Administration Of Ethambutol Research Articles

Ethambutol-induced ovarian, uterine and placental oxidative stress: Implication for reproductive outcome in female Wistar rats

Tuberculosis is a major global challenge, potentially infecting more individuals than other pathogens. Ethambutol, a first line drug used in tuberculosis treatment, lacks adequate research regarding its impact on female reproductive health. This study investigates ethambutol-induced oxidative stress to the ovary, uterus and placenta with implications to reproductive outcome in female Wistar rats. Twenty adult female Wistar rats weighing between 170g-190g were divided into two groups (A and B) of ten rats each. Group A served as control and received only food and water ad libitum. Group B was administered with 15 mg/kg body weight of ethambutol, orally, daily for 28 days. After 28 days, five animals from each group were sacrificed by cervical dislocation and the ovaries and uterus were harvested for oxidative stress analysis. The remaining animals from each group were mated, and ethambutol administration continued until gestational day 19 when they were sacrificed, and the placentae were harvested for oxidative stress analysis. The fetuses were used to study pregnancy outcomes. From the result, ovarian glutathione peroxidase was significantly elevated, uterine superoxide dismutase and catalase levels were significantly decreased while malondialdehyde activity was significantly elevated, placental catalase activity was significantly decreased while glutathione peroxidase and malondialdehyde activities was significantly elevated following ethambutol administration. On pregnancy outcomes, ethambutol significantly decreased crown rump length, litter weight, placental weight and fetal/placental weight ratio. In conclusion, evidence from this study suggests that ethambutol is toxic to the ovary, uterus and placenta via mechanisms that involve oxidative stress resulting in poor pregnancy outcomes.

Prospective evaluation of ethambutol toxic optic neuropathy in patients of pulmonary tuberculosis

AimThe aim of the study was to evaluate visual parameters for early detection of ethambutol toxicity to prevent irreversible optic nerve damage. MethodThis cohort study included 50 newly diagnosed cases of pulmonary tuberculosis, i.e. 100 eyes, in people aged 18–72 years, who received ethambutol as part of the antitubercular therapy. Before starting antitubercular treatment, at each monthly visit, ophthalmic examination was done that included best corrected visual acuity, optic disc evaluation, colour vision, contrast sensitivity, pupil cycle time and automated perimetry for a period of six months. Ethambutol was discontinued in patients who showed signs of visual impairment. These patients were observed for another three months for reversibility of toxicity. ResultsVisual functions were normal in all patients at baseline. Out of 50 patients, 47 didn't show any signs of deterioration in visual functions even after six months of oral administration of ethambutol. However, 3 out of 50 patients, i.e. 6 eyes (6 %), showed signs of toxicity after 4–5 months – LogMAR visual acuity deteriorated from 0.00 to 1.08 (±0.40); mean contrast sensitivity deteriorated from 1.725 (±0.075) to 1.12 (±0.18); mean deviation in visual fields got impaired from −1.37 (±0.15) to −10.93 (±2.66); and colour vision got severely affected. All the affected patients were aged above 65. ConclusionIn the present study, six percent of 50 patients showed ethambutol toxic optic neuropathy. It was concluded that patients should be comprehensively evaluated for visual parameters before starting the ethambutol treatment. They should be closely monitored by an ophthalmologist for visual functions every month to detect ethambutol toxicity at the early reversible stage to prevent irreversible damage to the optic nerve. Patients should be asked to report immediately if they detect any blurring of vision or colour vision abnormality.

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study.

Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.

O10‐4: Effectiveness of intravenous isoniazid and ethambutol administration in patients with drug‐susceptible pulmonary tuberculosis with TB‐meningoencephalitis and HIV co‐infection in the intensive phase of treatment

O10‐4: Effectiveness of intravenous isoniazid and ethambutol administration in patients with drug‐susceptible pulmonary tuberculosis with TB‐meningoencephalitis and HIV co‐infection in the intensive phase of treatment

Effectiveness of intravenous isoniazid and ethambutol administration in patients with tuberculosis meningoencephalitis and HIV-infection

