Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.

Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.

Desfechos clínicos do tratamento de tuberculose utilizando o esquema básico recomendado pelo Ministério da Saúde do Brasil com comprimidos em dose fixa combinada na região metropolitana de Goiânia / Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil

OBJETIVO: Descrever as taxas de cura, falência e abandono do tratamento da tuberculose com o esquema básico preconizado pelo Ministério da Saúde (tratamento com rifampicina, isoniazida, pirazinamida e etambutol por dois meses seguido de isoniazida e rifampicina por quatro meses) utilizando comprimidos em dose fixa combinada em regime autoadministrado e descrever os eventos adversos e seus possíveis impactos nos desfechos do tratamento. MÉTODOS: Estudo descritivo utilizando dados coletados prospectivamente dos prontuários médicos de pacientes com tuberculose (idade > 18 anos) tratados com o esquema básico em duas unidades básicas de saúde da região metropolitana de Goiânia, GO. RESULTADOS: A amostra foi composta por 40 pacientes com tuberculose. A taxa de cura foi de 67,5%, a taxa de abandono foi de 17,5%, e não ocorreram casos de falência. Nessa amostra, 19 pacientes (47%) relataram reações adversas aos medicamentos. Essas foram leves e moderadas, respectivamente, em 87% e 13% dos casos. Em nenhum caso houve necessidade de mudança do esquema ou suspensão do tratamento. CONCLUSÕES: A taxa de cura do esquema básico com o uso de comprimidos em dose fixa combinada sob regime autoadministrado foi semelhante às taxas históricas do esquema anterior. A taxa de abandono, na amostra estudada, foi muito acima da taxa preconizada como adequada (até 5%).

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Tratamiento directamente observado de la tuberculosis en un hospital de la Ciudad de Buenos Aires / Directly observed treatment for tuberculosis in a Buenos Aires City hospital

Se describe la experiencia en la aplicación del tratamiento directamente observado de tuberculosis (TDO) en el período 1/1/1979-31/12/2009 y la comparación de los resultados obtenidos en el periodo 1979-1999 versus los de 2000- 2009. En un hospital de la Ciudad de Buenos Aires, 582 pacientes HIV negativos recibieron inicialmente rifampicina, isoniazida, pirazinamida y etambutol o estreptomicina. En la segunda fase 424 de estos pacientes tratados entre 01/01/1979 y 31/12/1999 (G1), recibieron esquemas bisemanales con rifampicina/isoniazida o isoniazida/estreptomicina y otros 158 pacientes, tratados entre 01/01/2000 y 31/12/2009 (G2) recibieron un esquema bisemanal o trisemanal con rifampicina/isoniazida. Se siguieron las recomendaciones de los programas de control de la Nación y la Ciudad. Los pacientes bajo TDO tuvieron tasas de tratamiento completo más elevadas (82.8% versus 48.7%), (p < 0.0001) con respecto a otros 483, que siguieron tratamiento autoadministrado (AUTO); la edad promedio fue de 36.3 ± 15.3 años, 63.1% eran varones y 69.4% tenían nacionalidad argentina. Presentaron tratamiento previo el 8.9%, comorbilidades el 6.1% y el 70.6% de las formas pulmonares fueron confirmadas bacteriológicamente. El 9.5% presentó efectos adversos a drogas y el sexo masculino presentó mayor frecuencia de abandonos (p = 0.004). Con respecto al G1, en el G2 hubo menor proporción de pacientes argentinos (48.7% vs. 77.1%), (p ≤ 0.0001), mayor frecuencia de comorbilidades (10.7% vs. 4.4%), (p = 0.005), de formas clínicas pulmonares con confirmación bacteriológica (95% vs. 87%), (p = 0.02) y de efectos adversos a drogas (17% vs. 6.6%), (p ≤ 0.0001). Hallamos tasas de cumplimiento total elevadas en TDO (82.8%), similares a las otras publicaciones.

