic (10m), linoleic (11m), caprylic (15m), and stearic (16m) acids. All derivatives were evaluated against a panel of standard and clinical bacterial strains, as well as towards mycobacteria. The highest activity towards standard isolates was observed for the acetic acid derivative 14m, followed by conjugates of unsaturated crotonic (1m) and sorbic (2m) acids. The activity of conjugates tested against an expanded panel of clinical coagulase-negative staphylococci showed that the compound (14m) was recognized as a leading structure with an MIC of 0.5 μg/mL denoted for all quinolone-susceptible isolates. In the group of CP derivatives, sorbic (2) and geranic (3) acid amides exhibited the highest bactericidal potential against clinical strains. The M. tuberculosis Spec. 210 strain was the most sensitive to sorbic (2m) conjugate and to conjugates with medium- and long-chain polyunsaturated acids. To establish the mechanism of antibacterial action, selected CP and MXF conjugates were examined in both topoisomerase IV decatenation assay and the DNA gyrase supercoiling assay, followed by suitable molecular docking studies.

PMID:35682940 | DOI:10.3390/ijms23116261

NPJ Genom Med. 2022 Jun 9;7(1):33. doi: 10.1038/s41525-022-00303-2.

ABSTRACT

In pharmacogenetic (PGx) studies, drug response phenotypes are often measured in the form of change in a quantitative trait before and after treatment. There is some debate in recent literature regarding baseline adjustment, or inclusion of pre-treatment or baseline value as a covariate, in PGx genome-wide association studies (GWAS) analysis. Here, we provide a clear statistical perspective on this baseline adjustment issue by running extensive simulations based on nine statistical models to evaluate the influence of baseline adjustment on type I error and power. We then apply these nine models to analyzing the change in low-density lipoprotein cholesterol (LDL-C) levels with ezetimibe + simvastatin combination therapy compared with simvastatin monotherapy therapy in the 5661 participants of the IMPROVE-IT (IMProved Reduction of Outcomes: Vytroin Efficacy International Trial) PGx GWAS, supporting the conclusions drawn from our simulations. Both simulations and GWAS analyses consistently show that baseline-unadjusted models inflate type I error for the variants associated with baseline value if the baseline value is also associated with change from baseline (e.g., when baseline value is a mediator between a variant and change from baseline), while baseline-adjusted models can control type I error in various scenarios. We thus recommend performing baseline-adjusted analyses in PGx GWASs of quantitative change.

PMID:35680959 | DOI:10.1038/s41525-022-00303-2