Biotransformation of rifampicin by Aspergillus niger and antimicrobial activity of proposed metabolites.

Drug biotransformation studies emerges as an alternative to pharmacological investigations of metabolites, development of new drug candidates with reduced investment and most efficient production. The present study aims to evaluate the capacity of biotransformation of rifampicin by the filamentous fungus Aspergillus niger ATCC 9029. After incubation for 312 h, the drug was metabolized to two molecules: an isomer (m/z 455) and the rifampicin quinone (m/z 821). The monitoring of metabolite formation was performed by high-performance liquid chromatography, followed by their identification through ultra-high-performance liquid chromatography coupled to tandem mass spectrometer. In vitro antimicrobial activity of the proposed metabolites was evaluated against Staphylococus aureus microorganism, resulting in the loss of inhibitory activity when compared with the standards, with minimum inhibitory concentration of 7.5 µg/ml. The significant biotransformation power of the ATCC 9029 strain of A. niger was confirmed in this study, making this strain a candidate for pilot studies in fermentation tanks for the enzymatic metabolization of the antimicrobial rifampicin. The unprecedented result allows us to conclude that the prospect of new biotransforming strains in species of anemophilic fungi is a promising choice.

Community-Based Intervention for Active Detection and Provision of Single-Dose Rifampicin Post-Exposure Prophylaxis to Household Contacts of Leprosy in Bolivia.

BACKGROUND: To achieve zero leprosy cases in Santa Cruz, Bolivia, we designed a community-based active detection and provision of single-dose rifampicin post-exposure prophylaxis (SDR-PEP) to household contacts with new leprosy patients. METHODS: From July to August 2021, we assessed the current knowledge, attitude, and practices through structured interviews and focus group discussions with community representatives and health staff. This was followed by sensitization sessions, the training of health staff, and the reinforcement of referral mechanisms. Teams, including health staff and community volunteers, visited all new leprosy patients detected in 2021-2023 and household contacts. RESULTS: Among 115 community representatives, knowledge about leprosy etiology was attributed to non-biological factors (74%); fear accounted for 77%, and access to care was perceived as weak (74%), but the outlook was improved by SDR-PEP (80%). Among the 217 health staff interviewed, the programmatic barriers identified were a lack of referral feedback (67%), limited supplies for diagnosis and prevention, and ineffective training (64%). We visited 70 new patients and 258 household contacts. The median age in household contacts was 25 years old; 49% were women, 98% were eligible for SDR-PEP, and all who were eligible accepted it. Those who were non-eligible included one tuberculosis patient and six newly detected leprosy patients (23‱). CONCLUSIONS: A community-based intervention was successful in Santa Cruz, Bolivia. Misbeliefs and a lack of knowledge were identified as barriers. Programmatic components should be reinforced for SDR-PEP extension.

Concomitant Treatment with Doxycycline and Rifampicin in Balb/c Mice Infected with Brucella abortus 2308 Fails to Reduce Inflammation and Motor Disability.

Brucellosis is an infection widely distributed around the world, and in some countries it is considered a public health problem. Brucellosis causes insidious symptoms that make it difficult to diagnose. Infection can also trigger chronic pain and neuropsychiatric complications. Antibiotics are not always effective to eradicate infection, contributing to chronicity. We aimed to investigate the effects of antibiotic treatment on proinflammatory cytokines, neurotransmitters, corticosterone, and behavior in a murine model of infecrion of B. abortus strain 2308. Four study groups were created: (a) control; (b) antibiotic control; (c) infected with B. abortus 2308; and (d) infected and treated with rifampicin and doxycycline. We determined B. abortus 2308 colony-forming units (CFUs), the count of dendritic cells, and macrophages in the spleen; serum levels of cytokines and corticosterone; levels of serotonin, dopamine, epinephrine, and norepinephrine in the brain; and equilibrium, physical strength, anxiety, and hopelessness tests. The infected and treated mice group was compared with the control and infected mice to assess whether treatment is sufficient to recover neuroimmunoendocrine parameters. Our results showed that despite the treatment of brucellosis with rifampicin and doxycycline, antibiotic-treated mice showed a persistence of B. abortus 2308 CFUs, an increased count in macrophage number, and higher circulating levels of corticosterone. Furthermore, the levels of IL-12, IL-6, and TNF-α remained higher. We found a decrease in muscular strength and equilibrium concomitant to changes in neurotransmitters in the hippocampus, cerebellum, and frontal cortex. Our data suggest that the remaining bacterial load after antibiotic administration favors inflammatory, neurochemical, and behavioral alterations, partly explaining the widespread and paradoxical symptomatology experienced by patients with chronic brucellosis.

