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PubMed1999

Physiological role of the N-terminal processed P4501A1 targeted to mitochondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis.

Recently, we showed that the major species of beta-naphthoflavone-inducible rat liver mitochondrial P450MT2 consists of N-terminal truncated microsomal P4501A1 (+33/1A1) and that the truncated enzyme exhibits different substrate specificity as compared with intact P4501A1. The results of the present study show that P450MT2 targeted to COS cell mitochondria by transient transfection of P4501A1 cDNA is localized inside the mitochondrial inner membrane in a membrane-extrinsic orientation. Co-expression with wild type P4501A1 and adrenodoxin (Adx) cDNAs resulted in 5-7-fold higher erythromycin N-demethylation (ERND) in the mitochondrial fraction but minimal changes in the microsomal fraction of transfected cells. Erythromycin, a potent inhibitor of bacterial and mitochondrial protein synthesis, caused 8-12-fold higher accumulation of CYP1A1 mRNA, preferential accumulation of P450MT2, and 5-6-fold higher ERND activity in the mitochondrial compartment of rat C6 glioma cells. Consistent with the increased mitochondrial ERND activity, co-expression with P4501A1 and Adx in COS cells rendered complete protection against erythromycin-mediated mitochondrial translation inhibition. Mutations that specifically affect the mitochondrial targeting of P4501A1 also abolished protection against mitochondrial translation inhibition. These results for the first time suggest a physiological function for the xenobiotic inducible cytochrome P4501A1 against drug-mediated mitochondrial toxicity.

Animals↗
PubMed1999

Studies of erythromycin maltobionate, a new derivative of erythromycin.

Erythromycin maltobionate, a new water-soluble derivative of erythromycin, was prepared, and its physiochemical and biological properties were evaluated. The derivative has considerable solubility in organic solvents. Its partition coefficient data in different organic solvent-water systems indicate it is possibly well distributed in various tissues in vivo. Antimicrobial potency in vitro of the derivative is 589 micrograms/mg, and its antimicrobial spectrum is comparable to that of the parent antibiotic. The LD50 value of the new derivative in mice intraperitoneally is 244.7 mg/kg. Results of this and the previous investigation of pharmacokinetics and protein binding indicate that the new derivative erythromycin maltobionate has a potential for possible clinical application.

Animals↗
PubMed1988

Efficacy and tolerability of erythromycin acistrate and erythromycin stearate in acute skin infections of patients with atopic eczema.

The efficacy and tolerability of a new erythromycin derivative, erythromycin acistrate (EA), were compared with that of erythromycin stearate (ES) in 42 patients with infected atopic eczema. The dosage of EA was 400 mg tid and that of ES 500 mg tid. The duration of treatment ranged from five to 12 days. The patients were hospitalized and evaluated before treatment and on the last day in hospital. The infective pathogen was usually Staphylococcus aureus in both groups. Without local antibacterial treatment both drugs eradicated the bacteria in more than 60% of the cases. Gastrointestinal side effects were frequently reported with both drugs, more often in the ES- than in the EA-group, but the difference was only statistically significant (p less than 0.05) with respect to diarrhoea. One patient in each group discontinued treatment because of gastrointestinal side effects. No elevations in liver enzymes of clinical significance were reported in either group.

Administration, Cutaneous↗
PubMed1988

Comparison of erythromycin acistrate and enterocoated erythromycin base in acute respiratory infections.

The efficacy and tolerability of erythromycin acistrate (EA), a new erythromycin derivative, and enterocoated erythromycin base (EB) were studied in 183 outpatients belonging to the personnel of Helsinki University Central Hospital. The patients had acute respiratory tract infections. The dosage of EA was 400 mg tid and that of EB 500 mg tid, and the treatment period ranged from seven to 14 days. The cure rate of patients taking full courses of treatment was good in both treatment groups, 96% in the EA-(n = 81) and 93% in the EB-group (n = 73). EA caused statistically significantly (P less than 0.05) less gastrointestinal side effects than EB. These side effects were also milder in the EA- than in the EB-group. The treatment was discontinued in seven patients (7%) in the EA- and in 12 patients (13%) in the EB-group because of gastrointestinal side effects. Neither of the drugs caused clinically important elevations in liver enzymes, nor were changes observed in the laboratory safety parameters measured. EA seems thus to be as effective as and better tolerated than enterocoated EB.

