Acetyl Erythromycin Research Articles

Penetration of erythromycin into periapical lesions after repeated doses of erythromycin acistrate and erythromycin stearate: A pilot study

In 26 patients who had undergone apicectomy and extirpation of granulomas ( n = 9) or radicular cysts ( n = 17), concentrations of erythromycin, 2′-acetyl erythromycin, and their anhydro forms were determined with a novel chemical method in plasma and periapical lesions after at least 2 days of treatment with erythromycin acistrate (EA) (400 mg three times daily, n = 11) or erythromycin stearate (ES) (500 mg three times daily, n = 15). Oral surgery was performed 2 1 2 to 3 hours after the last dose. Blood samples were collected at the time of operation, and immediately before antibiotic treatment, and 1, 2, and 6 hours after treatment. At all time points EA produced at least twice the total antibiotic (2′-acetyl erythromycin plus erythromycin) concentrations in plasma as ES. Erythromycin levels in plasma were at least as high after EA treatment as after ES. In periapical lesions erythromycin concentration after EA was three times higher (1.34 ± 0.28 μg/gm) than after ES treatment (0.40 ± 0.17 μg/gm). Although the total drug concentration in periapical lesions was about the same after EA (2.64 μg/ml) and ES (3.41 μg/ml), most of the drug recovered after ES was antimicrobially inactive anhydroerythromycin (3.01 μg/gm). The concentration of anhydroerythromycin in plasma was approximately the same as that of erythromycin after ES throughout the dose interval. After EA treatment both plasma and the peripical lesion samples contained hardly detectable amounts of anhydroerythromycin. Hence EA has a good bioavailability essential for treatment and prophylaxis of bacterial infections in dentistry.

Effect of erythromycin on the oro-caecal transit time in man

Erythromycins often cause gastrointestinal side-effects due to an increase in motility or to change in the intestinal bacterial flora. In order to evaluate the effect of erythromycin on gastrointestinal motility. 11 healthy volunteers were given placebo, erythromycin stearate (ES) 1000 mg or a therapeutically equivalent single dose of erythromycin acistrate (EA.2'-acetyl erythromycin stearate) 800 mg in a double-blind trial. The oro-caecal transit time was measured using the hydrogen breath test with lactulose as the substrate. The transit time was estimated from the H2-peak (ppm) in end-expiratory breath by two methods, t1 representing the "front" and t2 the "bulk" of lactulose reaching the colon. t1 was 51 min in the placebo group, 38 min in the EA and 31 min in the ES group (p less than 0.05, ES vs placebo). t2 was 74 min, 64 min, and 46 min, respectively (p less than 0.05, ES vs placebo). The difference between EA and ES was also significant. Six subjects in the ES group but none in the EA group recorded adverse gastrointestinal effects attributable to medication. It was concluded that erythromycin shortens the oro-caecal transit time in man and that EA effects the transit time slightly less than ES.

Concentrations of erythromycin, 2'-acetyl erythromycin, and their anhydro forms in plasma and tonsillar tissue after repeated dosage of erythromycin stearate and erythromycin acistrate.

The concentrations of erythromycin, 2'-acetylerythromycin (2'-AE) and their anhydro forms in plasma and tonsillar tissue were analyzed after a 3-day repeated-dosage regimen of erythromycin stearate (ES; 500 mg twice a day [b.i.d]) and erythromycin acistrate (EA), a new erythromycin prodrug, at two doses (400 and 500 mg b.i.d.). The tonsils of 40 patients were removed at 112 to 329 min after intake of the last dose. Blood samples were collected at the time of tonsillectomy and at 0, 2, and 6 h after the last dose. At all time points, EA produced severalfold more total antibiotic (erythromycin + 2'-AE) concentrations in plasma compared with ES. There were two nonabsorbers in the ES group, but none in the two EA groups. The mean total antibiotic levels in tonsillar tissue after EA treatment exceeded the levels after treatment with ES by a factor of 3 (for EA at 400 mg b.i.d.) and 4.5 (for EA at 500 mg b.i.d.). The ratios of erythromycin concentration in tonsil to that in plasma at the time of tissue removal were quite similar for all groups (means, 0.51 to 0.54). In the EA groups, 2 of 26 (8%) patients had no measurable erythromycin in the tonsillar tissue samples, whereas in the ES group, 3 of 14 (21%) patients had no measurable erythromycin in the same tissue. The degree of hydrolysis of 2'-AE to erythromycin was about 25% in plasma at the time of tonsillectomy for both EA groups and about 40% in tonsillar tissue. There were negligible amounts of anhydro forms in plasma after EA administration, whereas in the ES group, anhydroerythromycin levels were, from time to time, even higher than erythromycin levels. Very high levels of anhydro forms were detected in tonsillar tissue after ES treatment, whereas only low levels were found after EA administration.

Determination of 2'-acetyl erythromycin and erythromycin in human tonsil tissue by HPLC with coulometric detection.

