In controlled release applications a drug is molecularly dispersed in a polymer phase. In the presence of a thermodynamically compatible solvent, swelling occurs and the polymer releases its content to the surrounding medium. The rate of the drug release can be controlled by interfering with the swelling rate of the beads or by influencing diffusion through the viscosity of the polymer. Beads that contain chitosan were prepared through the ionotropic gelation method where tripolyphosphate (TPP) was used as the crosslinking agent. Beads that consisted of 3% w/v isoniazid (lNH) and 5% w/v chitosan were prepared in a 5% w/v TPP solution (pH 8.7) as the primary beads. To improve the drug loading of chitosan isoniazid beads (ClB) the TPP concentration, pH of the TPP solution and the INH concentrations were altered for maximum drug loading. To increase the porosity of the beads of chitosan beads Explotab® (EXPL), Ac-Di-Sol® (ADS) and Vitamin C (VC) were added individually to chitosan solutions at concentrations of 0.1, 0.25 and 0.5% w/v before adding the mixture to the TPP solution. Morphology, swelling and drug loading studies were used to evaluate the different formulations. After these excipients were added individually they were also added in combinations of two excipients respectively and characterised. From the results of the drug loading studies the beads that contained only chitosan and isoniazid showed a percentage drug loading of (43.92%) which is the best of all the beads that were analyzed. The multi excipient combination of Ac-Di-Sol® and Explotab® showed the best swelling capability at both pH levels. Dissolution studies were conducted on all the formu lations over a period of 6 hours (360 minutes) at pH 5.6 and pH 7.4. From the dissolution results it were clear that no chitosan dissolved at both pH values. The dissolution of single pharmaceutical excipient (SPE) and multi pharmaceutical excipient (MPE) formulations can be arranged in the following order: VC/ADS < VC < ADS/EXPL < ADS < VC/EXPL < CIB < EXPL. Explotab® is a potential excipient for enhanced drug release over a wide pH range. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

A tuberculose, causada por Mycobacterium tuberculosis, ainda é uma emergência de saúde pública global. O surgimento das cepas multirresistentes (MDR) e das cepas extensivamente resistentes (XDR) agravam a situação, diminuindo o número de fármacos disponíveis para o tratamento. Embora a isoniazida seja uma das primeiras moléculas introduzidas no tratamento da tuberculose, diferentes mecanismos de resistência têm sido propostos e o tema ainda não foi totalmente esclarecido. Neste trabalho foi realizada a caraterização estrutural e biofísica de 7 mutantes da proteína InhA identificadas a partir de isolados clínicos de M. tuberculosis resistentes à isoniazida. Os ensaios de calorimetria de titulação isotérmica (ITC) mostram diminuições nos valores da constante de dissociação (Kd) dos mutantes para os NADH em aproximadamente cinco vezes quando comparado com a proteína selvagem. As estruturas cristalográficas dos mutantes de InhA mostram novas moléculas de água que parecem estar envolvidas nas variações entrópicas e entálpicas observadas em dados calorimétricos. Estes resultados corroboram e sugerem que a diminuição na afinidade pelo NADH e a desestabilização do tetrâmero de InhA podem ser fenômenos associados a resistência à isoniazida. / Tuberculosis, caused by the infection of Mycobacterium tuberculosis, still remains as a global health emergency. The emergence of multidrug-resistant strains (MDR) and extensively drug-resistant strains (XDR) strains further aggravates the crisis, reducing the limited number of drugs available for the treatment of the disease. Even though isoniazid was one of the first drugs introduced in the antitubercular therapy, many resistance mechanisms were proposed and the subject is still not clear. In this work, a structural and biophysical characterization of seven mutant InhA proteins identified in clinical M. tuberculosis strains resistant to isoniazid were performed. Isothermal titration calorimetry (ITC) assays showed a decrease in the dissociation constant (Kd) values of the InhA mutants by up to almost five-fold when compared to the wild-type protein. Crystallographic structures of InhA mutants showed new water molecules that appear to be involved in the entropic and enthalpic variations described by the thermodynamic assays. These results corroborate and suggest that the decrease in affinity for NADH and the destabilization of the InhA tetramer may be the phenomena associated to isoniazid resistance.