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At least 253 records · Page 14Linked to original sources
PubMed1985

Toxic effects on the visual system of diaminodiphenoxybutane, quinine, and ethambutol in conscious dogs.

The effects of diaminodiphenoxybutane (DAPB), quinine, and ethambutol (EB) on the electroretinogram (ERG) and the visual evoked potential (VEP) were examined in conscious dogs. In dogs receiving repeated oral doses of 100 mg/kg/day for 4 days or a single iv dose of 30 mg/kg of DAPB, the amplitudes of the ERG a- and b-waves were markedly depressed and the peak latency of the VEP first wave was prolonged. Thereafter, ophthalmoscopic changes consisted of mottled discoloration of the fundus, loss of visual placing reaction, and dilatation of the pupils with reduction of the pupillary light reflex were observed. These abnormal signs disappeared even though the marked depression in amplitudes of the ERG a- and b-waves and the prolongation in latency of the VEP first wave continued. A single iv dose of quinine at 50 mg/kg caused a slight depression of the amplitude of the ERG, whereas the VEP remained relatively unaffected. In a dog receiving a single iv dose of quinine at 100 mg/kg, both the ERG and VEP were depressed, and a slight dilatation of the pupils with reduction of the pupillary light reflex and an impairment of visual placing reaction were observed transiently. There was no abnormality in the ocular fundus in either animal receiving quinine. The dogs receiving repeated sc doses of EB at 100, 200, and 400 mg/kg/day for 4 weeks each, for a total of 12 weeks, showed extensive decoloration of the tapetal fundus. However, neither the ERG nor VEP showed any significant abnormalities, and no behavioral signs of visual disturbance were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Uveitis during treatment of disseminated Mycobacterium avium-intracellulare complex infection with the combination of rifabutin, clarithromycin and ethambutol.

Three patients with a cellular immunodeficiency were treated with rifabutin, clarithromycin and ethambutol for a disseminated infection with Mycobacterium avium-intracellulare complex (MAC). The patients developed uveitis, sometimes in combination with a transient rash, arthralgia, arthritis, jaundice and pseudojaundice. It seems likely that these reactions were caused by rifabutin, alone or together with other drugs such as clarithromycin. These adverse reactions probably depend on the dose, metabolism and excretion of the drug. Inhibition of cytochrome P450 seems to be an important mechanism.

AIDS-Related Opportunistic Infections↗
PubMed2006

Analysis of ethambutol and methoxyphenamine by capillary electrophoresis with electrochemiluminescence detection.

A capillary electrophoresis (CE) coupled with electrochemiluminescence (ECL) detection method for the analysis of ethambutol (EB) and methoxyphenamine (MP) has been investigated. Complete separation of EB and MP was achieved in 8 min using a background electrolyte of 20 mM sodium phosphate at pH 10.0 and a separation voltage of 9 kV. ECL detection was performed with an indium/tin oxide (ITO) working electrode biased at 1.4 V (versus a Pt wire reference) in a 200 mM sodium phosphate buffer (pH 8.0) containing 3.5 mM Ru(bpy)3(2+) (where bpy = 2,2'-bipyridyl). Linear correlation (r > or = 0.993) between ECL intensity and drug concentration was obtained in the range 2-50 ng/ml. The limits of detection (LODs) for EB and MP in water were 1.0 and 0.9 ng/ml, respectively. The relative standard deviation values on peak size (10 ng/ml level) and migration time for the two drugs were in the ranges 5-8 and 0.2-0.7% (n = 7), respectively. Applicability of the CE-ECL method to the analysis of human plasma spiked with EB and MP was examined. The LODs for EB and MP in plasma were 0.4 and 0.3 microg/ml, respectively.

Electrophoresis, Capillary↗
PubMed2004

Simultaneous estimation of pharmacokinetic properties in mice of three anti-tubercular ethambutol analogs obtained from combinatorial lead optimization.

