Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

Propolis modulates cellular biochemistry, antioxidants, cytokine profile, histological and ultra-morphological status against antituberculosis drugs induced hepatic injury

To evaluate hepatic injury induced by antituberculosis drugs(ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis(bee hive product) against ATDs induced hepatic injury. Methods: The ATDs were administered for 8 weeks as well as propolis extract at three different doses(100, 200, 400 mg/kg) conjointly for 8 weeks in rats. Silymarin(50 mg/kg) was given as positive control. Animals were euthanized after 8 weeks; blood and liver samples were collected to perform various biochemicals, serological and histopathological and ultramorphological studies. Results: Significant increase(P < 0.05) in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglyceride and cholesterol along with reduction in glucose and albumin level were noted after ATDs induced hepatic injury. Significant increase(P < 0.05) in lipid peroxidation, triglyceride, cholesterol and CYP2E1 activity; decline in reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glucose-6-phosphatase dehydrogenase activity were observed after ATDs intoxication. Due to presence of a wide range of flavonoids and polyphenols in propolis extract, its administration reduced hepatic injury and maintained biochemical indices towards control. Histopathological and electron microscopic observations indicated hepatoprotective potential of propolis at cellular level whereas, TNF-α, IL-6 and IGF-1 confirmed therapeutic potential of propolis at molecular level. Conclusions: It can be concluded that propolis possess hepatoprotective potential against ATDs induced hepatic injury that may prove itself as a clinically useful natural product in management of drug induced liver injury.

Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors

Background/Aims: Antituberculosis drug-induced liver injury (TB DILI) is a frequent medical problem in Pakistan. Critical understanding of various aspects of TB DILI is not only important to manage liver injury but may also prevent unnecessary discontinuation of antituberculosis treatment. The study is aimed to determine the frequency, types, severity and patterns of TB DILI. Study further evaluates various risk factors of TB DILI. Materials and Methods: This is a prospective cohort study of two seventy-eight patients with the diagnosis of tuberculosis, where patients were followed during tuberculosis treatment. TB DILI was defined in accordance to international DILI expert working group. Results: Out of two seventy eight-patients, ninety-five (34.14%) had TB DILI. The most common pattern of TB DILI was hepatocellular (63.15%) followed by mixed (23.15%) and Cholestatic (13.68%). Most of the patients had mild DILI (43.15%) followed by moderate (30.52%), severe (20.01%) and very severe (5.26%). Age > 35 years, concomitant hepatotoxic drugs, extrapulmonary TB and malnutrition are important risk factors for TB DILI. Conclusion: All patterns of TB DILI with varying severity were present. Age > 35 years, malnutrition, extrapulmonary TB and concomitant use of hepatotoxic drugs were risk factors for TB DILI.

Synergistic Effects of 18β-glycyrrhetinic Acid Combined with Antituberculosis Drugs against Mycobacterium tuberculosis

The in vitro antibacterial activities of 18β-glycyrrhetinic acid alone or combined with first-line antituberculosis drugs including isoniazid（INH）,rifampicin（RFP） and streptomycin（SM） against Mycobacterium tuberculosis were detected using MABA method.The minimum inhibitory concentrations（MICs） of18β-glycyrrhetinic acid against M.tuberculosis H37Rv（ATCC 27294） and M.bovis（ATCC 19210） were 50 and 100 μg/m L,respectively.The MICs of two clinical drug-susceptible isolates and six drug-resistant isolates were 25-50 and 100-200 μg/m L,respectively.As 18β-glycyrrhetinic acid combined with INH,RFP and SM,they exhibited synergistic effects against six drug-resistant isolates,and MICs decreased significantly：MIC of INH decreased by 2-32 folds（FICIs 0.125-0.375）;MIC of RFP decreased by 4-8 folds（FICIs 0.240-0.490）;MIC of SM decreased by 4-16 folds（FICIs 0.165-0.460）.Traditional medicine monomer had low cytotoxicity on normal cell BHK-21 and could restraint SMMC fission.The results showed that 18β-glycyrrhetinic acid combined with anti-TB drugs（INH,RFP and SM） had good antibacterial activity against M.tuberculosis.These findings indicated that 18β-glycyrrhetinic acid might serve as the potential therapeutic compound for future development of anti-TB drugs.

