Combination Of Anti-tuberculosis Drugs Research Articles

Fetal protective effect of Indonesian propolis from Apis mellifera against rifampicin-pyrazinamide induced impaired pregnancy in BALB/c mice.

Anti-tuberculosis drugs rifampicin and pyrazinamide combination in pregnancy can cause morphological, visceral and skeletal damage. Several studies showed that propolis improves pregnancy outcomes. This study aims to determine the fetal protective effect of propolis in BALB/c mice given the anti-tuberculosis drug combination rifampicin and pyrazinamide. A total of 21 pregnant mice were randomly divided into three groups: the normal group (N)was given distilled water as a vehicle, the positive control group (RP) were given rifampicin 15 mg/kg BW, pyrazinamide 35 mg/kg BW and the treatment group (IP) were given rifampicin 15 mg/kg BB, pyrazinamide 35 mg/kg BW and propolis 400 mg/kg BW. The treatment was given during the period of organogenesis, from day 6 to day 15. Laparotomy was performed on the 18th day of pregnancy. Maternal and fetal body weight, fetal length, number of fetuses, and skeletal defects of fetuses were used as parameters to identify the teratogenic effect. All data were analyzed using the ANOVA. All groups significantly differed between maternal and fetal body weights (p<0.05). The administration of rifampicin-pyrazinamide and propolis during pregnancy did not significantly affect the number of fetuses (p>0.05). The administration of propolis protects the fetus from skeletal abnormalities. While in the RP and IP groups, we can find resorption sites and haemorrhagic. This study may suggest the protective effects of propolis against rifampicin pyrazinamide-induced impaired pregnancy.

Acetic Acid Enables Molecular Enumeration of Mycobacterium tuberculosis from Sputum and Eliminates the Need for a Biosafety Level 3 Laboratory.

Improved monitoring of Mycobacterium tuberculosis response to treatment is urgently required. We previously developed the molecular bacterial load assay (MBLA), but it is challenging to integrate into the clinical diagnostic laboratory due to a labor-intensive protocol required at biosafety level 3 (BSL-3). A modified assay was needed. The rapid enumeration and diagnostic for tuberculosis (READ-TB) assay was developed. Acetic acid was tested and compared to 4 M guanidine thiocyanate to be simultaneously bactericidal and preserve mycobacterial RNA. The extraction was based on silica column technology and incorporated low-cost reagents: 3 M sodium acetate and ethanol for the RNA extraction to replace phenol-chloroform. READ-TB was fully validated and compared directly to the MBLA using sputa collected from individuals with tuberculosis. Acetic acid was bactericidal to M. tuberculosis with no significant loss in 16S rRNA or an unprotected mRNA fragment when sputum was stored in acetic acid at 25°C for 2 weeks or -20°C for 1 year. This novel use of acetic acid allows processing of sputum for READ-TB at biosafety level 2 (BSL-2) on sample receipt. READ-TB is semiautomated and rapid. READ-TB correlated with the MBLA when 85 human sputum samples were directly compared (R2 = 0.74). READ-TB is an improved version of the MBLA and is available to be adopted by clinical microbiology laboratories as a tool for tuberculosis treatment monitoring. READ-TB will have a particular impact in low- and middle-income countries (LMICs) for laboratories with no BSL-3 laboratory and for clinical trials testing new combinations of anti-tuberculosis drugs.

