Effects of Solanum lycopersicum L. (tomato) against isoniazid and rifampicin induced hepatotoxicity in wistar albino rats / Efeitos de Solanum lycopersicum L. (tomate) contra hepatotoxicidade induzida por isoniazida e rifampicina em ratos albinos wistar

Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferroni's post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

As drogas antituberculose são relatadas como causadoras de hepatotoxicidade, ocasionando o aumento assintomático das enzimas hepáticas. As plantas hepatoprotetoras desempenham um papel importante na proteção do fígado. Este estudo investigou o potencial hepatoprotetor de Solanum lycopersicum em ratos que foram intoxicados com isoniazida e rifampicina (INH + RIF) para induzir hepatotoxicidade. Trinta ratos wistar albinos foram divididos em cinco grupos de seis animais cada. Os ratos do grupo 1 representaram o grupo controle, enquanto os ratos dos grupos II, III, IV e V receberam INH + RIF (75 + 150 mg/kg) por via oral, por sete dias consecutivos. Para o tratamento, os ratos do grupo III receberam silimarina, enquanto os animais do grupo IV e V receberam 40 mg/kg e 80 mg/kg de extrato de S. lycopersicum, respectivamente. Nos dias 0 e 8, foram coletadas amostras de sangue para análise de biomarcadores hepáticos. Os dados foram submetidos a teste unilateral (ANOVA) e post hoc de Bonferroni para análise estatística. A hepatotoxicidade induzida por INH + RIF resultou em elevação significativa das enzimas hepáticas séricas, incluindo aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina (ALP) e bilirrubina total, enquanto houve a diminuição do nível de albumina. O S. lycopersicum, na dose de 80 mg / kg, reduziu significativamente as enzimas hepáticas AST, ALT, ALP e bilirrubina, enquanto o nível de albumina aumentou de forma significativa. O tratamento não teve efeito significativo no peso corporal e hepático. A hepatotoxicidade induzida por drogas pode ser tratada de forma eficaz com S. lycopersicum na dose de 80 mg/kg.

Isoniazid use, effectiveness, and safety for treatment of latent tuberculosis infection: a systematic review

ABSTRACT Background: The treatment strategy for latent tuberculosis infection is to reduce the number of tuberculosis cases and consequently reduce the transmission of pathogenic bacteria. This study aimed to determine the safety, effectiveness, and adherence of isoniazid use for latent tuberculosis infection treatment. Methods: To identify studies on isoniazid use for latent tuberculosis infection, five electronic databases were searched. The methods and results are presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Most studies (53) used isoniazid for 9 months. The prevalence of use and adherence to treatment varied considerably (18% to 100%), and were evaluated by participant completion of isoniazid treatment for latent tuberculosis infection. The adverse events most frequently reported were hepatotoxicity, gastric intolerance, and neuropathy; the rates of occurrence ranged from < 1% to 48%. In the studies that evaluated the effectiveness of isoniazid for latent tuberculosis infection, the rate varied from 0 to 19.7% for patients who did not have active tuberculosis after the follow-up period. Conclusions: The importance of maintaining follow up for patients using isoniazid should be emphasized due to the risk of developing adverse events. Despite the treatment challenges, the rates of patients who used isoniazid and developed active tuberculosis during the follow-up period were low. We believe that isoniazid continues to contribute to tuberculosis control worldwide, and better care strategies are required.

Effects of Solanum lycopersicum L. (tomato) against isoniazid and rifampicin induced hepatotoxicity in wistar albino rats

Abstract Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferronis post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

Resumo As drogas antituberculose são relatadas como causadoras de hepatotoxicidade, ocasionando o aumento assintomático das enzimas hepáticas. As plantas hepatoprotetoras desempenham um papel importante na proteção do fígado. Este estudo investigou o potencial hepatoprotetor de Solanum lycopersicum em ratos que foram intoxicados com isoniazida e rifampicina (INH + RIF) para induzir hepatotoxicidade. Trinta ratos wistar albinos foram divididos em cinco grupos de seis animais cada. Os ratos do grupo 1 representaram o grupo controle, enquanto os ratos dos grupos II, III, IV e V receberam INH + RIF (75 + 150 mg/kg) por via oral, por sete dias consecutivos. Para o tratamento, os ratos do grupo III receberam silimarina, enquanto os animais do grupo IV e V receberam 40 mg/kg e 80 mg/kg de extrato de S. lycopersicum, respectivamente. Nos dias 0 e 8, foram coletadas amostras de sangue para análise de biomarcadores hepáticos. Os dados foram submetidos a teste unilateral (ANOVA) e post hoc de Bonferroni para análise estatística. A hepatotoxicidade induzida por INH + RIF resultou em elevação significativa das enzimas hepáticas séricas, incluindo aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina (ALP) e bilirrubina total, enquanto houve a diminuição do nível de albumina. O S. lycopersicum, na dose de 80 mg / kg, reduziu significativamente as enzimas hepáticas AST, ALT, ALP e bilirrubina, enquanto o nível de albumina aumentou de forma significativa. O tratamento não teve efeito significativo no peso corporal e hepático. A hepatotoxicidade induzida por drogas pode ser tratada de forma eficaz com S. lycopersicum na dose de 80 mg/kg.

