Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis: development, characterization, biocompatibility, and anti-toxoplasma activity.

Ocular toxoplasmosis is the major cause of infectious posterior uveitis worldwide, inducing visual field defect and/or blindness. Despite the severity of this disease, an effective treatment is still lacking. In this study, spiramycin-loaded PLGA implants were developed aiming at the treatment of ocular toxoplasmosis. Implants were manufactured by a hot-molding technique, characterized by Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Differential Scanning Calorimetry, Scanning Electron Microscopy; evaluated in terms of ocular biocompatibility by immunofluorescence, flow cytometry, cell migration, Hen's egg test-chorioallantoic membrane (HET-CAM) irritation test; and investigated in terms of in vitro efficacy against Toxoplasma gondii . Characterization techniques indicated that spiramycin was dispersed into the polymeric chains and both substances preserved their physical structures in implants. The HET-CAM test indicated that implants did not induce hemorrhage or coagulation, being non-irritant to the CAM. ARPE-19 cells showed viability by MTT assay, and normality in cell cycle kinetics and morphology, without stimulating cell death by apoptosis. Finally, they were highly effective against intracellular parasites without inducing human retinal pigment epithelial cell death. In conclusion, spiramycin-loaded PLGA implants represent a promising therapeutic alternative for the local treatment of ocular toxoplasmosis.

Fractional kinetics on thermal analysis: application to lumefantrine thermal decomposition.

The fractional derivative concept to treat non-isothermal solid state thermal decomposition was employed in this work. Simulated data were compared with the exact solutions for the method validation. Calculated fractional kinetics data for four heating rates were initially considered and the Kissinger-Akahira-Sunose (KAS) method demonstrate that, although the activation energy is not retrieved, it can be useful to determine a single or multistep process. Experimental thermal decomposition data of lumefantrine heated at 5, 10 ,15, and 20 oC min- 1 were fitted for a single-step process. The kinetic parameters were retrieved for integer and fractional kinetics, considering some ideal and general models. Application of the KAS method to these data demonstrated an activation energy dependent on the conversion rate, indicating a multistep process. Five data subintervals were fitted separately using the general model with variable derivative order. It was found a process that occours with integer order derivative until α = 0.3 and fractional order for α > 0.3 with combination of simultaneous reactions, since the parameters do not correspond to any ideal model. The determined activation energies showed the same increasing behavior observed in the KAS approach. The results for multistep process presented an error 102 times smaller if compared with the best result, considering a single-step process. Therefore, the fractional kinetic model presents a powerful extension to the usual thermal data analysis.

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay / Redução da genotoxicidade induzida pela doxorrubicina por Handroanthus impetiginosus na medula óssea de camundongos revelada pelo ensaio do micronúcleo

Abstract Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.

Resumo Handroanthus impetiginosus tem sido usada durante um longo período pela medicina tradicional e vários estudos têm demonstrados a presença de compostos químicos e potencial fitoterapêutico. Esta pesquisa avaliou a genotoxicidade da tintura da casca liofilizada de H. impetiginosus (THI) usando o ensaio do micronúcleo em medula óssea de camundongos. A interação entre THI e os efeitos genotóxicos induzidos pelo quimioterápico doxorrubicina (DXR) também foram analisados. Grupos experimentais foram analisados a 24-48 h após o tratamento com N-Nitroso-N-etiluréia (NEU; 50 mg/kg), DXR (5 mg/kg), NaCl (150 mM) e THI (0,5-2 g/kg). O ensaio antigenotóxico foi conduzido utilizando THI (0,5 g/kg) em combinação com NEU ou DXR. A análise de eritrócitos policromáticos micronucleados (EPCMNs) não mostrou diferenças significativas entre as doses de tratamento (0,5-2 g/kg) e NaCl. As proporções de eritrócitos policromáticos (EPC)/eritrócitos normocromáticos (ENC) não revelaram diferenças estatísticas entre DXR e THI ou NaCl, porém houve diferenças entre THI e NaCl. Uma redução significativa em EPCMNs e na razão EPC/ENC foi observada quando THI foi administrado em combinação com DXR. Essa pesquisa sugere ausência de genotoxicidade de THI, dose-, tempo- e sexo-independente, e moderada toxicidade sistêmica dose-independente, mas tempo- e sexo-dependente. A associação do THI e DXR também sugere efeitos antigenotóxicos. Por conseguinte, THI pode reduzir os efeitos genotóxicos induzidos pelo quimioterapêutico.

