Application of Accelerated Predictive Stability Studies in Extemporaneously Compounded Formulations of Chlorhexidine to Assess the Shelf Life.

Industrially fabricated medicines have a well-defined shelf life supported by rigorous studies before their approval for commercialization. However, the shelf life of extemporaneous compounding topical formulations prepared at hospitals tends to be shorter, especially when no data are available to prove a longer stability period. Also, the storage conditions are unknown in many circumstances. Accelerated Predictive Stability (APS) studies have been shown to be a useful tool to predict in a faster and more accurate manner the chemical stability of extemporaneously compounded formulations requiring a minimum amount of formulation, thereby reducing the chemical drug waste per study. Shelf life will be allocated based on scientific data without compromising drug efficacy or safety. In this work, the APS approach was applied to the commercially available Cristalmina® (CR) and an extemporaneously compounded formulation of chlorhexidine (DCHX). A different degradation kinetic was found between DCHX and CR (Avrami vs. zero-order kinetics, respectively). This can explain the different shelf life described by the International Council for Harmonisation of Technical Requirements Registration Pharmaceuticals Human Use (ICH) conditions between both formulations. A predicted stability for the DCHX solution was obtained from the extrapolation of the degradation rate in long-term conditions from the Arrhenius equation. The estimated degradation from the Arrhenius equation for DCHX at 5 °C, 25 °C, and 30 °C at 365 days was 3.1%, 17.4%, and 25.9%, respectively. The predicted shelf life, in which the DCHX content was above 90%, was 26.67 months under refrigerated conditions and 5.75 and 2.24 months at 25 and 30 °C, respectively. Currently, the Spanish National Formulary recommends a shelf life of no longer than 3 months at room temperature for DCHX solution. Based on the predicted APS and confirmed by experimental long-term studies, we have demonstrated that the shelf life of DCHX extemporaneously compounded formulations could be prolonged by up to 6 months.

Outbreak of Dermatophyte Infections on the Head and Neck Related to Shave Haircuts: Description of a Multicenter Case Series. / Brote de dermatofitosis en región de cabeza y cuello asociadas al rasurado en peluquerías: estudio descriptivo multicéntrico de una serie de casos.

INTRODUCTION: Since 2021, an increase in cases of tinea capitis has been detected in adolescents who shave their hair with fade haircut. PATIENTS AND METHODS: Multicenter retrospective observational study of cases of cephalic pole dermatophytosis with a history of having been acquired after frequent shaving in hairdressing. A call was made to dermatologists from the Spanish Academy of Dermatology and Venereology (AEDV) to provide cases observed between January 2021 and December 2022. Patients with microbiological confirmation by culture or direct examination with KOH were included. RESULTS: 107 cases were collected, 106 of which were male. 78 non-inflammatory forms were observed, compared to 29 inflammatory. The most frequently isolated fungus was Trichophyton tonsurans (75.7% of cases). The lesions appeared predominantly on the nape of the neck and temporal area. CONCLUSIONS: The distribution by sex, age and lesional location seems to indicate that a new social trend, in which male adolescents regularly go to hairdressers to shave the occipital and temporal areas, would be the cause of this grouping of cases of ringworm of the scalp. The most frequent microorganism in our study (T.tonsurans) coincides with the most prevalent in our environment. This study shows an accumulation of cases that can be taken into account by competent Public Health agencies, which are responsible for ensuring compliance with the rules of disinfection of the material used for shaving.

[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Outcomes After Vascular Surgery Procedures in Patients with COVID-19 Infection: A National Multicenter Cohort Study (COVID-VAS).

