J Clin Med. 2023 Oct 25;12(21):6742. doi: 10.3390/jcm12216742.

ABSTRACT

This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.

PMID:37959208 | DOI:10.3390/jcm12216742

Int J Mol Sci. 2023 Nov 3;24(21):15937. doi: 10.3390/ijms242115937.

ABSTRACT

The molecular mechanisms regulating homeostasis in the developing fetus have not been satisfactorily elucidated. Meconium contains substances accumulated in the fetal intestines. Measurements of transferrin and ferritin concentrations in meconium and assessment of transferrin-ferritin relationships could enhance knowledge about specific processes of the intrauterine period involving the two proteins and their effects on the development and growth of the fetus. Transferrin and ferritin concentrations were measured by ELISA in the homogenates of first meconium portions from 125 neonates. Higher birth weight was associated with lower ferritin concentrations in meconium (r = -0.22, p = 0.015). In neonates with a birth weight of more than 3750 g, there was a positive correlation between transferrin and ferritin concentrations (r = 0.51, p = 0.003). With meconium transferrin concentrations above 43.52 µg/g, a negative correlation between transferrin and ferritin was established (r = -0.37, p = 0.036), while with transferrin concentrations below 43.52 µg/g, the correlations between the birth weight and the meconium transferrin and ferritin concentrations were negative (r = -0.61, p < 0.001 and r = -0.43, p = 0.017, respectively). Measurements of transferrin and ferritin in meconium specimens create a new use for these common biomarkers to improve our understanding of the effects of homeostasis in utero on the fetal development and growth. Establishing reference ranges of meconium transferrin and ferritin concentrations and their association with the clinical parameters during pregnancy could aid in the assessment of the impact of intrauterine life on the health status of the neonate and its adaptation to extrauterine life.

PMID:37958917 | DOI:10.3390/ijms242115937

Diagnostics (Basel). 2023 Nov 1;13(21):3365. doi: 10.3390/diagnostics13213365.

ABSTRACT

Dengue is an arboviral disease that has spread globally and become a major public health concern. A small proportion of patients may progress from symptomatic dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Findings from a previous genome-wide association study (GWAS) demonstrated that variations in the major histocompatibility complex (MHC) class I chain-related B (MICB) and the phospholipase C epsilon 1 (PLCE1) genes were related to DSS in a Vietnamese population. This study investigated associations of variations in MICB (rs3132468) and PLCE1 (rs3740360, rs3765524) with dengue severity and thrombocytopenia in both the Indonesian and Taiwanese populations. We sampled 160 patients from the Indonesian population and 273 patients from the Taiwanese population. None of the patients had DSS in the Taiwanese population. Based on age demographics, we found that dengue is more prevalent among younger individuals in the Indonesian population, whereas it has a greater impact on adults in the Taiwanese population. Our results showed the association between MICB rs3132468 and DSS. In addition, an association was identified between PLCE1 rs3740360 and DHF in secondary dengue in Indonesian patients. However, there is no association of MICB or PLCE1 variants with thrombocytopenia. This study highlights the value of genetic testing, which might be included in the clinical pathway for specific patients who can be protected from severe dengue.

PMID:37958261 | DOI:10.3390/diagnostics13213365

Comb Chem High Throughput Screen. 2023 Nov 7. doi: 10.2174/0113862073244102231020050502. Online ahead of print.

ABSTRACT

BACKGROUND: Ginseng-ophiopogon injection (GOI) is a clinically commonly used drug for Qi deficiency syndrome characterized by decreased physical function in China. This study aimed to clarify common pharmacological mechanisms of GOI in enhancing physical function.

METHODS: We performed an integrative strategy of weight-loaded swimming tests in cold water (5.5 °C), hepatic glycogen and superoxide dismutase (SOD) detections, GC-TOF/MS-based metabolomics, multivariate statistical techniques, network pharmacology of known targets and constituents, and KEGG pathway analysis of GOI.

RESULTS: Compared with the control group, GOI showed significant increases in the weightloaded swimming time, hepatic levels of glycogen and SOD. Additionally, 34 significantly differential serum metabolites referred to glycolysis, gluconeogenesis and arginine biosynthesis were affected by GOI. The target collection revealed 98 metabolic targets and 50 experimentreported drug targets of ingredients in GOI involved in enhancing physical function. Further, the PPI network analysis revealed that 8 ingredients of GOI, such as ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, and notoginsenoside R1, were well-associated with 48 hub targets, which had good ability in enhancing physical function. Meanwhile, nine hub proteins, such as SOD, mechanistic target of Rapamycin (mTOR), and nitric oxide synthases, were confirmed to be affected by GOI. Finally, 98 enriched KEGG pathways (P<0.01 and FDR<0.001) of GOI were obtained from 48 hub targets of the PPI network. Among them, pathways in cancer, Chagas disease, lipid and atherosclerosis, and PI3K-Akt signaling pathway ranked top four.