The outcomes of directly observed therapy of tuberculosis (DOT) between 1/1/1979 and 12/31/2009 were analyzed. Results obtained in the 1979-1999 period were compared with those achieved in the 2000-2009 period. In a Buenos Aires City hospital, 582 HIV negative TB patients received rifampin, isoniazid, pyrazinamide and ethambutol or streptomycin in the initial stage, followed by a second stage where patients were included in two groups: G1 composed by 424 patients (period 1/1/1979-12/31/1999) who received either rifampin and isoniazid or rifampin and streptomicin twice a week, and G2, with 158 patients (period 1/1/2000-12/31/2009) who received either rifampin and isoniazid twice or three times a week. National and Buenos Aires City TB Control Programs recommendations were followed. Patients who underwent DOT had higher completeness rates than those included in self-administered therapy (82.8% vs. 48.7%), (p <0.0001). Mean age: 36.3±15.3 years, males: 63.1% and 69.4% were Argentine citizens. A 8.9% had been previously treated, 6.1% had co-morbidities. A 70.6% of pulmonary cases was bacteriologically confirmed, 82.8% of them completed the treatment, while 11.5% defaulted. Adverse effects to antituberculosis drugs were observed in 9.5% of cases; male patients showed higher rates of non adherence. G2 had a lower proportion of native people (48.7% vs. 77.1%), (p ≤ 0.0001), higher frequency of co-morbidities (10.7% vs. 4.4%), (p = 0.005), of bacteriologically confirmed pulmonary cases (95% vs. 87%), (p = 0.02) and more adverse effects than G1 (17% vs. 6.6%), (p ≤ 0.0001). In coincidence with other experiences, this work shows high treatment success rates in patients treated under DOT strategy.

Falla hepática secundaria a toxicidad por tuberculostáticos: Caso clínico / Fulminant hepatic failure due to tuberculostatic drugs: Case report

La toxicidad hepática por isoniacida, sobre todo asociada a rifampicina, es un raro efecto adverso de la terapia antituberculosa. En EE.UU., es la causa de 0,2% de los trasplantes hepáticos pediátricos y del 14% de los trasplantes por toxicidad medicamentosa. Comunicamos el caso de una paciente de 10 años de edad con falla hepática fulminante que requirió trasplante hepático luego de cuarenta días de tratamiento tuberculostático con isoniacida, rifampicina y pirazinamida.

Hepatoxicity of isoniazid, mainly in association with rifampin, is a rare secondary effect of tuberculostatic treatment. In the United States, it accounts for 0.2% of all pediatric orthotropic liver transplant, and 14% of transplants for drug hepatotoxicity. We report the case of a 10 year-old patient who presented with acute liver failure requiring orthotropic liver transplant after forty days of tuberculostatic treatment with isoniazid, rifampin and pyrazinamide.

Resposta paradoxal após o início de tratamento para tuberculose: relato de caso / Paradoxical response after initiation of tuberculosis treatment: case report

JUSTIFICATIVA E OBJETIVOS: A reação paradoxal pode ser identificada em até 30% de todos os pacientes após o início de tratamento para tuberculose, embora seu diagnóstico permaneça um desafio, já que não existem testes confiáveis que o corroborem. O objetivo deste estudo foi relatar um caso em que o diagnóstico de reação paradoxal foi realizado.RELATO DO CASO: Paciente do sexo masculino, 31 anos,um mês após o início de uso de fármacos para tratamento de tuberculose miliar, com diagnóstico realizado por lavado broncoalveolar, apresentou plegia no membro inferior direito, parestesia no membro superior direito e membro inferior esquerdo, incontinência urinária e fecal. Ressonância nuclear magnética do encéfalo evidenciou múltiplas áreas com hipersinal em T2, predominando em substância branca subcortical em ambos os hemisférios, com realce de lesões nodulares, sugestivas de infecção oportunista. Antivírus da imunodeficiência humana 1/2 foi negativo. PCR DNA para M. tuberculosis no líquor foi negativa. Iniciou-se, então, dexametasona. O paciente apresentou melhora significativa, porém permaneceu com incontinência urinária.Tomografia computadorizada de crânio realizada posteriormente não evidenciou quaisquer alterações. CONCLUSÃO: Apesar de sua elevada prevalência, continua difícilr ealizar o diagnóstico de reação paradoxal após o início de tratamento para tuberculose. Mais estudos são necessários para melhor definir os parâmetros diagnósticos e para orientar diretrizes terapêuticas mais efetivas.

