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 / Despite the availability of highly effective treatment regimens for tuberculosis, cure rates remain low for tuberculosis mainly due to patient non-compliance which results in the occurrence of multi drug resistance tuberculosis. To avoid the problem of further creation and propagation of multi drug-resistant tuberculosis, patients should be given fixed-dose combinations of anti-tubercular drugs whenever self-administration of drugs iJ permitted. During this study, an anti-tuberculosis extemporaneous powder for suspension was optimized in order to formulate a fixed combination of rifampicin. isoniazid, pyrazinamide and ethambutol hydrochloride as a powder to be ' . constituted with water by the patient prior to administration. Once an effective manufacturing method was established, different suspending agents were evaluated by their influence on powder flow properties and sedimentation volume on the powder blends. Sodium starch glycollate was chosen as the suspending agent of choice because as the concentration of sodium starch glycollate was increased, the powder flow properties of the powder blends improved. The sedimentation volume also. increased with the increasing concentration of sodium starch glycollate in the powder blends. A suitable flavour and colour was also determined to increase the acceptability of the preparation to the patient. Liquorice flavour was the most acceptable in terms of colour and flavour. An evaluation of the dissolution characteristics of the extemporaneous powder for suspension was also conducted in comparison to the dissolution profiles from commercially available tablet dosage forms. The dissolution rates from the powder tor suspension for rifampicin, isoniazid and pyrazinamide was faster than from the commercially available tablet dosage form, while the dissolution race of ethambutol HCl from the powder closely resembles the dissolution profile from the Rolab-Ethambutol HCIR tablet dosage form Therefore. a fixed combination powder for suspension was achieved and with its ease of administration would increase the compliance amongst tuberculosis patients. and increase therapeutic outcomes. / MT2017

After declining for many years, the incidence of tuberculosis (TB) is on the increase again. With TB resurgence there is also resistance of some TB strains to the commonly used TB drugs. This condition is kno wn as multi-drug resistance tuberculosis (MDR TB). Among all factors that increase TB and MDR TB, treatment compliance and completion is the greatest challenge. MDR TB is mainly caused by poor adherence to TB treatment by either the patient or the prescriber. In order to improve patient adherence to treatment. Directly Observed Therapy (DOT) has been implemented in many countries including South Africa. DOT means that each consumption of TB drugs by the patient is observed by a reliable person. Even with DOT in place, many patients still do not adhere to the prescribed treatment. This study aimed at determining from health workers the following: • Problems experienced by the health workers when giving treatment to TB patients, • causes for non-adherence to TB treatment, and • what could be done to make DOT more effective. A questionnaire was used to gather information. Ail clinics rendering TB services in Gauteng were considered in this study. Two questionnaires were sent to each of the 138 participating clinics and had to be completed by any two health workers involved in the treatment of TB patients. Only 69 of the 276 questionnaires sent, were returned completed (25%). Information gathered from the questionnaires revealed that patients seen at TB clinics in Gauteng came from various residential areas including townships, suburban rural and informal settlement. The Pearson chi squared test showed that there was no association between the percentage of patients who completed treatment and the number of patients seen at a clinic, or between the percentage of patients who completed treatment and the working hours at a particular clinic. The main cause of non-compliance shown by the results of this study was that patients discontinued treatment as soon as they felt better. Other causes of non-compliance mentioned by health workers included patient denial of having TB, ignorance, long treatment periods and many drugs that were to be taken during treatment. Health workers revealed that the main problem experienced in giving treatment to TB patients was that of deiaulting. The majority of these respondents suggested education as one way of making DOT more effective. In terms o f this study, it can be concluded that education on TB at various levels namely the patient, the health care worker and the community, is recommended. Education on the disease TB and its optimal treatment will improve patient compliance, decrease defaulting in delivering TB drugs to patients and make DOT more effective.

