Ethambutol Treatment Research Articles

Antimycobacterial Potential of Indian Spices: A Review

Natural products and their plant-derived analogs are often a source of drugs or drug templates with limited toxicity, which has the potential to mitigate compliance issues during protracted administration.Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) infection, represents a major health problem globally. Despite the introduction of inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen 40 years ago, TB continues to cause considerable morbidity and mortality worldwide. Global efforts are underway to eradicate TB using new drugs with new modes of action, higher activity, and fewer side effects in combination with vaccines. Since ancient times, different plant part extracts have been used as traditional medicines against diseases including tuberculosis. This knowledge may be useful in developing future powerful drugs. In this regard this review article is an attempt to investigate the antimycobacterial activity of the spices as an alternative and highlight them for further investigation as leads for drug development. The choice of spice as an alternative is based on two basic reasons: firstly, plants have been the model source of medicine since ancient times and secondly, the increasing acceptance of herbal medicines by general population.

The Effect of Zinc Distribution for New TB Patients who Have Ethambutol Therapy Toward Visual Field Defect

Background: Tuberculosis is an infection disease that is caused by Mycobacterium tuberculosis. Ethambutol therapy for TB patients can cause side effect such as decreased visual acuity, visual field defect, decreased contrast sensitivity, and disturbance of colour detection. Zinc in TB patients has decreased that causes broken cell on retina ganglion and disturbance of mytochondria function. The aim of this study is the effect of zinc supplementation for new TB patients who have ethambutol therapy toward visual field defect.Methods: This study involved 40 new TB patients who have ethambutol therapy which is classified as 20 patients who have ethambutol therapy with zinc supplementation and 20 patients who have ethambutol therapy without zinc supplementation. Each patient underwent a routine examination including visual acuity using Snellen chart which is converted to LogMAR, anterior segment using slit lamp biomicroscope, non-contact tonometry for intraocular pressure examination, posterior segment using direct ophthalmoscope, and Humphrey perimetry for visual field examination which is performed three times on first time when initial patient came, first month, and second month duration.Results: This study showed no correlation between gender with visual field defect (p=0,554), there is no correlation between age with visual field defect (p=0,418), no correlation between smoking behaviour with visual field defect (p=1), no correlation between amount of meals consumption containing Zn with visual field defect (p=0,608), and also no correlation between systematic illness history with visual field defect (p=0,305). The effect of Zn treatment to visual field defect was significant with p=0,0085. Conclusion: Zinc treatment for new TB patients with ethambutol treatment may prevent visual field defect. Â Keywords: ethambutol, new TB patients, zinc, visual field defect

Predictive factors for a one-year improvement in nontuberculous mycobacterial pulmonary disease: An 11-year retrospective and multicenter study.