BACKGROUND AND OBJECTIVES: Paradoxical response can be identified in up to 30% of all patients after initiation of tuberculosis treatment, although your diagnosis still remains a challenge, mainly because do not exist trustworthy tests to confirm it. These study aimed to describe a case were the diagnosis of a paradoxical response was made.CASE REPORT: Male patient, 31 year-old, a month after the initiation of miliary tuberculosis treatment, with the diagnosis realized by bronchoalveolar lavage, presented right lower limb plegia, right upper limb paresthesia, urge and fecal incontinence. Brain Magnetic Resonance Imaging evidenced hyper signs of T2 in multiple areas, in which predominated in white subcortical substance, beyond enhancing nodular lesions, suggesting an opportunistic infection. Anti human immunodeficiency virus 1/2 was negative. PCR DNA to M. tuberculosis in liquor was negative. After, dexamethasone treatment was started. The patient presented a significant improvement, but urge incontinence remained unchanged. Brain computed tomography realized after not evidence any alteration. CONCLUSION: Despite paradoxical response presents high occurrence, it continuous to be difficult to make the diagnosis of paradoxical response after initiation of tuberculosis treatment. Further studies are necessary in order to improve the diagnostic parameters and to orientate more effective therapeutic consensus.

Desfechos do retratamento de pacientes com tuberculose com o uso do esquema 3 em Porto Alegre, Brasil / Retreatment of tuberculosis patients in the city of Porto Alegre, Brazil: outcomes

OBJETIVO: Descrever os desfechos do retratamento de pacientes com tuberculose com o uso do esquema 3 (estreptomicina, etambutol, etionamida e pirazinamida por 3 meses + etambutol e etionamida por 9 meses) devido à falência do tratamento com o esquema básico (rifampicina, isoniazida e pirazinamida por 2 meses + rifampicina e isoniazida por 4 meses). MÉTODOS: Estudo descritivo de coorte histórica, não controlada, com adultos que foram tratados com o esquema 3. Foram avaliados os desfechos desse tratamento, as reações adversas aos fármacos, as recidivas e os fatores associados. RESULTADOS: Foram incluídos no estudo 229 pacientes. A taxa de cura geral foi de 62 por cento. Entre os pacientes que usaram a medicação regularmente e aqueles que a usaram irregularmente, a taxa de cura foi de 88 por cento e 31 por cento, respectivamente. Observaram-se reações adversas em 95 pacientes (41,5 por cento), principalmente digestivas. Ocorreram 17 recidivas (12,0 por cento) nos cinco anos de seguimento. CONCLUSIONS: Os desfechos com o uso do esquema 3, em geral, não foram satisfatórios, pois esse esquema foi aplicado em uma população selecionada com alto risco de não adesão ao tratamento e apresenta altas taxas de reações adversas, especialmente as de tipo digestivo, possivelmente causadas pela etionamida. No entanto, para aqueles que conseguiram tomar a medicação regularmente, a taxa de cura foi satisfatória. A taxa de recidiva foi superior àquela preconizada por consensos internacionais, possivelmente devido ao tempo de tratamento curto (apenas 12 meses). Acreditamos que o esquema 3 estendido para 18 meses poderia ser uma alternativa para pacientes com comprovada adesão ao tratamento.

OBJECTIVE: To describe the outcomes of retreatment in tuberculosis patients receiving the regimen known, in Brazil, as regimen 3 (streptomycin, ethambutol, ethionamide, and pyrazinamide for 3 months + ethambutol and ethionamide for 9 months) after treatment failure with the basic regimen (rifampin, isoniazid, and pyrazinamide for 2 months + rifampin and isoniazid for 4 months). METHODS: A descriptive, uncontrolled, historical cohort study involving adult tuberculosis patients treated with regimen 3. We evaluated adverse drug effects, recurrence, treatment outcomes, and associated factors. RESULTS: The study included 229 patients. The overall cure rate was 62 percent. For the patients who used the medications regularly and those who did not, the cure rate was 88 percent and 31 percent, respectively. Adverse events occurred in 95 patients (41.5 percent), and most of those events were related to the gastrointestinal tract. In the five-year follow-up period, relapse occurred in 17 cases (12.0 percent). CONCLUSIONS: Overall, the outcomes of treatment with regimen 3 were unsatisfactory, in part because this regimen was administered to a selected population of patients at high risk for noncompliance with treatment, as well as because it presents high rates of adverse effects, especially those related to the gastrointestinal tract, which might be caused by ethionamide. However, for those who took the medications regularly, the cure rate was satisfactory. The recurrence rate was higher than that recommended in international consensus guidelines, which might be attributable to the short (12-month) treatment period. We believe that regimen 3, extended to 18 months, represents an option for patients with proven treatment compliance.