Acute Disease↗
PubMed1988

Erythromycin acistrate and enterocoated pellets of erythromycin base in acute respiratory infections of hospitalized conscripts.

The efficacy and tolerability of a new erythromycin ester, erythromycin acistrate (EA), and erythromycin base (EB) as enterocoated pellets were studied in 100 conscripts at the Central Military Hospital. The patients were admitted to hospital for acute respiratory tract infection. The dosage of EA was 400 mg tid and that of EB 500 mg tid. The patients were hospitalized during the treatment which ranged from seven to 12 days. The cure rate was good in both groups, 96% in the EA- and 87% in the EB-group. Gastrointestinal side effects were reported in 18% of the patients in the EA-group and in 46% in the EB-group (P less than 0.01). The gastrointestinal side effects were mild in all patients in the EA-group, while they were moderate in half and mild in half in the EB-group. None of the patients in the EA-group discontinued treatment because of gastrointestinal side effects, while the number in the EB-group was five (P less than 0.05). However one EA patient discontinued treatment because of testicular pain and one because of an urticarial rash. Neither of the drugs caused elevations of clinical significance in liver enzymes, and there were no changes in the measured laboratory safety parameters. In this trial EA was as effective as and caused significantly less gastrointestinal side effects than EB.

Acute Disease↗
PubMed1974

Correlation of effects of erythromycin analogues on intact bacteria and on [14C]erythromycin binding to Escherichia coli ribosomes.

The dissociation constants for binding to ribosomes from Escherichia coli and concentrations at which 50% inhibition of [(14)C]erythromycin binding to ribosomes occurred were determined for 45 erythromycin analogues. These values were correlated with their antibacterial activities against Bacillus subtilis. Compounds which bound to ribosomes best showed the greatest activities; those which were poorly bound to ribosomes showed little or no antibacterial activity. The ribosomal binding assays therefore reflected the general antibacterial potential of the erythromycin analogues.

Carbon Radioisotopes↗
PubMed1997

Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives.

The methylmalonyl coenzyme A (methylmalonyl-CoA)-specific acyltransferase (AT) domains of modules 1 and 2 of the 6-deoxyerythronolide B synthase (DEBS1) of Saccharopolyspora erythraea ER720 were replaced with three heterologous AT domains that are believed, based on sequence comparisons, to be specific for malonyl-CoA. The three substituted AT domains were "Hyg" AT2 from module 2 of a type I polyketide synthase (PKS)-like gene cluster isolated from the rapamycin producer Streptomyces hygroscopicus ATCC 29253, "Ven" AT isolated from a PKS-like gene cluster of the pikromycin producer Streptomyces venezuelae ATCC 15439, and RAPS AT14 from module 14 of the rapamycin PKS gene cluster of S. hygroscopicus ATCC 29253. These changes led to the production of novel erythromycin derivatives by the engineered strains of S. erythraea ER720. Specifically, 12-desmethyl-12-deoxyerythromycin A, which lacks the methyl group at C-12 of the macrolactone ring, was produced by the strains in which the resident AT1 domain was replaced, and 10-desmethylerythromycin A and 10-desmethyl-12-deoxyerythromycin A, both of which lack the methyl group at C-10 of the macrolactone ring, were produced by the recombinant strains in which the resident AT2 domain was replaced. All of the novel erythromycin derivatives exhibited antibiotic activity against Staphylococcus aureus. The production of the erythromycin derivatives through AT replacements confirms the computer predicted substrate specificities of "Hyg" AT2 and "Ven" AT and the substrate specificity of RAPS AT14 deduced from the structure of rapamycin. Moreover, these experiments demonstrate that at least some AT domains of the complete 6-deoxyerythronolide B synthase of S. erythraea can be replaced by functionally related domains from different organisms to make novel, bioactive compounds.

Acyl Coenzyme A↗
PubMed1998

Preparation and evaluation of erythromycin fumarate--a new derivative of erythromycin.

Erythromycin fumarate, a new water-soluble derivative of erythromycin, was prepared and its physicochemical and biological properties were evaluated. The derivative also has considerable solubility in organic solvents. Its partition coefficient data in different organic solvent-water systems may indicate that it is well-distributed in various tissues in vivo. Antimicrobial potency in vitro of the derivative, 725 micrograms/mg, is much higher than that of the existing derivatives and its antimicrobial spectrum is comparable to that of the parent antibiotic. The LD50 value of the new derivative in mice intraperitoneally is 402.7 mg/kg. Results of this and the previous investigation on pharmacokinetics and protein binding indicate that erythromycin fumarate has high potential for possible clinical application and further investigation may be undertaken.

