Made available in DSpace on 2014-06-11T19:28:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-06-28Bitstream added on 2014-06-13T18:32:32Z : No. of bitstreams: 1 pinto_lsr_me_arafcf.pdf: 1125998 bytes, checksum: d180b32c1876b87cf52761d5cd5e4873 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / 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

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 etambutol / Abstract: 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 / Orientador: Rosângela Gonçalves Peccinini / Coorientador: Márcia da Silva / Banca: Jean Leandro dos Santos / Banca: Vera Lúcia Lanchote / Mestre

>Magister Scientiae - MSc / Tuberculosis (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.

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, 1998 / Tuberculosis 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

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-08-18T14:46:04Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) PRISCILA ROCHA. DISSERTAÇÃO.DIGITAL.pdf: 900577 bytes, checksum: 21461faf83aca3f0a9ae61d40c9c66e3 (MD5) / Made available in DSpace on 2016-08-18T14:46:04Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) PRISCILA ROCHA. DISSERTAÇÃO.DIGITAL.pdf: 900577 bytes, checksum: 21461faf83aca3f0a9ae61d40c9c66e3 (MD5) Previous issue date: 2015-08-26 / 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.

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

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Thesis (M.Sc. (Pharmaceutical Chemistry))--Mahidol University, 2007. / LICL has E-Thesis 0029 ; please contact computer services.

Philosophiae Doctor - PhD / Tuberculosis (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