Cts-Clinical and Translational Science最新文献

Eosinophilic esophagitis (EoE) is an atopic inflammatory disease with limited treatment options. Though swallowed topical steroids are commonly used, they are not effective in all patients. We investigated the presence of CYP3A4/5 and ABCB1 (P-glycoprotein) mRNA in esophageal tissue and its differential expression by genotype in pediatric patients. Esophageal tissue biopsies were obtained from pediatric patients undergoing standard of care endoscopy. Levels of CYP3A4, CYP3A5, and ABCB1 mRNA were measured using droplet digital PCR and compared across patients with and without EoE. Genotypes for common, clinically relevant CYP3A5 variants were evaluated in a cohort of individuals with and without EoE. Levels of CYP3A4 and ABCB1 in the esophagus were negligible in all patients. CYP3A5 mRNA expression was highest with two wild type alleles (*1/*1) and lowest with no wild type alleles. Further investigation into the function of esophageal CYP3A5 and its ability to metabolize budesonide delivered to the esophagus is warranted.

Real-world data investigating CYP2D6 on the efficacy of ondansetron for nausea and vomiting in pregnancy (NVP) is lacking. Evidence shows CYP2D6 ultrarapid metabolizers are at risk of ondansetron nonresponse due to increased metabolism. We conducted a retrospective cohort study of early pregnant patients on ondansetron for NVP. Genotype data for 11 CYP2D6 variants and copy number variations were translated into activity score (AS) and metabolizer status: poor (PM), intermediate (IM), normal (NM), and ultrarapid (UM) metabolizers. A total of 264 women met inclusion/exclusion criteria (99 cases and 165 controls). Multivariate regression analyses of metabolizer status and AS were adjusted for significant independent variables. The majority had gravidity of two, singleton pregnancy, a median age of 28 (interquartile range [IQR] 24-31) years, and identified as White (65.5%). Ondansetron dose was similar among the cohort and half received other antiemetics simultaneously. Clinical characteristics between cases and controls did not differ except for gestational age (8 vs. 10 weeks, p = 0.004) and primigravida rate (45.5% vs. 32.7%, p = 0.017). When adjusted for covariates, metabolizer status was not associated with response. UM/NM had non-significantly higher risk of nonresponse (odds ratio [OR] 1.53, 95% confidence interval [CI], 0.88-2.66) compared to PM/IM. Similar trends were observed with higher CYP2D6 AS showing increased risk of nonresponse (OR 1.22, 95% CI [0.81-1.85]). This study found no significant differences in ondansetron response in early pregnancy based on CYP2D6 UM/NM versus PM/IM and AS. Additional prospective investigations are necessary to confirm the CYP2D6 effect on ondansetron efficacy in pregnant patients.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors are being investigated for chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Ocadusertib is a potent and selective allosteric inhibitor of RIPK1 and is currently being studied in clinical trials. Here, we present data on the development of ocadusertib, including preclinical studies and pharmacokinetic, safety, and target engagement results from phase 1 trials. Preclinically, ocadusertib inhibited RIPK1 enzymatic activity with high potency (half-maximal inhibitory concentration [IC₅₀] = 12-38 nM) and inhibited necroptotic responses in multiple cell-based assays. Ocadusertib was highly selective for RIPK1, showing no significant inhibition of more than 100 other kinases representative of the full kinome. In mouse studies, ocadusertib treatment prevented RIPK1-dependent hypothermia in response to tumor necrosis factor (TNF) challenge and significantly reduced disease severity in a model of chronic proliferative dermatitis. In a first-in-human study of ocadusertib in healthy participants, single oral doses exhibited linear pharmacokinetics and dose-proportional exposure, with a time to maximum concentration of 1-4 h and a half-life of 13-15 h. Steady state was attained at 4-6 days after multiple once-daily dose administrations. Ocadusertib was well tolerated, with no deaths, serious adverse events, or significant treatment-emergent adverse events reported. In a phase 1, double-blind, randomized, multiple-dose study in healthy participants, greater than 90% RIPK1 target engagement was achieved at Day 14 with ocadusertib treatment. Taken together, these findings support further assessment of ocadusertib for the treatment of chronic inflammatory diseases.

Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent worldwide, especially in developing countries such as Vietnam; however, data on diabetes knowledge and medication adherence among Vietnamese high-risk T2DM patients, particularly those living in the rural areas, remains scarce. This study aimed to evaluate the levels of diabetes knowledge and medication adherence, along with their relationship, among high-risk T2DM patients in a rural area of Vietnam. A cross-sectional study was conducted at Quang Thanh General Hospital, a tertiary care hospital in Nghe An Province, Vietnam, between May and July 2024. Diabetes knowledge and adherence were assessed using the Vietnamese versions of the Spoken Knowledge in Low Literacy Patients with Diabetes (SKILLD) and the General Medication Adherence Scale (GMAS), respectively. Binary logistic regression was used to assess the association between diabetes knowledge and medication adherence. A total of 230 high-risk, T2DM patients met the inclusion criteria and were included in the study. The mean age was 67.9 ± 6.6 years, while 43.9% were male. The mean SKILLD score was 36.7 ± 20.03, with 82.6% classified as having low diabetes knowledge. For medication adherence, the mean GMAS score was 30.4 ± 3.07, with 16.1% of patients classified as being non-adherent. Binary logistic regression showed that better knowledge significantly increased the likelihood of medication adherence (OR = 8.3, 95% CI: 1.1-64.8, p = 0.043). In conclusion, diabetes knowledge was low among Vietnamese high-risk T2DM patients. A strong relationship existed between high diabetes knowledge and better medication adherence.

In cat sensitized children, decision to eliminate exposure to cats depends on the clinical outcome. In this study, we aimed to examine the relationship between molecular cat allergen sensitization and exhaled breath condensate (EBC) IL-4, IL-5, and IL-13 as markers of allergic airway inflammation. We enrolled subjects with skin prick test diagnosis of cat allergen sensitization aged 4-17 years. Age, sex, diagnosis, and clinical symptoms as well as family history of allergic diseases were recorded at enrollment along with the association of symptoms and cat exposure. Asthma severity and allergic rhinitis symptom score were recorded. Blood samples were collected for Fel d1 based component resolved diagnosis (CRD/FEL D1) and exhaled breath samples were collected for measurement of IL-4, IL-5, and IL-13. Among the 80 subjects (40 boys) enrolled, antibody positivity for Fel d1 was 74%. Cat exposure outdoors was more common in children with Fel d1 positivity (37% vs. 14%, p = 0.02). Asthma respiratory symptom severity score was significantly higher in Fel d1 antibody positive subjects (p = 0.01). On the other hand, EBC levels of IL-4, IL-5 or IL-13 were not found to be significant different between subjects with and without Fel d1 positivity (48.8 vs. 63.3, p = 0.59; 6.9 vs. 14.4, p = 0.62; 4.0 vs. 5.3, p = 0.83, respectively) The results of our study suggest a possible association between CRD/FEL D1 positivity and more severe respiratory symptoms in asthmatic children but not airway inflammation emphasizing the importance of interpretation of CRD results in the context of clinical findings.

Fenebrutinib is a Bruton's tyrosine kinase inhibitor under investigation for the treatment of multiple sclerosis. The goal of this study was to investigate the effect of fenebrutinib on cardiac repolarization (QT interval) as well as its safety, tolerability, and pharmacokinetics in healthy participants. Part A was a randomized, double-blind, placebo-controlled, single-ascending dose study of therapeutic (400 mg) and supratherapeutic (700 mg) doses of fenebrutinib. Part B was a randomized, double-blind, single-dose, four-way crossover study that included both therapeutic and supratherapeutic fenebrutinib doses, a positive control (moxifloxacin 400 mg), and placebo. The QT interval was corrected for heart rate using the Fridericia formula (QTcF). Part A (n = 16) showed that both doses were well tolerated, with no serious adverse events (AEs), AEs of special interest, or Grade ≥ 2 AEs. In Part B (n = 85), all upper bounds (UBs) of one-sided 95% confidence intervals (CIs) for the least squares mean placebo-adjusted ΔQTcF (ΔΔQTcF) values were < 10 ms; maximum observed values were 5.3 and 8.2 ms at 1 h after the therapeutic and supratherapeutic doses, respectively. All predefined timepoints after moxifloxacin administration had a 99% CI lower bound of ΔΔQTcF of > 5 ms, which confirmed assay sensitivity. In the regression analysis, UBs of one-sided 95% CIs for ΔΔQTcF at the maximum concentration of fenebrutinib were < 10 ms: 4.4 and 7.8 ms with the therapeutic and supratherapeutic doses, respectively. Overall, both doses of fenebrutinib had no clinically meaningful impact on QT interval and were well tolerated, supporting fenebrutinib's favorable safety profile and continued clinical development.