OBJECTIVES: To analyze the outcome of vascular procedures performed in patients with COVID-19 infection during the 2020 pandemic. METHODS: This is a multicenter, prospective observational cohort study. We analyzed data from 75 patients with COVID-19 infection undergoing vascular surgery procedures in 17 hospitals across Spain and Andorra between March and May 2020. The primary end point was 30-day mortality. Clinical Trials registry number NCT04333693. RESULTS: The mean age was 70.9 (45-94) and 58 (77.0%) patients were male. Around 70.7% had postoperative complications, 36.0% of patients experienced respiratory failure, 22.7% acute renal failure, and 22.7% acute respiratory distress syndrome (ARDS). All-cause 30-days mortality rate was 37.3%. Multivariate analysis identified age >65 years (P = 0.009), American Society of Anesthesiologists (ASA) classification IV (P = 0.004), preoperative lymphocyte count <0.6 (×109/L) (P = 0.001) and lactate dehydrogenase (LDH) >500 (UI/L) (P = 0.004), need for invasive ventilation (P = 0.043), postoperative acute renal failure (P = 0.001), ARDS (P = 0.003) and major amputation (P = 0.009) as independent variables associated with mortality. Preoperative coma (P = 0.001), quick Sepsis Related Organ Failure Assessment (qSOFA) score ≥2 (P = 0.043), lymphocytes <0.6 (×109/L) (P = 0.019) leucocytes >11.5 (×109/L) (P = 0.007) and serum ferritin >1800 mg/dL (P = 0.004), bilateral lung infiltrates on thorax computed tomography (P = 0.025), and postoperative acute renal failure (P = 0.009) increased the risk of postoperative ARDS. qSOFA score ≥2 was the only risk factor associated with postoperative sepsis (P = 0.041). CONCLUSIONS: Patients with COVID-19 infection undergoing vascular surgery procedures showed poor 30-days survival. Age >65 years, preoperative lymphocytes <0.6 (x109/L) and LDH >500 (UI/L), and postoperative acute renal failure, ARDS and need for major amputation were identified as prognostic factors of 30-days mortality.

What does the freshwater clam, Corbicula largillierti, have to tell us about chlorothalonil effects?

Chlorothalonil (CLT) is a broad spectrum, and non-systemic fungicide applied in foliar structures to prevent and treat pathogens. This compound reaches to aquatic environments and affects the biota. In this context, the main goal of this study was to assess the effects of CLT at biochemical, tissular, and individual levels of biological organization using the invasive bivalve Corbicula largillierti as a bioindicator species. Clams were exposed to different sublethal concentrations (0, 10, 20 and 50 µg. L-1 CLT) for 96 h. At biochemical level, the enzymatic activity (Glutathione-s-Transferase, Catalase, Acetyl-, Butiryl- and Carboxyl-esterases) and lipid peroxidation were measured in gills and the visceral mass. Also, the digestive gland morphometry through quantitative histological indexes was registered at the tissular level. Finally, filtering activity and burial behavior at the individual level were measured. At the highest CLT concentration, the most significant changes were observed in enzymatic activity (except for butyrylcholinesterase), lipid peroxidation and in digestive gland morphometry. It was also registered increases of the filtering activity and the latency time to burial. Most of the biomarkers assessed showed significant responses under CLT exposure. Therefore, taking into account that C. largillierti was affected by CLT, it can be expected that other species could be in a potential risk if this fungicide is present in freshwater systems.

Oral Fixed-Dose Combination Pharmaceutical Products: Industrial Manufacturing Versus Personalized 3D Printing.

Fixed-dose combination (FDC) products containing at least two different active pharmaceutical ingredients are designed to treat more effectively different pathologies as they have demonstrated to enhance patient compliance. However, the combination of multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. The manufacturing process of FDC products can be challenging, especially when it is required to achieve different drug release profiles within the same dosage form to overcome physicochemical drug interactions. Monolithic, multiple-layer, and multiparticulate systems are the most common type of FDCs. Currently, the main manufacturing techniques utilized in industrial pharmaceutical companies rely on the use of combined wet and dry granulation, hot-melt extrusion coupled with spray coating, and compression of bilayered tablets. Nowadays, personalized medicines are gaining importance in clinical settings and 3D printing is taking a highlighted role in the manufacturing of complex and personalized 3D solid dosage forms that could not be manufactured using conventional techniques. In this review, it will be discussed in detail current marketed FDC products and their application in several diseases with an especial focus on antimicrobial drugs. Current industrial conventional techniques will be compared with 3D printing manufacturing of FDCs. Graphical Abstract.