Integrating combinatorial lead optimization of [1,2]-diamine core structure based on ethambutol with high-throughput screening has led us to focus on three promising analogs (SQ37, SQ59 and SQ109) as potential anti-tubercular drug candidates from thousands of synthesized diamine analogs for further characterization of their biopharmaceutical and pharmacokinetic properties by using liquid chromatography/tandem mass spectrometry (LC/MS/MS) and cassette dosing for pharmacokinetic screening. Simultaneous separation of the three analogs was achieved on reversed phase HPLC using a gradient mobile phase composed of MeOH/CH(3)COONH(4) (5mM)/trifluoroacetic acid: 80/20/0.1 (v/v/v). After extraction with acetonitrile from biomatrices, samples were analyzed on the LC/MS/MS system in the positive mode using an electrospray ion source. The retention time for the analogs ranged from 3.70 to 4.48 min. Incubation of SQ37 with plasma at 37 degrees C for 6h resulted in its degradation in human and rat plasma (20-35%), but no significant degradation was observed in mouse and dog plasma. SQ59 was relatively stable in the plasma of the four species. SQ109 was degraded in human and dog plasma (30-40%), but stable in mouse and rat plasma during the 6h incubation. A rapid multiple pharmacokinetic screening was taken by cassette dosing of the three analogs to mice and simultaneous analysis of their plasma concentrations. The analogs showed large Vd(ss) ranging from 11,300 (SQ37), 12,800 (SQ109) to 63,900 ml/kg (SQ59). The clearance ranged from 3240 (SQ109), 3530 (SQ37) and 8043 ml/kg/h (SQ59). The elimination t(1/2) ranged from 4.4 to 21.1h dependent on the routes. The oral bioavailability was 5.1 (SQ59), 20.1 (SQ37) and 7.8% (SQ109), respectively. Both SQ37 and SQ109 possess good pharmacokinetic properties.

Animals↗
PubMed2004

Rapid detection of ethambutol-resistant Mycobacterium tuberculosis strains by PCR-RFLP targeting embB codons 306 and 497 and iniA codon 501 mutations.

Mutations at embB gene codons 306 and 497 and iniA gene codon 501 occur frequently in ethambutol (EMB)-resistant Mycobacterium tuberculosis strains worldwide. The identification of these mutations in resistant strains has been achieved by labor-intensive DNA sequencing or by tedious amplification protocols followed by restriction endonuclease digestion. In this report, we describe PCR-restriction fragment length polymorphism (RFLP)-based methods for determining substitutions at embB codons 306 and 497 and iniA codon 501 directly in BACTEC cultures of M. tuberculosis isolates. The wild-type and mutant alleles are revealed by easily interpretable and different RFLP patterns. The methods optimized initially on reference strains were tested directly on BACTEC cultures of 25 randomly selected clinical M. tuberculosis isolates, seven of which were determined to contain EMB-resistant strains by phenotypic drug susceptibility testing. The PCR-RFLP methods identified mutations in four of seven EMB-resistant strains with three isolates containing mutated embB codon 306 and one isolate containing mutated embB codon 497. The results of PCR-RFLP were confirmed by DNA sequencing. The worldwide prevalence figures for mutations at embB codons 306 and 497 and iniA codon 501 suggest that nearly half of EMB-resistant M. tuberculosis strains could be identified within one working day even in developing countries equipped with simple PCR technology instead of weeks required for phenotypic drug susceptibility testing. Further, since EMB resistance is also associated with multiple-drug resistance from some geographical locations, detection of EMB resistance may also lead to rapid identification of multidrug-resistant strains of M. tuberculosis.

Codon↗
PubMedDate not supplied

P-VECP can reveal visual toxicity in pigmented rats of repeated doses of ethambutol.

We determined if pattern visually evoked cortical potentials (P-VECPs) in pigmented rats would reveal visual toxicity induced by a drug even when in cases of repeated doses. We obtained appropriate conditions of P-VECPs measurement; the spatial frequency, 0.16 cycle/degree; the mean stimulation luminance, 25 cd/m(2); and the stimulation frequency, 2 Hz. Twelve adult male pigmented rats (Iar: Long-Evans), weighing 210-301 g, were grouped into two (six per group): the control and the ethambutol (EB) 500 mg/kg administered groups. In the EB 500 mg/kg group, the rats were administered EB subcutaneously once daily for 6 weeks. Rats in the control group were given the vehicle subcutaneously once daily for 6 weeks. P-VECPs were carried out prior to initiation of drug administration and at the first, second, third, fourth, and sixth week of the administration. Prolongation of P1 latency in the P-VECPs was evident in the EB 500 mg/kg at fourth and sixth weeks, and there were no marked changes in the control group and no marked changes in P1N1 amplitude in either group. These findings suggest that P-VECPs in pigmented rats can detect chemically induced visual toxicity even in cases of repeated dosing of a drug. This approach is useful for evaluating the visual toxicity of drugs given repeatedly.

Animals↗
PubMed2004

Characterisation of rpsL, rrs and embB mutations associated with streptomycin and ethambutol resistance in Mycobacterium tuberculosis.