Mycobacterium tuberculosis resistente a Rifampicina en la provincia de El Oro-Ecuador / Rifampicin-resistant mycobacterium tuberculosis in the province of Oro-Ecuador / Mycobacterium tuberculosis resistente à Rifampicina na província de Oro-Equador

Introducción. La tuberculosis es una de las enfermedades infecciosas más antiguas y comunes, causada por una bacteria en forma de bastón, o bacilo, llamada Mycobacterium tuberculosis. Esta enfermedad es tratable con antibióticos, los cuales se prescriben durante meses debido a la lenta tasa de crecimiento de las bacterias. Entre los fármacos utilizados la Rifampicina se utiliza terapéuticamente para combatir esta enfermedad, sin embargo, algunos pacientes pueden presentar o desarrollar resistencia a este antibiótico, por lo que, es importante completar el tratamiento para evitar el desarrollo de bacterias farmacorresistentes y la re ocurrencia de la enfermedad. Objetivo. Caracterizar el Mycobacterium tuberculosis resistente a Rifampicina en la provincia de El Oro. Materiales y métodos. Se realizó un estudio con un enfoque cuantitativo, de tipo descriptivo y no experimental. La muestra se obtuvo de la base de datos del laboratorio clínico del área de micobacterias del Hospital Teófilo Dávila en el período 2019 - 2022, quienes luego de aplicar la prueba molecular rápida GeneXpert MTB/RIF o ULTRA determinaron que 48 pacientes presentaron resistencia a la Rifampicina en el tratamiento de la Mycobacterium tuberculosis. Resultados. El reporte del laboratorio evidenció que en el año 2022 se estableció el mayor número de casos de resistencia a Rifampicina para el tratamiento de Mycobacterium tuberculosis, alcanzando el 33,3%; el grupo etario de mayor afectación fue el adulto joven (20 a 49 años) con un 52,1%, y con una frecuencia elevada de 66,7% el sexo masculino. La comorbilidad con mayor predominio estuvo en los pacientes diagnosticados Diabetes Mellitus tipo 2 con un 27,1% y la condición de ingreso de pacientes con resistencia a Rifampicina, son de nuevos casos con 75%. Conclusiones. En la provincia de El Oro, entre el año 2019 - 2022 se presentaron 48 casos resistentes al antibiótico Rifampicina en el tratamiento de la TB, entre ellos el 75% corresponden a una resistencia inicial, es decir, pacientes que no fueron tratados contra la enfermedad, el otro 25% engloba a aquellos pacientes que recayeron en la enfermedad, fracaso o perdida de seguimiento por parte del laboratorio de vigilancia, área de micobacterias del Hospital Teófilo Dávila.

Introduction. Tuberculosis is one of the oldest and most common infectious diseases, caused by a rod-shaped bacterium, or bacillus, called Mycobacterium tuberculosis. This disease is treatable with antibiotics, which are prescribed for months due to the slow growth rate of the bacteria. Among the drugs used, Rifampicin is used therapeutically to combat this disease, however, some patients may present or develop resistance to this antibiotic, therefore, it is important to complete the treatment to avoid the development of drug-resistant bacteria and the reoccurrence of the disease. Objective. To characterize the Mycobacterium tuberculosis resistant to Rifampicin in the province of El Oro. Materials and methods. A quantitative, descriptive and non-experimental study was carried out. The sample was obtained from the database of the clinical laboratory of the mycobacteria area of the Teófilo Dávila Hospital in the period 2019 - 2022, who after applying the rapid molecular test GeneXpert MTB/RIF or ULTRA determined that 48 patients presented resistance to Rifampicin in the treatment of Mycobacterium tuberculosis. Results. The laboratory report showed that in the year 2022 the highest number of cases of resistance to Rifampicin for the treatment of Mycobacterium tuberculosis was established, reaching 33.3%; the age group most affected was young adults (20 to 49 years) with 52.1%, and with a high frequency of 66.7% in the male sex. The most prevalent comorbidity was in patients diagnosed with Diabetes Mellitus type 2 with 27.1% and the condition of admission of patients with resistance to Rifampicin, are new cases with 75%. Conclusions. In the province of El Oro, between 2019 - 2022 there were 48 cases resistant to the antibiotic Rifampicin in the treatment of TB, among them 75% correspond to an initial resistance, that is, patients who were not treated against the disease, the other 25% encompasses those patients who relapsed in the disease, failure or loss of follow-up by the surveillance laboratory, mycobacteria area of the Teófilo Dávila Hospital.

