Cost-Effectiveness Analysis of Monoclonal Antibodies Associated With Chemotherapy in First-Line Treatment of Metastatic Colorectal Cancer.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-epidermal growth factor receptor (cetuximab and panitumumab) or anti-vascular endothelial growth factor (bevacizumab) monoclonal antibodies associated with conventional chemotherapy (CT) (fluorouracil and leucovorin with irinotecan) as a first-line treatment for unresectable metastatic colorectal cancer. METHODS: A partitioned survival analysis model was adopted to simulate direct health costs and benefits comparing therapeutic options in a 10 years' time horizon. Model data were extracted from the literature and costs were obtained from Brazilian official government databases. The analysis considered the perspective of the Brazilian Public Health System; costs were measured in local currency (BRL) and benefits in quality-adjusted life-years (QALY). A 5% discount rate was applied to costs and benefits. Alternative willingness-to-pay scenarios, varying from 3 to 5 times the cost-effectiveness threshold established in Brazil, were estimated. The results were presented incremental cost-effectiveness ratio (ICER), and both deterministic and probabilistic sensitivity analyses were performed. RESULTS: The most cost-effective choice would be the association of CT with panitumumab, with an ICER of $58 330.15/QALY compared with isolated CT. The second-best option was CT with bevacizumab and panitumumab, with an ICER of $71 195.40/QALY compared with panitumumab alone. Although having higher costs, the second-best option was the most effective. Both strategies were cost-effective in part of the Monte Carlo iterations, considering the 3× threshold. CONCLUSIONS: The therapeutic option CT + panitumumab + bevacizumab represents the most significant effectiveness gain in our study. It is the second-lowest cost-effectiveness, and this option includes monoclonal antibodies association for patients with and without KRAS mutation.

Intramuscular compatibility of an injectable anti-inflammatory nanodispersion from a standardized Bixa orellana oil (Chronic®): a toxicological study in Wistar rats.

Bixa orellana L. is a plant popularly known as "ucurum", "annatto", and "achiote". It is native to South America, and its seeds are an abundant source of geranylgeraniol and tocotrienols. Nanoencapsulation is a valuable technique that can decrease the drug needed to achieve an effect, decreasing potential toxicity, side effects and potentiate the anti-inflammatory effect. This study aimed to evaluate the acute toxicity of an intramuscular application of a nanodispersion containing a standardized extract from the seeds of Bixa orellana (NBO) in Wistar rats. The chemical evaluation showed δ-tocotrienol at 0.725 ± 0.062 mg/mL (72.6 ± 0.9%). The stability study showed the nanoparticles had an average size from 53.15 ± 0.64 to 59.9 ± 3.63 nm, with a polydispersity index ranging from 0.574 ± 0.032 to 0.574 ± 0.32, Zeta potential from 18.26 ± 0.59 to 19.66 ± 1.45 mV. After testing the intramuscular application of NBO with doses from 1 to 5 mg/kg in animals, it was observed that the acute treatment did not elicit any toxic effects within this range. The dose of 10 mg/kg, although not affecting hematological and biochemical parameters (CPK, LDH, myoglobin, AST, ALT, TC, TG, glucose levels, creatinine, and urea), could induce some muscle tissue changes, including leukocyte infiltration, morphological chances, and potentially necrosis. In conclusion, the results showed that the treatments devoided toxicity between 1 and 5 mg/kg.

Potential of the Compounds from Bixa orellana Purified Annatto Oil and Its Granules (Chronic®) against Dyslipidemia and Inflammatory Diseases: In Silico Studies with Geranylgeraniol and Tocotrienols.

Some significant compounds present in annatto are geranylgeraniol and tocotrienols. These compounds have beneficial effects against hyperlipidemia and chronic diseases, where oxidative stress and inflammation are present, but the exact mechanism of action of such activities is still a subject of research. This study aimed to evaluate possible mechanisms of action that could be underlying the activities of these molecules. For this, in silico approaches such as ligand topology (PASS and SEA servers) and molecular docking with the software GOLD were used. Additionally, we screened some pharmacokinetic and toxicological parameters using the servers PreADMET, SwissADME, and ProTox-II. The results corroborate the antidyslipidemia and anti-inflammatory activities of geranylgeraniol and tocotrienols. Notably, some new mechanisms of action were predicted to be potentially underlying the activities of these compounds, including inhibition of squalene monooxygenase, lanosterol synthase, and phospholipase A2. These results give new insight into new mechanisms of action involved in these molecules from annatto and Chronic®.

An overview of the immune response and Arginase I on CHIKV immunopathogenesis.

Chikungunya virus (CHIKV) is mosquito-borne alphavirus that has caused epidemics around the world. Many individuals affected by the disease may experience joint pain that persists for months after the acute phase. The pathophysiology of viral arthritis is not completely elucidated. And it is important to emphasize that the effects of the viral infection in each host may depend on host factors that include immune response, as well as factors specific to the virus as tissue tropism. The main pathway for the response against viral infection is through induction of type I interferon (IFN-I), whose function is important to control viral replication. Beside this, T cell and macrophage mediated immunopathology in CHIKV infections has been reported. It has been demonstrated that some association with the Arginase I and macrophages type II are involved in the infection profile along with myeloid-derived suppressor cells (MDSC) that are responsible for T cell suppression. Therefore, in this review, will be discuss an overview on CHIKV immunopathogenesis and the importance of Arginase I.

Evaluation of using aluminum sulfate and water-soluble Moringa oleifera seed lectin to reduce turbidity and toxicity of polluted stream water.

