UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

BACKGROUND: Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. METHODS: Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. CONCLUSION: This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

A case of improvement of clozapine-induced low leukocyte counts by adenine, cepharanthin and ninjin-yoei-to in a patient with treatment-resistant schizophrenia.

BACKGROUND: Although clozapine is the optimal drug for patients with treatment-resistant schizophrenia, the drug has harmful adverse effects such as leukopenia. Adenine and cepharanthine are known to be effective for radiation- or drug-induced leukopenia. Furthermore, ninjin-yoei-to, a Chinese herbal medicine, augments the production of granulocyte-macrophage colony-stimulating factor. Thus, these drugs may be useful for clozapine-induced leukopenia. CASE PRESENTATION: A 21 years-old woman with schizophrenia was hospitalized for initiation of clozapine treatment. Despite concomitant use of adenine, cepharanthine, and lithium carbonate having activities of increasing leukocytes, a decrease in leukocyte counts occurred after the initiation of clozapine. Additional administration of ninjin-yoei-to increased leukocyte counts, which prevented the development of leukopenia. CONCLUSIONS: This is the first case that concomitant use of adenine, cepharanthin, and ninjin-yoei-to exhibited the effectiveness of reversing the decrease in leukocytes caused by clozapine. Monitoring leukocyte counts and preventing leukopenia are essential for successful treatment with clozapine for refractory schizophrenia. These medicines may be a potential option for preventing clozapine-induced leukopenia.

Interaction between Pirenzepine and Ninjinto, a Traditional Japanese Herbal Medicine, on the Plasma Gut-Regulated Peptide Levels in Humans.

The Japanese herbal medicine (Kampo) Ninjinto has been used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia. The pharmacological effects of Ninjinto on the gastrointestine are due to changes in the levels of gut-regulated peptide, such as motilin, somatostatin, calcitonin gene-related peptide (CGRP), substance P, and vasoactive intestinal polypeptide (VIP). The release of these peptides is controlled by acetylcholine (ACh) from the preganglionic fibers of the parasympathetic nerve. Thus, we examined the effects of the selective M1 muscarinic receptor antagonist pirenzepine on the elevation of Ninjinto-induced plasma the area under the plasma gut-regulated peptide concentration-time curve from 0 to 240 min (AUC0→240 min) in humans. Oral pretreatment with pirenzepine significantly reduced the Ninjinto-induced elevation of plasma motilin and substance P release (AUC0→240 min). Combined treatment with Ninjinto and pirenzepine significantly increased the release of plasma somatostatin (AUC0→240 min) compared with administration of Ninjinto alone or placebo. Ninjinto appeared to induce the release of substance P and motilin into plasma mainly through the activation of M1 muscarinic receptors, and pirenzepine may affect the pharmacologic action of Ninjinto by the elevation of plasma substance P, motilin, and somatostatin.