Development and evaluation of the in vitro schistosomicidal activity of solid dispersions based on 2-(-5-bromo-1-H-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide.

Among all the neglected diseases, schistosomiasis is considered the second most important parasitic infection after malaria. Praziquantel is the most widely used drug for this disease, but its exclusive use may result in the development of drug-resistant schistosomiasis. To increase the control of the disease, new drugs have been developed as alternative treatments, among them 2-(-5-bromo-1-h-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide (LQIT/LT-50), which showed promising schistosomicidal activity in nonclinical studies. However, LQIT/LT-50 presents low solubility in water, resulting in reduced bioavailability. To overcome this solubility problem, the present study aimed to develop LQIT/LT-50 solid dispersions for the treatment of schistosomiasis. Solid dispersions were prepared through the solvent method using Soluplus©, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP K-30) as hydrophilic carriers. The formulations with the best results in the compatibility tests, aqueous solubility and preliminary stability studies have undergone solubility tests and physicochemical characterizations by Fourier-transform infrared spectroscopy (FTIR), x-ray diffractometry (XRD), exploratory differential calorimetry (DSC), thermogravimetry (TG) and Raman spectroscopy. Finally, the schistosomicidal activity was evaluated in vitro. The phycochemical analyzes showed that when using PVP K-30, there was an interaction between the PVP K-30 and LQIT/LT-50, proving the successful development of the solid dispersion. Furthermore, an increase in the solubility of the new system was observed (LQIT/LT-50:PVP K-30) in addition to the improvement in the in vitro shistosomidal activity at 1:4 (w/w) molar ratio (i.e., 20% drug loading) when compared to LQIT/LT-50 alone. The development of the LQIT/LT-50:PVP K-30 1:4 solid dispersion is encouraging for the future development of new pharmaceutical solid formulations, aiming the schistosomicidal treatment.

A systematic review of research conducted by pioneer groups in ecotoxicological studies with bees in Brazil: advances and perspectives.

Brazil presents the most threatened endemic or rare species among neotropical regions, with the Hymenoptera order, to which bees belong, classified as a high-risk category. In Brazil, the main cause of bee death is the indiscriminate use of pesticides. In this context, groups such as Bee Ecotoxicology and Conservation Laboratory (LECA in Portuguese) and Bees and Environmental Services (ASAs in Portuguese) have become a reference in studies evaluating the impacts of pesticides on bees since 1976. Thus, the objective of this review was to conduct a quantitative and qualitative review of the studies conducted by these groups to evaluate and compile the advances made over the years, identify potential knowledge gaps for future studies, and support the sensitivities of stingless bees when compared to the species Apis mellifera. The quantitative analyses showed that most studies were carried out in the genus Apis, under laboratory conditions. However, more recently (since 2003), studies have also focused on stingless bees and the neonicotinoid class of insecticides. The most relevant gaps identified were the lack of studies under field conditions and on bee biology. The qualitative analyses indicated that Brazilian stingless bees are more susceptible to pesticides than A. mellifera and require a much lower average dose, concentration, or lethal time to display morphological and behavioral damage or decreased lifespan. Thus, future studies should work towards establishing more representative protocols for stingless bees. Furthermore, public policies must be created for the protection and conservation of bees native to Brazil.

Optimization of in vitro culture of honeybee nervous tissue for pesticide risk assessment.

The most used pesticides have neurotoxic action on the neurotransmitter system of target and non-targeted insects, such as honeybees. However, honeybees have foremost importance worldwide, which has encouraged the development of tools to evaluate the action of specific pesticide molecules on their nervous system, providing accurate data on damage to their brain. In this sense, our study aimed to optimize in vitro honeybee nervous tissue culture to assess pesticide risks. To this end, six forager honeybee brains were dissected and transferred to different combinations of Leibovitz-15 (L-15) culture medium supplemented with Fetal Bovine Serum (FBS), Hank's Balanced Salt Solution (HBSS), and Insect Medium Supplement (IMS). Nervous tissues were collected after different incubation times (1, 6, 12, and 24 h) for morphology and Kenyon cell analyses. Our results showed that L-15 medium supplemented with HBSS and with HBSS plus FBS were the best media for culturing honey nervous tissue for 24 h, as they resulted in less tissue spacing and cell disarrangement. Therefore, they may be assessed in future ecotoxicological tests.