Introdução. A tuberculose é uma das doenças infecciosas mais antigas e mais comuns, causada por uma bactéria em forma de bastonete, ou bacilo, chamada Mycobacterium tuberculosis. A doença pode ser tratada com antibióticos, que são prescritos por meses devido à lenta taxa de crescimento da bactéria. Entre os medicamentos utilizados, a rifampicina é usada terapeuticamente para combater essa doença; no entanto, alguns pacientes podem desenvolver resistência a esse antibiótico, por isso é importante concluir o tratamento para evitar o desenvolvimento de bactérias resistentes aos medicamentos e a recorrência da doença. Objetivo. Caracterizar o Mycobacterium tuberculosis resistente à rifampicina na província de El Oro. Materiais e métodos. Foi realizado um estudo quantitativo, descritivo e não experimental. A amostra foi obtida do banco de dados do laboratório clínico da área de micobactérias do Hospital Teófilo Dávila no período de 2019 a 2022, que, após aplicar o teste molecular rápido GeneXpert MTB/RIF ou ULTRA, determinou que 48 pacientes apresentavam resistência à rifampicina no tratamento de Mycobacterium tuberculosis. Resultados. O laudo laboratorial demonstrou que o maior número de casos de resistência à Rifampicina para o tratamento do Mycobacterium tuberculosis se estabeleceu em 2022, atingindo 33,3%; a faixa etária mais afetada foi a de adultos jovens (20-49 anos) com 52,1%, e com alta frequência de 66,7% no sexo masculino. A comorbidade mais prevalente foi em pacientes diagnosticados com Diabetes Mellitus tipo 2 com 27,1% e a condição de admissão de pacientes com resistência à Rifampicina, são casos novos com 75%. Conclusões. Na província de El Oro, entre 2019 e 2022, houve 48 casos resistentes ao antibiótico Rifampicina no tratamento da TB, entre eles 75% correspondem a uma resistência inicial, ou seja, pacientes que não foram tratados contra a doença, os outros 25% incluem aqueles pacientes que recaíram na doença, falha ou perda de monitoramento pelo laboratório de vigilância, área de micobactérias do Hospital Teófilo Dávila.

Adverse reactions induced by MDT/WHO (Rifampicin+Clofazimine+Dapsone) and ROM (Rifampicin+Ofloxacin+Minocycline) regimens used in the treatment of leprosy: a cohort study in a National Reference Center in Brazil.

Background: Recommended standard treatment for leprosy is multidrugtherapy (MDT/WHO), consisting Rifampicin+Dapsone+Clofazimine. Other medications are recommended in cases of resistance, adverse reactions and intolerances, including ROM regimen, Rifampicin+Ofloxacin+Minocycline. Therefore, pharmacovigilance is an important tool in understanding these adverse drug reactions (ADRs), supporting pharmacotherapy management and medication safety. This study seeks to evaluate ADRs comparing two therapeutic regimens, MDT and ROM, used in treatment of patients with leprosy, analyzing prognostic factors regarding risk and safety. Methods:A retrospective cohort study was performed by assessing medical records of 433 patients diagnosed with leprosy from 2010 to 2021 at a National Reference Center in Brazil. They were subject to 24 months or more of treatment with MDT or ROM regimens. ADR assessments were analyzed by two experienced researchers, who included clinical and laboratory variables, correlating them with temporality, severity and the causality criteria of Naranjo and WHO. Results: The findings observed an average of 1.3 reactions/patient. Out of individuals experiencing reactions, 67.0% (69/103) were utilizing MDT/MB, while 33.0% (34/103) were using ROM. The median time for ADR of 79 days for MDT and 179 days for ROM. In first reaction, Dapsone was the most frequently involved medication; the most affected system was hematopoietic. As compared to Clofazimine, results indicated that use of Dapsone was associated with 7% increased risk of ADR occurrence (HR: 1.07; p = 0.866). Additionally, Rifampicin was linked to 31% increased risk of ADRs (HR: 1.31; p = 0.602); and Ofloxacin showed 35% elevated risk (HR: 1.35; p = 0.653). Conversely, results for Minocycline indicated 44% reduction in the risk of ADRs (HR: 0.56; p = 0.527), although statistical significance was not reached. The use of MDT conferred 2.51 times higher risk of developing ADRs in comparison to ROM. Conclusion: The comparison between MDT and ROM revealed that MDT caused more ADRs, and these reactions were more severe, indicating less safety for patients. Dapsone was the most common medication causing ADRs, followed by Rifampicin. The combination with Clofazimine was associated with an additional risk of ADRs, warranting further studies to confirm this hypothesis. Given the high magnitude of ADRs, healthcare teams need to monitor patients undergoing leprosy treatment with focus on pharmacovigilance.

