J Clin Med. 2024 Oct 8;13(19):5995. doi: 10.3390/jcm13195995.

ABSTRACT

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.

PMID:39408056 | DOI:10.3390/jcm13195995

BMC Psychiatry. 2024 Oct 15;24(1):690. doi: 10.1186/s12888-024-06162-8.

ABSTRACT

BACKGROUND: There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram.

METHODS: The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21).

RESULTS: At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response.

CONCLUSIONS: These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy.

PMID:39407134 | DOI:10.1186/s12888-024-06162-8

Inflammopharmacology. 2024 Oct 16. doi: 10.1007/s10787-024-01578-w. Online ahead of print.

ABSTRACT

As of the 7th of July 2024, 775,754,322 confirmed cases of COVID-19, including 7,053,902 deaths worldwide, had been reported to the WHO (World Health Organization). Nevertheless, untill the 15th of July 2024, a total of 13,578,710,228 vaccine doses had been administered, with almost no country spared from COVID-19 attacks. The pathophysiology of this virus is complicated, and several symptoms require a deep understanding of the actual mechanisms. It is unclear why some patients develop severe symptoms while others do not, although literature suggests a role for vitamin D. Vitamin D plays a crucial role in the infection or in ameliorating the severity of symptoms. The mechanism of action of vitamin D and vitamin D deficiency (VDD) is well understood. VDD is associated with increased hospitalization of severely ill patients and increased levels of COVID-19-caused mortality. Recent studies suggest that vitamin D levels and genetic variations in the vitamin D receptor (VDR) gene significantly impact the severity and outcomes of COVID-19, especially in the infections caused by Delta and Omicron variants. Furthermore, VDD causes immune system dysregulation upon infection with SARS-CoV-2, indicating that vitamin D sufficiency is crucial in fighting against COVID-19 infection. The therapeutic effect of vitamin D raises interest in its potential role as a prophylactic and treatment adjunct. We evaluate the immunomodulatory effects of vitamin D and its ability to enhance the efficacy of new antiviral drugs like molnupiravir and paxlovid against SARS-CoV-2. This review discusses the role of vitamin D sufficiency and VDD in COVID-19 initiation and progression, emphasizing the molecular mechanisms by which vitamin D exerts its actions as a proactive step for the next pandemic. However, there is still no clear evidence of vitamin D's impact on prevention and treatment, leading to contradictory findings. Therefore, large-scale randomized trials are required to reach a definitive conclusion. A bibliometric analysis of publications related to vitamin D, immunity, and COVID-19 revealed a significant increase in research activity in this area, particularly in 2020-2024, underscoring the growing recognition of vitamin D's potential role in the context of the pandemic.

PMID:39406981 | DOI:10.1007/s10787-024-01578-w

Pharmacol Rev. 2024 Oct 15:PHARMREV-AR-2023-001049. doi: 10.1124/pharmrev.124.001049. Online ahead of print.

ABSTRACT

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

PMID:39406507 | DOI:10.1124/pharmrev.124.001049

Diagn Microbiol Infect Dis. 2024 Oct 10;110(4):116553. doi: 10.1016/j.diagmicrobio.2024.116553. Online ahead of print.

ABSTRACT

Omadacycline is a novel tetracycline antibiotic that has a strong in vitro antibacterial activity against atypical pathogen such as Legionella. It is approved for the treatment of adults with community-acquired bacterial pneumonia, including Legionella pneumonia. However, clinical data on the use of omadacycline in Legionella pneumonia is limited. In the present paper, we report a case of severe pneumonia induced by Legionella pneumophila (L.pneumophila) presenting with septic shock and multiple organ dysfunction including lung, liver and kidney. With omadacycline treaetment, inflammation indices of the patient markedly decreased, and the patient significantly improved with multiple organ dysfunction and was discharged from home. Due to its strong antibacterial activity against L.pneumophila, good safety profile and no dosage adjustment in patients with severe hepatic or renal impairment, omadacycline can be considered as an optimal treatment strategies for severe infections by such special pathogen. Whereas, more case reports are needed to support this conclusion.

PMID:39406043 | DOI:10.1016/j.diagmicrobio.2024.116553

Am J Health Syst Pharm. 2024 Oct 15:zxae294. doi: 10.1093/ajhp/zxae294. 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 human leukocyte antigen (HLA)-related genotype-guided prescribing in Singapore.