Aims and objectives: of our study was to investigate the effectiveness of intravenously (i/v) isoniazid (H) and ethambutol (E) administration in patients with new sputum positive drug-susceptible pulmonary tuberculosis (TB) with tuberculous meningoencephalitis (TM) and human immunodeficiency virus (HIV) co-infection in the intensive phase of treatment. Methods: Fifty-four patients with TB / TM and HIV co-infection were enrolled in this study. Group 1 included 23 patients treated with E and H i/v, while rifampicin and pyrazinamide were prescribed orally. Group 2 consisted of 31 patients treated with the first-line anti-TB drugs orally. Concentrations of H and E in blood serum were detected using a chromatographic method. Results: A significant improvement in clinical symptoms and X-ray signs in patients treated i/v with H and E was observed compared with group 2. Sputum Mycobacterium tuberculosis positivity was observed during the second month of treatment in 25.0 % of patients from group 1 and 76.1% of patients from the control group (p&lt;0.01). In addition, 9 (39.1%) patients died up to six months when H and E were prescribed i/v compared with 22 (70.9%) in group 2 (p=0.02). Conclusions: In TB / TM with HIV, i/v H and E treatment was more effective than oral H and E treatment at 2 months of intensive treatment in sputum conversion as well as in clinical improvement, accompanied by significantly higher mean serum concentrations. In addition, the mortality rate was lower in i/v H and E treatment than oral.

KOMORBIDITAS PADA EPISODE REKUREN SINDROM POSNER-SCHLOSSMAN DAN NEUROPATI OPTIK KARENA ETAMBUTOL

Pendahuluan: Posner-Schlossman Syndrome (PSS) atau glaucomatocyclitic crisis merupakan kelainan pada mata dengan karakteristik munculnya serangan unilateral yang akut dan rekuren, diikuti dengan peningkatan tekanan intraokular (TIO) dan inflamasi ringan pada segmen mata anterior tanpa adanya faktor pencetus yang jelas. Laporan kasus ini memaparkan mengenai neuropati optik karena ethambutol (EON) bersamaan dengan munculnya episode serangan rekuren PSS. Kombinasi dari kedua komorbid sangat jarang terjadi, namun dapat memengaruhi prognosis dari kedua kondisi.Kasus: Seorang wanita 41 tahun dengan nyeri dan pandangan kabur pada mata kiri dalam 24 jam terakhir. Pada pemeriksaan fisik didapatkan adanya uveitis anterior mata kiri dan peningkatan tekanan intraokular ODS 21,4 / 56,7 mmHg. Pasien didiagnosis sebagai PSS. 5 tahun kemudian pasien menderita EON setelah 5 bulan penggunaan etambutol dalam terapi tuberkulosis. Pemeriksaan koreksi visus terbaik saat itu 20/80 OD, 20/70 OS, dengan skotoma sekosentral yang tidak spesifik. 1 bulan setelah etambutol dihentikan, pasien mengalami episode serangan rekuren PSS dan mulai memengaruhi progresivitas dari penurunan visus kedua mata mencapai 20/400 OD, 20/200 OS. Pasien ditangani dengan injeksi metilprednisolon 500 mg intravena, setelah beberapa dosis pemberian visus mulai membaik (VODS 20/100).Simpulan: Evaluasi secara berkelanjutan oleh dokter spesialis mata dibutuhkan sebelum dan selama pemberian etambutol, yang difokuskan kepada penggalian riwayat penyakit, faktor risiko sebelumnya, danstatus oftalmologi selama pengobatan. Pemeriksaan lengkap untuk mencari etiologi pada PSS penting untuk mengurangi risiko rekurensi. Faktor psikogenik juga perlu dipertimbangkan.