Experience of Fixed-Dose Combinations of Anti-Tuberculosis Drugs for Preventive Treatment in Children

The objective: to evaluate the effectiveness and safety of preventive treatment with fixed-dose combination of anti-tuberculosis drugs (FDCs) in children from groups at high risk of developing tuberculosis.Subjects and Methods. Effectiveness of preventive treatment was analyzed in 318 children from groups at high risk of developing tuberculosis. Also, we studied the possibility of successful completion of the full course of treatment using FDCs and preventive treatment regimens containing at least two single drugs. Inclusion criteria were as follows: the child at high risk of developing tuberculosis; no clinical and radiological signs of active tuberculosis; lack of information about the resistance to first-line drugs at the suspected source of infection; and negative HIV status. A group of children (172 people) underwent preventive treatment using FDCs, of them 126 patients received FDCs containing isoniazid 150 mg + pyrazinamide 500 mg + pyridoxine hydrochloride 15 mg, and 46 patients received FDCs containing isoniazid 150 mg + ethambutol 400 mg + pyridoxine hydrochloride 15 mg. The comparison group (CG) included 146 children who received preventive treatment with single drugs: 111 children received isoniazid and pyrazinamide, and 35 children received isoniazid and ethambutol.Results. When assessing the safety and effectiveness, no statistically significant differences were found when using FDCs and single-drug regimens. 91.9% of children receiving FDCs and 86.3% of children receiving single-drug regimens successfully completed the full course of treatment. When taking FDCs, there was a tendency to lower incidence of adverse events. With the FDC (isoniazid 150 mg + pyrazinamide 500 mg + pyridoxine hydrochloride 15 mg), the proportion of adverse events did not exceed 4.0%. There were no adverse events with the FDC (isoniazid 150 mg + ethambutol 400 mg + pyridoxine hydrochloride 15 mg).Conclusion. Preventive treatment of children with tuberculosis infection with FDC is a modern and effective technology.

Preparation and in vitro osteogenic evaluation of high-strength ceramic artificial bone loaded with anti-tuberculosis drug PaMZ

The objective of this study was to prepare a high-strength ceramic artificial bone loaded with the anti-tuberculosis drug PaMZ (delamanid, moxifloxacin, and pyrazinamide) and evaluate its physical characteristics and osteogenic potential. We utilized 3D printing technology to fabricate artificial bones and then obtained a high-strength ceramic artificial bone by high-temperature firing. Then, a triple combination of anti-tuberculosis drugs, including delamanid (Pa), moxifloxacin (M), pyrazinamide (Z), and polylactic acid-co-glycolic acid mixed in a ratio of 3:12:45:140, was incorporated onto the surface of the ceramic artificial bone. Consequently, a high-strength ceramic artificial bone, loaded with anti-tuberculosis drugs, was successfully obtained. The physical characteristics of the drug-loaded artificial bone were assessed using an electronic universal testing machine and scanning electron microscopy. The osteogenic performance of the artificial bone was evaluated through rat bone marrow mesenchymal stem cell (rBMSCs) co-culture experiment, cell counting kit-8 (CCK-8) cell proliferation assay, alkaline phosphatase staining, and alizarin red staining. The drug-loaded ceramic artificial bone exhibited favorable physical characteristics, void interconnection, a porosity of 30.6% ± 0.7%, and a compressive strength of 17.65 ± 0.46 MPa. The rBMSCs co-culture experiment and CCK-8 cell proliferation experiment demonstrated excellent cell compatibility, while alkaline phosphatase and alizarin red staining indicated good in vitro osteogenic performance. In summary, the high-strength ceramic artificial bone loaded with the anti-tuberculosis drug PaMZ exhibited a favorable morphological structure and compressive strength. In addition, it demonstrated good biocompatibility and osteogenic properties.

Primary Hepatic Tuberculosis: An Unexpected Diagnosis

Background: Primary hepatic tuberculosis (PHT) is a rare form of extrapulmonary tuberculosis that affects the liver and is difficult to diagnose. The present case report describes a patient who was diagnosed with PHT and was successfully treated with a combination of anti-tuberculosis drugs. A 55-year-old diabetic male presented with a history of abdominal pain, fever and weight loss. An abdominal ultrasound and computed tomography (CT) scan revealed multiple hepatic lesions, and fine needle aspiration cytology confirmed the diagnosis of PHT. The patient was treated with a standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for another four months. The patient showed improvement in symptoms and the disappearance of hepatic lesions, as seen on follow-up ultrasound scans. This case highlights the importance of considering PHT in the differential diagnosis of patients with hepatic lesions, particularly in regions with a high burden of tuberculosis. Early diagnosis and prompt treatment can lead to a good outcome in PHT. J Com Med Col Teachers Asso Jan 2023; 27(1): 38-41

