Urogynecology (Phila). 2025 Feb 14. doi: 10.1097/SPV.0000000000001668. Online ahead of print.

ABSTRACT

IMPORTANCE: Pharmacogenetics could address the challenge of predicting an individual's response to anticholinergic medications for urgency urinary incontinence (UUI).

OBJECTIVES: Our objectives were to evaluate whether the metabolizer status of cytochrome p450 2D6 (CYP2D6), the drug metabolizing enzyme for fesoterodine, is associated with effectiveness or moderate/severe adverse events (AEs) from fesoterodine fumarate in women with UUI.

STUDY DESIGN: In this pilot pharmacogenetics study, 58 women aged ≥50 with ≥3 UUI episodes on a 3-day bladder diary were treated with fesoterodine. Participants were categorized as normal metabolizers (NM), intermediate (IM), or poor metabolizers (PM) based on their genetic CYP2D6 sequence. Effectiveness was measured by Treatment Benefit Scale (responders were "improved" or "greatly improved" versus nonresponders were "not changed" or "worsened"). Moderate and severe AEs were defined by the National Cancer Institute Common Terminology Criteria for Adverse Events.

RESULTS: Among 58 women, 34 (58.6%) were NM, 22 (37.9%) were IM, and 2 (3.4%) were PM. Given the small proportion of PM, we compared the NM and IM groups. Regarding effectiveness for UUI, there was no significant difference between metabolizer cohorts at 4 weeks (82.8% vs 94.4%, P = 0.38 for NM vs IM, respectively). Metabolizer status was also not associated with moderate-severe AEs (14.7% vs 13.6% for NM vs IM, P = 1.0).

CONCLUSIONS: In this pilot study with limited sample size, CYP2D6 normal and IM metabolizer status was not associated with effectiveness or moderate-severe AEs to fesoterodine fumarate. The proportion of poor metabolizers was low; thus, further investigation in this population is warranted.

PMID:40105750 | DOI:10.1097/SPV.0000000000001668

Clin Transl Sci. 2025 Mar;18(3):e70144. doi: 10.1111/cts.70144.

ABSTRACT

Integration of clinical pharmacogenomics (PGx) within routine cancer care is limited despite frequent use of medicines impacted by PGx, evidence for the benefits of PGx, and the availability of international PGx clinical guidelines. Our study objective was to develop survey tools to assess PGx knowledge, attitudes, practices, perceptions, and education needs among (a) doctors, nurses, and pharmacists involved in cancer care (healthcare professionals, HCPs) and (b) adults who have received cancer treatment or their carers (consumers), with the view to informing implementation strategies for PGx in solid and hematologic cancers. Survey tools were developed in a three-phase (ph) mixed-methods approach. Content was informed by systematic literature review findings and framed by determinants of behavior as informed by the Theoretical Domains Framework (ph-1). Refinement occurred through four separate priority partnership meetings (ph-2). Meetings focused on clinical PGx practices within select cancer streams, and consumers' knowledge, attitudes, and preferences for PGx testing. Content/face validity and health literacy (Flesch Kincaid Grade Level) assessments informed final refinements (ph-3). Separate HCP and consumer survey tools were developed with six common sections: (1) introduction; (2) demographics; (3) experience; (4) knowledge, attitudes, practices and perceptions; (5) education; and (6) vignettes. Content and face validity were rated highly with acceptable health literacy assessments for questions within the consumer survey (median grade level 6; range 1-8). The developed survey tools will be used to generate evidence to inform local implementation strategies for PGx in cancer and promote broader integration of pharmacogenomics in routine clinical care.

PMID:40103279 | DOI:10.1111/cts.70144

J Nanobiotechnology. 2025 Mar 18;23(1):217. doi: 10.1186/s12951-025-03310-4.