Retraction notice to "Influence of hypertonic volume replacement on the microcirculation in cardiac surgery" [Br J Anaesth 67 (1991) 595-602].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief, Professor Hugh Hemmings, based on the recommendations of Justus-Liebig-University Giessen following an internal review of research conducted by Joachim Boldt at the University. This is further described in 'Further Retractions of Articles by Joachim Boldt', https://doi.org/10.1016/j.bja.2020.02.024.

Retraction notice to "The role of enoximone in cardiac surgery" [Br J Anaesth 69 (1992) 45-50].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief, Professor Hugh Hemmings, based on the recommendations of Justus-Liebig-University Giessen following an internal review of research conducted by Joachim Boldt at the University. This is further described in 'Further Retractions of Articles by Joachim Boldt', https://doi.org/10.1016/j.bja.2020.02.024.

Improving the Outcomes of Organs Obtained From Controlled Donation After Circulatory Death Donors Using Abdominal Normothermic Regional Perfusion.

The use of donation after circulatory death (DCD) has increased significantly during the past decade. However, warm ischemia results in a greater risk for transplantation. Indeed, controlled DCD (cDCD) was associated with inferior outcomes compared with donation after brain death. The use of abdominal normothermic regional perfusion (nRP) to restore blood flow before organ recovery in cDCD has been proposed as better than rapid recovery to reverse the effect of ischemia and improve recipients' outcome. Here, the first Spanish series using abdominal nRP as an in situ conditioning method is reported. A specific methodology to avoid restoring circulation to the brain after death determination is described. Twenty-seven cDCD donors underwent abdominal nRP during at least 60 min. Thirty-seven kidneys, 11 livers, six bilateral lungs, and one pancreas were transplanted. The 1-year death-censored kidney survival was 91%, and delayed graft function rate was 27%. The 1-year liver survival rate was 90.1% with no cases of ischemic cholangiopathy. Transplanted lungs and pancreas exhibited primary function. The use of nRP may represent an advance to increase the number and quality of grafts in cDCD. Poor results in cDCD livers could be reversed with nRP. Concerns about restoring brain circulation after death are easily solved.

Evaluation of the Health Status of the Silverside (Odontesthes bonariensis) at a RAMSAR Site in South America.

The objective of this work was to evaluate the health status of an economic and ecologically important fish species from Mar Chiquita Lake, a RAMSAR site located in Cordoba, Argentina, relative to the levels of selected persistent organic pollutants (POPs) in lake water and fish tissues. Odontesthes bonariensis was used as a model species, and its health was estimated by means of histological indices in gills and liver. Sampling was performed according to rainy and dry seasons (i.e. dry, rainy and post-rainy). Gill and liver histopathology were evaluated by semi-quantitative indices and morphometric analysis. Although epithelial lifting in gills and lipid degeneration in liver were frequently registered, they are considered as reversible if environmental conditions improve. During rainy and post-rainy seasons fish presented significantly higher scores of liver and total indices. These higher index scores were correlated with increased levels of POPs in gill and liver tissue. Therefore, preventive measures are needed to mitigate the entry of these compounds into the lake.

Polymorphism G1359A of the cannabinoid receptor gene (CNR1): allelic frequencies and influence on cardiovascular risk factors in a multicentre study of Castilla-Leon.