Animals↗
PubMed1990

Chemical modification of erythromycins. II. Synthesis and antibacterial activity of O-alkyl derivatives of erythromycin A.

A series of O-alkyl erythromycin A derivatives have been synthesized and their antibacterial activities compared with those of erythromycin A (1) and 6-O-methylerythromycin A (3). Methylation of the hydroxyl groups of erythromycin A analogue proceeded stepwise by the two main pathways beginning at the C-6 and C-11 positions, individually. O-Alkylation, other than methylation, took place at the C-11 hydroxyl group exclusively. Among O-alkyl derivatives, 6,12-di-O-methylerythromycin A (5) showed comparable in vitro antibacterial activity to those of 1 and 3. 11-O-Methylerythromycin A (8) was slightly less active than 1. O-Methylation at the C-4" position resulted in a decrease of antibacterial activity.

Animals↗
PubMed2000

Erythromycin for feeding intolerance in preterm infants.

BACKGROUND: Functional immaturity of gastointestinal motility predisposes preterm infants to feeding intolerance. Motilin, a gastrointestinal peptide, stimulates propagative contractile activity during phase III of the migratory motor complex in the interdigestive state. Erythromycin (EM) is a motilin agonist with prokinetic effect at low doses (1-3mg/kg). OBJECTIVES: To evaluate the effectiveness of EM in promoting gastrointestinal motility in preterm infants with feeding intolerance and assess clinically significant adverse effects associated with its use. SEARCH STRATEGY: Systematic literature search in accordance with the Cochrane Neonatal Collaborative Review Group search strategy. Randomized and quasi-randomized controlled trials of EM use, at any dose, in preterm infants to promote gastrointestinal motility were identified by searching MEDLINE, EMBASE, CINAHL, the Cochrane Library, reference lists of published studies, personal files, and abstracts published in Pediatric Research. SELECTION CRITERIA: Randomized controlled trials of oral or intravenous EM use at dose range of 3 to 12 mg/kg/day in preterm infants less than or equal to 36 weeks gestational age with feeding tolerance were included in this review. DATA COLLECTION AND ANALYSIS: Data regarding the primary clinical outcome of days to achieve full enteral feeding were compared among studies. Data on secondary outcomes including adverse effects associated with the use of EM (diarrhea, nosocomial infections, cardiac arrhythmias, or theophylline toxicity), duration of parenteral nutrition, weight gain, incidence of necrotizing enterocolitis (NEC), hypertrophic pyloric stenosis, and length of hospital stay were assessed. MAIN RESULTS: Two randomized controlled studies of EM use in preterm infants for improving gastrointestinal motility were identified. Since both studies involved preterm infants treated with EM at dose >12mg/kg/day at commencement of feeding, they did not meet inclusion criteria defined a priori for this review. There was no statistically significant difference in the incidence of NEC (RR 0.59, 95%CI 0.11, 3.01; RD -0.021, 95%CI -0. 087, 0.045). No statistically significant difference was noted in days to achieve full enteral feeds, length of hospital stay, and adverse events between groups. REVIEWER'S CONCLUSIONS: EM at antimicrobial doses may not be effective in preterm infants with feeding intolerance. Further studies are needed to determine whether EM in lower doses is effective as a prokinetic agent in such infants.

Anti-Bacterial Agents↗
PubMed1998

In vitro activity of quinupristin/dalfopristin against erythromycin-susceptible and erythromycin-resistant Streptococcus pneumoniae.

Minimal inhibitory concentrations (MICs) of quinupristin/dalfopristin, penicillin, erythromycin, and clindamycin were determined by a standard agar dilution method for 93 Streptococcus pneumoniae strains isolated from patients with invasive disease in Germany. Quinupristin/dalfopristin showed good activity against 32 penicillin-susceptible/erythromycin-susceptible strains (MIC90 0.5 mg/l; range 0.25-0.5 mg/l) and 31 penicillin-intermediate/erythromycin-susceptible strains (MIC90 0.5 mg/l; range 0.25-1 mg/l). Erythromycin-resistant strains (n=30) were slightly less susceptible (MIC90 1 mg/l; range 0.125-2 mg/l). Quinupristin/dalfopristin was bactericidal (99.9% killing) for all six strains investigated after 2 h at a concentration of 4 mg/l.