ABSTRACT

Non-small cell lung cancer (NSCLC) represents the most prevalent form of lung cancer, exerting a substantial impact on global health. Cisplatin-based chemotherapy is the standard treatment for NSCLC, but resistance and severe side effects present significant clinical challenges. Recently, novel tetravalent platinum compounds have attracted significant interest. While numerous studies concentrate on their functional modifications and targeted delivery, tumor-induced platinum resistance is frequently overlooked. Previous tetravalent platinum compound demonstrated antitumor activity, yet proved ineffective against cells exhibiting resistance to cisplatin. In order to enhance the efficacy and potential applications of tetravalent platinum in NSCLC, a glutathione (GSH)-responsive albumin nanoquadrivalent platinum (HSA@Pt) have been constructed. In light of previous research into drug conjugation, this study was to develop a combined chemo-immunotherapy approach. The HSA@Pt demonstrated high efficacy and low toxicity, with targeted tumor accumulation. Furthermore, Ammonium Tetrathiomolybdate (TM) has been demonstrated to exert a synergistic inhibitory effect on ATPase Copper Transporting Beta (ATP7B) and Programmed Death Ligand 1 (PD-L1), impede platinum efflux, induce cellular stress, and activate antitumor immunity. The findings suggest HSA@Pt's potential for clinical use and a novel chemo-immunotherapy strategy for NSCLC, enhancing the utility of established drugs through synergistic sensitization.

PMID:40102840 | DOI:10.1186/s12951-025-03310-4

Curr Psychiatry Rep. 2025 Mar 18. doi: 10.1007/s11920-025-01605-9. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Suicidal behaviour remains a critical public health issue, with limited progress in reducing suicide rates despite various prevention efforts. The introduction of precision psychiatry offers hope by tailoring treatments based on individual genetic, environmental, and lifestyle factors. This approach could enhance the effectiveness of interventions, as current strategies are insufficient-many individuals who die by suicide had recently seen a doctor, but interventions often fail due to rapid progression of suicidal behaviour, reluctance to seek treatment, and poor identification of suicidal ideation.

RECENT FINDINGS: Precision medicine, particularly through the use of machine learning and 'omics' techniques, shows promise in improving suicide prevention by identifying high-risk individuals and developing personalised interventions. Machine learning models can predict suicidal risk more accurately than traditional methods, while genetic markers and environmental factors can create comprehensive risk profiles, allowing for targeted prevention strategies. Stratification in psychiatry, especially concerning depression, is crucial, as treating depression alone does not effectively reduce suicide risk. Pharmacogenomics and emerging research on inflammation, psychological pain, and anhedonia suggest that specific treatments could be more effective for certain subgroups. Ultimately, precision medicine in suicide prevention, though challenging to implement, could revolutionise care by offering more personalised, timely, and effective interventions, potentially reducing suicide rates and improving mental health outcomes. This new approach emphasizes the importance of suicide-specific strategies and research into stratification to better target interventions based on individual patient characteristics.

PMID:40100585 | DOI:10.1007/s11920-025-01605-9

Per Med. 2025 Mar 18:1-9. doi: 10.1080/17410541.2025.2476392. Online ahead of print.

ABSTRACT

PURPOSE: To investigate patient reactions to and understanding of secondary genomic findings with limited to no medical actionability (LMA-SFs) from diagnostic genome sequencing.

METHODS: We analyzed LMA-SFs returned to 47 adults who elected to receive a broad set of these results from 6 categories. Findings indicated elevated risk (reportable/positive) or not (negative/normal). Most participants (N = 43) also completed surveys to report their distress, decision regret, expected health anxiety, and whether and how they perceived results as reassuring or troubling.

RESULTS: Most participants received some reportable LMA-SFs for common risk, pharmacogenetic, and carrier status variants. Fewer received reportable APOE haplotype or monogenetic condition variants. None received results indicating high risk for severe neurological disease. Overall, participants (76.7% female, 97.7% White) had low distress, decision regret, and expected health anxiety. None described negative/normal findings as troubling. However, their interpretations of reportable/positive results varied. Even within the same result type, some participants found them troubling, while others found them reassuring based on their perception of the results' utility.

CONCLUSION: Participants' short-term well-being was not reduced by receiving LMA-SFs. Their interpretations suggested varied personal utilities and the need for post-test resources to aid understanding of these types of results and their health significance.

PMID:40100039 | DOI:10.1080/17410541.2025.2476392

Clin Pharmacol Ther. 2025 Mar 18. doi: 10.1002/cpt.3642. Online ahead of print.