In order to characterise molecular mechanisms of first-line drug resistance in Mycobacterium tuberculosis and to evaluate the use of molecular markers of resistance (gene point mutations), we analysed 66 multi-drug-resistant (MDR) isolates from Latvian tuberculosis patients. They were all resistant to rifampin (RIF), isoniazid (INH) and streptomycin (SM), and 33 were resistant to ethambutol (EMB). Enzymatic digestion by MboII and nucleotide sequencing of the rpsL gene fragment detected a single nucleotide substitution K43R in 40 (61%) of the 66 SM-resistant M. tuberculosis isolates. Of the other 26 SM-resistant isolates, 16 (24%) had mutations at positions 513A-->C and 516C-->T of the rrs gene and 10 (15%) had the wild-type sequence. The single-stranded DNA conformation polymorphism (SSCP) method was used to detect mutations in the embB gene associated with EMB resistance. Substitutions in the embB gene were found by SSCP analysis in 15 (45%) and by sequencing in 17 (52%) of the 33 EMB-resistant isolates. Surprisingly, SSCP revealed a nucleotide mutation at codon M306 in five (15%) of 33 in vitro EMB-susceptible MDR isolates.

Anti-Infective Agents↗
PubMed2003

Visually evoked cortical potentials obtained using checker patterns can detect ethambutol-induced visual toxicity in albino rats.

We determined whether visually evoked cortical potentials obtained using checker patterns (P-VECPs) and albino rats would reveal visual damage induced by ethambutol (EB). Findings were compared in cases of detection of visual damage between by P-VECPs and by flash visually evoked cortical potentials (F-VECPs). Twelve adult albino male Crj:CD(SD)IGS rats were grouped into four, three per group: control, 250PS, 500PS, and 500SC groups. In the 250PS and 500PS groups, rats were administered EB orally for the first 2 weeks and then subcutaneously for the second 2 weeks to 250 and 500 mg/kg, respectively. In the 500SC group, rats were given 500 mg/kg of EB subcutaneously for 4 weeks. Rats in the control group were given the vehicle orally for the first 2 weeks and then subcutaneouly for the second 2 weeks. P-VECPs and F-VECPs were carried out prior to initiation of drug administration and at the 1st, 2nd, 3rd, and 4th weeks of the administration. Prolongation of P1 latency in the P-VECPs was evident in both the 500PS and the 500SC groups at the 4th week, while no marked changes were observed in the F-VECPs. Thus, P-VECPs in albino rats can detect visual damage induced by EB even when F-VECPs cannot do so. These studies suggest that P-VECPs are useful for evaluating the visual toxicity of drugs.

Animals↗
PubMed1976

Polyarthritis, hepatitis and anti-native DNA antibodies after treatment with ethambutol and rifampicin.

After seven months' continuous treatment for suspected tuberculosis with rifampicin and ethambutol a nine-year-old boy developed polyarthritis, rash and hepatitis in association with anti-native DNA antibodies and positive antinuclear factor. Six weeks after withdrawal of the antituberculosis drugs and conservative management, the boy was clinically well and ten months later he remained well clinically and liver function tests, anti-DNA antibody and antinuclear factor tests were normal.

Antibodies↗
PubMed1999

Ethambutol affects the spectral and polarisation sensitivity of on-responses in the optic nerve of rainbow trout.

Juvenile rainbow trout (Oncorhynchus mykiss) were given ethambutol (900 mg kg-1 body mass per day) for 4 weeks to examine its effects on vision. Using multi-unit recording from the optic nerve, spectral sensitivity of the on-responses were significantly affected in two regions, 340-440 nm and 600-660 nm. Off-responses were statistically unaffected. Changes in sensitivity to polarised light were also observed with on-responses to vertically-polarized light decreasing relative to horizontally-polarised light. In contrast, off-responses were less affected. The treatment effects were attributed to changes in the relative contribution of the photoreceptor channels as recorded at the level of the optic nerve.

Animals↗
PubMed2002

The use of the Box-Behnken experimental design in the optimisation and robustness testing of a capillary electrophoresis method for the analysis of ethambutol hydrochloride in a pharmaceutical formulation.