BACKGROUND: A polymorphism (1359 G/A) of the CNR1 gene was reported as a common polymorphism in Caucasian populations and was related to cardiovascular risk factors. The present study aimed to investigate the allelic distribution of polymorphism (G1359A) of the CB1 receptor gene in a geographical area of Spain (Community of Castilla y Leon) and to evaluate the influence of this polymorphism on obesity anthropometric parameters and cardiovascular risk factors in the fasted state in obese patients. METHODS: A population of 341 obese subjects was analysed. Tetrapolar electrical bioimpedance measurement, blood pressure measurement, a serial assessment of nutritional intake with 3 days of written food records and a biochemical analysis were all performed. RESULTS: One hundred and seventy-seven patients (51.9%) had the genotype G1359G (wild-type group) and 164 (48.1%) patients were A carriers: G1359A (136 patients; 39.9%) or A1359A (28 patients; 8.2%) (mutant type group). The Health Area of Palencia had a lower frequency of wild-type genotype and G allelic frequency than all the other Health Areas. Segovia and Burgos Areas had a higher frequency of wild-type genotype and G allelic frequency than the other Health Areas. High-density lipoprotein (HDL) cholesterol was higher in the mutant type group and blood tryglicerides were lower in the same group. CONCLUSIONS: In conclusion, the novel finding of the present study is the association of the mutant type group G1359A and A1359A with a better lipid profile (triglycerides and HDL cholesterol) than the wild-type group. The frequencies of this polymorphism are different among Health Areas of Castilla y Leon (Spain).

Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles.

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within N-palmitoyl-N-methyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index.

Enhancing seedling production of native species to restore gypsum habitats.

Gypsum habitats are widespread globally and are important for biological conservation. Nevertheless, they are often affected by human disturbances and thus require restoration. Sowing and planting have shown positive results, but these actions are usually limited by the lack of native plant material in commercial nurseries, and very little information is available on the propagation of these species. We address this issue from the hypothesis that gypsum added to a standard nursery growing medium (peat) can improve seedling performance of gypsum species and, therefore, optimise the seedling production for outplanting purposes. We test the effect of gypsum on emergence, survival, and growth of nine native plant species, including gypsophiles (exclusive to gypsum) and gypsovags (non-exclusive to gypsum). We used four treatments according to the proportions, in weight, of gypsum:standard peat (G:S), i.e. high-g (50G:50S), medium-g (25G:75S), low-g (10G:90S), and standard-p (0G:100S). Our results showed that the gypsum treatments especially benefited the emergence stage, gypsophiles as group, and Ononis tridentata as a taxon. In particular, the gypsum treatments enhanced emergence of seven species, survival of three species, and growth of two gypsophiles, while the use of the standard peat favoured only the emergence or growth of three gypsovags. Improving emergence and survival at the nursery can provide a reduction of costs associated with seed harvesting, watering, and space, while enlarging seedlings can favour the establishment of individuals after outplanting. Thus, we suggest adding gypsum to standard peat for propagating seedlings in species from gypsum habitats, thereby potentially cutting the costs of restoring such habitats. Our assessment enables us to provide particular advice by species. In general, we recommend using between 25 and 50% of gypsum to propagate gypsophiles, and between 0 and 10% for gypsovags. The results can benefit not only the production of widely distributed species commonly affected by gypsum quarrying, but also of narrow and threatened endemic species that require particularly efficient use of their seeds. In addition, our study highlights the importance of using appropriate growing media to propagate plants characteristic of special substrates for restoration purposes.

Experience of a Maastrich type II non heart beating donor program in a small city: preliminary results.