Antimicrobial activity of carvacrol and its derivatives on Mycobacterium spp.: systematic review of preclinical studies.

Background: The scope of the study was to analyze original preclinical studies on the antimicrobial effects of carvacrol and derivatives on the Mycobacterium genus. Materials & methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, four databases (PubMed, Web of Science, SCOPUS and EMBASE) were searched. Results: The search retrieved 392 records, of which 11 papers were selected. Heterogeneity in the techniques and mycobacterial targets was observed. Carvacrol demonstrated synergistic antimycobacterial activity with rifampicin against multidrug-resistant Mycobacterium tuberculosis on membranes and biofilms. In silico approaches showed specific targets in mycobacteria, by inhibition and molecular docking assays, on the enzyme chorismate mutase and the heat shock protein 16.3. Conclusion: Carvacrol has been shown to be a scaffold candidate for future molecules with activity against mycobacteria.

Long-Term Protective Effect of Tuberculosis Preventive Therapy in a Medium/High Tuberculosis Incidence Setting.

BACKGROUND: The duration of the protective effect of tuberculosis preventive therapy (TPT) is controversial. Some studies have found that the protective effect of TPT is lost after cessation of therapy among people with human immunodeficiency virus (HIV) in settings with very high tuberculosis incidence, but others have found long-term protection in low-incidence settings. METHODS: We estimated the incidence rate (IR) of new tuberculosis disease for up to 12 years after randomization to 4 months of rifampin or 9 months of isoniazid, among 991 Brazilian participants in a TPT trial in the state of Rio de Janeiro, with an incidence of 68.6/100 000 population in 2022. The adjusted hazard ratios (aHRs) of independent variables for incident tuberculosis were calculated. RESULTS: The overall tuberculosis IR was 1.7 (95% confidence interval [CI], 1.01- 2.7) per 1000 person-years (PY). The tuberculosis IR was higher among those who did not complete TPT than in those who did (2.9 [95% CI, 1.3-5.6] vs 1.1 [.4-2.3] per 1000 PY; IR ratio, 2.7 [1.0-7.2]). The tuberculosis IR was higher within 28 months after randomization (IR, 3.5 [95% CI, 1.6-6.6] vs 1.1 [.5-2.1] per 1000 PY between 28 and 143 months; IR ratio, 3.1 [1.2-8.2]). Treatment noncompletion was the only variable associated with incident tuberculosis (aHR, 3.2 [95% CI, 1.1-9.7]). CONCLUSIONS: In a mostly HIV-noninfected population, a complete course of TPT conferred long-term protection against tuberculosis.

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental-Theoretical Study.

Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug-coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (Tg) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.

Assessing Polymorphic Purity of Rifampicin in Double and Triple-Drug Fixed-Dose Combination Products.

First-line tuberculostatic agents, Rifampicin (RIF), Isoniazid (ISH), Ethambutol (ETB), and Pyrazinamide (PZA) are generally administered as a fixed-dose combination (FDC) for improving patient adherence. The major quality challenge of these FDC products is their variable bioavailability, where RIF and its solid state are key factors. In this work, the analysis of the impact of the polymorphism in the performance of RIF in RIF-ISH and PZA-RIF-ISH combined products was carried out by an overall approach that included the development and validation of two methodologies combining near-infrared (NIR) spectroscopy and partial least squares (PLS) to the further evaluation of commercial products. For NIR-PLS methods, training and validation sets were prepared with mixtures of Form I/Form II of RIF, and the appropriate amount of ISH (for double associations) or ISH-PZA (for triple associations). The corresponding matrix of the excipients was added to the mixture of APIs to simulate the environment of each FDC product. Four PLS factors, reduced spectral range, and the combination of standard normal variate and Savitzky-Golay 1st derivative (SNV-D') were selected as optimum data pre-treatment for both methods, yielding satisfactory recoveries during the analysis of validation sets (98.5±2.0%, and 98.7±1.8% for double- and triple-FDC products, respectively). The NIR-PLS model for RIF-ISH successfully estimated the polymorphic purity of Form II in double-FDC capsules (1.02 ± 0.02w/w). On the other hand, the NIR-PLS model for RIF-ISH-PZA detected a low purity of Form II in triple FDC tablets (0.800 ± 0.021w/w), these results were confirmed by X-ray powder diffraction. Nevertheless, the triple-FDC tablets showed good performance in the dissolution test (Q=99-102%), implying a Form II purity about of 80% is not low enough to affect the safety and efficacy of the product.

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.

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.

Effect of interindividual variability in metabolic clearance and relative bioavailability on rifampicin exposure in tuberculosis patients with and without HIV co-infection: does formulation quality matter?

The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetylrifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV− group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation.