Hígado y terapia antituberculosa / Hepatotoxicity of antituberculosis therapy

La toxicidad hepática en pacientes tratados con drogas antituberculosas es relativamente infrecuente, probablemente debido a este hecho no contamos con una buena definición de toxicidad hepática. Existen algunas condiciones de los enfermos en que la hepatotoxicidad es más frecuente, tales como pacientes envejecidos, bebedores de alcohol, desnutrición, uso de ciertas drogas e hipoalbuminemia. Las drogas antituberculosas más frecuentemente involucradas en hepatotoxicidad son la pirazinamida, la isoniacida y la rifampicina. En este artículo analizamos el problema clínico de la hepatotoxicidad de la terapia antituberculosa y proponemos el manejo de diferentes situaciones. Discutimos cuando se debe suspender la administración de una droga, cómo se debe evaluar el daño hepático y qué drogas alternativas pueden usarse durante el tratamiento de la tuberculosis.

Liver toxicity in patients being treated with antituberculosis drugs is relatively uncommon, although transient elevation of liver enzymes is very common. Probably because of this there is not a good definition for liver toxicity. There are conditions in which hepatotoxicity is more frequent, such as elderly patients, alcohol consumption, malnutrition, use of certain drugs, and hypoalbuminemia. Pirazinamide, isoniazid and rifampicin are the antituberculosis drugs more commonly involved in liver toxicity. In this article we analyze the clinical problem of hepatotoxicity of antituberculosis therapy and propose the management of different situations. We discuss when a drug administration should be discontinued, how liver damage should be assesed and which alternative drugs should be used during the antituberculosis treatment.

Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity / Hepatotoxicidade induzida pelos tuberculostáticos: comparação em pacientes com e sem soropositividade para o vírus da imunodeficiência humana

INTRODUCTION: The prevalence and risk factors for rifampin, isoniazid and pyrazinamide hepatotoxicity were evaluated in HIV-infected subjects and controls. METHODS: Patients with tuberculosis (30 HIV positive and 132 HIV negative), aged between 18 and 80 years-old, admitted to hospital in Brazil, from 2005 to 2007, were selected for this investigation. Three definitions of hepatotoxicity were used: I) a 3-fold increase in the lower limit of normal for alanine-aminotransferase (ALT); II) a 3-fold increase in the upper limit of normal (ULN) for ALT, and III) a 3-fold increase in the ULN for ALT plus a 2-fold increase in the ULN of total bilirubin. RESULTS: In groups with and without HIV infection the frequency of hepatotoxicity I was 77 percent and 46 percent, respectively (p < 0.01). Using hepatotoxicity II and III definitions no difference was observed in the occurrence of antituberculosis drug-induced hepatitis. Of the 17 patients with hepatotoxicity by definition III, 3 presented no side effects and treatment was well tolerated. In 8 (36.4 percent) out of 22, symptoms emerged and treatment was suspended. Alcohol abuse was related to hepatotoxicity only for definition I. CONCLUSIONS: Depending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. No death was related to drug-induced hepatotoxicity. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one third of the cases.