Avances en tuberculosis en el 54° Congreso Chileno de enfermedades respiratorias. 3a parte: Prevención de la tuberculosis activa mediante el tratamiento de la tuberculosis latente / Advances in tuberculosis at the 54th Chilean Congress of Respiratory Diseases. Part 3: prevention of active tuberculosis by treating latent tuberculosis

La infección tuberculosa latente (ITL) es un estado asintomático de la infección por Mycobacterium tuberculosis incapaz de transmitir la infección a otros, pero con el potencial de originar una tuberculosis (TBC) activa en el infectado, especialmente ante la presencia de factores de riesgo inmunológico. Es importante en personas de riesgo de desarrollar TBC reconocer la ITL utilizando test como la reacción a la tuberculina (PPD o TST) y los ensayos de liberación de Interferón-γ (IGRAs). Sin embargo, estos tests tienen limitaciones en su capacidad de predicción de riesgo de evolución de infección a enfermedad lo que conlleva a tener que tratar muchas personas para evitar algún caso de enfermedad. Nuevos tests se encuentran en desarrollo para mejorar la sensibilidad de reconocimiento de la ITL, distinguir infecciones recientes (que tienen el mayor riesgo de progresión a enfermedad) e incluso con la capacidad de detectar enfermedad subclínica o inicial. Para reducir la probabilidad de enfermar por TBC se utilizan tratamientos preventivos con fármacos, pero la cobertura mundial de esta terapia es reducida y la adherencia a terapias auto-administradas, como en el caso del uso de isoniazida diaria oral, es también baja. Otro problema de esta terapia son los riesgos de reacciones adversas (hepatitis, erupciones cutáneas) aunque no frecuentes. La recomendación de terapia actual de la ITL incluye el uso de rifamicinas y sus derivados. La asociación de isoniazida con rifapentina en una dosis semanal durante tres meses, administrada bajo supervisión, es la terapia de primera línea para mayores de 2 años, mostrando menos riesgo de hepatotoxicidad y mayor adherencia.

Latent Tuberculosis infection (LTBI) is the asymptomatic state of infection caused by Mycobacterium tuberculosis. Although untransmissible, LTBI can progress to active tuberculosis (TB), especially in people with immune risk factors. It is important to recognize LTBI in people at risk of developing TB; tuberculin skin test (PPD or TST) or interferon-γ release assays (IGRAs) are current diagnostic tests. However, these tests have limitations in their ability to predict subjects who will evolve from infection to disease; consequently, a large number of people with LTBI need treatment to avoid a reduced number of future TB disease cases. Newer tests are under development to improve the sensitivity in recognizing LTBI, distinguish recent infections with highest risk of progression to disease, and even be able to detect initial subclinical disease. Antimicrobial preventive treatment effectively reduces the probability of getting sick with TB, but worldwide availability of TB preventive therapy is limited, and adherence to self-administered therapies, as in the case of the use of daily oral isoniazid, is low. Adverse reactions risk (hepatitis, skin rash) although infrequent, is another problem with these therapies. Currently, LTBI management guidelines include regimens with use of rifamycins and their derivatives. The combination of isoniazid and rifapentine in a weekly dose for three months administered under supervision is the first line choice for LTBI therapy in those over 2 years of age, showing less hepatoxicity risk and greater adherence.

Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis

ABSTRACT Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

Avances en tuberculosis en el 54° congreso chileno de enfermedades respiratorias. 1ra parte: nuevos esquemas acortados para tuberculosis drogoresistente ¿son adecuados para todos? / New shortened schemes for drug-resistant tuberculosis: are they suitable for everyone?

En esta presentación se realiza un recorrido a través de los diferentes esquemas terapéuticos de la tuberculosis drogo-resistente. Se muestra como los investigadores utilizan los nuevos fármacos disponibles y desarrollan diferentes esquemas cada vez más acortados y de administración por vía oral exclusiva, con la intención de lograr una mayor eficacia de curación de la tuberculosis resistente, con menos efectos colaterales y menor letalidad. La búsqueda de esquemas con una duración similar a las terapias de casos sensibles de tuberculosis (esquemas primarios de 6 meses) es el objetivo principal. Las pruebas moleculares como el Xpert ayudan enormemente a seleccionar los esquemas de terapia, según el perfil de susceptibilidad de los casos (resistencia a isoniazida, rifampicina, fluorquinolonas y combinaciones). Las terapias actuales de la tuberculosis drogo-resistente se basan en nuevos fármacos como fluorquinolonas, bedaquilina y linezolid, pero otros fármacos como pretomanid y delamanid también están siendo recomendados.

This presentation takes a tour through the different therapeutic schemes of drug-resistant tuberculosis. It shows how researchers use the new drugs available and develop different increasingly shortened schedules and exclusive oral administration, with the intention of achieving greater efficacy in curing resistant tuberculosis, with fewer side effects and lower lethality. The search for regimens with a duration similar to therapies of sensitive cases of tuberculosis (primary regimens of 6 months) is the main objective. Molecular tests, such as Xpert, greatly help in selecting therapy regimens, according to the susceptibility profile of the cases (resistance to isoniazid, rifampicin, fluorquinolones and combinations). Current drug-resistant tuberculosis therapies are based on new drugs such as fluorquinolones, bedaquiline and linezolid, but other drugs such as pretomanid and delamanid are also being recommended.