Diagnóstico de tuberculosis con ensayo Xpert® MTB/RIF en la región oriental de Cuba / Diagnosis of tuberculosis withXpert® MTB/RIF test in the easternregion of Cuba / Diagnosis of tuberculosis withXpert® MTB/RIF test in the easternregion of Cuba / Diagnóstico de tuberculose com ensaio Xpert® MTB/RIF na região leste de Cuba

Introducción: La infección por tuberculosis repercute en el mundo a pesar de los años de estudio y avances tecnológicos en su diagnóstico. El ensayo Xpert® MTB/RIF permite, en gran medida, la identificación del bacilo de Koch en cualquier muestra patológica, y lo hace con una alta sensibilidad, especificidad y rapidez con respecto a otros métodos. Objetivo: Realizar el diagnóstico de tuberculosis con ensayo Xpert® MTB/RIF. Método: Se realizó un estudio transversal en 46 muestras analizadas (n=46) de las provincias orientales de Cuba con ensayo Xpert® MTB/RIF, entre abril y septiembre de 2023, por el Centro Provincial de Higiene, Epidemiología y Microbiología de Holguín. Las variables estudiadas fueron: provincia de procedencia, edad, sexo, tipo de muestra, factores de riesgo, resultado al ensayo y resistencia a la rifampicina. Resultados: Santiago de Cuba y Guantánamo fueron las provincias que mayor cantidad de casos reportaron, con 14 casos cada una (30,4 porciento). El sexo masculino fue el de mayor incidencia, 33 casos (71,7 porciento), independientemente de la provincia. El grupo de edad de 25 a 34 años fue el de mayor prevalencia, con el 26,1 porciento. Los grupos de riesgos más afectados fueron: los fumadores (37,0 porciento), los reclusos (32,6 porciento), los adultos mayores de 60 años (26,6 porciento) y los alcohólicos (23,9 porciento). Conclusiones: La introducción del GeneXpert en su diagnóstico es muy efectivo, por su alta sensibilidad y especificidad con relación a los estudios tradicionales, como son la baciloscopia y el cultivo, además de la rapidez en la obtención del resultado.Informa también sobre la resistencia a la rifampicina, atribuible al gen rpoβ lo que resulta muy oportuno en momentos en que la multidrogorresistencia aumenta aceleradamente.(AU)

Introduction: Tuberculosis infection affects the world despite years of study and technological advances in its diagnosis.The Xpert® MTB/RIF test allows, to a largeextent, the identification of Koch bacillus in any pathological sample, and does so with high sensitivity, specificity and speed compared too ther methods. Objective: To diagnose tuberculosis with the Xpert® MTB/RIF test. Method: A cross-sectional study was carried out on 46 analyzed samples (n 46) from the eastern provinces of Cuba with the Xpert® MTB/RIF test, between April and September 2023, by the Centro Provincial de Higiene, Epidemiología y Microbiología de Holguín (Provincial Center of Hygiene, Epidemiology and Microbiology of Holguín).The variables studied were: province of origin, age, sex, type of sample, risk factors, test resultand resistance to rifampicin. Results: Santiago de Cuba and Guantánamo were the provinces that reported the highest number of cases, with 14 cases each(30.4 percent).The maleshad the highest incidence, 33 cases (71.7 percent), regardless of the province.The age group of 25 to 34 years was the one with the highest prevalence, with 26.1 percent.The most affected risk groups were: smokers (37.0 percent), prisoners (32.6 percent), adults over 60 years of age (26.6 percent) and alcoholics (23.9 percent). Conclusions: The introduction of GeneXpert in tuberculosis diagnosis is very effective, due to its high sensitivity and specificity in relation to traditional studies, such as smear microscopy and culture, in addition to the speed in obtaining the result. It also reports on resistance to rifampicin, attributable to the rpoβ gene, which is timely at a moment when multidrug resistance is increasing rapidly.(AU)