Molecular iodine catalyzed synthesis of tetrazolo[1,5-a]-quinoline based imidazoles as a new class of antimicrobial and antituberculosis agents

A series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 6a-i have been synthesized by a reaction of tetrazolo[ 1,5-a]quinoline-4-carbaldehyde 3a-d, benzil 4, aromatic amine 5a--c and ammonium acetate in the presence of iodine through one-pot multi-component reaction （MCR） approach. All the derivatives were screened for antimicrobial and antituberculosis activities and results worth further investigations.

Antituberculosis and cytotoxic activities of triorganotin(Ⅳ) complexes

Five triorganotin（IV） （1-5） complexes of cinnamic acid, （Z）-2-acetamido-3-phenylacrylic acid, 3-methylbut-2-enoic acid, and 2,2-diphenylacetic acid have been synthesized and characterized by IH-13C-119Sn NMR, UV, and IR. The spectroscopic investigation demonstrated that the carboxylate group acts as a monodentate ligand in triorganotin（IV） compounds. Five triorganotin（IV） complexes were screened against the log phase culture of Mycobacterium tuberculosis H37Rv by colorimetric method using XTT dye as growth indicator. The MICs were found to he 0.08 and 1.25μg/mL.

New antituberculosis drugs targeting the respiratory chain

With the emergence of multidrug-resistant tuberculosis and extensive drug-resistant tuberculosis strains,there is an urgent need to develop novel drugs for the treatment of tuberculosis.The respiratory chain is a promising target for the development of newantimycobacterial agents,and a growing number of compounds have been reported and some have entered clinical trials.In this review,we summarize the main features and the electron transfer process of the mycobacterial respiratory chain,and the recent progress in the search for new small molecule inhibitors to rgeting the three main potential targets in the respiratory chain of Mycrobacterium tuberculosis.Our emphasis is on the optimization strategy of QcrB inhibitors and the challenges of developing QcrB inhibitors as antituberculosis drugs due to the alternate bd-type oxidase oxidative compensation pathway are discussed.

Organizing pneumonia secondary to pulmonary tuberculosis:A case report

BACKGROUND Organizing pneumonia secondary to pulmonary tuberculosis is rare.Moreover,the temporal boundary between pulmonary tuberculosis and secondary organizing pneumonia has not been defined.We report a case of secondary organizing pneumonia associated with pulmonary tuberculosis occurring after nine months of antituberculosis treatment.CASE SUMMARY A 54 years old man,previously diagnosed with pulmonary tuberculosis and tuberculous pleurisy,underwent nine months of antituberculosis treatment.Follow-up lung computed tomography revealed multiple new subpleural groundglass opacities in both lungs,and a lung biopsy confirmed organizing pneumonia.Treatment continued with anti-tuberculosis agents and hormone therapy,and subsequent dynamic pulmonary computed tomography exams demonstrated improvement in lesion absorption.No disease recurrence was observed after corticosteroid therapy discontinuation.CONCLUSION When treating patients with active pulmonary tuberculosis,if an increase in lesions is observed during anti-tuberculosis treatment,it is necessary to consider the possibility of tuberculosis-related secondary organizing pneumonia,timely lung biopsy is essential for early intervention.