Augmentation of the Clinical Efficacy of Levofloxacin and Antituberculosis Drugs by Chinese Herbal Preparations in Pulmonary Tuberculosis

This study was designed to explore whether Chinese herbals could enhance the clinical efficacy of levofloxacin and a combination of antituberculosis drugs. To this end, a group of pulmonary patients were treated with pyrazinamide, isoniazid, ethambutol, and levofloxacin (control), and the other group (treatment) also received a combination of extra Chinese herbal compounds. After 6 months of therapy, the total efficiency of lesion absorption in the treatment group was higher than in the control group. The treatment group had a higher peak expiratory flow rate, a higher percentage of forced vital capacity, a higher percentage of the first second of forced expiration, higher levels of immunoglobulin A, immunoglobulin G, immunoglobulin M, and CD4+, and lower levels of CD8+ compared to the control group. The levels of proinflammatory cytokines were lower, the sputum conversion rate was higher, and the recurrence rate was lower in the treatment group than the control group. After therapy, the treatment group had higher scores in the quality of daily life, spirit, appetite, fatigue, and sleep assessments. In conclusion, therapy with levofloxacin and antituberculosis drugs combined with Chinese herbal compounds for patients with pulmonary tuberculosis could effectively relieve the inflammatory reaction, promote lesion absorption, and thus improve their lung function and promote recovery.

A rare case of primary tuberculosis complex in the abdomen

Cutaneous tuberculosis (CTB) is the rarest form of tuberculosis (TB). CTB cases account for less than 1% of all TB cases and about 15% of all extrapulmonary tuberculosis (EPTB) cases. CTB is rare even in communities where it is endemic. CTB has a variety of manifestations and can appear similar to other disease processes. Therefore, many clinicians have difficulty recognizing CTB because CTB is known to be a great imitator. We present an unusual case of CTB which happened to be a primary tuberculous complex (PTC) manifested as an ulcerated abdomen in a 33-year-old woman. Previous medications received showed no improvement and referred to the hospital for further treatment. Histopathology of the skin lesion showed fibrous connective tissue that contained granulomas composed by epithelioid histiocytes, lymphocytes, plasma cells, and multinucleated giant cells. Patients were given therapy in the form of a fixed-dose combination of antituberculosis drugs (fixed-dose combination/FDC) and vitamin B6. Despite being rare,PTC is important to consider in patients with suggestive clinical pictures of the infection.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed Mycobacterium smegmatis synergistically or additively in combinations with rifampicin or ethambutol, respectively. The susceptibility to rifampicin and ethambutol was increased by knockdown of inhA, which encodes a target molecule of isoniazid. Additionally, knockdown of rpoB, which encodes a target molecule of rifampicin, increased the susceptibility to isoniazid and ethambutol, which act synergistically with rifampicin in the checkerboard assay. Moreover, CRISPRi could successfully predict the synergistic action of cyclomarin A, a novel TB drug candidate, with isoniazid or rifampicin. These results demonstrate that CRISPRi is a useful tool not only for drug target exploration but also for screening the combinatorial effects of novel combinations of anti-TB drugs. This study provides a rationale for anti-TB drug development using CRISPRi.