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As leishmanioses são um grupo de doenças causadas por protozoários do gênero Leishmania spp que afetam 98 países. No Brasil, no ano de 2013, foram relatados 3.253 casos de leishmaniose visceral e 18.226 casos de Leishmaniose Tegumentar Americana. O tratamento de primeira escolha continua sendo realizado com antimoniais pentavalentes, e em casos de insucessos os fármacos de segunda escolha são a pentamidina e a anfotericina B. Tais medicamentos causam intensos efeitos adversos e ultimamente têm surgido cepas resistentes aos mesmos. Em áreas endêmicas têm sido cada vez mais comum o surgimento da co-infecção Leishmania com Mycobacterium tuberculosis. O tratamento para a tuberculose com pirazinamida (PZA) e isoniazida (INZ), controla a leishmaniose. Esses dados sugerem atividade anti-leishmania da PZA e da INZ. O objetivo deste trabalho foi avaliar a atividade in vitro da INZ e da PZA e seus compostos derivados (série G e série R, respectivamente) sobre Leishmania (Viannia) braziliensis. As moléculas foram testadas em monocamadas de macrófagos peritoneais de camunongos infectados com L. (V) braziliensis durante 48h. Todas as moléculas testadas inibiram o índice de infecção de forma dose dependente em comparação aos controles. As moléculas da série R foram mais ativas do que a PZA, porém o resultado foi significativo somente para a R02 (p < 0,005). Apenas a molécula R05 (76,64M) foi relativamente tóxica para macrófagos. Os compostos mais ativos foram R02, G01 e G02, cujos índices de seletividade foram 14,31, 19 e 30, respectivamente. A dosagem de nitrito foi feita em sobrenadantes de monocamadas de macrófagos peritoniais infectados e tratados com as substâncias nas concentrações 10 e 100M. A G01 e a G02 estimularam a produção de NO2 nas duas concentrações, entretanto o resultado foi estatisticamente significativo para a G02 em 100M (p < 0,0001), a G05 só estimulou óxido nítrico na maior concentração. Todos os compostos da série R estimularam NO2, contudo, o resultado foi estatisticamente significativo para a R03 e R05 a 100M (p < 0,001). Adicionalmente, foi realizado uma análise preditiva in sílico de parâmetros farmacocinéticos das moléculas mais ativas in vitro, utilizando o software admetSAR. Os dados obtidos mostraram que de forma semelhante às suas moléculas originais a G01, G02 e R02 apresentaram alta capacidade de serem absorvidas pelo trato gastrointestinal, baixo potencial hepatotoxico e carcinogênico. Juntos, esses dados demonstram que essas moléculas são seletivamente tóxicas para o parasito com potencial para serem testadas pela via oral em estudos em modelo experimental de infecção. / Leishmaniasis are a group of diseases caused by protozoan of genus Leishmania spp affecting of 98 countries. In Brazil, in the year 2013 were 3.253 reported cases of visceral leishmaniasis and 18.226 cases of cutaneous leishmaniasis. The first choice of treatment is still performed with pentavalent antimonials and in cases of failures drugs of second line of treatment are pentamidine and anfotericin B. These drugs cause many adverse effects and has lately emerged resistant strains. In endemic areas it has been increasingly common the appearance of co-infection Leishmania and Mycobacterium tuberculosis. The treatment of tuberculosis with pyrazinamid and isoniazid control the leishmaniasis.The aim of this study was evaluate the anti-leishmania activity in vitro of INZ and PZA and yours derivatives compounds (serie G and serie R,respectively) on the Leishmania (Viannia) braziliensis. The molecules were tested on infected monolayers of peritoneal murine macrophages for 48h. All the molecules te inhibited the infection index in a dose-dependent manner in relation to controls. The molecules of the R series were more active than PZA, but the result was only significant for R02 (p < 0,005). Only R05 (CC50 = 76,64M) was relatively toxic to macrophages. The most active compounds were R02, G01 and G02 whose select index were 14,31, 19 and 30, respectively. Nitrite assay was performed in supernatants of infected monolayers of peritonial macrophages treated with the substancies at 10 and 100M. G01 and G02 stimulated NO2 prodution, however, the result was only statistically significant for G02 at 100M (p < 0,001). All the compounds of R serie stimulated NO2 production however the results were statistically significant for the R03 and R05 at 100M (p < 0,001). Additionally, a in silico preditive pharmacokinetic analysis was performed to active molecules using the admetSAR software the data showed that G01, G02 and R02 were similar to their original molecules as to high capacity to be absorbed by the gastrointestinal tract, low hepatotoxic and carcinogenic potencial. Together, these data demonstrate that these molecules are selectively toxic to the parasite with the potencial to be tested orally on studies in experimental infection.