Mild obstructive sleep apnea (OSA) is often underdiagnosed but contributes to treatment-resistant hypertension through oxygen deprivation and activation of the renin-angiotensin-aldosterone system. Spironolactone, an aldosterone antagonist, may help manage both hypertension and OSA-related symptoms. This study aims to evaluate the effectiveness and safety of spironolactone in patients with mild OSA and resistant hypertension. This retrospective observational cohort study included 96 patients diagnosed with mild OSA and resistant hypertension between December 2022 and October 2023. Patients were grouped according to whether they received spironolactone (20 mg/day) in addition to conventional antihypertensive treatment. Outcomes included blood pressure (office, ambulatory, and daytime), apnea-hypopnea index (AHI), lowest oxygen saturation (SaO2), and biochemical parameters (blood urea nitrogen [BUN], potassium, sodium, and creatinine). Missing data were handled using multiple imputation. After 12 weeks, the spironolactone group showed greater reductions in blood pressure compared with the control group: office systolic blood pressure (OSBP) decreased by 5.75 mm Hg (95% CI: -8.84 to -2.66) and office diastolic blood pressure (ODBP) decreased by 3.67 mm Hg (95% CI: -6.46 to -0.88). The AHI improved by 1.85 events/hour (95% CI: -3.23 to -0.47), and SaO2 increased by 3.33% (95% CI: 0.93-5.73). No cases of hyperkalemia or clinically significant kidney dysfunction were observed, and the treatment was well tolerated. Spironolactone was associated with improved blood pressure control and modest improvements in sleep-related parameters in patients with mild OSA and resistant hypertension, with a favorable short-term safety profile. The small sample size and relatively young cohort limit the generalizability of the findings.

Cardiorenal syndrome in dogs, particularly those with myxomatous mitral valve degeneration (MMVD), involves complex neurohormonal interactions, yet molecular mechanisms linking heart and kidney dysfunction remain poorly understood. This study aimed to identify serum peptide and protein signatures that differentiate disease stages and clarify pathophysiology. We hypothesized that alterations in the serum peptide mass fingerprint and protein profile would serve as sensitive biomarkers for kidney disease progression in MMVD-affected dogs. Dogs were classified into five groups following ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dog and IRIS Staging of chronic kidney disease (CKD): Healthy, MMVD Stage B1, MMVD Stage C without azotemia, MMVD Stage C with azotemia, and CKD IRIS Stage 2. Serum peptide profiling was performed using Matrix-Assisted Laser Desorption/Ionization - Time-of-Flight Mass Spectrometry (MALDI-TOF MS) for peptide mass fingerprint analysis and Nanoscale Liquid Chromatography-Tandem Mass Spectrometry for protein identification. MALDI-TOF MS effectively discriminated healthy dogs from diseased groups through discrete clustering in Partial Least-Squares Discriminant Analysis plots. Proteomic profiling identified 100 statistically significant proteins, with a critical subset of shared proteins including Peroxisomal biogenesis factor 14, Glutaredoxin-2, Creatine kinase mitochondrial 2, and Selenocysteine insertion sequence-binding protein identified between the MMVD C WAZ and CKD Stage 2 groups. These proteins are associated with the arginine and proline metabolism and peroxisome pathways, which were found to be influenced by standard medications such as pimobendan, furosemide, spironolactone, benazepril, and sildenafil. These findings reflect a systemic failure of cellular redox and energetic homeostasis driven by renin angiotensin aldosterone system activation and oxidative stress. The convergence of peroxisomal and mitochondrial dysfunction suggests a unifying mechanism for parallel cardiac and renal deterioration. These proteomic markers persist despite standard medical therapy, highlighting their potential as auxiliary tools for risk stratification and the monitoring of treatment efficacy in canine cardiorenal syndrome.

The Pediatric Research Equity Act mandates new drugs be tested in children before Food and Drug Administration (FDA) approval, though roughly one-fifth of these drugs are granted complete waivers from pediatric testing. With the high prevalence of these waivers, US children may be at risk of being treated by drugs without pediatric testing (and therefore with unclear risk-benefit profiles). We evaluated how often drugs granted pediatric testing waivers are prescribed in US children using a large commercial claims database. Using public FDA data, we identified drugs granted pediatric testing waivers from 2007 to 2022 that did not report pediatric testing prior to FDA approval. We used the Merative MarketScan Commercial Database to determine monthly pediatric users for the first 36 months after approval. We defined "pediatric users" as the number of unique pediatric patients with ≥1 dispensing in a month. Among 291 drugs granted waivers from pediatric testing, 147 (51%) had observable pediatric use in the first 3 years following approval. Median summed users was 17 (interquartile range [IQR], 3-102), with median 0.47 users/month (IQR, 0.08-2.83). Among the top 20 most-used drugs, pediatric users ranged from 508 (valsartan/hydrochlorothiazide) to 22,111 (conjugated estrogen cream) (median 1,050.5; IQR, 709.5-1,690.8), with a median of 29.2 users/month (IQR, 19.7-47.0). Among drugs granted waivers from pediatric trials, half have observable off-label use in children in the 3 years after FDA approval. Routine clinical use evidence from these prescriptions could be collected to inform drug labeling updates, and some drugs have sufficient use to make post-approval pediatric studies feasible.