ABSTRACT

Major depressive disorder is a common disorder in pregnancy. Although citalopram/escitalopram is the second most frequently prescribed antidepressant for pregnant people, information about its pharmacokinetics in pregnancy is limited. We investigated plasma (S)-citalopram concentration to dose (C/D) ratios across pregnancy and postpartum and the effect of pharmacogenetics on its elimination. This prospective observational cohort study enrolled 30 participants with a singleton pregnancy who chose to continue citalopram/escitalopram during pregnancy for a prior diagnosis of major depression. Monthly blood samples were obtained 24 hours post-dose across pregnancy and twice postpartum for measurement of plasma citalopram, desmethylcitalopram, and didesmethylcitalopram enantiomer concentrations. Compared with the 36-week reference, (S)-citalopram C/D ratios were not significantly different throughout pregnancy. However, the mean (S)-citalopram C/D ratio was elevated by 63% (P < 0.001) 6 to 8 weeks after delivery before it decreased to a mean C/D ratio in the later post-birth period that was marginally different than at 36 weeks (1.20 ± 0.64 vs. 0.92 ± 0.46, respectively; P = 0.06). Analyzing the results by cytochrome P 450 (CYP) 2C19 phenotype, the mean late postpartum (S)-citalopram concentration to dose ratio in intermediate metabolizers was approximately twice that in extensive, rapid, or ultrarapid metabolizers. However, at the 36-week reference point, the mean concentration to dose ratio in pregnant CYP2C19 intermediate metabolizers was 35.7% lower than the distant postpartum ratio, while the ratios in extensive and rapid/ultrarapid metabolizers were 15.4% and 18.5% lower, respectively. Without dose adjustment, people with intermediate or poor CYP2C19 activity may be at risk for subtherapeutic S-citalopram concentrations during pregnancy.

PMID:40099712 | DOI:10.1002/cpt.3642

Br J Clin Pharmacol. 2025 Mar 18. doi: 10.1002/bcp.70047. Online ahead of print.

ABSTRACT

Thiopurines are a class of immunosuppressant and antineoplastic agents. They are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at 10-fold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

PMID:40099566 | DOI:10.1002/bcp.70047

J Bone Metab. 2025 Feb;32(1):21-30. doi: 10.11005/jbm.24.787. Epub 2025 Feb 28.

ABSTRACT

BACKGROUND: This study aims to investigate the effect of genetic polymorphisms of vitamin D receptor (VDR), estrogen receptor 1 (ER1), and Col1a1 on the response to bisphosphonate (BP) therapy in women with postmenopausal osteoporosis (OP).

METHODS: Twenty-one women with postmenopausal OP who received alendronate, ibandronate, or zoledronic acid for one year were enrolled in this study. Bone mineral density (BMD) at the lumbar spine and femoral neck were assessed by dual energy X-ray absorptiometry at baseline and after 12 months. Serum osteocalcin levels were measured at baseline and after 12 months. Polymorphic sites of the genes encoding ER1, VDR and Col1a1 proteins were amplified by polymerase chain reaction and examined using restriction fragment length polymorphism. Response to BP treatment and change in osteocalcin levels were compared among women with different gene polymorphisms.

RESULTS: Ratio of responders to treatment regarding improvements in the BMD of lumbar spine and femoral neck was adequate in 76% and 62%, respectively. There was no significant difference in treatment response regarding BMD in either region or change in serum osteocalcin levels among different gene polymorphisms.

CONCLUSIONS: These findings did not support the potential role of VDR BsmI, Col1a1 Sp1, ER1 PvuII, or XbaI polymorphisms in predicting the response to BP therapy in women with postmenopausal OP. Further investigation with larger prospective studies is required.

PMID:40098426 | DOI:10.11005/jbm.24.787

Clin Transl Sci. 2025 Mar;18(3):e70200. doi: 10.1111/cts.70200.