QX008N, a humanized IgG1 monoclonal antibody against thymic stromal lymphopoietin (TSLP) with Fc engineering to extend half-life, was developed with the aim of exploring whether its extended half-life and cost-effective production could potentially address unmet needs in severe asthma therapy, such as the need for less frequent dosing and improved accessibility. This first-in-human, phase I trial evaluated pharmacokinetics (PK), tolerability, and immunogenicity of QX008N in healthy Chinese subjects following subcutaneous (SC) and intravenous (IV) administration. SC group dosing demonstrated dose-proportional exposure; for the 280 mg and 560 mg SC doses, AUC₀-∞ values were 37,611 and 81,450 h·μg/mL, respectively, with delayed Tmax (5-8 days) and absolute bioavailability of 62%-67%. Following SC administration, Cmax values were 30.0 μg/mL (280 mg) and 63.9 μg/mL (560 mg), whereas IV administration produced a Cmax of 225.83 μg/mL at 2 h. QX008N exhibited a prolonged half-life (median 30.4 days (range 25.0-47.1) for the 560 mg SC dose), surpassing tezepelumab's 26 days, supporting potential every 6-8 week dosing. All pharmacokinetic parameters, including terminal elimination half-life (t½), were derived from plasma concentration-time data. Tolerability profiles were favorable: all adverse events were mild/moderate (e.g., self-resolving rash). No injection-site reactions were observed following single-dose administration in healthy subjects. Immunogenicity was low (5.6% ADA incidence; no neutralizing antibodies), with no PK or tolerability impact. Overall, QX008N demonstrated predictable pharmacokinetics, low immunogenicity, and a tolerability profile consistent with single-dose administration of monoclonal antibodies in healthy subjects. These findings provide foundational PK and tolerability data to support subsequent clinical evaluation in patients.

We evaluated the renal outcomes and safety of spironolactone added to renin-angiotensin system inhibitors (RASis) among patients with type 2 diabetes (T2D), given its uncertain role alongside RASis, the cornerstone of T2D with renal disease management. In this retrospective study at National Cheng Kung University Hospital (2014-2021), we identified adult T2D patients receiving RASis alone or combined with spironolactone. Propensity score matching between treatment groups was implemented to achieve between-group comparability. The primary outcome was a composite renal outcome (including end-stage renal disease [ESRD], renal transplant, or a ≥ 30% estimated glomerular filtration rate [eGFR] decline). Secondary outcomes included proteinuria, major adverse cardiovascular events, and hyperkalemia. Cox proportional hazard model analyses were adopted to assess the treatment outcomes. 404 PS-matched pairs of RASis-alone and RASis+spironolactone users were included. Adding spironolactone to RASis was associated with increased composite renal event (hazard ratio [95% CI]: 1.27 [1.06-1.51]), persistent eGFR decline ≥ 30% (1.31 [1.09-1.58]), and hyperkalemia (1.57 [1.21-2.04]) risks while associated with a higher likelihood of achieving ≥ 30% proteinuria reduction (HR 1.34 [1.12-1.60]). Having heart failure (HF) was a significant effect modifier, that is, using RASis+spironolactone versus RASis alone was associated with a lower ESRD/renal transplant risk among patients with HF (0.62 [0.38-1.02]) but an increased risk for those without HF (1.32 [0.98-1.78]) (p for interaction = 0.011). Adding spironolactone to RASis might increase renal adverse events and hyperkalemia but reduce proteinuria in T2D patients. Notably, heart failure status significantly modified these associations, underscoring the importance of personalized medicine.

Coproporphyrin I (CPI) is increasingly recognized as a reliable endogenous biomarker for hepatic OATP1B transporters. However, confounding mechanisms such as increased heme biosynthesis driven by induction of CYP enzymes, which are hemoproteins, may affect CPI levels independently of OATP1B1 inhibition. The aim of this study was to investigate whether activation of nuclear receptors and subsequent CYP induction by efavirenz affects CPI levels in vitro and in vivo. We first evaluated the potential of efavirenz to interact with OATP1B1 in vitro. We then assessed efavirenz-induced changes in vitro, analyzing the mRNA expression of CYP2B6 and both mRNA and protein expression of ALAS1 (5-aminolevulinate synthase 1), the rate-limiting enzyme in heme biosynthesis. Additionally, we quantified CPI levels in the cell culture supernatant. Finally, we determined plasma CPI levels in healthy volunteers pre- and post-induction with efavirenz. In transport studies, efavirenz did not alter OATP1B1-mediated uptake of CPI, whereas rosuvastatin reduced their intracellular accumulation. Treatment with efavirenz significantly increased CYP2B6 mRNA expression, confirming CYP induction in vitro, but had no effect on ALAS1 expression at either mRNA or protein level. Correspondingly, CPI levels in the cell supernatant remained unchanged after efavirenz treatment compared to solvent control. In vivo, plasma CPI levels were also unaffected by efavirenz. Our in vitro findings demonstrate that while efavirenz induces CYP expression, it does not impact ALAS1 expression or alter CPI levels, supported by our in vivo findings where efavirenz did not change plasma CPI, suggesting that CYP enzyme induction does not relevantly affect coproporphyrin levels.