SUMMARY: Various HLA alleles have been implicated in drug hypersensitivity syndromes (DHS). These include HLA-B*15:02, which has been associated with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis, HLA-B*58:01, which has been associated with increased risk of severe cutaneous adverse reactions with allopurinol use, and HLA-B*57:01, which has been associated with increased risk of hypersensitivity reactions with abacavir use. Integrating pharmacogenomics into patient care through genotype-guided prescribing potentially optimizes use of these drugs by reducing DHS-related and healthcare costs. We describe the prevalence of HLA-related DHS in Singapore, the cost-effectiveness of genotype-guided prescribing, and local policies and guidelines, as well as the impact of genotype-guided prescribing where available.

CONCLUSION: HLA-related genotype-guided prescribing has the potential to reduce the incidence of DHS and decrease healthcare costs, as seen in the success with carbamazepine. However, not all genotype-guided prescribing is cost-effective when implemented across the population, as was evident from local studies for allopurinol and abacavir. The cost-effectiveness of such measures may change over time with new data (eg, allele frequencies, test costs, drug prices, genotyping approach) and should be evaluated periodically and locally. Implementation of preemptive pharmacogenomics panel testing as part of routine clinical care may shift the threshold for cost-effectiveness and brings promise of further optimization of pharmacotherapy through precision medicine.

PMID:39405418 | DOI:10.1093/ajhp/zxae294

Genet Med. 2024 Oct 14:101228. doi: 10.1016/j.gim.2024.101228. Online ahead of print.

ABSTRACT

The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with >2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on clinicalgenome.org and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen's knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to https://www.clinicalgenome.org/start.

PMID:39404758 | DOI:10.1016/j.gim.2024.101228

Clin Transl Sci. 2024 Oct;17(10):e70044. doi: 10.1111/cts.70044.

ABSTRACT

Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient-specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health-system-wide, mixed-methods study. Clinicians representing multiple practices and care settings (N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient-specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0-100 points) of each alert, the perceived impact of each alert on stress and decision-making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision-making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician-guided design of PGx alerts in the era of digital medicine.

PMID:39402925 | DOI:10.1111/cts.70044

JAMIA Open. 2024 Oct 12;7(4):ooae101. doi: 10.1093/jamiaopen/ooae101. eCollection 2024 Dec.

ABSTRACT

OBJECTIVE: Understand perceived barriers to and facilitators of using clinical informatics applications for pharmacogenomic (PGx) implementation in resource-limited settings.

MATERIALS AND METHODS: We conducted a qualitative research study using a semi-structured interview guide informed by the Consolidated Framework for Implementation Research (CFIR). Interview questions assessed CFIR contextual determinants related to: electronic health record (EHR) infrastructure; clinical informatics personnel and resources; EHR integration of PGx test results; PGx clinical decision support (CDS) tools; institutional resources; and partner receptivity. Transcripts were coded and analyzed to identify themes.

RESULTS: We interviewed 24 clinical informaticists and executive leaders working in rural or underserved health care settings in Montana (n = 15) and Colorado (n = 9) and identified three major themes: (1) EHR infrastructure limitations, (2) insufficient supporting resources, and (3) unique contextual considerations for resource-limited settings. EHR infrastructure limitations included limited agency related to EHR build and interoperability concerns. Theme 1 highlighted challenges associated with integrating structured data into the EHR and inadequate vendor support. Theme 2 included limited familiarity with PGx across the care team, cost concerns, and allocation of non-financial resources. Theme 3 highlighted perceptions about the clinical utility of PGx within rural and underrepresented populations. Potential facilitators, such as being able to act nimbly, were found to coexist among the reported barriers.

DISCUSSION AND CONCLUSION: Our results provide insight into the clinical informatics infrastructure in resource-limited settings and identify unique considerations for clinical informatics-facilitated PGx implementation. Future efforts in these settings should consider innovative partnerships and strategies to leverage facilitators and minimize barriers associated with integrating PGx CDS applications.

PMID:39399271 | PMC:PMC11471000 | DOI:10.1093/jamiaopen/ooae101

Pharmacogenomics. 2024 Oct 11:1-8. doi: 10.1080/14622416.2024.2404819. Online ahead of print.