Results from the ACCOMPLISH (Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension) trial suggest that combining benazepril with amlodipine, rather than hydrochlorothiazide, provides superior cardiovascular protection potentially in a BP-independent manner. We employed random survival forest, a powerful machine learning approach, to compare the relative importance of risk factors (i.e., variable importance factor (VIF)), focusing on in-trial BP control for predicting the primary composite cardiovascular outcome in the 2 treatment limbs. Among the 6 risk factors with significantly different VIFs between treatments, all were lower under benazepril/amlodipine combination. The VIF for achieved systolic BP at 6-months was 35% lower in the benazepril/amlodipine (0.082) versus the benazepril/hydrochlorothiazide (0.126) limb. The fact that in-trial BP control was less important for preventing cardiovascular events during benazepril/amlodipine treatment provides novel support for our contention that this combination regimen provides a degree of clinically-relevant cardio-protective actions in a BP-independent manner.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and associated with substantial morbidity and mortality. The clinical benefit of mineralocorticoid receptor antagonist (MRA) therapy in this population remains uncertain. A meta-analysis was conducted in accordance with the PRISMA 2020 guidelines, searching PubMed, Embase, and Scopus from inception through the most recent available data to identify randomized controlled trials and observational cohort studies comparing MRAs with placebo or no MRA therapy in adults with HFpEF. Primary outcomes were all-cause mortality, cardiovascular mortality and heart failure hospitalization, while secondary outcomes included hyperkalemia. Random-effects models were used to pool risk ratios or hazard ratios with 95% confidence intervals. Twenty-one reports representing 11 unique studies comprising 50,983 patients met the inclusion criteria; 8,976 received MRA therapy, and 28,999 served as controls. MRA use was not associated with a statistically significant reduction in all-cause mortality (RR 0.91, 95% CI 0.81-1.02) or cardiovascular mortality (RR 0.84, 95% CI 0.66-1.05; P = 0.13). MRA therapy, however, was associated with a significant reduction in heart failure hospitalization (RR 0.81, 95% CI 0.73-0.90; P < 0.0001). MRA use was also associated with an increased risk of hyperkalemia (RR 2.04, 95% CI 1.55-2.68; P < 0.00001). In conclusion, MRA therapy in HFpEF reduces heart failure hospitalization without a significant mortality benefit and is associated with increased hyperkalemia risk.

Diabetes-induced liver damage is a significant complication of hyperglycemia, which results in oxidative stress, inflammation, and fibrosis. Conventional treatment strategies remain limited, necessitating novel therapeutic approaches. This study evaluates the hepatoprotective effects of valsartan-loaded self-nanoemulsifying drug delivery system (SNEDDS) in streptozotocin (STZ)-induced hyperglycemic rats, focusing on oxidative stress modulation, suppression of inflammatory cytokines, and metabolic regulation. Male Sprague-Dawley rats were divided into six groups: control, STZ-induced diabetic model, and treatment diabetic groups receiving valsartan (Val) or valsartan/hydrochlorothiazide (Val/HCT) in either SNEDDS-loaded liquisolid tablets or directly compressed tablets. Liver function, oxidative stress biomarkers, lipid profiles, histopathological changes, and gene expression levels of NF-κB, TGF-β, and Nrf2 were assessed. Val and Val/HCT-loaded-SNEDDS significantly reduced fasting blood glucose to ~ 95 mg/dl, serum ALT levels (34-50%), and pro-inflammatory cytokines (NF-κB and IL-1) (21% and 40%, respectively). They also enhanced antioxidant defenses by increasing hepatic glutathione levels (34-39%) while reducing malondialdehyde (36-39%) and nitric oxide (50%). Histopathological analysis confirmed improved liver architecture with diminished inflammatory cell infiltration and fibrosis. Gene expression analysis revealed a downregulation of TGF-β and NF-κB, alongside upregulation of Nrf2, indicating reduced fibrogenesis and an oxidative stress response. In conclusion, Val-loaded SNEDDS effectively mitigates STZ-induced hepatotoxicity. This hepatoprotective effect is due to blocking the angiotensin II type 1 receptor (AT1R), leading to inhibition of TGF-β and other TGF-β-mediated inflammatory markers, such as NF-κB and IL-1. This nanoformulation offers a promising therapeutic strategy for diabetes-associated liver injury and warrants further investigation for clinical applications.

