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A dissertation submitted to the Faculty of Health Sciences, university of the witwatersrand, in fulfilment ofthe requirements for the degree of Master of Medicine (paediatrics) Johannesburg, 20 I 6 / Background: Though features of infants with congenital tubercuiosis (TB) are known including being low-birth-weight (LBw), features of in-utero TB-exposed infants including non-infected are not well reported. Infants bom to TB-infected women are at risk of contracting TB post-delivery, therefore chemoprophylaxis is recommended, and this includes use of isoniazid and rifampicin combination, but littie is known about its effectiveness. Objective: To determine features of in-utero TB-exposed infants and proportion with TB after chemoprophylaxis with isoniazid and rifampicin. Methods: Retrospective review of records of TB-infected women and their infants, from ZA07-20rc. Clinical features of mothers and infants at time of delivery; and follow-up of infants after completion of isoniazid and rifampicin are described. Results: Eighty-eight infants bom to 86 women with a diagnosis of TB were studied. TB diagnosis was made peripartum in24.4Yoof women, 23.3%had exka-pulmonary TB. Among those diagnosed antepa$um 46.2o/owere on treatment for >2 months. Human immunodeficiency virus (HIV) was positive in 97.7Yo;wi& CD4 count <200 cells/mm3 in 74'6yo' Eight mothers (9.3%) died before discharge. There were 56 {63.6%)LBW and 45 (51'2W preterun infants. Culture for acid-fast-bacilli was positive in 4 (4.5%)infants. At 3- months follow-up, 17 (20.2%)defaulted, and among 67 who returned, 7 OAoA)did not return for Mantoux test reading, 1160 (1.7%)had positive Manroux. Conclusion: Majority of TB-exposed infants are born to mothers with TB/ HIV co-infection. A high proportion of TB-exposed infants are born preterm and LBW. The high attrition rate made it difficult to assess effectiveness of chemoprophylaxis with isoniazid and rifampicin / MT2016

A Dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. 21 May 2015 / Crystal polymorphism is the capacity of a solid crystalline form to exist in more than one structural arrangement. In the pharmaceutical setting investigations into the polymorphic forms of potential drugs are of vital importance since different crystalline forms can affect bioavailability, mechanical, thermal, and chemical properties. One such example is isonicotinic acid-(1-phenylethylidene) hydrazide (IPH), a derivative of the popular drug isoniazid (used as first line treatment against Mycobacterium tuberculosis) was found to crystallise in six different polymorphic forms. Each crystal structure was determined using X-ray diffraction techniques and including the thermal phase relationships of the polymorphic compound were delineated. In addition to polymorph elucidation, isonicotinic acid-(1-phenylethylidene) hydrazide was modified with –OH and –NH2 at various aromatic positions, creating geometric pyridyl isomers. In-depth studies of these pyridyl isomers revealed a diverse range of supramolecular aggregates. Preliminary thermal screening suggests that only a small selection of these pyridyl isomers present potential polymorphic activity for further study.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 111-137).

Background: The incidence of tuberculosis (TB) among Inuit is over 400 times that of Canadian-born non-indigenous people. To address this, more patients will need to complete preventative treatment. Methods: First, data were extracted retrospectively for all patients with a tuberculin skin test (TST) implanted in Iqaluit, Nunavut between January 2012 and March 2016 and used to identify sources of loss from the latent TB infection (LTBI) cascade of care. Associations between demographic and clinical factors and treatment non-initiation and treatment non-completion were identified using regression models. Second, using a slightly expanded version of the retrospective dataset plus other sources, a Markov model was utilized to assess the cost-effectiveness of a novel shortened regimen for LTBI (12 weeks of once weekly isoniazid and rifapentine (3HP)) compared to the current standard of care (9 months of isoniazid monotherapy (9H)). Results: Treatment non-initiation and non-completion were the largest sources of loss of TST positive patients from the cascade of care. LTBI testing via employment screening was associated with treatment non-initiation while older age was associated with both treatment noninitiation and non-completion. In cost-effectiveness analysis, 3HP was dominant over 9H: costs were lower ($835 vs $1229 per person) and health outcomes slightly improved (20.14 vs 20.13 QALYs gained per person treated), largely due to an improved treatment completion with 3HP. Conclusions: Interventions to increase LTBI treatment initiation and completion in Iqaluit are needed. This could include the use of 3HP instead of 9H for LTBI treatment which may improve treatment completion and result in cost savings and slightly improved health outcomes.