OBJECTIVE: To study the results of a non-controlled cardiac death (Maastricht type II) donor program in a city of 200,000 inhabitants. The study was initially focused on lung donation and was extended to kidney donation after 9 months. DESIGN: A prospective observational study was conducted between October 2012 and December 2013. SETTING: The Intensive Care Unit of Marqués de Valdecilla University Hospital in Santander (Spain), and surrounding areas. POPULATIONS: Patients (< 55 years) who died of out-of-hospital cardiac arrest. INTERVENTIONS: All out-of-hospital cardiac arrests were treated with mechanical cardiac compression (LUCAS II). The diagnosis of death and organ preservation were performed in the ICU. RESULTS: A total of 14 calls were received, of which three were discarded. Of the 11 potential donors, 7 were effective donors with a median age of 39.5 years (range: 32-48). A total of 5 single lung transplants and four kidney transplants were performed. In addition, corneas and tissues were harvested. The non-valid donors were rejected mainly due to technical problems. There were no donation refusals on the part of the patient relatives. The lung transplant patient survival rate was 100% after one month and 80% after one year. One month after transplantation, the kidney recipients had a serum creatinine concentration of<2mg/dl. The interval from cardiac arrest to renal preservation was 80minutes (range: 71-89), and the interval from cardiac arrest to lung preservation was 84minutes (range: 77-94). CONCLUSIONS: A Maastricht type II donation program in a small city is viable for both abdominal and thoracic organs. The program was initially very cautious, but its potential is easily improvable by increasing donor and by equipping mobile ICU ambulances with mechanical cardiac compression systems. Full management of the donor in the ICU, avoiding the emergency department or operating rooms, reduces the warm ischemia time, thereby improving transplant outcomes.

Effects of antibiotic administration delay and inadequacy upon the survival of septic shock patients.

OBJECTIVE: To assess how antibiotic administration delay and inadequacy influence survival in septic shock patients. DESIGN: A prospective, observational cohort study was carried out between September 2005 and September 2010. SCOPE: Patients admitted to the ICU of a third level hospital. PATIENTS: A total of 342 septic shock patients INTERVENTIONS: None VARIABLES OF INTEREST: The time to antibiotic administration (difference between septic shock presentation and first administered dose of antibiotic) and its adequacy (in vitro susceptibility testing of isolated pathogens) were determined. RESULTS: ICU and hospital mortality were 26.4% and 33.5%, respectively. The median delay to administration of the first antibiotic dose was 1.7h. Deceased patients received antibiotics significantly later than survivors (1.3±14.5h vs. 5.8±18.02h; P=.001). Percentage drug inadequacy was 12%. Those patients who received inadequate antibiotics had significantly higher mortality rates (33.8% vs. 51.2%; P=.03). The coexistence of treatment delay and inadequacy was associated to lower survival rates. CONCLUSIONS: Both antibiotic administration delay and inadequacy exert deleterious effects upon the survival of septic shock patients, independently of their characteristics or severity.

Antioxidant, phase II and III responses induced by lipoic acid in the fish Jenynsia multidentata (Anablapidae) and its influence on endolsulfan accumulation and toxicity.

Antioxidants like lipoic acid (LA) are known to trigger augmented antioxidant and phase II and III responses. This study aimed to evaluate the effect of LA in P-glycoprotein (Pgp) expression, glutathione-S-transferase (GST) activity, total antioxidant competence, levels of lipid peroxides (TBARS) and accumulation of the organochlorine insecticide endosulfan (Endo: α-, ß-isomers and sulfate metabolite) in different organs of the fish Jenynsia multidentata. One hundred and twenty females (1.55±0.07 g) were fed during 8 days with (n=60) or without (n=60) a LA enriched ration (6000 mg/kg). Four experimental groups were defined: -LA/-Endo; +LA/-Endo; -LA/+Endo; and +LA/+Endo. Endo groups were exposed during 24 h to 1.4 µg of insecticide/L. Results showed that only LA induced a significant increment in liver Pgp expression. GST activity was augmented in liver after exposure to LA or Endo. TBARS levels were lowered in liver and gills after LA pre-treatment. Total antioxidant capacity was lowered in liver of Endo exposed fish, a result that was reversed by LA pre-treatment. It is concluded that LA induced the expected effects in terms of Pgp expression, GST activity and reduced TBARS levels although favored α-Endo accumulation in brain. However, the Endo metabolism to the more persistent endosulfan sulfate was not facilitated by LA pre-treatment.