A Systematic Review of Functionalized Polymeric Nanoparticles to Improve Intestinal Permeability of Drugs and Biological Products.

BACKGROUND: The oral route is the most frequently used and the most convenient route of drug administration since it has several advantages, such as ease of use, patient compliance, and better costeffectiveness. However, physicochemical and biopharmaceutical limitations of various active pharmaceutical ingredients (API) hinder suitability for this route, including degradation in the gastrointestinal tract, low intestinal permeability, and low bioavailability. To overcome these problems, while maintaining therapeutic efficacy, polymeric nanoparticles have attracted considerable attention for their ability to increase drug solubility, promote the controlled release, and improve stability. In addition, the functionalization of nanocarriers can increase uptake and accumulation at the target site of action, and intestinal absorption, making it possible to obtain more viable, safe and efficient treatments for oral administration. OBJECTIVE: This systematic review aimed to seek recent advances in the literature on the use of polymeric nanoparticles functionalization to increase intestinal permeability of APIs that are intended for oral administration. METHODS: Two bibliographic databases were consulted (PubMed and ScienceDirect). The selected publications and the writing of this systematic review were based on the guidelines mentioned in the PRISMA statement. RESULTS: Out of a total of 3036 studies, 22 studies were included in this article based on our eligibility criteria. The results were consistent for the application of nanoparticle functionalization to increase intestinal permeability. CONCLUSION: The functionalized polymeric nanoparticles can be considered as carrier systems that improve the intestinal permeability and bioavailability of APIs, with the potential to result, in the future, in the development of oral medicines.

Enhanced Solubility of Albendazole in Cyclodextrin Inclusion Complex: A Molecular Modeling Approach and Physicochemical Evaluation.

BACKGROUND: Albendazole (ABZ) is the drug of choice for the treatment of a variety of human and veterinary parasites. However, it has low aqueous solubility and low bioavailability. Cyclodextrins (CD) are pharmaceutical excipients with the ability to modulate the solubilization property of hydrophobic molecules. OBJECTIVE: The aim of the study was to analyze through in vitro and in silico studies (Autodock Vina software and CycloMolder platform) the formation of inclusion complexes between ABZ, ß-cyclodextrin (ß-CD) and its derivatives Methyl-ß-cyclodextrin (M-ß-CD) and Hydroxypropyl-ß-cyclodextrin (HP-ß-CD). METHODS: The most stable inclusion complexes were produced by the kneading method and characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), determination of the ABZ content and in vitro dissolution profile. RESULTS: Molecular modeling revealed that inclusion complexes between HP-ß-CD:ABZ (in the proportion 1:1 and 2:1) presented the lowest formation energy and the highest number of intermolecular interactions, showing that the use of more cyclodextrins does not generate gains in the stability of the complex. On the characterization tests, the complexes experimentally obtained by the kneading method demonstrated highly suggestive parameters, including ABZ in HP-ß-CD in both molar proportions, suppression of bands in the infrared spectrum, displacement of the drug's melting temperature in DSC, crystallinity halos instead of the characteristic peaks of ABZ crystals in the XRD and a release of more than 80% of ABZ in less than 5 minutes, dissolution efficiency of up to 92%. CONCLUSION: In silico studies provided a rational selection of the appropriate complexes of cyclodextrin, enabling the elaboration of more targeted complexes, decreasing time and costs for elaboration of new formulations, thereby increasing the oral biodisponibility of ABZ.

Drug associations as alternative and complementary therapy for neglected tropical diseases.

