This work deals with the preparation of amine derivatives of 3-chloro-5(8?)-nitro-1,4-naphthoquinone which are to be tested for anti-tubercular activity by Parke, Davis and Company.

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

<p>Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is&nbsp / known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection&nbsp / and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB&nbsp / patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative&nbsp / patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some&nbsp / of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB)&nbsp / were excluded from the study. Data were retrospectively collected from each patient&rsquo / s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94&nbsp / (27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51&nbsp / (54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and&nbsp / efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5%&nbsp / and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without&nbsp / antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but&nbsp / could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned,&nbsp / there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-)&nbsp / group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting&nbsp / anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also&nbsp / hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes.</p>

<p>Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is&nbsp / known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection&nbsp / and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB&nbsp / patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative&nbsp / patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some&nbsp / of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB)&nbsp / were excluded from the study. Data were retrospectively collected from each patient&rsquo / s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94&nbsp / (27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51&nbsp / (54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and&nbsp / efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5%&nbsp / and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without&nbsp / antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but&nbsp / could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned,&nbsp / there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-)&nbsp / group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting&nbsp / anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also&nbsp / hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes.</p>

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Magister Pharmaceuticae - MPharm / Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB) were excluded from the study. Data were retrospectively collected from each patient’s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94 (27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51 (54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5% and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned, there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-) group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes. / South Africa

Tuberculosis (TB) and fungal infections are two of the most lethal infectious diseases worldwide due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) and fungal strains that can resist the most potent antimicrobial drugs currently employed. Due to the rise of these drug resistant strains, effective treatment options for these two infections are limited. This dissertation aims at exploring novel drug scaffolds to help combat drug resistance in TB and fungal infections. TB caused by the pathogenic Mtb is, alongside with human immunodeficiency virus acquired immunodeficiency virus (HIV), the deadliest infectious disease worldwide with approximately 2-3 billion people infected yearly. The situation has become increasingly intensified due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains.Aminoglycoside (AG) antibiotics such as amikacin and kanamycin A (KAN) are heavily relied upon for the treatment of MDR- and XDR-Mtb strains. However, the success rate for the treatment of these MDR- and XDR-TB cases is decreasing as a result of increased KAN resistance. It was reported by the Centers for Disease Control and Prevention (CDC) that upregulation of the enhanced intracellular survival (eis) gene was the cause of resistance to KAN in a large portion of Mtb clinical isolates. Our lab previously demonstrated that Eis is an AG acetyltransferase that can inactivate AGs via chemoenzymatic modification of the AG scaffolds. As Eis has been shown to acetylate a wide variety of AG scaffolds, the development of novel AGs that can completely escape the action of Eis remains highly challenging. Therefore, we suggested an alternative therapeutic approach involving inhibiting Eis enzyme and still employing the current FDA-approved KAN. As exemplified by the clinically successful combination of penicillin and b-lactamase inhibitors, we hypothesized that an Eis inhibitor may be used as adjuvant therapy in combination with KAN to treat MDR- and XDR-tuberculosis. Using high-throughput screening, we were able to identify several small-molecule scaffolds capable of inhibiting Eis. We performed structure activity relationship (SAR) studies using purified Eis enzyme and optimized lead compounds. Additionally, we also showed that co-administration of Eis lead inhibitors with KAN led to recovery of KAN activity against a KAN-resistant Mtb cell line that overexpressed Ei Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Unlike antibiotics that are greatly diverse in categories and mechanisms of action, our current antifungal drug repertoire is greatly limited and insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. We report a number of lead compounds with potent antifungal activitiy. The MIC values of these compounds were as low as 0.02 mg/mL against the fungal strains tested. Our compounds are derived from the ebselen core structure, which has been shown to be safe in multicenter clinical trials. Notably, fungal cells treated with our compounds showed the accumulation of ROS, which may further contribute to the growth inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.