Cutaneous Adverse Drug Reaction Among HIV-Infected Patients Starting Antituberculosis Treatment

Introduction. Treatment of tuberculosis (TB) in HIV patients is complicated due to numerous comorbidities and possible adverse effects. One of which is cutaneous adverse drug reaction (CADR). This adverse event is often difficult to manage because of multiple medications the patients get. The objective of this study was to know the prevalence and risk factors of CADR among HIV-infected patients starting anti-TB treatment. Methods. This retrospective study reviewed data from medical records of new patients at Working Group on AIDS outpatient clinic at Cipto Mangunkusumo Hospital, Indonesia in January 2008-December 2010 that had started anti-TB treatment. Risk factors of CADR among HIV patients treated with antituberculosis drugs evaluated were sex, age, route of HIV transmission, TB manifestation, and baseline CD4+ cell count. Numeric data were analyzed using independent T-test if normally distributed, otherwise Mann Whitney U test were used. Chi-square or Fisher’s exact test were used for categorical data. p-value was considered significant if below 0.05. Results. Of 454 HIV-infected patients that started anti-TB treatment, median age was 30 years. Most patients were male and intravenous drug users/IDU. Median baseline CD4+ cell count was 61 cells/ μL. There were 10.6% subjects that developed CADR. Most common manifestations were maculopapular rashes (66.7%), followed by erythema multiforme (14.6%), and Stevens Johnson Syndrome (8.3%). Anti-TB drugs were stopped and then re-challenge was conducted in 54.2% patients. Anti-TB drugs were continued and only the suspected drug was stopped in 29.2% patients. The offending drugs were cotrimoxazole (41.7%), rifampicine (41.7%), ethambutol (16.7%), pyrazinamide (14.6%), pyrimethamine (12.5%), isoniazide (10.4%), streptomycin (8.3%), efavirenz (8.3%), fixed dose combination of antituberculosis drugs (8.3%), and nevirapine (4.2%). The proportion of CADR was higher in woman than man (12% vs. 10.3%, p=0.66), non-IDU than IDU (13% vs. 9.2%, p=0.20), without extrapulmonary TB than extrapulmonary TB (11.1% vs. 9.4%, p=0.29), but the associations weren’t statistically significant. Median age was higher (31 vs. 30 years, p=0.32) and CD4 cell count (59.5 vs. 62 sel/μL, p=0.96) was lower in CADR group than non CADR group. Conclusion. The prevalence of CADR among HIV-infected patients starting anti-TB treatment was 10.6%. Sex, age, route of HIV transmission, TB manifestation, and baseline CD4+ did not have statistically significant association with CADR.

Bedaquiline in the complex treatment of HIV-associated respiratory tuberculosis

Introduction. The continued decline in the number of patients shedding multidrug-resistant mycobacteria (MDR MDR), which has continued since 2018, determines the priority of measures to improve the effectiveness of treatment of newly diagnosed patients, including HIV-associated tuberculosis, with the mandatory inclusion of new anti-tuberculosis drugs in the treatment regimens of patients. drugs.Aim. To evaluate the efficacy and safety of bedaquiline in the complex treatment of patients with HIV-associated respiratory tuberculosis.Materials and methods. In the prospective study was included 60 patients with newly diagnosed HIV-associated respiratory tuberculosis, randomized into 2 groups: group 1 – 30 patients who received bedaquiline in the combination of anti-tuberculosis drugs; group 2 – 30 patients who received therapy without the addition of bedaquiline. Bacterial excretion was detected in all patients of the 1st and 2nd groups, the MBT drug sensitivity test confirmed the presence of pre-XDR MBT. Patients in both study groups received antiretroviral therapy. The follow-up period for patients was 12 months.Results. In the group of patients treated with bedaquiline, higher treatment results were noted both in terms of the criterion “closing of decay cavities” (by 14.7%) (p &gt; 0.05) and by the criterion “cessation of bacterial excretion” (by 23.3%) ((p &lt;0.05).Conclusions. The high clinical efficacy and safety of the use of bedaquiline in the complex treatment of patients with HIV-associated respiratory tuberculosis has been demonstrated. The data obtained make it possible to recommend the use of bedaquiline in the treatment of patients with newly diagnosed HIV-associated tuberculosis, isolating MBT with pre-XDR, to increase the effectiveness of the main course of chemotherapy, prevent the amplification of MBT drug resistance and develop extensive MBT drug resistance.