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Preventative interventions often demand that resources be consumed in the present in exchange for future benefits. Cost-effectiveness analysis is a tool to understand these trade-offs, and inform decision-making under resource constraints. Targeted testing and treatment (TTT) for latent tuberculosis infection (LTBI) consists in identifying people at high risk for LTBI for preventive treatment to decrease the risk of active tuberculosis disease (ATBD). The state of Tennessee began conducting TTT statewide in 2001. This study uses a decision tree to evaluate the cost and outcomes of TTT for LTBI in Tennessee, compared to passive ATBD case finding (PACF). Key probabilities were obtained from the Tennessee TTT program and the literature. Outcomes are measured in terms of Quality Adjusted Life Years (QALY). The cost-effectiveness threshold was $100,000/QALY saved. One-way sensitivity analyses around factors related to study design, the program’s environment, and program performance were conducted, as was probabilistic sensitivity analysis (PSA) which takes into account the uncertainty in multiple parameters simultaneously. The base case, with a 25-year analytic horizon and 3% discount rate, shows that TTT prevents 47 ATBD cases, and saves 31 QALYs per 100,000 patients screened at a societal cost of $12,579 per QALY saved. Sensitivity analyses identified value thresholds that would trigger a change in preferred policy. PSA shows that the likelihood that TTT would be cost-effective is low. Decision makers should carefully assess the characteristics of the local TB epidemic and expected program performance to determine whether TTT is preferable over PACF from a cost-effectiveness viewpoint.

In controlled release applications a drug is molecularly dispersed in a polymer phase. In the presence of a thermodynamically compatible solvent, swelling occurs and the polymer releases its content to the surrounding medium. The rate of the drug release can be controlled by interfering with the swelling rate of the beads or by influencing diffusion through the viscosity of the polymer. Beads that contain chitosan were prepared through the ionotropic gelation method where tripolyphosphate (TPP) was used as the crosslinking agent. Beads that consisted of 3% w/v isoniazid (lNH) and 5% w/v chitosan were prepared in a 5% w/v TPP solution (pH 8.7) as the primary beads. To improve the drug loading of chitosan isoniazid beads (ClB) the TPP concentration, pH of the TPP solution and the INH concentrations were altered for maximum drug loading. To increase the porosity of the beads of chitosan beads Explotab® (EXPL), Ac-Di-Sol® (ADS) and Vitamin C (VC) were added individually to chitosan solutions at concentrations of 0.1, 0.25 and 0.5% w/v before adding the mixture to the TPP solution. Morphology, swelling and drug loading studies were used to evaluate the different formulations. After these excipients were added individually they were also added in combinations of two excipients respectively and characterised. From the results of the drug loading studies the beads that contained only chitosan and isoniazid showed a percentage drug loading of (43.92%) which is the best of all the beads that were analyzed. The multi excipient combination of Ac-Di-Sol® and Explotab® showed the best swelling capability at both pH levels. Dissolution studies were conducted on all the formu lations over a period of 6 hours (360 minutes) at pH 5.6 and pH 7.4. From the dissolution results it were clear that no chitosan dissolved at both pH values. The dissolution of single pharmaceutical excipient (SPE) and multi pharmaceutical excipient (MPE) formulations can be arranged in the following order: VC/ADS < VC < ADS/EXPL < ADS < VC/EXPL < CIB < EXPL. Explotab® is a potential excipient for enhanced drug release over a wide pH range. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

The aim of this in vitro study was to investigate the feasibility of the transdermal delivery of isoniazid (INH) and rifampicin (RMP) by means of the novel PheroidTM technology system. 'The application of the latter is being investigated in combination with various actives such as peptides (insulin, human growth hormone), anti-malarial drugs (chloroquine), anti-fungals (ketoconazole), local anaesthetics (lidocaine, prilocaine) as well as tuberculostatics (ethambutol, pyrazinamide etc.) via different administration routes at the North- West University. PheroidTM, a stable skin-friendly carrier, comprises of a submicron (200 nm - 2 m) emulsion type formulation for which previous studies have confirmed the ability to penetrate keratinised tissue, skin, intestinal linings, the vascular system, fungi, bacteria and even parasites. Studies involving an oral PheroidTM formulation containing the current approved regime of four anti-tuberculosis drugs showed improved efficacy results whilst an