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Pinto, Leonardo Santos Ribeiro [UNESP]. "Síntese, atividade antibacteriana e farmacocinética pré-clínica de pró-fármaco do etambutol com potencial terapêutico para meningite tuberculosa." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/96243.
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O etambutol é preconizado no tratamento da meningite tuberculosa sempre associado a outro fármaco tuberculostático. Mas, embora útil quanto à sua ação, o fármaco não atravessa satisfatoriamente a barreira hematoencefálica. Desta forma, este trabalho propôs a síntese e caracterização estrutural de um pró-fármaco de etambutol (DEREMB) para melhorar a sua penetração no SNC; assim como a realização de estudos de atividade antibacteriana, estabilidade in vitro e ex vivo e, ainda, investigação da disposição cinética do composto; comparando-a com a do etambutol, em ratos wistar (machos, n=20, peso~200g) tratados com dose única via endovenosa (25 mg/kg) e via gavagem (100 mg/kg). A modificação molecular do etambutol alterou a lipossolubilidade do composto, expressa pelo log P, aumentando a possibilidade de penetração no sistema nervoso central, e o aumento da permeabilidade celular, haja vista que o DEREMB apresentou atividade, ainda que menor contra o M. tuberculosis quando comparada ao fármaco matriz. Os resultados obtidos nos ensaios de hidrólise em diferentes pHs (1,2 e 7,4) e na submissão à ação de enzimas plasmáticas permitem observar estabilidade do produto no período de 24 horas. Os parâmetros farmacocinéticos expressos através das médias (IC95%) foram: DEREMB (endovenoso): Cmax (ug/mL)= 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0-µ(ug/mL.min)= 294,3; Vd (L/kg)=4,3 ; CIT (mL/min/kg)=86,4 ; t ½ (min) =43,1;b (min-1)= 0,021. As baixas concentrações plasmáticas obtidas na administração oral do DEREMB não permitiram o calculo do parâmetros farmacocinéticos por esta via. Apenas os parâmetros Cmax e Vd do DEREMB não apresentaram diferenças estatísticas significativas quando comparados ao etambutol
Ethambutol is a tuberculostatic drug indicated for tuberculous meningitis treatment. But, although useful as for its action, the drug does not cross the blood-brain barrier satisfactorily; certainly reducing its effectiveness in the treatment of the tuberculous meningitis. In this way, this work proposed the synthesis and structural characterization of a prodrug of ethambutol (DEREMB) to improve its penetration in SNC; as well as the accomplishment of studies of antibacterial activity, in vitro and ex vivo stability studies and, still, the investigation of the kinetic disposition of the compound comparing it with the pharmacokinetic profile of ethambutol, in rats wistar (males, n=20, weigth~200g) treated with single iv dose(25 mg/kg) and by gavage (100 mg/kg). The produced prodrug presents a greater lipophilicity – expressed by logp - what could increase its permeation through the blood-brain barrier and its cellular permeability, once the DEREMB presented antimycobacterial activity, although smaller when compared to ethambutol. The in vitro and ex vivo (plasma) hydrolysis studies demonstrates that ethambutol derivative is stable and is not converted to ethambutol in the different pHs which occur in digestory tract or by plasmatic enzymes.. The pharmacokinetic parameters of DEREMB (iv) were: Cmax (ug/mL) = 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0 - (ug/mL.min) = 294,3; Vd (L/kg)=4,3; CIT (mL/min/kg)=86,4; t ½ (min) =43,1; (min-1) = 0,021. The low plasmatic concentrations obtained in the oral administration of DEREMB did not allow to calculate its pharmacokinetic parameters. Only Cmax and Vd parameters of DEREMB did not present significant statistical differences when compared to ethambutol
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Pinto, Leonardo Santos Ribeiro. "Síntese, atividade antibacteriana e farmacocinética pré-clínica de pró-fármaco do etambutol com potencial terapêutico para meningite tuberculosa /." Araraquara : [s.n.], 2010. http://hdl.handle.net/11449/96243.
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Resumo: O etambutol é preconizado no tratamento da meningite tuberculosa sempre associado a outro fármaco tuberculostático. Mas, embora útil quanto à sua ação, o fármaco não atravessa satisfatoriamente a barreira hematoencefálica. Desta forma, este trabalho propôs a síntese e caracterização estrutural de um pró-fármaco de etambutol (DEREMB) para melhorar a sua penetração no SNC; assim como a realização de estudos de atividade antibacteriana, estabilidade in vitro e ex vivo e, ainda, investigação da disposição cinética do composto; comparando-a com a do etambutol, em ratos wistar (machos, n=20, peso~200g) tratados com dose única via endovenosa (25 mg/kg) e via gavagem (100 mg/kg). A modificação molecular do etambutol alterou a lipossolubilidade do composto, expressa pelo log P, aumentando a possibilidade de penetração no sistema nervoso central, e o aumento da permeabilidade celular, haja vista que o DEREMB apresentou atividade, ainda que menor contra o M. tuberculosis quando comparada ao fármaco matriz. Os resultados obtidos nos ensaios de hidrólise em diferentes pHs (1,2 e 7,4) e na submissão à ação de enzimas plasmáticas permitem observar estabilidade do produto no período de 24 horas. Os parâmetros farmacocinéticos expressos através das médias (IC95%) foram: DEREMB (endovenoso): Cmax (ug/mL)= 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0-µ(ug/mL.min)= 294,3; Vd (L/kg)=4,3 ; CIT (mL/min/kg)=86,4 ; t ½ (min) =43,1;b (min-1)= 0,021. As baixas concentrações plasmáticas obtidas na administração oral do DEREMB não permitiram o calculo do parâmetros farmacocinéticos por esta via. Apenas os parâmetros Cmax e Vd do DEREMB não apresentaram diferenças estatísticas significativas quando comparados ao etambutolAbstract: Ethambutol is a tuberculostatic drug indicated for tuberculous meningitis treatment. But, although useful as for its action, the drug does not cross the blood-brain barrier satisfactorily; certainly reducing its effectiveness in the treatment of the tuberculous meningitis. In this way, this work proposed the synthesis and structural characterization of a prodrug of ethambutol (DEREMB) to improve its penetration in SNC; as well as the accomplishment of studies of antibacterial activity, in vitro and ex vivo stability studies and, still, the investigation of the kinetic disposition of the compound comparing it with the pharmacokinetic profile of ethambutol, in rats wistar (males, n=20, weigth~200g) treated with single iv dose(25 mg/kg) and by gavage (100 mg/kg). The produced prodrug presents a greater lipophilicity - expressed by logp - what could increase its permeation through the blood-brain barrier and its cellular permeability, once the DEREMB presented antimycobacterial activity, although smaller when compared to ethambutol. The in vitro and ex vivo (plasma) hydrolysis studies demonstrates that ethambutol derivative is stable and is not converted to ethambutol in the different pHs which occur in digestory tract or by plasmatic enzymes.. The pharmacokinetic parameters of DEREMB (iv) were: Cmax (ug/mL) = 10,4; AUC 0-t(ug/mL.min)=252,7; AUC 0 - (ug/mL.min) = 294,3; Vd (L/kg)=4,3; CIT (mL/min/kg)=86,4; t ½ (min) =43,1; (min-1) = 0,021. The low plasmatic concentrations obtained in the oral administration of DEREMB did not allow to calculate its pharmacokinetic parameters. Only Cmax and Vd parameters of DEREMB did not present significant statistical differences when compared to ethambutol
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Tshoko, Siphokazi. "Spectroelectrochemical graphene-silver/zinc oxide nanoparticulate phenotype biosensors for ethambutol and pyrazinamide." University of the Western Cape, 2019. http://hdl.handle.net/11394/6842.
