Pharmacogenomics. 2023 May 11. doi: 10.2217/pgs-2023-0040. Online ahead of print.

ABSTRACT

Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p < 0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.

PMID:37166414 | DOI:10.2217/pgs-2023-0040

Pharmacogenomics. 2023 May 11. doi: 10.2217/pgs-2023-0014. Online ahead of print.

ABSTRACT

Background: The authors aimed to assess outcomes with a pharmacogenetic (PGx)-informed, pharmacist-guided, personalized consult service for warfarin dosing. Methods: This retrospective cohort study included patients admitted with thromboembolic events. Eligible subjects received either PGx-informed (n = 389) or historical non-PGx pharmacist-guided warfarin dosing (Hx; n = 308) before hospital discharge. The composite of admission with bleeding or thromboembolic events over 90 days after the discharge was compared between the PGx and Hx groups. Results: The rate ratio (95% CI) of the composite of bleeding or thromboembolic admissions for PGx versus Hx was 0.32 (0.12-0.82). The estimated hazard ratio was 0.43 (0.16-1.12). Conclusion: A PGx-informed warfarin dosing service was associated with decreased bleeding and thromboembolic encounters.

PMID:37166395 | DOI:10.2217/pgs-2023-0014

Pharmacogenomics. 2023 May 11. doi: 10.2217/pgs-2023-0037. Online ahead of print.

ABSTRACT

Aim: To evaluate the association between OPRK1 rs963549 and rs997917 and opioid use disorder (OUD) and related phenotypes. Methods: A sample of 208 individuals with (n = 100) and without (n = 108) OUD were enrolled. OPRK1 rs963549 and rs997917 were analyzed by PCR-RFLP. Craving, opioid withdrawal and the intensity of depressive and anxiety symptoms were measured by the appropriate scales. Results: OPRK1 rs963549 variation showed a trend of association with decreased opioid withdrawal. No significant associations were found between OPRK1 rs963549 and rs997917 polymorphisms and craving, depression or anxiety symptoms. Neither single OPRK1 SNPs nor OPRK1 haplotypes were associated with OUD. Conclusion: Our results could be useful for treatment failures of individuals who experience greater opioid withdrawal due to their OPRK1 rs963549 genotypes.

PMID:37166316 | DOI:10.2217/pgs-2023-0037

Am J Health Syst Pharm. 2023 May 11:zxad099. doi: 10.1093/ajhp/zxad099. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience.

SUMMARY: Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, which may contribute to the risk of treatment failure due to subtherapeutic concentrations and adverse effects (eg, infection, bone fracture, renal dysfunction) with sustained supratherapeutic concentrations. Based on evidence available prior to the availability of pertinent Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the UF Health Precision Medicine Program (PMP) developed clinical recommendations, provided through automated alerts at the time of a PPI order, to (1) increase the PPI dose for individuals with genotypes linked to increased CYP2C19 enzyme activity (ie, rapid and ultrarapid metabolizers) to improve the likelihood of drug effectiveness and (2) decrease the dose for individuals with decreased CYP2C19 activity (ie, intermediate and poor metabolizers) to reduce the risk of harm. The CYP2C19-PPI implementation was an iterative process that taught us key implementation lessons. Most notably, physician engagement is essential, problem lists in the medical record are unreliable, and special populations (eg, pediatric patients) need to be considered.

CONCLUSION: Guiding PPI prescribing based on CYP2C19 genotype is a practical approach to potentially improve the benefit-risk ratio with PPI therapy. Physician engagement is key for successful implementation. A CPIC guideline on CYP2C19 genotype-guided PPI dosing is now available, and automated alerts may be instituted to facilitate implementation.

PMID:37166240 | DOI:10.1093/ajhp/zxad099

Adv Sci (Weinh). 2023 May 11:e2300806. doi: 10.1002/advs.202300806. Online ahead of print.

ABSTRACT

Poor immunogenicity seriously hampers the broader implementation of antitumor immunotherapy. Enhanced immunogenicity capable of achieving greater antitumor immunity is urgently required. Here, a novel polymer that contains hydrophobic ferrocene (Fc) units and thioketal bonds in the main chain, which further delivered a prodrug of oxaliplatin and artesunate, i.e., Artoxplatin, to cancer cells is described. This polymer with Fc units in the nanoparticle can work as a polyigniter to spark the peroxide bonds in Artoxplatin and generate abundant reactive oxygen species (ROS) to kill cancers as nanobombig for cancer therapy. Moreover, ROS can trigger the breakdown of thioketal bonds in the polymer, resulting in the biodegradation of the polymer. Importantly, nanobombig can facilitate the maturation of dendritic cells and promote the activation of antitumor immunity, through the enhanced immunogenic cell death effect by ROS generated in situ. Furthermore, metabolomics analysis reveals a decrease in glutamine in nanobombig -treated cancer cells, resulting in the upregulation of programmed death ligand 1 (PD-L1). Consequently, it is further demonstrated enhanced tumor inhibitory effects when using nanobombig combined with anti-PD-L1 therapy. Overall, the nanosystem offers a rational design of an efficient chemo-immunotherapy regimen to promote antitumor immunity by improving tumor immunogenicity, addressing the key challenges cancer immunotherapy faced.