Clinical characteristics and prognostic factors analysis of ethambutol-induced optic neuropathy

Objective To observe the clinical features and visual prognostic factors of ethambutol-induced optic neuropathy (EON). Methods A cohort study. Twenty-four inpatients (46 eyes) identified as EON in Neuro-Ophthalmology Department of Chinese PLA General Hospital from January 2014 to December 2017 were enrolled, including 14 males (26 eyes) and 10 females (20 eyes) with a ratio of 1.4/1 male/female. The average age was 42.79±15.12 years and the average weight was 62.46±12.31 kg. The average time duration between oral administration of ethambutol and occurrence of EON was 9.94±16.49 months. The average time of ethambutol duration was 7.06±11.68 months, with an average accumulative dose of 156.7±1 779.0 g and the average daily dose of 15.07±8.95 mg/(kg·d). All patients were tested with visual acuity, fundus photos, colour vision, OCT, visual field, VEP, orbital MRI and the gene of OPA1 and mitochondrial deoxyribonucleic acid(mtDNA). All the patients accepted drug withdrawal immediately after diagnosis, and were given the treatment of systemic nerve nutrition and improvement of microcirculation for 2 weeks. The time of follow-up was more than 12 months. According to whether the visual acuity (VA) in any of eyes was over than 0.1 at the last follow- up, all the patients were divided into two groups: the bad VA group (VA less than or equal to 0.1) and the better VA group (VA over than 0.1) group. The χ2 test and Fisher's exact probabilistic method test were used to compare the counting data between groups, and the Wlincox rank sum test was used to compare the measurement data. Multiple factors of VA outcome between the patients with bad or better va were analyzed by logistic regression. Results Thirty eyes (65.2%) had VA less than or equal to 0.1 and 5 eyes (10.9%) had VA over than 0.5 at EON onset. The VA of the rest 11 eyes (23.9%) was higher than 0.1 and lower than 0.5. At the last follow- up, 20 eyes (43.5%) had VA less than or equal to 0.1 and 9 eyes (19.6%) had VA over than 0.5, the VA of the rest 17 eyes (36.9%) was higher than 0.1 and lower than 0.5. Fundus examination revealed 7 eyes (15.3%) with optic disc edema. OCT revealed significant loss of the retinal nerve fiber layer (RNFL) in the affected eyes, mainly in the temporal RNFL of the optic disc. All patients had dyschromasia, mainly in distinguishing the color of red and green. The types of visual field defect was as following: central dark spot (52.2%), diffuse visual acuity decreased (30.4%), temporal hemianopsia (17.4%). Orbital MRI revealed that 12/24 (50.0%) patients had T2 lesions with T1 enhancement in 6/24 patients (25.0%). Genetic test showed that 4 patients (16.7%) had gene mutation. Among them, there were 2 patients with OPA1 mutation, 1 with mtDNA 14340 point mutation and 1 with the mtDNA 11778 point mutation. Thirteen patients showed better VA outcomes (over than 0.1) while 11 showed bad VA outcomes after discontinuation of ethambutol. Between the better VA group and the bad VA group, there were statistically significant differences in the daily dose of ethambutol and gene mutation(P=0.031, 0.023). The daily dose was related to visual prognosis of EON while only the daily dose of more than 18 mg/(kg·d) may lead to bad VA outcomes according to the logistic analysis (95% CI 0.007-0.736, OR=0.069, P=0.027). Conclusions EON may have OPA1 and mtDNA mutation with more bilateral eyes involved and less optic edema, which about 43.5% of the patients showed irreversible visual impact. The daily dose of ethambutol is related to the vision recovery. Key words: Ethambutol/adverse effects; Optic nerve diseases; Disease attributes; Prognosis; Root cause analysis

Treatment Outcomes after Discontinuation of Ethambutol due to Adverse Events in Mycobacterium avium Complex Lung Disease.

