The current study aimed to improve the dissolution rate and physical stability of two antihypertensive drugs, hydrochlorothiazide, and valsartan, through the development of a co-amorphous system. A co-amorphous system was successfully prepared at molar ratios of 1:1, 1:2, and 1:6 employing rotary evaporation technique. Characterization of the formulations was performed using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Powder X-ray diffraction confirmed the amorphous nature of all samples, which remained physically stable under ambient dry conditions for at least 8 months. Differential scanning calorimetry confirmed the formation of a single-phase system. The experimental glass transition temperature values revealed a negative deviation from those calculated by the Gordon-Taylor equation, indicating nonideal mixing and intermolecular interactions. Fourier transform infrared spectroscopy spectra supported these findings, showing peak broadening in regions corresponding to the functional groups of the parent drugs. The thermogravimetric analysis demonstrated that the samples were thermally stable, with no degradation observed up to 100°C. Dissolution studies performed in phosphate buffer (pH 6.8, 25°C) revealed significant enhancements in the dissolution rates of both hydrochlorothiazide and valsartan from the co-amorphous formulations compared to their unprocessed forms and corresponding physical mixtures. A validated high-performance liquid chromatography method was developed for the simultaneous analysis of hydrochlorothiazide and valsartan using a Shimadzu LC-2030C 3D Plus system with a photodiode array detector. Separation was achieved on a Waters C18 column (250 × 4.6 mm, 5 μm) using a mobile phase of acetonitrile, methanol, and ammonium acetate buffer (20:50:30, v/v) at a flow rate of 0.70 mL/min. Detection wavelengths were set at 271 nm for hydrochlorothiazide and 249 nm for valsartan. The method showed good linearity in the range from 0.0033 to 0.0670 mM (3.3-67.0 μM), precision (RSD < 2%), and reproducibility, with hydrochlorothiazide and valsartan eluting at 3.5 and 7.2 min, respectively. At the first minute, hydrochlorothiazide release increased by approximately 8.5-, 8.7-, and 7.1-fold from the 1:1, 1:2, and 1:6 co-amorphous systems relative to the unprocessed drug, and by 4.5-, 4.8-, and 2.4-fold, respectively, compared to the corresponding physical mixtures. For valsartan, the co-amorphous systems showed 2.9-, 2.6-, and 1.9-fold improvements over the unprocessed drug, and 1.5-, 1.8-, and 1.5-fold improvements over the matching physical mixtures at the same molar ratios. Calcium carbonate was physically mixed with all samples to minimize gelation upon aqueous exposure. These results suggest that co-amorphous formulation is a promising strategy for enhancing the dissolution rate and physical stability of hydrochlorothiazide and valsartan.

Translating adsorption performance from batch experiments to continuous-flow operation is a key step toward practical water-treatment applications. In this study, a laboratory-scale continuous adsorption system based on a water-insoluble β-cyclodextrin-epichlorohydrin (β-CD-EPI) polymer was validated from hydrodynamic, adsorptive, and operational perspectives. Downflow operation caused progressive bed compaction and excessive pressure development, whereas a 90 mm column operated in upflow mobile-bed mode, with visually observed bed expansion, showed comparatively stable pressure-drop behavior at superficial linear velocities below approximately 12 m h[-1]. Under these controlled high-loading conditions, removal was strongly contaminant-dependent: cyproconazole exceeded 90%, acetaminophen reached 72-77%, hydrochlorothiazide reached 40-65%, ciprofloxacin reached 24-50%, and furosemide remained below 30%. The relative performance for furosemide and hydrochlorothiazide differed from that predicted by previous batch-derived adsorption parameters, demonstrating that batch results cannot be directly extrapolated to dynamic operation. Competitive adsorption in binary and ternary mixtures reduced contaminant removal, while cyproconazole removal decreased from >90% in tap water to 48-55% in secondary-treated wastewater, demonstrating the relevance of the aqueous matrix under the tested continuous-flow conditions. Operational screening tests showed that desorption with 220 mM acetate buffer at pH 4.0 recovered >80% of the retained cyproconazole within 10 min in the tested sequence, followed by a two-stage rinse that restored the operational pH. These preliminary conditions require confirmation through replicated adsorption-desorption cycles under continuous-flow operation. These results identify laboratory-scale hydrodynamic, adsorption, matrix, and regeneration considerations that require confirmation through fixed-condition, long-term testing during subsequent process development.

