Isolation, identification and in silico toxicity predictions of two isomers from cefotiam hydrochloride.

Two structural isomers of cefotiam in cefotiam hydrochloride for injection were observed, and the structures of the isomers were determined by mass spectrometry and various 1D and 2D NMR techniques. The thermo-isomerization mechanism of cefotiam was also discussed. Thermo-isomerization occurred not only in cefotiam but also in cephalosporins containing a 1-alkyl-1H-tetrazole-5-thiol side chain at C-3. Furthermore, the toxic effects of the two impurities of cefotiam hydrochloride were predicted and it is thought that they could be more toxic than cefotiam. The results reported in this article may be important for quality control and stability studies of this class of drugs.

[Determination of unknown impurities in cefotiam hexetil by HPLC-MS/MS].

OBJECTIVE: To detect unknown impurities in raw drug material of cefotiam hexetil. METHODS: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed for the determination of impurities in cefotiam hexetil. Agilent SB-C18 column (150 mm x 2.1 mm i. d. , 3.5 microm particles) was used for chromatographic separations of cofotiam hexetil dissolved in deionized water, with mobile phase consisting of (A) 0.1% formic acid and (B) acetonitrile and timed gradient program T (min)/B (%): 0/3, 5/3, 15/20, 20/40, 30/60, 40/80. The flow rate was set at 0. 3 mL/min with DAD detector wavelength fixed at 254 nm. Electrospray ionization source was applied and operated in positive ion MRM mode. The source voltage was kept at 4 kV and cone voltage was 100 V with the mass range m/z 50-1000. Nitrogen was used as nebulizing gas and the nebulizer pressure was 40 psi. The drying gas temperature was 350 degrees C and the drying gas flow was 10 L/min. Results Unknown impurities of cefotiam hexetil were identified. Substance 1 was delta3-isomer of cefotiam hexetil. The structures of 3 other substances were also determined. CONCLUSION: The method is sensitive, rapid and credible for the analysis of cefotiam hexetil and its related impurities, which can be applied in quality control of cefotiam hexetil.

Effect of side chains including the N-methyl-tetrazole-thiol group of beta-lactam antibiotics on transport in cultured kidney epithelial cells LLC-PK1.

In this study, the transcellular transport characteristics of four beta-lactam antibiotics (cefotaxime, cefmenoxime, cefmetazole, and cefotiam) were investigated in a kidney epithelial cell line LLC-PK1, especially focusing on the effect of the N-methyl-tetrazole-thiol (NMTT) group attached to 7-amino-cephalosporanic acid. There were no directional differences between the apical-to-basolateral and basolateral-to-apical transport of cefotaxime, cefmenoxime, and cefmetazole, suggesting that the NMTT group does not influence the transcellular transport behaviors of beta-lactam antibiotics. In contrast, cefotiam transport across LLC-PK1 cell monolayers was 1.3-fold greater in the basolateral-to-apical direction than in the apical-to-basolateral direction. It is considered that the ionization of nitrogen in the N-dimethylaminoethyl group attached to NMTT is a factor in the secretory-oriented movement of cefotiam. The transcellular transport of cefotiam in both directions was significantly depressed at a low temperature (4 degrees C) and by 2,4-dinitrophenol. The basolateral-to-apical transport of cefotiam was also shown to be concentration-dependent. These results suggest that a specialized transport process might participate in the transcellular transport of cefotiam. The lipophilicities of these beta-lactam antibiotics were not correlated to the degree of transcellular transport, directly.

Cefotiam-induced IgE-mediated occupational contact anaphylaxis of nurses; case reports, RAST analysis, and a review of the literature.

Cefotiam (CTM) is one of the most popular cephem antibiotics in Japan. Recently we experienced two cases of nurses with CTM-induced contact anaphylaxis. When they were preparing drip infusions of antibiotics or working around other nurses doing so, they suddenly fell into shock with other symptoms such as flushing, urticaria, abdominal distress, vomiting, dyspnoea and/or loss of consciousness. The symptoms never occurred after they avoided exposure to CTM. Passive cutaneous or open patch tests were positive for CTM. Histamine release was induced by CTM from washed leucocytes. RAST analysis using CTM-human serum albumin-coupled discs showed high % RAST count, suggesting that these reactions were mediated by IgE antibodies. A RAST inhibition test suggested that the methyl-thiotetrazole side-chain was the main antigenic determinant. Both patients had hand dermatitis that had appeared preceding the episodes of anaphylaxis. Although the dermatitis had been resistant to treatments, it also disappeared after they avoided exposure to CTM. It seemed likely that it was also induced or exacerbated by CTM and facilitated the penetration of CTM to cause anaphylaxis. The literature is also reviewed.