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Objectives: The Fluconazole pharmacokinetic-pharmacodynamic relationship was investigated in a few clinical settings and only limited studies regarding burned patients are available. Thus, the authors aimed to investigate fluconazole pharmacokinetics changes and its impact on antifungal therapy coverage against dose-dependent Candida spp. applying the PK/PD approach in critically ill severely burned patients., Methods: Fluconazole was administered as a one-hour intravenous infusion of 200 mg q12h. Doses were increased according to the coverage based on the PK/PD approach. Blood samples were collected at the end of the infusion (1 st hour), two hours after (3 rd hour), and before the next dose (12 th or 24 th hour). Serum concentrations were obtained by HPLC-UV. Pharmacokinetic parameters were estimated by noncompartmental analysis and compared with data described in healthy subjects. The effectiveness predictive index was based on the AUC ss 0-24h /MIC ratio, with a target above 25., Results: Every pharmacokinetic parameter was reduced throughout all three sets of the study. Compared to healthy subjects, the volume of distribution was decreased about 3‒7 times, biological half-life was 2‒3 times shorter and total body clearance was slightly altered but statistically significant. Both half-life and total body clearance were correlated to the volume of distribution. Consequently, an increase in fluconazole daily dose was necessary to improve empiric coverage., Conclusions: Fluconazole pharmacokinetics is altered in critically ill severely burned patients, mainly related to the volume of distribution. Doses higher than usual may be necessary to reach the PK/PD target and guarantee antifungal coverage against dose-dependent Candida spp. up to MIC 32 mg/L., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: Despite significant advancements in understanding risk factors and treatment strategies, ischemic heart disease (IHD) remains the leading cause of mortality worldwide, particularly within specific regions in Brazil, where the disease is a burden. Therefore, the aim of this study was to estimate the risk of hospitalization and mortality from IHD in the state of Paraná (Brazil), using spatial analysis to identify areas with higher risk based on socioeconomic, demographic and health variables., Methods: This is an ecological study based on secondary and retrospective IHD hospitalization and mortality data obtained from the Brazilian Hospitalization and Mortality Information Systems during the 2010-2021 period. Data were analyzed for 399 municipalities and 22 health regions in the state of Paraná. To assess the spatial patterns of the disease and identify relative risk (RR) areas, we constructed a risk model by Bayesian inference using the R-INLA and SpatialEpi packages in R software., Results: A total of 333,229 hospitalizations and 73,221 deaths occurred in the analyzed period, and elevated RR of hospitalization (RR = 27.412, CI 21.801; 34.466) and mortality (RR = 15.673, CI 2.148; 114.319) from IHD occurred in small-sized municipalities. In addition, medium-sized municipalities also presented elevated RR of hospitalization (RR = 6.533, CI 1.748; 2.006) and mortality (RR = 6.092, CI 1.451; 2.163) from IHD. Hospitalization and mortality rates were higher in white men aged 40-59 years. A negative association was found between Municipal Performance Index (IPDM) and IHD hospitalization and mortality., Conclusion: Areas with increased risk of hospitalization and mortality from IHD were found in small and medium-sized municipalities in the state of Paraná, Brazil. These results suggest a deficit in health care attention for IHD cases in these areas, potentially due to a low distribution of health care resources., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Introduction: Immunological skin dysfunctions trigger the synthesis and release of inflammatory cytokines, which induce recurrent skin inflammation associated with chronic itching, inefficient barrier behavior, and reduced skin hydration. These features characterize a multifactorial chronic inflammatory disease atopic dermatitis (AD). AD therapy includes anti-inflammatory drugs and immunosuppressors as well as non-pharmacological alternatives such as emollients, moisturizers, and lipids (ceramides, phospholipids) for modulating the skin hydration and the barrier repair. However, these treatments are inconvenient with low drug skin penetration and insufficient maintenance on the application site., Areas Covered: Nanotechnology-based therapies can be a great strategy to overcome these limitations. Considering the particular skin morphological organization, SC lipid matrix composition, and immunological functions/features related to nanocarriers, this review focuses on recent developments of nanoparticulate systems (polymeric, lipid-based, inorganic) as parent or hybrid systems including their chemical composition, physico-chemical and biopharmaceutical properties, and differential characteristics that evaluate them as new effective drug-delivery systems for AD treatment., Expert Opinion: Despite the several innovative formulations, research in nanotechnology-based carriers should address specific aspects such as the use of moisturizers associated to pharmacological therapies, toxicity studies, scale-up production processes and the nanocarrier influence on immunological response. These approaches will help researchers choose the most appropriate nanocarrier system and widen nanomedicine applications and commercialization.