The present paper aims to establish different treatments for neglected tropical disease by a survey on drug conjugations and possible fixed-dose combinations (FDC) used to obtain alternative, safer and more effective treatments. The source databases used were Science Direct and PubMed/Medline, in the intervals between 2015 and 2021 with the drugs key-words or diseases, like "schistosomiasis", "praziquantel", "malaria", "artesunate", "Chagas' disease", "benznidazole", "filariasis", diethylcarbamazine", "ivermectin", " albendazole". 118 works were the object of intense analysis, other articles and documents were used to increase the quality of the studies, such as consensuses for harmonizing therapeutics and historical articles. As a result, an effective NTD control can be achieved when different public health approaches are combined with interventions guided by the epidemiology of each location and the availability of appropriate measures to detect, prevent and control disease. It was also possible to verify that the FDCs promote a simplification of the therapeutic regimen, which promotes better patient compliance and enables a reduction in the development of parasitic resistance, requiring further studies aimed at resistant strains, since the combined APIs usually act by different mechanisms or at different target sites. In addition to eliminating the process of developing a new drug based on the identification and validation of active compounds, which is a complex, long process and requires a strong long-term investment, other advantages that FDCs have are related to productive gain and gain from the industrial plant, which can favor and encourage the R&D of new FDCs not only for NTDs but also for other diseases that require the use of more than one drug.

Isolation and Characterization of Biosurfactant-Producing Bacteria from Amapaense Amazon Soils.

The objective of this research was to perform screening of biosurfactant-producing bacteria from Amapaense Amazon soils. Floodplain- and upland-forest soils of three municipalities of the Amapá state were isolated and identified. The isolates were cultured in nutrient broth with olive oil, and their extracts were evaluated according to drop collapse, oil dispersion, emulsification, and surface tension tests. From three hundred and eighteen isolates, the 43 bacteria were selected and identified by 16S rDNA gene sequencing, indicating the presence of three different genera, Serratia, Paenibacillus, and Citrobacter. The extracellular biosurfactant production pointed out the 15 most efficient bacteria that presented high emulsification capacity (E 24 > 48%) and stability (less than 10% of drop after 72 h) and great potential to reduce the surface tension (varying from 49.40 to 34.50 mN·m-1). Cluster analysis classified genetically related isolates in different groups, which can be connected to differences in the amount or the sort of biosurfactants. Isolates from Serratia genus presented better emulsification capacity and produced a more significant surface tension drop, indicating a promising potential for biotechnological applications.

Obtainment of the spray-dried extracts of Peperomia pellucida L. (H.B.K.) using different atomization temperatures: physicochemical characterization and technological development for pharmaceutical applications.

Spray-dried extracts are prepared as powders or granules after solvent removal, which can be obtained in the presence or absence of pharmaceutical adjuvants. This work aimed to optimize the process of obtaining dried extracts of Peperomia pellucida L. (HBK) by spray drying. The characterization of the extract was performed by thermal analysis, specific surface area, particle size and high performance liquid chromatography (HPLC); then, capsules were developed for antimicrobial treatment, evaluating four bench lots by the determination of the angle of repose and time of flow, scanning electron microscopy, porosity and physicochemical quality control. There were no significant differences between the extracts obtained by spray drying at atomization temperatures of 140 °C, 160 °C and 180 °C, which was confirmed by thermal analysis. Specific surface area varied inversely with the mean particle size. Regarding the marker content by HPLC, no significant differences were found between the samples, although the flavonoid fraction was more stable at 160 °C. Bench lots (I to IV) were developed using the diluents Flowlac®, Starch® 1500, microcrystalline cellulose 250 and Cellactose® 80. Based on the results, the bench lot I, containing Flowlac®, was selected. The results of physicochemical quality control demonstrated that the selected formulation meets the pre-established parameters, and proving to be economically viable.

Beta-lapachone: Natural occurrence, physicochemical properties, biological activities, toxicity and synthesis.