INF-γ and IL-2 Profile as Therapeutic Markers in Tuberculosis Patients at the Jamot Hospital of Yaounde-Cameroon

Background: Tuberculosis (TB) is one of the top lethal infectious diseases worldwide. In recent years, interferon-γ (INF-γ) release assays (IGRAs) have been established as routine tests for diagnosing TB infection. However, produced INF-γ assessment cannot permit to distinguish active ATB from latent TB infection (LTBI), especially in TB epidemic areas. In addition to IFN-γ, interleukin-2 (IL-2), secreted by activated T cells, is involved in immune response against Mycobacterium tuberculosis. This could be involved in the follow up of treatment response. The aim of our study was to determine IFN-γ and IL2 cytokines profiles of patients under antituberculosis treatment. Materials and Methods: A six months’ cross-sectional study was conducted at the Jamot Hospital of Yaoundé, from May to August 2021. Sociodemographic and clinical data as well as 5 mL of blood were collected from each participant. INF-γ and IL-2 were determined using indirect Enzyme linked Immuno-Sorbent Assay (ELISA) according to the manufacturer’s recommendations and spectrum exam in combination with radiography and GeneXpert were used as standard. P-values Results: The results showed that men were more infected 14/61 (31.8%) with a high presence in active and resistant TB groups. The mean age was 41.3 ± 13.1 years with a 95% CI = [38.2 - 44.7], the age group with the highest infection rate was ranged between 31 and 40 years. The IL-2 and INF-γ means were respectively 327.6 ± 160.6 pg/mL and 26.6 ± 13.0 pg/mL in ATB patients, 251.1 ± 30.9 pg/mL and 21.4 ± 9.2 pg/mL in patients with resistant tuberculosis, while it was 149.3 ± 93.3 pg/mL and 17.9 ± 9.4 pg/mL in cured patients, 15.1 ± 8.4 pg/mL and 5.3 ± 2.6 pg/mL in participants presumed healthy (p γ and IL-2rates were observed between the different groups. Conclusion: Monitoring the serum levels of INF-γ and IL-2 would be useful for the follow-up of anti-tuberculosis patients, particularly in the both cytokines association case.

Insight of Natural Compounds Halimane Diterpenoids against Mycobacterium tuberculosis: Virtual Screening, DFT, Drug-Likeness, and Molecular Dynamics Approach

In the purpose to design novel antituberculosis (anti-TB) drugs agents against Mycobacterium tuberculosis (Mtb), we have built a molecular library around 42 Halimane Diterpenoids isolated from natural sources. Two Mtb enzymes drug targets (Mtb Mycothiol S-transferase and Mtb Homoserine transacetylase) have been adopted. The pharmacological potential was investigated through molecular docking, molecular dynamics simulation, density functional theory (gas phase and water) and ADMET analysis. Our results indicate that (2R,5R,6S)-1,2,3,4,5,6,7,8-octahydro-5-((E)-5-hydroxy-3-methylpent-3-enyl)-1,1,5,6-tetramethylnaphtha-lene-2-ol (compound 20) has displays higher docking score with each of the selected drug targets. In addition, this molecule exhibits a satisfactory drug potential activity and a good chemical reactivity. Its improved kinetic stability in the Mtb Mycothiol S-transferase enzyme reflects its suitability as a novel inhibitor of Mtb growth. This molecule has displayed a good absorption potential. Our results also show that its passive passage of the intestinal permeability barrier is more effective than that of first-line treatments (ethambutol, isoniazid). In the same way, this anti-TB druglikeness has shown to be able to cross the blood brain barrier.

克拉霉素联合抗痨药治疗老年人复治肺结核临床观察

目的观察克拉霉素联合氧氟沙星、力克肺疾和利福喷丁治疗老年人复治肺结核的临床疗效。方法选择住院60例老年人复治肺结核病人为研究对象,随机分为治疗组和对照组。治疗组采用克拉霉素和氧氟沙星联合力克肺疾、利福喷丁四联抗痨;对照组采用力克肺疾、利福喷丁、氧氟沙星三联抗痨。疗程均为6个月(强化期2个月,维持期4个月,维持期均以力克肺疾和利福喷丁治疗),6个月后随访所有患者的症状、复查肝肾功能及胸片。结果治疗组在胸片病灶吸收方面,较对照组有明显改善(P<0.05);但在药物不良反应方面两种方案无显著差异(P>0.05)。结论克拉霉素联合氧氟沙星、力克肺疾及利福喷丁比氧氟沙星联合力克肺疾、利福喷丁治疗老年人复治肺结核疗效好。

