A physically motivated Langmuir-Freundlich loading-response framework was formulated to describe the sonochemical degradation of nonvolatile organic contaminants in water. Acoustic cavitation was represented as a heterogeneous oxidative microenvironment in which contaminant degradation depends on apparent occupation of the bubble-liquid interfacial region and the finite oxidative capacity generated under fixed operating conditions. The framework was evaluated using naphthol blue black (NBB) and furosemide as chemically distinct nonvolatile contaminants. For NBB, increasing the initial concentration from 3 to 120 mg/L increased the initial degradation rate from 0.22268 to 2.1502 mg/L·min, while the 30-min removal efficiency decreased from 100 % to 43.46 % and the net H2O2 formation rate decreased from 5.4794 to 3.9161 μmol/L·min. Initial-rate calibration gave rmax = 3.8324 mg/L·min, KLF = 1.1298 × 10[-2] L/mg, and n = 0.8256. To reduce parameter redundancy, all concentration-time profiles for each compound were described using four global parameters, r0,ref,T, βT, KLF,T, and nT, without concentration-specific fitted coefficients. The calibration RMSE values were 0.0196 for NBB and 0.0399 for furosemide. Blocked leave-one-concentration-out validation gave pooled RMSE values of 0.0391 and 0.0566, respectively. For NBB, 30-min removal measurements at 7, 10, 40, and 120 mg/L, which were excluded from time-resolved parameter estimation, were calculated with an RMSE of 1.79 percentage points. Comparison with simpler formulations showed that the loading-dependent pseudo-first-order model gave the lowest cross-validated RMSE for NBB, whereas the classical Langmuir and Langmuir-Freundlich formulations gave comparable cross-validated performance for furosemide. Parameter confidence intervals and covariance-based correlation analysis identified strong compensation among the initial-rate parameters but lower correlations in the four-parameter time-resolved formulation. The fitted coefficients are therefore interpreted as condition-specific apparent descriptors rather than direct measurements of interfacial adsorption, radical flux, or molecular cooperativity. The framework provides a reduced-order tool for interpolation and treatment-time calculations within a calibrated operating domain, but application to other compounds, reactors, or solution matrices requires recalibration and independent validation.

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.

Very heterogeneous data have been published concerning prevalence and clinical management of Hypertensive Emergencies (HE) and Uncontrolled Hypertension (UH). The aim of our study was to characterize HE and UH patients evaluating: (i) Blood Pressure (BP) management in Emergency Department (ED), the pharmacological treatment and its adherence to guidelines recommendation; (ii) variables associated with the presence of organ damage; and (iii), as an exploratory analysis, the impact of BP on in-hospital mortality. We performed a multicentre (Niguarda Hospital - Milan and Pio XI Hospital - Desio) retrospective study evaluating patients admitted to ED with BP values ≥ 180/120 mmHg during 2017 and 2019. 1838 patients were admitted to the ED with a BP ≥ 180/120 mmHg (0.95% of total admissions) of whom 37.7% were HE and the remaining (62.3%) were UH. The reduction in Systolic and Diastolic BP (SBP/DBP respectively) was similar in HE (40.6/16.9 ± 26.3/17.7 mmHg) and UH (39.3/15.5 ± 22.4/16.0 mmHg). The most used drugs were intravenous furosemide, nitroglycerin, clonidine and labetalol for HE. Age, smoking, heart failure, previous acute coronary syndrome, chronic kidney disease and diabetes mellitus present a positive association HEs while female sex and chronic anti-hypertensive therapies with 2 or more drugs results as protective variables. Finally, regarding the exploratory analysis, BP at ED admission and its management didn't present significant association with in-hospital mortality. In conclusions, our study demonstrated that adherence to guidelines in the management of HE/UH could be further improved.

Background: Patients with chronic kidney disease (CKD) undergoing hemodialysis commonly present multiple comorbidities and require complex medication regimens. Polypharmacy increases the risk of clinically relevant drug interactions that may compromise treatment safety and effectiveness. Objective: To estimate the prevalence of potential drug interactions among patients with CKD undergoing hemodialysis and classify these interactions according to clinical risk and mechanism of action. Methods: A cross-sectional study was conducted with patients undergoing hemodialysis at a dialysis clinic in Southern Santa Catarina, Brazil. Potential drug interactions were identified using the Medscape and Drugs.com databases and classified according to severity (major, moderate, or minor) and mechanism of action. Results: A total of 151 patients were included. Potential drug interactions were identified in all participants (973 interactions; mean 6.4 per patient). Of these, 234 (24.0%) were classified as major, 545 (56.0%) as moderate, and 194 (19.9%) as minor. The most frequent major interactions involved furosemide + losartan (n = 8) and acetylsalicylic acid + clopidogrel (n = 6). Among moderate interactions, the most common were sevelamer + calcium carbonate (n = 14) and losartan + amlodipine (n = 12). The most frequent minor interactions involved epoetin alfa + acetylsalicylic acid (n = 14) and epoetin alfa + calcium carbonate (n = 10). Pharmacodynamic interactions predominated, mainly involving additive effects of cardiovascular medications. Conclusions: Potential drug interactions were highly prevalent among patients undergoing hemodialysis, with moderate-severity interactions predominating. Routine screening for potential drug interactions may support safer prescribing, optimize pharmacotherapy, and strengthen multidisciplinary medication management in this high-risk population.