ß-Lapachone is an ortho-naphthoquinone originally isolated from the heartwood of Handroanthus impetiginosus and can be obtained through synthesis from lapachol, naphthoquinones, and other aromatic compounds. ß-Lapachone is well known to inhibit topoisomerase I and to induce NAD(P)H: quinone oxidoreductase 1. Currently, phase II clinical trials are being conducted for the treatment of pancreatic cancer. In view of ever-increasing scientific interest in this naphthoquinone, herein, the authors present a review of the synthesis, physicochemical properties, biological activities, and toxicity of ß-lapachone. This natural compound has shown activity against several types of malignant tumors, such as lung and pancreatic cancers and melanoma. Furthermore, this ortho-naphthoquinone has antifungal and antibacterial activities, underscoring its action against resistant microorganisms and providing anti-inflammatory, antiobesity, antioxidant, neuroprotective, nephroprotective, and wound-healing properties. ß-Lapachone presents low toxicity, with no signs of toxicity against alveolar macrophages, dermal fibroblast cells, hepatocytes, or kidney cells.

A Systematic Review of the Anti-inflammatory Effects of Gallium Compounds.

BACKGROUND: Inflammation is an essential response provided by the immune system, ensuring the survival during microbial infection, tissue injury and other noxious conditions. However, prolonged inflammatory processes are often associated with severe side effects on health. OBJECTIVE: This systematic review aimed to provide the evidence in the literature of the preclinical and human anti-inflammatory activity of gallium compounds from 2000 to 2019 focused on elucidating the mechanisms involved in the inflammatory process. METHODS: Seven bibliographical databases were consulted (PubMed, Medline, ScienceDirect, Scopus, Springer, Web of Science, and EBSCOhost). The selection of appropriate publications and writing of this systematic review were based on the guidelines mentioned in the PRISMA statement. Moreover, the assessment of the methodological quality of the selected studies was also performed. RESULTS: From a total of 3018 studies, 16 studies were included in this paper based on our eligibility criteria, which showed promising and consistent results. CONCLUSION: Further research concerning specific inflammatory conditions is required.

Comparison between Thin-Layer Models and Non-Traditional Methods in the Modelling of Drying Kinetics of Crustacean Wastes

Abstract This research aims to compare the classical thin-layer models, stepwise fit regression method (SRG) and artificial neural networks (ANN) in the modelling of drying kinetics of shrimp shell and crab exoskeleton. Thus, drying curves were obtained using a convective dryer (3.0 m/s) at temperatures of 30.45 and 60oC. The results showed a decreasing tendency for the drying time as the temperature increased for both materials. Drying curves modelling of both materials showed fitted results with R 2 adj >0.998 and MRE<13.128% for some thin-layer models. On the other hand, by SRG a simple model could be obtained as a function of time and temperature, with the greatest accuracy being found in the modelling of experimental data of crab exoskeleton, with MRE<10.149%. Finally, the ANNs were employed successfully in the modelling of drying kinetics, showing high prediction quality with the trained recurrent ANN models.

ZIF-8 as a promising drug delivery system for benznidazole: development, characterization, in vitro dialysis release and cytotoxicity.

Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is one of the major public health problems in developing countries. Benznidazole (BNZ) is the only drug available for CD treatment in most countries, however, it presents high toxicity and low bioavailability. To address these problems this study used Zeolitic Imidazolate Framework-8 (ZIF-8), which has garnered considerable attention due to its potential applications, enabling the controlled delivery of drugs. The present work developed and characterized a BNZ@ZIF-8 system, and the modulation of BNZ release from the ZIF-8 framework was evaluated through the in vitro dialysis release method under sink conditions at different pH values. Moreover, the in vitro evaluation of cell viability and cytotoxicity by MTT assay were also performed. The dissolution studies corroborated that a pH sensitive Drug Delivery System capable of vectorizing the release of BNZ was developed, may leading to the improvement in the bioavailability of BNZ. The MTT assay showed that no statistically significant toxic effects occurred in the developed system, nor significant effects on cell viability.