Association of Interleukin-2 (IL-2) Levels With Acid-Fast Bacillus (AFB) Sputum Conversion In Drug-Resistant Pulmonary Tuberculosis Patient

Background: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb) which can be found on multiple organs, but mostly infect the lung. AFB smear is used to diagnose and evaluate therapy response, to show bacterial burden and the patient’s infectious status. Combination of antituberculosis drugs for a long period of time could cause poor compliance and increased risk of resistance. Mtb infection induce immune response and release cytokines, one of which is interleukin-2 (IL-2) that regulate T lymphocyte cell. Higher IL-2 levels is found on patient with high bacterial burdern. This study aims to see the assossciation between IL-2 levels before and 30 days after DR-TB treatment, to see pre and post-treatment IL-2 levels with conversion of AFB smear, and correlation between pre-treatment IL-2 levels and AFB smear. Method: This was a cohort prospective study at RSUD dr Saiful Anwar Malang. Thirty nine DR-TB patients underwent AFB smear before and 30 days after treatment, while IL-2 levels was also measured by Enzym-Linked Immunosorbent Assay (ELISA) technique. Results: The levels of IL-2 before treatment was significantly higher compared to 30 days after treatment (P&lt;0.001). There was no significant IL-2 levels difference between conversion and non-conversion group (P=0.23), and a weak, not-significant correlation between IL-2 levels and AFB smear (r=0.28; P=0.06). Conclusion: The levels of IL-2 was significantly higher before than after treatment and it cannot be used to determine the positivity of acid-resistant bacilli smears in the sputum of patients with DR-TB. The limited timeframe and biomarker in this study raise the possibility to observe IL-2 as well as other biomarkers after intensive phase of TB treatment for future studies.

CRISPR Interference-based Screening for Prediction of Synergistic/Additive Effects of Novel Combinations of Anti-Tuberculosis Drugs

CRISPR Interference-based Screening for Prediction of Synergistic/Additive Effects of Novel Combinations of Anti-Tuberculosis Drugs

Anti-tuberculosis drugs used in a directly observed treatment short course (DOTS) schedule alter endocrine patterns and reduce the ovarian reserve and oocyte quality in the mouse.

Tuberculosis is one of the major infectious diseases, with people of reproductive age group having a high risk of infection. The present study was designed to understand the consequences of anti-tuberculosis drugs (ATDs) used in DOTS (directly observed treatment short course) schedule on ovarian function. Adult female Swiss albino mice were orally administered with combinations of ATDs used in the DOTS schedule every day for 4weeks. At 2weeks after the cessation of ATDs administration, the endocrine changes and ovarian function were assessed in mice. Administration of ATDs to mice resulted in a prolonged estrous cycle, reduced ovarian follicle reserve, alteration in FSH, LH, and progesterone level, and decreased the number of ovulated oocytes. Further, the degree of fragmentation, degeneration, abnormal distribution of cytoplasmic organelles, abnormal spindle organisation, and chromosomal misalignment were higher in oocytes that were ovulated following superovulation. Blastocysts derived from ATDs treated mice had significantly lower total cell numbers and greater DNA damage. A marginal increase in the number of resorbed fetuses was observed in all the ATDs treated groups except in the multidrug resistance treatment group. Male progeny of ATDs treated mice had decreased sperm count and lower progressive motility, while female progeny exhibited a non-significant reduction in the number of oocytes ovulated. Theresults of this study suggest that ATDs can have significant adverse effects on the ovarian reserve, cytoplasmic organisation of oocytes, and can potentially cause transgenerational changes. The findings of the present study indicate ovarian toxicity of ATDs and warrant further research in the direction of identifying alternate drugs with minimal toxicity, and strategies to mitigate the ovarian toxicity induced by these drugs.