Synthesis, spectral characterization, anti-bacterial, cytotoxic evaluation and docking studies of new urea and thiourea derivatives

Isoniazid is one of the main API’s used in the combination treatment of tuberculosis recommended by the WHO. Urea and its derivatives are an important class of heterocyclic compounds that possess a wide range of therapeutic and pharmacological properties, while thiourea is an organosulphur compound in that it resembles urea except that the atom oxygen has been replaced by a Sulphur atom, but the properties of urea and thiourea are significantly different. The current work concerns the synthesis of a new class of urea and thiourea derivatives of isoniazid with various isocyanates and isothiocyanates in the presence of trimethylamine. The IR and NMR spectral data were performed for the urea and thiourea derivatives of the compounds [(3c & 3f) & (3d & 3e)], respectively. Molecular docking studies of the compounds (3a-h) revealed the binding mode involved in the active site of DNA gyrase. The synthesized urea and thiourea derivatives of isoniazid with various isocyanates and isothiocyanates were tested for their antibacterial activity against gram-positive and gram-negative bacteria using the “disc diffusion method”. Of all compounds tested, the urea derivatives (3a &3d), the thiourea derivatives (3e & 3g) showed more potent activity than the other compounds. The MTT assay revealed concentration dependent cytotoxic effects over a concentration range 25-200 µg/mL.

ISOLATION IDENTIFICATION AND PATTERNS OF ANTI-TUBERCULOSIS DRUG RESISTANCE FROM TERTIARY CARE HOSPITAL UDAIPUR (RAJASTHAN)

Objective: Resistance against Mycobacterium tuberculosis (MTB) is important in the sense that it has an implication in the control of tuberculosis. The terms used to describe resistance to antituberculosis drugs are resistance among new cases (or primary resistance) and resistance among previously treated patients. The resistance among previously treated patients may be due to faulty treatment like prescription of inadequate treatment regimens, interrupted availability or poor quality of drugs, or incomplete treatment adherence while subsequent transmission of these resistant organisms to others will lead to development of disease which is resistant from the beginning called primary resistance. Pakistan is ranked eighth in terms of global estimated burden of tuberculosis cases. Multi-Drug Resistant (MDR) tuberculosis among new cases and MDR among previously treated patients is 3.2% and 35% respectively. Material and methods: - AFB smear examination and grading: - AFB smear examination was carried out by direct microscopy using the Ziehl Neelsen (ZN) method. Sputum smear result was examined and interpreted according to the AFB grading. AFB culture and drug susceptibility test: - Culture examinations were done on all diagnostic specimens of AFB smear positivity. Sputum specimens from each patient were processed with sodium hydroxide (NaOH) method-Modi?ed Petroff 's procedure and cultured on Lowenstein-Jensen (LJ) slopes.10 All inoculated LJ drug and control media were incubated at 37ºC. All cultures were examined 48-72 hours after inoculation to detect gross contaminants. Thereafter, cultures were examined weekly, up to eight weeks on a speci?ed day of the week. Typical colonies of M. tuberculosis were rough, crumbly, waxy, non-pigmented (buff coloured) and slow-growers, i.e., only appeared two to three weeks after inoculation. The colony was con?rmed by ZN staining. Detection time for MOTT was 25 days. M. tuberculosis positive strains were culture negative when they grew on p-nitro benzoate (PNB) containing medium. Only a few colonies of non-tuberculosis Mycobacteria (NTM – often pigmented, with smooth morphology or PNB positive) were grown as visible colonies on PNB containing medium. Anti-TB drug susceptibility testing: - anti-susceptibility testing perform on pre-formed LJ media with antitubercular drugs Tuberculosis First Line Kit (Total 7 slants) Containing ?ve antitubercular agent (Isoniazid, Streptomycin, Ethambutol, Rifampicin and Pyrazinamide) 2 controls without any antimicrobial agent. Results: out of 119 samples antitubercular testing against ?rst line antitubercular drugs such as Pyrazinamide were shows 12 (10.08%) sample were resistance which accounts maximum resistance among ?rst line antitubercular another ?rst line antitubercular drugs shows resistance as follows Streptomycin (9.24%), Ethambutol (8.40%), Isoniazid (7.56%), Rifampicin (6.72%), drugs out of 119 samples in which 107 samples were susceptible to the Pyrazinamide drug in in-vitro antitubercular susceptibility testing. Antitubercular resistance against second line antitubercular drugs were shows as follows out of 119 samples antitubercular testing Ethionamide were shows 9 (8.18%) sample were resistance which accounts maximum resistance among second line antitubercular another second line antitubercular drugs shows resistance as follows Clarithromycin (6.72%), Cipro?oxacin (5.88%), D- Cycloserine (5.88%), Amikacin (5.04%), Kanamycin (4.20%), P- aminosalicylic acid ( 4.20%) and Rifabutin (3.36%) drugs out of 119 samples in which 107 samples were susceptible to the Pyrazinamide drug in in-vitro antitubercular susceptibility testing. MDR-TB emerged in patients who were resistant to Rifampicin and Isoniazide was 6 in number during this study.