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>Magister Scientiae - MScTuberculosis (TB), a deadly disease second to HIV/AIDS, is a global health problem. Diagnosis of active tuberculosis is tedious and requires expensive procedures since there is no recognizable method for sole detection of active TB. Although this is a deadly disease, treatment drug toxicity is also an issue that also causes fatalities in diagnosed patients. Therefore, a rapid sensitive and specific diagnostic method is imperative for TB drug management. In this study spectroscopic and/or electrochemical biosensors were developed for the detection and quantification of TB treatment drugs. The biosensors were constructed with electroactive layers of graphene oxide coupled to silver nanoparticles and/or zinc oxide nanoparticles. These nanoparticles coupled with graphene oxide sheets were covalently attached onto the enzymes such as Cytochrome P450-2D6 to achieve the electrochemical detection of the TB treatment drugs and obtain the required electron transfer between the electrode surface and enzyme. The surface morphology of graphene oxide, nanoparticles as well as the green synthesized nanocomposites were achieved using High-Resolution Transmission Electron Microscopy (HRTEM), Atomic Force Microscopy (AFM), and High- Resolution Scanning Electron Microscopy (HRSEM) while the elemental analysis were obtained using Fourier Transform Infrared Spectroscopy (FTIR), Energy Dispersive X-Ray (EDX), Raman spectroscopy and X-Ray diffraction (XRD). Additionally, the optical properties of the developed nanocomposites where further characterised using Small Angle X-ray Scattering (SAXS), Photoluminescence Spectroscopy (PL) and Ultraviolet Spectroscopy (UV-vis). The electrochemical studies were obtained using cyclic voltammetry (CV) and showed an increase in electron conductivity for the green synthesized zinc oxide nanoparticles coupled with graphene oxide (ZnONPs/GO) and silver nanoparticles coupled with graphene oxide (AgNPs/GO) nanocomposite which was an indication that they were suitable as platforms towards biosensor development. Furthermore, amperometric technique was also used for biotransformation of the TB treatment drugs (Ethambutol and Pyrazinamide) in standard solutions of 0.1 M phosphate buffer (pH 7.0). Furthermore, the sensitivity value of 0.0748 μA/μM was determined for the ethambutol biosensor while a value of 0.1715 μA/μM was determined for the pyrazinamide biosensors. Very good detection limits were obtained for the standard solutions of ethambutol and pyrazinamide where a value of 0.02057 nM was determined for ethambutol at concentration linear range of 50 μM – 400 μM. Additionally, a value of 0.8975 x 10-2 nM was determined for pyrazinamide at the concentration linear range of 100 μM – 300 μM. The determined limit of detections have provided a clear indication that these biosensors have potential of being used in human samples since these values are below the peak serum concentrations of these drugs in TB diagnosed patients as reported in literature. This was further confirmed by the limit of quantification values determined for each biosensor where a value of 0.8975 x 10-2 nM was determined for pyrazinamide and a value of 0.02057 nM was determined for ethambutol.
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Nyo, Mi Swe Pisamai Kulkanjanatorn. "Spectral characteristics of ethambutol-copper (II) ion complex and its application for quantitative analysis /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd405/4837396.pdf.
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McIlleron, Helen. "Determinants and consequences of the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in a cohort of tuberculosis patients." Doctoral thesis, University of Cape Town, 2004. http://hdl.handle.net/11427/3290.
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Includes bibliographical references (leaves 190-203).A prospectlve pharmacokinetic study was conducted amongst a cohort of 142 patients with tuberculosis (TB) susceptible to rifampicin and isoniazid at Brewelsleloof Hospital, Worcester, in the Western Cape.
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MARQUES, Priscila Rocha de Lima. "Efeitos adversos decorrentes do uso de fármacos antituberculose do es-quema quádruplo em serviço de referência da Paraíba." Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/17703.
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Objetivo: Descrever as reações adversas decorrentes do uso dos fármacos antituberculose do novo esquema preconizado pelo Ministério da Saúde (rifampicina, isoniazida, pirazinamida e etambutol) utilizando comprimidos em dose fixa combinada. Métodos: Estudo descritivo utilizando dados coletados em prontuários médicos de pacientes com tuberculose pulmonar tratados com esquema básico no serviço de referência para tuberculose da Paraíba no período de 2010-2014. Resultados: A amostra foi composta por 257 pacientes com tuberculose pulmonar e houve reação adversa em 71 pacientes (27,63%) totalizando 118 eventos. Esses eventos dividiram-se em reações menores e maiores respectivamente 47,9% e 43,7%, e em 8,5% dos casos, ocorreram ambas as reações. O sistema mais comprometido foi o gastrointestinal em 68,4%, seguido pelo osteoarticular em 13,56%. A hepatotoxicidade foi isoladamente a reação adversa mais comum (30,5%). A toxicidade visual ocorreu em apenas um paciente (0,38%). Houve necessidade de suspender o tratamento em 7,39% e de troca de esquema terapêutico em 1,95%. A frequência de reações adversas observada com o novo esquema foi inferior a de outros estudos nacionais e semelhante aos estudos que utilizaram o esquema antigo. Conclusão: As reações adversas foram principalmente alterações gastrointestinais, sendo a mais comum a hepatotoxicidade. Houve apenas um caso de alteração visual. Na maioria dos casos, não houve necessidade de suspensão nem troca do tratamento.
Objective: To describe the adverse reactions due to the use of antituberculosis drugs under the new regimen recommended by the Health Ministry (rifampicin, isoniazid, pyrazinamide and ethambutol) using tablets in fixed doses combination. Methods: A descriptive study using data collected from medical records of patients with pulmonary tuberculosis treated with basic outline reference service of tuberculosis in Paraíba during the period from 2010 to 2014. Results: The sample consisted of 257 patients with pulmonary tuberculosis, and adverse effects occurred in 71 patients (27.63%) totalizing 118 events. These events were divided into smaller and bigger reactions respectively 47.9% and 43.7%, and in 8.5% of the cases both reactions occurred. The most compromised system was the gastrointestinal at 68.4%, followed by osteoarticular at 13.56%. The hepatotoxicity alone was the most common adverse reaction (30.5%). The visual toxicity occurred in only one patient (0.38%). It was necessary to discontinue the treatment in 7.39% and change the regimen for 1.95%. The frequency of adverse reactions observed with the new scheme was lower than other national studies and similar to studies that used the old scheme. Conclusion: The adverse reactions were mainly gastrointestinal disorders, being hepatotoxicity the most common one, there was only one case of visual change. In most cases there was no need to suspend neither to change the treatment.
