Instrumentos de avaliação da neuropatia periférica induzida por quimioterapia no paciente com mieloma múltiplo / Evaluation instruments of peripheral neuropathy induced by chemotherapy in patients with multiple myeloma

Objetivo: Identificar instrumentos de avaliação da neuropatia periférica induzida por quimioterapia que possam ser traduzidos ou adaptados para monitoramento dessa reação adversa a medicamentos em pacientes com mieloma múltiplo.Método: Revisão narrativa, realizada entre julho de 2018 a maio de 2019. Foram elegíveis artigos publicados em inglês e português, entre junho de 2007 a janeiro de 2019, disponíveis na íntegra de maneira livre ou em periódicos do Portal da CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Foram excluídos estudos com animais, monografias, guidelines, teses, casos clínicos e estudos que não da área de saúde.Resultados: Foram identificados cinco instrumentos: Patient Neurotoxicity Questionnaire; Funcional Assessment of Cancer Therapy/ Gynecologyc Group – Neurotoxicity; Chemotherapy-Induced Peripheral Neuropathy Assessment Tool; Funcional Assessment Cancer Therapy/Taxane; Indication for Common Toxicity Criteria – Grading of Peripheral Neuropathy Questionnaire (ICPNQ). Após análise de cada ferramenta apresentada, o ICPNQ se mostrou válido e aplicável na prática clínica, porém, encontra-se em língua inglesa.Conclusão: A tradução e validação do instrumento ICPNQ para o português, possibilitaria sua incorporação à prática clínica no monitoramento da neuropatia periférica induzida por quimioterapia em pacientes com Mieloma Múltiplo. (AU)

Objective: To identify instruments for evaluation of peripheral neuropathy induced by chemotherapy that can be translated or adapted to monitor this adverse drug reaction in patients with multiple myeloma.Method: Narrative review, conducted between July 2018 and may 2019. Articles published in English and Portuguese were eligible between June 2007 and January 2019, available in full in a free manner or in periodicals of the CAPES Coordination Portal for Improvement of Level Personnel Higher. Animal studies, monographs, guidelines, theses, clinical cases and non-health studies were excluded.Results: Five instruments were identified: Patient Neurotoxicity Questionnaire; Funcional Assessment of Cancer Therapy/Gynecologyc Group – Neurotoxicity; Chemotherapy-Induced Peripheral Neuropathy Assessment Tool; Funcional Assessment Cancer Therapy/Taxane; Indication for Common Toxicity Criteria – Grading of Peripheral Neuropathy Questionnaire (ICPNQ). After analyzing each tool presented, the ICPNQ proved to be valid and applicable in clinical practice, however, it is in the English language.Conclusion: The translation and validation of the ICPNQ instrument into Portuguese would allow its incorporation into clinical practice in the monitoring of peripheral neuropathy induced by chemotherapy in patients with multiple myeloma. (AU)

Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection.

OBJECTIVES: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs. RESULTS: Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC90 values of 6.67 µM and 9.84 µM, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 µM) and clinical MDR strains (MIC90 values ranging from 3.09 to 42.95 µM). Time-kill experiments with compound (14c) showed early bactericidal effects that were superior to those of the first- and second-line anti-tuberculosis drugs currently used in therapy. The safety of compounds (14b) and (14c) was demonstrated by the Ames test because these molecules were not mutagenic under the tested conditions. Finally, we confirmed the safety, and high efficacy of compounds (14b) and (14c), which reduced M. tuberculosis to undetectable levels in a mouse aerosol model of infection. CONCLUSION: Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection.

Emergent subharmonic band gaps in nonlinear locally resonant metamaterials induced by autoparametric resonance.

With the aim of developing high-performance locally resonant metamaterials, the effect of nonlinear hyperelastic interactions between a rubberlike elastomeric local resonator and the host matrix is investigated. The results reveal a new emergent physical phenomenon not previously reported within the framework of elastoacoustic metamaterials: The appearance of a half subharmonic attenuation zone complementing the local resonance band gap around the fundamental frequency. Evidence of the emergent attenuation zone is provided by direct numerical simulations as well as semianalytical developments via the method of multiple scales. The analyses demonstrate that, in the considered nonlinear locally resonant metamaterial, the combined effects of autoparametric and local resonance induce saturation of the primary wave at certain conditions and, subsequently, promote energy exchange from a primary propagating wave to an evanescent subharmonic wave, giving rise to an additional attenuation zone. This opens new possibilities for the design of passive filtering devices for elastoacoustic waves.