Treatment outcome and influencing factors of isoniazid mono-resistant pulmonary tuberculosis / 中华传染病杂志

Objective:To analyze the outcomes of isoniazid (INH) mono-resistant pulmonary tuberculosis, and risk factors associated with adverse treatment outcomes of INH mono-resistant pulmonary tuberculosis.Methods:A total of 114 cases of INH mono-resistant pulmonary tuberculosis in Xi′an Chest Hospital from January 1, 2018 to December 31, 2020 were retrospectively recruited for analysis. The general information, clinical symptoms, and laboratory test results of patients were collected. With treatment success and adverse treatment outcomes as dependent variables, binary logistic regression analysis was used to analyze the risk factors for the adverse treatment outcome of INH mono-resistant pulmonary tuberculosis.Results:Among 114 patients with INH mono-resistant tuberculosis, 46 cases (40.4%) were cured and 41 cases (36.0%) completed treatment with the success rate of 76.3%(87/114), while 11 cases (9.6%) failed treatment, 13 cases (11.4%) lost to follow up, three cases (2.6%) died.The binary logistic regression analysis showed that male (odds ratio ( OR)=7.22, 95% confidence interval ( CI) 1.47 to 35.43)), no fever at onset ( OR=12.97, 95% CI 2.74 to 61.55), not containing amikacin in the regimen ( OR=5.28, 95% CI 1.20 to 23.31), sputum bacteria load >1+ ( OR=5.87, 95% CI 1.76 to 19.60) were the risk factors for adverse treatment outcomes of INH mono-resistant tuberculosis. Conclusions:The treatment success rate of INH mono-resistant pulmonary tuberculosis patients is high. The risk factors for adverse treatment outcome are male, no fever at the onset, not containing amikacin in the regimen, and sputum bacteria load >1+ .

Pharmacokinetics of isoniazid in Wistar rats exposed to ethanol

Abstract Tuberculosis treatment consists of a drug combination, where isoniazid is the core drug and alcoholism is a factor highly related to poor patient compliance with the therapy. CYP2E1 is an enzyme involved both in the metabolism of ethanol and in the formation of hepatotoxic compounds during the metabolism of isoniazid. The shared metabolism pathway accounts for the possibility of pharmacokinetic interaction in cases of concomitant alcohol use during tuberculosis treatment. The aim of this study was to evaluate the effect of repeated exposure of Wistar rats (males, 250 g, n=6) to ethanol on the pharmacokinetics of a single dose of isoniazid in combination with pyrazinamide and rifampicin (100 mg/kg, 350 mg/kg and 100 mg/kg, respectively). An animal group received the combination of drugs and ethanol and was compared to a control group, which received the combination of drugs without exposure to ethanol. The plasma concentrations of isoniazid were determined by a UHPLC/UV bioanalytical method that was previously validated. Biochemical markers of liver function were measured to assess potential damage. A lower elimination half-life of isoniazid was observed in the ethanol group than in the control group (t1/2 0.91 h versus 1.34 h). There was no evidence of hepatotoxicity through the biomarker enzymes evaluated. The results allow us to infer that although there are no biochemical changes related to liver damage, there is a slight influence of ethanol exposure on the pharmacokinetic profile of isoniazid. This change may have a relevant impact on the efficacy of isoniazid in the outcome of tuberculosis treatment.

Discourses of health professionals on latent tuberculosis infection and the use of isoniazid / Discursos de profesionales de la salud sobre infección tuberculosis latente y uso de isoniazida / Discursos de profissionais de saúde sobre infecção latente por tuberculose e uso de isoniazida

ABSTRACT Objective to understand the collective thinking and action of health workers in relation to Latent Tuberculosis Infection and its treatment with Isoniazid. Method qualitative study with 22 health professionals from four cities in Brazil and the Federal District. Data collection occurred through a semi-structured group interview in March 2019, with an average duration of one hour and thirty minutes. Content analysis was performed using the Collective Subject Discourse technique. Results the professionals' discourses revealed uncertainties related to the prevention and treatment of Latent Tuberculosis Infection, the "fear of error" and inadequate forms of use of Isoniazid 300 mg, the power of the decision on the treatment of Latent Tuberculosis Infection, the difficulties of integration between services and the organization of care flows. Conclusion although the emphasis in the professionals' discourse considers objective aspects in the management of Latent Tuberculosis Infection, subjective manifestations related to the need to address the fears that affect the decision about treatment and possible medication errors were identified, among others, and to think about this process in a collaborative way, which considers autonomy in acting, both of professionals and of the person with Latent Tuberculosis Infection.

RESUMEN Objetivo comprender el pensamiento y la acción colectiva de los trabajadores de la salud en relación con la Infección Latente de Tuberculosis y el uso de Isoniazida en el enfrentamiento de la enfermedad. Método estudio cualitativo con 22 profesionales de la salud de cuatro ciudades de Brasil y del Distrito Federal. La recolección de datos ocurrió a través de una entrevista colectiva semiestructurada, en marzo de 2019, con una duración promedio de una hora y treinta minutos. El análisis de contenido se realizó mediante la técnica del Discurso del Sujeto Colectivo. Resultados los discursos de los profesionales revelaron incertidumbres relacionadas con la prevención y el tratamiento de la Infección Tuberculosa Latente, el "miedo a equivocarse" y las formas inadecuadas de uso de Isoniazida 300 mg, el poder de decisión sobre el tratamiento de la Infección Tuberculosa Latente, las dificultades para la integración de servicios y la organización de los flujos de atención. Conclusión aunque el énfasis en el discurso de los profesionales considera aspectos objetivos en el manejo de la Infección Tuberculosa Latente, se identificaron manifestaciones subjetivas relacionadas con la necesidad de abordar los miedos que afectan la decisión sobre el tratamiento y posibles errores de medicación, entre otros, y pensar sobre este proceso de forma colaborativa, que considera la autonomía de actuación, tanto de los profesionales como de la persona con Infección Tuberculosa Latente.

