Development and evaluation of praziquantel solid dispersions in sodium starch glycolate

Purpose: To develop and characterize solid dispersions of praziquantel (PZQ) with sodium starch glycolate (SSG) for enhanced drug solubility. Methods: PZQ solid dispersion (SD) was prepared using co-precipitation method by solvent evaporation. The ratios of PZQ to SSG were 2:1, 1:1, 1:2, 1:3 (w/w). PZQ solubility was evaluated in purified water, and PZQ dissolution test was carried out in 0.1N HCl. Structural characterization of the dispersions was accomplished by x-ray diffraction (XRD) and infrared spectroscopy (FTIR) while the external morphology of the SDs, SSG and PZQ were studied by scanning electron microscopy (SEM). Mucoadhesion properties of the SD (1:3) and SSG, on mucin disks were examined using texture profile analysis. Results: The highest solubility was obtained with 1:3 solid dispersion, with PZQ solubility of 97.31 %, which is 3.65-fold greater than the solubility of pure PZQ and physical misture (PM, 1:3). XRD results indicate a reduction in PZQ crystallinity while infrared spectra showed that the functional groups of PZQ and SSG were preserved. SEM showed that the physical structure of PZQ was modified from crystalline to amorphous. The amount of PZQ in PM and SD (1:3) that dissolved in 60 min was 70 and 88 %, respectively, and these values increased to 76 and 96 %, respectively. The solid dispersion reduced the mucoadhesive property of the glycolate. Conclusion: Solid dispersion formulation using SSG is a good alternative approach for increasing the dissolution rate of PZQ. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.

Structural and Phylogenetic Studies with MjTX-I Reveal a Multi-Oligomeric Toxin - a Novel Feature in Lys49-PLA2s Protein Class

The mortality caused by snakebites is more damaging than many tropical diseases, such as dengue haemorrhagic fever, cholera, leishmaniasis, schistosomiasis and Chagas disease. For this reason, snakebite envenoming adversely affects health services of tropical and subtropical countries and is recognized as a neglected disease by the World Health Organization. One of the main components of snake venoms is the Lys49-phospholipases A2, which is catalytically inactive but possesses other toxic and pharmacological activities. Preliminary studies with MjTX-I from Bothrops moojeni snake venom revealed intriguing new structural and functional characteristics compared to other bothropic Lys49-PLA2s. We present in this article a comprehensive study with MjTX-I using several techniques, including crystallography, small angle X-ray scattering, analytical size-exclusion chromatography, dynamic light scattering, myographic studies, bioinformatics and molecular phylogenetic analyses.Based in all these experiments we demonstrated that MjTX-I is probably a unique Lys49-PLA2, which may adopt different oligomeric forms depending on the physical-chemical environment. Furthermore, we showed that its myotoxic activity is dramatically low compared to other Lys49-PLA2s, probably due to the novel oligomeric conformations and important mutations in the C-terminal region of the protein. The phylogenetic analysis also showed that this toxin is clearly distinct from other bothropic Lys49-PLA2s, in conformity with the peculiar oligomeric characteristics of MjTX-I and possible emergence of new functionalities inresponse to environmental changes and adaptation to new preys. © 2013 Salvador et al.