ABSTRACT

Data on the effects of Roux-en-Y gastric bypass (RYGB) surgery on lansoprazole pharmacokinetics in morbidly obese patients are limited. This study aimed to evaluate the impact of RYGB surgery on the pharmacokinetic profile of lansoprazole in Thai morbidly obese patients. Participants received 30 mg of lansoprazole twice daily for 7 days before surgery and continued the regimen for 6 weeks post-surgery. Plasma lansoprazole concentrations were measured at predose (0), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h after dosing, both pre- and post-surgery, using a validated high-performance liquid chromatography technique. CYP2C19 genotyping classified participants as normal metabolizers (*1/*1) or intermediate metabolizers (*1/*2 and *1/*3). Pharmacokinetic parameters, including the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8 h), maximum plasma concentration (Cmax), and time to maximum concentration (Tmax), were compared before and after surgery. A total of 13 patients (mean age 37.0 ± 3.9 years; body mass index 54.0 ± 4.8 kg/m2) were enrolled. Post-surgery, AUC0-8 h and Cmax decreased by 16% (p = 0.009) and 31% (p = 0.003), respectively, while Tmax remained unchanged. A 30% reduction in Cmax (p = 0.007) was observed in CYP2C19 normal metabolizers, whereas no significant changes were noted in intermediate metabolizers. In conclusion, RYGB surgery significantly reduced lansoprazole systemic exposure, particularly in CYP2C19 normal metabolizers. Further studies are needed to explore the clinical implications of these pharmacokinetic changes and develop optimized treatment strategies for post-RYGB patients. Trial Registration: ClinicalTrials.gov identifier: TCTR20220118001.

PMID:40098302 | DOI:10.1111/cts.70200

Pharmacogenomics. 2025 Mar 17:1-14. doi: 10.1080/14622416.2025.2479414. Online ahead of print.

ABSTRACT

Receptor tyrosine kinase pathways are frequently deregulated in cancer. Inhibiting these pathways with small molecule inhibitors or monoclonal antibodies has become a crucial addition to the therapeutic armamentarium in oncology. Since the introduction of drugs that target receptor tyrosine kinase pathways, it has become evident that not all patients respond to treatment. Therefore, biomarkers to predict response and benefit of drugs targeting tyrosine kinases have been sought. Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), one of the four receptors of the EGFR family were among the first targeted therapies used in solid tumors. Two drugs of this class, cetuximab and panitumumab, have been used in patients with metastatic colorectal cancer initially without any biomarker requirement. Soon, it became clear that responses were mostly observed in patients without mutations in KRAS oncogene. Currently, additional mutations of the pathway, including non-exon 2 mutations in KRAS, mutations in the homologous GTPase NRAS, in kinase BRAF and PIK3CA and other pathway proteins, have been added in the evaluation for responsiveness prediction to cetuximab and panitumumab. In this review, the predictive biomarker landscape for anti-EGFR monoclonal antibody inhibitors in metastatic colorectal cancers with no extended RAS and BRAF mutations will be examined.

PMID:40097366 | DOI:10.1080/14622416.2025.2479414

medRxiv [Preprint]. 2025 Mar 5:2025.03.03.25323247. doi: 10.1101/2025.03.03.25323247.

ABSTRACT

African Americans (AAs) are underrepresented in pharmacogenomics which has led to a significant gap in knowledge. AAs are admixed and can inherit specific loci from either their African or European ancestor, known as local ancestry (LA). A previous study in AAs identified single nucleotide polymorphisms (SNPs) located in the CYP2C cluster that are associated with warfarin dose. However, LA was not considered in this study. An IWPC cohort (N=340) was used to determine the LA-adjusted association with warfarin dose. Ancestry-specific GWAS's were conducted with TRACTOR and ancestry tracts were meta-analyzed using METAL. We replicated top associations in the independent ACCOuNT cohort of AAs (N=309) and validated associations in a warfarin pharmacokinetic study in AAs. To elucidate functional roles of top associations, we performed short-read RNA-sequencing from AA hepatocytes carrying each genotype for expression of CYP2C9 and CYP2C19 . We identified 6 novel genome-wide significant SNPs (P<5E-8) in the CYP2C locus (lead SNP, rs7906871 (P=3.14E-8)). These associations were replicated (P≤2.76E-5) and validated with a pharmacokinetic association for S-Warfarin concentration in plasma (P=0.048). rs7906871 explains 6.0% of the variability in warfarin dose in AAs. Multivariate regression including rs7906871, previously associated SNPs, clinical and demographic factors explain 37% of dose variability, greater than previously reported studies in AAs. RNA-seq data in AA hepatocytes identified a significant alternate exon inclusion event between exons 6 and 7 in CYP2C19 for carriers of rs7906871. In conclusion, we have found and replicated a novel CYP2C variant associated with warfarin dose requirement and potential functional consequences to C YP2C19 .