INTRODUÇÃO: Avaliou-se a prevalência e os fatores de risco para hepatotoxicidade aos tuberculostáticos em pacientes HIV positivos e controles. MÉTODOS: Selecionou-se 162 pacientes com tuberculose, tratados com rifampicina, isoniazida e pirazinamida, na faixa etária de 18 a 80 anos, internados em hospital público no Brasil, entre 2005 e 2007. Eles foram divididos em dois grupos: 30 infectados pelo HIV e 132 controles. Adotou-se três definições para hepatotoxicidade: I) aumento de três vezes no valor inferior normal da alanina-aminotransferase (ALT); II) aumento de três vezes no valor superior normal (VSN) da ALT; III) aumento de três vezes no VSN da ALT e duas vezes no VSN da bilirrubina total. RESULTADOS: Nos grupos com e sem infecção pelo HIV, a frequência de hepatotoxicidade I foi de 77 por cento e 46 por cento, respectivamente (p<0,01). Para as definições II e III a frequência de hepatotoxicidade não diferiu entre os grupos estudados. De 17 pacientes com hepatotoxicidade induzida por droga (definição III), três não apresentaram sintomas e o tratamento foi mantido sem intercorrências. Oito (36,4 por cento) de 22 indivíduos apresentaram efeitos colaterais e interromperam o tratamento, mas não apresentavam hepatotoxicidade pela definição III. O abuso de álcool associou-se à hepatotoxicidade apenas para a definição I. CONCLUSÕES: Na dependência da definição escolhida, a infecção pelo HIV pode ou não associar-se à hepatotoxicidade. Foi grande o impacto que pequenas alterações na definição de hepatotoxicidade tiveram nos resultados. Nenhuma morte associou-se ao uso de tuberculostáticos. O surgimento de sintomas não pôde ser atribuído aos tuberculostáticos em um terço dos casos.

Hepatotoxicity of ATT

To determine the frequency of hepatotoxicity with standard ATT. Descriptive. Department of Medicine, Combined Military Hospital Lahore. Feb 2007 to April 2008. 250 patients aged 18 years or greater having pulmonary TB were selected through non-probability convenience sampling technique. All patients were given four drugs for two months indoors, followed by two drugs for four months in outdoor. Symptoms suggestive of hepatotoxicity were enquired from the patients regularly. Serum bilirubin and ALT were measured on monthly basis and finally on completion of therapy. Hepatotoxicity was defined as a five fold rise in serum ALT. In patients developing hepatotoxicity, treatment was modified accordingly. This study was done on 189 male and 61 female patients [total: 250]. Hepatotoxicity developed in 13 [5.2%] patients, mostly during the initial phase of treatment [84.6% incidence during the first month]. Risk factors included: age [4 out of 156 young patients and 9 out of 94 older patients; p: 0.016] and nutritional status [8 malnourished patients and 5 well nourished patients; p: 0.031]. Hepatotoxicity was not related to the gender [9 males and 4 females; p: 0.585] or the results of baseline sputum smears [7 out of 102 smear positive cases and six out of 148 smear negative cases; p: 0.064]. Hepatotoxicity with ATT is fairly common, especially in the elderly, malnourished patients and during the initial phase of treatment

Análise do tratamento da tuberculose pulmonar em idosos de um hospital universitário do Rio de Janeiro, RJ, Brasil / Analysis of the treatment of pulmonary tuberculosis in elderly patients at a university hospital in Rio de Janeiro, Brazil

OBJETIVOS: Descrever os aspectos clínicos e terapêuticos da tuberculose pulmonar e comparar os efeitos adversos e resultados do tratamento entre idosos e não idosos. MÉTODOS: Foi realizado um estudo caso-controle com 117 indivíduos idosos (acima de 60 anos) e 464 não idosos (15-49 anos) portadores de tuberculose pulmonar atendidos no Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro no período de 1980 a 1996. RESULTADOS: No grupo de idosos, houve associação entre diabetes mellitus (OR = 3,98; IC95 por cento = 2,07-7,65; p = 0,001), doenças pulmonares (OR = 7,24; IC95 por cento = 3,64-14,46; p = 0,001) e cardiovasculares (OR = 5,86; IC95 por cento = 2.88-11.95; p = 0,001). O tabagismo (OR = 2,07; IC95 por cento = 1,26-3,42; p = 0,002) e o etilismo (OR = 1,63; IC95 por cento = 1,01-2,68; p = 0,041) também foram mais freqüentes neste grupo. O tratamento levou a freqüentes reações adversas nos idosos (OR = 1,62; IC95 por cento = 1,04-2,54; p = 0,024), principalmente de origem gastrintestinal (OR = 1,64; IC95 por cento = 1,01-2,77; p = 0,047), e sua eficácia foi menor neste grupo: apenas 51 por cento de cura e 24 por cento de óbitos. O abandono do tratamento foi elevado nos dois grupos, em torno de 23 por cento. CONCLUSÕES: As reações adversas e o resultado do tratamento foram piores nos idosos, com maior freqüência de complicações e letalidade, devido a uma maior toxicidade farmacológica e a uma maior prevalência de doenças associadas neste grupo etário.