PMID:37166035 | DOI:10.1002/advs.202300806

J Am Pharm Assoc (2003). 2023 May 8:S1544-3191(23)00144-9. doi: 10.1016/j.japh.2023.05.004. Online ahead of print.

NO ABSTRACT

PMID:37164263 | DOI:10.1016/j.japh.2023.05.004

Clin Pharmacol Ther. 2023 May 10. doi: 10.1002/cpt.2936. Online ahead of print.

ABSTRACT

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx-relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In two years since launching this program, ~3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx-informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research-only genetic data repositories to expand the number of patients who benefit from PGx-informed treatment while we continue to work toward wide-scale adoption of PGx testing and implementation.

PMID:37163252 | DOI:10.1002/cpt.2936

Basic Clin Pharmacol Toxicol. 2023 May 10. doi: 10.1111/bcpt.13884. Online ahead of print.

NO ABSTRACT

PMID:37162098 | DOI:10.1111/bcpt.13884

J Cancer Res Clin Oncol. 2023 May 9. doi: 10.1007/s00432-023-04814-y. Online ahead of print.

ABSTRACT

PURPOSE: The updated guidelines highlight gene expression-based multigene panel as a critical tool to assess overall survival (OS) and improve treatment for lung adenocarcinoma (LUAD) patients. Nevertheless, genome-wide expression signatures are still limited in real clinical utility because of insufficient data utilization, a lack of critical validation, and inapposite machine learning algorithms.

METHODS: 2330 primary LUAD samples were enrolled from 11 independent cohorts. Seventy-six algorithm combinations based on ten machine learning algorithms were applied. A total of 108 published gene expression signatures were collected. Multiple pharmacogenomics databases and resources were utilized to identify precision therapeutic drugs.

RESULTS: We comprehensively developed a robust machine learning-derived genome-wide expression signature (RGS) according to stably OS-associated RNAs (OSRs). RGS was an independent risk element and remained robust and reproducible power by comparing it with general clinical parameters, molecular characteristics, and 108 published signatures. RGS-based stratification possessed different biological behaviors, molecular mechanisms, and immune microenvironment patterns. Integrating multiple databases and previous studies, we identified that alisertib was sensitive to the high-risk group, and RITA was sensitive to the low-risk group.

CONCLUSION: Our study offers an appealing platform to screen dismal prognosis LUAD patients to improve clinical outcomes by optimizing precision therapy.

PMID:37160628 | DOI:10.1007/s00432-023-04814-y

Int J Antimicrob Agents. 2023 May 7:106840. doi: 10.1016/j.ijantimicag.2023.106840. Online ahead of print.

ABSTRACT

BACKGROUND: Ethambutol (EMB)'s ability to suppress bacterial resistance is demonstrated in a time-dependent manner. Through the development of a population pharmacokinetics (PK) model, this study aimed to suggest the PK/pharmacodynamics (PD) target and identify the significant covariate that influenced IIV in the PK of EMB.

METHODS: A total of 837 patients from 20 medical centers across Korea were enrolled in our study. The nonlinear mixed-effect method was used to establish and validate the population PK model.

RESULTS: A model consisting of two-compartment with transit compartment absorption was sufficient to describe the PK of EMB. Body weight and renal function were identified as significant covariates that affect the IIV of the apparent clearance (CL/F) of EMB. A total of 35% and 55% lower CL/F (CL/F: 89.9 L/h) of moderate renal function compared to mild and normal functions, respectively, can be observed. All the renal function groups with simulated doses ranging from 800-1200 mg could achieve the AUC/MIC > 119 and maintain T>MIC for > 23 h of the given MIC 0.5 μg/mL. Based on our data, we suggest that doses of 800, 1000, and 1200 mg should obtain the 25% percentile of the T>MIC target of 4, 6, and 8 hours, respectively. Our model was internally and externally validated.

CONCLUSION: Herein, we provide insight into the PK/PD indexes of EMB among three different renal function groups and T>MIC targets for different doses. Our results could be used further to provide an optimal-dose suggestions for EMB.

PMID:37160240 | DOI:10.1016/j.ijantimicag.2023.106840

J Am Heart Assoc. 2023 May 9:e027981. doi: 10.1161/JAHA.122.027981. Online ahead of print.