by Cheung Wah. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 64-68). / Tuberculosis in the Elderly : Presentation and Therapeutic Problems -a Clinical and Pharmacological Study / Contents / Chapter 1. --- Summary --- p.6 / Chapter 2. --- Introduction --- p.7 / Chapter 3. --- Aims of the Study --- p.11 / Chapter 4. --- Subjects and Methods --- p.12 / Chapter 5. --- Results --- p.36 / Chapter 6. --- Discussion --- p.55 / Chapter 7. --- Conclusion --- p.61 / Chapter 8. --- Acknowledgement --- p.63 / Chapter 9. --- References --- p.64

Thesis (MScMedSc)--Stellenbosch University, 2012. / Includes bibliography / ENGLISH ABSTRACT: In this thesis, research results are reported on the role of dipalmitoyl phosphatidyl choline (DPPC) and DPPC-liposomes on the in vitro permeability characteristics of various antimycobacterial drugs across porcine bronchial tissue. The permeability flux values of the different compounds (isoniazid, ofloxacin and moxifloxacin) and their relevant DPPC formulations were determined using a continuous flow through perfusion system. Mean steady state flux values were compared statistically by means of a t-test at a significance level of 5% as well as an F-test using whole curve comparisons. The results indicated that the different formulations of drug and their DPPC combinations retard the permeation of drug through bronchial tissue. However, moxifloxacin permeation was significantly enhanced when in a DPPC-liposomal formulation. These results demonstrate the important role that molecular weight, electrostatic charge, partitioning of the molecules in DPPC and DPPC-liposomes play in transmembrane diffusion. In addition, the effect of individual drugs and their DPPC combinations on the surface tension lowering property of DPPC was evaluated. The results obtained showed minimal decreases in the surface tension lowering capability of DPPC; however, the minimal increases in surface tension do not alter the integrity of DPPC to a large extent. Drug susceptibility testing of Mycobacterium tuberculosis cultures against the individual antitubercular drugs and their DPPC combinations was done by using the Radiometric BACTEC 460TB™ system. Drug-entrapped DPPC liposomes were tested at concentrations comparable to their relative minimum inhibitory concentrations (MIC). The results for the BACTEC assay indicated that the mycobacteria were susceptible to the developed drug entrapped liposomes; of which their encapsulation efficiencies for the relevant drugs were approximately ± 50%. It was concluded that drug-entrapped DPPC liposomes could fulfill the dual role of pulmonary drug delivery and alveolar stabilization due to antiatelectatic effect of DPPC which can improve the distribution of anti-tubercular drugs in the lung / AFRIKAANSE OPSOMMING: Hierdie tesis doen verslag oor navorsingsresultate met betrekking tot die rol van dipalmitoïel-fosfatidiel-cholien (DPPC) en DPPC-liposome in die in vitro-permeasiekenmerke van verskeie antimikobakteriese middels oor vark- brongiale weefsel. Die permeasievloedwaardes van die verskillende verbindings (isoniasied, ofloksasien en moksifloksasien) en hul betrokke DPPC-formules is met behulp van ’n deurlopende-deurvloei-perfusiestelsel bepaal. Gemiddelde vloedwaardes in ’n bestendige staat is statisties vergelyk met behulp van ’n t-toets op ’n beduidendheidsvlak van 5%, sowel as ’n F-toets met behulp van heelkurwevergelykings. Die resultate dui daarop dat die verskillende middelformules en hul DPPC-kombinasies middelpermeasie oor brongiale weefsel vertraag. Tog is die permeasie van moksifloksasien aansienlik versterk in ’n DPPC-liposomale formule. Hierdie resultate bevestig die belangrike rol van molekulêre gewig, elektrostatiese lading, die verdeling van molekules in DPPC sowel as DPPC-liposome in transmembraandiffusie. Daarbenewens is die uitwerking van individuele middels en hul DPPC-kombinasies op die oppervlakspanningsverligtingsvermoë van DPPC beoordeel. Die resultate toon minimale afnames in die oppervlakspanningsverligtingsvermoë van DPPC. Die minimale toenames in oppervlakspanning het egter meestal geen noemenswaardige effek op die integriteit van DPPC gehad nie. Voorts is die vatbaarheid van Mycobacterium tuberculosis-kwekings vir die individuele anti-tuberkulêre middels en hul DPPC-kombinasies met behulp van die radiometriese BACTEC 460TB™-stelsel getoets. Middel-ingeslote DPPC-liposome is getoets in konsentrasies wat met hul relatiewe minimum inhibisiekonsentrasies (MIK) vergelyk kan word. Die resultate van die BACTEC-toets toon dat die mikobakterieë vatbaar was vir die ontwikkelde middel-ingeslote liposome, met ’n enkapsuleringsdoeltreffendheid van ongeveer 50% vir die betrokke middels. Die studie kom tot die gevolgtrekking dat middel-ingeslote DPPC-liposome die dubbele rol van pulmonêre middel-lewering en alveolêre stabilisering kan vervul weens die anti-atelektatiese werking van DPPC, wat die verspreiding van anti-tuberkulêre middels in die long kan verbeter.

