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Background Hypothesis/Objectives Animals Methods Results Conclusions and Clinical Importance Furosemide, a commonly used diuretic, activates the renin‐angiotensin‐aldosterone system (RAAS) in other species. Little is known about RAAS peptide activation in horses.To evaluate equilibrium analysis as a practical method for RAAS quantification in horses and describe the RAAS response to a single dose of furosemide. We hypothesize that furosemide would cause transient increase in RAAS peptides in horses.14 healthy adult thoroughbreds from a university teaching herd.Horses received either furosemide (1 mg/kg IV) or saline IV in a crossover study design. Protease‐inhibited samples were compared with equilibrium analysis samples with Deming regression analysis. Renin‐angiotensin‐aldosterone system hormones were evaluated at 0, 0.25, 0.5, 4, and 24 hours postadministration, via equilibrium analysis. Values were compared with a mixed effects model.Correlation between protease inhibition and equilibrium analysis was high for angiotensin I peptide (AngI) and angiotensin II peptide (AngII) (r = .92 and .95, respectively). Baseline RAAS peptide concentrations were below the limit of detection except AngII (median, 7.5 [range, 3.5‐14.0] pmol/L). Furosemide administration resulted in an increase in AngI (8.0 [0.5‐15.5] pmol/L, P = .03), AngII (33.7 [9.6‐57.9] pmol/L, P = .0008), angiotensin III peptide (AngIII) (2.9 [0.9‐4.9] pmol/L, P = .0005), angiotensin IV peptide (AngIV) (2.0 [0.6‐3.4] pmol/L, P = .0005), and angiotensin 1‐5 peptide (Ang1‐5) (5.6 [1.2‐5.9] pmol/L, P = .003) at 4 hours. Differences are reported as difference in the mean (95% confidence interval [CI]).Furosemide produced an increase in hormones associated with both the classical and alternative RAAS pathways. Serum equilibrium analysis is practical for RAAS analysis in horses. [ABSTRACT FROM AUTHOR]