OBJECTIVE: To describe the clinical and therapeutic aspects of pulmonary tuberculosis and compare the adverse effects of the treatment and its outcome in elderly and nonelderly patients. METHODS: This was a case-control study of 117 elderly individuals (over the age of 60 years) and 464 nonelderly individuals (aged 15-49 years). All subjects presented pulmonary tuberculosis that had been diagnosed and treated at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro between 1980 and 1996. RESULTS: In the elderly group, pulmonary tuberculosis was found to be correlated with diabetes (OR = 3.98; 95 percent CI = 2.07-7.65; p = 0.001), lung disease (OR = 7.24; 95 percent CI = 3.64-14.46; p = 0.001) and heart disease (OR = 5.86; 95 percent CI = 2.88-11.95; p = 0.001). Smoking (OR = 2.07; 95 percent CI = 1.26-3.42; p = 0.002) and alcohol abuse (OR = 1.63; 95 percent CI = 1.01-2.68; p = 0.041) were also more common in the elderly group. In the elderly group, the treatment more frequently resulted in adverse reactions (OR = 1.62; 95 percent CI = 1.04-2.54; p = 0.024), especially gastrointestinal reactions (OR = 1.64; 95 percent CI = 1.01-2.77; p = 0.047), and treatment efficacy was lower: cure rate, 51 percent; mortality rate, 24 percent. Treatment adherence was low (approximately 77 percent) in both groups. CONCLUSIONS: In the elderly group, adverse reactions were more common, treatment outcomes were less favorable, there was a greater frequency of clinical complications and deaths related to drug toxicity, and the prevalence of concomitant diseases was higher.

Pyrazinamide induced hyperuricaemia presenting as severe bilateral leg cramps.

Pyrazinamide is one of the first line drugs used for the treatment of tuberculosis. Hepatotoxicity and hyperuricaemia are important and common untoward effects seen after administration of pyrazinamide. The drug inhibits elimination of urates resulting in hyperuricaemia, the presenting features of which are arthralgia, arthritis or even gout. A-case of bilateral leg cramps due to hyperuricaemia following pyrazinamide therapy is reported here.

Tuberculous ulcer of tongue with oral complications of oral antituberculosis therapy.

Tuberculosis (TB) is an infectious disease affecting humans of all ages in all parts of the world. The dentist plays an important role in the identification and control of this condition by early recognition of oral lesions that may precede the detection of the pulmonary form. Occurrence of increased incidence of mycobacterial infections as a part of the spectrum of AIDS only emphasizes the importance of early diagnosis. A case of a tuberculous ulcer on the tongue along with oral ulcerations, which occurred as a consequence of oral antituberculosis therapy (ATT), is presented. Such complications have rarely been reported in the literature and the management of these is described herein. The tuberculous ulcer healed uneventfully in five weeks after institution of ATT and the other ATT-induced ulcers healed after a week of topical anesthetic application. The clinical presentations, differential diagnoses to be considered, and management of such oral manifestations is discussed. The occupational risk posed by TB to the dentist and appropriate precautions to be observed have been highlighted.

Antituberculous therapy-induced toxicity.

Antituberculous drugs are generally safe but can occasionally be associated with life-threatening complications. This is a case report of neurotoxicity, acute respiratory distress syndrome (ARDS) and drug fever, occurring in a patient after initiation of antituberculous therapy (ATT).