Box-Behnken experimental designs do not appear to be extensively used in optimisation of analytical methods using capillary electrophoresis (CE). This paper describes the use of the Box-Behnken experimental design to optimise the factors affecting the separation of ethambutol hydrochloride (EB), its impurity 2-amino-1-butanol and the internal standard (phenylephrine hydrochloride) in a CE method for a pharmaceutical tablet assay. The three factors studied simultaneously were: buffer pH, buffer concentration and applied electric field, each at three levels. The method was optimised with respect to three responses: resolution between peaks, theoretical plate count and the migration time of the EB peak. A statistical programme, which applies a multiple response optimisation algorithm, was used to calculate and optimise the three responses simultaneously. The optimum conditions were established to be 58.0 mM sodium borate buffer at pH 9.50 and an applied electric field of 412 V/cm. The robustness of the method was also determined and confirmed using a second Box-Behnken design, as part of the validation exercise. System suitability values for the method were derived from the regression surface analysis. The CE method for a pharmaceutical tablet formulation was further validated according to current regulatory requirements, with respect to linearity and range, precision, specificity, accuracy and limit of quantitation. The optimised method gives a fast and efficient separation under 4 min, with complete resolution between the three peaks, and represents an improvement over the existing USP method. It can be concluded that the Box-Behnken experimental design provides a suitable means of optimising and testing the robustness of a CE pharmaceutical method.

Amino Alcohols↗
PubMed2001

Ethambutol analogues as potential antimycobacterial agents.

A range of new ethambutol analogues was synthesised and their inhibitory potencies were probed with Mycobacterium smegmatis. Interestingly, apparently even minor deviation from the structure of the parent compound resulted in reduced antimycobacterial activity.

Antitubercular Agents↗
PubMedDate not supplied

Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates.

Despite relatively modest potency, ethambutol (EMB, (S,S)-[N,N-di-2-amino-1-butanol]ethylenediamine) is a mainstay of contemporary chemotherapy for the treatment of tuberculosis. We have developed a solid-phase synthesis of 1,2-diamine analogues of EMB using a novel acylation-reduction sequence that is compatible with high-throughput 96-well format chemistry. Using this procedure, we have synthesized 63 238 diamine analogues in pools of 10 that are suitable for testing. MIC and a target-based reporter assay were used to direct deconvolution of 2796 individual compounds from these mixtures, and the 69 most potent molecules were resynthesized in milligram quantities for hit confirmation. Purification of these individual active diamine analogues allowed the identification of 26 compounds with activity equal to or greater than EMB. Amines which occurred most frequently in active compounds included many with large hydrophobic moieties, suggesting that optimization was perhaps selecting for the isoprenoid binding site of the arabinosyltransferase target of EMB. N-Geranyl-N'-(2-adamantyl)ethane-1,2-diamine (109), the most active of these diamines, displayed a 14-35-fold improvement in activity in vitro against Mycobacterium tuberculosis, as compared to EMB.

Antitubercular Agents↗
PubMed1997

The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol.

Ethambutol (EMB), a frontline antituberculous drug, targets the mycobacterial cell wall, a unique structure among prokaryotes which consists of an outer layer of mycolic acids covalently bound to peptidoglycan via the arabinogalactan. EMB inhibits the polymerization of cell wall arabinan, and results in the accumulation of the lipid carrier decaprenol phosphoarabinose, which suggests that the drug interferes with the transfer of arabinose to the cell wall acceptor. Unfortunately, resistance to EMB has been described in up to 4% of clinical isolates of Mycobacterium tuberculosis and is prevalent among isolates from patients with multidrug-resistant tuberculosis. We used resistance to EMB as a tool to identify genes participating in the biosynthesis of the mycobacterial cell wall. This approach led to the identification of the embCAB gene cluster, recently proposed to encode for mycobacterial arabinosyl transferases. Resistance to EMB results from an accumulation of genetic events determining overexpression of the Emb protein(s), structural mutation in EmbB, or both. Further characterization of these proteins might provide information on targets for new chemotherapeutic agents and might help development of diagnostic strategies for the detection of resistant M. tuberculosis.

Amino Acid Sequence↗
PubMed1985

[Myambutol (ethambutol)-induced retinoneuritis].

A retinoneuritis due to ethambutol (Myambutol) occurs with Myambutol doses of over 20 mg/kg per day after 3 weeks to 15 months. Visual acuity can deteriorate within the following 6 months even after immediate discontinuation of treatment with Myambutol. It may recover 2 months (though in some cases only 16 months) after the onset of the deterioration; in cases of optic atrophy a more severe loss of vision usually remains. If there was loss of vision to 1/10 or less there was in most cases no change in the visual acuity. On the other hand, a primary loss of vision to only 0.3 or 0.4 usually ended with recovery of full vision. The occasionally observed clinical picture of a reddish optic disk, retinal hemorrhages, a very fine granular pigment alteration of the macular region, and loss of vision for more than a year without optic disk pallor suggests a toxic retinitis or retinoneuritis rather than neuritis. This is confirmed by electrophysiological observations.