ABSTRACT

Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend echocardiography and serum cardiac biomarkers such as BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal proBNP) evaluation before and 6 to 12 months after treatment. Our objective was to evaluate associations between racial and ethnic groups in cardiac surveillance of survivors of cancer after exposure to anthracyclines. Methods and Results Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% CIs for receiving cardiac surveillance at baseline before anthracycline therapy, 6 months after, and 12 months after anthracycline exposure among different racial and ethnic groups. Among the entire cohort of 5430 patients, 63.4% had a baseline echocardiogram, with 22.3% receiving an echocardiogram at 6 months and 25% at 12 months. Non-Hispanic Black (NHB) patients had a lower likelihood of receiving a baseline echocardiogram than Non-Hispanic White (NHW) patients (OR, 0.75 [95% CI, 0.63-0.88]; P=0.0006) or any baseline cardiac surveillance (OR, 0.76 [95% CI, 0.64-0.89]; P=0.001). Compared with NHW patients, Hispanic patients received significantly less cardiac surveillance at the 6-month (OR, 0.84 [95% CI, 0.72-0.98]; P=0.03) and 12-month (OR, 0.85 [95% CI, 0.74-0.98]; P=0.03) time points, respectively. Conclusions There were significant racial and ethnic differences in cardiac surveillance among survivors of cancer at baseline and following anthracycline-based treatment in NHB and Hispanic cohorts. Health care providers need to be cognizant of these social inequities and initiate efforts to ensure recommended cardiac surveillance occurs following anthracyclines.

PMID:37158063 | DOI:10.1161/JAHA.122.027981

Clinics (Sao Paulo). 2023 May 6;78:100214. doi: 10.1016/j.clinsp.2023.100214. eCollection 2023.

NO ABSTRACT

PMID:37156205 | DOI:10.1016/j.clinsp.2023.100214

J Invest Dermatol. 2023 May 6:S0022-202X(23)02057-2. doi: 10.1016/j.jid.2023.04.017. Online ahead of print.

ABSTRACT

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor; DPP-4i), have been reported to trigger BP. To identify genetic variants associated with BP, genome-wide association study (GWAS) and human leukocyte antigen (HLA) fine-mapping analysis were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (DPP-4i-BP) and 737 controls (1st cohort) and the 8 cases and 164 controls (2nd cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significance association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of noninflammatory DPP-4i-BP (allele T carrier of 72.4 % [21/29] in cases vs. 15.3% [138/901] in controls; dominant model, odds ratio [OR] = 14, P = 1.8 ×10-9). HLA fine-mapping revealed that HLA-DQA1*05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of noninflammatory DPP-4i-BP (79.3% [23/29] cases vs. 16.1% [145/901] controls; dominant model, OR = 21, P = 2.0 × 10-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on noninflammatory DPP-4i-BP.

PMID:37156394 | DOI:10.1016/j.jid.2023.04.017

Drug Metab Pers Ther. 2023 May 8. doi: 10.1515/dmpt-2023-0037. Online ahead of print.

NO ABSTRACT

PMID:37155924 | DOI:10.1515/dmpt-2023-0037

Ann Fam Med. 2023 Jan 1;(21(Suppl 1)). doi: 10.1370/afm.21.s1.3462.

ABSTRACT

Context: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for many medications commonly prescribed prior to hospital discharge, yet there is limited data regarding the contribution of gene-x-drug interactions to hospital readmissions. Objective: The present study evaluated the relationship between prescription of CPIC medications prescribed within 30 days of hospital admission and 90-day hospital readmission from 2010-2020. Study Design and Analysis: Retrospective cohort study. Multivariable logistic regression analyzed the association between one or more gene-x-drug interactions with 90-day readmission. Population Studied: Primary care patients (N=10,104) who underwent sequencing with a 14-gene pharmacogenetic panel. Intervention/Instrument: Primary care physicians ordered a Color genetic panel that included pharmacogenetic genes reported through electronic health records. Outcome Measures: The primary endpoint was 90-day hospital readmission. The presence of at least one pharmacogenetic indicator for a medication prescribed within 30 days of hospital admission was considered a gene-x-drug interaction. Results: There were 2,211/2,354 (93.9%) admitted patients who were prescribed at least one CPIC medication. Univariate analyses indicated that the presence of at least one identified gene-x-drug interaction increased risk of 90-day readmission by more than 40% (OR=1.42, 95% confidence interval (CI) 1.09-1.84)(p=0.01). A multivariable model adjusting for age, race, sex, employment status, body mass index, and medical conditions, slightly attenuated the effect (OR=1.32, 95% CI 1.02-1.73)(p=0.04). Conclusions: Our results suggest that the presence of one or more CPIC gene-x-drug interactions increases the risk of 90-day hospital readmission, even after adjustment for demographic and clinical risk factors.