RESUMO Objetivo compreender o pensar e o agir coletivo de trabalhadores da saúde em relação à Infecção Latente por Tuberculose e ao uso da Isoniazida no enfrentamento da doença. Método estudo qualitativo com 22 profissionais de saúde de quatro cidades do Brasil e do Distrito Federal. A coleta de dados ocorreu mediante realização de entrevista coletiva semiestruturada, em março de 2019, com duração média de uma hora e trinta minutos. Realizou-se análise de conteúdo pela técnica do Discurso do Sujeito Coletivo. Resultados os discursos dos profissionais revelaram incertezas relacionadas à prevenção e ao tratamento da Infecção Latente por Tuberculose, ao "medo de errar" e formas inadequadas de uso da Isoniazida 300 mg, ao poder da decisão sobre o tratamento da Infecção Latente por Tuberculose, às dificuldades da integração entre os serviços e à organização de fluxos assistenciais. Conclusão embora a ênfase no discurso dos profissionais considere aspectos objetivos no manejo da Infecção Latente por Tuberculose, foram identificadas, dentre outras, manifestações subjetivas relacionadas à necessidade de trabalhar os receios que afetam a decisão sobre o tratamento e os possíveis erros de medicação, e de pensar esse processo de forma colaborativa, que considere autonomia no agir, tanto dos profissionais quanto da pessoa com Infecção Latente por Tuberculose.

Quality analysis of some drugs against tuberculosis an in vitro study / Монголын эм зүй, эм судлал

Introduction@#According to the statistical data of 2019, 10 million people in 202 countries have been registered as tuberculosis cases, 1.6 million people has died around the world. In 2019, 4,089 new tuberculosis cases were determined, of which 265 died in Mongolia.@*Purpose@#The purpose of this study is analyze quality of some drugs used in the treatment of certain groups of tuberculosis in accordance with international standards.@*Materials and methods@#Isoniazid 300 mg, Rifampicin 150 mg, Pyrazinamide 400 mg and Ethambutol 400 mg, which are commonly used in Mongolia, were analyzed according to the pharmacopoeia methods of United States, Chinese and British.@*Results@#Appearance - Complies with the requirements of the certificate for sensory examination. Identification - It was determined by an infrared spectrophotometry. Average weight - Isoniazid 547.5 mg, Rifampicin 277.6 mg, Pyrazinamide 640.8 mg, Etambutol 399.6 mg. DisintegrationIsoniazid decomposes in 2.5 minutes, Pyrazinamide decomposes in 4.6 minutes, Etambutol decomposes in 8.5 minutes. Friability – Isoniazid - 0.4%, Pyrazinamide 10.4%, Hardness – Isoniazid 0.4%, Pyrazinamide is - 49.7 N, Dissolution – Isoniazid not less than - 95.7%, Rifampicin - 78.7%, Pyrazinamide - 95.7%, Assay - Etambutol is - 399.6 mg, Rifampicin is 139.94 mg, Isoniazid is - 293.6 mg Pyrazinamide - 492.5 mg complied with the standard requirements. @*Conclusion@#Analysis of tuberculosis drugs quality by pharmacopoeia methods including its appearance, identification, average weight, friability, hardness, disintegration, dissolution and assay, the isoniazid 300 mg tablets are complied with the United States pharmacopoeia, Rifampicin 150 mg tablets met British pharmacopoeia, and Ethambutol 400 mg tablets are complied with Chinese pharmacopoeia. Pyrazinamide 400 mg tablets did not complies the friability requirements of the United States Pharmacopoeia and also satisfied with the other requirements.

Study on genes for cross-resistance to isoniazid and ethionamidein Mycobacterium tuberculosis / 预防医学

Objective@#To examine the association between the cross-resistance to ethionamide (Eto) and isoniazid (INH) and mutations of drug resistant genes in Mycobacterium tuberculosis (MTB), so as to provide the evidence for clinical diagnosis and treatment for multidrug-resistant (MDR) tuberculosis.@*Methods@#Totally 126 MTB clinical isolates were selected, including 88 MDR-MTB clinical isolates and 38 INH- and rifampicin (RFP)-sensitive isolates. The resistance to INH and Eto was tested in MTB clinical isolates using the drug susceptibility test, and the mutations in the spacer region of INH and Eto resistance-related katG, inhA, ethA, mshA, ndh, spacer region of oxyR-ahpC and inhA promoter were detected using PCR assay. The phenotypic resistance served as a gold standard, and the sensitivity, specificity and accuracy of gene mutation tests were calculated for detection of MTB clinical isolates cross-resistant to INH and Eto.@*Results@#Of the 126 MTB clinical isolates, there were 37 isolates cross-resistant to INH and Eto (29.37%), 51 isolates with resistance to INH and susceptibility to Eto (40.48%), 4 isolates with susceptibility to INH and resistance to Eto (3.17%) and 34 isolates with susceptibility to INH and Eto (26.98%). Among the 41 Eto-resistant MTB clinical isolates, there were 37 isolates with resistance to INH (90.24%). There were 64 MTB clinical isolates detected with katG mutations (50.79%), 4 isolates with mutation in the spacer region of oxyR-ahpC (3.17%), 2 isolates with inhA mutations (1.59%), and these isolates were all resistant to INH. There were 11 MTB clinical isolates detected with mutation in the inhA promoter (8.73%) and one isolate with ndh mutation, and all these isolates were cross-resistant to INH and Eto. There were 23 MTB clinical isolates detected with ethA mutations (18.25%) and 40 isolates with mshA mutations (31.75%), in which Eto-susceptible and -resistant isolates were detected. The diagnostic sensitivity, specificity and accuracy of inhA promoter tests for detection of cross-resistance to INH and Eto were 29.73% (95%CI: 16.44%-47.17%), 100.00% (95%CI: 87.36%-100.00%) and 63.38% (95%CI: 51.76%-73.63%) in MTB clinical isolates.@*Conclusions@#The prevalence of INH resistance is high in Eto-resistant MTB clinical isolates. Mutation in the inhA promoter region correlates with the cross-resistance to INH and Eto in MTB clinical isolates, and detection of mutation in the inhA promoter may be feasible to detect the cross-resistance to INH and Eto in MTB clinical isolates.