Cerebellar abnormalities have been associated with attention-deficit/hyperactivity disorder (ADHD) in human studies. Animal models also implicate cerebellar microcircuit dysfunction, particularly reduced inhibitory control of granule cells (GCs) in mice lacking Git1, an ADHD risk gene. Excitatory GCs are the most abundant neuronal population in the cerebellum and are enriched in α6 subunit-containing GABAA (α6GABAA) receptors. Thus, α6GABAA receptor-selective positive allosteric modulators (PAMs), such as pyrazoloquinolinones (PQs), may represent a novel therapeutic approach for ADHD. Here, we tested this hypothesis using PQ Compound 6 in juvenile (P28) ICR mice treated with dizocilpine (MK-801, 0.2 mg/kg, intraperitoneally, i.p.), an NMDA receptor antagonist. In both sexes, MK-801 induced behavioral abnormalities resembling the three core symptoms of ADHD- hyperlocomotion, impulsivity, and inattention-as assessed by locomotor activity, cliff avoidance reaction, and novel object recognition tests, respectively. Compound 6 (3 mg/kg, i.p.) normalized these ADHD-like behavioral impairments. Atomoxetine, an approved ADHD medication, also attenuated ADHD-like phenotypes, although with sedative effects. The therapeutic-like effects of Compound 6 were abolished by intracerebellar microinjection of furosemide, an α6GABAA receptor antagonist, and were absent in Gabra6 (α6-encoding gene)-knockout mice, indicating that positive modulation of cerebellar α6GABAA receptors underlies the observed behavioral improvements. Together, these findings provide proof-of-concept that enhancing cerebellar α6GABAA receptor-mediated inhibition can ameliorate ADHD-relevant behavioral impairments and highlight α6GABAA receptor-selective PAMs as a potential pharmacotherapeutic strategy for ADHD.

Loop diuretics are first-line therapy for hypervolemia. They block the sodium-potassium-2-chloride cotransporter type 1 on the renal afferent arteriole that mediates vasoconstriction and the sodium-potassium-2-chloride cotransporter type 2 on the macula densa cells that mediates the tubuloglomerular feedback response and raises intrarenal pressure that inhibits the myogenic response. These should reduce afferent arteriolar vasoconstriction and increase the glomerular filtration rate; however, more often, the glomerular filtration rate is reduced. This has been attributed to diuretic-induced extracellular volume depletion that activates a systemic neurohormonal response. Accordingly, a fall in glomerular filtration rate can lead to strategies to restore body fluid volumes while reducing the diuretic dosage. Here, we review the regulation of renal hemodynamics during loop diuretic therapy. We propose that a passive, obstructive component of reduced renal blood flow combines with activation of renal afferent nerves, macula densa-derived renin release with intrarenal Ang II (angiotensin II) formation, and generation of vasoconstrictor prostaglandins and thromboxane to provide intrarenal mechanisms of passive and active increases in renal vascular resistance that together can reduce the glomerular filtration rate. The hypothesis that a reduction in the glomerular filtration rate with loop diuretics can derive from intrarenal mechanisms of vasoconstriction rather than from volume depletion suggests novel approaches to manage diuretic resistance and worsening renal function in heart failure.

Loop diuretics are widely used in the treatment of hypertension and edema caused by cardiovascular, renal, and hepatic dysfunction. Furosemide and bumetanide are 2 of the more commonly prescribed loop diuretics. Sharing a common mechanism of action of blocking the Na+-K+-2Cl- cotransporter in the thick ascending loop of Henle, these drugs can be used to promote diuresis and electrolyte excretion. This article reviews the uses of these loop diuretics and compares and contrasts the pharmacology, efficacy in treating congestive heart failure, adverse effects, and clinical trials comparing the 2 drugs to evaluate whether one drug has higher efficacy and under which circumstances it is preferable to use one drug over another. Numerous studies have shown that furosemide and bumetanide are both equally effective in treating congestive heart failure and the peripheral edema associated with it. As they both possess side effects that can be caused by low electrolyte levels, it is important to monitor these values during administration. Furosemide possesses a lower relative dose ratio to bumetanide, allowing the dosage to be more easily titrated for individual requirements, while bumetanide has a lower risk of ototoxicity and has a higher bioavailability.

Flavonoids are widely consumed dietary polyphenols that modulate drug disposition via membrane transporters. Increasing attention has been paid to methoxyflavones (MeO-FLVs) because methoxylation can increase membrane permeability and metabolic stability, potentially elevating transporter-mediated drug-drug interaction risk; however, position-specific effects are poorly defined. We profiled a series of structurally related flavones (3-OH-FLV, 3-MeO-FLV, 5-MeO-FLV, 6-MeO-FLV, and 7-MeO-FLV) across major uptake and efflux transporters. In vitro uptake and bidirectional transport assays demonstrated that methoxyflavones inhibited renal organic anion transporters 1 and 3 (OAT1/OAT3), organic cation transporter 2 (OCT2), and efflux transporters P-glycoprotein (MDR1)/breast cancer resistance protein (BCRP) more potently than 3-OH-FLV, although the inhibitory potency varied depending on the methoxy substitution position, particularly for OAT1 and OCT2. Cytotoxicity reversal assays supported functional inhibition of MDR1 and BCRP by the methoxyflavones. In vivo interaction studies were performed for the selected methoxyflavones using metformin and furosemide as transporter-relevant probe drugs in rats. Metformin pharmacokinetics were measurably altered by 3-MeO-FLV and 7-MeO-FLV, consistent with transporter-related modulation of metformin disposition, potentially involving OCT2. For furosemide, a clear interaction was observed with 6-MeO-FLV and 7-MeO-FLV. Overall, these findings suggest that the methoxylation pattern influences transporter inhibition profiles and in vivo pharmacokinetic effects, although further studies with larger compound sets are needed to define structure-activity relationships and transporter selectivity.