PMID:37155913 | DOI:10.1370/afm.21.s1.3462

Am J Health Syst Pharm. 2023 May 8:zxad100. doi: 10.1093/ajhp/zxad100. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: To compare rates of prescriber acceptance of interruptive and noninterruptive clinical decision support (CDS) alerts regarding potential diminished therapeutic effectiveness and safety risks associated with proton pump inhibitor (PPI) use in carriers of gene variants affecting cytochrome P450 (CYP) isozyme 2C19 metabolism.

METHODS: A retrospective study was conducted at a large rural health system to examine different approaches to improving CDS alert acceptance while minimizing alert fatigue. Manual reviews were conducted to identify alerts regarding CYP2C19 metabolizer status displayed at the time of PPI ordering over 30-day periods before and after the transition from interruptive to noninterruptive CDS alert functionality. A chi-square test was conducted to analyze prescriber acceptance CDS recommendations by alert modality and type of treatment modification.

RESULTS: Overall, interruptive alerts had an acceptance rate of 18.6% (64/344), compared to 8.4% acceptance (30/357 alerts) for noninterruptive alerts (P ≤ 0.0001). Analysis of acceptance criteria revealed the noninterruptive alert cohort had higher acceptance, as determined by documented medication dose adjustments, than the interruptive alert cohort (53.3% [16/30] and 4.7% [3/64], respectively). The difference in acceptance rates by CDS modality and treatment modification was statistically significant (P ≤ 0.00001). The predominant indication for PPI use was gastroesophageal reflux disease (GERD) in both cohorts.

CONCLUSION: Interruptive alerts that actively influenced workflow had higher acceptance rates than noninterruptive alerts that served an informational purpose without a direct disruption of workflow. The study results suggest the utilization of noninterruptive alerts may be a beneficial tool for prompting clinicians to alter dosing regimens rather than transition to an alternative agent.

PMID:37155711 | DOI:10.1093/ajhp/zxad100

JAMA Netw Open. 2023 May 1;6(5):e2312443. doi: 10.1001/jamanetworkopen.2023.12443.

ABSTRACT

IMPORTANCE: Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects.

OBJECTIVE: To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD).

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications.

INTERVENTION: In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage.

MAIN OUTCOMES AND MEASURES: The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores).

RESULTS: Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548675.

PMID:37155164 | DOI:10.1001/jamanetworkopen.2023.12443

Front Mol Biosci. 2023 Apr 19;10:1160063. doi: 10.3389/fmolb.2023.1160063. eCollection 2023.

ABSTRACT

Eukaryotic translation initiation factor 3 subunit A (eIF3a) is the largest subunit of the eukaryotic translation initiation factor 3 (eIF3). eIF3a plays an integral role in protein biosynthesis, hence impacting the onset, development, and treatment of tumors. The proteins regulated by eIF3a are still being explored in vivo. In this study, a Cre-loxP system was used to generate eIF3a conditional knockout mice. Tandem mass tag (TMT) labeling with LC-MS/MS analysis was used to identify differentially expressed proteins (DEPs) in fat, lungs, skin, and spleen tissue of the eIF3a knockout mice and controls. Bioinformatics analysis was then used to explore the functions and molecular signaling pathways of these protein landscapes. It was observed that eIF3a is essential for life sustenance. Abnormal tissue pathology was found in the lungs, fat, skin, spleen, and thymus. In total, 588, 210, 324, and 944 DEPs were quantified in the lungs, fat, skin, and spleen, respectively, of the eIF3a knockout mice as compared to the control. The quantified differentially expressed proteins were tissue-specific, except for eight proteins shared by the four tissues. A broad range of functions for eIF3a, including cellular signaling pathway, immune response, metabolism, defense response, phagocytes, and DNA replication, has been revealed using bioinformatics analysis. Herein, several pathways related to oxidative stress in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, including nitrogen metabolism, peroxisome, cytochrome P450 drug metabolism, pyruvate metabolism, PPAR signaling pathway, phospholipase D signaling pathway, B-cell receptor signaling pathway, ferroptosis, and focal adhesion, have been identified. Collectively, this study shows that eIF3a is an essential gene for sustaining life, and its downstream proteins are involved in diverse novel functions beyond mRNA translational regulation.

PMID:37152897 | PMC:PMC10154561 | DOI:10.3389/fmolb.2023.1160063

Heliyon. 2023 Apr 14;9(4):e15423. doi: 10.1016/j.heliyon.2023.e15423. eCollection 2023 Apr.

ABSTRACT

The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain. ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity. In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance.

PMID:37151704 | PMC:PMC10161610 | DOI:10.1016/j.heliyon.2023.e15423

Cancer Rep (Hoboken). 2023 May 7:e1830. doi: 10.1002/cnr2.1830. Online ahead of print.

ABSTRACT

BACKGROUND: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.

RECENT FINDINGS: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed.

CONCLUSION: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

PMID:37150853 | DOI:10.1002/cnr2.1830