Delayed diagnosis and comprehensive treatment of cutaneous tuberculosis:A case report

BACKGROUND Tuberculosis(TB)is a widespread infectious disease,with an incidence that is increasing worldwide.Cutaneous TB(CTB)occurs rarely,accounting for less than 1%of all TB cases.Due to the clinical presentation and diagnostic difficulties,CTB is often clinically neglected and misdiagnosed.CASE SUMMARY A 32-year-old man underwent several debridement surgeries and skin flap transplantation after trauma.The wound remained unhealed,accompanied by sinus formation.According to empirical judgment,T-cell spot of TB test,and bacterial culture of pyogenic fluids,he was diagnosed with CTB due to infection with exogenous Mycobacterium tuberculosis.A comprehensive anti-TB regimen that included isoniazid,rifampicin,ethambutol,and pyrazinamide was applied.The sinus was filled with a hydrophilic fiber-containing silver dressing,and woundprotecting sponges were applied to part of the wound.The wound healed after 40 d.No ulceration was found within 2 mo after discharge;further follow-up will be conducted.CONCLUSION A non-healing wound may be caused by TB infection.Comprehensive treatment of CTB is effective.

Ameliorative effect of Pergularia daemia(Forssk.) Chiov. leaves extract against anti-tuberculosis drugs induced liver injury in rats

Objective:To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia(P.daemia) against anti-tuberculosis drugs(ATDs) induced liver injury.Methods:Wistar albino rats were divided into seven groups of six animal in each.The ATDs and P.daemia extract(100,200 and 400 mg/kg,p.o.) were conjointly administered for 8 weeks and various biochemical,histoarchitectural,ultrastructural studies were performed.Results:Administration of ATDs significantly increased aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,triglycerides,cholesterol,bilirubin and decreased glucose and albumin level.Increased lipid peroxidation and reduction in glutathione,superoxide dismutase,catalase,glutathione peroxidase,glutathione reductase and glucose-6-phosphate dehydrogenase were found after ATDs exposure.Administration of P.daemia extract maintained serum biochemical indices as well as antioxidant status similar to control and diminished oxidative stress in dose dependent manner.Histological and ultra-structural observations substantiated biochemical findings.Conclusions:P.daemia has therapeutic potential against ATDs induced liver injury and may be of clinical significance after extensive studies.

A narrative review on inhibitory effects of edible mushrooms against malaria and tuberculosis-the world’s deadliest diseases

The isolated secondary metabolites from 39 edible mushrooms are reported,among which 107 compounds were active,61 demonstrated antitubercular activities with IC_(50) range of 0.2-50μg/mL and 46 manifested antimalarial effects with IC_(50) range of 0.061-36μg/mL.While more than 2000 strains of edible mushrooms are identified,this review shows the paucity of research in these rich organisms featuring a vital culinary ingredient worldwide.A thorough search was conducted on basidiomycetes to discuss the chemistry and biology of the isolated compounds,structure activity relationships(SAR)as well as the cytotoxicity profiles of,primarily,the active anti-plasmodial and antitubercular molecules.With a safe cellular profile,lanostane triterpenoids were found to be the only molecules with combined activities against both diseases.SAR correlations reviewed here indicated the significance of 3β-and 7α-hydroxylation in the anti-tuberculosis activity and the terminal unsaturated moiety between C-4 and C-28 in the antimalarial activity in the same terpene skeleton.This review will attract the attention of medicinal chemists,and food scientists to optimize and rationalize the use of mushrooms both as unexploited sources of novel molecules and as nutraceuticals to treat two of the deadliest infectious diseases,malaria,and tuberculosis.