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi.

Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

Copper(II) complex-loaded castor oil-based nanostructured lipid carriers used against Mycobacterium tuberculosis : Development, characterisation, in vitro and in vivo biological assays.

A copper(II) complex-loaded castor oil-based nanostructured lipid carrier was evaluated to enhance the poor water solubility of antimicrobial compounds, improving their biological properties and antimicrobial activity against Mycobacterium tuberculosis. Nanostructured lipid carriers were composed of the castor oil, polyoxyethylene 40 stearate and caprylic/capric triglyceride, poloxamer 407, cetyltrimethylammonium bromide and three different copper(II) complexes. The systems were ultrasonicated at an amplitude of 8% for 20 min and an ice bath was used throughout the procedure. The blank nanostructured lipid carrier (F5) and nanostructured lipid carriers loaded with copper(II) complex 1, 2 and 3 (F5.1, F5.2 and F5.3, respectively) for 45 days presented values of mean diameter, poly dispersity index and zeta potential ranging from 186 to 199 nm, 0.14 to 0.2 and 24 to 30 mV, respectively. Atomic force microscopy indicated that the nanostructured lipid carriers were distributed at the nanoscale, corroborating the mean diameter data. Differential scanning calorimetry determined the melting points of the constituents of the nanostructured lipid carriers. The antimicrobial activity of copper(II) complexloaded F5 against M. tuberculosis H37Rv showed better anti-tuberculosis activity than the free complexes. In vivo biological assays of complex-loaded F5 demonstrated reduced toxicity. Our results suggest that nanostructured lipid carriers could be a potential nanotechnological strategy to optimise tuberculosis treatment.

Repurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity.

Statins are inhibitors of cholesterol synthesis, but other biological properties, such as antimicrobial effects, have also been assigned to them, leading to their designation as pleiotropic agents. Our goal was to investigate the activity and selectivity of atorvastatin (AVA) against Trypanosoma cruzi by using in vitro models, aiming for more effective and safer therapeutic options through drug repurposing proposals for monotherapy and therapy in combination with benznidazole (BZ). Phenotypic screening was performed with different strains (Tulahuen [discrete typing unit {DTU} VI] and Y [DTU II]) and forms (intracellular forms, bloodstream trypomastigotes, and tissue-derived trypomastigotes) of the parasite. On assay of the Tulahuen strain, AVA was more active against intracellular amastigotes (selectivity index [SI] = 3). Also, against a parasite of another DTU (Y strain), this statin was more active (2.1-fold) and selective (2.4-fold) against bloodstream trypomastigotes (SI = 51) than against the intracellular forms (SI = 20). A cytomorphological approach using phalloidin-rhodamine permitted us to verify that AVA did not induced cell density reduction and that cardiac cells (CC) maintained their typical cytoarchitecture. Combinatory approaches using fixed-ratio methods showed that AVA and BZ gave synergistic interactions against both trypomastigotes and intracellular forms (mean sums of fractional inhibitory concentration indexes [∑FICIs] of 0.46 ± 0.12 and 0.48 ± 0.03, respectively). Thus, the repurposing strategy for AVA, especially in combination with BZ, which leads to a synergistic effect, is encouraging for future studies to identify novel therapeutic protocols for Chagas disease treatment.

Effects of wobble board training on single-leg landing neuromechanics.

Balance training programs have been shown to reduce ankle sprain injuries in sports, but little is known about the transfer from this training modality to motor coordination and ankle joint biomechanics in sport-specific movements. This study aimed to investigate the effects of wobble board training on motor coordination and ankle mechanics during early single-leg landing from a lateral jump. Twenty-two healthy men were randomly assigned to either a control or a training group, who engaged in 4 weeks of wobble board training. Full-body kinematics, ground reaction force, and surface electromyography (EMG) from 12 lower limb muscles were recorded during landing. Ankle joint work in the sagittal, frontal, and transverse plane was calculated from 0 to 100 ms after landing. Non-negative matrix factorization (NMF) was applied on the concatenated EMG Pre- and Post-intervention. Wobble board training increased the ankle joint eccentric work 1.2 times in the frontal (P < .01) and 4.4 times in the transverse plane (P < .01) for trained participants. Wobble board training modified the modular organization of muscle recruitment in the early landing phase by separating the activation of plantar flexors and mediolateral ankle stabilizers. Furthermore, the activation of secondary muscles across motor modules was reduced after training, refocusing the activation on the main muscles involved in the mechanical main subfunctions for each module. These results suggest that wobble board training may modify motor coordination when landing from a lateral jump, focusing on the recruitment of specific muscles/muscle groups that optimize ankle joint stability during early ground contact in single-leg landing.