Background: Modified furosemide responsiveness index (mFRI) is a novel biomarker for assessing diuretic response and AKI progression in patients with early AKI. However, the comparative predictive performance of mFRI and novel renal biomarkers for adverse renal outcomes remains unclear. In a single-center prospective study, we aimed to evaluate the discriminatory abilities of mFRI and other novel renal biomarkers in predicting AKI progression and prognosis in patients with initial mild and moderate AKI (KDIGO stage 1 to 2). Results: Patients with initial mild and moderate AKI within 48 h following cardiac surgery were included in this study. The mFRI, renal biomarkers (including serum or urinary neutrophil gelatinase-associated lipocalin [sNGAL or uNGAL], serum cystatin C, urinary N-acetyl-beta-D-glycosaminidase [uNAG], urinary albumin-to-creatinine ratio) and cytokines (TNF, IL-1β, IL-2R, IL-6, IL-8, and IL-10) were measured at AKI diagnosis. The mFRI was calculated for each patient, which was defined as 2-hour urine output divided by furosemide dose and body weight. Of 1013 included patients, 154 (15.2%) experienced AKI progression, with 59 (5.8%) progressing to stage 3 and 33 (3.3%) meeting the composite outcome of hospital mortality or receipt of renal replacement therapy (RRT). The mFRI showed non-inferiority or potential superiority to renal biomarkers and cytokines in predicting AKI progression (area under the curve [AUC] 0.80, 95% confidence interval [CI] 0.77–0.82), progression to stage 3 (AUC 0.87, 95% CI 0.85–0.89), and composite outcome of death and receipt of RRT (AUC 0.85, 95% CI 0.82–0.87). Furthermore, the combination of a functional biomarker (mFRI) and a urinary injury biomarker (uNAG or uNGAL) resulted in a significant improvement in the prediction of adverse renal outcomes than either individual biomarker (all P < 0.05). Moreover, incorporating these panels into clinical model significantly enhanced its predictive capacity for adverse renal outcomes, as demonstrated by the C index, integrated discrimination improvement, and net reclassification improvement (all P < 0.05). Conclusions: As a rapid, cost-effective and easily accessible biomarker, mFRI, exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers in cardiac surgical patients with mild to moderate AKI. Trial registration: Clinicaltrials.gov, NCT04962412. Registered July 15, 2021, https://clinicaltrials.gov/ct2/show/NCT04962412?cond=NCT04962412&draw=2&rank=1. Highlights: The mFRI is a rapid, cost-effective and easily accessible biomarker. The mFRI exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers and cytokines in cardiac surgical patients with mild to moderate AKI. Combining the functional biomarker mFRI with a urinary injury biomarker (uNAG or uNGAL) enhanced predictive accuracy for adverse renal outcomes. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion The TRANSFORM‐HF trial found no difference in clinical outcomes between torsemide versus furosemide after hospitalization for heart failure. This analysis aimed to assess the impact of diuretic dosing on the primary and secondary clinical outcomes.This post‐hoc analysis of TRANSFORM‐HF categorized patients into three groups by discharge diuretic dose: (1) ≤40 mg, (2) >40–80 mg, and (3) >80 mg of furosemide equivalents. The associations between discharge dose and 12‐month clinical events, and change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS), were assessed. Overall, 2379 patients were included, aged 65 years (interquartile range 56–75), 883 (37.1%) women, and 812 (34.2%) Black. Furosemide had adjusted hazard ratios (aHR) for all‐cause mortality of 1.21 (95% confidence interval [CI] 0.91–1.59) for discharge dose group 2 and 1.40 (95% CI 1.04–1.88) for group 3, compared with group 1. For torsemide, aHRs were 1.74 (95% CI 1.32–2.30) for group 2 and 1.58 (95% CI 1.14–2.19) for group 3. No evidence of heterogeneity for the association between increased mortality and higher dose was found by loop diuretic type (pinteraction = 0.17). Higher doses of furosemide and torsemide were associated with increased risk of all‐cause hospitalization and the composite of all‐cause mortality and hospitalization, without evidence of heterogeneity by loop diuretic type (pinteraction > 0.2). Changes in KCCQ‐CSS from baseline at 12 months was similar across dose groups for both drugs.Following hospitalization for heart failure, higher loop diuretic dosing was independently associated with worse clinical and patient‐reported outcomes. The correlation between higher loop diuretic dose and outcomes was consistent, regardless of loop diuretic used. [ABSTRACT FROM AUTHOR]

Background: The use of continuous infusion or IV boluses to treat acute decompensated heart failure (ADHF) with loop diuretics is still debatable. Aim and Objective: To evaluate differences between the two administration routes on the thoracic fluid content (TFC) and the renal functions. Methods: Sixty patients with ADHF admitted to the critical care medicine department, Saifee Hospital, Mumbai, were initially enrolled in the study. Twenty patients were excluded due to EF > 40%, myocardial infarction within 30 days, and baseline serum creatinine level > 4.0 mg/dL. Furosemide (120 mg/day) was given to the remaining 50 pts who continued the study after 1:1 randomization to either continuous infusion (group-I, 25 pts) or three equal intermittent daily doses (group-II, 25 pts). Subsequent dose titration was allowed after 24 h, but not earlier, according to patient's response. No other diuretic medications were allowed. All patients were daily evaluated for NYHA class, urine output, TFC, body weight, serum K+, and renal chemistry. Results: The mean and SD age (Q1-Q3) was 55.95±5.27years old with 28 (56%) males. Apart from TFC which was significantly higher in group-I, the admission demographic, clinical, laboratory and comorbid conditions were similar in both groups. There was statistically insignificant tendency for increased urine output during the 1st and 2nd days in group-I compared to group-II (p = .08). The mean and SD values of TFC on admission were high for all patients 66.52±6.84 kΩ-1 compared to normal range of 25-35 kΩ-1 [20] reflecting pulmonary congestion. In both groups, the TFC was significantly reduced after 24 h of furosemide therapy compared to baseline. It decreased from 1 to 66.52±6.84 kΩ-1 in group I (P = <0.001) and from 51±7.65kΩ-1 to 50.5 (41-60.8) in group II (P = .001). The admission TFC values were significantly higher in group I compared to group II (P = .0001). Conclusions: Continuous furosemide infusion in ADHF patients may result in increased diuresis and decreased TFC, but at the expense of a higher risk of renal function degradation and a lack of symptom relief or shorter ICU stays. [ABSTRACT FROM AUTHOR]