A simple and sensitive high-performance liquid chromatographic method was developed for the determination of 2'-acetyl erythromycin and erythromycin in human tonsil tissue. Methyl tert-butyl ether was used as the extraction solvent after alkalization of tissue homogenates. Separation was achieved on a reverse phase C-18 column. The mobile phase consisted of acetonitrile-methanol-tetrahydrofuran-sodium acetate buffer, pH 4.5. Eluted compounds were monitored by a coulometric detector in the oxidative screen mode. The quantitation limits of 2'-acetyl erythromycin and erythromycin were 0.20 and 0.30 mg/kg of tissue, respectively. The method was linear over the concentration range of 0.60-10.0 mg/kg of tissue for 2'-acetyl erythromycin and erythromycin.

Hydrolysis of 2'-esters of erythromycin.

Hydrolysis rates were determined for 2'-acetyl erythromycin, three of its homologues (2'-propionyl, 2'-butyryl and 2'-valeryl) and 2'-ethylsuccinyl erythromycin in buffer solution (pH 7.0, 37 degrees C) and in human plasma (37 degrees C) at concentrations of 5 and 100 mg/l. Ester concentrations were measured by fast atom bombardment mass spectrometry. Hydrolysis in buffer followed pseudo first-order kinetics. The half-lives of the esters ranged from 24.3 to 89.5 min (2'-ethyl-succinyl less than 2'-acetyl less than 2'-propionyl less than 2'-valeryl less than 2'-butyryl). Hydrolysis in plasma followed more complex kinetics. The half-lives were generally longer than in buffer and dependent on the initial ester concentration. Apparent first-order half-lives ranged from 35.5 to 492 min (2'-ethylsuccinyl less than 2'-acetyl less than 2'-propionyl less than 2'-butyryl less than 2'-valeryl). In case of homologous esters, the stabilizing effect of plasma and concentration dependence varied with lipophilicity. In buffer solution the hydrolysis half-life of 2'-acetyl erythromycin was dependent on the concentration of alpha 1-acid glycoprotein. Of the homologous esters, 2'-acetyl erythromycin was hydrolysed most rapidly, but it was hydrolysed more slowly than 2'-ethylsuccinyl erythromycin.

Time course of the antibacterial activity of erythromycin stearate and erythromycin acistrate against two Staphylococcus aureus strains in vitro.

The antibacterial efficacy of erythromycin stearate (ES) and a new erythromycin prodrug, erythromycin acistrate (EA, 2'-acetyl erythromycin stearate), was compared in two Staphylococcus aureus strains, one sensitive and the other resistant to erythromycin. The growth was continuously monitored turbidometrically for 24 h. With the sensitive S. aureus, the inhibitory effects of both ES and EA were visible within 1-2 h when the antibiotics were added at 0 or 1.5 h after the beginning of the incubation. When they were added at 3 h, their action was immediate at 0.5 and 1 mg/l, and 5 mg/l caused a complete inhibition of the growth. At 0.5 and 1 mg/l, however, ES was much more effective than EA. When EA and ES (1, 5 or 10 mg/l) were added at 0 or 1.5 h to the resistant staphylococcal culture, the lag phases (no detectable growth) were prolonged as a function of drug concentration but eventually the growth was restored. The action of EA was weaker and the lag phases were 2-5 h shorter than those after ES. When the compounds were added at 3 h, the antibacterial effect was visible immediately. The increase of absorbance was slowed down even by 1 mg/l of ES and almost prevented by 5 mg/l. At these concentrations EA was less effective than ES, but the two erythromycins were equally active at 10 mg/l. These results show that addition of EA acts on both staphylococci as rapidly as addition of ES but to a lesser extent. Evidently EA is antibacterially weaker than ES, or rapidly hydrolyzed to erythromycin after it has been added to the test system.

Effects of two erythromycins, doxycycline and phenoxymethylpenicillin on human leucocyte chemotaxis in vitro.

The effect of erythromycin, doxycycline and phenoxymethylpenicillin on human polymorphonuclear leucocyte (PMNL) chemotaxis was studied in vitro with Boyden's filter technique. Both erythromycin base and 2'-acetyl erythromycin stearate increased the PMNL chemotaxis significantly at concentrations greater than or equal to 50 microM, 2'-acetyl erythromycin stearate also at concentrations of 2.5-5 microM. Phenoxymethyl-penicillin reduced migration at 500 microM but lower concentrations had no significant effect. Doxycycline prevented migration significantly at concentrations greater than or equal to 50 microM.

Determination of 2′-acetyl erythromycin and erythromycin in plasma by HPLC using manual and robotic sample preparation

A simple and specific HPLC method with coulometric detection was developed for the determination of 2′-acetyl erythromycin and erythromycin in human plasma. Methyl tert-butyl ether was used as the extraction solvent after alkalization of plasma samples. The plasma extracts were chromatographed on a reverse phase column using 4-component mobile phase. The manual sample preparation procedure was modified so that it could also be applied to the robotic system (Zymate™ Laboratory Automation System). The linear range was 0.25–7.0 µg/ml. The quantitation limit for 2′-acetyl erythromycin and erythromycin was 0.05 µg/ml. Equivalent manual and robotic sample preparation methods were used to analyze a large number of plasma samples.