BackgroundNontuberculous mycobacterial pulmonary disease (NTM-PD) has become an emerging infectious disease and is responsible for more deaths than tuberculosis in industrialized countries. NTM-PD mortality remains high in some series reportedly ranging from 25% to 40% at five years and often due to unfavorable evolution of NTM-PD despite established treatment. The purpose of our study was to search for early factors that could predict the favorable or unfavorable evolution of NTM-PD at the first year of treatment.MethodsIn this retrospective and multicenter study, we selected 119 patients based on clinical, radiological and microbiological data from 2002 to 2012 from three French university hospitals (Guadeloupe, Martinique, Montpellier) with definite (meeting the criteria of the American Thoracic Society and the Infectious Disease Society of America in 2007; ATS/IDSA) or probable (one positive sputum culture) NTM-PD. We compared two patient groups: those who improved at one year (clinical symptoms, radiological lesions and microbiology data) and those who did not improve at one year. The data were analyzed for all patients as well as for subgroups by gender, HIV-positive patients, and Mycobacterium avium complex (MAC) infection.ResultsThe average patient age was 50 years ± 19.4; 58% had respiratory comorbidities, 24% were HIV positive and 19% had cystic fibrosis. Coughing concerned 66% of patients and bronchiectasis concerned 45%. The most frequently isolated NTM were MAC (46%). 57% (n = 68) of patients met the ATS criteria and improved status concerned 38.6% (n = 46). The improvement factors at one year of NTM-PD were associated with the duration of ethambutol treatment: (Odds ratio adjusted [ORa]: 2.24, 95% Confidence interval [CI]; 2.11–3.41), HIV-positive status: (ORa: 3.23, 95% CI; 1.27–8.45), and male gender: (ORa: 2.34, 95% CI; 1.26–8.16). For the group with NTM-PD due to MAC, improvement was associated with the duration of macrolide treatment (ORa: 3.27, 95% CI; 1.88–7.30) and an age <50 years (ORa: 1.88, 95% CI; 1.55–8.50).ConclusionIn this retrospective multicenter study, improvement at one year in patients with definite or probable NTM-PD was associated with the duration of ethambutol treatment, HIV-positive status and male gender. For the group of patients infected with MAC, improvement was associated with the duration of macrolide treatment and an age <50 years. Identifying predictors of improvement at one year of NTM-PD is expected to optimize the management of the disease in its early stages.

Clinical features of patients with bacteraemia caused by Mycobacterium avium complex species and antimicrobial susceptibility of the isolates at a medical centre in Taiwan, 2008–2014

Advanced molecular typing methods have greatly expanded the taxonomy of Mycobacterium avium complex (MAC) species; however, little is known about the epidemiology and clinical features of bacteraemia caused by different MAC species. In this study, the clinical characteristics of patients treated for MAC bacteraemia in a tertiary-care centre in northern Taiwan during 2008–2014 were investigated. Isolates were identified to species level by rpoB gene and 16S–23S rRNA internal transcribed spacer region sequencing. Among 30 patients with bacteraemia due to MAC, the majority (n = 26) had concomitant human immunodeficiency virus (HIV) infection. Of the 30 blood isolates obtained from patients, 24 were M. avium subsp. hominissuis, 4 were Mycobacterium colombiense and 2 were Mycobacterium intracellulare. All four M. colombiense isolates were from HIV-infected patients. Bacteraemia due to M. colombiense was associated with higher 30-day mortality than bacteraemia due to M. avium subsp. hominissuis [2/4 (50%) vs. 1/24 (4%); P = 0.045, Fisher's exact test]. All four M. colombiense isolates were susceptible to clarithromycin, moxifloxacin and linezolid. Among the five patients who received ethambutol treatment and four patients who received fluoroquinolone treatment for various durations between positive MAC cultures, two and three patients, respectively, had isolates with significantly increased (≥4-fold) ethambutol and fluoroquinolone minimum inhibitory concentrations. M. colombiense was the second leading causative pathogen of MAC bacteraemia, comprising 15% of all MAC isolates obtained from HIV-positive patients. Monitoring the susceptibility of MAC isolates to ethambutol and fluoroquinolones is warranted in patients with persistent MAC bacteraemia.

The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria.

ABSTRACTMembers of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall composition (mAGP) is conserved among all CMN group bacteria. The arabinogalactan and mycolic acid synthesis pathways constitute effective drug targets for tuberculosis treatment. Ethambutol (EMB), a classical antituberculosis drug, inhibits the synthesis of the arabinose polymer. Although EMB acts bacteriostatically, its underlying molecular mechanism remains unclear. Here, we used Corynebacterium glutamicum and Mycobacterium phlei as model organisms to study the effects of EMB at the single-cell level. Our results demonstrate that EMB specifically blocks apical cell wall synthesis, but not cell division, explaining the bacteriostatic effect of EMB. Furthermore, the data suggest that members of the family Corynebacterineae have two dedicated machineries for cell elongation (elongasome) and cytokinesis (divisome).