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay / Redução da genotoxicidade induzida pela doxorrubicina por Handroanthus impetiginosus na medula óssea de camundongos revelada pelo ensaio do micronúcleo

Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.(AU)

Handroanthus impetiginosus tem sido usada durante um longo período pela medicina tradicional e vários estudos têm demonstrados a presença de compostos químicos e potencial fitoterapêutico. Esta pesquisa avaliou a genotoxicidade da tintura da casca liofilizada de H. impetiginosus (THI) usando o ensaio do micronúcleo em medula óssea de camundongos. A interação entre THI e os efeitos genotóxicos induzidos pelo quimioterápico doxorrubicina (DXR) também foram analisados. Grupos experimentais foram analisados a 24-48 h após o tratamento com N-Nitroso-N-etiluréia (NEU; 50 mg/kg), DXR (5 mg/kg), NaCl (150 mM) e THI (0,5-2 g/kg). O ensaio antigenotóxico foi conduzido utilizando THI (0,5 g/kg) em combinação com NEU ou DXR. A análise de eritrócitos policromáticos micronucleados (EPCMNs) não mostrou diferenças significativas entre as doses de tratamento (0,5-2 g/kg) e NaCl. As proporções de eritrócitos policromáticos (EPC)/eritrócitos normocromáticos (ENC) não revelaram diferenças estatísticas entre DXR e THI ou NaCl, porém houve diferenças entre THI e NaCl. Uma redução significativa em EPCMNs e na razão EPC/ENC foi observada quando THI foi administrado em combinação com DXR. Essa pesquisa sugere ausência de genotoxicidade de THI, dose-, tempo- e sexo-independente, e moderada toxicidade sistêmica dose-independente, mas tempo- e sexo-dependente. A associação do THI e DXR também sugere efeitos antigenotóxicos. Por conseguinte, THI pode reduzir os efeitos genotóxicos induzidos pelo quimioterapêutico.(AU)

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay.

Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay

Abstract Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.

Resumo Handroanthus impetiginosus tem sido usada durante um longo período pela medicina tradicional e vários estudos têm demonstrados a presença de compostos químicos e potencial fitoterapêutico. Esta pesquisa avaliou a genotoxicidade da tintura da casca liofilizada de H. impetiginosus (THI) usando o ensaio do micronúcleo em medula óssea de camundongos. A interação entre THI e os efeitos genotóxicos induzidos pelo quimioterápico doxorrubicina (DXR) também foram analisados. Grupos experimentais foram analisados a 24-48 h após o tratamento com N-Nitroso-N-etiluréia (NEU; 50 mg/kg), DXR (5 mg/kg), NaCl (150 mM) e THI (0,5-2 g/kg). O ensaio antigenotóxico foi conduzido utilizando THI (0,5 g/kg) em combinação com NEU ou DXR. A análise de eritrócitos policromáticos micronucleados (EPCMNs) não mostrou diferenças significativas entre as doses de tratamento (0,5-2 g/kg) e NaCl. As proporções de eritrócitos policromáticos (EPC)/eritrócitos normocromáticos (ENC) não revelaram diferenças estatísticas entre DXR e THI ou NaCl, porém houve diferenças entre THI e NaCl. Uma redução significativa em EPCMNs e na razão EPC/ENC foi observada quando THI foi administrado em combinação com DXR. Essa pesquisa sugere ausência de genotoxicidade de THI, dose-, tempo- e sexo-independente, e moderada toxicidade sistêmica dose-independente, mas tempo- e sexo-dependente. A associação do THI e DXR também sugere efeitos antigenotóxicos. Por conseguinte, THI pode reduzir os efeitos genotóxicos induzidos pelo quimioterapêutico.

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay

Abstract Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.