Pyrazinamide-isoniazid hybrid: synthesis optimisation, characterisation, and antituberculous activity / Híbrido pirazinamida-isoniacida: optimización de síntesis, caracterización y actividad antituberculosa / Híbrido pirazinamida-isoniazida: otimização da síntese, caracterização e atividade antituberculose

Abstract Over time, the effective resistance mechanisms to various first- and second-line drugs against the disease of tuberculosis make its treatment extremely difficult. This work presents a new approach to synthesizing a hybrid of antituberculosis medications: isoniazid (INH) and pyrazinamide (PZA). The synthesis was performed using ultrasound-assisted synthesis to obtain an overall yield of 70%, minimizing the reaction time from 7 to 1 h. The evaluation of the biological activity of the hybrid (compound 2) was tested using the tetrazolium microplate assay (TEMA), showing inhibition in the growth of Mycobacterium tuberculosis H37Rv at a concentration of 0.025 mM at pH 6.0 and 6.7.

Resumen Debido a los grandes mecanismos de resistencia a lo largo del tiempo de diversos fármacos de primera y segunda línea contra la enfermedad de la tuberculosis, el tratamiento sigue dificultándose. Este trabajo presenta un nuevo enfoque para sintetizar un híbrido de fármacos antituberculosos: isoniazida (INH) y pirazinamida (PZA). La síntesis fue asistida por ultrasonido con el fin de obtener un rendimiento global del 70%, minimizando el tiempo de reacción de 7 a ' h. La evaluación de la actividad biológica del híbrido (compuesto 2) se probó usando el ensayo de microplaca de tetrazolio (TEMA), que mostró una inhibición en el crecimiento de Mycobacterium tuberculosis H37Rv a una concentración de 0,025 mM a pH 6,0 y 6,7.

Resumo Devido aos grandes mecanismos de resistência ao longo do tempo a diversos fármacos de primeira e segunda linha contra a tuberculose, o que torna seu tratamento extremamente difícil. Este trabalho apresenta uma nova abordagem para sintetizar um híbrido de fármacos antituberculose: isoniazida (INH) e pirazinamida (PZA) A síntese foi realizada utilizando a síntese assistida por ultrassom de forma a obter um rendimento global de 70%, minimizando o tempo de reação de 7 h para ' h. A avaliação da atividade biológica do híbrido (composto 2) foi testada utilizando o ensaio de microplaca de tetrazólio (TEMA), mostrando uma inibição no crescimento de Mycobacterium tuberculosis H37Rv na concentração de 0,025 mM em pH 6,0 e 6,7.

Synthesis and antileishmanial activity of naphthoquinone-based hybrids / Síntesis y actividad antileishmania de híbridos naftoquinónicos / Síntese e atividade antileishmania de híbridos naftoquinónicos

SUMMARY Introduction: Leishmaniasis is a disease caused by protozoa of the genus Leishmania and is considered endemic in 98 countries. Treatment with pentavalent antimonials has a high toxicity, which motivates the search for effective and less toxic drugs. α- and β-lapachones have shown different biological activities, including antiprotozoa. In recent studies, the isonicotinoylhydrazone and phthalazinylhydrazone groups were considered innovative in the development of antileishmania drugs. Molecular hybridization is a strategy for the rational development of new prototypes, where the main compound is produced through the appropriate binding of pharmacophoric subunits. Aims: To synthesize four hybrids of α- and β-lapachones, together with the isonicotinoylhydrazone and phthalazinylhydrazone groups and to determine the antileishmania activity against the promastigotic forms of L. amazonensis, L. infantum and L. major. Results: β-lapachone derivatives were more active against all tested leishmania species. βACIL (IC50 0.044μM) and βHDZ (IC50 0.023μM) showed 15-fold higher activity than amphotericin B. The high selectivity index exhibited by the compounds indicates greater safety for vertebrate host cells. Conclusion: The results of this work show that the hybrids βACIL and (3HDZ are promising molecules for the development of new antileishmania drugs.