Introdução: A infecção tuberculosa afeta o mundo apesar de anos de estudo e avanços tecnológicos no seu diagnóstico.O ensaio Xpert® MTB/RIF permite, em grande medida, a identificação do bacilo de Koch em qualquer amostra patológica, e fá-lo com elevada sensibilidade, especificidade e rapidez em comparação com outros métodos. Objetivo: Diagnosticar tuberculose com o ensaio Xpert® MTB/RIF. Método: Foi realizado um estudo transversal em 46 amostras analisadas (n 46) das províncias orientais de Cuba com o ensaio Xpert® MTB/RIF, entre abril e setembro de 2023, pelo Centro Provincial de Higiene, Epidemiologia e Microbiologia de Holguín.As variáveis estudadas foram: província de origem, idade, sexo, tipo de amostra, fatores de risco, resultado de exame e resistência à rifampicina. Resultados: Santiago de Cuba e Guantánamo foram as províncias que notificaram o maior número de casos, com 14 casos cada (30,4 porcento).O sexo masculino teve a maior incidência, 33 casos (71,7 porcento), independentemente da província.A faixa etária de 25 a 34 anos foi a que apresentou maior prevalência, com 26,1 porcento.Os grupos de risco mais acometidos foram: fumantes (37,0 porcento), presidiários (32,6 porcento), adultos acima de 60 anos (26,6 porcento) e alcoolistas (23,9 porcento). Conclusões: A introdução do GeneXpert no seu diagnóstico é muito eficaz, devido à sua alta sensibilidade e especificidade em relação aos estudos tradicionais, como baciloscopia e cultura, além da rapidez na obtenção do resultado.Também relata a resistência à rifampicina, atribuível ao gene rpoβ, que é muito oportuna numa altura em que a resistência a múltiplos medicamentos está a aumentar rapidamente.(AU)

Safety and Tolerability of Six Months of Isoniazid Plus Pyridoxine or Three Months of Rifampicin for Tuberculosis among Subjects with Diabetes Mellitus: A Randomized Trial.

Tuberculosis (TB) associated with diabetes mellitus (DM) is a growing problem, particularly in low- and medium-resource countries. We conducted an open-label, parallel-group, randomized, and controlled trial in a tertiary care center in Mexico City to assess TB preventive treatment (TPT) with isoniazid (INH) or rifampicin (RIF) in people with type 2 DM. Participants were assigned six months of INH 300 mg/day plus pyridoxine 75 mg or three months of RIF 600 mg/day. The primary outcomes were adverse events resulting in permanent treatment cessation and considered possibly or probably related to study drugs. We included 130 subjects, 68 randomized to INH and 62 to RIF. We prematurely halted the study based on recommendations of the Adverse Event Safety Panel. There was no difference between arms in the overall frequency of adverse events. However, the INH group had significantly more permanent treatment interruptions due to grade 2 recurrent or grade 3 or 4 hepatoxicity. In comparison, the RIF arm had more treatment interruptions due to grade 3 or 4 gastrointestinal intolerance. TPT using INH or RIF is not safe enough to be considered a universal indication to patients with type 2 DM and TB infection. These results underline the need to search for alternative TB preventions with better safety profiles for type 2 DM patients.

Dried Blood Spot Sampling to Assess Rifampicin Exposure and Treatment Outcomes among Native and Non-Native Tuberculosis Patients in Paraguay: An Exploratory Study.

The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis (TB) patients from both native and non-native populations receiving oral rifampicin 10 mg/kg once-daily dosing. Steady-state DBS samples were collected at 2, 4, and 6 h after intake of rifampicin. The area under the time concentration curve 0-24 h (AUC0-24) was calculated using a Bayesian population PK model. Rifampicin AUC0-24 < 38.7 mg*h/L was considered as low. The probability of target attainment (PTA) was calculated using AUC0-24/MIC > 271 as a target and estimated MIC values of 0.125 and 0.25 mg/L. In total, 50 patients were included. Native patients (n = 30) showed comparable drug exposure to the non-natives (n = 20), median AUC0-24 24.7 (17.1-29.5 IQR) and 21.6 (15.0-35.4 IQR) mg*h/L (p = 0.66), respectively. Among total patients, only 16% (n = 8) had a rifampicin AUC0-24 > 38.7 mg*h/L. Furthermore, PTA analysis showed that only 12 (24%) of the patients met a target AUC0-24 /MIC ≥ 271, assuming an MIC of 0.125 mg/L, which plummeted to 0% at a wild-type MIC of 0.25 mg/L. We successfully used DBS and limited sampling for the AUC0-24 estimation of rifampicin. Currently, our group, the EUSAT-RCS consortium, is preparing a prospective multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects using the DBS technique for AUC0-24 estimation.

Montmorillonite-Rifampicin Nanohybrid for pH-Responsive Release of the Tuberculostatic.

The present work describes the development of a hybrid and pH-responsive system for rifampicin using the clay mineral 'montmorillonite' as a nanocarrier. The influence of operational variables on the drug incorporation process was evaluated using 24 factorial designs. Under optimized conditions, the experiment allowed an incorporated drug dose equivalent to 98.60 ± 1.21 mg/g. Hybrid systems were characterized by different characterization techniques (FTIR, XRD, TGA, DSC, and SEM) to elucidate the mechanism of interaction between the compounds used. Through in vitro release studies, it was possible to verify the efficacy of the pH-dependent system obtained, with approximately 70% of the drug released after sixteen hours in simulated intestinal fluid. The adjustment of the experimental release data to the theoretical model of Higuchi and Korsmeyer-Peppas indicated that the release of rifampicin occurs in a prolonged form from montmorillonite. Elucidation of the interactions between the drug and this raw clay reinforces its viability as a novel carrier to develop an anti-TB/clay hybrid system with good physical and chemical stability.