Effects of quadruple antituberculous drugs in combination with linezolid and moxifloxacin on CSF cytology, NSE, NGF and its receptors in patients with refractory tuberculous meningitis

Objective: To investigate the effects of linezolid and moxifloxacin combined with quadruple antituberculosis drugs on CSF cytology, NSE (neuronal specific enolase), NGF(nerve growth facor) and its receptors, endothelin and its receptors and CRP (C reaction protein) in patients with refractory tuberculous meningitis. Method: A total of 56 patients were selected with tuberculous meningitis in our hospital from February 2014 to December 2017,randomly divided them into 2 groups, each group was 28 cases, set as the observation group and the control group, both groups were treated with quadruple antituberculosis drugs, the observation group was given ilinezolid on this basis, and the control group was combined with moxifloxacin, The course of treatment was 4 weeks, compared the levels of CSF cytology, NSE, NGF and NGF receptors, endothelin and endothelin receptors, and CRP after treatment in the two groups. Result:The CSF cytology, NSE, NGF and NGF receptors, endothelin and endothelin receptor, and CRP levels remained unchanged before treatment, the difference was not statistically significant. After treatment, the chloride and glucose levels in the observation group were higher than those before treatment and that of the control group, the protein, white blood cell count, and cerebrospinal fluid pressure levels were lower than before treatment and that of the control group, the difference was statistically significant;The NSE level in the observation group after treatment was lower than before treatment and that of the control group, the difference was statistically significant;After treatment, the levels of NGF and its receptors in the observation group were higher than those before treatment and that of the control group, and the levels of endothelin, and its receptor, CRP were lower than those before treatment and that of the control group, the difference was statistically significant. Conclusion:The use of linezolid in combination with quadruple antituberculosis drugs to treat refractory tuberculous meningitis has better clinical effect, effectively improve cerebrospinal fluid cytology, regulate cerebrospinal fluid NSE levels, restore NGF, endothelin and its receptor function, reduce inflammatory response, recommended for clinical promotion and application.

Primary Prostatic Tuberculosis: A Rare Entity

Objectives: To clarify the clinical, histological and therapeutic features of prostatic tuberculosis. Methods: We conducted a single-centre retrospective descriptive study of all patients presenting with prostatic tuberculosis between January 2002 and December 2020. Patients who were lost to follow-up, could not be reached by telephone or whose records were not usable were excluded from this study. Results: 240 patients were treated for urogenital tuberculosis, including 13 for isolated prostatic tuberculosis. The average age of the patients was 75 years. None of our patients had a history of tuberculosis. The average of international prostate symptom score (IPSS) was 27. Lower urinary tract symptoms in the filling phase were predominant. The digital rectal examination was suspicious in only one patient. The mean preoperative PSA was 9.24 ng/ml. 46.15% of patients underwent transurethral resection of the prostate and 53.85% underwent ultrasound-guided prostate biopsy. Histological examination showed epithelioid gigantocellular granuloma with isolated caseous necrosis in 61.53% of patients and associated adenomyomatous hyperplasia in 38.47% of patients. Antituberculosis treatment was given for 6 months. The average of follow up was 15 months. All patients reported an improvement in clinical signs with a mean post operative IPSS score of 17 and a normalisation of PSA levels. Conclusion: Isolated prostatic tuberculosis is a rare entity, it can simulate a cancer. In front of the symptoms of the lower urinary tract, the clinicians must think of it especially in the developing countries where tuberculosis still prevails in an endemic state.

Biosafety materials for tuberculosis treatment

Tuberculosis(TB)is among the deadliest infectious diseases worldwide.Although the existing antituberculosis(anti-TB)drugs remain to be effective,the administration of these complex anti-TB drug combinations with obvious toxicity often leads to patients’nonadherence.This may contribute toward the emergence of drug-resistant strains as well as lead to treatment failure and relapse.Therefore,in the past half century,the main focus of anti-TB drug research was to reduce the frequency of administration and toxicity and improve patients’compliance and drug sensitivity.Following these principles,the development of engineered biosafety materials is one of the most effective and promising methods in resolving these challenges.Compared with traditional drugs,biosafety materials provide a viable platform for treating TB,which are beneficial in reducing the frequency of drug administration and systemic toxicity,improving patients’compliance and drug sensitivity,and enhancing drug targeting.In this review,we summarized the application of biosafety materials in treatment of TB in recent years and discussed the challenges faced when developing a safe,more effective,and economical pharmacotherapy against TB.