in vitro analysis of bacterial growth indicated a reduction in drug resistance in multidrug resistant tuberculosis (MDR-TB) strains. Therefore we thought it prudent to ascertain whether or not the PheroidTM system would be able to improve the transdermal delivery of a combination of INH and RMP as a possible treatment against cutaneous tuberculosis (tuberculosis involving the skin). The latter refers to pathological lesions of the skin caused by any one of the following: Mycobacterium tuberculosis, Mycobacterium bovis or the bacilli Calmette- Guerin (BCG) vaccine. Demonstration of M. tuberculosis within the infected tissues by traditional acid-fast bacilli (AFB) staining, culture or polymerase chain reaction (PCR) confirms the diagnosis. CTB lesions are associated with various degrees of one or more of the following ulceration, plaque formation, hyperkeratosis or the presence of necrotic matter. Seeing as C-TB is mostly associated with systemic involvement, current treatment comprises of the standard three/four drug regimens used for pulmonary 'TB in general. Cases of CTB usually show improvement within 1 month of therapy with anti-TB drugs, but complete resolution is only attained after 4 - 6 months. 'The major drawback to current therapy is that patients not only remain a source of infection (viable organisms can still be demonstrated in the lesions), but they also suffer from constant embarrassment due to the disfiguring nature of CTB until these lesions have healed completely. No evidence of an already existing topical formulation of this kind could be found. Therefore in vitro permeation studies were conducted using vertical Franz diffusion cells and female abdominal skin as permeation membrane over a period of 12 hours. Concentrations of 5 mg/ml and 10 mg/ml for isoniazid( INH) and rifampicin (RMP) respectively, were applied to the donor phase suspended in either phosphate buffered saline (PBS) or entrapped in PheroidTM. Permeation studies were conducted at pH 5.5. In vitro penetration of INH and RMP were assayed directly by HPLC. Particle size distribution for rifampicin and entrapment of actives within the PheroidTM carrier system was determined by polarized light and laser scanning microscopy (CLSM) respectively and revealed definite entrapment. Permeation profiles obtained for INH in PheroidTM indicated a biphasic character, whilst that obtained for RMP in PheroidTM showed a triphasic character. The PheroidTM delivery system proved more efficacious for delivery of both anti-tubercular drugs and resulted in greater percentage yield as well as flux values than that for a PBS solution. Furthermore, the PheroidTM formulation was able to deliver, the entrapped INH and RMP in concentrations sufficient to exceed their respective minimum inhibitory concentrations (MIC). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

The aim of this in vitro study was to investigate the feasibility of the transdermal delivery of isoniazid (INH) and rifampicin (RMP) by means of the novel PheroidTM technology system. 'The application of the latter is being investigated in combination with various actives such as peptides (insulin, human growth hormone), anti-malarial drugs (chloroquine), anti-fungals (ketoconazole), local anaesthetics (lidocaine, prilocaine) as well as tuberculostatics (ethambutol, pyrazinamide etc.) via different administration routes at the North- West University. PheroidTM, a stable skin-friendly carrier, comprises of a submicron (200 nm - 2 m) emulsion type formulation for which previous studies have confirmed the ability to penetrate keratinised tissue, skin, intestinal linings, the vascular system, fungi, bacteria and even parasites. Studies involving an oral PheroidTM formulation containing the current approved regime of four anti-tuberculosis drugs showed improved efficacy results whilst an in vitro analysis of bacterial growth indicated a reduction in drug resistance in multidrug resistant tuberculosis (MDR-TB) strains. Therefore we thought it prudent to ascertain whether or not the PheroidTM system would be able to improve the transdermal delivery of a combination of INH and RMP as a possible treatment against cutaneous tuberculosis (tuberculosis involving the skin). The latter refers to pathological lesions of the skin caused by any one of the following: Mycobacterium tuberculosis, Mycobacterium bovis or the bacilli Calmette- Guerin (BCG) vaccine. Demonstration of M. tuberculosis within the infected tissues by traditional acid-fast bacilli (AFB) staining, culture or polymerase chain reaction (PCR) confirms the diagnosis. CTB lesions are associated with various degrees of one or more of the following ulceration, plaque formation, hyperkeratosis or the presence of necrotic matter. Seeing as C-TB is mostly associated with systemic involvement, current treatment comprises of the standard three/four drug regimens used for pulmonary 'TB in general. Cases of CTB usually show improvement within 1 month of therapy with anti-TB drugs, but complete resolution is only attained after 4 - 6 months. 