ABSTRACT

Aim: To investigate the associations between genetic polymorphisms in immunorelated genes and PBMC-induced cytotoxicity to breast cancer cell with the treatment of trastuzumab in vitro.Methods: Trastuzumab-mediated cytotoxicity of peripheral blood mononuclear cells (PBMC) from 148 healthy donors and 13 BC patients was analyzed by flow cytometry. 16 SNPs in 7 immunorelated genes were genotyped by Sequenom Mass Array Genotype Platform.Results: Cytotoxicity in the trastuzumab treated PBMCs were significantly higher than those of the basal group. A wide variability in trastuzumab-mediated cytotoxicity was observed, and PBMC from individuals with the CD247 rs16859030 T genotype generated increased cytotoxicity than those with the CC genotype.Conclusion: The CD247 rs16859030 polymorphism affects trastuzumab-mediated cytotoxicity in vitro.

PMID:39392082 | DOI:10.1080/14622416.2024.2404819

iScience. 2024 Sep 10;27(10):110916. doi: 10.1016/j.isci.2024.110916. eCollection 2024 Oct 18.

ABSTRACT

Genetic ancestry plays a major role in pharmacogenomics, and a deeper understanding of the genetic diversity among individuals holds immerse promise for reshaping personalized medicine. In this pivotal study, we have conducted a large-scale genomic analysis of 1,136 pharmacogenomic variants employing machine learning algorithms on 3,714 individuals from publicly available datasets to assess the risk proximity of experiencing drug-related adverse events. Our findings indicate that Admixed Americans and Europeans have demonstrated a higher risk of experiencing drug toxicity, whereas individuals with East Asian ancestry and, to a lesser extent, Oceanians displayed a lower risk proximity. Polygenic risk scores for drug-gene interactions did not necessarily follow similar assumptions, reflecting distinct genetic patterns and population-specific differences that vary depending on the drug class. Overall, our results provide evidence that genetic ancestry is a pivotal factor in population pharmacogenomics and should be further exploited to strengthen even more personalized drug therapy.

PMID:39391720 | PMC:PMC11465127 | DOI:10.1016/j.isci.2024.110916

Br J Clin Pharmacol. 2024 Oct 10. doi: 10.1111/bcp.16277. Online ahead of print.

ABSTRACT

AIM: Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.

METHODS: We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.

RESULTS: Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively.

CONCLUSION: Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.

PMID:39390741 | DOI:10.1111/bcp.16277

J Child Adolesc Psychopharmacol. 2024 Oct 10. doi: 10.1089/cap.2024.0069. Online ahead of print.

ABSTRACT

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

PMID:39387268 | DOI:10.1089/cap.2024.0069

Planta Med. 2024 Oct 10. doi: 10.1055/a-2416-8584. Online ahead of print.

ABSTRACT

Wound infections are a significant medical problem, with Staphylococcus species being one of the most common etiological factors. Treatment is complex due to bacterial antibiotic resistance and the ability to form a biofilm. The aim of this study was to determine the drug susceptibility of the clinical isolates of Staphylococcus species obtained from wound infections, assess their ability to form a biofilm in vitro, evaluate the level of extracellular slime synthesis, and test the antistaphylococcal properties of selected plant extracts against plate-cultured bacteria and activity against mature biofilms. A total of 20 Staphylococcus strains were evaluated. The antibiotic susceptibility and sensitivity of the strains to the tested extracts were determined using the disc diffusion method. The production of extracellular bacterial slime was assessed using Congo Red agar plates. The biofilm formation and the effect of plant extracts on the biofilm layer were examined using the MTT method on polystyrene microtiter plates. Diverse drug susceptibility profiles, slime production ability, and in vitro biofilm formation were observed among the tested strains. It was found that aqueous extracts from the Serpylli herba, Arctii lappae folium, Taraxaci folium, and Galii aparini herba showed antibacterial activity against some of the tested strains. In contrast, their antibiofilm activity was not confirmed. Among all tested preparations, the most promising antimicrobial extracts in both planktonic cultures and biofilm were Thymus serpyllum herb and Taraxacum officinale leaf extracts. These results allowed us to conclude their potential application in medicine to support the treatment of challenging wound conditions.