DRESS (drug reaction with eosinophilia and systemic symptom) syndrome caused by both first-line and second-line antitubercular medications: A case report with a brief literature review

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially fatal drug-induced systemic hy persensitivity response characterized by erythematous eruption, fever, leukocytosis with eosinophilia, and internal organ involve ment. Antitubercular agents are potential causative agents for DRESS syndrome but difficult to verify as a culprit drug, since antitu bercular agents are coadministered as a combination regimen. A 42-year-old female with endobronchial tuberculosis was diag nosed with DRESS syndrome after 4-week treatment of isoniazid, rifampicin, ethambutol, and pyrazinamide with prednisolone 50 mg. All the antitubercular agents were stopped and replaced with levofloxacin, cycloserine, p-aminosalicylic acid, and kanamycin. However, severe exacerbation of DRESS syndrome compelled the patient to discontinue the administration of the second-line anti tubercular agents. Two months later, the patient underwent a patch test for all the antitubercular agents which had been used, and the results showed positivity to isoniazid and cycloserine. We report a rare case of DRESS syndrome that reacted to cycloserine as well as isoniazid. Development of coreactivity to other drugs should be differentiated with a flare-up reaction in the management of DRESS syndrome. (Allergy Asthma Respir Dis 2017:5:111-116)

Paradoxical response to ethambutol: Time to reconsider in term of vision

Tuberculosis is a widely prevalent disease in the Indian and African subcontinent. India is among the largest countries to implement the revised National Tuberculosis Control Program. Optic neuropathy is a severe and well-known complication of ethambutol treatment. If not detected early, it may lead to profound and irreversible vision loss. Here, we are reporting case series of optic neuropathy secondary to antitubercular therapy and to highlight possible consequences which can be alarming for the medical fraternity.

The Effect of Zinc Distribution for New TB Patients who Have Ethambutol Therapy Toward Visual Field Defect

Background: Tuberculosis is an infection disease that is caused by Mycobacterium tuberculosis. Ethambutol therapy for TB patients can cause side effect such as decreased visual acuity, visual field defect, decreased contrast sensitivity, and disturbance of colour detection. Zinc in TB patients has decreased that causes broken cell on retina ganglion and disturbance of mytochondria function. The aim of this study is the effect of zinc supplementation for new TB patients who have ethambutol therapy toward visual field defect.Methods: This study involved 40 new TB patients who have ethambutol therapy which is classified as 20 patients who have ethambutol therapy with zinc supplementation and 20 patients who have ethambutol therapy without zinc supplementation. Each patient underwent a routine examination including visual acuity using Snellen chart which is converted to LogMAR, anterior segment using slit lamp biomicroscope, non-contact tonometry for intraocular pressure examination, posterior segment using direct ophthalmoscope, and Humphrey perimetry for visual field examination which is performed three times on first time when initial patient came, first month, and second month duration.Results: This study showed no correlation between gender with visual field defect (p=0,554), there is no correlation between age with visual field defect (p=0,418), no correlation between smoking behaviour with visual field defect (p=1), no correlation between amount of meals consumption containing Zn with visual field defect (p=0,608), and also no correlation between systematic illness history with visual field defect (p=0,305). The effect of Zn treatment to visual field defect was significant with p=0,0085.Conclusion: Zinc treatment for new TB patients with ethambutol treatment may prevent visual field defect.Keywords: ethambutol, new TB patients, zinc, visual field defect

