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Os extratos etanólico e hidroalcoólico de Ageratum fastigiatum são usados ​​na medicina popular como agentes antiinflamatório e analgésico. Neste estudo, o extrato etanólico da parte aérea da planta e suas frações foram avaliados quanto à sua toxicidade em Artemia salina e nas células do tecido conjuntivo de camundongos (L929). O extrato foi particionado e suas fases hexânica, diclorometânica e hidroalcoólica foram submetidas ao mesmo teste. A triagem fitoquímica das fases do extrato foi realizada por meio de testes visando a detecção de classes de metabólitos secundários e GC-MS. Em relação a A. salina, a fase hidroalcoólica apresentou a maior toxicidade (CL50, 1,33 mg/mL) e o extrato etanólico bruto foi o menos tóxico (CL50, 4,81 mg / mL). No ensaio de células L929, a fase de diclorometânica foi a mais tóxica (95,48% de redução na viabilidade celular; LC50, 11,39 μg / mL), enquanto a fase hidroalcoólica foi a menos tóxica (porcentagem de morte celular, 55,67% –19,38%; LC50 , 174,20 μg / mL). O estudo fitoquímico indicou a provável presença de alcalóides, cumarinas, saponinas, triterpenos / esteróides e taninos. A análise por GC-MS identificou a presença de terpenóides e um derivado de licopsamina (alcalóide pirrolizidínico). Esses resultados sugerem que o extrato etanólico de A. fastigiatum possui constituintes (ou seja, compostos fenólicos) que corroboram seu uso na medicina popular como agente antiinflamatório. No entanto, a toxicidade detectada e a presença da 3¢-acetil licopsamina (um marcador quimiotaxonômico do gênero, que é hepatotóxico) indicam que essa planta medicinal deve ser usada com cautela.

Most drugs used in therapy have low water-solubility, a factor that could reduce their dissolution rate and oral bioavailability, representing a challenge in pharmaceutical development. Nanonization of drugs is the reduction of particles to nanoscale, increasing the surface area and consequently the saturation solubility and dissolution rate and resulting in higher bioavailability.This review provides an overview of the consequences of the poor water-solubility and the main strategies applied to increase the solubility of poorly water-soluble drugs. The relationship between the biopharmaceutical classification system and the solubilization process of the drug is also considered. Finally, it includes how drug nanoparticles and nanocarriers, especially lipid-based nanosystems, can overcome these challenges and which of these approaches are already available on the market.Due to the growing importance of nanomedicines, especially for applications in poorly water-soluble drugs, it is important to clearly establish the specifications and quality criteria for nanonized drugs to ensure the quality and safety of nanoparticles.

This work proposes a strategy that uses solid-phase peptide synthesis associated with copper(I)-catalyzed azide alkyne cycloaddition reaction to promote the glycosylation of an antimicrobial peptide (HSP1) containing a carboxyamidated C-terminus (HSP1-NH2). Two glycotriazole-peptides, namely [p-Glc-trz-G1]HSP1-NH2 and [p-GlcNAc-trz-G1]HSP1-NH2, were prepared using per-O-acetylated azide derivatives of glucose and N-acetylglucosamine in the presence of copper(II) sulfate pentahydrate (CuSO4·5H2O) and sodium ascorbate as a reducing agent. In order to investigate the synergistic action of the carbohydrate motif linked to the triazole-peptide structure, a triazole derivative [trz-G1]HSP1-NH2 was also prepared. A set of biophysical approaches such as DLS, Zeta Potential, SPR and carboxyfluorescein leakage from phospholipid vesicles confirmed higher membrane disruption and lytic activities as well as stronger peptide-LUVs interactions for the glycotriazole-peptides when compared to HSP1-NH2 and to its triazole derivative, which is in accordance with the performed biological assays: whereas HSP1-NH2 presents relatively low and [trz-G1]HSP1-NH2 just moderate fungicidal activity, the glycotriazole-peptides are significantly more effective antifungal agents. In addition, the glycotriazole-peptides and the triazole derivative present strong inhibition effects on ergosterol biosynthesis in Candida albicans, when compared to HSP1-NH2 alone. In conclusion, the increased fungicidal activity of the glycotriazole-peptides seems to be the result of (A) more pronounced membrane-disruptive properties, which is related to the presence of a saccharide ring, together with (B) the inhibition of ergosterol biosynthesis, which seems to be related to the presence of both the monosaccharide and the triazole rings.