CONCLUSIONS: This study provided an integrative and efficient approach to understanding the molecular mechanism of GOI in enhancing physical function.

PMID:37957852 | DOI:10.2174/0113862073244102231020050502

Cancer Chemother Pharmacol. 2023 Nov 13. doi: 10.1007/s00280-023-04611-x. Online ahead of print.

ABSTRACT

PURPOSE: We report the case of an adult patient diagnosed with Hodgkin's lymphoma who was scheduled for Pembrolizumab after failure of standard therapy. After three well-tolerated courses of Pembrolizumab, a PET scan showed a favorable outcome and a fourth course of Pembrolizumab was started. Unexpectedly, extremely severe toxicities (i.e., autoimmune peripheral hypothyroidism, rhabdomyolysis and severe acute renal failure) occurred after this last course, requiring transfer to the intensive care unit.

METHODS: Therapeutic drug monitoring was performed to measure residual Pembrolizumab levels at intervals from the last dose (i.e., 120 and then 170 days), as well as pharmacogenetics investigations on the FCγR gene.

RESULTS: Pembrolizumab plasma concentrations that were still pharmacologically active months after the last administration, suggesting impaired elimination of Pembrolizumab in this patient. Further pharmacokinetic modeling based on the population approach showed that both half-life (47.8 days) and clearance (0.12 L/day) values were significantly different from the standard values usually reported in patients. Further in silico simulations showed that pharmacologically active concentrations of Pembrolizumab were maintained for up to 136 days after the last dose. The search for possible polymorphisms affecting the genes coding for FCγR (i.e., rs1801274 on FCGR2A and rs396991 on FCGR3A gene) was negative. Further TDM showed that Pembrolizumab could be detected up to 263 days after the last administration.

CONCLUSION: This case report suggests that persistent overexposure in plasma could lead to life-threatening toxicities with Pembrolizumab.

PMID:37957436 | DOI:10.1007/s00280-023-04611-x

Food Chem Toxicol. 2023 Nov 11:114171. doi: 10.1016/j.fct.2023.114171. Online ahead of print.

ABSTRACT

To identify additional genetic markers contributing to variability in CPT-11 disposition and toxicity, we assessed impact of the multiple drug-resistant transporters 1, 2, and 3 (MRP1, MRP2, and MRP3) on the intestinal toxicity, pharmacokinetics, tissue distribution and biliary excretion of CPT-11 using a knockout mouse model. Mrp1/3 knockout had minor impact on intestinal toxicity of CPT-11, tissue distribution, biliary excretion, and PK parameter of its active metabolites SN38. Conversely, Mrp2-/- mice, with low carboxylesterase activity, displayed insensitivity to CPT-11 toxicity due to reduced intestinal exposure to SN38. In PK studies, Mrp1/2 knockout significantly increased the AUC of CPT-11 compared to their AUC in FVB mice. However, the AUC of SN38 in Mrp2 -/- mice was decreased by 3.25-fold. Mrp3 knockout only slightly increased SN38 plasma exposure. Lastly, Mrp2/3 knockout increased biliary excretion amount of CPT-11 by 67.2% and 48.5% compared to wild-type mice, respectively. Consequently, Mrp1/3 deficiency didn't change SN38 tissue distribution. Finally, correlation analysis demonstrated that tissue exposure to SN38 was better correlated with toxicity than plasma AUC of SN38. Mrp1/2/3 deficiency showed a minor impact on PK, biliary excretion, distribution and intestinal exposure of SN38, and as a result, did not affect the intestinal toxicity of CPT-11.

PMID:37956707 | DOI:10.1016/j.fct.2023.114171

OMICS. 2023 Nov 14. doi: 10.1089/omi.2023.0122. Online ahead of print.