IniBAC induction Is Vitamin B12- and MutAB-dependent in Mycobacterium marinum

Tuberculosis can be treated with a 6-month regimen of antibiotics. Although the targets of most of the first-line antibiotics have been identified, less research has focused on the intrabacterial stress responses that follow upon treatment with antibiotics. Studying the roles of these stress genes may lead to the identification of crucial stress-coping mechanisms that can provide additional drug targets to increase treatment efficacy. A three-gene operon with unknown function that is strongly up-regulated upon treatment with isoniazid and ethambutol is the iniBAC operon. We have reproduced these findings and show that iniBAC genes are also induced in infected host cells, although with higher variability. Next, we set out to elucidate the genetic network that results in iniBAC induction in Mycobacterium marinum By transposon mutagenesis, we identified that the operon is highly induced by mutations in genes encoding enzymes of the vitamin B12 biosynthesis pathway and the vitamin B12-dependent methylmalonyl-CoA-mutase MutAB. Lipid analysis showed that a mutA::tn mutant has decreased phthiocerol dimycocerosates levels, suggesting a link between iniBAC induction and the production of methyl-branched lipids. Moreover, a similar screen in Mycobacterium bovis BCG identified that phthiocerol dimycocerosate biosynthesis mutants cause the up-regulation of iniBAC genes. Based on these data, we propose that iniBAC is induced in response to mutations that cause defects in the biosynthesis of methyl-branched lipids. The resulting metabolic stress caused by these mutations or caused by ethambutol or isoniazid treatment may be relieved by iniBAC to increase the chance of bacterial survival.

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Tuberculosis (TB) remains one of the world's deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95-98% under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (C max), especially of rifampicin and isoniazid, are well below the proposed target C max concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment's success rate in these studies was typically at least 85%. The proposed target C max concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C max based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C max (or area under the curve (AUC)) and C max/MIC (or AUC/MIC). Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.

Visual function test for early detection of ethambutol induced ocular toxicity at the subclinical level

Context: Tuberculosis in developed countries is on the rise, and the main treatment ethambutol is known to induce ocular toxicity. However, to date, there are unknown tests or protocols for detecting subclinical ethambutol-induced ocular toxicity, which is important as early detection is related to symptom reversibility. We defined the ethambutol induced ocular toxicity as stastically siginificant change of visual function which was induced by ethambutol.Objective: We aimed to identify a visual function test for the early detection of subclinical ethambutol-induced ocular toxicity. Furthermore, we also investigated the continuity or reversibility of early subclinical changes that were observed during the visual function tests after stopping ethambutol treatment.Materials and methods: The age range of 31 patients was from 13 to 72 years. The range of dosage was 15–19 mg/kg/day. The average period of dosage was 5 months. We performed a visual acuity test, visual field test, color vision test, contrast sensitivity test, fundus examination, retinal nerve fiver layer optical coherence tomography test (RNFL OCT) per month and pattern visual evoked potential test (pattern VEP) every 2 months before and during ethambutol treatment in 62 eyes of 31 patients. Among these patients, selected 21 patients were rexamined by these tests at the 3, 6 and 12 months after stopping ethambutol treatment. We compared the test results from the last follow-up during ethambutol treatment and after ethambutol stoppage with those obtained before ethambutol treatment (baseline).Results: RNFL OCT showed that average RNFL thickness increased 5 months after ethambutol treatment (p = 0.032), and pattern VEP showed that P100 latency was delayed in 2 and 4 months after ethambutol treatment (p = 0.001; p < 0.001, respectively). These early changes observed on RNFL OCT and pattern VEP progressed 6 months after ethambutol stoppage in 21 patients. Twelve months after ethambutol stoppage, these early changes returned to baseline levels. During the study, no changes in visual acuity, color vision, fundus, contrast sensitivity or visual field were observed.Conclusions: Pattern VEP and RNFL OCT are suitable tests for the early detection of subclinical ethambutol-induced ocular toxicity. These tests should be performed until 12 months after ethambutol stoppage.