Malgré la disponibilité d’un traitement curatif et un vaccin largement utilisé, l’OMS estime qu’approximativement un tiers de la population mondiale est infectée par Mycobacterium tuberculosis, l’agent étiologique de la tuberculose, et qu’environ 2 millions de personnes en meurent chaque année. La compréhension de l’épidémiologie de la tuberculose et les actions de contrôle de la maladie ont été, récemment, compliquées par l’émergence de bacilles tuberculeux résistants aux antibiotiques et par la synergie fournie par la co-infection avec le VIH. Une tendance alarmante pour la santé publique est l’émergence de souches résistantes à plusieurs antibiotiques (multi-résistantes, MDR), définies comme des isolats résistants au moins à l’isoniazide (INH) et la rifampicine (RIF), les deux agents anti-tuberculeux les plus puissants.<p><p>La sélection de mutants résistants se produit chez le patient lorsque les taux d’antibiotiques présents dans le corps sont sub-thérapeutiques ou lorsque la thérapie est inappropriée. Un des facteurs favorisant est l’exceptionnelle durée de la chémothérapie. Le besoin de maintenir des taux élevés d’antibiotiques pendant des mois, combiné avec la toxicité inhérente des agents, résultent en une observance incomplète du traitement par le patient et le risque d’acquérir des résistances. La résistance aux antibiotiques chez M. tuberculosis résulte d’altérations dans des gènes chromosomiques spécifiques. Les causes génétiques de la résistance ont été définies pour certains antibiotiques bien que plusieurs inconnues persistent. <p><p>Le présent travail a consisté en l’étude du problème de la résistance aux antibiotiques anti-tuberculeux par différentes approches :l’analyse génétique des mécanismes de résistance, l’évaluation de l’activité thérapeutique de nouvelles molécules et la caractérisation du profil de résistance de souches cliniques. <p><p>L’acide p-aminosalicylique (PAS) est un antibiotique bactériostatique de deuxième ligne dont le mécanisme d'action sur le bacille tuberculeux est incompris. Récemment, en utilisant la mutagenèse par transposon, la résistance au PAS fut associée à des mutations de la thymidylate synthase encodée par le gène thyA. Suite à cette découverte, nous avons entrepris une étude moléculaire de souches cliniques et de mutants spontanés résistants au PAS. Des mutations du gène thyA furent identifiées chez seulement 37% des souches. En tout, vingt-quatre mutations différentes furent identifiées dans le gène thyA. Les séquences nucléotidiques de cinq autres gènes de la voie de synthèse du folate et de la thymine (dfrA, folC, folP1, folP2, et thyX) ainsi que de 3 gènes encodant des N-acétyltransférases (nhoA, aac1 et aac2) furent également analysées mais aucune mutation associée à la résistance au PAS n’a pu être mise en évidence. L’utilisation de techniques bioinformatiques de prédiction structurelle révèle que les mutations identifiées affectent soit la structure soit le site fonctionnel de ThyA. L’étude des profils de croissance des organismes résistants au PAS nous permit de constater que les organismes porteurs d’une mutation de la protéine ThyA présentent un profil de croissance constant en présence de concentrations croissantes de PAS. Les organismes résistants au PAS possédant une protéine ThyA sauvage répondent, quant à eux, aux concentrations croissantes de PAS de façon dose-dépendante, indiquant que le(s) mécanisme(s) alternatif(s) de résistance au PAS est (sont) dose-dépendant(s).<p><p>La thymidylate synthase est également une des cibles du 5-fluorouracil (5-FU), l’agent chimiothérapeutique le plus largement utilisé pour le traitement du cancer colorectal avancé. Etant donné l’augmentation du nombre de souches résistantes de M. tuberculosis, de nouveaux composés anti-tuberculeux sont nécessaires de façon urgente. Ici, nous avons évalué l’efficacité in vitro et in vivo du 5-FU sur M. tuberculosis. La concentration minimale inhibitrice du 5-FU fut déterminée sur une collection de souches cliniques sensibles et multi-résistantes ainsi que sur des mutants spontanés résistants au PAS. Tous les isolats montrèrent une sensibilité au 5-FU à des concentrations allant de 0.4 à 1.8 µg/ml, et ce indépendamment de leur profil de sensibilité/résistance aux agents anti-tuberculeux actuels. Les études in vivo du 5-FU (sur un modèle murin de tuberculose active) montrèrent une efficacité de celui-ci durant les deux premières semaines de traitement puis une perte d’activité à la troisième semaine, vraisemblablement engendrée par les effets secondaires du 5-FU.<p><p>L’éthionamide (ETH) est un autre antibiotique de deuxième ligne dont l’utilisation est limitée aux tuberculoses multi-résistantes étant donné les effets secondaires qu’il engendre. Ces dernières années, les études ont montré que l’ETH est un pro-médicament, transformé en forme active par l’enzyme monooxygénase EthA dont l’expression est contrôlée par le répresseur transcriptionnel EthR. Notre étude décrit l’élaboration d’inhibiteur d’EthR capable d’augmenter la sensibilité de M. tuberculosis à l’ETH suite à l’amélioration de son activation. Les composés synthétisés et sélectionnés pour leur capacité à inhiber l’interaction EthR-ADN furent co-cristallisés avec EthR. Les structures tridimensionnelles des complexes furent utilisées pour la synthèse d’analogues capables d’améliorer la puissance de l’ETH en culture. Les molécules les plus prometteuses furent testées sur un modèle murin de tuberculose. Pour un des inhibiteurs d’EthR testés, nous avons montré que sa co-administration avec l’ETH permet une réduction de la dose d’ETH utilisée de 3 fois, pour l’obtention d’une même réduction de charge mycobactérienne pulmonaire. Ce travail démontre la possibilité d’augmenter l’index thérapeutique de l’éthionamide en agissant pharmacologiquement sur le mécanisme régulateur de son activation.<p><p>Dans certaines régions du monde, le problème de la multi-résistance devient très présent. Nous avons étudié l’état de la situation à Mourmansk (Fédération russe), une région à haute incidence de tuberculose. La résistance aux antibiotiques et l’épidémiologie moléculaire de la tuberculose furent étudiées sur des isolats collectés en 2003 et 2004 dans cette région. Une extrêmement haute prévalence de tuberculose multi-résistante (MDR-TB) fut constatée à la fois pour les nouveaux cas (primaires) (26%) et les cas précédemment traités (72.9%). Le typage des souches MDR primaires révèle une appartenance au génotype Beijing pour la plupart des isolats (79.8%) et l’homogénéité génétique des souches suggère une transmission active au sein de la population. L’analyse moléculaire des gènes impliqués dans la résistance à l’INH et à la RIF montre la présence des mutations katG codon 315 et rpoB codon 531 chez, respectivement, 98,2% et 76,3% des isolats MDR-TB primaires. La haute fréquence de ces mutations « communes » suggère la possible utilisation de tests moléculaires ciblant spécifiquement ces mutations pour détecter rapidement la plupart des cas de MDR-TB.<p><p>Nos travaux illustrent les différentes voies à suivre pour maitriser le problème de la résistance aux antibiotiques :l’élucidation des mécanismes de résistance, le développement de nouveaux médicaments et la détection rapide des cas de résistance.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished