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PubMed1982

Formation of nitroso compounds and mutagens from cinnarizine, ethambutol, piromidic acid, pyridinol carbamate and tiaramide by drug/nitrite interaction.

The formation of nitroso compounds and mutagens from 5 nitrogen-containing drugs (cinnarizine, ethambutol, piromidic acid, pyridinol carbamate and tiaramide) by drug/nitrite interaction was examined. On the reaction of 50 micrometers drug and 500 micrometers nitrite at pH 3.0--3.4 and 37 degrees C for 4 h, the considerable formation of nitroso compounds was observed for ethambutol, cinnarizine and pyridinol carbamate. The reaction product of pyridinol carbamate and nitrite was remarkably mutagenic to Salmonella typhimurium TA100 in the absence of S-9 mix. Under conditions presumed to resemble those in the stomach after ingestion of a therapeutic dose of the drug, the formation of nitroso compounds was observed for ethambutol and significant mutagenicity was detected in the reaction product of pyridinol carbamate.

Benzothiazoles↗

PubMed1990

Labeling of ethambutol with 99mTc using a new reduction procedure. Pharmacokinetic study in the mouse and rat.

Certain 99mTc-labeled derivatives of ethylene diamine substituted in NN', when labeled with 99mTc, have been proposed for studying renal excretion, and others for brain imaging. Ethambutol, a well known antituberculosis drug, possesses a structure very similar to these derivatives. We prepared a complex of [99mTc]ethambutol using hypophosphorus acid as the reducing agent. The complex was then analyzed by paper and cellulose F chromatography and by FAB mass spectrometry. A pharmacokinetic study in the mouse and rat indicated that the complex is eliminated by the kidney faster than DTPA, slower than [131I]hippuran and without significant renal retention. The [99mTc]ethambutol complex is easy to prepare and shows good stability in water at physiological pH, making it potentially useful in renal excretion studies.

Animals↗

PubMed1975

Ethambutol regimen in renal tuberculosis.

A 10-year experience with an ethambutol regimen for renal tuberculosis is presented. Precaution must be taken with ethambutol since optic nerve atrophy can occur. This oral therapy is now given as a single, daily dose before breakfast and has proved successful in therapy and patient acceptance. No urine reversions have occurred in the 10 years. The regimen of ethambutol, isoniazid, cycloserine and pyridoxine may now be considered a first choice in therapy for renal tuberculosis.

Adult↗

PubMed1997

Synergistic antimycobacterial activity between ethambutol and the beta-lactam drug cefepime.

The activity of cefepime alone and in combination with ethambutol was assessed, using the BACTEC radiometric system, on 33 mycobacterial strains, 14 Mycobacterium avium complex (MAC), 6 isolates of M. malmoense, and 13 multidrug-resistant (MDR) isolates of M. tuberculosis. All tested mycobacteria were resistant to 8 mg/l cefepime. However, at a concentration of 32 mg/l cefepime was active on 7/13 (54%) MDR isolates of M. tuberculosis and 2/6 (33%) M. malmoense strains. All MAC strains were also resistant to this concentration. Synergistic antimycobacterial effects were seen for the combination of cefepime and ethambutol against all isolates of MAC and M. malmoense and on 4/13 (31%) MDR M. tuberculosis isolates. Moreover, this drug combination rendered 17/24 (71%) initially resistant mycobacterial strains susceptible. These promising results suggest that the antimycobacterial activity of combinations of beta-lactam drugs and ethambutol should be studied further.

Antitubercular Agents↗

PubMed2001

Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.

BACKGROUND: A mycobacterial infection may be the cause of Crohn's disease in some patients. Measurement of intestinal permeability may identify Crohn's disease patients with a high likelihood of relapse and may quantify the severity of intestinal injury. AIM: To assess the effect of 3 months of clarithromycin and ethambutol on the disease activity and intestinal permeability in patients with Crohn's disease at high risk of relapse. METHODS: Patients with Crohn's disease, with a lactulose-mannitol permeability test above 0.03, were randomly assigned to receive either clarithromycin, 500 mg twice daily, and ethambutol, 15 mg/kg daily, or identically appearing placebo for 3 months in addition to their regular therapy. The Harvey-Bradshaw index and the lactulose-mannitol test were assessed in a blind fashion every 3 months for 12 months. RESULTS: Thirty-one patients were randomized to receive either drugs (n=15) or placebo (n=16). The groups were similar in age, sex, duration of disease, location of disease, past complications and disease severity. Specifically, there was no difference between the drug or placebo groups in the mean Harvey-Bradshaw index (4.8 vs. 4.4), number with active disease (33% vs. 44%) and mean lactulose-mannitol test (0.06 vs. 0.10). During the 12-month follow-up period, there were no consistent, statistically significant differences in the mean Harvey-Bradshaw index or lactulose-mannitol test between treatment and placebo groups. Individual patients showed either improvement or worsening of these indices, but these were not related to study medication. Specifically, no 'cures' were noted with anti-mycobacterial treatment. CONCLUSIONS: Three months of treatment with clarithromycin and ethambutol does not benefit Crohn's disease patients who are receiving standard medical therapy.