Gitelman syndrome (GS) is an inherited salt-wasting, hypokalemic tubulopathy caused mainly by biallelic loss-of-function variants in the SLC12A3 gene. Despite being classically diagnosed in adolescence, delayed recognition may occur. We present the case of a 74-year-old man with a history of hypokalemia, in whom the diagnostic evaluation revealed hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria, and secondary hyperreninemic hyperaldosteronism, consistent with renal potassium wasting. Given the late presentation, the main challenge was the need to distinguish an inherited tubulopathy from common acquired causes of hypokalemia. Genetic testing was performed, identifying a previously unreported homozygous out-of-frame deletion in exon 25 of the SLC12A3 gene, predicted to result in loss of protein function and therefore to be pathogenic. Treatment with supplementation plus spironolactone achieved sustained biochemical improvement and clinical stability during long-term follow-up. This case highlights that GS should be considered in patients with chronic unexplained hypokalemia regardless of age, and that genetic testing is essential for definitive diagnosis.

We investigated seasonal variation in the office and ambulatory blood pressure control in hypertensive patients treated with two single-pill dual-combination antihypertensive therapies. The study participants (n = 560) were hypertensive patients enrolled in a 24-week therapeutic study. Antihypertensive treatment was initiated with amlodipine/benazepril 5/10 mg/day or benazepril/hydrochlorothiazide 10/12.5 mg/day, with the possible up-titration to 10/20 mg/day or 20/25 mg/day during follow-up, respectively. Office blood pressure was measured at each clinic visit, and ambulatory blood pressure monitoring was performed at baseline and 24-week follow-up. At 24 weeks of follow-up, in patients who continued antihypertensive treatment (n = 511), the proportion of up-titration to higher dosages was significantly different across seasons of treatment commencement in the benazepril/hydrochlorothiazide group (P = 0.002), but not in the amlodipine/benazepril group (P = 0.84). The between-group difference was significantly different in 134 patients who commenced treatment in winter (18.9% vs. 5.0%, P = 0.02), but not in 377 patients who commenced treatment in the other seasons (P ≥ 0.33). The control rate of office blood pressure (<140/90 mmHg) was significantly different across seasons of treatment commencement in the amlodipine/benazepril group (P = 0.01), but not in the benazepril/hydrochlorothiazide group (P = 0.16). The mean changes from baseline to 24-week follow-up tended to be smaller in the benazepril/hydrochlorothiazide than amlodipine/benazepril group in 24-h (mean between-group difference, -2.8 mmHg) and daytime diastolic blood pressure (mean between-group difference, -3.2 mmHg) in patients who commenced treatment in winter, though statistical significance was not achieved (P ≥ 0.07). In conclusion, there was seasonality in the clinic and ambulatory blood pressure-lowering effect of antihypertensive drug combinations, with a marginally significant difference in treatment intensity and blood pressure control between treatment with amlodipine or hydrochlorothiazide in combination with benazepril.

Pairwise drug-drug interaction databases flag co-prescribed pairs, but they under-weight multi-drug combinations that drive adverse drug events in older adults. We studied that gap in Virginia All-Payer Claims Database records (2016-2019) for adults aged 65-114 years with non-opioid emergency department visits (n = 1182 cases; 16,105 matched controls across three geriatric age bands). Features came from pharmacy and medical claims in a short pre-index window optimized for acute ADE timing (21-30 days by age band; 21 days for ages 65-84). We trained gradient-boosting models separately among patients with similar pre-index healthcare contact volume (2016-2018 training; 2019 holdout), then used Formal Feature Attribution to score drug pairs and triplets and Intervention Rate ranks to order deprescribing review. On the 2019 holdout, geriatric AUPRC was 0.101-0.335 (PR lift 1.6×-4.2×). FFA flagged 115 synergistic pairs and 312 high-confidence triplets (e.g., furosemide + hydrochlorothiazide + lisinopril; digoxin + furosemide + amiodarone, IE = 8.7). Top Intervention Rate drugs included simvastatin, furosemide, and alprazolam. Moderate preventive Z-code monitoring (Q2) was protective (OR = 0.25; 95% CI 0.18-0.34) versus no monitoring, while fragmented high-intensity monitoring (Q4) was not. The framework prioritizes medication combinations for pharmacist review in claims data; it does not replace pharmacokinetic confirmation or prove that changing a drug caused fewer ED visits.

Primary aldosteronism is the most common cause of secondary hypertension but remains frequently underdiagnosed in primary care. We report a 71-year-old man with resistant hypertension and low-normal serum potassium in whom a minimal increase in hydrochlorothiazide dosage (12.5 to 25 mg) precipitated severe hypokalaemia (1.6 mmol/L), metabolic alkalosis, and rhabdomyolysis. An office electrocardiogram showed hypokalaemia-related changes, prompting urgent referral to the emergency department. Further evaluation revealed an elevated aldosterone-to-renin ratio and a left adrenal nodule, supporting the diagnosis of primary aldosteronism. This case highlights the importance of recognizing a disproportionate hypokalaemic response to thiazide treatment as a potential indicator of underlying primary aldosteronism. It also underscores the role of family physicians in early detection through appropriate screening.