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Estop, Valérie. "Toxicologie de l'éthambutol." Paris 5, 1988. http://www.theses.fr/1988PA05P139.
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Nieuwoudt, Liezl-Marié. "The impact of PheroidTM technology on the bioavailability and efficacy of anti-tuberculosis drugs in an animal model / L. Nieuwoudt." Thesis, North-West University, 2009. http://hdl.handle.net/10394/4316.
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Rassie, Candice. "Electrochemical cytochrome P450 enzymatic biosensors for the determination of the reactivity of TB drugs." University of Western Cape, 2020. http://hdl.handle.net/11394/7235.
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Philosophiae Doctor - PhDTuberculosis (TB) remains a global epidemic despite the fact that treatment has been available since the 1950’s. This disease is highly contagious and spreads via transmission of the Mycobacterium Tuberculosis (MTB) tubercle via coughing, sneezing and spitting. The disease has various side effects including weight loss, fatigue and even death. To date no cure has been found for TB and thus optimisation of treatment is a constant focus in health related research. TB is highly prevalent in South Africa due to the increased level of patients who are co-infected with HIV. Treatment for TB consists of first line drugs including isoniazid (INH), ethambutol (ETH), pyrazinamide (PYR) and rifampicin (RIF). These drugs are highly effective but also produce many adverse drug reactions (ADR’s) over the 6-month course of treatment. These reactions lead to patients not completing the course, losing quality of life and ultimately adding to the development of drug resistant strains of TB. A method of minimising these ADR’s is the development of a phenotype sensor, which is able to determine the metabolic profile of patients. Metabolic profiles play a huge role in the efficacy of treatment by tailoring treatment in order for patients to stay within the therapeutic range of treatment. This would in turn minimise both toxicity and ineffective treatment. Various methods for the quantification of drugs have been developed such as high performance liquid chromatography (HPLC), mass spectrometry (MS) and ultra-violet visible spectroscopy (UV-vis).
2023-12-01
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Lopez, Marcos. "Novel Diazeniumdiolates Nitric Oxide Donors and Devices for Biomedical Applications." University of Akron / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=akron1134746253.
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Faugeroux, Vanessa. "Vers de nouveaux inhibiteurs glycosyltransférases : synthèse asymétrique de C-alkyliminosucres et d'analogues de l'éthambutol." Toulouse 3, 2007. http://www.theses.fr/2007TOU30009.
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Lima, Patrícia Condé. "Desenvolvimento de um método de análise para a determinação simultânea do teor de Rifampicina, Isoniazida, Pirazinamida e Etambutol em comprimidos 4 em 1 utilizados no tratamento da tuberculose." Instituto Nacional de Controle de Qualidade em Saúde, 2014. https://www.arca.fiocruz.br/handle/icict/8647.
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Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Química. Rio de Janeiro, RJ, Brasil.
Oscomprimidosutilizadosno tratamento da tuberculose possuem quatro fármacos associados, Isoniazida(INH), Pirazinamida(PYA), Etambutol(EMB) e Rifampicina(RMP) e são distribuídos gratuitamente pelo Sistema Único de Saúde. Até o momento, os métodos analíticos oficiais para a análise dos teores dos fármacos presentes neste medicamento de dose fixa combinada são aqueles especificados na Farmacopeia Americana 36ª edição e na Farmacopeia Internacional 4ª edição. Porém, nenhum destes compêndios oficiais possui monografias para análise simultânea dos quatro fármacos. O desenvolvimento de métodos analíticos adequados para determinar simultaneamente as concentrações dos quatro fármacos em comprimidos dose fixa combinada é de grande importância para o controle da qualidade do medicamento em questão. O objetivo deste estudo foi desenvolver um método analítico para determinar simultaneamente todos os princípios ativos do comprimido para o tratamento da tuberculose por cromatografia a líquido de alta eficiência com detector de ultravioleta-visível. O método desenvolvido utilizou uma coluna cromatográfica com fase estacionária octadecilsila no, 250mm de comprimento, 4,6mm de diâmetro e5 μm de tamanho de partícula e fase móvel constituída de uma fase aquosa(85% tampão formiato de amônio 0,3 mol/L pH 5, 15%metanol e 0,005 mol/L de Cu2+ou 250 mg/L de CuSO4.5H2O) e fase orgânica(metanol, 0,1% de trietilamina e 0,2% de ácido fórmico). O fluxo empregado foi de 1,0 mL/min e comprimento de onda265 nm, quando o software do equipamento permitiu, para a INH, PYA e o EMB um comprimento de onda de 265 e de 335 nm para a RMP. Este estudo demonstrou que o método desenvolvido apresentou linearidade entre 0,05 a 0,10 mg/mL para INH, 0,27 a 0,52 mg/mL para PYA, 0,19 a 0,36 mg/mL para EMB e 0,05 a 0,1 mg/mL para RMPe mostrou-se satisfatório quanto ao parâmetro de precisão, com desvio padrão relativo inferior a 2,0% para os quatro fármacos estudados.
Tablets used to treat tuberculosis contain four drugs, isoniazid (INH), pyrazinamide (PYA), ethambutol (EMB) and rifampicin (RMP) and are freely distributed by the National Health System. So far, the official analytical methods for testing the amount of the ingredients present in the fixed-dose combination tablet are those described in the 36th editionof U.S. Pharmacopeia and in the 4th editionof International Pharmacopoeia. However, none of these official compendium present monographs for the simultaneous analysis of the four drugs. The development of suitable analytical methods for simultaneously determining the concentrations of the four drugs in fixed-dose combination tablets is of great importance to the quality control of the medicinal product concerned. The aim of this study was to develop an analytical method to simultaneously determine all the active ingredients of the tablet for tuberculosis treatment by high-performance liquid chromatography with ultraviolet-visible detector. The developed method used a chromatographic column with octadecylsilane stationary phase, with 250mm length, 4,6mm diameter and 5 μm particle size. The mobile phase was aqueous (85% ammonium formate buffer 0,3 mol/LpH 5, 15% methanol and 0,005 mol/Lof Cu2+or250 mg/LCuSO4.5H2O), and the organic phase(methanol, 0,1% triethylamine and 0,2 % formic acid). The used flow was 1,0mL/min, at a wavelength of 265 nm or when the equipment alloweda wavelength of 265 nm for INH, EMB, and PYA and 335nmfor RMP. This study showned that the developed method was linear from 0,05 to 0,10 mg/mL for INH, 0,27 to 0,52 mg/mL for PYA, 0,19 to 0,36 mg/mL for EMB and 0,05 to0,1 mg/mL for RMP and was satisfactory regarding the precision parameter, with relative standard deviation lower than 2,0 % for the four studied drugs.
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Ngece, Rachel Fanelwa. "Nanoparticulate of silver-modified poly (8-anilino-1-naphthalene sulphonic acid) nanobiosensor systems for the determination of Tuberculosis treatment drugs." Thesis, University of the Western Cape, 2011. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_8724_1320925367.
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This study firstly reports the development and characterization of PVP-AgNPs, PANSA and PVPAgNPs/ PANSA nanocomposite on gold. AFM and TEM analyses revealed highly electroactive nanocomposites whose morphogy and properties were essential for the immobilization of CYP2E1. Secondly, the development and characterization of Au/PVPAgNPs/ PANSA/CYP2E1, Au/PVP-AgNPs/PANSA/SA-CYP2E1 and Au/PVPAgNPs/ PANSA/EG-CYP2E1 nanobiosensors are reported. AFM studies displayed globular morphologies with large roughness for the enzyme modified electrodes as opposed to those electrodes without enzymes. Finally, the biotransformation of standard solutions of TB drugs (isoniazid, ethambutol, pyrazinamide and rifampicin) in pH 7.4, 0.1 M phosphate buffer solution is reported. The biotransformations of the TB drugs were successfully studied using cyclic voltammetry (CV), square wave voltammetry (SWV), differential voltammetry (DPV) and steady state amperometry under aerobic conditions. Very good detection limits were obtained for the standard solutions of TB drugs and were found to be in the micromolar range. The detection limit values for the individual TB drugs were 0.55 μM (isoniazid), 0.7 μM (ethambutol), 0.054 μM (pyrazinamide) and 0.05 μM (rifampicin). The detection limit results showed that the nanobiosensors were more sensitive and suitable for the determination of the respective drugs in plasma and serum.
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Lavor, Edilene Pereira. "Estudo de pr?-formula??o para dose fixa combinada dos tuberculost?ticos rifampicina, isoniazida, pirazinamida e etambutol (4 em 1)." Universidade Federal do Rio Grande do Norte, 2010. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13458.
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Previous issue date: 2010-02-26According to the global framework regarding new cases of tuberculosis, Brazil appears at the 18th place. Thus, the Ministry of Health has defined this disease as a priority in the governmental policies. As a consequence, studies concerning treatment and prevention have increased. Fixed-dose combination formulations (FDC) are recognized as beneficial and are recommended by WHO, but they present instability and loss on rifampicin bioavailability. The main purpose of this work was to carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs: rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients (lactose, cellulose, magnesium stearate and talc), in order to develop an FDC product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250 mg of ethambutol). The studies consisted of the determination of particle size and distribution (Ferret s diameter) and shape through optical microscopy, as well as rheological and technological properties (bulk and tapped densities, Hausner Factor, Carr s Index, repose angle and flux rate) and interactions among drugs and drug excipient through thermal analysis (DSC, DTA, TG and your derivate). The results showed that, except isoniazid, the other drugs presented poor rheological properties, determined by the physical characteristics of the particles: small size and rod like particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol, beyond its low density. The 4 drug mixture also not presented flowability, particularly that one containing drug quantity indicated for the formulation of FDC products. In this mixture, isoniazid, that has the best flowability, was added in a lower concentration. The addition of microcrystalline cellulose, magnesium stearate and talc to the drug mixtures improved flowability properties. In DSC analysis probable interactions among drugs were found, supporting the hypothesis of ethambutol and pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3- formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the mixtures containing lactose Supertab? DSC curves evidenced incompatibility among drugs and excipient. In the DSC curves of mixtures containing cellulose MC101?, magnesium stearate and talc, no alterations were observed comparing to the drug profiles. The TG/DTG of the binary and ternary mixtures curves showed different thermogravimetrics profiles relating that observed to the drug isolated, with the thermal decomposition early supporting the evidences of incompatibilities showed in the DSC and DTA curves
De acordo com o quadro mundial da tuberculose, o Brasil ocupa o 18? lugar em n?mero de casos novos, assim o Minist?rio da Sa?de definiu a doen?a como prioridade entre as Pol?ticas Governamentais de Sa?de. Desde ent?o se intensificaram os estudos relacionados ao tratamento e preven??o desta doen?a. As formula??es em dose fixa combinada (DFC) s?o reconhecidas como ben?ficas e apoiadas pela OMS, mas apresentam problemas de instabilidade e queda na biodisponibilidade da rifampicina. O objetivo principal desse trabalho foi realizar estudo de pr?-formula??o com os f?rmacos que integram o esquema 1 para o tratamento da tuberculose: rifampicina, isoniazida, pirazinamida e etambutol e excipientes farmac?uticos (lactose, celulose, estearato de magn?sio e talco), visando o desenvolvimento de um produto em dose fixa combinada (150 mg de rifampicina + 75 mg de isoniazida + 400 mg de pirazinamida + 250 mg de etambutol). Os estudos consistiram na determina??o do tamanho e distribui??o das part?culas (di?metro de Ferret) e forma por microscopia ?ptica, al?m das propriedades reol?gicas e tecnol?gicas (densidades aparente e de compacta??o, Fator de Hausner, ?ndice de Carr, ?ngulo de repouso e velocidade de escoamento) e das intera??es entre os f?rmacos e f?rmacos-excipientes por an?lise t?rmica (DSC, DTA, TG e sua derivada). Os resultados mostraram que ? exce??o da isoniazida, os demais f?rmacos apresentaram propriedades reol?gicas pobres, determinadas pelas caracter?sticas f?sicas das part?culas: tamanho reduzido e forma de agulhas da rifampicina; forma retangular da pirazinamida e etambutol, al?m da baixa densidade deste ?ltimo. A mistura dos quatro ativos tamb?m n?o apresentou fluxo, especialmente a prepara??o contendo a quantidade de f?rmacos preconizada para a formula??o de produtos em dose fixa combinada, uma vez que nessa mistura, a isoniazida, que possui o melhor fluxo, foi adicionada a uma concentra??o menor. A adi??o de celulose microcristalina, estearato de magn?sio e talco ?s misturas dos f?rmacos, melhorou as propriedades de fluxo. Nas an?lises por DSC foram encontradas prov?veis intera??es entre as subst?ncias ativas, refor?ando a hip?tese de cat?lise por etambutol e pirazinamida para a rea??o entre rifampicina e isoniazida que resulta no produto de degrada??o 3-(isonicotinoilhidrazinometil)rifamicina. Nas curvas de DSC das misturas contendo lactose Supertab? foi evidenciada a ocorr?ncia de incompatibilidade entre os f?rmacos e o excipiente. As curvas de DSC das misturas contendo celulose MC101?, estearato de magn?sio e talco n?o apresentaram altera??es em rela??o ao perfil dos f?rmacos. As curvas de TG/DTG das misturas bin?rias e tern?rias apresentaram perfis termogravim?tricos diferentes em rela??o ao observado para os f?rmacos isoladamente, com in?cio da decomposi??o t?rmica antecipada, dando suporte as evid?ncias de incompatibilidades encontradas nas curvas de DSC e DTA
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Oliveira, Severina Denise Sales de. "Aplica??o das t?cnicas eletroanal?ticas (voltametria c?clica e de pulso diferencial) usando o eletrodo de diamante dopado com boro para o estudo da isoniazida, etambutol, rifampicina e pirazinamida." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17761.
