Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats.

"Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90\xC2\xA0mg/kg), higher dose (110-140\xC2\xA0mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11\xC2\xA0g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean C" - " 86.2\xC2\xA0ng/ml vs. 26.2\xC2\xA0ng/ml in the lower dose group and 152\xC2\xA0ng/ml vs. 51.8\xC2\xA0ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3\xC2\xA0ng/g for high-dose male and 27.3\xC2\xA0ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

Educational Project as a Biological-Agricultural Model for the Teaching of Agronomy at the Universidad Veracruzana in Orizaba-Córdoba Región

The Academic Group UV-CA-456 “Biotecnología y Modelos Biológicos Agropecuarios” is linked to the learning’s Agronomy students through academic strategies and activities, in order to achieve learning for their professional life and for professors, activities that are related to research, teaching and social spreading of knowledge. As a result, the applied and developed activities in the teaching-learning process in the field of agricultural producers are relevant for the implementation and professionalization in the improvement and/or understanding in agricultural production. The educational project refers to the production of coffe that takes place at the maquiladora farm “Barrios Jacome” that is located in Boca del Monte, Comapa, Ver. For this project it was necessary to visit the place and participate in the process of production with the objective of determining the stages. It turned out to be a great process of learning with practical agricultural experiences for the students

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

Ivermectin is a widely used antiparasitic drug with known efcacy against several single-strain RNA viruses. Recent data shows signifcant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80–90 mg/kg), higher dose (110–140 mg/kg) or ethanol vehicle only. A toxicology profle including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profle of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals

Nebulized ivermectin for COVID‑19 and other respiratory diseases, a proof of concept, dose‑ranging study in rats

Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals

Willingness to pay for a quality-adjusted life year: an evaluation of attitudes towards risk and preferences

BACKGROUND: This paper examines the Willingness to Pay (WTP) for a quality-adjusted life year (QALY) expressed by people who attended the healthcare system as well as the association of attitude towards risk and other personal characteristics with their response. METHODS: Health-state preferences, measured by EuroQol (EQ-5D-3L), were combined with WTP for recovering a perfect health state. WTP was assessed using close-ended, iterative bidding, contingent valuation method. Data on demographic and socioeconomic characteristics, as well as usage of health services by the subjects were collected. The attitude towards risk was evaluated by collecting risky behaviors data, by the subject’s self-evaluation, and through lottery games. RESULTS: Six hundred and sixty two subjects participated and 449 stated a utility inferior to 1. WTP/QALY ratios varied significantly when payments with personal money (mean €10,119; median €673) or through taxes (mean €28,187; median €915) were suggested. Family income, area income, higher education level, greater use of healthcare services, and the number of co-inhabitants were associated with greater WTP/QALY ratios. Age and female gender were associated with lower WTP/QALY ratios. Risk inclination was independently associated with a greater WTP/QALY when “out of pocket” payments were suggested. Clear discrepancies were demonstrated between linearity and neutrality towards risk assumptions and experimental results. CONCLUSIONS: WTP/QALY ratios vary noticeably based on demographic and socioeconomic characteristics of the subject, but also on their attitude towards risk. Knowing the expression of preferences by patients from this outcome measurement can be of interest for health service planning

More than one HMG-CoA Lyase: The classical mitochondrial enzyme plus the peroxisomal and the cytosolic ones

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes

Antiviral capacity of sanitizers against infectious viruses in process water from the produce industry under batch and continuous conditions

The presence of human enteric viruses in produce has extensively been reported. However, the significance of the quality of process water (PW) used by the produce industry and the viral inactivation capacity of water disinfection agents used to maintain the microbiological quality of PW has received limited attention. This study evaluates the antiviral disinfection efficacy of chlorine, chlorine dioxide (ClO2) and peracetic acid (PAA) at recommended operational limits in PW using hepatitis A virus (HAV), the cultivable norovirus surrogate, murine norovirus (MNV-1), and MS2 coliphages. Defined commodity representative crops (baby leaves, bell peppers, and the vegetable mix of tomatoes, cucumbers, peppers, and onions) associated with specific water-based processes were studied. Two systems classified as either batch or continuous system were used. The continuous system allows the continuously entrance of sanitizer solution and organic matter added to the washing tank to simulate the conditions of an industry wash tank. Batch scale experiments showed that 20 mg/L chlorine and 3 mg/L chlorine dioxide completely inactivated MNV-1 and MS2 (mean of 5 log) after 1 min contact time regardless of the PW type. However, the infectivity of HAV was reduced only by less than 2 log after 1 min for chlorine and chlorine dioxide and the complete inactivation was not observed even after 10 min. On the contrary, residual viral infectivity/viability of HAV, MNV-1 and MS2 was observed for PAA in the three types of PW. The inactivation kinetic models for MS2 coliphages were developed based on the data obtained under the continuous system comparing the three types of PW. Chlorine (5 mg/L) and chlorine dioxide (2-3 mg/L) avoided the accumulation of MS2 below the detection limit while PAA (80 mg/L) was unable to prevent it independently of the type of PW. In summary, in the washing operation, it is a key objective to reach virus inactivation through the selection of the most effective sanitizer by guaranteeing that sufficient concentration and contact times prevent the risk of viral cross-contamination

In situ immune response in human dermatophytosis: possible role of Langerhans cells (CD1a+) as a risk factor for dermatophyte infection

Dermatophytosis is a cutaneous mycosis caused by a plethora of keratinophilic fungi, but Trichophyton rubrum is the most common etiological agent. Despite its high prevalence worldwide, little is known about the host defense mechanisms in this infection, particularly the in situ immune response. Using an immunohistochemistry approach, we investigated the density of CD1a+, factor XIIIa+ and CD68+ cells in the skin of dermatophytosis patients. Langerhans cells (CD1a+ cells) were significantly decreased in the epidermis of patients, both in affected and unaffected areas. In the dermis, however, no differences in the density of macrophages (CD68+ cells) and dermal dendrocytes (factor XIIIa+ cells) were observed. These results suggest that the decreased number of Langerhans cells may be a risk factor for development of dermatophytosis

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

The Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins

A gene expression assay based on chronic lymphocytic leukemia activation in the microenvironment to predict progression

Several gene expression profiles with a strong correlation with patient outcome have been previously described in chronic lymphocytic leukemia (CLL), although their applicability in clinical practice as biomarkers has been particularly limited. Here we describe the training and validation of a gene expression signature for predicting early progression of patients with CLL based on the analysis of 200 genes related to microenvironment signaling on the NanoString platform. In the training cohort (n=154), the CLL15 assay containing a 15-gene signature was associated with time to first treatment (TtFT) (HR: 2.83, 95%CI 2.17-3.68; p<0.001). The prognostic value of the CLL15 score (HR 1.71, [95%CI 1.15-2.52]; p=0.007) was further confirmed in an external independent validation cohort (n=112). Of note, the CLL15 score improved the prognostic capacity over the IGHV mutational status and the International Prognostic Score for asymptomatic early-stage (IPS-E) CLL. In multivariate analysis, the CLL15 score (HR: 1.83, 95%CI 1.32-2.56; p<0.001) and the IPS-E CLL (HR: 2.23, 95%CI 1.59-3.12; p<0.001) were independently associated with TtFT. The newly developed and validated CLL15 assay successfully translates previous gene signatures, such as the microenvironment signaling, into a new gene expression-based assay with prognostic implications in CLL