PMID:40093246 | PMC:PMC11908343 | DOI:10.1101/2025.03.03.25323247

Infect Agent Cancer. 2025 Mar 17;20(1):18. doi: 10.1186/s13027-025-00647-1.

ABSTRACT

BACKGROUND: Despite the success of antiretroviral therapy in HIV treatment, cervical cancer remains a leading malignancy in HIV-infected women. Additionally, co-infection by HIV and HPV further accelerates cervical cancer development. There are limited studies on the role of host somatic variations in HIV infected and HIV-negative women with cervical cancer. Therefore, this study aimed to investigate and compare host somatic genetic variation in cervical biopsies obtained from HIV infected and HIV-negative women with cervical intraepithelial neoplasia 3 to understand the genomic landscape. The distribution of HPV types was also investigated between HIV infected and HIV-negative women.

METHODS: The project used an age-matched case-control study utilizing archived cervical biopsies from 88 women (44 HIV infected, 44 HIV-negative) attending Groote Schuur Hospital Cancer Clinic between 2020 and 2022. HPV infection and type were confirmed using the Anyplex™ II HPV28 Detection kit. Six hotspot regions in the four commonly mutated genes (TP53, PIK3CA, PTEN, and EGFR) in cervical cancer were genotyped using PCR and Sanger Sequencing. Variant pathogenicity was assessed using SIFT, Polyphen-2, and ClinVar tools.

RESULTS: The median age was 37 years (IQR: 34-41) for HIV infected women and 35 years (IQR:32- 43) for HIV-negative women. Significantly more HIV-negative women (51% vs. 12%) reported tobacco smoking (p < 0.0001), menstruation irregularities (74% vs. 35%; p = 0.005), and contraception usage (77% vs. 59%; p = 0.019), when compared to their HIV-infected counterparts. Common HPV types identified were HPV16 (n = 43/88, 49%), HPV35 (n = 12/88, 14%), and HPV58 (n = 10/88, 11%). A total of 232 genetic variants were reported. HIV infected women had a significantly higher (p = 0.0406) burden of pathogenic variants (31%) compared to the HIV-negative (15%). The spectrum of observed mutations included stop-gain, missense, synonymous, and intronic changes. Most of the stop gain mutations in TP53 and PIK3CA were reported among HIV infected women (n = 4/5), compared to HIV-negative women (n = 1/5). Damaging variants were more prevalent in women under 50 in both cohorts. We also report on rare HPV subtypes currently not included in the diagnostic HPV test kits in this cohort (HPV 82, 42, 43 and 53).

CONCLUSION: HIV-infection status and age appear to be risk factors for higher burden of pathogenic mutations in genes that predispose to cervical cancer. Mutation profiles in PIK3CA and TP53 genes could be biomarkers of cervical cancer progression but more studies are needed.

PMID:40091081 | DOI:10.1186/s13027-025-00647-1

CNS Neurosci Ther. 2025 Mar;31(3):e70330. doi: 10.1111/cns.70330.

ABSTRACT

BACKGROUND: Gliomas represent the most aggressive malignancies of the central nervous system, with posttranslational modifications (PTMs) emerging as critical regulators of oncogenic processes through dynamic protein functional modulation. Despite their established role in tumor biology, the systematic characterization of PTM-mediated molecular mechanisms driving glioma progression remains unexplored. This study aims to uncover the molecular mechanisms of glioma, with a focus on the role of PTMs.

METHODS: We analyzed the PTM pathway to classify glioma patients into distinct clusters. Comprehensive analyses compared intercluster differences in clinical outcomes, mutational landscapes, and immune microenvironment profiles. Differentially expressed genes (DEGs) were identified to construct a robust prognostic prediction model with machine learning approaches. Among the genes included in the model, TOM1L1 (Target of Myb1 Like 1 Membrane Trafficking Protein) was selected for in vitro experimental validation to assess its role in glioma progression.

RESULTS: PTMs were found to influence glioma prognosis significantly. Dysregulation in specific pathways, such as glutathionylation and citrullination, was correlated with more aggressive clinical features. The prognostic model, comprising DEGs such as TOM1L1, demonstrated high predictive accuracy (c-index = 0.867)-the scores derived from the model strongly correlated with glioma progression indicators. In vitro experiments revealed that TOM1L1 facilitates malignant progression by modulating PTM pathways, confirming its functional role in glioma.

