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European Heart Journal Aug 2023To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide.
METHODS AND RESULTS
A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments.
CONCLUSION
In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04860011.
Topics: Humans; Metolazone; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Heart Failure; Diuretics; Sodium
PubMed: 37210742
DOI: 10.1093/eurheartj/ehad341 -
European Heart Journal Aug 2023Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection...
AIMS
Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.
METHODS AND RESULTS
In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).
CONCLUSION
In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.
Topics: Humans; Diuretics; Heart Failure; Furosemide; Benzhydryl Compounds; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Ventricular Function, Left
PubMed: 37220093
DOI: 10.1093/eurheartj/ehad283 -
Chest Jan 2024Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective treatment for Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients with and without HIV... (Observational Study)
Observational Study
Low-Dose vs Conventional-Dose Trimethoprim-Sulfamethoxazole Treatment for Pneumocystis Pneumonia in Patients Not Infected With HIV: A Multicenter, Retrospective Observational Cohort Study.
BACKGROUND
Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective treatment for Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients with and without HIV infection; however, a high incidence of adverse events has been observed. Low-dose TMP-SMX is a potentially effective treatment with fewer adverse events; however, evidence is limited.
RESEARCH QUESTION
What is the efficacy and safety of low-dose TMP-SMX for non-HIV PCP compared with conventional-dose TMP-SMX after adjusting for patient background characteristics?
STUDY DESIGN AND METHODS
In this multicenter retrospective cohort study, we included patients diagnosed with non-HIV PCP and treated with TMP-SMX between June 2006 and March 2021 at three institutions. The patients were classified into low-dose (TMP < 12.5 mg/kg/d) and conventional-dose (TMP 12.5-20 mg/kg/d) groups. The primary end point was 30-day mortality, and the secondary end points were 180-day mortality, adverse events grade 3 or higher per the Common Terminology Criteria for Adverse Events v5.0, and initial treatment completion rates. Background characteristics were adjusted using the overlap weighting method with propensity scores.
RESULTS
Fifty-five patients in the low-dose group and 81 in the conventional-dose group were evaluated. In the overall cohort, the average age was 70.7 years, and the proportion of women was 55.1%. The average dose of TMP-SMX was 8.71 mg/kg/d in the low-dose group and 17.78 mg/kg/d in the conventional-dose group. There was no significant difference in 30-day mortality (6.7% vs 18.4%, respectively; P = .080) or 180-day mortality (14.6% vs 26.1%, respectively; P = .141) after adjusting for patient background characteristics. The incidence of adverse events, especially nausea and hyponatremia, was significantly lower in the low-dose group (29.8% vs 59.0%, respectively; P = .005). The initial treatment completion rates were 43.3% and 29.6% in the low-dose and conventional-dose groups (P = .158), respectively.
INTERPRETATION
Survival was similar between the low-dose and conventional-dose TMP-SMX groups, and low-dose TMP-SMX was associated with reduced adverse events in patients with non-HIV PCP.
Topics: Humans; Female; Aged; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumonia, Pneumocystis; Retrospective Studies; HIV Infections; Treatment Outcome
PubMed: 37574166
DOI: 10.1016/j.chest.2023.08.009 -
The Brazilian Journal of Infectious... 2023Nocardiosis is a rare bacterial infection caused by Nocardia spp. However, an increasing incidence has been described whereby data about epidemiology and prognosis are... (Review)
Review
INTRODUCTION
Nocardiosis is a rare bacterial infection caused by Nocardia spp. However, an increasing incidence has been described whereby data about epidemiology and prognosis are essential.
METHODS
A retrospective descriptive study was conducted among patients with positive Nocardia spp. culture, from January 2019 to January 2023, at a Terciary Hospital in Portugal.
RESULTS
Nocardiosis was considered in 18 cases with a median age of 63.8-years-old. At least one immunosuppressive cause was identified in 70% of patients. Five patients had Disseminated Nocardiosis (DN). The lung was the most common site of clinical disease (77.8%) and Nocardia was most commonly identified in respiratory tract samples. The most frequently isolated species were Nocardia nova/africana (n = 7) followed by Nocardia cyriacigeorgica (n = 3) and Nocardia pseudobrasiliensis (n = 3). The majority of the patients (94.4%) received antibiotic therapy, of whom as many as 55.6% were treated with monotherapy. The most frequently prescribed antibiotic was trimethoprim-sulfamethoxazole. Selected antimicrobial agents were generally effective, with linezolid and cotrimoxazole (100% Susceptibility [S]) and amikacin (94% S) having the most activity against Nocardia species. The median (IQR) duration of treatment was 24.2 (1‒51.4) weeks for DN; The overall one-year case fatality was 33.3% (n = 6) and was higher in the DN (66.7%). No recurrence was observed.