'The major drawback to current therapy is that patients not only remain a source of infection (viable organisms can still be demonstrated in the lesions), but they also suffer from constant embarrassment due to the disfiguring nature of CTB until these lesions have healed completely. No evidence of an already existing topical formulation of this kind could be found. Therefore in vitro permeation studies were conducted using vertical Franz diffusion cells and female abdominal skin as permeation membrane over a period of 12 hours. Concentrations of 5 mg/ml and 10 mg/ml for isoniazid( INH) and rifampicin (RMP) respectively, were applied to the donor phase suspended in either phosphate buffered saline (PBS) or entrapped in PheroidTM. Permeation studies were conducted at pH 5.5. In vitro penetration of INH and RMP were assayed directly by HPLC. Particle size distribution for rifampicin and entrapment of actives within the PheroidTM carrier system was determined by polarized light and laser scanning microscopy (CLSM) respectively and revealed definite entrapment. Permeation profiles obtained for INH in PheroidTM indicated a biphasic character, whilst that obtained for RMP in PheroidTM showed a triphasic character. The PheroidTM delivery system proved more efficacious for delivery of both anti-tubercular drugs and resulted in greater percentage yield as well as flux values than that for a PBS solution. Furthermore, the PheroidTM formulation was able to deliver, the entrapped INH and RMP in concentrations sufficient to exceed their respective minimum inhibitory concentrations (MIC). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Orientador: Valdecir Farias Ximenes / Banca: Rosângela Gonçalves Peccinini Machado / Banca: Regina Lúcia Moraes Moreau / Resumo: Este trabalho teve como objetivo estudar os efeitos da rifampicina (RMP) sobre os parâmetros farmacocinéticos da isoniazida (INH), sobre a produção de seus metabólitos e sobre a sua hepatotoxicidade. Foram utilizados 140 ratos (Wistar, machos, peso médio 250g) que receberam, por gavagem, durante 21 dias: Grupo I - água estéril (n = 20); Grupo II - INH (100mg/Kg) (n = 50); Grupo III - RMP (100mg/Kg) (n = 20) e Grupo IV- INH (100mg/Kg) + RMP (100mg/Kg) ( n= 50). Anteriormente ao início do experimento, o sangue de todos os animais foi coletado pela cauda para determinação da atividade sérica de AST e ALT, cujos valores foram considerados como basais. No 21o do experimento os animais foram sacrificados por decapitação e o material biológico obtido foi utilizado para a determinação da atividade de AST e ALT e para a análise dos parâmetros farmacocinéticos da INH nos grupos II e IV. A cinética da isoniazida e de seus metabólitos foi investigada com base na relação concentração plasmática x tempo a partir de amostras seriadas de sangue em 10 tempos diferentes (0; 15þ; 30þ; 45þ; 60þ; 1,5h; 3h; 6h; 12h; e 24h); para cada tempo de coleta foram empregados 5 ratos (5 replicatas). As amostras de soro foram desproteinizadas com ácido tricloroacético 10%, derivatizeda com cinamaldeído 1% e analisada por HPLC...(Resumo completo, clicar acesso eletrônico abaixo). / Abstract: The aim of the present study was to evaluate the hepatotoxicity, pharmacokinetic parameters and biotransformation of isoniazid when rats were treated with isoniazid (INH); rifampicin (RMP); and INH + RMP. Daily doses of the tuberculostatic drugs were administrated intragastrically to the animals (Wistar rats) for one period of 21 days as follow: sterile water (group I, control); INH (100mg/Kg) (group II), RMP (100mg/Kg) (group III); INH (100mg/Kg) + RMP (100mg/Kg) (group IV). The serum levels of the biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined before the administration of the drugs (basal) and after the 21 days treatments. On day 21, blood samples were obtained before and 15þ; 30þ; 45þ; 60þ; 1,5; 3h; 6h; 12h and 24 hours after the dose. (five animals for each point). The blood samples were deproteinized with 10% trichloroacetic acid, derivatized by 1% cinnamaldehyde and analyzed by liquid chromatograph. For the determination of the acetylated metabolites acetylisoniazid (AcINH) and acetylhydrazine (AcHz) a previous hydrolysis with 6 M hydrochloride acid was performed. The results are presented as mean and SEM. The pharmacokinetic parameter of the INH and its metabolites AcINH and hydrazine (Hz) were compared between the groups (p < 0.05, Student t-test)...(Complete abstract, click electronic address below). / Mestre