ADVANCES IN ANTI-TUBERCULOSIS DRUGS

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development.Key Words: MDR-TB, XDR-TB, TDR-TB, Bedaquiline, DelamanidÂ

Paradoxical response to disseminated non-tuberculosis mycobacteriosis treatment in a patient receiving tumor necrosis factor-α inhibitor: a case report

BackgroundBiological agents such as tumor necrosis factor-α inhibitors are known to cause mycobacterium infections. Here, we report a disseminated non-tuberculosis case caused by TNF-α inhibitor therapy and a probable paradoxical response to antimycobacterial therapy.Case presentationA 68-year-old man with relapsing polychondritis was refractory to glucocorticoid therapy; adalimumab was therefore administered in combination with oral glucocorticoids. Treatment with 40 mg of adalimumab led to rapid improvement of his clinical manifestations. The administration of tacrolimus (1 mg) was started as the dosage of oral glucocorticoids was tapered. However, the patient developed an intermittent high fever and productive cough 15 months after starting adalimumab treatment. A chest computed tomography scan revealed new granular shadows and multiple nodules in both lung fields with mediastinal lymphadenopathy, and Mycobacterium intracellulare was isolated from 2 sputum samples; based on these findings, the patient was diagnosed with non-tuberculosis mycobacteriosis. Tacrolimus treatment was discontinued and oral clarithromycin (800 mg/day), rifampicin (450 mg/day), and ethambutol (750 mg/day) treatment was initiated. However, his condition continued to deteriorate despite 4 months of treatment; moreover, paravertebral and subcutaneous abscesses developed and increased the size of the mediastinal lymphadenopathy. Biopsy of the mediastinal lymphadenopathy and a subcutaneous abscess of the right posterior thigh indicated the presence of Mycobacterium avium complex (MAC), and the diagnosis of disseminated non-tuberculosis mycobacteriosis was confirmed. Despite 9 months of antimycobacterial therapy, the mediastinal lymphadenopathy and paravertebral and subcutaneous abscesses had enlarged and additional subcutaneous abscesses had developed, although microscopic examinations and cultures of sputum and subcutaneous abscess samples yielded negative results. We considered this a paradoxical reaction similar to other reports in tuberculosis patients who had discontinued biological agent treatments, and increased the dose of oral glucocorticoids. The patient’s symptoms gradually improved with this increased dose and his lymph nodes and abscesses began to decrease in size.ConclusionsClinicians should consider the possibility of a paradoxical response when the clinical manifestations of non-tuberculosis mycobacteriosis worsen in spite of antimycobacterial therapy or after discontinuation of tumor necrosis factor-α inhibitors. However, additional evidence is needed to verify our findings and to determine the optimal management strategies for such cases.

Clinical management of drug resistant tuberculosis: A comprehensive review

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. This is because of development of drug resistance in tuberculosis strains, usually called as MDR/XDR-TB. Consequently, novel drugs and regimens for management of these drug resistant TB forms are emerging. Such regimens probably utilize both repurposed drugs and new chemical drugs. This article covers current concepts and recent advances in TB drug discovery and development. An updated review of the mechanisms of action and resistance of the main old and new anti-tuberculosis agents has been described. The consensus statements from RNTCP for management of MDR/XDR-TB have also been discussed.Asian Journal of Medical Science, Volume-5(3) 2014: 1-9DOI: http://dx.doi.org/10.3126/ajms.v5i3.9698

Hémianopsie bitemporale révélatrice d’une atteinte toxique sévère à l’éthambutol

Optic neuropathy is a severe and well-known complication of ethambutol treatment. If not detected early, it may lead to profound and irreversible vision loss. We report the case of a 83-year-old female patient, referred for rapidly progressive, painless, bilateral visual loss, unimproved after bilateral cataract surgery. Automated Humphrey 24-2 visual field demonstrated bitemporal hemianopia associated with bilateral central scotoma. Brain MRI did not demonstrate any compressive lesion in the chiasmal region. However, on T2-weighted sequences, an area of elevated signal intensity appeared within the optic chiasm, enhancing after gadolinium injection. On detailed history, it was noted that the patient had been on ethambutol for the last 18months, for the treatment of a Mycobacterium avium-related pneumonitis. The incidence of ethambutol-related toxic optic neuropathy has dramatically decreased since the recommendations for regular follow-up of patients treated with ethambutol. This treatment is classically responsible for bilateral central or ceco-central scotoma due to optic neuropathy, although a few cases of bitemporal hemianopia have been reported in the literature, mimicking a compressive chiasmal lesion. However, none of these cases demonstrated a hypersignal in the optic chiasm on brain magnetic resonance imaging (MRI). Bitemporal hemianopia on visual field testing is very suggestive of a chiasmal lesion, which is generally due to a compressive, or more rarely inflammatory, lesion in the sellar region. Toxic chiasmal lesions are rare, but in the absence of any tumoral lesion in the sellar area, a detailed history must be obtained in order to rule out drug toxicity, so as to prevent irreversible visual loss.