BackgroundLong-term administration of ethambutol (EMB) for Mycobacterium avium complex lung disease (MAC-LD) sometimes leads to permanent discontinuation of EMB due to various adverse events. This study aimed to investigate treatment outcomes after discontinuation of EMB.MethodsAmong patients diagnosed with MAC-LD between January 2001 and December 2014, 508 patients whose treatment was initiated with standard regimen until May 2018 were enrolled at a tertiary referral center in Korea. Of these 508 patients, 60 (11.8%) discontinued EMB due to various adverse effects. Among these 60 patients, treatment outcomes were analyzed for 44 patients by comparing their outcomes with those of matched subjects who received the standard treatment regimen without EMB discontinuation.ResultsThe mean age of the 60 patients who discontinued EMB was 64.4 years. Ocular toxicity was the most common cause of discontinuation of EMB (75.0%, 45/60). The mean duration of EMB administration before its discontinuation was 7.0 ± 4.6 months. The treatment failure rate of the 44 patients with EMB discontinuation analyzed for treatment outcome was 29.6%, which was higher than that of the matched patients who received the standard regimen (18.3%), although the difference was not significant (P = 0.095). Of these 44 patients, EMB was substituted with later-generation fluoroquinolone in 23 patients, and the treatment failure rate of these 23 patients was significantly higher than that of the matched patients who received the standard regimen (39.1% vs. 19.3%, P = 0.045).ConclusionThese findings suggest that treatment outcomes are unsatisfactory in patients with MAC-LD who discontinue EMB owing to adverse events. Notably, there was a statistically significant high failure rate in patients who were prescribed fluoroquinolone to replace EMB.

A survey of clarithromycin monotherapy and long-term administration of ethambutol for patients with MAC lung disease in Japan: A retrospective cohort study using the database of health insurance claims.

The number of patients with nontuberculous mycobacteriosis (NTM) has increased exponentially in recent years. In Japan, approximately 88.8% of patients with NTM suffer from Mycobacterium avium-intracellulare complex (MAC) lung disease. Incidence of MAC lung disease is increasing in particularly among the middle-aged and elderly women owing to a rapid increase in nontuberculous mycobacterial infections. General treatment for MAC lung disease is chemotherapy. The type of chemotherapy recommended by specialists to prevent the development of a drug-resistant strain of the bacteria consists of a combination of clarithromycin (CAM), rifampicin, and ethambutol (EB). CAM monotherapy is contraindicated by specialists owing to its high potential to induce drug-resistant bacterial strains in patients with MAC lung disease. In addition, administering EB at doses not less than 1000 mg d-1 is not recommended to avoid adverse drug reactions. However, it is unclear how much such treatment cases exist in real world clinical settings. This is because no long-term investigation has been carried out. This study investigated treatment with these drugs from 2005 to 2017, by studying 1135 patients with MAC lung disease based on health insurance claims database. Results showed that approximately 9.2% (101 cases) were prescribed long-term CAM monotherapy for 3 months or longer and approximately 3.6% (18 cases) were prescribed high doses of EB. CAM monotherapy over a long period of time is potentially detrimental to some patients. Better awareness of the types of treatments and their potential negative effects will be beneficial to clinical practitioners.

Effectiveness of Intravenous Isoniazid and Ethambutol Administration in Patients with Tuberculosis Meningoencephalitis and HIV Infection.

BackgroundThe aim of this study was to investigate the effectiveness of intravenous isoniazid (H) and ethambutol (E) administered in patients with new sputum positive drug-susceptible pulmonary tuberculosis (TB) with tuberculous meningoencephalitis (TM) and human immunodeficiency virus (HIV) co-infection in the intensive phase of treatment.MethodsFifty-four patients with TB/TM and HIV co-infection were enrolled for this study. Group 1 comprised of 23 patients treated with E and H intravenously, while rifampicin and pyrazinamide were prescribed orally. Group 2 consisted of 31 patients treated with the first-line anti-TB drugs orally. The concentrations of H and E in blood serum were detected using a chromatographic method.ResultsA significant improvement in the clinical symptoms and X-ray signs in patients treated intravenously with H and E was observed and compared to group 2. The sputum Mycobacterium tuberculosis positivity was observed during the second month of the treatment in 25.0% of patients from group 1 and 76.1% of the patients from the control group (p=0.003). In addition, nine patients (39.1%) died up to 6 months when H and E were prescribed intravenously compared with 22 (70.9%) in group 2 (p=0.023).ConclusionIn TB/TM with HIV, the intravenous H and E treatment was more effective than oral H and E treatment at 2 months of intensive treatment in sputum conversion as well as in clinical improvement, accompanied by significantly higher mean serum concentrations. In addition, the mortality rate was lower in intravenous H and E treatment compared to oral treatment.