ABSTRACT

A One Health lens is increasingly significant to address the intertwined challenges in planetary health concerned with the health of humans, nonhuman animals, plants, and ecosystems. A One Health approach can benefit the public health systems in Africa that are overburdened by noncommunicable, infectious, and environmental diseases. Notably, the COVID-19 pandemic revealed the previously overlooked two-fold importance of pharmacogenetics (PGx), for individually tailored treatment of noncommunicable diseases and environmental pathogens. For example, dyslipidemia, a common cardiometabolic risk factor, has been identified as an independent COVID-19 severity risk factor. Observational data suggest that patients with COVID-19 infection receiving lipid-lowering therapy may have better outcomes. However, among African patients, the response to these drugs varies from patient to patient, pointing to the possible contribution of genetic variation in important pharmacogenes. The PGx of lipid-lowering therapies may underlie differences in treatment responses observed among dyslipidemia patients as well as patients comorbid with COVID-19 and dyslipidemia. Genetic variations in APOE, ABCB1, CETP, CYP2C9, CYP3A4, CYP3A5, HMGCR, LDLR, NPC1L1, and SLCO1B1 genes affect the pharmacogenomics of statins, and they have individually been linked to differential responses to dyslipidemia and COVID-19 treatment. African populations are underrepresented in PGx research. This leads to poor accounting of additional diverse genetic variants that could be important in understanding interindividual and between-population variations in therapeutic responses to dyslipidemia and COVID-19. This expert review examines and synthesizes the salient and priority PGx variations, as seen through a One Health lens in Africa, to improve and inform personalized medicine in both dyslipidemia and COVID-19.

PMID:37956269 | DOI:10.1089/omi.2023.0122

Pharmacogenomics. 2023 Nov 13. doi: 10.2217/pgs-2023-0198. Online ahead of print.

ABSTRACT

Tweetable abstract Present evidence supports the use of intensified pharmacologic monitoring of #imatinib including #TherapeuticDrugMonitoring and #PGx to improve outcomes in patients with GI stromal tumor. Future studies need to address emerging questions to facilitate implementation in clinics.

PMID:37955064 | DOI:10.2217/pgs-2023-0198

Ther Adv Rare Dis. 2023 Nov 8;4:26330040231204643. doi: 10.1177/26330040231204643. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Currently, HD can only be managed symptomatically, including a large variety of prescribed drugs. Many HD patients experience negative medication effects (e.g. side effects or non-response). Pharmacogenetic (PGx) studies show how genetic variation affects both medication efficacy and toxicity and holds the potential to improve these outcomes of drug treatment.

PRIMARY OBJECTIVE: To classify the effect of the PGx profile of CYP2C19 and CYP2D6 in HD gene expansion carriers on negative medication effects of HD-related medication.

DESIGN: Multicenter, observational study with 1-year follow-up. Adult HD gene expansion carriers who use one or more HD-related medications are eligible to participate.

METHODS AND ANALYSIS: A detailed overview of medication use, medication efficacy, and side effects is retrospectively and prospectively collected via medication diaries, questionnaires, phone calls, and pharmacy medication verification schemes. PGx analysis on whole blood-extracted DNA is performed with Agena Bioscience VeriDose® Core Panel and long-range polymerase chain reaction copy number variation analysis. Per the study protocol-defined negative medication effects in HD gene expansion carriers with a genotype predicted poor or ultrarapid metabolizer phenotype will be compared with HD gene expansion carriers with a predicted intermediate and normal metabolizer phenotype. Frequencies will be analyzed via χ2 and logistic multivariate regression analysis. In addition, we summarize in this manuscript HD-relevant PGx prescription recommendations to improve drug therapy.

ETHICS: The original study protocol was approved by the medical research ethics committee Leiden Den Haag Delft on 26 November 2019.

DISCUSSION: HD-MED is a low-risk study that will generate personalized PGx results that can immediately be implemented in clinical practice, thus potentially improving pharmacovigilance and patients' quality of life.

REGISTRATION: This study is registered in the International Clinical Trial Registry Platform under registration number NL8251, URL https://trialsearch.who.int/Trial2.aspx?TrialID=NL8251.

PMID:37955016 | PMC:PMC10634258 | DOI:10.1177/26330040231204643

Neurogastroenterol Motil. 2023 Nov 12:e14705. doi: 10.1111/nmo.14705. Online ahead of print.

ABSTRACT

BACKGROUND: Amitriptyline (AT) is recommended as first-line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice.

METHODS: This pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well-characterized cohort of adults with CVS.

KEY RESULTS: Of 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra-rapid metabolizers. There was no statistically significant association between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result.

CONCLUSIONS AND INFERENCES: A subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy.

PMID:37953495 | DOI:10.1111/nmo.14705

Steroids. 2023 Nov 9:109335. doi: 10.1016/j.steroids.2023.109335. Online ahead of print.

ABSTRACT

Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.

PMID:37951289 | DOI:10.1016/j.steroids.2023.109335

Lancet Gastroenterol Hepatol. 2023 Dec;8(12):1072-1073. doi: 10.1016/S2468-1253(23)00323-0.