Este artigo apresenta os resultados de um projeto de extensão com experimentação, realizado na cidade de Diamantina, Minas Gerais, nos anos de 2016-2017. O projeto foi operacionalizado por meio de experimentos práticos com o objetivo de incentivar o interesse dos alunos e complementar com atividades experimentais as disciplinas de Física, Química e Biologia no processo de ensino aprendizagem. Teve como público alvo discentes do ensino médio – 1º ao 3º ano – e contou com a participação de 662(seiscentos e sessenta e dois) alunos oriundos das Escolas Estaduais Ayna Torres e Gabriel Mandacaru localizadas na cidade de Diamantina e a Escola Estadual Joviano de Aguiar localizada na cidade de Gouveia, ambas no norte de Minas Gerais. Os resultados apresentam a importância das atividades experimentais para o ensino e aprendizagem de ciências que despertaram a atenção dos alunos, estimulando-os a adotar atitudes críticas diante dos problemas, capazes de desenvolver a capacidade de compreender alguns fenômenos presentes em seu dia a dia e incentivando-os a utilizar esse instrumento para a construção e transmissão de saberes, além de possibilitar a aproximação universidade-comunidade.

Progress toward the improvement of meglumine antimoniate (MA), commercially known as Glucantime, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control of its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl5) or potassium hexahydroxyantimonate [MA-KSb(OH)6] and prepared under a low polymerization state. These compounds were compared to Glucantime regarding chemical composition, permeation properties across a cellulose membrane and Caco-2 cell monolayer, and uptake by peritoneal macrophages. MA-SbCl5 and MA-KSb(OH)6 were characterized as less polymerized and more permeative 2:2 Sb-meglumine complexes than Glucantime, which consisted of a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activities and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as a model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg of body weight/12 h for 30 days significantly reduced spleen and liver parasite burdens, in contrast to those for Glucantime at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl5 given orally was as efficacious as Glucantime by the parenteral route (80 mg Sb/kg/24 h intraperitoneally). These data taken together suggest that treatment with a less-polymerized form of MA by the oral route may be effective for the treatment of VL.

Pentavalent antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, São Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected with Leishmania infantum were treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of pentavalent antimonials with low residue of Sb(III) and the association of pentavalent antimonials with AA, as effective strategies to reduce side effects in antimonial therapy.

A política de medicamentos genéricos foi implantada no Brasil em 1999 com o objetivo de estimular a concorrência comercial, melhorar a qualidade dos medicamentos e facilitar o acesso da população ao tratamento medicamentoso. O processo de implementação dessa política permitiu a introdução e a discussão de conceitos nunca antes utilizados para o registro de medicamentos no Brasil: biodisponibilidade, bioequivalência, equivalência farmacêutica, medicamentos genéricos, sistema de classificação biofarmacêutica e bioisenção. Este artigo apresenta a definição desses conceitos no contexto das leis brasileiras e oferece uma descrição histórica e cronológica da implementação da política de genéricos no Brasil, listando ainda as resoluções que atualmente estão em vigor. Os resultados contribuem para a compreensão do processo e facilitam a busca e a identificação de ensaios necessários para satisfazer os critérios legais.The Brazilian generic drugs policy was implemented in 1999 with the aim of stimulating competition in the market, improve the quality of drugs and improve the access of the population to drug treatment. The process of implementing this policy allowed the introduction and discussion of concepts that had never before been used in the context of drug registration in Brazil: bioavailability, bioequivalence, pharmaceutical equivalence, generic drugs, biopharmaceutical classification system, biowaiver. The present article provides definitions for these concepts in the context of Brazilian legislation as well as a historical and chronological description of the implementation of the generic drugs policy in Brazil, including a list of current generic drug legislation. This article contributes to the understanding of the Brazilian generic drugs policy and facilitates the search for information concerning the legal requirements for registration of drugs in Brazil.