CONCLUSION
Nocardiosis is an emerging infectious disease with a poor prognosis, particularly in DN. This review offers essential epidemiological insights and underscores the importance of gaining a better understanding of the microbiology of nocardiosis. Such knowledge can lead to the optimization of antimicrobial therapy and, when necessary, guide appropriate surgical interventions to prevent unfavorable outcomes.
Topics: Humans; Middle Aged; Retrospective Studies; Nocardia; Nocardia Infections; Anti-Bacterial Agents; Trimethoprim, Sulfamethoxazole Drug Combination; Anti-Infective Agents
PubMed: 37802128
DOI: 10.1016/j.bjid.2023.102806 -
Pharmaceutics Jun 2023The aim of this study was to examine homopolymeric poly(-isopropylacrylamide), p(NIPAM), hydrogels cross-linked with ethylene glycol dimethacrylate as carriers for...
The aim of this study was to examine homopolymeric poly(-isopropylacrylamide), p(NIPAM), hydrogels cross-linked with ethylene glycol dimethacrylate as carriers for sulfanilamide. Using FTIR, XRD and SEM methods, structural characterization of synthesized hydrogels before and after sulfanilamide incorporation was performed. The residual reactants content was analyzed using the HPLC method. The swelling behavior of p(NIPAM) hydrogels of different crosslinking degrees was monitored in relation to the temperature and pH values of the surrounding medium. The effect of temperature, pH, and crosslinker content on the sulfanilamide release from hydrogels was also examined. The results of the FTIR, XRD, and SEM analysis showed that sulfanilamide is incorporated into the p(NIPAM) hydrogels. The swelling of p(NIPAM) hydrogels depended on the temperature and crosslinker content while pH had no significant effect. The sulfanilamide loading efficiency increased with increasing hydrogel crosslinking degree, ranging from 87.36% to 95.29%. The sulfanilamide release from hydrogels was consistent with the swelling results-the increase of crosslinker content reduced the amount of released sulfanilamide. After 24 h, 73.3-93.5% of incorporated sulfanilamide was released from the hydrogels. Considering the thermosensitivity of hydrogels, volume phase transition temperature close to the physiological temperature, and the satisfactory results achieved for sulfanilamide incorporation and release, it can be concluded that p(NIPAM) based hydrogels are promising carriers for sulfanilamide.
PubMed: 37376197
DOI: 10.3390/pharmaceutics15061749 -
Critical Care Medicine Dec 2023Trimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition...
OBJECTIVES
Trimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition and clinical evaluation for a novel adverse drug reaction (ADR) based on a series of recently identified rare cases of life-threatening ADRs.
DESIGN
A retrospective study was conducted. All medical records were evaluated. Available pathology samples were sent to Massachusetts General for clinical consultation. Blood samples from surviving patients were obtained and human leukocyte antigen (HLA) analysis was performed by the Children's Mercy Hospital Genomic Center and Vanderbilt University Medical Center.
SETTING
U.S. ICUs, 1996-2021.
PATIENTS
Nineteen young patients (10-37) were identified. Patients were previously healthy, with no preexisting pulmonary disease, no other cause for respiratory failure, and no chronic history of smoking/vaping.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Through our retrospective analysis, we analyzed clinical characteristics associated with TMP-SMX. Pathology samples were reviewed, and HLA analysis was performed on available samples by the study team or as standard of care at treatment hospitals in some cases. In 19 critically ill patients, we identified a pattern of severe respiratory failure requiring ICU admission, mechanical ventilation, and frequent extracorporeal membrane oxygenation use. We describe the first three-part clinical diagnosis and evaluation strategy: 1) Clinical definition: Unexplained severe respiratory failure in a patient receiving greater than or equal to 6 days of TMP-SMX at treatment dose (not prophylaxis). TMP-SMX ARDS is a diagnosis of exclusion. 2) Genetic association: One hundred percent of currently available TMP-SMX respiratory failure patient genomic data, ( n = 11) have been carriers of both HLA-B*07:02 and HLA-C*07:02 alleles. HLA allele evaluation could be considered in patients with suspected TMP-SMX respiratory failure. 3) Lung pathology: A unique pulmonary pathologic pattern of lung injury termed diffuse alveolar injury with delayed epithelialization has been observed in these cases. In suspected cases, surgical lung biopsy early in the clinical course could be considered.
CONCLUSIONS
TMP-SMX is a commonly prescribed antibiotic. However, we find it imperative to share this relatively rare but life-threatening condition with clinicians as the mortality rate approaches 40%.
Topics: Child; Humans; Trimethoprim, Sulfamethoxazole Drug Combination; Retrospective Studies; Anti-Bacterial Agents; Respiratory Distress Syndrome; Respiratory Insufficiency
PubMed: 37449964
DOI: 10.1097/CCM.0000000000006002 -
International Journal of Molecular... Apr 2024The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their... (Review)
Review
The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.
Topics: Humans; Antibodies, Monoclonal; Pyrimethamine; Sulfadiazine
PubMed: 38612744
DOI: 10.3390/ijms25073935