Adult↗

PubMed1995

Visual function in recovered ethambutol optic neuropathy.

The visual acuity of the patient with ethambutol optic neuropathy will recover within 3 to 4 months after discontinuing the drug. We studied the extent of the recovery of other visual functions. Thirty-six axial type ethambutol optic neuropathy patients, who visited our neuro-ophthalmology clinic from January, 1990, to December, 1993, were included in this study. Fifteen patients (29 eyes) regained their visual acuity to better than 1.0. The average follow-up period following the recovery is 21.7 months. Pattern reversal VEP, Farnsworth-Munsell 100-Hue color vision test, critical flicker frequency (CFF), visual field perimetry, contrast sensitivity and edge-light pupil cycle time were assessed for every affected eye. Latency (P100) of visually evoked potential was delayed in 34.5% (10/29) of eyes. In color vision, 48.3% (14/29) of eyes had deutan or tritan defect. An abnormality of red CFF with value lower than 31 Hz was revealed 51.7% (15/29) eyes. In the visual field, 58.6% (17/29) of eyes had paracentral scotoma, arcuate scotoma, or enlargement of physiologic blind spot. Contrast sensitivity was depressed in 62.1% (18/29) of eyes, mainly at middle and low spatial frequency. Pupil cycle time was prolonged in 72.4% (21/29) of eyes. Aside from visual acuity, other visual functions of the recovered ethambutol optic neuropathy patients were incomplete. The extent of recovery of the visual function is as follows: visual acuity-VEPs-color sense-CFF-visual field-contrast sensitivity-pupil cycle time.

Adult↗

PubMed1989

In-vitro synergistic activity between ethambutol and fluorinated quinolones against Mycobacterium avium complex.

Ciprofloxacin, ofloxacin and norfloxacin were ineffective at clinically relevant concentrations against the Mycobacterium avium complex (MAC) in vitro as measured by radiometric respirometry. Only two of 30 clinical isolates of MAC were susceptible to any of the tested quinolones. By contrast good antibacterial activity was obtained when any of the quinolones was combined with ethambutol. The synergistic effect was most pronounced for the combination of ethambutol and ciprofloxacin, to which 76 of 100 strains were susceptible. It is suggested that the synergism is based on an enhanced penetration of the quinolones by ethambutol.

Anti-Infective Agents↗

PubMed1996

Activity of rifabutin, clarithromycin, ethambutol, sparfloxacin and amikacin, alone and in combination, against Mycobacterium avium complex in human macrophages.

Disseminated infection with Microbacterium avium complex (MAC) in patients with AIDS is currently treated with a combination of antimycobacterial agents in order to prevent the selection of resistant mutant strains. Although clinical and microbiological responses can generally be achieved within a few weeks, relapses are common and require modification of the combination regimen or identification of effective alternate therapies. In this study we investigated the activities of rifabutin 0.5 mg/L, sparfloxacin 1 mg/L, clarithromycin 4 mg/L, amikacin 16 mg/L and ethambutol 2 mg/L, alone and in combination, against nine strains of M. avium isolated from the blood of patients with AIDS in order to identify regimens with the greatest therapeutic potential. Macrophages derived from human monocytes were infected with M. avium and inoculated with a single drug or a combination of drugs; cfu counts were performed at 0, 4 and 7 days after infection. At day 4 and at day 7, the combination of rifabutin, clarithromycin, amikacin and sparfloxacin displayed the highest degree of activity. However, the activity did not differ significantly from that of the combination of rifabutin, clarithromycin and ethambutol. The results of this study confirm the activity of combinations including rifabutin and clarithromycin (+/- ethambutol) in human monocyte-derived macrophages and suggest potentially useful associations in incorporating sparfloxacin and amikacin.

Amikacin↗

PubMed1998

Susceptibility of multidrug-resistant strains of Mycobacterium tuberculosis to amoxycillin in combination with clavulanic acid and ethambutol.

Thirty clinical isolates of Mycobacterium tuberculosis, 20 of which were multidrug-resistant (MDR), were tested for susceptibility to different combinations of amoxycillin, clavulanic acid and subinhibitory concentrations of ethambutol. beta-Lactamase production was assessed semiquantitatively with the nitrocefin method and susceptibility testing was performed with the BACTEC method. All isolates were beta-lactamase positive and were resistant to 16 mg/L amoxycillin. The MIC of amoxycillin in combination with clavulanic acid was > or =2 mg/L for 27/30 (90%) isolates. Addition of subinhibitory concentrations of ethambutol significantly reduced the MIC of amoxycillin for all tested isolates. Twenty-nine (97%) isolates had an MIC of amoxycillin of < or =0.5 mg/L when subinhibitory concentrations of ethambutol were added; this is well below the concentrations achievable in serum and tissue.