CONCLUSION: Our study establishes the first comprehensive PTM atlas in gliomas, revealing subtype-specific modification patterns with clinical and therapeutic implications. TOM1L1 emerges as a promising prognostic biomarker and a potential therapeutic intervention target. Targeting PTM pathways may offer novel strategies for glioma treatment, enhancing patient outcomes.

PMID:40090864 | DOI:10.1111/cns.70330

Am J Med. 2025 Mar 14:S0002-9343(25)00166-4. doi: 10.1016/j.amjmed.2025.03.011. Online ahead of print.

NO ABSTRACT

PMID:40090392 | DOI:10.1016/j.amjmed.2025.03.011

Eur J Pharmacol. 2025 Mar 13:177509. doi: 10.1016/j.ejphar.2025.177509. Online ahead of print.

ABSTRACT

The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.

PMID:40089262 | DOI:10.1016/j.ejphar.2025.177509

J Allergy Clin Immunol. 2025 Mar 13:S0091-6749(25)00274-X. doi: 10.1016/j.jaci.2025.02.037. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled corticosteroids (ICS) are frequently prescribed medications for asthma symptoms, but higher doses can increase risks of adrenal insufficiency through suppression of endogenous cortisol production. Understanding which patients may be at increased risk for developing adrenal suppression related to ICS use may help providers improve treatment regimens for asthma patients; however, the mechanisms underlying ICS-related adrenal insufficiency have not been clarified.

OBJECTIVE: This study identifies metabolite signatures and biochemical pathways associated with ICS-related adrenal insufficiency in asthma patients.

METHODS: Global metabolite profiling (metabolomics) was integrated with electronic medical records data including the development of adrenal suppression, in two independent asthma cohorts. The discovery cohort, Pharmacogenomics of Adrenal Suppression with Inhaled Corticosteroids (PhASIC), included 711 adult asthma patients on ICS. Untargeted metabolomic profiling identified 1,397 metabolites, of which 810 were selected for further analysis. Using plasma cortisol as a biomarker for adrenal status (outcome), linear regression models were implemented to identify associations between metabolites and plasma cortisol, adjusted for potential confounders. Metabolite associations were validated in an additional 575 patients on ICS. Pathway and network analyses were performed using bioinformatic approaches to identify altered metabolic pathways related to the outcome.

RESULTS: Of 810 endogenous metabolites, 12 demonstrated significant associations with adrenal insufficiency after correction for multiple comparisons. In the validation cohort, three of these 12 replicated, including two steroid metabolites (tetrahydrocortisol glucuronide and tetrahydrocortisol glucuronide (5)) and homocitrulline. Pathway and network analyses revealed alterations in biochemical pathways related to the metabolism of steroids, bile acids, urea cycle and long-chain polyunsaturated fatty acids.

CONCLUSIONS: We have identified specific metabolites within steroid and non-steroid metabolic pathways that are associated with adrenal insufficiency with ICS use.

PMID:40089116 | DOI:10.1016/j.jaci.2025.02.037

Liver Int. 2025 Apr;45(4):e70069. doi: 10.1111/liv.70069.

NO ABSTRACT

PMID:40087980 | DOI:10.1111/liv.70069

Eur J Med Res. 2025 Mar 14;30(1):170. doi: 10.1186/s40001-025-02412-x.

ABSTRACT

The present systematic review investigates whether different doses of vitamin D and calcium supplementation in women with postmenopausal osteoporosis undergoing antiresorptive therapy have an association with BMD (spine, hip, femur neck), serum markers of osteoporosis (bone-ALP, NTX, CTX), the rate of pathological vertebral and non-vertebral fractures, adverse events, and mortality. This systematic review was conducted according to the PRISMA 2020 guidelines. PubMed, Google Scholar, Embase, and Scopus databases were accessed in September 2024. All randomised clinical trials (RCTs) comparing two or more treatments for postmenopausal osteoporosis supplemented with vitamin D and/or calcium were accessed. Only studies that indicated daily vitamin D and/or calcium supplementation doses were accessed. Data from 37 RCTs (43,397 patients) were retrieved. Patients received a mean of 833.6 ± 224.0 mg and 92.8 ± 228.7 UI of calcium and vitamin D supplementation, respectively. The mean length of the follow-up was 25.8 ± 13.3 months. The mean age of the patients was 66.4 ± 5.6 years, and the mean BMI was 25.2 ± 1.6 kg/m2. There was evidence of a statistically significant negative association between daily vitamin D supplementation and gastrointestinal adverse events (r = - 0.5; P = 0.02) and mortality (r = - 0.7; P = 0.03). No additional statistically significant associations were evidenced. In postmenopausal women who undergo antiresorptive treatment for osteoporosis, vitamin D was associated with a lower frequency of gastrointestinal adverse events and mortality. Calcium supplementation did not evidence an association with any of the endpoints of interest.Level of evidence Level I, systematic review of RCTs.