While Wernicke encephalopathy (WE) is well-recognized as a condition most frequently associated with chronic excessive alcohol consumption, non-alcoholic WE (NAWE) remain underrecognized despite their clinical importance. An 85-year-old nursing home resident was brought to the Emergency Department (ED) with impaired consciousness. She had been taking furosemide 40 mg and spironolactone 25 mg daily for chronic heart failure for five months prior to presentation. One month before admission, she began receiving parenteral nutrition without thiamine due to poor oral intake accompanied by vomiting. On arrival, her Glasgow Coma Scale score was 3, exhibiting flaccid quadriplegia and absent deep tendon and oculocephalic reflexes. Brain MRI demonstrated hyperintensities in the peri-central sulcus cortex as well as typical WE-related regions, including the periaqueductal gray and bilateral medial thalami, on diffusion-weighted imaging (DWI) and T2-weighted imaging. Intravenous high-dose thiamine therapy was initiated based on a clinical diagnosis of WE, subsequently confirmed by a thiamine level below the detection limit (<5 ng>/mL). Although follow-up MRI showed radiological improvement after seven days, neurological recovery remained minimal despite 35 days of treatment. Nonspecific clinical manifestation of NAWE makes early diagnosis difficult, often resulting in progression to more advanced stages with cortical lesions. To prevent irreversible and potentially fatal neurological sequelae, it is crucial to be aware of NAWE in its early stages, particularly in patients with known risk factors, such as malnutrition (poor nutritional intake), parenteral nutrition without thiamine, gastric bypass surgery, malabsorption, dialysis, diuretic use, infections/sepsis, and hyperthyroidism.

Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-label randomized trial (POLY-HF) at two centers enrolling a predominantly underserved population to test whether a polypill strategy improves cardiac function in heart failure. Adults with heart failure and left ventricular ejection fraction ≤40% were randomized to a once-daily polypill containing metoprolol succinate (25/50/100/150 mg), spironolactone 12.5 mg and empagliflozin 10 mg, or rapid uptitration of individual guideline-directed medical therapy medications ('enhanced usual care'). Participants also continued treatment with a renin-angiotensin system inhibitor or sacubitril/valsartan as a separate pill. The primary endpoint was ejection fraction as assessed by cardiac magnetic resonance imaging at 6 months. Secondary endpoints included clinical outcomes and adherence. We randomized 212 patients (median age 54 years, 22% female, 54% Black). Follow-up magnetic resonance imaging data were available for 187 (88%) participants who were included in the modified intention-to-treat analysis. Polypill treatment was associated with greater improvement in ejection fraction compared to enhanced usual care (between-group difference, 3.3 percentage points, 95% confidence interval, 0.2-6.4; P = 0.039), meeting the primary outcome. Individuals randomized to the polypill also had a 60% lower rate of heart failure hospitalizations or emergency department visits (adjusted rate ratio, 0.40; 95% confidence interval, 0.18-0.88; P = 0.024). Adherence, assessed by blood concentrations of metoprolol and spironolactone, was higher with polypill treatment than with enhanced usual care (79% versus 54%, P = 0.001). The polypill was well tolerated, with fewer adverse events with polypill treatment as compared to enhanced usual care. A polypill for heart failure was associated with a significant improvement in cardiac function as compared with enhanced usual care. ClinicalTrials.gov registration: NCT04633005 .

Micropollutant abatement in granular activated carbon (GAC) filters is governed by both sorption and biodegradation processes. Yet a comprehensive understanding of which micropollutants are biodegraded, how much biodegradation contributes to GAC's performance, and how GAC's properties affect biodegradation, remains limited. This study addresses these knowledge gaps by combining reactive transport modeling with pilot-scale experiments, investigating the fate of 45 micropollutants in parallel GAC and sand filters operated at contact times of up to 100 min. Tracer tests and modeling showed that GAC's high intragrain porosity (40%) prolongs solute-biomass contact times by a factor of 1.7 compared to sand. Higher respiration activity in GAC was attributed to prolonged contact times for biodegradation of both micropollutants and other dissolved organics. Significantly enhanced abatement at contact times exceeding 25 min suggested biodegradation for 25 of 45 micropollutants. The formation of biotransformation products further confirmed biodegradation of diclofenac and the highly sorptive compounds venlafaxine and hydrochlorothiazide exclusively in GAC. Overall, these findings demonstrate that (i) GAC enables biodegradation of more micropollutants than sand (24 vs. 16), regardless of sorption affinity; (ii) intragrain porosity prolongs solute-biomass contact times, being relevant for degradable compounds featuring little sorption; and (iii) GAC hosts functionally distinct microbial biomass capable of unique biotransformation compared to sand.