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Previous issue date: 2013-07-31Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
In this work a study was done using electrochemical cyclic voltammetry and differential pulse voltammetry for isoniazida (INH), ethambutol (EMB), rifampicina (RIF) and pyrazinamide (PZA) using the electrode boron-doped diamond (BDD) as working electrode. It also verified the applicability of the technique of differential pulse voltammetry in the quantification of the active compounds used in the treatment of tuberculosis, subsequently applying in samples of pharmaceutical formulation. Among the four active compounds studied, isoniazid showed the best results for the detection and quantification using differential pulse voltammetry. At pH 4 and pH 8, for the calibration curves to INH showed good linearity, with quantification limits of 6.15 mmol L-1 (0,844 ppm) and 4.08 mmol L-1 (0.560 ppm) for the respective pH. The proposed method can be used to determine drug isoniazid, for recovery values were obtained in approximately 100%
Neste trabalho foi feito um estudo eletroqu?mico utilizando a voltametria c?clica e voltametria de pulso diferencial para os f?rmacos isoniazida (INH), etambutol (EMB), rifampicina (RIF) e pirazinamida (PZA) usando o eletrodo de diamante dopado com boro (BDD) como eletrodo de trabalho. Foi tamb?m verificado a aplicabilidade da t?cnica de voltametria de pulso diferencial na quantifica??o dos princ?pios ativos usados no tratamento da tuberculose, posteriormente aplicando em amostras de formula??o farmac?utica. Dentre os quatro princ?pios ativos estudados, a isoniazida apresentou os melhores resultados de detec??o e quantifica??o com o uso da voltametria de pulso diferencial. Em pH 4 e pH 8, as curvas de calibra??o para a INH apresentaram boa linearidade, apresentando os limites de quantifica??o de 6,15 μmol L-1 (0,844 ppm) e 4,08 μmol L-1 (0,560 ppm), para os respectivos pH. O m?todo proposto pode ser usado para a determina??o de isoniazida em f?rmacos, pois foram obtidos valores de recupera??o em torno de 100%
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Clewe, Oskar. "Novel Pharmacometric Methods for Informed Tuberculosis Drug Development." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-303872.
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With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens. The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens. With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.
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Chen, Chunli. "Pharmacokinetic-Pharmacodynamic Evaluations and Experimental Design Recommendations for Preclinical Studies of Anti-tuberculosis Drugs." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-318845.
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Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.
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Faria, Adriana Ferreira. "Desenvolvimento, otimização e validação de metodologias por eletroforese capilar para análise de fármacos utilizados no tratamento da tuberculose." Universidade Federal de Juiz de Fora (UFJF), 2010. https://repositorio.ufjf.br/jspui/handle/ufjf/4460.
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CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
O objetivo principal da tese em questão foi o desenvolvimento, otimização e validação de metodologias analíticas para análise de formulações farmacêuticas utilizadas no tratamento da tuberculose, as quais contêm como princípio ativo etambutol (ETB), isoniazida (ISO), rifampicina (RIF) e pirazinamida (PIR), isolados ou em associação. Inicialmente, duas metodologias analíticas para análise de ETB em comprimidos foram desenvolvidas: a primeira permitiu a análise simultânea de ETB e da impureza 2-amino-1-butanol por eletroforese capilar de zona (CZE) utilizando um eletrólito de corrida contendo 60,0 mmol L-1 de tampão ácido acético/acetato de sódio e 5,0 mmol L-1 de Cu2+, polaridade normal (+25 kV) e detecção UV em 262 nm. A segunda foi realizada por espectrofotometria com diluição dos padrões e amostras em 5,0 mmol L-1 de tampão ácido acético/acetato de sódio e 0,5 mmol L-1 de Cu2+ e detecção UV em 262 nm. A formação do complexo CuETB foi necessária em ambas as metodologias desenvolvidas, uma vez que ETB apresenta baixa absortividade molar. Algumas figuras de mérito, tais como, linearidade, repetitividade, exatidão, limite de detecção e limite de quantificação foram avaliadas para as duas metodologias. Os dois métodos foram comparados e não apresentaram diferenças significativas no intervalo de 95% usando o teste t não pareado com variância agrupada. Em um segundo momento, um novo método para análise simultânea de dose fixa combinada (DFC), contendo ETB, ISO, RIF e PIR por CZE com detecção UV foi desenvolvido, otimizado e validado. A condição experimental consistiu em um eletrólito contendo 50,0 mmol L-1 de tampão ácido acético/acetato de sódio e 12,5 mmol L-1 de Cu2+ e polaridade normal (+22 kV). Essa metodologia foi aplicada com sucesso na análise de 2-DFC (ISO e PIR) em comprimidos e 4-DFC (ETB, ISO, RIF e PIR) em sache. Finalmente, uma metodologia por CZE utilizando detecção UV para a análise simultânea de ISO, suas impurezas e produtos de degradação, como o ácido isonicotínico, isonicotinato de etila, 4-cianopiridina e isonicotinamida foi otimizada. A condição experimental consistiu em um eletrólito contendo 50,0 mmol L-1 de tampão ácido acético/acetato de sódio e 12,5 mmol L-1 de Cu2+, polaridade normal (+20 kV) e detecção UV em 270 nm. É importante ressaltar que planejamentos de experimentos, tais como, planejamento fatorial completo 32 e Box-Behnken 33 foram utilizados como ferramenta auxiliar no desenvolvimento e otimização das metodologias analíticas (CZE e espectofotométrica) e na avaliação da robustez para a análise de 4-DFC.
The main focus of this thesis was the development, optimization and validation of analytical methodologies for analysis of pharmaceutical preparations used for tuberculosis treatment, which contain as active ingredients, ethambutol (ETB), isoniazid (ISO), rifampicin (RIF) and pyrazinamide (PYR) isolated or in association. Two analytical methodologies for ETB analysis in tablets were developed initially: the first one took into account the capillary zone electrophoresis (CZE) approach for simultaneous analysis of ETB and its impurity 2-amino-1-butanol using an electrolyte consisting of 60.0 mmol L-1 of acetic acid/acetate buffer, 5.0 mmol L-1 of Cu2+, under normal polarity (+25 kV) and UV detection at 262 nm. The second one was performed by spectrophotometry using 5.0 mmol L-1 of acetic acid/acetate buffer and 0.5 mmol L-1 of Cu2+ for standards and sample dilutions under UV detection at 262 nm. The CuETB complex was necessary for the two methodologies, since ETB presents low molar absorptivity. Some merit figures such as linearity, repeatability, accuracy, limit of detection and limit of quantification were evaluated for both methodologies. These methodologies were compared and they did not present significant differences at the 95% confidence level using the parametric independent sample t test. In a second phase a novel method for the simultaneous analysis of fixed dose combination (FDC) containing ETB, ISO, RIF and PYR by CZE under UV detection was developed, optimized and validated. The experimental condition optimized consisted of an electrolyte containing 50.0 mmol L-1 of acetic acid/acetate buffer and 12.5 mmol L-1 of Cu2+ under normal polarity (+22 kV). This methodology was successfully applied to the analysis of 2-FDC (ISO and PYR) in tablet samples and 4-FDC (ETB, ISO, RIF and PYR) in a sachet sample. Finally, a CZE methodology using UV detection for simultaneous analysis of ISO, its impurities and degradation products such as isonicotinic acid, ethyl isonicotinate, 4-cyanopyridine and isonicotinamide was ptimized. The optimized experimental condition consisted of an electrolyte containing 50.0 mmol L-1 of acetic acid/acetate buffer and 12.5 mmol L-1 of Cu2+ under normal polarity (+20 kV) and UV detection at 270 nm. It is important to stress that design of experiment such as 32 full factorial design and 33 Box-Behnken design were used as auxiliary tools in the development and optimization of the analytical methodologies (CZE and spectrophotemetric) and robustness evaluation for 4-FDC analysis.