Anti-hyperuricemic and nephroprotective effect of geniposide in chronic hyperuricemia mice

Hyperuricemia is a key risk factor for kidney disease. Geniposide possesses various pharmacological activities, however, to our knowledge, no previous work investigated the therapeutic effect of geniposide on urate nephropathy. The present study established a chronic hyperuricemia model using a combination of adenine and ethambutol administration. The potential beneficial effects and mechanisms of geniposide on hyperuricemia and nephropathy were also investigated. The results demonstrated that geniposide significantly decreased SUA levels via inhibition of the XOD activity and increasing the excretion of urinary uric acid. Geniposide also markedly improved kidney damage related to hyperuricemia. Further investigation indicated that geniposide improved the symptoms of nephropathy via decreasing the production of proinflammatory cytokines, including IL-1β, PG-E2, and TNF-α, and inhibiting the expression of TGF-β1. The molecular mechanism of action may be associated with suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β and TNF-α production respectively in hyperuricemic mice.

Drug resistance in patients with tuberculous pleural effusions.

To summarize data regarding categories, detection methods, prevalence and patterns of drug resistance among patients with tuberculous pleural effusion (TPE) and to comment on the management of suspected drug-resistant TPE. Pleural and pulmonary tuberculosis (TB) present similar patterns of drug resistance. Approximately 10% and 6-10% of pleural Mycobacterium tuberculosis isolates are resistant to at least one first-line anti-TB drug or at least isoniazid, respectively. The prevalence of multidrug-resistant-pleural and extensively drug-resistant-pleural TB is 1-3% and 0-1%, respectively. Although guidelines suggest the empirical standard anti-TB regimen (i.e. 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampicin) for TPE treatment, the data regarding drug resistance among TPE patients are limited. The few studies examining the issue report a notable drug resistance. In suspected drug-resistant TPE, every effort is warranted to isolate M. tuberculosis to perform drug susceptibility testing and provide guided therapy. For this purpose, the use of cultures or molecular methods with pleural biopsies is superior to their use in pleural fluid. If still M. tuberculosis cannot be detected, prolonged administration of ethambutol with isoniazid and rifampicin during the continuation phase of treatment might be considered.

Resistance to first- and second-line antituberculosis drugs in Southern Taiwan: Implications for empirical treatment.

Multidrug-resistant and extensively drug-resistant tuberculosis infections cause public health concerns worldwide. Local epidemiologic data about the drug resistance of Mycobacterium tuberculosis isolate (Mtb) is critical to guide appropriate empirical therapy to cure patients and restrain the spread of tuberculosis. Antituberculosis susceptibility testing was performed for 287 Mtbs, including 63 MDR-Mtbs collected in southern Taiwan from 2011 to 2015. Tuberculosis patients were classified into newly diagnosed cases and previously treated cases based on patients' medical history. Almost no resistance was found to the tested second-line antituberculosis drugs in non-MDR-Mtbs. Higher resistance rates to ethambutol, ofloxacin, and streptomycin were observed in MDR-Mtbs compared to non-MDR-Mtbs. Among 63 MDR-Mtbs, 61.9% of patients were newly diagnosed and 38.1% were previously treated cases. For MDR-Mtb, the drug-resistance rates in previously treated cases were significantly higher for ethambutol, pyrazinamide, ofloxacin, moxifloxacin, streptomycin, and p-aminosalicylic acid. When MDR-Mtbs are identified in previously treated cases, empirical administration of ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment. The resistance rates to these drugs were all more than 50%. Furthermore, 25% of MDR-Mtbs from previously treated patients were resistant to p-aminosalicylic acid. We observed almost no resistance to the tested second-line antituberculosis drugs among non-MDR-Mtbs. Anti-tuberculosis regimen with pyrazinamide, ethambutol, fluoroquinolone, kanamycin, cycloserine and p-aminosalicylic acid can be empirically used for newly diagnosed MDR-TB cases. For previously treated MDR-TB patients, empirical ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment because the resistance rates to these drugs were all >50%.

Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats.

Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats' fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.