PMID:39389560 | DOI:10.1055/a-2416-8584

PLoS One. 2024 Oct 10;19(10):e0311267. doi: 10.1371/journal.pone.0311267. eCollection 2024.

ABSTRACT

BACKGROUND: Pharmacogenetic testing in routine care could provide benefits for patients, doctors and statutory health insurances. Therefore, the aim of the retrospective, observational study Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung (EMPAR) was to analyze the relationship between pharmacogenetic profiles, the risk of adverse drug reactions, and patients' perceptions of drug therapy in 10748 adult (≥18 years) participants in Germany.

METHODS: A questionnaire was used to assess views and beliefs about medicines and participants individual perception of sensitivity to drug therapies. The questionnaire consisted of the Beliefs about Medicines Questionnaire (BMQ)-General scales (Overuse, Harm, Benefit), the Perceived Sensitivity to Medicines (PSM), Natural Remedy, and Gene Testing scales. The influence of gender, age, study collective, genotype and phenotype of relevant pharmacogenes on participant's perception were evaluated.

RESULTS: Overuse, PSM and Benefit scores were significantly higher among patients of the collective International Classification of Diseases and Health Related Disorders (ICD)-10 Y57.9! diagnosis, which indicates complications related to drugs, compared to the anticoagulant/antiplatelet and cholesterol-lowering drug collective. Age and gender also played a significant role in patients' perceptions, with younger patients and female participants more likely to believe in medication overuse according to the Overuse scale score compared to older and male participants. Female participants compared to male participants and the old age group compared to the young and/or middle-age subgroup, scored higher in PSM and/or Harm scales, respectively. Only a tendency of increased Harm, Overuse and PSM scores was observed in the participant group with five or more relevant actionable variants compared to subgroups with 0 up to 4 variants.

CONCLUSIONS: In conclusion, patients' beliefs about medicines and their drug sensitivity perceptions are influenced by various factors including age, gender, previous complications with medicines, and with some tendency also pharmacogenetic profiles. The higher association with more negative views related to treatment indicates that there is a need to target the underlying issues in affected patient groups in order to improve compliance to treatment and outcomes in routine care. Trial registration: EMPAR was registered in the German Clinical Trials Register (DRKS) on 06 July 2018 (DRKS00013909).

PMID:39388460 | PMC:PMC11466409 | DOI:10.1371/journal.pone.0311267

Front Pharmacol. 2024 Sep 24;15:1432906. doi: 10.3389/fphar.2024.1432906. eCollection 2024.

ABSTRACT

INTRODUCTION: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population.

METHOD: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations.

RESULTS: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans.

CONCLUSION: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong.

PMID:39386031 | PMC:PMC11462547 | DOI:10.3389/fphar.2024.1432906

Clin Exp Allergy. 2024 Oct 9. doi: 10.1111/cea.14565. Online ahead of print.

ABSTRACT

Anaphylaxis affects up to 5% of people during their lifetime. Although anaphylaxis usually resolves without long-term physical consequences, it can result in anxiety and quality of life impairment. Rarely and unpredictably, community anaphylaxis can cause rapid physiological decompensation and death. Adrenaline (epinephrine) is the cornerstone of anaphylaxis treatment, and provision of adrenaline autoinjectors (AAI) has become a standard of care for people at risk of anaphylaxis in the community. In this article, we explore the effectiveness of AAIs for preventing fatal outcomes in anaphylaxis, using information drawn from animal and human in vivo studies and epidemiology. We find that data support the effectiveness of intravenous adrenaline infusions for reversing physiological features of anaphylaxis, typically at doses from 0.05 to 0.5 μg/kg/min for 1-2 h, or ~ 10 μg/kg total dose. Intramuscular injection of doses approximating 10 μg/kg in humans can result in similar peak plasma adrenaline levels to intravenous infusions, at 100-500 pg/mL. However, these levels are typically short-lived following intramuscular adrenaline, and pharmacokinetic and pharmacodynamic outcomes can be unpredictable. Epidemiological data do not support an association between increasing AAI prescriptions and reduced fatal anaphylaxis, although carriage and activation rates remain low. Taken together, these data suggest that current AAIs have little impact on rates of fatal anaphylaxis, perhaps due to a lack of sustained and sufficient plasma adrenaline concentration. Effects of AAI prescription on quality of life may be variable. There is a need to consider alternatives, which can safely deliver a sustained adrenaline infusion via an appropriate route.