Case Reports on Severe Antituberculosis-Drug Induced Hepatotoxicity in Tuberculosis Patients: The Post-Incidence Therapy

Introduction: The first-line regimen for tuberculosis (TB) treatment comprises Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol. However, these drugs are known to potentially cause hepatotoxicity. This study aimed to evaluate hepatotoxicity incidence in patients during intensive phase of anti-tuberculosis treatment focusing on post-incidence therapy. Methods: The study involved pulmonary TB patients who were admitted to the National Lung Health Center due to hepatotoxicity after receiving fixed-dose combination of antituberculosis drugs (FDC-AT) in September-October 2019. Drug-related hepatotoxicity is defined as an increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times of the normal upper limit (ULN) with an increase in bilirubin level. Results: There were 8 patients admitted to the center due to hepatotoxicity, 4 of them experienced grade 3 (severe) hepatotoxicity, during which the ALT, AST, bilirubin levels increased 5-10 times of the ULN. The post-hepatotoxicity treatment includes the cessation of FDC-AT treatment followed by hepatoprotective supplements. Following two weeks of treatments, the biomarker levels of two out of four patients went back to normal and the AT therapy was resumed. Meanwhile, the other two patients continued to receive the hepatoprotective therapy for up to 8 weeks. However, when the treatment failed to bring the transaminase level back to normal, a different AT regimen was prescribed. Conclusions: The cessation of FDC-AT and the use of hepatoprotective supplements for two to eight weeks were able to alleviate the AT-induced severe hepatotoxicity. A close monitoring of liver biomarkers is warranted to prevent the incidence of hepatotoxicity in patients receiving antituberculosis

A hydrogel-based implantable multidrug antitubercular formulation outperforms oral delivery.

We present a non-immunogenic, injectable, low molecular weight, amphiphilic hydrogel-based drug delivery system (TB-Gel) that can entrap a cocktail of four front-line antitubercular drugs, isoniazid, rifampicin, pyrazinamide, and ethambutol. We showed that TB-Gel is more effective than oral delivery of the combination of four drugs in reducing the mycobacterial infection in mice. Results show that half the dose of chemotherapeutic drugs is sufficient to achieve a comparable therapeutic effect to that of oral delivery.

Kleinhovia hospita extract alleviates experimental hepatic and renal toxicities induced by a combination of antituberculosis drugs

Introduction: Antituberculosis drugs are associated with hepatic and renal toxicities due to drug’s radical metabolites. Kleinhovia hospita L extract possesses a potent antioxidant capacity that can be beneficial in eradication of oxidative-induced cell damage. This study aimed to evaluate the effects of K. hospita hydro-alcoholic extract on biomarkers and structure changes in liver and kidney induced by a combination of antituberculosis drugs (CAD), comprising isoniazid, rifampicin, pyrazinamide and ethambutol in Wistar rats. Methods: Thirty-five male Wistar rats were assigned into one of the five groups: control, CAD, and CAD with K. hospita extract in three different doses (125, 250 and 500 mg/kg). The extract was administered three hours prior to CAD and all treatments were carried out for 28 days. Following the last day of treatment, blood samples and organs were collected for biomarker analysis and histopathological examinations. Results: Twenty-eight days of CAD treatment in rats induced marked elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serum creatinine and urea levels compared to controls. K. hospita extract at higher doses (250 mg/kg and 500 mg/kg) significantly improved ALT, urea and creatinine levels in the rats treated with CAD (P&lt;0.05), although it did not significantly reduce AST. Furthermore, liver and renal tissue damages induced by CAD were restored with K. hospita extract treatment, especially at higher doses. Conclusion: Kleinhovia hospita extract treatment has the potential to protect the liver and renal damage induced by toxic doses of CAD.