Background: Poly(ϵ-caprolactone) nanocapsules (NC + ATZ) are an efficient carrier system for atrazine and were developed as an alternative to reduce the harmful environmental effects of this herbicide. Here, we analyzed the pre-emergence herbicidal activity of NC + ATZ against Bidens pilosa and evaluated its residual effect on soybean plants after different periods of soil treatment with the formulations., Results: In contrast to non-nanoatrazine, NC + ATZ treatment led to very high mortality rates of B. pilosa seedlings even after a tenfold dilution, which suggests that atrazine nanoencapsulation improved its pre-emergence herbicidal activity. In a short-term assay (17 days), soil treatment with all atrazine-containing formulations resulted in intense toxicity to soybean plants. NC + ATZ at 200 g ha -1 had the same inhibitory effects on the physiological and growth parameters of soybean plants compared with non-nanoatrazine at 2000 g ha -1 , which suggests that atrazine nanoencapsulation increased the short-term residual effect of the herbicide. In a long-term assay (60 days), a gradual recovery of soybean plants from atrazine phytotoxicity was observed. When comparing the effects of nano- and non-nanoatrazine at the same concentrations, the growth and physiological parameters of soybean plants were mainly affected to the same extent. This indicates that encapsulation of atrazine into poly(ϵ-caprolactone) nanocapsules did not enhance the long-term residual effect of the herbicide on soybean., Conclusion: NC + ATZ could be applied for efficient weed control without additional phytotoxicity to susceptible crops compared with non-nanoatrazine, provided that a safe interval is respected from atrazine application to sowing. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

In recent years, the use of substances of natural origin, such as botanical pesticides, has emerged as a preferred alternative to the use of synthetic pesticides, the excessive use of which has raised a lot of concern over safety to human/animal health and the environment. Recent developments in nanotechnology have opened up a new avenue for the development of more efficient formulations that can overcome many of the obstacles generally faced in their use in the field, such as loss of activity because of degradation, instability, volatilization, and so on. This Review discusses the key developments in this area, as well as the challenges in relation to nanoscale formulation of botanical pesticides. It presents an appraisal of the recent scientific research, along with an account of the products that have already reached the market. While it acknowledges the great potential of nanotechnology-derived formulations of botanical pesticides for increasing agricultural productivity and reducing health and the environmental impacts, it also highlights the technological challenges that must be addressed to enable adoption of the technology for wider use in agri-food production.

The extensive use of pesticides is causing environmental pollution, affecting animal organisms in different habitats and also leading human health at risk. In this study, we present as an alternative the use of nanoparticles loaded with pesticides and report their toxicological assessment to a soil organism, Caenorhabditis elegans. Three nanoparticle formulations were analyzed: solid lipid nanoparticles loaded or not with atrazine and simazine, SLN; polymeric nanoparticles, NC_PCL loaded with atrazine; and chitosan/tripolyphosphate, CS/TPP, loaded or not with paraquat. All formulations, loaded or not with pesticides, increased lethality in a dose- dependent manner with similar LC50. Both loaded and unloaded NC_PCL were the most toxic formulations to developmental rate, significantly reducing worms length, even at low concentrations. In contrast, both CS/TPP nanoparticles were the least toxic, not affecting reproduction and body length at higher concentrations, probably due to the biocompatibility of chitosan. The physico-chemical characterization of nanoparticles after incubation in saline solution (used in exposure of organisms) has shown that these colloidal systems are stable and remain with the same initial characteristics, even in the presence of saline environment. Notably, our results indicate that the observed effects were caused by the nanoparticles per se. These results suggest that the development of nanoparticles aiming agriculture applications needs more studies in order to optimize the composition and then reduce their toxicity to non-target organisms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A major challenge of agriculture is to increase food production to meet the needs of the growing world population, without damaging the environment. In current agricultural practices, the control of pests is often accomplished by means of the excessive use of agrochemicals, which can result in environmental pollution and the development of resistant pests. In this context, biopesticides can offer a better alternative to synthetic pesticides, enabling safer control of pest populations. However, limitations of biopesticides, including short shelf life, photosensitivity, and volatilization, make it difficult to use them on a large scale. Here, we review the potential use of neem oil in crop protection, considering the gaps and obstacles associated with the development of sustainable agriculture in the not too distant future.