Background/Objectives: Many clinical trials have shown beneficial effects of low-dose dopamine on renal function, diuresis and symptom relief, or cardiac function in hospitalized patients with acute decompensated heart failure (HF). The aim is to assess the neurohormonal effects and the effects on clinical outcomes of the addition of low-dose dopamine in furosemide treatment in patients hospitalized for acute decompensated HF. Methods: A total of 62 patients hospitalized for acute decompensation of HF, were randomly allocated to one of the following three groups: i. LDF (low-dose furosemide), ii. HDF (high-dose furosemide) and, iii. LDFD (low-dose furosemide and dopamine). Primary outcomes of the present analysis were biochemical and neurohormonal indices (i.e., urea, creatinine, hemoglobin, electrolytes, natriuretic peptides, troponin, renin, angiotensin, aldosterone, adrenaline, noradrenaline). Secondary endpoints included clinical outcomes (i.e., length of stay, in-hospital mortality, 2-month mortality and rehospitalization, and 1-year mortality and rehospitalization). Results: Urea and creatinine levels were similar for each day among the three groups (p > 0.05). The amount of urine was similar among the three groups per measurement at 2, 4, 6 and at 8 h (p > 0.05). Biochemical and neurohormonal indices as well as clinical outcomes did not differ among patients receiving different doses of furosemide, nor in patients receiving furosemide in combination with dopamine (p > 0.05). Conclusions: Although the addition of low-dose dopamine to intravenous furosemide was considered to have some theoretical advantages in maintaining renal function, no significant differences in neurohormonal effects and clinical outcomes were observed in patients hospitalized for acute decompensation of HF. [ABSTRACT FROM AUTHOR]

Hospitalized patients often develop acute renal failure (ARF), which causes severe morbidity and death. This research investigates the potential renoprotective benefits of sildenafil and furosemide in glycerol-induced ARF, and measures kidney function metrics in response to nanoparticle versions of these medications. Inducing ARF is commonly done by injecting 50% glycerol intramuscularly. Rats underwent a 24-h period of dehydration and starvation before slaughter for renal function testing. We investigated urine analysis, markers of oxidative stress, histology of kidney tissue, immunohistochemistry analysis of caspase-3 and interleukin-1 beta (IL-1 β), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase–associated lipocalin (NGAL), which are specific indicators of kidney tissue damage. The results of our study showed that the combination of sildenafil and furosemide, using both traditional and nanoparticle formulations, had a greater protective effect on the kidneys compared to using either drug alone. The recovery of renal tissue indicators, serum markers, and urine markers, which are indicative of organ damage, provides evidence of improvement. This was also indicated by the reduction in KIM-1 and NGAL tubular expression. The immunohistochemistry tests showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of caspase-3 and IL-1β. According to the findings, a glycerol-induced rat model demonstrates that sildenafil and furosemide, either alone or in combination, in conventional or nanoparticulate forms, improve ARF dysfunction. The synergistic nanoparticulate compositions show remarkable effectiveness. This observation highlights the possible therapeutic implications for ARF treatment. [ABSTRACT FROM AUTHOR]