The impact of the COVID-19 pandemic in tuberculosis preventive treatment in Brazil: a retrospective cohort study using secondary data.

Background: Disruptions in tuberculosis services have been reported around the world since the emergence of the COVID-19 pandemic. However, the pandemic's effect on tuberculosis preventive treatment (TPT) has been poorly explored. We compared TPT-notified prescriptions and outcomes before and during the pandemic in Brazil. Methods: Retrospective cohort using secondary data from the Brazilian TPT information system in five cities with over 1000 notifications. The number of TPT prescriptions was analysed from 6 months after healthcare workers' training, in 2018, to July 2021. The proportion of TPT outcomes by the date of treatment initiation was analysed up to the end of 2020, as most outcomes of TPT started in 2021 were still unknown in July 2021. Joinpoint regression was used to evaluate trends. Findings: 14,014 TPT prescriptions were included, most from São Paulo (8032) and Rio de Janeiro (3187). Compared to the same epidemiological weeks in 2019, the number of TPT prescribed in 2020 increased in Rio de Janeiro (82%) and São Paulo (14%) and decreased in Recife (65%), Fortaleza (31%) and Manaus (44%). In 2021, however, there was a 93% reduction in TPT prescriptions in all cities. The proportion of completed TPT remained constant (median = 74%). Interpretation: The COVID-19 pandemic in Brazil was associated with a dramatic decrease in TPT prescriptions in 2021. Treatment adherence remained constant, suggesting that health services were able to keep people on treatment but did not perform well in providing opportunities for people to enter care. Efforts are needed to expand access to TPT. Funding: Brazilian Ministry of Science, Technology and Innovation, CNPq.

Evolution of pediatric pharmaceutical forms for treatment of Hansen's disease (leprosy).

INTRODUCTION: Leprosy is a neglected, infectious, granulomatous and chronic disease caused by the pathological agent Mycobacterium leprae. The course of the disease is more aggressive in patients under 15 years of age, but the current treatment offered worldwide consists of solid forms, by the combination of antibiotics such as rifampicin, clofazimine and dapsone. This represents results in lack of adherence in pediatric patients and drug therapy failure, although numerous formulations and technologies have already been developed. AREA COVERED: This study aims to analyze the technological evolution of the pharmaceutical treatment of leprosy, aimed at children. A review of patents around the world was conducted to look for technical and clinical aspects of formulations and devices. EXPERT OPINION: Innovative formulations for pediatric patients were classified according to the routes of administration as oral, inhalable, injectable and transdermal. The formulations were organized as alternatives for pediatric therapy, taking into account the physicochemical aspects of drugs and the physiological aspects of pediatric patients. Among the difficulties for the patented formulations to reach the market, of special note is the low stability of the physicochemical characteristics of the drugs. Optimization of formulations would favor the pediatric treatment of leprosy, aiming at therapeutic success.

Development and Characterization of Pharmaceutical Systems Containing Rifampicin.

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was evaluated by phase-solubility studies. The mechanism of interaction was established through proton nuclear magnetic resonance spectroscopy and molecular modeling. Physicochemical characterization was investigated using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. The dissolution properties, antimicrobial activity (antibacterial, antibiofilm, and antileishmanial), and stability of the different samples were studied. The results obtained in this investigation demonstrate that multicomponent complexes can improve the water solubility and dissolution rate of rifampicin, as well as its antibacterial and antileishmanial action, and present suitable stability. In conclusion, rifampicin complexed with γ-cyclodextrin and arginine is an attractive approach for developing pharmaceutical dosage forms of rifampicin with increased antimicrobial activities.