Introdução: O Tratamento Preventivo com Isoniazida (TPI) é indicado para os pacientes com HIV/aids e infecção latente por Micobacterium tuberculosis (ILMTb) para os quais não haja contraindicação à Isoniazida. Entretanto, barreiras de acesso podem impedir que os pacientes realizem este tratamento. Objetivos: O presente estudo avaliou a taxa de acesso à prescrição médica do TPI em sujeitos com HIV/aids e ILMTb em seguimento em um serviço especializado de HIV/aids no período de fevereiro de 2005 a dezembro de 2009. Para os sujeitos que não tiveram acesso à prescrição do TPI, buscou-se, em prontuário, justificativas para esta conduta. Também foi identificado o perfil epidemiológico, clínico e demográfico dos sujeitos com HIV/aids e ILMTb e foi descrita a característica do médico que solicitou o teste tuberculínico (TT) e do que prescreveu o TPI. Métodos: No período de 02 de fevereiro de 2005 a 31 de dezembro de 2009 que estavam em seguimento no SEAP HIV/Aids foram incluídos sujeitos com HIV/Aids e ILMTB, diagnosticada através do Teste Tuberculínico (TT). Informações referentes às variáveis analisadas foram coletadas nos prontuários médicos e através de consulta ao Sistema de Informação e Gestão Hospitalar (SIGH) - Módulo Farmácia. Resultados: Foram incluídos 238 sujeitos dentre os 310 que tiveram TT > 5 mm no período do estudo. Destes, 70,6% (168) eram do sexo masculino; a média de idade foi de 42,6 anos; 88,2% (210) dos sujeitos tiveram acesso à prescrição do TPI. O acesso à prescrição do TPI foi associado à idade, ao tamanho da resposta ao TT, ao nadir de Linfócitos TCD4+ dos sujeitos em TARV e à presença de cicatriz de BCG. Sujeitos mais jovens, com resposta ao TT igual ou maior do que 10 mm e com cicatriz de BCG tiveram maior acesso à prescrição do TPI. Uma das questões a ser explorada em futuros estudos se refere aos fatores que influenciam, ou não, a decisão do profissional de introduzir este tratamento na situação em que o mesmo está recomendado tecnicamente. Conclusão: Os sujeitos mais jovens, com melhor situação imunológica de base, maior valor de resposta ao TT e com presença da cicatriz de BCG, tiveram maior acesso ao TPI. Neste estudo foi evidenciada a necessidade de que as instituições de saúde invistam em educação continuada de seus profissionais para elevarem a cobertura de ações programáticas, como é o tratamento da ILMTB, previsto nos programas nacionais de tuberculose e de HIV/aids. Além disso, é necessário que as equipes interdisciplinares atuem de forma integrada e harmônica, para garantir o acesso às ações de saúde. É possível identificar, porém muitas barreiras que restam para a serem rompidas de modo que os cidadãos que vivem com HIV/aids tenham acesso a este e aos demais tratamentos de que tenham necessidade / Background: Isoniazid Preventive Treatment (IPT) is recommended for patients with HIV/AIDS and Latent Infection by Mycobacterium tuberculosis (ILMTb) and no contraindication to isoniazid. However, access barriers may prevent patients to undergo to this treatment. Objectives: This study evaluated the rate of access to the prescription of IPT in subjects with HIV/aids and ILMTb followed up in a specialized HIV/aids from February 2005 to December 2009. For subjects who did not have access to the prescription of IPT, we sought, on records, justification for this conduct. Also, the epidemiological, clinical and demographic profile of individuals with HIV/AIDS and ILMTb and the characteristic of the doctor who requested the tuberculin skin test (TST) and prescribed IPT were identified. Methods: from 02 February 2005 to 31 December 2009 subjects followed up at SEAP HIV/aids with HIV/aids and ILMTB, diagnosed by Tuberculin Test (TST) were included. Information was collected from the medical records and from the Hospital Information and Management System (SIGH) - Pharmacy Module. Results: 238 subjects were included, among the 310 who had TST > 5 mm during the study period. Of these, 70.6 % (168) were male and the average age was 42.6 years, 88.2 % (210) had access to the prescription of IPT. Access to IPT prescription was associated with age , size of response to TST, nadir of lymphocytes CD4 + in subjects on ART and presence of BCG scar: younger subjects with response to TST equal to or greater than 10 mm and BCG scar had higher access rate to IPT prescription. An issue to be explored in the future refers to variables that influence the professional\'s decision to prescribe this treatment when it is technically recommended. Conclusion: younger subjects with better immune status at baseline, greater response to TST and presence of BCG scar, had more access to IPT. This study highlighted the need of educational programs for health professionals, in order to improve the coverage of activities devoted to reduce morbidity and mortality in HIV/aids patients, as is the treatment of ILMTB, recommended in national tuberculosis and HIV/AIDS programs. Furthermore, it is crucial, for interdisciplinary health teams, to operate in an integrated and harmonious way, to ensure, for HIV/aids patients, a healthy and longer life