This document contains summaries of various research studies in the field of pharmacology and drug development. The studies cover a range of topics, including pharmacokinetic modeling, drug distribution, safety, dosing recommendations, cardiac safety, and the relationship between zinc deficiency and liver damage. The summaries provide concise and factual information about the studies, highlighting their key findings and implications. The document aims to provide library patrons with a quick overview of the research studies, allowing them to determine if they want to explore the full text further. The summaries are culturally sensitive and respectful of diverse perspectives, presenting the information objectively without adopting any judgments or biases. This document contains summaries of various research studies related to pharmacokinetics and drug interactions. The studies cover a range of topics, including the safety and efficacy of different medications, the impact of drug-drug interactions on exposure, and the demographic representation in clinical trials. The findings provide valuable insights into the pharmacokinetics of these drugs, potential drug interactions, and the need for diversity in clinical trial populations. Overall, these studies contribute to our understanding of drug safety and optimization of dosing regimens. [Extracted from the article]

We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin complex (mTORC)1, partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (normal salt) or 4.0% NaCl (high salt) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide [inhibitors of epithelial Na+ channel (ENaC), Na-K-2Cl cotransporter (NKCC2), or Na-Cl cotransporter (NCC), respectively] either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects. NEW & NOTEWORTHY: This study explored mechanisms underlying the natriuretic effects of mammalian target of rapamycin protein complex 2 inhibition using PP242 and revealed both epithelial Na+ channel and Na-Cl cotransporter in the distal tubular segments were potentially inhibited. These observations, with prior lab evidence, indicate that PP242 prevents hypertension via its potent inhibitory effects on these specific sodium transporters and by reducing renal immune responses. This dual action, coupled with potassium sparing effects, suggests an improved approach for managing hypertension and associated kidney damage. [ABSTRACT FROM AUTHOR]

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite. [ABSTRACT FROM AUTHOR]

A correction notice has been issued for an article analyzing adverse drug event reports and process outcomes. The correction states that a coding error was found, resulting in an increase in serious adverse drug events, deaths, hospitalizations, and life-threatening events. The correction also highlights that age, not sex, significantly impacts adverse drug event outcomes. The document provides tables showing the most commonly reported adverse drug events and associated drugs, as well as the incidence of serious adverse drug events for various medications. The data was collected as part of a study funded by the Canadian Institutes of Health Research. [Extracted from the article]

Background: Children treated in a pediatric intensive care unit (PICU) often receive several drugs together, among them drugs defined as high-alert medications (HAMs). Those drugs carry a high risk of causing patient harm, for example, due to a higher potential for interactions. HAMs should therefore be administered with caution, especially in a PICU. Objectives: The objective of the current study was to identify drug–drug interactions involving HAMs that increase the risk of interaction-associated symptoms in pediatric intensive care. Methods: In a retrospective study, we analyzed the electronic documentation of patients hospitalized for at least 48 h in a general PICU who received at least two different drugs within a 24-h interval. We assessed potential drug–drug interactions involving HAM on the basis of the two drug information databases UpToDate and drugs.com. Furthermore, we analyzed whether symptoms were observed after the administration of drug pairs that could lead to interaction-associated symptoms. For drug pairs involving HAM administered on at least 2% of patient days, and symptoms observed at least ten times after a respective drug pair, we calculated odds ratios, 95% confidence intervals, and p-values by using a univariate binary logistic regression. Results: Among 315 analyzed patients, 81.3% (256/315) received drugs defined as high-alert medication for pediatric patients. Those high-alert medications were involved in 20,150 potential drug–drug interactions. In 14.0% (2830/20,150) of these, one or more symptoms were observed that could be a possible consequence of the interaction, resulting in 3203 observed symptoms affecting 56.3% (144/256) of patients receiving high-alert medication. The odds ratios for symptoms observed after a drug–drug interaction were increased for eight specific symptoms (each p ≤ 0.05), especially hemodynamic alterations and disturbances of electrolyte and fluid balance. The odds ratio was highest for decreased blood pressure observed after the administration of the drug pair fentanyl and furosemide (OR 5.06; 95% confidence interval 3.5–7.4; p < 0.001). Increased odds ratios for specific symptoms observed after drug–drug interactions resulted from eight combinations composed of eight different drugs: digoxin, fentanyl, midazolam, phenobarbital, potassium salts and vancomycin (high-alert medications), and the diuretics furosemide and hydrochlorothiazide (non-high-alert medications). The resulting drug pairs were: potassium salts–furosemide, fentanyl–furosemide, vancomycin–furosemide, digoxin–furosemide, digoxin–hydrochlorothiazide, fentanyl–phenobarbital, potassium salts–hydrochlorothiazide, and midazolam–hydrochlorothiazide. Conclusions: In a cohort of PICU patients, this study identified eight specific drug pairs involving high-alert medications that may increase the risk of interaction-associated symptoms, mainly hemodynamic alterations and electrolyte/fluid balance disturbances. If the administration of those drug pairs is unavoidable, patients should be closely monitored. [ABSTRACT FROM AUTHOR]