Budesonide (BUD) is a glucocorticoid widely used for the treatment of ulcerative colitis. In this work, we propose the study of the system BUD-HP-β-CD inclusion complex incorporated into PL 407 and PL407-PL403 thermoreversible hydrogels, considering physico-chemical and pharmaceutical aspects. Complexation between BUD and HP-β-CD was confirmed by phase solubility studies (1:1 stoichiometry, Kc=8662.8 M(-1)), DSC, FTIR and microscopy analyzes. BUD solubility in simulated upper and lower colon fluids was improved in a dependence of HP-β-CD and PL 407 or PL407-PL403 association. Micellar hydrodynamic diameter studies showed the interaction between HP-β-CD and PL blocks, as well as the reorganization of the micellar system in the presence of BUD and its inclusion complex. Micellization temperature (Tm) was not shifted, but sol-gel phase transition studies showed that in the presence of BUD, HP-β-CD or BUD:HP-β-CD complex, the association PL407-PL403 favored the gel formation close to the physiological temperature. Physico-chemical and in vitro release assays studies revealed no competitive displacement of BUD from the HP-β-CD cavity evoked by PL407 or PL407-PL403 addition. These findings point out the BUD-HP-β-CD in PL-based hydrogels as strategies for future investigations on development of new pharmaceutical formulations for the treatment of ulcerative colitis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.

Polymeric nanoparticles have been developed for several applications, among them as carrier system of pesticides. However, few studies have investigated the fate of these materials in the environment in relation to colloidal stability and toxicity. In nature, humic substances are the main agents responsible for complexation with metals and organic compounds, as well as responsible for the dynamics of these nanoparticles in aquatic and terrestrial environments. In this context, the evaluation of the influence of aquatic humic substances (AHS) on the colloidal stability and toxicity of polymeric nanoparticles of chitosan/tripolyphosphate with or without paraquat was performed. In this study, the nanoparticles were prepared by the ionic gelation method and characterized by size distribution measurements (DLS and NTA), zeta potential, infrared and fluorescence spectroscopy. Allium cepa genotoxicity studies and ecotoxicity assays with the alga Pseudokirchneriella subcapitata were used to investigate the effect of aquatic humic substances (AHS) on the toxicity of this delivery system. No changes were observed in the physical-chemical stability of the nanoparticles due to the presence of AHS using DLS and NTA techniques. However some evidence of interaction between the nanoparticles and AHS was observed by infrared and fluorescence spectroscopies. The ecotoxicity and genotoxicity assays showed that humic substances can decrease the toxic effects of nanoparticles containing paraquat. These results are interesting because they are important for understanding the interaction of these nanostructured carrier systems with species present in aquatic ecosystems such as humic substances, and in this way, opening new perspectives for studies on the dynamics of these carrier systems in the ecosystem., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Enormous amounts of pesticides are manufactured and used worldwide, some of which reach soils and aquatic systems. Glyphosate is a non-selective herbicide that is effective against all types of weeds and has been used for many years. It can therefore be found as a contaminant in water, and procedures are required for its removal. This work investigates the use of biopolymeric membranes prepared with chitosan (CS), alginate (AG), and a chitosan/alginate combination (CS/AG) for the adsorption of glyphosate present in water samples. The adsorption of glyphosate by the different membranes was investigated using the pseudo-first order and pseudo-second order kinetic models, as well as the Langmuir and Freundlich isotherm models. The membranes were characterized regarding membrane solubility, swelling, mechanical, chemical and morphological properties. The results of kinetics experiments showed that adsorption equilibrium was reached within 4 h and that the CS membrane presented the best adsorption (10.88 mg of glyphosate/g of membrane), followed by the CS/AG bilayer (8.70 mg of glyphosate/g of membrane). The AG membrane did not show any adsorption capacity for this herbicide. The pseudo-second order model provided good fits to the glyphosate adsorption data on CS and CS/AG membranes, with high correlation coefficient values. Glyphosate adsorption by the membranes could be fitted by the Freundlich isotherm model. There was a high affinity between glyphosate and the CS membrane and moderate affinity in the case of the CS/AG membrane. Physico-chemical characterization of the membranes showed low values of solubility in water, indicating that the membranes are stable and not soluble in water. The SEM and AFM analysis showed evidence of the presence of glyphosate on CS membranes and on chitosan face on CS/AG membranes. The results showed that the glyphosate herbicide can be adsorbed by chitosan membranes and the proposed membrane-based methodology was successfully used to treat a water sample contaminated with glyphosate. Biopolymer membranes therefore potentially offer a versatile method to eliminate agricultural chemicals from water supplies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Solid lipid nanoparticles (SLN) containing the herbicides atrazine and simazine were prepared and characterized, and in vitro evaluation was made of the release kinetics, herbicidal activity, and cytotoxicity. The stability of the nanoparticles was investigated over a period of 120 days, via analyses of particle size, ζ potential, polydispersion, pH, and encapsulation efficiency. SLN showed good physicochemical stability and high encapsulation efficiencies. Release kinetics tests showed that use of SLN modified the release profiles of the herbicides in water. Herbicidal activity assays performed with pre- and postemergence treatment of the target species Raphanus raphanistrum showed the effectiveness of the formulations of nanoparticles containing herbicides. Assays with nontarget organisms (Zea mays) showed that the formulations did not affect plant growth. The results of cytotoxicity assays indicated that the presence of SLN acted to reduce the toxicity of the herbicides. The new nanoparticle formulations enable the use of smaller quantities of herbicide and therefore offer a more environmentally friendly method of controlling weeds in agriculture.