Inovação do método MIA-QSAR: aplicação para doenças tropicais negligenciadas

Multivariate image analysis applied to the quantitative structure-activity relationships (MIA-QSAR) is a 2D QSAR technique that has been presenting promising outcomes for the development of new drug candidates, due to its simplicity, rapidity and low cost. In this way, the present study aims at introducing, consolidating and improving the new dimensions named aug-MIA-QSAR and aug-MIA-QSARcolor, as well as applying them to the study of neglected diseases, in order to obtain new drug targets using chemico-biological interpretation of the MIA molecular descriptors. Four compound data sets with experimental bioactivities against Chagas disease, malaria, dengue and schistosomiasis were evaluated using three approaches: MIA-QSARt, aug-MIA-QSAR and aug-MIA-QSARcolor. In general, representations of atoms as spheres with different colors and sizes proportional to the corresponding van der Waals radii (aug-MIA approaches) improved the predictive ability and interpretability in all data sets. The use of colors proportional to the Pauling´s electronegativity showed that MIA descriptors are capable of identifying periodic properties relevant for the studied activity. Finally, solid colors instead of spotlighted atoms allowed a correct identification of atoms by means of pixel values in the studies for malaria, dengue and schistosomiasis, which were, subsequently, useful for the chemical interpretation related to the bioactivity. It can be inferred that semicarbazones and thiosemicarbazones derivative with a tri-substituted ring in R1 group and a trifluoro methyl group in the R 3 position instead of a chlorine antitripanossoma resulted in higher activity. The antimalarial activity of quinolon-4(1H)imines can be improved if: 1) R1 and R2 are electron donor groups, 2) R3 has long aminoalkyl chains, and 3) R4 possesses substituents with big atomic volume. In the study for dengue, it was found that tetrapeptides with unbranched small size amino acids in the A1 and A4 positions can increase the substrate affinity (Km) to the NS3 protein, and when in A1 and A2 positions, the substrate cleavage rate (kcat). On the other hand, acidic amino acids in the A2 and A4 positions were found to be related with low substrate affinity to the NS3 protein and when present in A1, with low substrate cleavage rate. Finally, the presence of metoxy substituents in R1 (or R2) and R5 in the neolignan backbone can favor their antischistosomal activity.

An assessment of the economic impact of climate change on the Agriculture, Health and Tourism sectors in Saint Lucia

This report analyses the agriculture, health and tourism sectors in Saint Lucia to assess the potential economic impacts of climate change on the sectors. The fundamental aim of this report is to assist with the development of strategies to deal with the potential impact of climate change in Saint Lucia. It also has the potential to provide essential input for identifying and preparing policies and strategies to help advance the Caribbean subregion closer to solving problems associated with climate change and attaining individual and regional sustainable development goals. Some of the key anticipated impacts of climate change for the Caribbean include elevated air and sea-surface temperatures, sea-level rise, possible changes in extreme events and a reduction in freshwater resources. The economic impact of climate change on the three sectors was estimated for the A2 and B2 IPCC scenarios until 2050. An evaluation of various adaptation strategies for each sector was also undertaken using standard evaluation techniques. The key subsectors in agriculture are expected to have mixed impacts under the A2 and B2 scenarios. Banana, fisheries and root crop outputs are expected to fall with climate change, but tree crop and vegetable production are expected to rise. In aggregate, in every decade up to 2050, these sub-sectors combined are expected to experience a gain under climate change with the highest gains under A2. By 2050, the cumulative gain under A2 is calculated as approximately US$389.35 million and approximately US$310.58 million under B2, which represents 17.93% and 14.30% of the 2008 GDP respectively. This result was unexpected and may well be attributed to the unavailability of annual data that would have informed a more robust assessment. Additionally, costs to the agriculture sector due to tropical cyclones were estimated to be $6.9 million and $6.2 million under the A2 and B2 scenarios, respectively. There are a number of possible adaptation strategies that can be employed by the agriculture sector. The most attractive adaptation options, based on the benefit-cost ratio are: (1) Designing and implementation of holistic water management plans (2) Establishment of systems of food storage and (3) Establishment of early warning systems. Government policy should focus on the development of these adaption options where they are not currently being pursued and strengthen those that have already been initiated, such as the mainstreaming of climate change issues in agricultural policy. The analysis of the health sector placed focus on gastroenteritis, schistosomiasis, ciguatera poisoning, meningococal meningitis, cardiovascular diseases, respiratory diseases and malnutrition. The results obtained for the A2 and B2 scenarios demonstrate the potential for climate change to add a substantial burden to the health system in the future, a factor that will further compound the country’s vulnerability to other anticipated impacts of climate change. Specifically, it was determined that the overall Value of Statistical Lives impacts were higher under the A2 scenario than the B2 scenario. A number of adaptation cost assumptions were employed to determine the damage cost estimates using benefit-cost analysis. The benefit-cost analysis suggests that expenditure on monitoring and information provision would be a highly efficient step in managing climate change and subsequent increases in disease incidence. Various locations in the world have developed forecasting systems for dengue fever and other vector-borne diseases that could be mirrored and implemented. Combining such macro-level policies with inexpensive micro-level behavioural changes may have the potential for pre-empting the re-establishment of dengue fever and other vector-borne epidemic cycles in Saint Lucia. Although temperature has the probability of generating significant excess mortality for cardiovascular and respiratory diseases, the power of temperature to increase mortality largely depends on the education of the population about the harmful effects of increasing temperatures and on the existing incidence of these two diseases. For these diseases it is also suggested that a mix of macro-level efforts and micro-level behavioural changes can be employed to relieve at least part of the threat that climate change poses to human health. The same principle applies for water and food-borne diseases, with the improvement of sanitation infrastructure complementing the strengthening of individual hygiene habits. The results regarding the tourism sector imply that the tourism climatic index was likely to experience a significant downward shift in Saint Lucia under the A2 as well as the B2 scenario, indicative of deterioration in the suitability of the island for tourism. It is estimated that this shift in tourism features could cost Saint Lucia about 5 times the 2009 GDP over a 40-year horizon. In addition to changes in climatic suitability for tourism, climate change is also likely to have important supply-side effects on species, ecosystems and landscapes. Two broad areas are: (1) coral reefs, due to their intimate link to tourism, and, (2) land loss, as most hotels tend to lie along the coastline. The damage related to coral reefs was estimated at US$3.4 billion (3.6 times GDP in 2009) under the A2 scenario and US$1.7 billion (1.6 times GDP in 2009) under the B2 scenario. The damage due to land loss arising from sea level rise was estimated at US$3.5 billion (3.7 times GDP) under the A2 scenario and US$3.2 billion (3.4 times GDP) under the B2 scenario. Given the potential for significant damage to the industry a large number of potential adaptation measures were considered. Out of these a short-list of 9 potential options were selected by applying 10 evaluation criteria. Using benefit-cost analyses 3 options with positive ratios were put forward: (1) increased recommended design speeds for new tourism-related structures; (2) enhanced reef monitoring systems to provide early warning alerts of bleaching events, and, (3) deployment of artificial reefs or other fish-aggregating devices. While these options had positive benefit-cost ratios, other options were also recommended based on their non-tangible benefits. These include the employment of an irrigation network that allows for the recycling of waste water, development of national evacuation and rescue plans, providing retraining for displaced tourism workers and the revision of policies related to financing national tourism offices to accommodate the new climate realities.