Study objectives: To examine the utilization of chemoprophylaxis for tuberculosis in certain high-risk groups, ie, infected contacts 50 years and older, and to study the safety of isoniazid (INH) preventive therapy in such persons. Design: From 1987 to 1992, two-part questionnaires were sent to each of the regional health offices within the 95 counties of Tennessee to document cases of purified protein derivative skin test conversion or reaction among close contacts of new patients with active tuberculosis. Infected contacts 50 years and older were included in the study. Methods: Data collected from these questionnaires were grouped according to age, sex, race, liver functions test (LFT), and whether chemotherapy was completed. Reasons for early discontinuation were also recorded. High values of LFTs were classified in the various groups as either twofold elevation or greater than threefold elevation. Results: Of the 829 responses for persons fitting the criteria for INH chemoprophylaxis, 415 began treatment; 249 (60%) of those completed the full course (9 months) and 166 stopped prematurely. Of the 414 persons (50%) who did not start preventive therapy, 233 (56.5%) respondents listed age as the reason. No patients started on a regimen of therapy developed hepatitis. Of those completing therapy, 6.9% had a rise in liver enzyme values but remained asymptomatic for hepatitis. Liver enzyme level elevation was significantly higher among patients who discontinued therapy, particularly white women, than those who completed the full course. Asymptomatic liver enzyme level elevation (≥3 times normal value), private practitioners' preferences, and patients arbitrarily stopping therapy were the leading reasons for incomplete INH preventive therapy. Conclusion: We conclude that 30% of tuberculosis-infected contacts deserving chemoprophylaxis were actually provided the full benefit of INH preventive therapy, indicating underutilization of this prevention strategy, particularly in contacts older than 50 years.

published_or_final_version / abstract / Microbiology / Doctoral / Doctor of Philosophy