Resumo Handroanthus impetiginosus tem sido usada durante um longo período pela medicina tradicional e vários estudos têm demonstrados a presença de compostos químicos e potencial fitoterapêutico. Esta pesquisa avaliou a genotoxicidade da tintura da casca liofilizada de H. impetiginosus (THI) usando o ensaio do micronúcleo em medula óssea de camundongos. A interação entre THI e os efeitos genotóxicos induzidos pelo quimioterápico doxorrubicina (DXR) também foram analisados. Grupos experimentais foram analisados a 24-48 h após o tratamento com N-Nitroso-N-etiluréia (NEU; 50 mg/kg), DXR (5 mg/kg), NaCl (150 mM) e THI (0,5-2 g/kg). O ensaio antigenotóxico foi conduzido utilizando THI (0,5 g/kg) em combinação com NEU ou DXR. A análise de eritrócitos policromáticos micronucleados (EPCMNs) não mostrou diferenças significativas entre as doses de tratamento (0,5-2 g/kg) e NaCl. As proporções de eritrócitos policromáticos (EPC)/eritrócitos normocromáticos (ENC) não revelaram diferenças estatísticas entre DXR e THI ou NaCl, porém houve diferenças entre THI e NaCl. Uma redução significativa em EPCMNs e na razão EPC/ENC foi observada quando THI foi administrado em combinação com DXR. Essa pesquisa sugere ausência de genotoxicidade de THI, dose-, tempo- e sexo-independente, e moderada toxicidade sistêmica dose-independente, mas tempo- e sexo-dependente. A associação do THI e DXR também sugere efeitos antigenotóxicos. Por conseguinte, THI pode reduzir os efeitos genotóxicos induzidos pelo quimioterapêutico.

[Pharmaceutical patents and the accessibility of drugs in Brazil]. / Patentes farmaceuticas e acessibilidade aos medicamentos no Brasil.

Passage of Patent Law 9279/96, in effect since April 1997, has made relations between pharmaceutical patents and accessibility to medicine in Brazil complex. Under the new law, patents may extend to chemical inventions (products and process) and transgenic microorganisms. The issue is analyzed from two specific yet inter-related approaches: science and technology policy and health-care policy. The conclusion draws attention to the main future consequences of current international trends, both legal and regulatory. Brazil should ready its legal framework to respond to the negative consequences that genome patenting can be expected to have on the flow of scientific information and on access to pharmaceutical drugs.

An overview of health-related industrial biotechnology in Latin America and the Caribbean.

There is some uncertainty about the extent to which Latin America and the Caribbean have participated in the advances of health-related industrial biotechnology. This article reviews the available literature and seeks to provide an overview of the prevailing situation. In general, national governments and multinational agencies have provided most of the health-related biotechnology investments within this region. Efforts to achieve technology transfers, a subject of prime concern, have been developed by a number of programs including the WHO Special Program for Research and Training in Tropical Diseases, the UNDP/UNESCO/UNIDO Regional Biotechnology Program for Latin America and the Caribbean; PAHO's Program for the Regional Development of Biotechnology as Applied to Health; The PAHO/WHO Expanded Program on Immunization (EPI); and PAHO's Regional System of Vaccines (SIREVA). Regarding current production capacity, some successful efforts have been made to produce a variety of therapeutic products including recombinant and natural interferons, interleukins, insulin, and recombinant streptokinase; but in general the region's current potential in this area is at best incipient and uncertain. However, the region does have a limited ability to make diagnostic products and a well-established capacity for vaccine development. Overall, this picture suggests that the region has the potential to play a small but significant role in health-related biotechnology.

[Assessing the Brazilian network of poison control centers]. / Avaliação da Rede Brasileira de Centros de Controle de Intoxicações a Envenenamento - CCIEs.

General concern about increasing reports of emergencies caused by or attributed to the exposure of human beings to various toxic agents has created demand for assessing the informational performance of a Brazilian network of 34 poison control centers (PCCs), located in different regions of the country and pertaining to the National Poison Information System (SINITOX). The primary purpose of these PCCs is to inform the public, prevent cases of poisoning, and provide medical care. This paper analyzes the available resources for identifying cases of poisoning, preventing new occurrences, and monitoring the consequences of toxic agents. This paper also analyzes data recorded front 1990 to 1992. The objective is to identify the main constraints to using health-data and management information as decision-making tools at the local level.