PMID:40087804 | DOI:10.1186/s40001-025-02412-x

Lancet Reg Health Southeast Asia. 2025 Feb 26;34:100555. doi: 10.1016/j.lansea.2025.100555. eCollection 2025 Mar.

ABSTRACT

Leprosy is effectively treated with multi-drug therapy (MDT), a regimen containing three antibiotic drugs, including dapsone - a sulfone drug associated with potentially life-threatening adverse drug reactions. Specifically, dapsone hypersensitivity syndrome (DHS), linked to HLA-B∗13:01 polymorphism, and hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Both of these pharmacogenetic polymorphisms can be prevented through diagnostic screening before MDT initiation averting potential complications. However, in leprosy-endemic areas like Indonesia, access to these tests often remains inaccessible due to high costs and limited laboratory capacity. Additionally, alternative dapsone-sparing treatment regimens are usually unavailable or unaffordable, restraining individuals onto suboptimal dual-therapy with rifampicin and clofazimine, which has uncertain efficacy. We raise concerns regarding the safety of dapsone-containing MDT without routine pharmacogenetic screening and the unavailability of alternative regimens. We call for action to address persisting global health inequities in care delivery, ensuring all individuals receive the safest and most effective leprosy treatment options.

PMID:40084155 | PMC:PMC11905890 | DOI:10.1016/j.lansea.2025.100555

Front Pediatr. 2025 Feb 27;13:1543136. doi: 10.3389/fped.2025.1543136. eCollection 2025.

ABSTRACT

IMPORTANCE: Gaucher disease (GD) is a rare lysosomal storage disorder with limited treatment options for pediatric patients. Oral substrate reduction therapy (SRT) with eliglustat offers a potential alternative, particularly for those with barriers to enzyme replacement therapy (ERT).

OBJECTIVE: Evaluate the safety and efficacy of eliglustat SRT in pediatric patients with type 1 Gaucher disease (GD1), both as initial therapy and as a switch from intravenous ERT.

DESIGN: A prospective case series was conducted from 2017 to 2024.

SETTING: Yale's National Gaucher Disease Treatment Center, New Haven, CT, United States.

PARTICIPANTS: Fourteen pediatric GD1 patients with significant barriers to receiving ERT.

INTERVENTION: Eliglustat SRT was dosed pharmacogenomically based on CYP2D6 metabolizer status.

PRIMARY OUTCOMES AND MEASURES: Primary outcomes included safety and efficacy in reversing indicators of disease activity. Secondary outcomes involved changes in patient and parent-reported quality of life, assessed using PROMIS questionnaires.

RESULTS: Eliglustat was initiated at a mean age of 12.5 years (range: 6-17 years) and administered for a mean duration of 3.6 years (range: 1-7 years). All patients remained on treatment and exhibited sustained reductions in glucosylsphingosine (GlcSph) levels compared to baseline (p = 0.005). Other disease indicators demonstrated corresponding improvements. Adverse effects were limited to transient gastroesophageal reflux in 3/14 patients (21%). Serial electrocardiograms (EKGs) were normal. Growth and developmental milestones were appropriate for age in all patients. Patients and their parents reported a global improvement in quality of life.

CONCLUSIONS: Eliglustat demonstrated significant clinical benefits in pediatric GD1 patients, as evidenced by reductions in GlcSph levels and other disease indicators. The therapy showed a favorable safety profile comparable to that observed in adults. These findings suggest eliglustat is a promising therapeutic option for pediatric GD1 patients, providing an effective alternative to ERT.

PMID:40083427 | PMC:PMC11903696 | DOI:10.3389/fped.2025.1543136