Erythromycin method

Other approaches to inhibiting intramolecular cycli2ations of erythromycin have also proven successhil. Erom a series of O-alkyl derivatives of erythromycin, clarithromycin (6-0-methylerythromycin) (37) was selected for clinical development (146,147). Another approach replaced the C-8 proton of erythromycin with duorine, which was accompHshed by both chemical and bioconversion methods to yield durithromycin (38) (148). 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

Increased transaminase activity has been observed when the dlazocolorlmetrlc method Is used. Unusually Increased activity has been reported In patients with ketosis and also In patients receiving erythromycin (n) or p-amlnosallcyllc acid (9). These test Interferences can be obviated by employing ultraviolet kinetic procedures. 

Intravenous antibiotic administration is the most common delivery method for surgical prophylaxis. Intravenous administration ensures complete bioavailability while minimizing the impact of patient-specific variables. Oral administration is also used in some bowel operations. Non-absorbable compounds like erythromycin base and neomycin are given up to 24 hours prior to surgery to cleanse the bowel. Note that oral agents are used adjunctively and do not replace IV agents. 

Since the order of increasing CL intensity for alkyl amines reacted with Ru(bpy)32+ is tertiary amines > secondary amines > primary amines, pharmaceutical compounds bearing a tertiary amine function (e.g., antihistamine drugs [99], anticholinergic drugs [100], erythromycin [101], and its derivatives [102]) have been sensitively determined after HPLC separation (Table 3). The method was applied to the detection of d- and L-tryptophan (Trp) after separation by a ligand-exchange HPLC [103], The detection limits for d- and L-Trp were both 0.2 pmol per injection. Oxalate in urine and blood plasma samples has also been determined by a reversed-phase ion-pair HPLC (Fig. 18) [104], Direct addition of... 

These authors14 later report using the GC method for enteric coated tablets of erythromycin, giving a recovery of 99.8% and a coefficient of variation of 2.3% based on placebo tablets spiked with erythromycin. 

Tsuji and Goetz24 developed a quantitative high performance liquid chromatographic method for separating and measuring erythromycins A, B, and C, their epimers and degradation products. This method uses a /iBondapak Ci 8 reverse column with acetonitrile-methanol-O.2m ammonium acetate-water (45 10 10 25) as solvent. The pH and composition of the mobile phase may be adjusted to optimize resolution and elution volume. The authors utilized the procedure on USP reference standard and report a relative standard deviation of 0.64%. 

Several common methods for the detection of these compounds in environmental media have been proposed such as microbiological assay and conventional chromatographic methods. However, only one example of the application of immunochemical methods to the analysis of environmental samples has been reported [84]. In this case, erythromycin could be measured at concentrations higher than 10 pg L 1 using the Charm II6600/7600 assay in water samples proximal to livestock farms. 

Erythromycin, a macrolide antibiotic, lacks a significant chromophore. Detection sensitivity was enhanced by using a wavelength of 200 nm and selecting an injection solvent of lower conductivity than the BGE. In order to facilitate the separation of erythromycin and its related substances, 35% (v/v) ethanol was incorporated into a 150 mM phosphate buffer pH 7.5. Resolution of all of the compounds was achieved in approximately 45 min. The method was employed as an assay method for erythromycin and for impurity determination. Peptide antibiotics, such as colistin and polymyxin, are mixtures of many closely related compounds. A validated CZE method for impurity analysis of polymyxin B was described, employing 130 mM triethanolamine-phosphate buffer at pH 2.5 to reduce the adsorption of analyte onto the capillary wall. Methyl-/l-cyclodextrin (M-/1-CD) and 2-propanol were found to be necessary for selectivity enhancement. Using similar buffer additives, the same group developed and validated a method for colistin analysis. ... 

The application of chromatographic methods to analyze the residues of macrolide antibiotics has been very limited. Moats (85) listed four TLC and one HPLC method for tylosin and one TLC method for erythromycin. In a comparison of the HPLC and microbiological methods for incurred residues in swine, the HPLC method was more sensitive and usually gave higher results (86). 

There are classes of natural products, such as erythromycins (14-membered ring), which contain macrocycles as building blocks and yet which still preserve conformational restrictions. Thus, it is possible to assign configurations using the arsenal of NMR methods. An example is the determination of the stereochemical position of a hydroxy group at C-9 in macrocycle 2 by a comparison of <5( H) and 3/HH values64. ... 

Erythromycin A, a widely used, macrolide, antibiotic substance, was crystallized as the hydriodide dihydrate. It would be expected that the iodine atom would be used as the heavy atom in solving the structure, and, indeed, the authors tried the heavy-atom method first.68 Unfortunately, the iodine atom lies on a crystallographic mirror-plane, and so this method failed. Because erythromycin con-... 

Coupling of LC with either ISP-MS or ISP-MS-MS has been also investigated as an attractive alternative for the determination of erythromycin A and its metabolites in salmon tissue (122). The combination of these methods permitted identification of a number of degradation products and metabolites of erythromycin, including anhydroerythromycin and N-demethyerythromycin at the level of 10-50 ppb. 

Several microbiological methods have been reported for analyzing residues within the groups of sulfonamides, tetracyclines, macrolides, and -lactams in fish tissues however, references for these groups of compounds are limited to sulfadiazine and trimethoprim, oxytetracydine and chlortetracycline, erythromycin, and ampicillin, respectively. 

Microbiological methods reported for detection of erythromycin in fish are based either on a cylinder plate assay using Sarcina lutea (ATCC 9341) (122),... 

Electrochemical detection is better suited to the analysis of erythromycin and lincomycin. This method of detection has been applied for the determination of erythromycin A (139) and lincomycin (154) residues in salmon tissues. Liquid chromatography coupled with mass spectrometry is particularly suitable for confirmatory analysis of the nonvolatile macrolides and lincosamides. Typical applications of this technique are through thermospray mass spectrometry, which has been used to monitor pirlimycin in bovine milk and liver (141,142), and chemical ionization, which has been applied for identification of tilmicosin (151) in bovine muscle, and for identification of spiramycin, tylosin, tilmicosin, erythromycin, and josamycin residues in the same tissue (150). 

LIQUID CHROMATOGRAPHIC METHODS Erythromycin A Salmon ACN extn, liq-liq flesh... 

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