Lipid Nanoparticles as a Skin Wound Healing Drug Delivery System: Discoveries and Advances.

Chronic wounds are a remarkable cause of morbidity, requiring long-time treatments with a significant impact on the quality of life and high costs for public health. Although there are a variety of topical skin preparations commercially available, they have several limitations that frequently impair wound healing, such as drug instability, toxicity, limited time of action and ineffective skin permeation. In recent years, researchers have focused on the development of new effective treatments for wound healing and shown frequent interest in nanometric drug delivery systems to overcome such obstacles. In dermatology, lipid nanoparticles (LNPs) have received great attention from researchers due to their great functionalities, greater adhesion to the skin and film formation, enabling the hydration and maintenance of skin integrity, as well as present a more effective penetration through the skin barrier. This review provides an update on topical formulations based on Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as wound healing treatments. Both SLNs and NLCs are able to increase solubility and stability of active pharmaceutical ingredients and increase skin penetration compared to the free drugs. Additionally, SLNs and NLCs can increase pharmacological activity, increase the release profile of the drugs, promote synergistic effects and improve the sensory properties of the final formulation. Topical dosage forms containing nanoparticles have been extensively evaluated for wound healing activity, mainly the dressings, films and scaffolds. Therefore, lipid nanoparticles have contributed in improving wound healing therapies when incorporated into other dosage forms with better efficacy and lesser adverse effects than conventional formulations.

Standardization of in vitro nervous tissue culture for honeybee: A high specificity toxicological approach.

Bees are important pollinators that help to maintain the biodiversity of wild and cultivated plants. However, the increased and inappropriate use of agrochemicals has caused an imbalance in the populations of these insects visiting flowers for pollen and nectar collection. Therefore, new research methods for understanding the mechanisms of action of pesticides and their impacts on the brains of bees, such as neurotoxicity and cellular changes, in response to different active characteristics and dosages of insecticides are necessary. Thus, with the aim of developing tests with greater specificity at the level of cells or tissues, this study sought to standardize a method for the in vitro culture of the nervous tissue of Apis mellifera. For this purpose, the brains of six foragers bees were transferred to three different insect cell culture media and it supplementation with 10% foetal bovine serum (FBS): Grace, Schneider, Leibovitz, Grace + FBS, Schneider + FBS and Leibovitz + FBS media for each collection time. Nervous tissue was collected after 1, 6, 12 and 24 h of incubation in a humidified CO2 incubator at 32 °C, and histological sections of the organs were analysed. The results showed that Leibovitz medium and Leibovitz medium + serum are potential culture media for the cultivation of nervous tissue, since they resulted in less tissue spacing and tissue disarrangement. Therefore, additional supplements are necessary to obtain an ideal medium for the cultivation of A.mellifera nervous tissue.

Formulation, Development and Scale-Up of Fixed-Dose Combination Tablets Containing Zidovudine, Lamivudine and Nevirapine.

BACKGROUND: The development of antiretroviral associations in a single dosage form aims to ensure improved efficacy, low costs and better adherence to treatment. OBJECTIVE: This work performed the pharmacotechnical development, coating, and stability studies of fixed-dose combination tablets of zidovudine, lamivudine and nevirapine (300 + 200 + 150 mg, respectively). METHODS: Qualitative and quantitative planning of diluents (101 and 250 microcrystalline cellulose, spray-dried monohydrate lactose and corn starch) and coating polymers (Opadry white II HP® and Instacoat Aqua Moistshield II®) were analyzed, and direct compression (DC) and wet granulation (WG) methods were tested aiming the development of the pharmaceutical form. Quality control was carried out according to the specifications set by official compendia. The chosen formulation was scaled-up and the industrial batches were submitted to accelerated and long-term stability studies. RESULTS: The batches obtained by WG met the requirements, using 101 microcrystalline cellulose, corn starch and Opadry white II HP® as excipients. The DC trial was not possible due to the need of a greater ratio of excipients to improve formulation properties. CONCLUSION: Thus, this study brings a new therapeutic alternative for HIV treatment, contributing to the development of another possibility to simplify drug administration.