This review article discusses the use of nanotechnology in combination with botanical insecticides in order to develop systems for pest control in agriculture. The main types of botanical insecticides are described, together with different carrier systems and their potential uses. The botanical insecticides include those based on active principles isolated from plant extracts, as well as essential oils derived from certain plants. The advantages offered by the systems are highlighted, together with the main technological challenges that must be resolved prior to future implementation of the systems for agricultural pest control. The use of botanical insecticides associated with nanotechnology offers considerable potential for increasing agricultural productivity, while at the same time reducing impacts on the environment and human health.

Introduction: To characterize the evolution of clinical and physiological variables in severe adult burn patients admitted to a Brazilian burn ICU, we hypothesized that characteristics of survivors are different from non-survivors after ICU admission., Methods: A five-year observational study was carried out. The clinical characteristics, physiological variables, and outcomes were collected during this period., Results: A total of 163 patients required ICU support and were analyzed. Median age was 34 [25,47] years. Total burn surface area (TBSA) was 29 [18,43]%, and hospital mortality rate was 42%. Lethal burn area at which fifty percent of patients died (LA50%) was 36.5%. Median SAPS3 was 41 [34,54]. Factors associated with hospital mortality were analyzed in three steps, the first incorporated ICU admission data, the second incorporated first day ICU data, and the third incorporated data from the first week of an ICU stay. We found a significant association between hospital mortality and SAPS3 [OR(95%CI)=1.114(1.062-1.168)], TBSA [OR(95%CI)=1.043(1.010-1.076)], suicide attempts [OR(95%CI)=8.126(2.284-28.907)], and cumulative fluid balance per liter within the first week [OR(95%CI)=1.090(1.030-1.154)]. Inhalation injury was present in 45% of patients, and it was not significantly associated with hospital mortality., Conclusions: In this study of an ICU in a developing country, the mortality rate of critically ill burn patients was high and the TBSA was an independent risk factor for death. SAPS3 at admission and cumulative fluid balance in the first seven days, were also associated with unfavorable outcomes. The implementation of judicious fluid management after an acute resuscitation phase may help to improve outcomes in this scenario., (Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.)

One of the current challenges in drug encapsulation concerns the development of carrier systems for hydrophilic compounds. Potential carriers include nanocapsules prepared with amphiphilic polymers, which consist of a polymeric coating surrounding an aqueous nucleus, or dense matrices such as nanospheres of alginate/chitosan, where the drug may be dispersed in the matrix or adsorbed on the surface. The development of new formulations of nanocarriers, for example the poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) nanocapsules and alginate/chitosan (AG/CS) nanospheres described in this work, is needed in the case of ionized drugs such as articaine. This amino amide local anesthetic is the drug of choice in dentistry for regional anesthesia as well as the relief of acute and chronic pain. Here, the physico-chemical properties of suspensions of the nanoparticles (considering diameter, polydispersion, and zeta potential) were determined as a function of time, in order to establish the stability of the systems. The formulations did not show any substantial changes in these parameters, and were stable for up to 120 days of storage at ambient temperature. Satisfactory encapsulation efficiencies were obtained for the PEG-PCL nanocapsules (60%) and the AG/CS nanospheres (45%). Cytotoxicity assays confirmed that the encapsulation of articaine reduced its toxicity, relative to the free drug. The most promising results were obtained using the vesicular system (PEG-PCL nanocapsules), which not only altered the release profile of the drug, but also resulted in the lowest toxicity. This carrier system therefore holds promise for use in future practical applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The objective of the study was to investigate vancomycin dose adjustment in pediatric burn patients by evaluating trough drug concentrations and the pharmacokinetic and pharmacodynamic (PK/PD) correlation., Methods: Study subjects included 13 patients who were 6.0 years old, 25 kg (median). with normal renal function. These had at least a 30% total burn surface area and inhalation injury were present in 7/13 patients. The patients were investigated prospectively. Plasma monitoring and PK assessments were performed by serial blood sample collections (30 sets). Only 0.2 mL of each plasma sample was required for our plasma measurements, which were made by high performance liquid chromatography. The vancomycin PK/PD target was set at AUC0-24(ss)/MIC>400., Results: Trough values less than 10 μg/mL were obtained in 16/30 sets (53%) as a consequence of increased plasma clearance and the apparent volume of distribution. The daily dose was subsequently increased from 43.4 ± 9.0mg/kg (mean ± SD) to 98.0 ± 17.9 mg/kg, p<0.05. The PK/PD target was reached for pathogens with 0.5mg/L, 1mg/L, 2mg/L and 4 mg/L MIC in 93.3% (28/30), 66.7% (20/30), 33.3% (10/30) and 3.3% (1/30) of the sets, respectively., Conclusions: To more rapidly achieve the PK/PD targets in pediatric burn patients with normal renal function, an initial dose of approximately 90-100mg/kg/day is recommended; however, this higher dosage regimen should be further evaluated in this population in terms of efficacy and toxicity as well as in terms of achieving pharmacodynamic goals., (Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.)