NO ABSTRACT

PMID:37951236 | DOI:10.1016/S2468-1253(23)00323-0

J Neurol. 2023 Nov 11. doi: 10.1007/s00415-023-12076-4. Online ahead of print.

ABSTRACT

Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.

PMID:37950760 | DOI:10.1007/s00415-023-12076-4

J Affect Disord. 2023 Nov 8:S0165-0327(23)01376-9. doi: 10.1016/j.jad.2023.11.016. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: CYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy.

METHODS: Nonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window.

RESULTS: Results showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects.

LIMITATION: All samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age.

CONCLUSION: The study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

PMID:37949237 | DOI:10.1016/j.jad.2023.11.016

Hypertens Res. 2023 Nov 9. doi: 10.1038/s41440-023-01491-9. Online ahead of print.

NO ABSTRACT

PMID:37945891 | DOI:10.1038/s41440-023-01491-9

Pharmacogenomics. 2023 Nov 9. doi: 10.2217/pgs-2023-0164. Online ahead of print.

ABSTRACT

Aim: Identify oncology healthcare providers' attitudes toward barriers to and use cases for pharmacogenomic (PGx) testing and implications for prescribing anticancer and supportive care medications. Materials & methods: A questionnaire was designed and disseminated to 71 practicing oncology providers across the MedStar Health System. Results: 25 of 70 (36%) eligible oncology providers were included. 88% were aware of PGx testing and 72% believed PGx can improve care. Of providers who had ordered a medication with PGx implications in the past month, interest in PGx for anticancer (90-100%) and supportive care medications (>75%) was high. Providers with previous PGx education were more likely to have ordered a test (odds ratio: 7.9; 95% CI: 1.1-56; p = 0.0394). Conclusion: Oncology provider prescribing practices and interest in PGx suggest opportunities for implementation.

PMID:37942634 | DOI:10.2217/pgs-2023-0164

Genet Res (Camb). 2023 Oct 31;2023:6105320. doi: 10.1155/2023/6105320. eCollection 2023.

ABSTRACT

INTRODUCTION: Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance.

METHODS: We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's p value was higher than 0.1. We used random models when the p value was less than 0.1.

RESULTS: Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations.

CONCLUSION: This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.

PMID:37942082 | PMC:PMC10630013 | DOI:10.1155/2023/6105320

J Crohns Colitis. 2023 Nov 6:jjad182. doi: 10.1093/ecco-jcc/jjad182. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD.

METHODS: We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling.

RESULTS: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001).

CONCLUSIONS: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses.

PMID:37941436 | DOI:10.1093/ecco-jcc/jjad182

Pharmacogenomics J. 2023 Nov 9. doi: 10.1038/s41397-023-00319-6. Online ahead of print.

ABSTRACT

Compound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD). Our previous work demonstrated no relationship between pre-treatment CACC and ORT buprenorphine doses; we hypothesised that CYP2D6 activity would partially account for this disconnection. One hundred six participants with CUD were compared to a published population sample of 5408 Australian patients. Mean age of participants with CUD at treatment entry was 35 years, with mean 6.1 years duration of CUD. Mean codeine dose was 660 mg/day (range 40-2700 mg). Mean calculated CYP2D6 activity scores were significantly higher in the codeine group (CUD 1.65 + 0.63 vs. Gen pop 1.39 + 0.65, Wilcoxon W = 347,001, p < 0.001). Pre-treatment CACC dose weakly predicted sublingual buprenorphine doses overall; there was a stronger relationship within ultrarapid metabolisers. While normal and ultrarapid metabolisers of codeine were more likely to have a diagnosis of CUD, poor or intermediate CYP2D6 metaboliser status may protect against CUD.

PMID:37940651 | DOI:10.1038/s41397-023-00319-6

Pharmacogenomics J. 2023 Nov 9. doi: 10.1038/s41397-023-00318-7. Online ahead of print.

ABSTRACT

Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable efficacy and toxicity. Drug-drug interactions can also affect the metabolism of codeine. A tool to adjust codeine dose based on these factors does not currently exist. Healthcare providers should use their clinical judgment and reference different established dosing guidelines to determine the appropriate dose of codeine for individual patients. The study provides a tool that assists prescribers in adjusting codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions. Highlighted is the need to consider pharmacogenetics and drug-drug interactions when determining the appropriate dosing of codeine and provide a framework for implementing individualized dosing based on these factors.

PMID:37940650 | DOI:10.1038/s41397-023-00318-7