Os antimoniais pentavalentes são fármacos de primeira escolha em vários países do mundo no tratamento das leishmanioses, como é o caso do antimoniato de meglumina no Brasil. Apesar de sua elevada eficácia, a quimioterapia antimonial apresenta importantes limitações, como a necessidade de doses repetidas por via parenteral e graves efeitos colaterais, que limitam a adesão dos pacientes. Os conhecimentos escassos sobre a composição química desses medicamentos e os mecanismos responsáveis pela sua toxicidade dificultam os progressos para a melhoria da quimioterapia antimonial. Buscando estabelecer estratégias para reduzir a toxicidade dos antimoniais pentavalentes durante o tratamento das leishmanioses, investigou-se, a composição química do antimoniato de meglumina, o papel do resíduo de antimônio trivalente (Sb(III)) na hepatotoxicidade deste fármaco em modelo murino de leishmaniose visceral (LV), o efeito do co-tratamento com ácido ascórbico (AA) e o benefício potencial da via de administração oral. A caracterização físico-química de formas sintéticas (AM1 e AM) e comercial (Gluc) do antimoniato de meglumina mostrou a predominância de um complexo Sb-meglumina (2:2) zwiteriônico no AM e AM1 e de um complexo Sb-meglumina (2:3) de carga positiva no Gluc. O teor de Sb(III) determinado por voltametria mostrou, no Gluc, valor correspondente a 24% do Sb total e, no AM1, teor 1,5 vez menor. Os teores de Sb(III) encontrados por fotometria foram muito menores e na seguinte ordem: AM > Gluc > AM1. AM apresentou também teores significativos dos elemento-traços potencialmente tóxicos, Pb e As. Os compostos AM, AM1 e Gluc apresentaram eficácias equivalentes no tratamento parenteral de camundongos Balb/c infectados com L. infantum. Porém, apenas AM e Gluc promoveram hepatotoxicidade, como evidenciada por avaliações histopatológicas e do índice apoptótico dos hepatócitos. O aumento da atividade peroxidase no fígado dos animais tratados com AM e Gluc sugeriu a indução de um estresse oxidativo. A menor hepatotoxicidade do AM1 correlacionou-se com o menor teor de Sb(III) deste composto, indicando que o Sb(III) residual poderia contribuir para a hepatotoxicidade do Gluc. O co-tratamento dos camundongos infectados com AA reduziu significativamente as alterações hepáticas induzidas pelo Gluc, sem comprometer a eficácia do antimonial. Os compostos sintéticos administrados por via oral em camundongos apresentaram uma maior taxa de absorção intestinal e maior concentração hepática de Sb, quando comparados ao Gluc. Os compostos sintéticos mostraram-se ainda mais eficazes por via oral que o fármaco comercial na redução da carga parasitária no baço no modelo murino de LV. Em conclusão, essa tese permitiu identificar três estratégias promissoras para reduzir os efeitos colaterais da quimioterapia antimonial: o uso de antimoniais pentavalentes com baixo teor de Sb(III); o co-tratamento com AA e o uso da via de administração oral para a LV. Pentavalent antimonials are the first-line drugs in several countries worldwide for treatment of leishmaniasis, as it is the case of meglumine antimoniate in Brazil. Despite its high efficacy, antimonial chemotherapy shows important limitations, such as the need for repeated parenteral doses and several side effects that limit patient compliance. The scarce knowledge about the chemical composition of these drugs and the mechanisms responsible for their toxicity has also hindered progress towards the improvement of antimonial chemotherapy. In the search for strategies to reduce pentavalent antimony toxicity during leishmaniasis treatment, we investigated the chemical composition of meglumine antimoniate, the role of residual trivalent antimony (Sb(III)) in the drug hepatotoxicity in a murine model of visceral leishmaniasis (VL), the effect of co-treatment with the antioxidant ascorbic acid (AA) and the potential benefit of the oral route of administration. The physicochemical characterization of the synthetic (AM1 and AM) and commercial (Gluc) forms of meglumine antimoniate showed the predominance of a zwitterionic 2:2 Sbmeglumine complex in AM1 and AM and of a positively-charged 2:3 Sb-meglumine complex in Gluc. The Sb(III) content determined by voltammetry showed, in Gluc, 24% of total Sb and, in AM1, 1.5 times lower level. The Sb(III) contents found by photometry were much smaller and in the following order: AM > Gluc > AM1. AM also showed significant levels of the potentially toxic trace elements, Pb and As. The compounds AM, AM1 and Gluc showed equivalent antileishmanial efficacies following parenteral treatment in BALB/c mice infected with L. infantum. However, only AM and Gluc promoted hepatotoxicity, as evidenced by histopathological analysis and apoptotic index of hepatocytes. The increase of peroxidase activity in the liver of animals treated with AM and Gluc suggested an induction of oxidative stress. The lower hepatotoxicity of AM1 correlated with its lower level of Sb(III), indicating that the residual Sb(III) may contribute to Gluc hepatotoxicity. The cotreatment of infected mice with AA significantly reduced the hepatotoxicity of Gluc, without compromising its antileishmanial efficacy. AM and AM1 given orally to mice showed a higher rate of intestinal absorption and an increased hepatic concentration of Sb, when compared to Gluc. The synthetic compounds showed higher effectiveness by the oral route than the commercial drug, when evaluating the supression of spleen parasite in mice infected with L. infantum. In conclusion, this thesis identified three promising strategies to reduce the side effects of antimonial chemotherapy: the use of pentavalent antimony with low content of Sb(III), the cotreatment with AA and the use of the oral route for treatment of the LV.