Anti-Bacterial Agents↗
PubMed1988

Erythromycin acistrate and erythromycin stearate in the treatment of non-gonococcal urethritis.

The antibacterial efficacy and tolerability of erythromycin acistrate (EA) and erythromycin stearate (ES) were compared in 100 male patients with non-gonococcal urethritis (NGU). The dosage of EA was 400 mg tid and that of ES 500 mg tid. Mean duration of treatment was ten days. When the final evaluation of the trial was made, the patient material was divided into two groups. One group consisted of patients with chlamydia-positive culture before treatment, the other of chlamydia-negative patients with signs of infection in the direct smear. There were 17 patients with chlamydial infection in the EA-group, and the microbiological cure rate was 100%. In the ES-group there were 21 patients with chlamydial infection and the microbiological cure rate was 95%. In the EA-group, the cure rate of chlamydia-negative NGU patients was 78%, and the corresponding figure in the ES-group was 86%. There was no difference in the cure rates between the two groups on either drug. In the EA-group, 25 patients (50%) reported side effects, in 22 these were gastrointestinal. In the ES-group, 26 patients (52%) reported side effects; in 22 these were gastrointestinal. Two patients in the EA-group discontinued the treatment because of gastrointestinal side effects. There were no differences between the groups in the frequency, severity and duration of side effects.

Adolescent↗
PubMed1993

Chemical modification of erythromycins. IX. Selective methylation at the C-6 hydroxyl group of erythromycin A oxime derivatives and preparation of clarithromycin.

Although erythromycin A contains five hydroxyl groups, regioselective methylation at the C-6 hydroxyl group was achieved to the extent of 90% when a 9-O-substituted erythromycin A 9-oxime was employed as substrate. The methylation and its selectivity are dependent on an O-protecting group at the 9-oxime, solvent, base, and methylating reagent. In particular, the use of a polar aprotic solvent is indispensable for the methylation. Among the 9-oxime derivatives, 2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A 9-[O-(2-chlorobenzyl)oxime] was the most important intermediate for the synthesis of clarithromycin (6-O-methylerythromycin A).

Clarithromycin↗
PubMed1993

Synthetic studies of erythromycin derivatives. Synthesis and antimicrobial activities of 3''-EPI-erythromycin A and (9S)-11-dehydroxy-9-deoxo-9-hydroxy-11- oxoerythromycin A.

Two new derivatives, 3''-epi-erythromycin A (2) and (9S)-11-dehydroxy-9-deoxo-9-hydroxy-11-oxoerythromycin A (3), have been synthesized by using glycosylation with glycal (Ferrier rearrangement), bromomethoxylation and bis(tributyltin) oxide-bromine oxidation as the key steps. Their antimicrobial activities were compared with those of erythromycin A (1).

Anti-Bacterial Agents↗
PubMed1989

Is neomycin necessary for bowel preparation in surgery of the colon? Oral neomycin plus erythromycin versus erythromycin-metronidazole.

In 132 patients who underwent elective surgery of the colon, the value of bowel preparation with a conventional oral antibiotic preparation of neomycin-erythromycin (N-E) was compared with erythromycin-metronidazole (E-M). Of 125 patients who were available for assessment, 61 received N-E and 64 E-M. The two groups were evenly matched. Two wound infections occurred in patients receiving E-M, neither due to anaerobic bacteria, but seven wound infections developed in patients given N-E (p = 0.057), five of them caused by anaerobic bacteria. Anaerobic bacteria of the colon are the dominant cause of postoperative wound infection in elective surgery of the colon. Adequate antibiotic preparation directed against these bacteria makes the use of neomycin unnecessary.

Administration, Oral↗
PubMed1980

Comparison of the mechanism of action of cyclic 11,12-erythromycin A carbonate and erythromycin A.

Synthesis of polyphenylalanine and polylysine in the E. coli MRE 600 and Q 13 cell-free systems was inhibited by erythromycin A and cyclic 11, 12-erythromycin A carbonate to a similar or identical extent. Both compounds inhibited translation of phage f2 RNA in the E. coli Q13 cell-free system. Neither antibiotic affected binding of initiator tRNA or phage f2 RNA to E. coli ribosomes, and neither inhibited translation of BMV RNA in the wheat-germ cell-free system.

Cell-Free System↗