Objectives: Furosemide (FSM), a potent loop diuretic, is used to treat edema due to hypertension, congestive heart failure, and liver and renal failures. FSM applications are limited by its low bioavailability. Our aim is to use different nanoencapsulation strategies to control the release of FSM and enhance its pharmacokinetic properties. Methods: Two types of FSM-loaded nanocapsules, namely FSM-loaded lipid nanocapsules (LNCs) and polymeric nanocapsules (PNCs), were developed, physicochemically characterized, and subjected to pharmacokinetic and pharmacodynamic studies. Lipid nanocapsules were prepared by the simple phase inversion method using LabrafacTM lipid, while the polymeric nanocapsules were prepared by nanoprecipitation method using polycaprolactone polymer. Results: Transmission electron microscopy ascertains spherical structures, corroborating the nanometric diameter of both types of nanocapsules. The particle size of the optimized FSM-loaded LNCs and FSM-loaded PNCs was 32.19 ± 0.72 nm and 230.7 ± 5.13 nm, respectively. The percent entrapment efficiency was 63.56 ± 1.40% of FSM for the optimized PNCs. The in vitro release study indicated prolonged drug release compared to drug solutions. The two loaded nanocapsules systems succeeded in enhancing the pharmacokinetic parameters in comparison to the marketed FSM solution with superior diuretic activity (p < 0.05). The results of the stability study and the terminal sterilization by autoclave indicated the superiority of LNCs over PNCs in maintaining the physical parameters under storage conditions and the drastic conditions of sterilization. Conclusions: LNCs and PNCs are considered promising nanosysems for improving the diuretic effect of FSM. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) in the ICU is one of the life-threatening situations that may need renal replacement therapy (RRT). Survival benefit of early initiation of RRT is still not proven. There is still a debate whether early or late RRT significantly affects morbidity and mortality.Methods This is a randomized controlled trial (RCT) that was conducted on 94 critically ill subjects with stage 2 AKI, according to KDIGO classification, who were on invasive mechanical ventilation. Recruited subjects were selected only if they failed to respond to furosemide stress test after volume status optimization. Subjects were randomly assigned into two groups according to timing of RRT initiation. In the early group, RRT was initiated without the presence of urgent indications for hemodialysis, whereas in the late group, RRT was implemented only in the presence of one or more of urgent indications such as severe metabolic acidosis or hyperkalemia. Primary outcomes of the study were ICU mortality and length of stay. Secondary outcomes included recovery of renal function in addition to duration of mechanical ventilation.Results There was no statistically significant difference in the primary outcomes, namely ICU mortality and ICU length of stay. About 51.1% of the subjects survived in the early RRT group, whereas 46.8% survived in the late group (p = .680). Although duration of mechanical ventilationwas not significantly different (p = .486), recovery of renal functionand less dependency on RRT after discharge, were significantly higher in the early RRT group (p = < .001).Conclusion Even after choosing AKI patients who failed to respond to furosemide stress test, timing of RRT initiation did not affect survival, ICU length of stay or duration of mechanical ventilation. However, early RRT may have positive effect on RRF for survived patients.