An economic assessment of the impact of climate change on the health sector in Montserrat

Climate change has the potential to impact on global, regional, and national disease burdens both directly and indirectly. Projecting and valuing these health impacts is important not only in terms of assessing the overall impact of climate change on various parts of the world, but also in terms of ensuring that national and regional decision-making institutions have access to the data necessary to guide investment decisions and future policy design. This report contributes to the research focusing on projecting and valuing the impacts of climate change in the Caribbean by projecting the climate change-induced excess disease burden for two climate change scenarios in Montserrat for the period 2010 - 2050, and by estimating the monetary value associated with this excess disease burden. The diseases initially considered in this report are variety of vector and water-borne impacts and other miscellaneous conditions; specifically, malaria, dengue fever, gastroenteritis/diarrheal disease, schistosomiasis, leptospirosis, ciguatera poisoning, meningococcal meningitis, and cardio-respiratory diseases. Disease projections were based on derived baseline incidence and mortality rates, available dose-response relationships found in the published literature, climate change scenario population projections for the A2 and B2 IPCC SRES scenario families, and annual temperature and precipitation anomalies as projected by the downscaled ECHAM4 global climate model. Monetary valuation was based on a transfer value of statistical life approach with a modification for morbidity. Using discount rates of 1%, 2% and 4%, results show mean annual costs (morbidity and mortality) ranges of $0.61 million (in the B2 scenario, discounted at 4% annually) – $1 million (in the A2 scenario, discounted at 1% annually) for Montserrat. These costs are compared to adaptation cost scenarios involving increased direct spending on per capita health care. This comparison reveals a high benefit-cost ratio suggesting that moderate costs will deliver significant benefit in terms of avoided health burdens in the period 2010-2050. The methodology and results suggest that a focus on coordinated data collection and improved monitoring represents a potentially important no regrets adaptation strategy for Montserrat. Also the report highlights the need for this to be part of a coordinated regional response that avoids duplication in spending.