Aluminum salts are used as coagulants in water treatment; however, the exposure to residual aluminum has been associated with human brain lesions. The water-soluble Moringa oleifera lectin (WSMoL), which is extracted with distilled water and isolated by chitin chromatography, has coagulant activity and is able to reduce the concentration of metal ions in aqueous solutions. This study evaluated the potential of using aluminum sulfate and WSMoL to reduce the turbidity and toxicity of water from the Cavouco stream located in Recife, Pernambuco, Brazil. The water sample used (called P1) was collected from the stream source, which was found to be strongly polluted based on physicochemical and water quality analyses, as well as ecotoxicity assays with Artemia salina and seeds of Eruca sativa and Lactuca sativa. The assays combining WSMoL and aluminum sulfate were more efficient than those that used these agents separately. Furthermore, the greatest reduction in turbidity (96.8%) was obtained with the treatment using aluminum sulfate followed by WSMoL, compared to when they were applied simultaneously (91.3%). In addition, aluminum sulfate followed by WSMoL treatment resulted in residual aluminum concentration (0.3 mg/L) that was much lower than that recorded after the treatment using only the salt (35.5 mg/L). The ecotoxicity of P1 was also strongly reduced after the treatments. In summary, the combined use of aluminum sulfate and WSMoL was efficient in promoting a strong reduction of turbidity and ecotoxicity of a polluted water sample, without resulting in a high residual aluminum concentration at the conclusion of the treatment.

Copper-induced adaptation, oxidative stress and its tolerance in Aspergillus niger UCP1261

Background The effects of exposure to copper, during growth, on the production of biomass, total protein, catalase, glutathione-S transferase, glutathione peroxidase, peroxidase, polyphosphate, acid and alkaline phosphatases, ultrastructure and the ability to remove this metal from Aspergillus niger, obtained from caatinga soil, were evaluated. Results All parameters tested were influenced by the concentration of metal in the culture medium. The presence of metal induced high levels of antioxidant enzymes, including lipid peroxidation, thereby revealing the appearance of an oxidative stress response. The variation in polyphosphate levels indicates the participation of the polymer in response to stress induced by copper. The activities of the phosphatases were positively influenced by growing them in the presence of copper. Ultrastructure changes in the cell surface, electron density, thickness, and septation were visualized by exposing cells to increasingly larger concentrations of metal. The isolate was able to remove the agent from the growth medium, while maintaining its physiological functions. The metal removed from the cultures exposed to 0.5 mM, 1 mM and 2 mM copper exhibited percentages of removal equivalent to 75.78%, 66.04% and 33.51%. Conclusions The results indicate that the isolate was able to grow in high concentrations of copper, activates mechanisms for adaptation and tolerance in the presence of metal, and is highly efficient at removing the agent. Such data are fundamental if a better understanding is to be reached of the cellular and molecular abilities of native isolates, which can be used to develop bioprocesses in environmental and industrial areas.

Cadmium tolerance and removal from Cunninghamella elegans related to the polyphosphate metabolism.

The aim of the present work was to study the cadmium effects on growth, ultrastructure and polyphosphate metabolism, as well as to evaluate the metal removal and accumulation by Cunninghamella elegans (IFM 46109) growing in culture medium. The presence of cadmium reduced growth, and a longer lag phase was observed. However, the phosphate uptake from the culture medium increased 15% when compared to the control. Moreover, C. elegans removed 70%-81% of the cadmium added to the culture medium during its growth. The C. elegans mycelia showed a removal efficiency of 280 mg/g at a cadmium concentration of 22.10 mg/L, and the removal velocity of cadmium was 0.107 mg/h. Additionally, it was observed that cadmium induced vacuolization, the presence of electron dense deposits in vacuoles, cytoplasm and cell membranes, as well as the distinct behavior of polyphosphate fractions. The results obtained with C. elegans suggest that precipitation, vacuolization and polyphosphate fractions were associated to cadmium tolerance, and this species demonstrated a higher potential for bioremediation of heavy metals.

Essential oil composition and acaricidal activity of Schinus terebinthifolius from Atlantic Forest of Pernambuco, Brazil against Tetranychus urticae.

The compositions of the essential oils from unripe (UFr) and ripe (RFr) fruits of Schinus terebinthifolius were analyzed by GC and GC/MS. The major compound identified in both oils was limonene (UFr = 44.1 +/- 1.3%; RFr = 31.8 +/- 1.2%), followed by alpha-phellandrene (15.7 +/- 0.4%) in the UFr oil and thujene (21.7 +/- 0.9%) in the RFr oil. Repellent and toxicity activities of the two oils were also evaluated, and the results compared with eugenol. The UFr oil was more active in the fumigation tests (LC50 = 1.46 microL/L of air), whereas the RFr oil was more active in the sealed dishes (SD) than open dishes (OD) contact assay (LC50 = 3.04 microL/cm2) and not significantly different from eugenol. Both oils exhibited significant repellent activity comparable with that of eugenol. The results suggest that the repellent activity of these oils in association with its toxicity could be a great advantage for the integrated management of T. urticae.

Role of the morphology and polyphosphate in Trichoderma harzianum related to cadmium removal.

This study concerns the metabolism of polyphosphate in Trichoderma harzianum, a biocontrol agent with innate resistance against most chemicals used in agriculture, including metals, when grown in the presence of different concentrations of cadmium. The biomass production was affected by the concentration of metal used. Control cultures were able to accumulate polyphosphate under the conditions used. Moreover, the presence of cadmium induced a reduction in polyphosphate content related to the concentration used. The morphological/ultrastructural aspects were characterized by using optical and scanning electron microscopy, and were affected by the heavy metal presence and concentration. The efficiency of cadmium removal revealed the potential of the microorganism for use in remediation. The data indicate the potential for polyphosphate accumulation by the fungus, as well as its degradation related to tolerance/survival in the presence of cadmium ions.