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Paiva, Marcelo Vitor de. "Otimiza??o e valida??o de m?todos anal?ticos para a determina??o simult?nea de tuberculost?ticos (4-FDC) por CLAE/DAD e CLUE/ DAD." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13477.
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Previous issue date: 2013-03-21Tuberculosis is a serious disease, but curable in practically 100% of new cases, since complied the principles of modern chemotherapy. Isoniazid (ISN), Rifampicin (RIF), Pyrazinamide (PYR) and Chloride Ethambutol (ETA) are considered first line drugs in the treatment of tuberculosis, by combining the highest level of efficiency with acceptable degree of toxicity. Concerning USP 33 - NF28 (2010) the chromatography analysis to 3 of 4 drugs (ISN, PYR and RIF) last in average 15 minutes and 10 minutes more to obtain the 4th drug (ETA) using a column and mobile phase mixture different, becoming its industrial application unfavorable. Thus, many studies have being carried out to minimize this problem. An alternative would use the UFLC, which is based with the same principles of HPLC, however it uses stationary phases with particles smaller than 2 ?m. Therefore, this study goals to develop and validate new analytical methods to determine simultaneously the drugs by HPLC/DAD and UFLC/DAD. For this, a analytical screening was carried out, which verified that is necessary a gradient of mobile phase system A (acetate buffer:methanol 94:6 v/v) and B (acetate buffer:acetonitrile 55:45 v/v). Furthermore, to the development and optimization of the method in HPLC and UFLC, with achievement of the values of system suitability into the criteria limits required for both techniques, the validations have began. Standard solutions and tablets test solutions were prepared and injected into HPLC and UFLC, containing 0.008 mg/mL ISN, 0.043 mg/mL PYR, 0.030 mg.mL-1 ETA and 0.016 mg/mL RIF. The validation of analytical methods for HPLC and UFLC was carried out with the determination of specificity/selectivity, analytical curve, linearity, precision, limits of detection and quantification, accuracy and robustness. The methods were adequate for determination of 4 drugs separately without interfered with the others. Precise, due to the fact of the methods demonstrated since with the days variation, besides the repeatability, the values were into the level required by the regular agency. Linear (R> 0,99), once the methods were capable to demonstrate results directly proportional to the concentration of the analyte sample, within of specified range. Accurate, once the methods were capable to present values of variation coefficient and recovery percentage into the required limits (98 to 102%). The methods showed LOD and LOQ very low showing the high sensitivity of the methods for the four drugs. The robustness of the methods were evaluate, facing the temperature and flow changes, where they showed robustness just with the preview conditions established of temperature and flow, abrupt changes may influence with the results of methods
A tuberculose ? uma doen?a grave, por?m cur?vel em praticamente 100% dos casos novos, desde que obedecidos os princ?pios da moderna quimioterapia. S?o considerados f?rmacos de 1? linha no tratamento ? tuberculose: isoniazida, pirazinamida, etambutol e rifampicina. De acordo com USP 33 - NF28 (2010) as an?lises cromatogr?ficas para 3 dos 4 f?rmacos (isoniazida, pirazinamida e rifampicina) duram em m?dia 15 minutos e mais 10 minutos para a obten??o do 4? f?rmaco (etambutol) utilizando outra coluna, com outra mistura de fase m?vel, tornando esta aplica??o na pr?tica industrial desfavor?vel. Uma das alternativas ? utilizar o CLUE, o qual baseia-se nos mesmos princ?pios da CLAE, por?m utiliza fases estacion?rias com part?culas menores que 2 ?m. Dessa forma pretende-se com o presente estudo desenvolver e validar novos m?todos anal?ticos para determina??o simult?nea de tuberculost?ticos por CLAE/DAD e CLUE/DAD. Para isto, foi realizado um screening anal?tico, o qual verificou que ? necess?rio um gradiente de sistema de fase m?vel A (tamp?o acetato:metanol 94:6 v/v) e B (tamp?o acetato:acetonitrila 55:45 v/v). Posteriormente, ao desenvolvimento e otimiza??o do m?todo em CLAE e CLUE com a obten??o dos valores de adequabilidade do sistema dentro dos limites de aceita??es vigente para ambos as t?cnicas, as valida??es deram-se in?cio. Solu??es padr?es e solu??es testes dos comprimidos foram preparadas e injetadas no CLAE e CLUE, contendo isoniazida, pirazinamida, etambutol e rifampicina nas concentra??es de 0,008, 0,043, 0,030 e 0,016 mg.mL-1, respectivamente. A valida??o dos m?todos anal?ticos foram realizadas para: especificidade / seletividade, intervalos da curva anal?tica, linearidade, limite de detec??o, limite de quantifica??o, exatid?o, precis?o (repetibilidade, precis?o intermedi?ria) e robustez. Os m?todos foram adequados para determina??o dos 4 f?rmacos separadamente sem interfer?ncia nos demais. Precisos, devido ao fato de que os m?todos demonstraram que mesmo com varia??o de dias, al?m da repetibilidade, os valores ficaram dentro da faixa preconizada na legisla??o vigente. Lineares (R > 0,99), ou seja, os m?todos foram capazes de demonstrar que os resultados obtidos eram diretamente proporcionais ? concentra??o do analito na amostra, dentro de um intervalo especificado. Exatos, uma vez que os m?todos foram capazes de apresentar valores de coeficiente de varia??o e porcentagem de recupera??o dentro dos limites exigidos (98 a 102%). Os m?todos mostraram LD e LQ com n?veis baixos demonstrando que os m?todos possuem elevada sensibilidade aos quarto f?rmacos. A robustez foi avaliada frente ?s altera??es de temperatura e fluxo, onde os m?todos demonstraram-se robustos apenas nas condi??es previamente estabelecidas de temperatura e fluxo, altera??es bruscas podem acarretar influ?ncia nos resultados dos m?todos
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Ngema, Xolani Terrance. "Metallic nanoparticles with polymeric shell: A multifunctional platform for application to biosensor." University of the Western Cape, 2018. http://hdl.handle.net/11394/6330.
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Philosophiae Doctor - PhD (Chemistry)Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever and chest pains. It was estimated that over 9.6 million people worldwide developed TB and 1.5 million died from the infectious disease of which 12 % were co-infected with human immunodeficiency virus (HIV) in the year 2015. In 2016 the statistics increased to a total of 1.7 million people reportedly died from TB with an estimated 10.4 million new cases of TB diagnosed worldwide. The development of the efficient point-of-care systems that are ultra-sensitive, cheap and readily available is essential in order to address and control the spread of the tuberculosis (TB) disease and multidrugresistant tuberculosis.