RESUMEN Introducción: Leishmaniasis es una enfermedad causada por protozoos del género Leishmania y se considera endémica en 98 países. El tratamiento con antimoniales pentavalentes tiene una alta toxicidad, lo que motiva la búsqueda de fármacos eficaces y menos tóxico. α- y β-lapachones han mostrado diferentes actividades biológicas, incluido los antiprotozoarios. En estudios recientes, los grupos isonicotinoilhidra-zona y ftalazinilhidrazona se consideraron innovadores en el desarrollo de fármacos antileishmania. La hibridación molecular es una estrategia para el desarrollo racional de nuevos prototipos, donde el compuesto principal se produce a través de la unión apropiada de subunidades farmacofóricas. Objetivos: Sintetizar cuatro híbridos de α- y β-lapachones, junto con los grupos isonicotinoilhidrazona y ftalazinilhidrazona y determinar la actividad antileishmania frente a las formas promastigotas de L. amazonensis, L. infantum y L. major. Resultados: Los derivados de β-lapachone fueron más activos contra todas las especies de leishmania probadas. La βACIL (CI50 0,044μM) y βHDZ (CI50 0,023μM) mostraron actividad 15 veces mayor que la anfotericina B. El alto índice de selectividad que presentan los compuestos indica una mayor seguridad para las células huésped del vertebrado. Conclusión: Los resultados de este trabajo demuestran que los híbridos (ACIL y (HDZ son moléculas prometodoras para el desarrollo de nuevos fármacos antileishmania.

RESUMO Introdução: A leishmaniose é uma doença causada por protozoários do género Leishmania e é considerada endémica em 98 países. O tratamento com antimoniais pentavalentes apresenta alta toxicidade, o que motiva a pesquisa por medicamentos eficazes e menos tóxicos. α- e β-lapachones tém mostrado diferentes atividades biológicas, incluindo antiprotozoários. Em estudos recentes, os grupos isonicotinoilhi-drazona e ftalazinilhidrazona foram considerados inovadores no desenvolvimento de drogas antileishmania. A hibridização molecular é uma estratégia para o desenvolvimento racional de novos protótipos, onde o composto principal é produzido através da ligação apropriada de subunidades farmacofóricas. Objetivos: Sintetizar quatro híbridos de α- e β-lapachones, juntamente com os grupos isonicotinoil-hidra-zona e ftalazinilhidrazona e determinar a atividade antileishmania contra as formas promastigóticas de L. amazonensis, L. infantum e L. major. Resultados: Os derivados de β-lapachona foram mais ativos contra todas as espécies de leishmania testadas. BACIL (IC50 0,044 μM) e βHDZ (IC50 0,023 μM) apresentaram atividade 15 vezes maior do que a anfotericina B. O alto índice de seletividade dos compostos indica maior segurança para células hospedeiras de vertebrados. Conclusaõ: Os resultados deste trabalho mostram que os híbridos βACIL e βHDZ são moléculas promissoras para o desenvolvimento de novos fármacos antileishmania.

Resistencia de Mycobacterium tuberculosis a quinolonas y fármacos inyectables en el departamento del Atlántico, 2013-2016 / Resistance of Mycobacterium tuberculosis to quinolone and injectable drugs in Atlántico department, 2013-2016

Introducción: En el departamento del Atlántico los estudios de resistencia del Mycobacterium tuberculosis se han limitado a drogas de segunda línea. Objetivo: Determinar prevalencia de resistencia a amikacina, kanamicina, capreomicina y ofloxacina en casos de tuberculosis resistente a isoniacida, rifampicina o a ambas drogas, en el periodo 2013 a 2016 en el departamento del Atlántico. Métodos: Estudio transversal de 194 aislamientos resistentes a isoniacida, rifampicina o ambas, por metodología Genotype MTBDR plus versión 2, enviados al Instituto Nacional de Salud en el periodo 2013 al 2016 para ser confirmados y procesados para drogas de segunda línea. La proporción de resistencia, se hizo según variables sociodemográficas, clínica y de vigilancia en salud pública. Resultados: Las comorbilidades frecuentes encontradas fueron desnutrición con el 18,56 por ciento, seguido de infección concomitante VIH-tuberculosis con el 13,40 por ciento. La ofloxacina en casos no tratados obtuvo la mayor resistencia global con el 1,50 por ciento (IC 95 por ciento 0,18-5,33). En los que fueron previamente tratados la resistencia global a capreomicina fue del 8,10 por ciento (IC 95 por ciento 2,7-17,8). En los resistentes a rifampicina, un caso fue extensivamente resistente y dos casos resistentes en los multidrogorresistente. Conclusiones: Se encontró baja resistencia a fluoroquinolonas y fármacos inyectables en pacientes no tratados resistentes a isoniacida, rifampicina o ambas, que muestra que todavía no constituye un problema mayor en el departamento del Atlántico. Se debe complementar su seguimiento con buen manejo tanto físico como psicológico y un equipo de salud fortalecido que actúe prontamente y ayude a la adherencia del paciente a los tratamientos(AU)