Production of non‐proteinogenic amino acids from α‐keto acid precursors with recombinant Corynebacterium glutamicum

In the present work, Corynebacterium glutamicum was metabolically engineered for the enantioselective synthesis of non-proteinogenic amino acids as valuable building blocks for pharmaceuticals and agrochemicals. The novel bio-catalytic activity of C. glutamicum was obtained by heterologous expression of the branched chain aminotransferase IlvE from Escherichia coli. Upon this modification, the recombinant cells converted the α-keto acid precursor 2-(3-hydroxy-1-adamantyl)-2-oxoethanoic acid (HOAE) into the corresponding amino acid 2-(3-hydroxy-1-adamantyl)-(2S)-amino ethanoic acid (HAAE). Similarly, also L-tert-leucine could be obtained from trimethyl pyruvate indicating a broader applicability of the novel strategy. In both cases, the amino group donor glutamate was supplied from the endogenous metabolism of the recombinant producer. Hereby, the uptake of the precursor and secretion of the product was supported by an enhanced cell permeability through treatment of ethambutol, which inhibits arabinosyl transferases involved in cell wall biosynthesis. The excretion of HAAE into the reaction medium was linked to the secretion of glutamate, indicating a similar mechanism for the export of both compounds. On the other hand, the efflux of L-tert-leucine appeared to be driven by active transport. Subsequent bioprocess engineering enabled HAAE and L-tert-leucine to be produced at a rate of 0.21 and 0.42 mmol (g dry cells)⁻¹ h⁻¹, respectively up to a final product titer of 40 mM. Beyond the given examples, integrated metabolic and cell envelop engineering might extend the production of a variety of other non-proteinogenic amino acids as well as chiral amines by C. glutamicum.

Advances in the development of new tuberculosis drugs and treatment regimens

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

The protective effects of caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity of rats

Purpose: This study intended to examine the effect of caffeic acid phenethyl ester (CAPE) on isoniazid (INH) and/or ethambutol (ETM)-induced retina and optic nerve toxicity in a rat model.Methods: This study included eight groups, each containing 10 rats. The groups were Control, INH, ETM, CAPE, INH+CAPE, ETM+CAPE, INH+ETM and INH+ETM+CAPE. Rats were given orally 50 mg/kg/d of INH and 50 mg/kg/d of ETM in tap water for 30 d. 10 μmol/kg of CAPE were intraperitoneally injected for 30 d. The first dose of CAPE was given 24 h before the INH and ETM treatment and continued until sacrifice. Control group was given only tap water for 30 d. Rats were anaesthetized and sacrificed on the 30th day of experiment. Superoxide dismutase (SOD) activities, malondialdehyde (MDA), total anti-oxidant status (TAS), total oxidant status (TOS) were measured on the dissected and excised retina and optic nerve samples. Fellow eyes were used for histopathologic evaluation and the retinal ganglion cell (RGC) count. In addition, CAPE, INH and ETM interaction with SOD isoforms were calculated in silico.Results: The SOD activity and TAS levels were found significantly higher in CAPE-treated groups compared to INH and/or ETM-treated groups (p < 0.0001). But the MDA, and TOS levels were significantly lower in CAPE-treated groups (p < 0.0001). The mean RGC count is significantly decreased in INH, ETM and INH+ETM groups compared with INH+CAPE, ETM+CAPE and INH+ETM+CAPE groups, respectively (p values 0.001, 0.042, and 0.001 respectively). Besides, in silico calculations showed that binding affinity of CAPE to SOD isotypes was higher than that of INH and ETM.Conclusion: This study demonstrates that CAPE treatment may decrease the oxidative stress in the retina and optic nerve of INH- and ETM-treated rats and may prevent RGC loss. As an underlying mechanism, CAPE and SOD interaction seems crucial for alleviation of ocular oxidative stress and RGCs toxicity.