Executive summary of the consensus document on the management of perioperative anemia in Spain.

Perioperative anemia is an independent risk factor for postoperative morbidity and mortality. However, conceptual, logistical and administrative barriers persist that hinder the widespread implementation of protocols for their management. The project coordinator convened a multidisciplinary group of 8 experienced professionals to develop perioperative anemia management algorithms, based on a series of key points (KPs) related to its prevalence, consequences, diagnosis and treatment. These KPs were assessed using a 5-point Likert scale, from "strongly disagree [1]" to "strongly agree [5]". For each KP, consensus was reached when receiving a score of 4 or 5 from at least 7 participants (>75%). Based on the 36 KPs agreed upon, diagnostic-therapeutic algorithms were developed that we believe can facilitate the implementation of programs for early identification and adequate management of perioperative anemia, adapted to the characteristics of the different institutions in our country.

[Antifungal prophylaxis in the postoperative period of lung transplant surgery in Spain]. / Profilaxis antifúngica en el postoperatorio de trasplante de pulmón en España.

OBJECTIVES: To examine the type and duration of antifungal prophylaxis provided during the postoperative period of lung transplant recipients, together with the most frequent complications during admission to Intensive Care Units in Spain. PATIENTS AND METHODS: A questionnaire was developed including demographic data on each transplant center, the type of antifungal prophylaxis used, its duration, and the most frequent complications. The questionnaire was distributed among the 7 Spanish national lung transplant centers, followed by analysis of the results obtained. RESULTS: All 7 centers completed the questionnaire. All of them provided universal prophylaxis in lung transplant patients. Monotherapy was the most widely used protocol (5/7; 71.4%), with amphotericin B in liposomal or conventional form being the most frequent drug, administered via the inhalatory route. In the case of combination therapy, a great diversity of drugs was observed. The most frequently administered second choice drug was anidulafungin (3/7; 43%), followed by voriconazole (2/7; 28.5%). Antifungal therapy was maintained on an indefinite basis by 43% of the centers. Invasive fungal infection (IFI) in the postoperative period of transplantation during admission to the Intensive Care Unit was suspected in 5-10% of the cases but was confirmed in less than 5%. Among other complications registered in these patients in the Intensive Care Unit, the most frequent problems were respiratory infections (5/7; 71.5%). CONCLUSIONS: Antifungal prophylaxis during the postoperative period of lung transplantation is provided on a universal basis, though consensus is lacking as to the drug of choice, the administration route and the duration of such treatment.

Co-Delivery of a High Dose of Amphotericin B and Itraconazole by Means of a Dry Powder Inhaler Formulation for the Treatment of Severe Fungal Pulmonary Infections.

Over the past few decades, there has been a considerable rise in the incidence and prevalence of pulmonary fungal infections, creating a global health problem due to a lack of antifungal therapies specifically designed for pulmonary administration. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action that have been widely employed in antimycotic therapy. In this work, microparticles containing a high dose of AmB and ITR (20, 30, and 40% total antifungal drug loading) were engineered for use in dry powder inhalers (DPIs) with an aim to improve the pharmacological effect, thereby enhancing the existing off-label choices for pulmonary administration. A Design of Experiment (DoE) approach was employed to prepare DPI formulations consisting of AmB-ITR encapsulated within γ-cyclodextrin (γ-CD) alongside functional excipients, such as mannitol and leucine. In vitro deposition indicated a favourable lung deposition pattern characterised by an upper ITR distribution (mass median aerodynamic diameter (MMAD) ~ 6 µm) along with a lower AmB deposition (MMAD ~ 3 µm). This offers significant advantages for treating fungal infections, not only in the lung parenchyma but also in the upper respiratory tract, considering that Aspergillus spp. can cause upper and lower airway disorders. The in vitro deposition profile of ITR and larger MMAD was related to the higher unencapsulated crystalline fraction of the drug, which may be altered using a higher concentration of γ-CD.