Introduction: In Atlántico department, resistance studies of Mycobacterium tuberculosis have been limited to second-line drugs. Objective: Determine prevalence of resistance to amikacin, kanamycin, capreomycin and ofloxacin in cases of tuberculosis resistant to isoniazid, rifampicin or both, in the period 2013 to 2016 in Atlántico department. Methods: Cross-sectional study of 194 isolations resistant to isoniazid, rifampicin or both, by Genotype MTBDR plus version 2 methodology, that were sent to the National Institute of Health from 2013 to 2016 to be confirmed and processed for second-line drugs. The resistance ratio was made according to sociodemographic, clinical and public health surveillance variables. Results: The common comorbilities found were malnutrition with 18.56 percent, followed by concomitant HIV-tuberculosis infection with 13.40 percent. Ofloxacin in non-treated cases achieved the highest overall resistance with 1.50 percent (95 percent CI 0.18-5.33). In those previously treated, global resistance to capreomycin was 8.10 percent (95 percent CI 2.7-17.8). In the ones resistant to rifampicin, one case was extensively resistant and two cases were resistant in multi-drugs resistant. Conclusions: Low resistance to fluoroquinolones and injectable drugs was found in non-treated patients who were resistant to isoniazid, rifampicin or both, showing that it is not yet a major problem in Atlántico department. Its follow-up should be complemented with good physical and psychological management and a strengthened health team that acts promptly and helps the patient adherence to treatments(AU)

Mutaciones genéticas que confieren resistencia a Isoniacida en pacientes con tuberculosis en Lima Centro, Perú 2017-2018 / Genetic mutations that confer resistance to Isoniazid in patients with Tuberculosis in Lima Centro, Perú 2017- 2018

RESUMEN Se reporta la frecuencia de mutaciones genéticas KatG e inhA que confieren resistencia a isoniacida en una muestra de 777 pacientes con resistencia a isoniacida. Se utilizó la prueba GenoType® MTBDRplus y la prueba de sensibilidad convencional por el método de agar en placa. Se encontró que 54 % presentó mutación en el gen KatG; este se asoció con resistencia a estreptomicina 76,6 % (p<0.05), rifampicina 66.7 % (p<0.05) y etionamida en un 33 % (p<0.05). La mutación en el gen inhA tuvo una frecuencia de 46 %, y se asoció con resistencia a etionamida en un 68,1 % (p<0.05), rifampicina 47,2 % (p<0,05) y estreptomicina 33 % (p<0,05). En estos pacientes, la presencia de genes que confieren resistencia a isoniazida se relacionó con resistencia a otros medicamentos antituberculosos.

ABSTRACT This a report of the frequency of KatG and inhA genetic mutations that confer resistance to isoniazid in a sample of 777 patients with resistance to isoniazid. GenoType® MTBDRplus test and conventional sensitivity tests by the agar plate method were used. It was found that 54% presented mutation in the KatG gene, associated with higher resistance to streptomycin 76.6% (p <0.05), rifampicin 66.7% (p <0.05) and ethionamide in 33% (p <0.05). inhA gene mutation has a frequency of 46% and was associated with resistance to ethionamide in 68.1% (p <0.05), rifampicin 47.2% (p <0.05) and streptomycin 33% (p <0.05). In this sample, the presences of mutations that confer resistance to isoniazid was associated with resistance to other antituberculosis drugs.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

Protective Effects of Caffeic Acid Phenethyl Ester on Isoniazid and Rifampicin-induced Hepatic and Pancreatic Injury

ABSTRACT Objective: To investigate the protective effects of caffeic acid phenethyl ester (CAPE) against isoniazid (INH)- and rifampicin (RFP)-induced hepatic and pancreatic damage. Methods: Eighty adult rats were randomly divided into eight groups: control, INH, RFP, INH+RFP, INH+CAPE, RFP+CAPE, INH+RFP+CAPE, and CAPE. Both INH and RFP were orally administered for 30 days at a dose of 50 mg/kg/day. Caffeic acid phenethyl ester was intraperitoneally injected for 30 days (10 μmol/kg). Blood samples, hepatic and pancreatic tissues were obtained on day 30. Results: Total oxidant status levels were significantly higher in INH and/or RFP-treated groups than those of control and CAPE groups, while total antioxidant status and paraoxonase levels were significantly reduced in INH-RFP groups compared with the group receiving CAPE. Histopathological deterioration was observed in RFP and INH groups in pancreatic and hepatic tissue. However, significant amelioration was observed in CAPE-treated groups. Conclusion: Our findings suggest that CAPE may be a promising agent to prevent the side effects of INH and RFP treatment on hepatic and pancreatic tissues.

Tuberculosis incidence in patients with human immunodeficiency virus, treated with isoniazid for latent tuberculosis infection

Tuberculosis is the leading cause of death amongst adults with human immunodeficiency virus (HIV) infection. The lifetime risk of tuberculosis disease for a person with latent infection is estimated at 5-10% with most cases occurring within five years of initial infection. The World Health Organization recommends isoniazid preventive therapy (IPT) for latent tuberculosis treatment, amongst other strategies. The aim was to assess tuberculosis incidence, survival (free of tuberculosis) and associated factors in HIV-positive patients. IPT was offered to participants with a positive (≥5mm) tuberculin skin test. Participants were followed from February 2003-December 2016. Kaplan-Meier was used for survival analysis. Variables with p-value ≤ 0.2 in the univariate analysis entered into the multivariate Cox-Model, keeping those with p-value ≤ 0.05. The 95% confidence interval of incidence of tuberculosis was estimated using Poisson distribution. One hundred nineteen patients completed the IPT and were followed for a median duration of 110.7 months (IQR 93.1-121.0). The probability of developing tuberculosis (10 years post-IPT) was 5.4%. Tuberculosis incidence was 0.58/100 patient/years (CI 95% 0.213-1.264). IPT over 6 months provided long-term protection against tuberculosis. AIDS-defining illness was the only statistically significant variable (HR=5.67) in the multivariate model.