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As leishmanioses são um grupo de doenças causadas por protozoários do gênero Leishmania spp que afetam 98 países. No Brasil, no ano de 2013, foram relatados 3.253 casos de leishmaniose visceral e 18.226 casos de Leishmaniose Tegumentar Americana. O tratamento de primeira escolha continua sendo realizado com antimoniais pentavalentes, e em casos de insucessos os fármacos de segunda escolha são a pentamidina e a anfotericina B. Tais medicamentos causam intensos efeitos adversos e ultimamente têm surgido cepas resistentes aos mesmos. Em áreas endêmicas têm sido cada vez mais comum o surgimento da co-infecção Leishmania com Mycobacterium tuberculosis. O tratamento para a tuberculose com pirazinamida (PZA) e isoniazida (INZ), controla a leishmaniose. Esses dados sugerem atividade anti-leishmania da PZA e da INZ. O objetivo deste trabalho foi avaliar a atividade in vitro da INZ e da PZA e seus compostos derivados (série G e série R, respectivamente) sobre Leishmania (Viannia) braziliensis. As moléculas foram testadas em monocamadas de macrófagos peritoneais de camunongos infectados com L. (V) braziliensis durante 48h. Todas as moléculas testadas inibiram o índice de infecção de forma dose dependente em comparação aos controles. As moléculas da série R foram mais ativas do que a PZA, porém o resultado foi significativo somente para a R02 (p < 0,005). Apenas a molécula R05 (76,64M) foi relativamente tóxica para macrófagos. Os compostos mais ativos foram R02, G01 e G02, cujos índices de seletividade foram 14,31, 19 e 30, respectivamente. A dosagem de nitrito foi feita em sobrenadantes de monocamadas de macrófagos peritoniais infectados e tratados com as substâncias nas concentrações 10 e 100M. A G01 e a G02 estimularam a produção de NO2 nas duas concentrações, entretanto o resultado foi estatisticamente significativo para a G02 em 100M (p < 0,0001), a G05 só estimulou óxido nítrico na maior concentração. Todos os compostos da série R estimularam NO2, contudo, o resultado foi estatisticamente significativo para a R03 e R05 a 100M (p < 0,001). Adicionalmente, foi realizado uma análise preditiva in sílico de parâmetros farmacocinéticos das moléculas mais ativas in vitro, utilizando o software admetSAR. Os dados obtidos mostraram que de forma semelhante às suas moléculas originais a G01, G02 e R02 apresentaram alta capacidade de serem absorvidas pelo trato gastrointestinal, baixo potencial hepatotoxico e carcinogênico. Juntos, esses dados demonstram que essas moléculas são seletivamente tóxicas para o parasito com potencial para serem testadas pela via oral em estudos em modelo experimental de infecção. / Leishmaniasis are a group of diseases caused by protozoan of genus Leishmania spp affecting of 98 countries. In Brazil, in the year 2013 were 3.253 reported cases of visceral leishmaniasis and 18.226 cases of cutaneous leishmaniasis. The first choice of treatment is still performed with pentavalent antimonials and in cases of failures drugs of second line of treatment are pentamidine and anfotericin B. These drugs cause many adverse effects and has lately emerged resistant strains. In endemic areas it has been increasingly common the appearance of co-infection Leishmania and Mycobacterium tuberculosis. The treatment of tuberculosis with pyrazinamid and isoniazid control the leishmaniasis.The aim of this study was evaluate the anti-leishmania activity in vitro of INZ and PZA and yours derivatives compounds (serie G and serie R,respectively) on the Leishmania (Viannia) braziliensis. The molecules were tested on infected monolayers of peritoneal murine macrophages for 48h. All the molecules te inhibited the infection index in a dose-dependent manner in relation to controls. The molecules of the R series were more active than PZA, but the result was only significant for R02 (p < 0,005). Only R05 (CC50 = 76,64M) was relatively toxic to macrophages. The most active compounds were R02, G01 and G02 whose select index were 14,31, 19 and 30, respectively. Nitrite assay was performed in supernatants of infected monolayers of peritonial macrophages treated with the substancies at 10 and 100M. G01 and G02 stimulated NO2 prodution, however, the result was only statistically significant for G02 at 100M (p < 0,001). All the compounds of R serie stimulated NO2 production however the results were statistically significant for the R03 and R05 at 100M (p < 0,001). Additionally, a in silico preditive pharmacokinetic analysis was performed to active molecules using the admetSAR software the data showed that G01, G02 and R02 were similar to their original molecules as to high capacity to be absorbed by the gastrointestinal tract, low hepatotoxic and carcinogenic potencial. Together, these data demonstrate that these molecules are selectively toxic to the parasite with the potencial to be tested orally on studies in experimental infection.