Amoxicillin↗

PubMed1992

Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum.

We tested the efficacy of rifabutin and ethambutol in combination in healing severe recurrent Crohn's disease in the neoterminal ileum. Sixteen patients who had undergone an ileal resection with partial colectomy and ileocolonic anastomosis and who had severe recurrent lesions in the neoterminal ileum at baseline ileocolonoscopy were included in the study. The patients received rifabutin in a dose of 5 mg/kg together with ethambutol, 20 mg/kg. Ten patients were treated for 6 months; six patients dropped out because of adverse events. As no effect was observed after 6 months, five patients completed a 12-month therapy course. Follow-up ileocolonoscopy was performed at 3, 6, and 12 months. In none of the 10 patients who completed the 6-month trial and in none of the five patients who completed 12 months of therapy was endoscopic improvement of the lesions observed. In four patients the disease was clinically progressive, and two patients underwent a reresection after 6 and 8 months, respectively. This study shows that long-term therapy with rifabutin and ethambutol does not heal Crohn's disease in the neoterminal ileum and does not prevent recurrence of symptoms and complications.

Adult↗

PubMed1980

Ethambutol neurophathy: clinical and electroneuromyographic studies.

Clinical features including changes in the peripheral nerve conduction were analzyed in 10 cases with ethambutol neuropathy. There were abnormalities in the visual field in seven and optic atrophy in five of 10 cases. Seven of 10 cases complained of numbness in the lower limbs. The age of onset and dose of ethambutol the patients continue to take after the occurrence of visual impairment were found to be important in determining the severity of neurological symptoms. A functional disturbance was more conspicuous in ethambutol neuropathy, particularly in the sensory system than in the motor system so far as the peripheral nerve conduction was serially examined. Some cases still had serious optic disturbances even about seven years after the onset of the disease and the presence of irreversible lesions was suspected.

Adolescent↗

PubMed2006

Ethambutol-induced alterations in Mycobacterium bovis BCG imaged by atomic force microscopy.

Progress in understanding the structure-function relationships of the mycobacterial cell wall has been hampered by its complex architecture as well as by the lack of sensitive, high-resolution probing techniques. For the first time, we used atomic force microscopy (AFM) to image the surface topography of hydrated Mycobacterium bovis bacillus Calmette Guérin cells and to investigate the influence of the antimycobacterial drug ethambutol on the cell wall architecture. While untreated cells showed a very smooth and homogeneous surface morphology, incubation of cells in the presence of ethambutol caused dramatic changes of the fine surface structure. At 4 micro g mL(-1), the drug created concentric striations at the cell surface and disrupted a approximately 8 nm thick cell wall layer, attributed to the outer electron-opaque layer usually seen by electron microscopy, while at 10 micro g mL(-1) an underlying approximately 12 nm thick layer reflecting the thick electron-transparent layer was also altered. These noninvasive ultrastructural investigations provide novel information on the macromolecular architecture of the mycobacterial envelope as well as into the destructuring effects of ethambutol.

Antitubercular Agents↗

PubMed1987

Ocular ethambutol toxicity. A case report with electrophysiological considerations and a review of Danish cases 1972-81.

A 76-year-old female with ocular ethambutol toxicity prompted two investigations. Firstly, she was followed electrophysiologically, with multichannel recorded pattern reversal visual evoked potential techniques using full-field, half-field, central-field and peripheral field stimulation, plus flash VEP and ERG. The examinations performed 2, 5 and 7 months after ethambutol withdrawal indicated damage to the papillomacular bundle, while a late follow-up after recovery showed potentials of near normal configuration. Secondly an epidemiological survey was attempted based on the 37 ethambutol toxicity cases registered to the Danish Board on Adverse Reactions 1972-81, making up 1% of those receiving antituberculous therapy. They showed a significant preponderance of elderly (24/37 greater than 65 years) and of females (29/37). There was only one foreigner in the series. A detailed analysis of visual function in a subsample of 22 cases (those registered 1977-81) showed that visual impairment lasted several months, and that usually recovery was not complete. Using the visual demands for driver's license as criterium, 20 fulfilled the demands prior to therapy, but only 12 after recovery.

Aged↗

PubMed1985

Specific inhibition of spermidine synthesis in Mycobacteria spp. by the dextro isomer of ethambutol.

Only the dextro isomer of ethambutol inhibited mycobacterial spermidine synthase and spermidine biosynthesis. Inhibition of mycobacterial spermidine synthase appeared to be specific. Spermidine synthase from Mycobacterium fortuitum, which was resistant to ethambutol in vitro, required a higher concentration of ethambutol for its inhibition than the enzyme of susceptible Mycobacterium bovis.