In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines.

Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 µM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 µM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 µM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 µM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.

Drug repurposing strategy against Trypanosoma cruzi infection: In vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy.

Metronidazole (Mtz) is a commercial broad-spectrum nitroimidazolic derivative with relevant antimicrobial activity and relative safety profile. Therefore, it is fair to consider Mtz a candidate for drug repurposing for other neglected conditions such as Chagas disease (CD), a parasitic pathology caused by Trypanosoma cruzi. CD is treated only with benznidazole (Bz) and nifurtimox, both introduced in clinics decades ago despite important limitations, including low efficacy on the later disease stage (chronic form) and severe side effects. New cheap and fast alternative treatments for CD are needed, thus the repurposing of Mtz was assessed in vitro and in vivo in mono- and combined therapy. In vitro assays demonstrated EC50>200µM for Mtz, while for Bz the values ranged from 2.51µM (intracellular forms) to 11.5µM (bloodstream trypomastigotes). When both drugs were combined in fixed-ratio proportions, Mtz promoted Bz potency (lower EC50 values). In vivo toxicity assays for Mtz in mice showed no adverse effects neither histopathological alterations up to 2000mg/kg. Regarding experimental T. cruzi infection, Bz 100mg/kg suppressed parasitemia while Mtz (up to 1000mg/kg) in monotherapy did not, but prolonged animal survival at 250 and 500 regimen doses. The combination of both drugs (Bz 10+Mtz 250) prevented mortality (70%) besides protected against electric cardiac alterations triggered by the parasite infection. Although not able to reduce parasite load, the combination therapy prevented animal mortality; this was possibly due to a protection of the electric cardiac physiology that is normally altered in experimental infection of T. cruzi. It also suggested that the interaction with Mtz could have improved the pharmacokinetics of Bz. Our study emphasizes the importance of drug repurposing and combined therapy for CD to contribute to alternative therapies for this neglected and silent pathology.

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi.

The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0.23 µM; selectivity index = 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 = 0.87 ± 0.05 µM) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (ß-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD.

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi.

Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 µM for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 µM). It was also active against the Colombiana strain (EC50= 3.8 µM). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 µM) was about 100-fold more active than Bz (2 µM). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.

Evaluation of the Acute Toxicity, Cytotoxicity, and Genotoxicity of Chresta martii (Asteraceae).

Chresta martii (Asteraceae), found in the Xingó region, northeastern Brazil, is used in the treatment of gastrointestinal (GIT) and liver disorders and malaria. However, there are few studies regarding efficacy and safety of use for this species. Thus, the objective of this study was to determine in vivo acute toxicity and in vitro cytotoxicity of organic extracts of C. martii as well as in vivo genotoxicity of its semipurified fraction. Dried aerial parts of C. martii were extracted using three organic solvents (cyclohexane [ECCm], ethyl acetate [EACm], and ethanol [EECm]), and these extracts were examined for acute toxicity (50-2000 mg/kg ip or po) and cytotoxicity (50 µg/ml) in carcinogenic human cell lines (HL-60, NCIH-292, and MCF-7). The EACm, which showed evidence of toxicity (in vivo and in vitro), was fractionated on a silica column, yielding four fractions (F1-F4). The F1 was utilized for genotoxicity (50 mg/kg ip), by in vivo micronucleus (MN) assay. ECCm showed no indication of acute toxicity or occurrence of death, while the LD50 estimated for the extracts (EACm and EECm) was 500 mg/kg po and 200 mg/kg ip. The EACm (50 µg/ml) inhibited growth of tumor cells HL-60 (96.54%), NCIH-292 (73.43%), and MCF-7 (15%). The F1 fraction induced MN formation in polychromatic erythrocytes of Swiss Webster mice. Organic extracts from C. martii exhibited acute toxicity classified as mild to moderate, in addition to cytotoxicity (in vitro), while the F1 semipurified fraction induced genotoxicity (in vivo).