[Emerging infectious diseases in the realm of complexity: implications for scientific and technological policies]. / Doenças infecciosas emergentes no reino da complexidade: implicações para as políticas científicas e tecnológicas.

The current emergence and global dissemination of some new and resurgent infectious diseases have surpassed national frontiers, increasingly affecting developing and also developed countries. This study stresses that this outburst is affecting the predictability of dominant health transition approaches. This paper analyses, from epistemological and policy viewpoints, alternative approaches in order to confront these new global epidemiological trends.

Effects of methylmercury exposure during the second stage of rapid postnatal brain growth on negative geotaxis and on delta-aminolevulinate dehydratase of suckling rats.

In the present study, we examined the effects of exposure to methylmercury (0, 2.3, 4.6, 6.9 and 9.2 mg/kg, daily for 5 consecutive days, sc) during the second stage of rapid postnatal brain development (8 to 12 days of age) on the sulfhydryl-containing enzyme delta-aminolevulinate dehydratase (ALA-D, E.C. 4.2.1.24) from brain, liver and kidney and on motor performance (latency to complete a negative geotaxis response) of rats. ALA-D specific activity of 13-day old rats of both sexes (7-12 per group) was reduced significantly in rats treated with 6.9 mg/kg and 9.2 mg/kg in brain (about 40%, P < 0.05) and in liver (about 25%, P < 0.05). Renal ALA-D specific activity was not affected by methylmercury treatment. The in vitro IC50 for inhibition of brain, liver and renal ALA-D was 79.3, 81.8 and 39.1 microM, respectively. The latency to complete the negative geotaxis response of 12-day old rats was increased by 6.9 (7.9 +/- 0.7 s, mean +/- SEM) and 9.2 mg/kg methylmercury (7.8 +/- 0.5 s) when compared with control rats (5.8 +/- 0.3 s), suggesting an impairment in motor performance of exposed rats. These results demonstrate that exposure to relatively high doses of methylmercury during the second stage of brain development causes a significant reduction in brain and hepatic ALA-D. The absence of inhibition of ALA-D by lower doses may be related to the relatively low in vitro sensitivity of the enzyme to methylmercury. The possible involvement of ALA-D inhibition on the neurotoxicity of methylmercury deserves additional investigation.

Effects of methylmercury exposure during the second stage of rapid postnatal brain growth on negative geotaxis and on delta-aminolevulinate dehydratase of suckling rats

In the present study, we examined the effects of exposure to methylmercury (0, 2.3, 4.6, 6.9 and 9.2 mg/kg, daily for 5 consecutive days, sc) during the second stage of rapid postnatal brain development (8 to 12 days of age) on the sulfhydryl-containing enzyme delta-aminolevulinate dehydratase (ALA-D, E.C. 4.2.1.24) from brain, liver and kidney and on motor performance (latency to complete a negative geotaxis response) of rats. ALA-D specific activity of 13-day old rats of both sexes (7-12 per group) was reduced significantly in rats treated with 6.9 mg/kg and 9.2 mg/kg in brain (about 40 per cent , P < 0.05) and in liver (about 25 per cent , P < 0.05). Renal ALA-D specific activity was not affected by methylmercury treatment. The in vitro IC50 for inhibition of brain, liver and renal ALA-D was 79.3, 81.8 and 39.1 microM, respectively. The latency to complete the negative geotaxis response of 12-day old rats was increased by 6.9 (7.9 +/- 0.7 s, mean +/- SEM) and 9.2 mg/kg methylmercury (7.8 +/- 0.5 s) when compared with control rats (5.8 +/- 0.3 s), suggesting an impairment in motor performance of exposed rats. These results demonstrate that exposure to relatively high doses of methylmercury during the second stage of brain development causes a significant reduction in brain and hepatic ALA-D. The absence of inhibition of ALA-D by lower doses may be related to the relatively low in vitro sensitivity of the enzyme to methylmercury. The possible involvement of ALA-D inhibition on the neurotoxicity of methylmercury deserves additional investigation