COMPARATIVE INVESTIGATION OF ANTI-TUBERCULOSIS DRUGS EFFECTS ON TESTICULAR CYP2Е1 EXPRESSION AND MALE REPRODUCTIVE PARAMETERS UNDER SEPARATE AND COMBINED ADMINISTRATION IN MALE RATS

Comparative study of anti-tuberculosis drugs anti-androgenic effects and effects on testicular CYP2E1 has been performed. Testicular CYP2E1 mRNA and protein expression, serum total testosterone level, fertility and spermatogenesis parameters in male rats under simultaneous and separate administration of ethambutol, isoniazid, rifampin and pyrazinamide have been investigated. Analysis of the obtained data has proved the prominent role of ethambutol and isoniazid in gonadal toxicity of antituberculosis drugs combination. Activation of CYP2Е1-dependent metabolizing systems in testicular steroidogenic cells could stipulate at least a part of ethambutol, isoniazid and anti-tuberculosis drugs combination negative effects on testosterone level and spermatogenesis processes. Mechanisms of spermatogenesis alteration by rifampin and pyrazinamide need to be explored more extensively, but in the light of our observations they do not depend from testicular CYP2E1.

Effect of memantine: A NMDA receptor blocker, on ethambutol-induced retinal injury

Ethambutol (ETM)-induced retinal injury is associated with a deterioration in visual function caused by a mechanism similar to many other retinal injuries; i.e. glutamate-induced N-methyl-d-aspartate (NMDA) receptor hyperexitability. Therefore, the current study was carried out to investigate the effect of memantine (MEM), NMDA receptor blocker, on ETM-induced retinal injury.A total of 36 rats were divided equally into: group I, control, group II (ETM administration, 100mg/kg/d, orally for 4 weeks) and group III (administration of ETM+MEM, 100 and 5mg/kg/d, respectively, orally for 4 weeks). Specimens of the retina were prepared for histological study by haematoxylin, eosin (H&E) as well as for immunohistochemical study by Bcl-2, cleaved caspase-3 and glial fibrillary acidic protein (GFAP).In the ETM group, the neural retina became significantly thinner (p<0.05) and the ganglion cell layer (GCL) was the main layer affected in the form of a significant decrease (p<0.001) in its cellularity, along with an obvious increase in Bcl-2 and GFAP expression as well as caspase-3 and oxidative stress markers level compared with other groups. On the other hand, on combining MEM with ETM, the retinal thickness, NFL appearance and GCL cellularity returned to amounts nearly similar to the control group coupled with a significant decrease (p<0.05) in the detected caspase-3, Bcl-2 levels and minimal GFAP expression. Therefore, memantine could be an effective neuroprotective agent in ETM-induced retinal injury by a mechanism that may involve correction of the pro/anti-apoptotic pathways and normalization of the oxidative and Müller cell stress responses.

Leber's Hereditary Optic Neuropathy Precipitated by Ethambutol

Leber's hereditary optic neuropathy (LHON) predominantly affects young men between 10 and 30 years of age. However, two cases of LHON during ethambutol administration have been reported in older men and one case in an older woman. We now report a second case of an older woman in whom administration of ethambutol triggered the development of LHON. A 70-year-old woman received ethambutol, rifampicin, isoniazid, and pyrazinamide for the treatment of tuberculosis. Three months after the beginning of this treatment, a marked decrease in visual acuity occurred in both eyes and ethambutol was discontinued. Her corrected visual acuity was 0.03 in both eyes. There was no hyperemia, swelling of the optic disc, or capillary dilatation in either eye. Centrocecal scotomas were found bilaterally. After 1 month, her visual acuity had further decreased to 0.01, and the scotomas had enlarged. At this time, genetic analysis revealed a point mutation in mitochondrial DNA 11778. Ethambutol can be a risk factor for LHON because the number of reported ethambutol-related LHON cases has increased to four, including the present one. Ethambutol administration to patients with a family history of LHON should be avoided.