Cognitive decline is a common occurrence in elderly individuals, leading to social issues, health concerns, and placing pressure on the healthcare system. Several factors can affect cognitive function, and medication is one of the most important factors for the elderly. Thus, understanding the impact of medications on cognitive decline in the elderly is crucial. This study aimed to investigate the association between commonly used drugs in the United States and cognitive function. The study utilized bivariate analysis and multiple regression analysis on cognitive function data, prescription medication data, and other covariates data from 2 cycles of the US National Health and Nutrition Examination Survey, conducted between 2011 and 2014. The study included 82 drugs after excluding missing data and selection criteria. The majority of these drugs were associated with lower cognitive scores compared to those who did not use prescription medications. Estradiol, naproxen, bupropion, and the combined use of triamterene and hydrochlorothiazide were found to enhance performance on 2 memory cognitive tests, immediate recall and delayed recall, but not on the processing cognitive tests, animal fluency, and digit symbol substitution test. The findings of this study provide a foundation for the selection of drugs with potential cognitive benefits for further investigation and expand knowledge on the cognitive implications of prescription medications, highlighting the possible advantages of certain drugs and the need for caution when using others.

Pharmaceuticals and personal care products (PPCPs) as well as current-use pesticides (CUPs) are considered to be contaminants of emerging concern (CECs), but there is limited information that exists about their occurrence and impact in the marine environment. A database of these CECs has been created as an overview of their occurrence and distribution in European marine waters by the ICES Marine Chemistry Working Group (MCWG) and collaborators from various European countries. The majority of the compiled data corresponded to pharmaceuticals in seawaters, but much less data were available for other matrices (biota and sediment) and CEC groups. Generally, concentrations were characterized for a limited spatial area and/or a small number of species/organisms. A Total Occurrence Index (TOI) was developed, taking into account the number of data available, the maximum concentrations and the frequency of detection together as indicators. The TOI provided estimates for the CECs in the database and has been used to identify the most relevant PPCPs and CUPs. The highest TOIs were found for the pharmaceuticals salicylic acid, hydrochlorothiazide, gemfibrozil, mefenamic acid, paracetamol and diclofenac; the PCPs 2-ethylhexyl-4-methoxycinnamate, 4-methylbenzylidene camphor, octocrylene, galaxolide, benzophenone-3 and tonalide; and the CUPs chlorpyrifos, chlorthal-dimethyl, simazine and irgarol. It is noted that additional data are required, particularly in the sediment and the biota matrices, to more fully understand the distribution and impact of these CECs in the marine environment, when considering the wide geographical distribution areas covered in this review. Further assessment is also required, to prioritise those CECs, based on which of them are expected to cause the most adverse toxic effects to marine ecosystems.

Previously, it was thought that ultraviolet radiation (UV) carcinogenesis was caused by accumulation of mutations related to cancer, including oncogenes and tumor suppressor genes. These genetic changes found in skin cancers are considered to be induced by UV, based on the findings that "UV-signature mutations" are predominant. However, recent findings revealed that UV carcinogenesis includes a more complicated process, and the importance of inflammation is emphasized. It is evident that DNA lesions cause inflammation. We showed that Ogg1 knockout mice, which fail to repair 8-OxoG, a representative oxidative DNA lesion, manifest a much higher frequency of UV-induced skin cancers without increasing p53 mutations. Gene expression analysis in this system revealed that 8-oxoG upregulates inflammatory pathway genes. Furthermore, a mice model of xeroderma pigmentosum, a DNA repair disorder, where patients manifest severe sunburn and high frequency of skin cancers, was demonstrated to express an extremely high level of CXCL1, an inflammatory chemokine. Inhibiting CXCL1 decreased the development of UV-induced skin cancers without repairing dipyrimidine photoproducts. Additionally, some anti-inflammatory medicines suppress the development of UV-induced skin cancers. The enhancement of photosensitive medications, including voriconazole and hydrochlorothiazide on UV carcinogenesis, has been indicated both epidemiologically and experimentally.