Drug Resistance, Microbial↗

PubMed1991

Extracellular and intracellular activities of clarithromycin used alone and in association with ethambutol and rifampin against Mycobacterium avium complex.

Mycobacterium avium complex bacteria are opportunistic human pathogens, and their chemotherapy remains a challenge since these organisms are resistant to a majority of routine antituberculous drugs. Recently, a wide range of new macrolide antibiotics has been developed, among which the drug clarithromycin appears to have a selective action against M. avium bacteria. In the present study, we have investigated the action of clarithromycin alone (MIC and MBC determinations) and in association with the routine antimycobacterial drugs ethambutol and rifampin at sublethal concentrations (1 micrograms/ml; below concentrations obtainable in human serum) against M. avium. Our viable count data showed that clarithromycin was bactericidal against all 10 strains of M. avium studied and that its activity was enhanced by ethambutol (in 8 of 9 strains) and rifampin (in 3 of 9 strains). The use of all three drugs in association resulted in higher bactericidal effects than found with any of the drugs used alone or in two-drug combinations in seven of nine strains. The bactericidal effects of various drugs used alone and in combination at concentrations obtainable in human serum were investigated against the type strain ATCC 15769 by using 7H9 broth and BACTEC radiometry (extracellular action) and a J-774 macrophage cell line (intracellular action). A good agreement between the extracellular and intracellular activities was found. Electron microscopy using a ruthenium red cytochemical staining of the bacteria showed that clarithromycin disorganized the outer wall layer and the cytoplasmic membrane in the mycobacterial cell envelope and resulted in formation of large vacuoles inside the cytoplasm, with solubilization of ribosomal structures and consequent plasmolysis. Its association with ethambutol and rifampin resulted in more drastic alterations in the bacterial morphology than were seen with any of the drugs used alone, leading to the removal of the bacterial outer layer, homogenization of cytoplasm, complete cell lysis, and formation of ghosts.

Cell Division↗

PubMed1992

Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement of its extracellular and intracellular activities by ethambutol.

Radiometric MICs of clarithromycin, a new macrolide drug, were determined against five mycobactin-dependent strains of Mycobacterium paratuberculosis (including two Crohn's disease clinical isolates) and compared with those of other drugs which included rifampin, ethambutol, amikacin, ofloxacin, ciprofloxacin, and sparfloxacin. Among the drugs screened, clarithromycin was the drug for which MICs were lowest against the five strains tested. As MICs were significantly below the reported Cmax levels (about 4 micrograms/ml), the intracellular activity of clarithromycin against the type strain of M. paratuberculosis maintained in cultured macrophages was screened. Clarithromycin was able to kill the initial inoculum by more than 1 log within 7 days, and this activity was further potentiated by ethambutol. Extracellular drug combination screened by using sublethal concentrations of the drugs showed that ethambutol was able to enhance clarithromycin activity in three out of four M. paratuberculosis strains instead of only one out of four strains (or none in the case of ofloxacin) when associated with other drugs. These results suggest that clarithromycin may be fruitful to treat human disease in which M. paratuberculosis may be etiologically involved.

Animals↗

PubMed1994

Activities of roxithromycin used alone and in combination with ethambutol, rifampin, amikacin, ofloxacin, and clofazimine against Mycobacterium avium complex.

Preliminary studies showed that roxithromycin possessed significant in vitro activity against a variety of atypical mycobacteria such as the Mycobacterium avium complex, M. scrofulaceum, M. szulgai, M. malmoense, M. xenopi, M. marinum, and M. kansasii and rare pathogens such as M. chelonae and M. fortuitum. In this investigation, radiometric MICs of roxithromycin, ethambutol, rifampin, amikacin, ofloxacin, and clofazimine for 10 clinical isolates of the M. avium complex (5 each from human immunodeficiency virus [HIV]-positive and HIV-negative patients) were determined. Roxithromycin MICs against all the isolates were below the reported maximum concentration of drug in serum at the routine pH of 6.8, and the MICs were further lowered by 1 to 2 dilutions at a pH of 7.4. In vitro enhancement of roxithromycin activity against all strains was further investigated by the previously established Bactec 460-TB method by combining the drugs at sub-MIC levels. Antibacterial activity of roxithromycin was enhanced in all 10 strains by ethambutol, in 3 strains each by rifampin and clofazimine, in 2 strains by amikacin, and in 1 strain by ofloxacin. In vitro screening of three-drug combinations showed that combinations of roxithromycin, ethambutol, and a third potential anti-M. avium drug (rifampin, amikacin, ofloxacin, or clofazimine) resulted in further enhancement of activity in 13 out of 20 drug combinations screened.

Amikacin↗

PubMed2006

Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection.

Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.

Adolescent↗