Introdução: O Tratamento Preventivo com Isoniazida (TPI) é indicado para os pacientes com HIV/aids e infecção latente por Micobacterium tuberculosis (ILMTb) para os quais não haja contraindicação à Isoniazida. Entretanto, barreiras de acesso podem impedir que os pacientes realizem este tratamento. Objetivos: O presente estudo avaliou a taxa de acesso à prescrição médica do TPI em sujeitos com HIV/aids e ILMTb em seguimento em um serviço especializado de HIV/aids no período de fevereiro de 2005 a dezembro de 2009. Para os sujeitos que não tiveram acesso à prescrição do TPI, buscou-se, em prontuário, justificativas para esta conduta. Também foi identificado o perfil epidemiológico, clínico e demográfico dos sujeitos com HIV/aids e ILMTb e foi descrita a característica do médico que solicitou o teste tuberculínico (TT) e do que prescreveu o TPI. Métodos: No período de 02 de fevereiro de 2005 a 31 de dezembro de 2009 que estavam em seguimento no SEAP HIV/Aids foram incluídos sujeitos com HIV/Aids e ILMTB, diagnosticada através do Teste Tuberculínico (TT). Informações referentes às variáveis analisadas foram coletadas nos prontuários médicos e através de consulta ao Sistema de Informação e Gestão Hospitalar (SIGH) - Módulo Farmácia. Resultados: Foram incluídos 238 sujeitos dentre os 310 que tiveram TT > 5 mm no período do estudo. Destes, 70,6% (168) eram do sexo masculino; a média de idade foi de 42,6 anos; 88,2% (210) dos sujeitos tiveram acesso à prescrição do TPI. O acesso à prescrição do TPI foi associado à idade, ao tamanho da resposta ao TT, ao nadir de Linfócitos TCD4+ dos sujeitos em TARV e à presença de cicatriz de BCG. Sujeitos mais jovens, com resposta ao TT igual ou maior do que 10 mm e com cicatriz de BCG tiveram maior acesso à prescrição do TPI. Uma das questões a ser explorada em futuros estudos se refere aos fatores que influenciam, ou não, a decisão do profissional de introduzir este tratamento na situação em que o mesmo está recomendado tecnicamente. Conclusão: Os sujeitos mais jovens, com melhor situação imunológica de base, maior valor de resposta ao TT e com presença da cicatriz de BCG, tiveram maior acesso ao TPI. Neste estudo foi evidenciada a necessidade de que as instituições de saúde invistam em educação continuada de seus profissionais para elevarem a cobertura de ações programáticas, como é o tratamento da ILMTB, previsto nos programas nacionais de tuberculose e de HIV/aids. Além disso, é necessário que as equipes interdisciplinares atuem de forma integrada e harmônica, para garantir o acesso às ações de saúde. É possível identificar, porém muitas barreiras que restam para a serem rompidas de modo que os cidadãos que vivem com HIV/aids tenham acesso a este e aos demais tratamentos de que tenham necessidade / Background: Isoniazid Preventive Treatment (IPT) is recommended for patients with HIV/AIDS and Latent Infection by Mycobacterium tuberculosis (ILMTb) and no contraindication to isoniazid. However, access barriers may prevent patients to undergo to this treatment. Objectives: This study evaluated the rate of access to the prescription of IPT in subjects with HIV/aids and ILMTb followed up in a specialized HIV/aids from February 2005 to December 2009. For subjects who did not have access to the prescription of IPT, we sought, on records, justification for this conduct. Also, the epidemiological, clinical and demographic profile of individuals with HIV/AIDS and ILMTb and the characteristic of the doctor who requested the tuberculin skin test (TST) and prescribed IPT were identified. Methods: from 02 February 2005 to 31 December 2009 subjects followed up at SEAP HIV/aids with HIV/aids and ILMTB, diagnosed by Tuberculin Test (TST) were included. Information was collected from the medical records and from the Hospital Information and Management System (SIGH) - Pharmacy Module. Results: 238 subjects were included, among the 310 who had TST > 5 mm during the study period. Of these, 70.6 % (168) were male and the average age was 42.6 years, 88.2 % (210) had access to the prescription of IPT. Access to IPT prescription was associated with age , size of response to TST, nadir of lymphocytes CD4 + in subjects on ART and presence of BCG scar: younger subjects with response to TST equal to or greater than 10 mm and BCG scar had higher access rate to IPT prescription. An issue to be explored in the future refers to variables that influence the professional\'s decision to prescribe this treatment when it is technically recommended. Conclusion: younger subjects with better immune status at baseline, greater response to TST and presence of BCG scar, had more access to IPT. This study highlighted the need of educational programs for health professionals, in order to improve the coverage of activities devoted to reduce morbidity and mortality in HIV/aids patients, as is the treatment of ILMTB, recommended in national tuberculosis and HIV/AIDS programs. Furthermore, it is crucial, for interdisciplinary health teams, to operate in an integrated and harmonious way, to ensure, for HIV/aids patients, a healthy and longer life