Effects of pyrazinamide on pregnant albino rats

Although being used for years in the treatment of tuberculosis, no data are available in the literature on the safety of pyrazinamide during pregnancy. Accordingly, we aimed to make a first approach to this problem by evaluating the effects of this drug administered during the entire pregnancy of albino rats. Fourty female, EPM-1 Wistar albino rats of about 250 g b.w. were used. Upon conception (day zero of pregnancy) the animals were randomly divided in 4 groups of 10 rats each and labeled as follows. Controls (C), animals treated with the drug vehicle (destilled water); experimental groups (E1, E2 and E3), animals treated with 35, 105 or 315 mg/kg b.w. pyrazinamide by gavage (oral route) once daily up to the term (20th day of pregnancy). Drug or vehicle volume was always 0.5 ml. Body weight gain was followed up every week. At term, upon sacrifice (in excess of anesthesia) and histerectomy, the following parameters have been studied: number of implantations and reabsorptions; intrauterine deaths; number of living foetuses and of placentae; weights of concepts and of placentae; major foetal malformations; maternal mortality index. No significant effects of pyrazinamide on rat pregnancy have been observed regarding the maternal body weight gain, the weights of concepts, the number of implantations and reabsorptions and the weights of placentae and foetuses. Also, no deleterious effects have been noticed regarding major foetal malformations, intrauterine deaths or maternal mortality. With the highest pyrazinamide dosis employed (315 mg/kg b.w.), however, a significant lowered uterine weight was recorded. Although otherwise safe, a high-dose regimen of pyrazinamide during rat pregnancy can induce a slight yet significant reduction of uterine weight.

Use od standard therapy for tuberculosis in associated with increased adverse reactions in patients with HIV

Hepatitis due to anti-tuberculosis therapy in an infrequent, but potentially devastating event. In HIV positive patients with tuberculosis (TB), the consequences are likely to be even greater, as they frequently require other hepatoptoxic medications. The object of our study was to determine the frequency to toxic hepatitis during therapy for TB. Included were 198 patients with a presumed or confirmed diagnosis of tuberculosis; of whom, 69 were HIV positive (35 percent), 75 were negative (38 percent) and 54 had unknown HIV status (27 percent). Toxic hepatitis occurred in 15/198 (8 percent) patients. The incidence of hepatitis in HIV patients was much greater than in HIV negative/unknown [RR=7.5 (2.2-25.6); p=0.0001] and the onset of hepatitis was short (median 7 days in HIV patients). During TB therapy, 1 in 8 (12.5 percent) patients taking ketoconazele developed hepatitis; 9/53 (17 percent) taking sulfamethoxazole-trimethoprim [RR=3.4 (1.1-9.3); p=0.03]. Among the 15 patients who developed hepatitis 11 required hospitalization (mean 19 days), 5 dfied (33.3 percent), 2/15 (13 percent) due to hepatitis. HIV positive patients had a significantly higher rate of toxic hepatitis during anti-tuberculosis therapy than those without HIV infection. Hepatitis occurred just after initiation of TB treatment. Clinical findings were non-specific and hepatic enzyme elevations were moderate, yet hospitalization and mortality rates were high. This suggests that in settings where careful monitoring of patients early in their course of TB treatment is routine, morbibity and mortality may be loe, but poor monitoring would have potentially serious consequences. There is a need for new drug treatments (schedules or regimens) for TB in an effort to reduce these adverse events.

Alteraçöes funcionais hepáticas induzidas pelo uso concomitante de isoniazida, pirazinamida e rifampicina no tratamento da tuberculose pulmonar / Hepatic changes induced by the use of isoniazid, pyrazinamide and rifampicin in the treatment of pulmonary tuberculosis

No Brasil, os portadores de tuberculose pulmonar sao tratados atravTs da associatpo rifampicina (600 mg), isoniazida (400 mg) e pirazinamida (2 g) ao dia, durante seis meses. Tal forma de terapOutica pode levar ao aparecimento de les)es hepßticas agudas ou cr(nicas. Com finalidade de caracterizß-las, estudamos 1096 portadores de tuberculose pulmonar, sendo 773 do sexo masculino e 323 do feminino. Destes, 66 desenvolveram sinais clfnicos e laboratoriais de agresspo as cTlulas parenquimatosas do ffgado. Do total, 21 (31,81 por cento) cursaram com elevat)es dos nfveis sTricos de bilirrubinas, enquanto 45 (68,19 por cento) com acentuatpo das concentrat)es plasmßticas de aminotransferases. Estas, foram mais freqnentes entre as mulheres, npo guardando relatpo entre ratas ou faixa etßria. Normalizatpo das taxas ocorreu mais rapidamente entre etilistas e npo-tabagistas. As alterat)es hepßticas foram caracterizadas como de pequena e mTdia intensidade, traduzidas por colestase pura ou reat)es hepßticas do tipo hepatocanalicular. Possivelmente, a rifampicina foi importante nesta evolutpo, atuando como potencializador das at)es despertadas pela isoniazida e pirazinamida.