Dose-range study of MF59-adjuvanted versus nonadjuvanted monovalent A/H1N1 pandemic influenza vaccine in six- to less than thirty-six-month-old children.

BACKGROUND: The successful vaccination of children 6 to 36 months of age against 2009 A/H1N1 influenza was essential to help reduce the burden of pandemic disease in both the pediatric and adult populations. OBJECTIVES: We compared the immunogenicity and safety of 4 alternative monovalent vaccine formulations to identify which provided optimal levels of seroprotection according to the US and European Union (EU) licensure criteria. SUBJECTS AND METHODS: A total of 654 healthy subjects (6 to <36 months old) were given 2 vaccine doses 3 weeks apart. Participants were assigned to 1 of the 4 immunization groups, receiving MF59-adjuvanted (Novartis Vaccines, Marburg, Germany) vaccine either containing 3.75 µg or 7.5 µg of A/H1N1 California/7/2009 antigen, or nonadjuvanted vaccine containing 7.5 µg or 15 µg of antigen. Antibody titers were assessed by hemagglutination inhibition assay 3 weeks, 3 months and 1 year after immunization. Vaccine safety was monitored throughout the study. RESULTS: After 1 dose, both adjuvanted formulations met the US and EU criteria for seroconversion; the 15 µg nonadjuvanted vaccine met the EU criterion for seroconversion alone. The US and EU criteria for seroprotection were only met by adjuvanted groups. MF59-adjuvanted formulations alone resulted in clinically significant persisting antibody titers after 12 months. All vaccines were well tolerated. CONCLUSIONS: A single dose of MF59-adjuvanted vaccine containing 3.75 µg A/H1N1 antigen was highly immunogenic, met both the US and EU licensure criteria and was well tolerated. These data support the suitability of this monovalent vaccine formulation for pandemic use in children 6 to <36 months of age.

Assessment of the safety, tolerability and kinetics of the immune response to A/H1N1v vaccine formulations with and without adjuvant in healthy pediatric subjects from 3 through 17 years of age.

BACKGROUND: The recent global A/H1N1v pandemic led to major efforts to develop effective vaccines against the novel virus, while global demand and limited production capacity focused attention on dose sparing and schedules. METHODS: An open-label phase III study of immunogenicity and safety of novel A/H1N1v vaccines included 392 Costa Rican children in two pediatric cohorts (3-8 and 9-17 years). They received two doses, of either an MF59®-adjuvanted formulation containing 7.5 µg antigen or non-adjuvanted formulations containing 15 or 30 µg antigen, three weeks apart. Immunogenicity was assessed as hemagglutination inhibition (HI) titers using the CBER licensure criteria. RESULTS: All three vaccines elicited immune responses in 9-17 year-olds meeting CBER criteria three weeks after one dose; responses were not enhanced by second dose. In 3-8 year-olds only the adjuvanted vaccine met the CBER criteria after one dose, but all three vaccines met criteria after second dose. All vaccines were well tolerated; no related Serious Adverse Events (SAE) and few severe solicited reactions were reported. MF59-adjuvanted vaccine was associated with more reports of injection site pain and tenderness and overall systemic solicited reactions, most notably in older subjects, all of which decreased after the second dose. CONCLUSION: One dose of non-adjuvanted A/H1N1v vaccine is adequate in 9-17 year-olds, but younger children require either one dose of MF59-adjuvanted vaccine or two doses of non-adjuvanted vaccine to achieve protective titers. Enhanced immunogenicity with MF59 is associated with a small increase in reactogenicity, but no safety issues.