Parameters of hepatotoxic reactions caused by the combination of first line anti-tuberculosis drugs in rats with different acetylation phenotypes

The objective:in the experiment, to study specific parameters of manifestations of hepatotoxic reactions to the combination of anti-tuberculosis drugs containing isoniazid and rifampicin in rats with different acetylation phenotypes.Subjects and methods.Liver damage was modeled in rats, old females, belonging to the phenotype of rapid acetylation, and in mature males, belonging to the phenotype of slow acetylation, with a combination of basic anti-tuberculosis drugs, which were administered for 14 days. Hepatotoxic reactions were assessed by clinical observations of rats, biochemical parameters and morphological changes in the liver, which were compared with intact animals.Results of the study:in female rats (fast acetylators of isoniazid), signs of the cytolytic mechanism of liver damage prevailed (more significant elevation of ALT activity, pronounced duration of thiopental sleep, pronounced hydropic degeneration of hepatocytes with the presence of hepatocyte necrosis, venous congestion and edema of the portal tracts). In males (with the phenotype of slow acetylation of isoniazid), a significant elevation of total and direct bilirubin levels, AST activity and, to a lesser extent, ALT were observed, i.e., signs of a mixed mechanism of liver damage (cholestatic and cytolytic).

Prospects for the use of new generation of anti-tuberculosis drugs in treatment of drug-resistant tuberculosis

The aim of this work was an experimental and clinical study of increasing of the efficiency of therapy of respiratory tuberculosis with drug resistant pathogen by including a combination of anti-tuberculosis drugs of new generation Bedaquiline (Bq) and Thioureidoiminomethylpyridi-nium perchlorate (perchlozone, Tpp) into treatment regimens. The presented results were obtained: in the experiment on a model of tuberculosis infection in 103 male C57black / 6 mice, reproduced by inserting into the lateral vein of the tail of a suspense of clinical strains of Mycobacterium tuberculosis with multi-drug resistance (MDR) and with various combinations of mutations in the genes; in the clinic on the basis of examination and treatment of 148 patients with multidrug-resistant respiratory tuberculosis. It is shown that the application of the therapy schemes for multiple and broad drug resistant tuberculosis, containing Bq and Tpp in combination with drugs, selected taking into account the drug sensitivity of mycobacteria, allows to significantly reduce the periods of relief of symptoms of intoxication, regression of inflammatory changes, abacillation and achieving positive X-ray dynamics. Undesirable phenomena against the background of combined prescription of new generation drugs, as a rule, corresponded to light and moderate severity, and in frequency of development and expression did not differ from control groups of observation.

Validation of a universal and highly sensitive two-dimensional liquid chromatography–tandem mass spectrometry methodology for the quantification of pyrazinamide, ethambutol, protionamide, and clofazimine in different biological matrices

A novel and potent anti-tuberculosis drug combination pyrazinamide (PZA), ethambutol (EMB), protionamide (PTO), and clofazimine (CFZ) that rapidly kills Mycobacterium tuberculosis (Mtb) in the lungs has been identified using the artificial-intelligence-enabled parabolic response surface approach. A universal and highly sensitive two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) method for the simultaneous determination of PZA, EMB, PTO, and CFZ in various biological samples in different states (liquid samples: plasma, bile, and urine; solid samples: tissue and feces) using simple pretreatment was established and validated. For the first dimension of this column-switching arrangement, the automated purification and enrichment of the drugs were achieved on a Polar-RP column. The subsequent analytical separation was performed on an Agilent Zorbax SB-Aq column, and the total loop time was 7.5 min. The positive-ionization mode with multiple reaction monitoring was used for detection. The sensitivity was good with no carry-over detected, and the lower limit of quantification ranged from 100 to 500 pg/mL. This quantification method was fully validated and proved to be robust in accordance with US Food and Drug Administration guidelines. High recoveries (85.3–111.4%) and accuracies (92.1–109.3%), together with high precision values (0.5–13.8%), were verified in all matrices. All standard curves showed favorable linearities with r2 > 0.995. This validated method was applied to study plasma pharmacokinetics, tissue distribution, and excretion in Sprague–Dawley rats after oral administration of the drug combination.