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Yngman, Gunnar. "Individualization of fixed-dose combination regimens : Methodology and application to pediatric tuberculosis." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-242059.
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Introduction: No Fixed-Dose Combination (FDC) formulations currently exist for pediatric tuberculosis (TB) treatment. Earlier work implemented, in the software NONMEM, a rational method for optimizing design and individualization of pediatric anti-TB FDC formulations based on patient body weight, but issues with parameter estimation, dosage strata heterogeneity and representative pharmacokinetics remained. Aim: To further develop the rational model-based methodology aiding the selection of appropriate FDC formulation designs and dosage regimens, in pediatric TB treatment. Materials and Methods: Optimization of the method with respect to the estimation of body weight breakpoints was sought. Heterogeneity of dosage groups with respect to treatment efficiency was sought to be improved. Recently published pediatric pharmacokinetic parameters were implemented and the model translated to MATLAB, where also the performance was evaluated by stochastic estimation and graphical visualization. Results: A logistic function was found better suited as an approximation of breakpoints. None of the estimation methods implemented in NONMEM were more suitable than the originally used FO method. Homogenization of dosage group treatment efficiency could not be solved. MATLAB translation was successful but required stochastic estimations and highlighted high densities of local minima. Representative pharmacokinetics were successfully implemented. Conclusions: NONMEM was found suboptimal for the task due to problems with discontinuities and heterogeneity, but a stepwise method with representative pharmacokinetics were successfully implemented. MATLAB showed more promise in the search for a method also addressing the heterogeneity issue.
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Chang, Sheng-Ming, and 張聖明. "The Ethambutol toxicity on Cultured Human Retinal Pigmented Epithelium." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/52700095841280758958.
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Chien, Hsieh Yi, and 謝依倩. "Analysis of Methoxyphenamine and Ethambutol by Capillary Electrophoresis with Electrochemiluminescence Detection." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/58780809313042854422.
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Wiens, Theresa M. "Development of liposome formulations of ethambutol, rifampicin, and isoniazid for pulmonary treatment of tuberculosis." Thesis, 2003. http://hdl.handle.net/2429/14645.
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Current tuberculosis treatment consists of rifampicin, isoniazid, ethambutol,
and pyrazinamide taken orally over a 6 to 12 month period. Although successful
when followed correctly, the drugs are relatively toxic, and drug resistance develops when treatment is not followed to completion. Simplification of this protocol,
resulting in decreased duration and/or dosage, has been identified as a goal for new
TB therapies by the Global Alliance for TB Drug Development and would be a significant improvement in tuberculosis therapy, leading to increased compliance and disease eradication. We have developed liposomal formulations of three first-line anti-tuberculosis drugs, isoniazid, rifampicin, and ethambutol, which are suitable for pulmonary delivery, with the goal of improving the pharmacokinetics of each drug such that concentrations will be maintained at the disease site for prolonged periods. All three drugs have been formulated using a remote loading method into
sphingomyelin/cholesterol (SM/CHOL) (63/37, mol/mol) liposomes. Although isoniazid and rifampicin have been formulated into liposomes previously, this lipid
composition and loading technique has not been utilized for these drugs. In addition,
no ethambutol formulation or a formulation combining two drugs, such as the
isoniazid and ethambutol formulation developed in this thesis, has been described
previously. Each formulation has been optimized in terms of drug/lipid ratio, buffering capacity, and loading kinetics and is capable of encapsulating 76-100% of available drug. Characterization of these formulations in vitro showed prolonged release kinetics, suggesting that drug pharmacokinetics can be altered, in vivo. Stability studies also indicate that each formulation is stable over 2 months at 5°C.
Our hypothesis is that liposome encapsulation of isoniazid, ethambutol, and
rifampicin by remote loading will maintain efficacy in vitro against Mycobacteria. In
vitro susceptibility testing against M. bovis Bacille Calmette-Guerin (BCG), as a
model organism for Mycobacterium tuberculosis, showed equivalent activity of each liposome formulation in comparison to the free drug in culture and in a THP-1 human
macrophage infection model. Fluorescent microscopy also showed that the liposomes
are taken up by infected macrophages, although they do not localize to the same
compartment as M. bovis BCG. Our opinion is that significant improvements in the therapeutic profile of firstline
agents can be achieved by optimizing drug delivery to the disease site. The
results presented in this thesis suggest that all four liposome formulations have the
potential to be administered by pulmonary delivery, providing an alternative approach
to the treatment of tuberculosis. The potential for altered pharmacokinetics in vivo will also permit decreased dosing and frequency of administration, resulting in
improved compliance and ultimately decreasing the development of resistance,
increasing eradication and decreasing relapse rates.
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Ebrahim, Salma. "The preformulation investigation of a combination anti-tuberculosis dosage form." Thesis, 1998. https://hdl.handle.net/10539/25753.
Full textAbstract:
A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Medicine (Pharmaceutical affairs)
Johannesburg, 1998Tuberculosis control in South Africa continues to be a major challenge with 90 000 new cases reported in 1995. Major contributory factors towards these epidemic proportions are patient non-compliance and the occurrence of drug resistant tuberculosis. Fixed drug combinations of anti-tuberculosis drugs have been reported to reduce the possibility of resistance arising to any one of the drugs in combination and to improve compliance. However, the combination anti-tuberculosis drugs available at present still suffer the disadvantage of patients having to take 6 tablets per day. Therefore, the purpose of this project was to investigate a formulation that would reduce this disadvantage.
IT2018
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Phuoc, Le Thanh. "Chemische und pharmakologische Untersuchungen über Ethambutol und seinen Metaboliten Ethylendiiminodibuttersäure (EDDB) bei der Bleivergiftung an Mensch, Ratte und Maus /." 1988. http://www.gbv.de/dms/bs/toc/015994589.pdf.
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Plinke, Claudia [Verfasser]. "Die Bedeutung von Mutationen im embCAB-Operon für die Entwicklung von Ethambutol-Resistenz in Mycobacterium tuberculosis / vorgelegt von Claudia Plinke." 2008. http://d-nb.info/99508985X/34.
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"CN column, indirect conductivity detection and HPLC determination of benzhexol hydrochloride and ethambutal hydrochloride tablets." Chinese University of Hong Kong, 1994. http://library.cuhk.edu.hk/record=b5887289.
Full textAbstract:
by Ma Chin Kwan.Thesis (M.Phil.)--Chinese University of Hong Kong, 1994.
Includes bibliographical references (leaves 129-131).