An assessment of the economic impact Of climate change on the health sector in Saint Lucia

Climate change has the potential to impact on global, regional, and national disease burdens both directly and indirectly. Projecting and valuing these health impacts is important not only in terms of assessing the overall impact of climate change on various parts of the world, but also of ensuring that national and regional decision-making institutions have access to the data necessary to guide investment decisions and future policy design. This report contributes to the research focusing on projecting and valuing the impacts of climate change in the Caribbean by projecting the climate change-induced excess disease burden for two climate change scenarios in Saint Lucia for the period 2010 - 2050, and by estimating the non-market, statistical life-based costs associated with this excess disease burden. The diseases initially considered in this report are a variety of vector and water-borne impacts and other miscellaneous conditions; specifically, malaria, dengue fever, gastroenteritis/diarrhoeal disease, schistosomiasis, leptospirosis, ciguatera poisoning, meningococcal meningitis, and cardio-respiratory diseases. Disease projections were based on derived baseline incidence and mortality rates, available dose-response relationships found in the published literature, climate change scenario population projections for the A2 and B2 IPCC SRES scenario families, and annual temperature and precipitation anomalies as projected by the downscaled ECHAM4 global climate model. Monetary valuation was based on a transfer value of statistical life approach with a modification for morbidity. Using discount rates of 1, 2, and 4%, results show mean annual costs (morbidity and mortality) ranges of $80.2 million (in the B2 scenario, discounted at 4% annually) -$182.4 million (in the A2 scenario, discounted at 1% annually) for St. Lucia.1 These costs are compared to adaptation cost scenarios involving direct and indirect interventions in health care. This comparison reveals a high benefit-cost ratio suggesting that moderate costs will deliver significant benefit in terms of avoided health costs from 2010-2050. In this context indirect interventions target sectors other than healthcare (e.g. water supply). It is also important to highlight that interventions can target both the supply of health infrastructure (including health status and disease monitoring), and households. It is suggested that a focus on coordinated data collection and improved monitoring represents a potentially important no regrets adaptation strategy for St Lucia. Also, the need for this to be part of a coordinated regional response that avoids duplication in spending is highlighted.

Preparação de dispersões sólidas de praziquantel com polivinilpirrolidona pelo processo do fluido supercrítico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

In Vitro Antiparasitic Activity and Chemical Composition of the Essential Oil Obtained from the Fruits of Piper cubeba

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação de sistemas lipidicos nanoestruturados utilizados como estratégia para melhorar as propriedades biofarmaceuticas do praziquantel no tratamento da esquistossomose

Pós-graduação em Nanotecnologia Farmacêutica - FCFAR

In Vitro Schistosomicidal Activity of Balsaminol F and Karavilagenin C

Five cucurbitane-type triterpenes (1-5), previously isolated from the African medicinal plant Momordica balsamina, along with five ester derivatives (6-10) of karavilagenin C (2), were evaluated for their potential schistosomicidal activity against Schistosoma mansoni adult worms. The natural compounds were isolated from the ethyl acetate-soluble fraction of the methanol extract of the aerial parts of M. balsamina. In a preliminary study, a significant schistosomicidal activity was observed for both the crude methanol extract and the ethyl acetate fraction. The compounds responsible for the activity were found to be balsaminol F (1) and karavilagenin C (2) with LC50 values of 14.7 +/- 1.5 and 28.9 +/- 1.8 mu M, respectively, after 24 h of incubation (positive control praziquantel, LC50 = 1.2 +/- 0.1 mu M). Both compounds (1, 2), at 10-50 mu M, induced significant reductions in the motor activity of the worms and significantly decreased the egg production. Furthermore, they were able (at 10-100 mu M) to separate the adult worm pairs into male and female after 24 h. Compounds 3-5, bearing a sugar moiety as a substituent, and the acylated derivatives of karavilagenin C (6-10) were inactive, suggesting that the presence of free hydroxyl groups in the tetracyclic skeleton might be important for the activity. A correlation between activity and the molecular volume/weight of compounds was also found.

Distribution and molecular characterization of hepatitis C virus (HCV) genotypes in patients with chronic infection from Pernambuco State, Brazil