The objective of this work was to develop a modified release system for the local anesthetic lidocaine (LDC), using poly(ε-caprolactone) (PCL) nanospheres (NSs), to improve the pharmacological properties of the drug when administered by the infiltration route. In vitro experiments were used to characterize the system and investigate the release mechanism. The NSs presented a polydispersion index of 0.072, an average diameter of 449.6 nm, a zeta potential of -20.1 mV, and an association efficiency of 93.3%. The release profiles showed that the release of associated LDC was slower than that of the free drug. Atomic force microscopy analyses showed that the spherical structure of the particles was preserved as a function of time, as well as after the release experiments. Cytotoxicity and pharmacological tests confirmed that association with the NSs reduced the toxicity of LDC, and prolonged its anesthetic action. This new formulation could potentially be used in applications requiring gradual anesthetic release, especially dental procedures., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The aim of this study was to determine the occurrence rate, demographics, clinical characteristics, and outcomes of patients with severe sepsis admitted to the emergency department., Methods: A prospective study evaluating all patients admitted to the emergency department unit in a public hospital of tertiary complexity in a six-month period was conducted. During this period, the emergency team was trained to diagnose sepsis. Patients who met the diagnostic criteria for severe sepsis were followed until their discharge from the hospital., Results: A total of 5,332 patients were admitted to the emergency department, and 342 met the criteria for severe sepsis/septic shock. The median (interquartile range) age of patients was 74 (65-84) years, and 52.1% were male. The median APACHE II and SOFA scores at diagnosis were 19 (15-25) and 5 (3-7), respectively. The median number of dysfunctional organ systems per patient was 2 (1-3). The median hospital length of stay was 10 (4.7-17) days, and the hospital mortality rate was 64%. Only 31% of the patients were diagnosed by the emergency department team as septic. About 33.5% of the 342 severe sepsis patients admitted to the emergency department were referred to an ICU, with a median time delay of 24 (12-48) hours. Training improved diagnosis and decreased the time delay for septic patients in arriving at the ICU., Conclusions: The occurrence rate of severe sepsis in the emergency department was 6.4%, and the rate of sepsis diagnosed by the emergency department team as well as the number of patients transferred to the ICU was very low. Educational campaigns are important to improve diagnosis and, hence, treatment of severe sepsis.

Ventilator-associated pneumonia (VAP) is the most commonly-acquired infection in patients in intensive care units. We analyzed epidemiological and microbiological characteristics and the outcome, in a cohort of critically-ill patients with confirmed diagnosis of VAP. All patients who had been on mechanical ventilation (MV) for more than 48 hours were included in our study; material collection for microbiological analysis was done within the first 24 hours after beginning treatment or after changing antibiotics. There were 55/265 (20.7%) VAP cases diagnosed, at a rate of 21.6 episodes per 1,000 days of mechanical ventilation. Mean age of the patients was 66 years, with a mean APACHE II score of 26.7 + 7.0; male patients were more prevalent. The mortality rates in the intensive care unit (ICU) and during the hospital stay were 71% and 80%, respectively. MV duration in patients with VAP was 17 (range 3-43) days and among patients who had not developed VAP, 6 (2-32) days (p < 0.0001). 98.2% of the samples were positive, with a high prevalence of Gram-negative bacteria, mainly Acinetobacter calcoaceticus. Risk factors for death included age, MV duration and surgery. VAP incidence in this sample of critically-ill patients was high, with a high mortality rate. Control and prevention strategies based on continuing education of healthcare workers, developed by a multidisciplinary team, should be encouraged to minimize morbimortality of this infection.