Adult↗
PubMed1988

[Interaction of cyclosporin and ethambutol-isoniazid].

A 34-year-old patient prophylactically received tuberculostatic treatment with ethambutol and isoniazide after having had an allogenic renal transplant and immunosuppression with methylprednisolone and cyclosporine. The tuberculostatic treatment was discontinued 165 days after the transplantation. The cyclosporine blood level, which was measured daily thereafter, gradually rose from 250 ng/ml to 400 ng/ml. It is possible that enzyme induction due by the tuberculostatic drugs was responsible for the increased breakdown of cyclosporine.

Adult↗
PubMed1996

The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol.

The antimycobacterial compound ethambutol [Emb; dextro-2,2'-(ethylenediimino)-di-1-butanol] is used to treat tuberculosis as well as disseminated infections caused by Mycobacterium avium. The critical target for Emb lies in the pathway for the biosynthesis of cell wall arabinogalactan, but the molecular mechanisms for drug action and resistance are unknown. The cellular target for Emb was sought using drug resistance, via target overexpression by a plasmid vector, as a selection tool. This strategy led to the cloning of the M. avium emb region which rendered the otherwise susceptible Mycobacterium smegmatis host resistant to Emb. This region contains three complete open reading frames (ORFs), embR, embA, and embB. The translationally coupled embA and embB genes are necessary and sufficient for an Emb-resistant phenotype which depends on gene copy number, and their putative novel membrane proteins are homologous to each other. The predicted protein encoded by embR, which is related to known transcriptional activators from Streptomyces, is expendable for the phenotypic expression of Emb resistance, but an intact divergent promoter region between embR and embAB is required. An Emb-sensitive cell-free assay for arabinan biosynthesis shows that overexpression of embAB is associated with high-level Emb-resistant arabinosyl transferase activity, and that embR appears to modulate the in vitro level of this activity. These data suggest that embAB encode the drug target of Emb, the arabinosyl transferase responsible for the polymerization of arabinose into the arabinan of arabinogalactan, and that overproduction of this Emb-sensitive target leads to Emb resistance.

Amino Acid Sequence↗
PubMed2004

Truncated structural variants of lipoarabinomannan in Mycobacterium leprae and an ethambutol-resistant strain of Mycobacterium tuberculosis.

Current knowledge on the structure of lipoarabinomannan (LAM) has resulted primarily from detailed studies on a few selected laboratory strains of Mycobacterium tuberculosis, Mycobacterium bovis BCG, and Mycobacterium smegmatis. Our previous work was the first to report on the salient structural features of M. tuberculosis clinical isolates and demonstrated significant structural variations. A prime effort is to correlate a particular structural characteristic with observed differences in eliciting an immunobiological response, especially in the context of CD1-restricted presentation of LAM to T cells. T cell clones derived from the cutaneous lesions of leprosy patients have been shown to recognize specifically LAM from Mycobacterium leprae and not from M. tuberculosis Erdman or H37Rv. Herein we provide further fine structural data on LAM from M. leprae (LepLAM) and a tuberculosis clinical isolate, CSU20 (CSU20LAM), which was unexpectedly recognized by the supposedly LepLAM-specific CD1-restricted T cell clones. In comparison with the de facto laboratory LAM standard from M. tuberculosis H37Rv (RvLAM), LepLAM derived from in vivo grown M. leprae is apparently simpler in its arabinan architecture with a high degree of exposed, non-mannose-capped termini. On the other hand, CSU20, an ethambutol-resistant clinical isolate, makes a vastly heterogeneous population of LAM ranging from rather small and non-mannose-capped to full-length and fully capped variants. LepLAM and CSU20LAM contain a higher level of succinylation than RvLAM, which, in the context of truncated or less elaborated arabinan, may contribute to selective recognition by T cells. LAM from all species could be resolved into discrete forms by isoelectric focusing based apparently on their arabinan heterogeneity. In the light of our current and more recent findings, we reason that all immunobiological data should be cautiously interpreted and that the actual LAM variants that may be present in vivo during infection and pathogenesis need to be taken into consideration.

Blotting, Western↗