Deletion of Cg-emb in Corynebacterianeae Leads to a Novel Truncated Cell Wall Arabinogalactan, whereas Inactivation of Cg-ubiA Results in an Arabinan-deficient Mutant with a Cell Wall Galactan Core

The cell wall of Mycobacterium tuberculosis has a complex ultrastructure that consists of mycolic acids connected to peptidoglycan via arabinogalactan (AG) and abbreviated as the mAGP complex. The mAGP complex is crucial for the survival and pathogenicity of M. tuberculosis and is the target of several anti-tubercular agents. Apart from sharing a similar mAGP and the availability of the complete genome sequence, Corynebacterium glutamicum has proven useful in the study of orthologous M. tuberculosis genes essential for viability. Here we examined the effects of particular genes involved in AG polymerization by gene deletion in C. glutamicum. The anti-tuberculosis drug ethambutol is thought to target a set of arabinofuranosyltransferases (Emb) that are involved in arabinan polymerization. Deletion of emb in C. glutamicum results in a slow growing mutant with profound morphological changes. Chemical analysis revealed a dramatic reduction of arabinose resulting in a novel truncated AG structure possessing only terminal arabinofuranoside (t-Araf) residues with a corresponding loss of cell wall bound mycolic acids. Treatment of wild-type C. glutamicum with ethambutol and subsequent cell wall analyses resulted in an identical phenotype comparable to the C. glutamicum emb deletion mutant. Additionally, disruption of ubiA in C. glutamicum, the first enzyme involved in the biosynthesis of the sugar donor decaprenol phosphoarabinose (DPA), resulted in a complete loss of cell wall arabinan. Herein, we establish for the first time, (i) that in contrast to M. tuberculosis embA and embB mutants, deletion of C. glutamicum emb leads to a highly truncated AG possessing t-Araf residues, (ii) the exact site of attachment of arabinan chains in AG, and (iii) DPA is the only Araf sugar donor in AG biosynthesis suggesting the presence of a novel enzyme responsible for "priming" the galactan domain for further elaboration by Emb, resulting in the final maturation of the native AG polysaccharide.

Delayed Visual Recovery from Severe Ethambutol Optic Neuropathy in Two Patients with Atypical Mycobacterium Infection

Two patients with atypical mycobacterium infection developed severe ethambutol optic neuropathy for a long period of time followed by good recovery. A 74-year-old female (Case 1) developed reduced visual acuity of 20/200 OD and 20/400 OS after oral administration of ethambutol for 14 months, and ethambutol was discontinued. A 63-year-old female (Case 2) developed a visual acuity of CF10' OD and 20/400 OS after oral administration of ethambutol for 10 months, and ethambutol was discontinued. Cases 1 and 2 had anemia after having undergone gastrectomy 10 years or 5 years earlier, respectively, and both had rheumatoid arthritis. At the onset of ethambutol optic neuropathy, both patients developed severe bilateral visual loss with bitemporal hemianopia-like visual field disturbance. However, Cases 1 and 2 did not show disc pallor nor nerve fiber layer defect (NFLD) at any time during the follow-up period, and had good recovery in visual function at 18 months or 19 months after the onset of optic neuropathy, respectively. In patients with severe ethambutol optic neuropathy, as long as disc pallor and NFLD are not observed, good visual recovery may be expected even if severe visual loss persists for a long period of time.

Treatment of pulmonary disease caused by Mycobacterium kansasii: Results of 18 vs 12 months' chemotherapy

Setting: Chest Clinic, Sant Pau Hospital, Barcelona, Spain. Objective: To assess the therapeutic response of pulmonary disease due to Mycobacterium kansasii to 12 and 18 months of chemotherapy. Design: 28 patients with criteria of pulmonary disease caused by M. kansasii not associated with HIV-infection were identified in our department in the period 1985-91 (24 male, 4 female, mean age 56 ± 12 years). 14 patients were treated with rifampicin-isoniazid-ethambutol daily for 12 months (ethambutol only for the first 6 months), and 14 with the same regimen for 18 months. The follow-up after treatment was 12–30 months. Results: All patients showed improvement of radiographic manifestation of disease and sputum conversion (mean time: 4.5 ± 2 months). The adverse drug effects were minimal. No failures were detected, and only one patient (3,5%), in the group of 12-month chemotherapy, relapsed after finishing the treatment. Conclusions: Our findings suggest that pulmonary disease due to M. kansasii has an effective response to 12-month chemotherapy regimen and that it is not necessary to prolong the administration of ethambutol for more than 6 months.