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

Novos sistemas de liberação de fármacos têm sido desenvolvidos com o intuito de melhorar a eficácia terapêutica de muitos fármacos no tratamento de diferentes patologias. Os sistemas microparticulados têm despertado grande interesse devido a suas propriedades, suas vantagens sobre os sistemas de distribuição convencional e, conseqüentemente, melhoria na adesão ao tratamento. As micropartículas de quitosana são exploradas como sistemas de liberação sítio-específico, devido suas propriedades biodegradáveis, biocompatíveis e mucoadesivas. Assim, visando o tratamento da tuberculose, que atualmente é causa prevalente de morte considerando as doenças infecciosas no mundo, neste trabalho micropartículas constituídas de quitosana foram desenvolvidas para veicular isoniazida. A isoniazida, uma hidrazida do ácido isonicotínico, é uma dos fármacos mais poderosos entre os fármacos de primeira linha utilizados no tratamento da tuberculose devido à sua alta eficiência, baixa dose e de baixo custo, tornando-o um bom candidato para o desenvolvimento de uma formulação de liberação sítio-específica. Por spray-drying, as micropartículas inertes e com isoniazida obtidas apresentaram-se esféricas e com ampla distribuição de tamanho de partículas que variou entre 5 e 12 m, potencial zeta positivo e elevada eficiência de encapsulação. O perfil liberação in vitro em tampão fosfato salino (PBS) pH 7,4 apresentou formação de produto de degradação, sendo confirmado por espectrometria de massa como o ácido isonicotínico. Entretanto, a isoniazida mostrou ter uma liberação rápida (1 hora) a partir das micropartículas de quitosana em meio aquoso. Dessa forma, as micropartículas de quitosana desenvolvidas constituem um sistema promissor para veiculação da isoniazida e administração pulmonar e, finalmente, melhoria da terapia da tuberculose. Ademais, adequações do método deverão ser testadas considerando a via de administração pretendida, bem como será necessária a realização de estudos in vivo para avaliar o comportamento dos sistemas desenvolvidos em condições fisiológicas reais e a biodisponibilidade e biodistribuição do fármaco no organismo. / New drug delivery systems have been developed in order to improve the therapeutic efficacy of many drugs in the treatment of different pathologies. Microparticles have attracted great interest due to its properties, its advantages over conventional delivery systems and, consequently, better treatment adherence. The chitosan-based microparticles are exploited as delivery systems for site-specific, because their biodegradable, biocompatible and mucoadhesive properties. Thus, chitosan-based microspheres containing isoniazid were developed to target the treatment of tuberculosis, which is currently prevalent cause of death considering infectious diseases in the world. Isoniazid, an isonicotinic acid hydrazide, is one of the most powerful drugs among first-line drugs used to treat tuberculosis due to its high efficiency, low dose and low cost, making it a good candidate for the development of site-specific delivery system. By spray-drying, the isoniazid-loaded and free microparticles obtained presented wide size particle distribution with particle size ranging between 5 and 12 m, spherical morphology, positive zeta potential and high encapsulation efficiency. The in vitro release profile in phosphate buffered saline (PBS) pH 7.4 showed the formation of degradation product, which was confirmed by mass spectrometry as isonicotinic acid. However, isoniazid release from the microparticles was fast (1 hour) in water. Thus, the developed chitosan microparticles are a promising system as a vehicle to isoniazid and pulmonary administration, and ultimately to improve the therapy of tuberculosis. Moreover, adaptations of the method should be tested considering the intended route of administration and it will be necessary to perform in vivo studies to evaluate the behavior of the systems developed under physiological conditions and actual bioavailability and biodistribution of the drug in the body.

>Magister Scientiae - MSc / This thesis reports on the syntheses of complexes of (arene) ruthenium (II) isoniazid Schiff base ligands for antimicrobial studies. Isoniazid Schiff base ligands; isonicotinyl acid (2-hydroxy-5- methyl-benzilidene)-hydrazide (L1), isonicotinyl acid (2-hydroxy-5-methoxy-benzilidene)- hydrazide (L2), isonicotinyl acid (-5-chloro-2-hydroxy-benzilidene)-hydrazide (L3), isonicotinyl acid (-5-bromo-2-hydroxy-benzilidene)-hydrazide (L4), isonicotinyl acid (2-hydroxy-5-nitrobenzilidene)- hydrazide (L5) were prepared by condensation reaction under reflux from equimolar amounts of isioniazid, which is an amine, with five different aldehyde moieties. Ruthenium (II) complexes of these isoniazid Schiff base ligands (C1 - C5) were prepared in an ethanolic solution under reflux and inert atmosphere at 60°C using Schlenk techniques. Fourier transform infrared spectroscopy (FTIR), ultraviolet – visible spectroscopy, thermogravimetric analysis, nuclear magnetic resonance and elemental analysis were the characterization techniques that confirmed the successful preparation of the ligands. All the ligands spectra displayed the imine functional group peak which confirmed the successful preparation. The ligands L1 – L5 and the complexes C1 – C5 were subjected to similar characterization techniques which further confirmed the successful syntheses and the coordination of metal and ligand by displaying a shift in their respective imine peaks and transitions values. All the synthesized compounds were subjected to a standard antimicrobial test using three microorganisms, Staphylococcus aureus, Methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa. Out the ten compounds tested, only ligand L5 gave the best results against Staphylococcus aureus.