Hepatitis C virus (HCV) is a public health problem throughout the world and 3% of the world population is infected with this virus. It is estimated that 3-4 millions individuals are being infected every year. It has been estimated that around 1.5% of Brazilian population is anti-HCV positive and the Northeast region showed the highest prevalence in Brazil. The aim of this study was to characterize HCV genotypes circulating in Pernambuco State (PE), Brazil, located in the Northeast region of the country. This study included 85 anti-HCV positive patients followed up between 2004 and 2011. For genotyping, a 380bp fragment of HCV RNA in the NS5B region was amplified by nested PCR. Phylogenetic analysis was conducted using Bayesian Markov chain Monte Carlo simulation (MCMC) using BEAST v.1.5.3. From 85 samples, 63 (74.1%) positive to NS5B fragment were successfully sequenced. Subtype 1b was the most prevalent in this population (42-66.7%), followed by 3a (16-25.4%), 1a (4-6.3%) and 2b (1-1.6%). Twelve (63.1%) and seven (36.9%) patients with HCV and schistosomiasis were infected with subtypes 1b and 3a, respectively. Brazil is a large country with many different population backgrounds; a large variation in the frequencies of HCV genotypes is predictable throughout its territory. This study reports HCV genotypes from Pernambuco State where subtype 1b was found to be the most prevalent. Phylogenetic analysis suggests the presence of the different HCV strains circulating within this population. (C) 2012 Elsevier B.V. All rights reserved.

In Vitro Schistosomicidal Activity of Some Brazilian Cerrado Species and Their Isolated Compounds

Miconia langsdorffii Cogn. (Melastomataceae), Roupala montana Aubl. (Proteaceae), Struthanthus syringifolius (Mart.) (Loranthaceae), and Schefflera vinosa (Cham. & Schltdl.) Frodin (Araliaceae) are plant species from the Brazilian Cerrado whose schistosomicidal potential has not yet been described. The crude extracts, fractions, the triterpenes betulin, oleanolic acid, ursolic acid and the flavonoids quercetin 3-O-beta-D-rhamnoside, quercetin 3-O-beta-D-glucoside, quercetin 3-O-beta-D-glucopyranosyl-(1-2)-alpha-L-rhamnopyranoside and isorhamnetin 3-O-beta-D-glucopyranosyl-(1-2)-alpha-L-rhamnopyranoside were evaluated in vitro against Schistosoma mansoni adult worms and the bioactive n-hexane fractions of the mentioned species were also analyzed by GC-MS. Betulin was able to cause worm death percentage values of 25% after 120 h (at 100 mu M), and 25% and 50% after 24 and 120 h (at 200 mu M), respectively; besides the flavonoid quercetin 3-O-beta-D-rhamnoside promoted 25% of death of the parasites at 100 mu M. Farther the flavonoids quercetin 3-O-beta-D-glucoside and quercetin 3-O-beta-D-rhamnoside at 100 mu M exhibited significantly reduction in motor activity, 75% and 87.5%, respectively. Biological results indicated that crude extracts of R. montana, S. vinosa, and M. langsdorffii and some n-hexane and EtOAc fractions of this species were able to induce worm death to some extent. The results suggest that lupane-type triterpenes and flavonoid monoglycosides should be considered for further antiparasites studies.

Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC50 values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

Modulation of Lung Allergic Response by Renal Ischemia and Reperfusion Injury

The Th1/Th2 balance represents an important factor in the pathogenesis of renal ischemia-reperfusion injury (IRI). In addition, IRI causes a systemic inflammation that can affect other tissues, such as the lungs. To investigate the ability of renal IRI to modulate pulmonary function in a specific model of allergic inflammation, C57Bl/6 mice were immunized with ovalbumin/albumen on days 0 and 7 and challenged with an ovalbumin (OA) aerosol on days 14 and 21. After 24 h of the second antigen challenge, the animals were subjected to 45 minutes of ischemia. After 24 h of reperfusion, the bronchoalveolar lavage (BAL) fluid, blood and lung tissue were collected for analysis. Serum creatinine levels increased in both allergic and non-immunized animals subjected to IRI. However, BAL analysis showed a reduction in the total cells (46%) and neutrophils (58%) compared with control allergic animals not submitted to IRI. In addition, OA challenge induced the phosphorylation of ERK and Akt and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung homogenates. After renal IRI, the phosphorylation of ERK and expression of COX-2 and iNOS were markedly reduced; however, there was no difference in the phosphorylation of Akt between sham and ischemic OA-challenged animals. Mucus production was also reduced in allergic mice after renal IRI. IL-4, IL-5 and IL-13 were markedly down-regulated in immunized/challenged mice subjected to IRI. These results suggest that renal IRI can modulate lung allergic inflammation, probably by altering the Th1/Th2 balance and, at least in part, by changing cellular signal transduction factors. Copyright (C) 2012 S. Karger AG, Basel