Chapter Chapter 1. --- Introduction --- p.1
Chapter Chapter 2. --- Theory --- p.4
Chapter Chapter 3. --- The Retention Mechanism of Cyano-Bonded Stationary Phase for Some Basic Drugs in Polar Eluents
Chapter 3.1 --- Introduction --- p.18
Chapter 3.2 --- Experimental
Chapter 3.2.1 --- Reagents --- p.20
Chapter 3.2.2 --- Equipment --- p.21
Chapter 3.2.3 --- Standard Preparation --- p.21
Chapter 3.2.4 --- Procedures --- p.22
Chapter 3.3 --- Results and Discussion
Chapter 3.3.1 --- Acetonitrile-Perchloric Acid Systems --- p.29
Chapter 3.3.2 --- Acetonitrile-Perchlorate Salts Eluent Systems --- p.42
Chapter 3.3.3 --- Retention and Acetonitrile Composition --- p.49
Chapter 3.4 --- Conclusion --- p.54
Chapter 3.5 --- References --- p.55
Chapter Chapter 4. --- Detector Response
Chapter 4.1 --- Introduction --- p.56
Chapter 4.2 --- Experimental
Chapter 4.2.1 --- Reagents and Equipment --- p.57
Chapter 4.3 --- Results and Discussion
Chapter 4.3.1 --- "The Relationship between Peak Area, Peak Height, and Detector Response" --- p.58
Chapter 4.3.2 --- Detector Response and Eluent Strength --- p.60
Chapter 4.3.3 --- Detector Response and Flow Rate --- p.74
Chapter 4.4 --- Conclusion --- p.77
Chapter 4.5 --- References --- p.78
Chapter Chapter 5. --- Determination of Benzhexol Hydrochloride and Ethambutol Hydrochloride tablets by HPLC
Chapter 5.1 --- Introduction --- p.79
Chapter 5.2 --- Experimental
Chapter 5.2.1 --- Reagents --- p.84
Chapter 5.2.2 --- Equipment --- p.85
Chapter 5.2.3 --- Samples --- p.86
Chapter 5.2.4 --- Preparation of Reagents and Standards --- p.88
Chapter 5.2.5 --- Sample Preparation and Determination --- p.89
Chapter 5.3 --- Results and Discussion
Chapter 5.3.1 --- Sample Treatment and Extraction of Active Ingredient(s) --- p.91
Chapter 5.3.2 --- Explanation of Chromatograms --- p.92
Chapter 5.3.3 --- Choice of Experimental Conditions --- p.96
Chapter 5.3.4 --- Linear Dynamic Response --- p.102
Chapter 5.3.5 --- Sensitivity --- p.102
Chapter 5.3.6 --- Analysis Results --- p.103
Chapter 5.3.7 --- Comparison of Results from the Methods --- p.106
Chapter 5.3.8 --- Precision and Accuracy --- p.113
Chapter 5.3.9 --- Effect of Methanol Content on the Chromatographic Behaviour in Analysing Benzhexol Hcl --- p.117
Chapter 5.3.10 --- Discussion on the Pharmacopoeial Assay of Benzhexol HC1 Tablets --- p.120
Chapter 5.3.11 --- Discussion on the Various Factors Influencing the Pharmacopoeial Assay of Ethambutol HC1 Tablets --- p.123
Chapter 5.4 --- Conclusion --- p.128
Chapter 5.5 --- References --- p.129
Appendix --- p.132
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Liou, Hsiang-Chi, and 柳湘琪. "Development of a Simplified Method to Generate Human Retinal Ganglion Cells from Induced Pluripotent Stem Cells to Study the Cytotoxic Effects of Ethambutol." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/4tuzxc.
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Araújo, Hugo Alexandre Almeida Quaresma de Albuquerque. "Pharmaceutical Ionic Liquids as an Effective Treatment against Mycobacterium tuberculosis." Master's thesis, 2022. http://hdl.handle.net/10362/134443.
Full textAbstract:
Tuberculosis (TB) is still today considered the major cause of death by infectious diseases in adults at the global scale. According to the WHO, 10.4 million cases of the disease were active in 2016, among which 1.6 million resulted in death. Over the last years, TB was mainly fought by resorting to the combination of several 1st and 2nd generation drugs, including rifampicin, ethambutol and isoniazid. However, such treatment regime is frequently ineffective to combat TB particularly for multi-resistant Mycobacterium tuberculosis cases. In this work, ethambutol (ETB) was selected as anti-TB drug and then to combine with suitable and biocompatible counter-ions in order to develop several ethambutol based organic salts and ionic liquids (OSILs). The employed sustainable methodologies allowed the quantitative preparation of mono- and di-cationic ETB-OSILs by direct protonation of the drug with one- and two equivalents of biocompatible sulfonic and carboxylic acids. All ETB-OSILs were characterized by NMR, FTIR and elemental analysis (C, H, N) in order to proof the desired compounds. Additionally, calorimetric studies by melting point determination or Differential Scanning Calorimetry (DSC) was performed for a better assessment of their thermal properties and polymorphic behaviour. Upon determination of the water and saline solubility studies (at 370C), three most promissory ETB-OSILs were selected for in vivo toxicity studies using zebrafish as biological model. In general, these ETB-OSILs showed similar toxicity profile to the original drug. Finally, a preliminary assessment of the in vitro activity studies against mycobacterium tuberculosis for the same dicationic and corresponding monocationic ETB-OSILs. These results showed a similar TB activity comparing to the original drug, but complementary biological studies should be required.A tuberculose (TB) ainda hoje é considerada a principal causa de morte por doenças infeciosas em adultos à escala global. Segundo a OMS, 10,4 milhões de casos da doença estavam ativos em 2016, entre os quais 1,6 milhão resultaram em óbitos. Nos últimos anos, o combate à TB foi principalmente feito com o recurso à combinação de vários fármacos de 1ª e 2ª geração, incluindo rifampicina, etambutol e isoniazida. No entanto, esse regime de tratamento é frequentemente ineficaz para combater a TB, particularmente nos casos de Mycobacterium tuberculosis multirresistentes. Neste trabalho, o etambutol (ETB) foi selecionado como fármaco anti-TB e combinado com contra-iões adequados e biocompatíveis a fim de desenvolver vários sais orgânicos e líquidos iônicos à base de etambutol (ETB-OSILs). As metodologias sustentáveis foram otimizadas de modo a permitiram a preparação quantitativa de ETB-OSILs mono e di-catiónicos através da protonação direta do fármaco com um e dois equivalentes de ácidos sulfónicos e carboxílicos biocompatíveis. Todos os ETB-OSILs foram caracterizados por NMR, FTIR e análise elementar (C, H, N) para comprovar a estrutura dos compostos desejados. Adicionalmente, estudos calorimétricos baseados na determinação do ponto de fusão ou Calorimetria Exploratória Diferencial (DSC) foram realizados para uma melhor avaliação de suas propriedades térmicas e do seu comportamento polimórfico. Após a determinação dos estudos de solubilidade em água e solução salina (a 37oC), três ETB-OSILs mais promissores foram selecionados para estudos de toxicidade in vivo usando peixe-zebra como modelo biológico. Em geral, esses ETB-OSILs testados apresentaram um perfil de toxicidade semelhante ao do ETB original. Finalmente, uma avaliação preliminar dos estudos de atividade in vitro contra o Mycobacterium tuberculosis para os mesmos ETB-OSILs (dicationicos e correspondentes monocatiónicos). Esses resultados mostraram uma atividade de TB semelhante por comparação com ETB original, mas serão necessários estudos biológicos complementares.