PMID:39383344 | DOI:10.1111/cea.14565

Pharmacogenomics. 2024 Oct 9:1-12. doi: 10.1080/14622416.2024.2403967. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is a practice that investigates the link between genetic differences and drug response in patients. This can improve treatment effectiveness and reduce harmful side effects. However, has yet to be adequately realized in developing nations. Three surveys were conducted between November 2022 to March 2023 in Egypt and Lebanon. The first survey assessed availability of PGx testing in different healthcare facilities; the second one assessed knowledge, interest and attitude toward learning about PGx among pharmacists and physicians; and the third one assessed interest in providing PGx education at academic levels. In Egypt, a few of the surveyed healthcare facilities are conducting some form of pharmacogenetic testing. In Lebanon, very few germline pharmacogenomic tests are offered in Greater Beirut's leading hospitals, and no other testing was recorded. PGx education attracts considerable interest, with 34.3% of pharmacists very interested and 48.8% interested. Similarly, 24.8% of total physicians were very interested while 44.8% were interested. Academic professionals in the surveyed institutions in both countries agreed on the need for educational programs in PGx and 78.2% agreed that there were good opportunities for implementing PGx testing. These findings clearly indicate the need to develop and implement educational programs in PGx in the Middle-East.

PMID:39382016 | DOI:10.1080/14622416.2024.2403967

Pharmacogenomics. 2024 Oct 9:1-7. doi: 10.1080/14622416.2024.2409058. Online ahead of print.

ABSTRACT

Aim: To survey Veterans Health Administration providers who prescribed tramadol or codeine to patients with known genotyping for cytochrome 2D6 (CYP2D6) to ascertain awareness of their patient's pharmacogenetic (PGx) test status, whether these results influenced prescribing, perceived benefit of PGx testing, and resources needed to obtain and deliver PGx testing information.Materials & methods: A provider survey was conducted of those who prescribed tramadol or codeine in a patient genotyped for CYP2D6.Results: Of 876 eligible providers, 220 completed the survey. Ten percent were aware that their patient received a PGx test, 64% had not ordered any PGx test related to any medication in the prior year, 55% strongly agreed or agreed that PGx testing is or will be valuable to guide pain medication prescriptions, 29% felt that the evidence base for PGx testing is very strong or moderately strong, 22% responded likely or extremely likely to order a future PGx test, and 51% felt that it would be either very important or fairly important to have a local subject matter expert as a resource for PGx testing.Conclusion: There are modifiable factors that the Veterans Health Administration could address to optimize PGx testing for pain management.

PMID:39382015 | DOI:10.1080/14622416.2024.2409058

Pharmacogenomics. 2024 Oct 9:1-10. doi: 10.1080/14622416.2024.2406739. Online ahead of print.

ABSTRACT

Aim: Thiopurine drugs are used in the treatment of various diseases including inflammatory bowel disease. Thiopurine-S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are the crucial enzymes involved in thiopurines metabolism. The present study aims to investigate in Tunisian patients, the influence of genetic and nongenetic factors on thiopurine drugs pharmacokinetics.Experimental approach: We have included patients having received thiopurine drugs and have undergone 6-thioguanine nucleotides (6-TGN) concentration monitoring. The identification of TPMT and ITPA polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. The impact of both genetic and nongenetic factors on the variability of the 6-TGN C/D ratio was analyzed through a stepwise multiple regression model.Key results: One hundred and twenty-three patients were included in the study. For TPMT, the most frequent variant allele was TPMT*3B (3.3%). For ITPA, the predominant polymorphism was the c.IVS2 + 21A> C (7%). We have demonstrated that only gender, the TPMT*3A and TPMT*3C alleles are significantly involved on the variability of thiopurines pharmacokinetics.Conclusion: Our study is the first to evaluate, in African patients, the impact of both genetic and nongenetic factors on the thiopurine drugs pharmacokinetics. Considering the narrow therapeutic range of these drugs, TPMT genotyping combined with 6-TGN blood concentration monitoring may enhance their efficacy and safety.

PMID:39382000 | DOI:10.1080/14622416.2024.2406739