In vitro investigation of the efficacy of novel diamidines against Trypanosoma cruzi.

Chagas' disease is a neglected tropical disease caused by Trypanosoma cruzi and constitutes a serious public health problem for Latin America. Its unsatisfactory chemotherapy stimulates the search for novel antiparasitic compounds. Amidines and related compounds exhibit well-known activity towards different microbes including T. cruzi. In this vein, our present aim was to evaluate the biological effect of 10 novel structurally related amidines in vitro against bloodstream and intracellular forms of the parasite as well as their potential toxicity on cardiac cell cultures. Our results show that although active against the extracellular forms, with some of them like DB2247 being 6-fold more effective than benznidazole and displaying very low toxicity (>96 µm), none presented superior trypanocidal effect against intracellular forms as compared with the reference drug. These results may be due to differences in susceptibility profiles related to distinct uptake/extrusion mechanisms and cellular targets between bloodstream and amastigote forms. The present study adds to the knowledge base for the future design of novel amidines that may provide promising activity against T. cruzi.

In vitro and in vivo studies of the biological activity of novel arylimidamides against Trypanosoma cruzi.

Fifteen novel arylimidamides (AIAs) (6 bis-amidino and 9 mono-amidino analogues) were assayed against Trypanosoma cruzi in vitro and in vivo. All the bis-AIAs were more effective than the mono-AIAs, and two analogues, DB1967 and DB1989, were further evaluated in vivo. Although both of them reduced parasitemia, protection against mortality was not achieved. Our results show that the number of amidino-terminal units affects the efficacy of arylimidamides against T. cruzi.

Fast changes in direction during human locomotion are executed by impulsive activation of motor modules.

This study investigated the modular control of complex locomotor tasks that require fast changes in direction, i.e., cutting manoeuvres. It was hypothesized that such tasks are accomplished by an impulsive (burst-like) activation of a few motor modules, as observed during walking and running. It was further hypothesized that the performance in cutting manoeuvres would be associated to the relative timing of the activation impulses. Twenty-two healthy men performed 90° side-step cutting manoeuvres while electromyography (EMG) activity from 16 muscles of the supporting limb and trunk, kinematics, and ground reaction forces were recorded. Motor modules and their respective temporal activations were extracted from the EMG signals by non-negative matrix factorization. The kinematic analysis provided the velocity of the centre of mass and the external work absorbed during the load acceptance (negative work, external work during absorption (W-Abs)) and propulsion phases (positive work, external work during propulsion (W-Prp)) of the cutting manoeuvres. Five motor modules explained the EMG activity of all muscles and were driven in an impulsive way, with timing related to the initial contact (M2), load acceptance (M3), and propulsion (M4). The variability in timing between impulses across subjects was greater for cutting manoeuvres than for running. The timing difference between M2 and M3 in the cutting manoeuvres was significantly associated to W-Abs (r(2)=0.45) whereas the timing between M3 and M4 was associated to W-Prp (r(2)=0.43). These results suggest that complex locomotor tasks can be achieved by impulsive activation of muscle groups, and that performance is associated to the specific timing of the activation impulses.

Uric acid levels are associated with microvascular endothelial dysfunction in patients with Type 1 diabetes.

AIMS: Recent data identified uric acid as an independent risk factor for cardiovascular disease. The aim of the present study was to assess the association between uric acid and endothelial dysfunction in 57 patients with Type 1 diabetes and 53 healthy control subjects. METHODS: Microvascular endothelial function was evaluated using laser Doppler perfusion monitoring coupled with pharmacological (iontophoretic administration of acetylcholine and sodium nitroprusside) and physiological (post-occlusive reactive hyperaemia and thermal hyperaemia) stimuli. RESULTS: Uric acid was higher in subjects without diabetes than in those with diabetes (P = 0.03). Microvascular vasodilator response to acetylcholine was significantly reduced in Type 1 diabetes (P = 0.002) and was correlated to disease duration (r = -0.3, P = 0.01), triglyceride (r = -0.37, P = 0.005), insulin dose (r = -0.28, P = 0.03), fasting plasma glucose levels (r = -0.3, P = 0.02), HbA(1c) (r = -0.34, P = 0.001) and uric acid (r = -0.3, P = 0.005). On stepwise multivariate analysis, age, HbA(1c) and uric acid were the most important independent variables that were associated with the endothelium-dependent response in Type 1 diabetes (P = 0.02). CONCLUSIONS: Glycaemic control and uric acid in the normal range were the most important contributing factors to the decreasing endothelium-dependent responses associated with Type 1 diabetes. Consequently, uric acid could be a new potential marker of microvascular endothelial dysfunction in these patients. Further studies are required to explore the clinical relevance of the relationship between uric acid levels, oxidative stress and endothelial dysfunction in patients with Type 1 diabetes, as well as whether treatment with uric acid-lowering drugs for slight elevations in uric acid would benefit these patients.

Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi.

Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT-rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD(50) values, good selectivity index, and good activity at 4 °C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection.

Avaliação do potencial alelopático, atividade antimicrobiana e antioxidante dos extratos orgânicos das folhas de Pyrostegia venusta (Ker Gawl. ) Miers (Bignoniaceae) / Evaluation of allelopathic potential, antimicrobial and antioxidant activities of Pyrostegia venusta (Ker Gawl. ) Miers (Bignoniaceae) leaf organic extracts

Este trabalho apresenta os resultados de atividade alelopática, antimicrobiana e antioxidante dos extratos orgânicos (hexano, acetato de etila e metanol) das folhas de Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Para alelopatia, foi estudado o desenvolvimento de Cucumis sativus (pepino), sendo avaliados o comprimento da raiz principal, o número de raízes secundárias e o comprimento do hipocótilo. Os dois primeiros parâmetros foram afetados por todos os três extratos testados enquanto o comprimento do hipocótilo só não foi afetado pelo extrato acetato de etila. Quanto à atividade antimicrobiana, avaliada pelo ensaio de CIM, o extrato hexânico apresentou inibição moderada frente ao Staphylococcus aureus (0,9 mg mL-1) e forte ao Enterococcus hirae (0,5 mg mL-1). O extrato acetato de etila apresentou forte atividade frente Candida albicans (0,3 mg mL-1) enquanto o extrato metanólico não mostrou-se ativo para os microrganismos testados. Por outro lado, o extrato metanólico apresentou a maior capacidade de seqüestrar radicais livres (Concentração Efetiva 50 por cento-CE50 =102,0 ± 56,9 mg mL-1, com TCE50 = 30 min) no ensaio com DPPH (2,2-difenil-1-picril-hidrazila) e o maior teor de compostos fenólicos (116,2 ± 83,0 mg ácido gálico g amostra-1), avaliado pelo ensaio de Folin-Ciocalteau.

This paper presents the results of allelopathic, antimicrobial and antioxidant activities of organic extracts (hexane, ethyl acetate and methanol) from the leaves of Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Allelopathic activity was assessed based on Cucumis sativus (cucumber) development for the parameters main root length, number of secondary roots and hypocotyl length. All tested extracts affected the first two parameters, while the hypocotyl length was not affected only by the ethyl acetate extract. For antimicrobial activity, assessed by MIC assay, hexane extract showed moderate inhibition for Staphylococcus aureus (0.9 mg mL-1) and strong inhibition for Enterococcus hirae (0.5 mg mL-1). Ethyl acetate extract showed strong activity against Candida albicans (0.3 mg mL-1), whereas methanolic extract was not active against the tested microorganisms. On the other hand, methanol extract showed the most promising radical scavenging capacity (Effective Concentration 50 percent - EC50 = 102.0 ± 56.9 mg mL-1, with TEC50 = 30 min) in DPPH assay (2,2-diphenyl-1-picryl-hidrazil) and the highest level of phenolic compounds (116.2 ± 83.0 mg acid garlic g sample-1), as indicated by Folin-Ciocalteau assay.

[Canine visceral leishmaniasis in northeast Brazil: epidemiological aspects]. / La leishmaniose viscérale canine dans le Nord-Est du Brésil: aspects épidémiologiques.

In a rural area of Northeast Brazil, the relatively high serological infection by Leishmania in dogs, the lack of classical vector Lutzomyia longipalpis and of American Visceral Leishmaniasis cases in human beings and the observation of Leishmania in ticks collected in infected dogs suggest that ticks may be responsible for the transmission between dogs.