Efeito protetivo em longo prazo do tratamento preventivo da tuberculose em uma região de moderada/alta incidência / Long-term protective effect of tuberculosis preventive treatment in a region of moderate/high incidence

O tratamento preventivo da tuberculose representa uma das principais estratégias para conter a propagação dessa doença em escala global. No entanto, existem diferentes recomendações de tratamento, dependendo das populações-alvo e das incidências das regiões. A eficácia sustentada do tratamento preventivo da tuberculose em populações que vivem com HIV é um tema mais debatido, enquanto sua aplicação em outros grupos de alto risco, como contatos próximos de pessoas com tuberculose pulmonar, ainda é pouco explorada. O objetivo deste estudo foi o de analisar a duração do efeito protetivo em longo prazo do tratamento preventivo em uma região com incidência moderada/alta de tuberculose. A amostra utilizada neste estudo foi baseada em dois ensaios clínicos randomizados multicêntricos que investigaram regimes terapêuticos de nove meses de isoniazida e quatro meses de rifampicina, essencialmente em contatos de pessoas com tuberculose pulmonar. O recrutamento ocorreu na cidade do Rio de Janeiro, caracterizada por uma incidência moderada/alta de tuberculose (93/100.000 habitantes, ou 0,93/1000 por 1000 pessoas por ano - ppa). Foi realizada consulta ao Sistema de Informação de Agravos de Notificação (Sinan) para identificar os participantes brasileiros que desenvolveram tuberculose (pulmonar ou extrapulmonar) após a randomização por um período de até 12 anos. Calculou-se as taxas de incidência por 1000 ppa de tuberculose entre aqueles que não completaram e os que completaram o tratamento preventivo e, também, as taxas correspondentes aos regimes, estratificadas por períodos: os primeiros 28 meses, após 28 meses e período integral (de zero a 143 meses). Utilizouse a função falha, ou seja, a probabilidade acumulada de falha, para se calcular a razão dos riscos (Hazard Ratio ­ HR) da ocorrência dos casos de tuberculose ao longo do tempo considerando os cenários de completude do tratamento e dos regimes. O teste de log-rank foi utilizado para verificar se havia diferença estatística entre as curvas. O resultado da taxa de incidência de tuberculose foi maior nos primeiros 28 meses entre aqueles que não completaram o TPT [6,69/1000 ppa [Intervalo de Confiança (IC) 95%: 2,17; 15,62)] em comparação ao período após os 28 meses [1,74/1000 ppa (IC 95%: 0,47; 4,45)]. Houve 16 casos de tuberculose, dos quais metade ocorreu nos 28 primeiros meses após a randomização. Houve maior proteção pelo tratamento completo (teste de log-rank p=0,042) neste período quando comparado ao tratamento incompleto. Estes resultados sugerem que não há risco aumentado de tuberculose até 12 anos após um curso de TPT em contatos que vivem em uma área de moderada∕ alta incidência de tuberculose, e que, portanto, neste cenário, não há evidência de que haja necessidade de retratamento com TPT. (AU)

Preventive treatment of tuberculosis represents one of the main strategies to contain the spread of this disease on a global scale. However, there are different treatment recommendations depending on the target populations and incidence rates in the regions. The sustained effectiveness of preventive tuberculosis treatment in populations living with HIV is a more debated topic, while its application in other highrisk groups, such as close contacts of people with pulmonary tuberculosis, is still little explored. The objective of this study was to analyze the duration of the long-term protective effect of preventive treatment in a region with a moderate/high incidence of tuberculosis. The sample used in this study was based on two multicenter randomized clinical trials that investigated therapeutic regimens of nine months of isoniazid and four months of rifampicin, essentially in contacts of people with pulmonary tuberculosis. Recruitment took place in the city of Rio de Janeiro, characterized by a moderate/high incidence of tuberculosis (93/100,000 inhabitants, or 0.93/1000 per 1000 people per year - ppa). The Notifiable Diseases Information System (Sinan) was consulted to identify Brazilian participants who developed tuberculosis (pulmonary or extrapulmonary) after randomization for a period of up to 12 years. The incidence rates per 1000 ppa of tuberculosis were calculated among those who did not complete and those who completed preventive treatment, and also the rates corresponding to the regimens, stratified by periods: the first 28 months, after 28 months and full period (from zero to 143 months). The failure function, that is, the accumulated probability of failure, was used to calculate the risk ratio (Hazard Ratio ­ HR) of the occurrence of tuberculosis cases over time considering the scenarios of completeness of treatment and regimens. The log-rank test was used to check whether there was a statistical difference between the curves. The tuberculosis incidence rate result was higher in the first 28 months among those who did not complete the TPT [6.69/1000 ppa [95% Confidence Interval (CI): 2.17; 15.62)] compared to the period after 28 months [1.74/1000 ppa (95% CI: 0.47; 4.45)]. There were 16 cases of tuberculosis, half of which occurred within the first 28 months after randomization. There was greater protection due to complete treatment (log-rank test p=0.042) in this period when compared to incomplete treatment. These results suggest that there is no increased risk of tuberculosis up to 12 years after a course of TPT in contacts living in an area of moderate∕ high incidence of tuberculosis, and that therefore, in this setting, there is no evidence that there is a need for retreatment. with TPT. (AU)