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.

Trivalent antimonial drugs, including tartar emetic (TA), are known to induce important cardiotoxicity observed by electrocardiographic abnormalities. Liposome encapsulation was found to reduce the overall acute toxicity of TA. The present work investigated the cardiovascular parameters alterations of rats submitted to the treatment with free and encapsulated TA in long-circulating liposomes. Liposomes were made using lipids DSPC, DSPE-PEG and cholesterol. The cardiovascular signals, electrocardiogram (ECG) and arterial blood pressure (AP), were recorded from anaesthetized Wistar rats after intravenous (IV) administration of a single specially high dose (17 mg/kg) of TA in liposomes and in free form. The IV administration of TA solution caused significant increase of QT interval of ECG and significant reduction of AP when compared to the control group. These alterations were not observed when liposomes TA were administered and the profile of ECG and AP data was quite similar to the control groups. In conclusion, a liposomal formulation of TA showed a reduced cardiotoxic profile for TA when compared to the free form.

The Brazilian generic drugs policy was implemented in 1999 with the aim of stimulating competition in the market, improve the quality of drugs and improve the access of the population to drug treatment. The process of implementing this policy allowed the introduction and discussion of concepts that had never before been used in the context of drug registration in Brazil: bioavailability, bioequivalence, pharmaceutical equivalence, generic drugs, biopharmaceutical classification system, biowaiver. The present article provides definitions for these concepts in the context of Brazilian legislation as well as a historical and chronological description of the implementation of the generic drugs policy in Brazil, including a list of current generic drug legislation. This article contributes to the understanding of the Brazilian generic drugs policy and facilitates the search for information concerning the legal requirements for registration of drugs in Brazil.

The Brazilian generic drugs policy was implemented in 1999 with the aim of stimulating competition in the market, improve the quality of drugs and improve the access of the population to drug treatment. The process of implementing this policy allowed the introduction and discussion of concepts that had never before been used in the context of drug registration in Brazil: bioavailability, bioequivalence, pharmaceutical equivalence, generic drugs, biopharmaceutical classification system, biowaiver. The present article provides definitions for these concepts in the context of Brazilian legislation as well as a historical and chronological description of the implementation of the generic drugs policy in Brazil, including a list of current generic drug legislation. This article contributes to the understanding of the Brazilian generic drugs policy and facilitates the search for information concerning the legal requirements for registration of drugs in Brazil.