Extra-pulmonary tuberculosis infection in the dialysis patients with end stage renal diseases: case reports and literature review

The diagnosis of extra-pulmonary tuberculosis (TB) seems relatively difficult due to the absence of specific symptoms and signs in patients on peritoneal dialysis or hemodialysis. We report four cases of extra-pulmonary tuberculosis on dialysis, with two cases on peritoneal dialysis and two cases on hemodialysis. The presentations, therapy, and outcomes of TB infection in these patients were reviewed. Otherwise, the English literature published in the PubMed database associating extra-pulmonary tuberculosis on dialysis over the last three decades is reviewed. A total of 61 studies containing 70 cases were included. The most common primary disease was diabetic nephropathy (22.86%, 16/70). The peritoneum (31.42%, 22/70), bone (21.42%, 15/70), and lymph node (20%, 14/70) were the most frequently infected. Single organ infection was common (90%, 63/70). Fever (58.57%, 41/70), pain (35.71%, 25/70), and enlarged lymph node (20%, 14/70) were the most common symptoms. Biopsy (67.14%, 47/70) and culture (40%, 28/70) provided most reliable methods for clear diagnosis of tuberculosis. The combined treatment of isoniazid, rifampicin, pyrazinamide, and ethambutol (44.29%, 31/70) was the most common therapy. The majority of patients improved (82.86%, 58/70); however, 12 cases got worse (17.14%), with 10 of them dying (14.29%). Physicians should be aware of the non-specific symptoms and location of infection, and consider tuberculosis in their differential diagnoses in dialysis patients presenting with symptoms such as fever, pain, and weight loss.

Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics

Two antimicrobial peptides (AMPs), named La47 and Css54, were isolated from the venom of the spider Lachesana sp. and from the scorpion Centruroides suffusus suffusus, respectively. The primary structures of both La47 and Css54 were determined using N-terminal sequencing and mass spectrometry. La47 is identical to the AMP latarcin 3a obtained previously from the venom of the spider Lachesana tarabaevi, but the primary structure of Css54 is unique having 60% identities to the AMP ponericin-W2 from the venom of the ant Pachycondyla goeldii. Both La47 and Css54 have typical α-helix secondary structures in hydrophobic mimicking environments. The biological activities of both La47 and Css54 were compared with the AMP Pin2 isolated from the venom of the scorpion Pandinus imperator. La47 has lower antimicrobial and hemolytic activities compared with Css54 and Pin2. In addition, La47 and Pin2 were evaluated in the presence of the commercial antibiotics, chloramphenicol, ampicillin, novobiocin, streptomycin and kanamycin. Interestingly, the best antimicrobial combinations were obtained with mixtures of La47 and Pin2 with the antibiotics chloramphenicol, streptomycin and kanamycin, respectively. Furthermore, the novel peptide Css54 was evaluated in the presence of antibiotics used for the treatment of tuberculosis, isoniazid, rifampicin, pyrazinamide and ethambutol. Although the mixtures of Css54 with isoniazid, pyrazinamide or ethambutol inhibit the growth of Staphylococcus aureus, the best effect was found with rifampicin. Overall, these data show a motivating outlook for potential clinical treatments of bacterial infections using AMPs and commercial antibiotics.