The action mechanism of a new candin antifungal agent, micafungin (MCFG), which was developed as the sixth antifungal agent in Japan, differs from that of conventional antifungal agents, and this agent may be clinically useful. MCFG has a broad spectrum against Candida and Aspergillus in vitro by inhibiting the biosynthesis of the main constituent comprising the fungal cellular wall, 1,3-b-D glucan.1,2) As this agent shows favorable lung transfer, 3) it may be useful for preventing and treating pulmonary mycosis.We previously reported the efficacy of this agent and the incidence of side effects in 17 patients with hematological diseases to whom MCFG was administered to treat/prevent pulmonary aspergillosis. 4) Our study suggested that 150 mg or more of MCFG is required to treat/prevent pulmonary aspergillosis; however, the necessity of adjusting the dose in patients with liver/kidney hypofunction and the presence or absence of interactions with other agents remain to be clarified. As an immunosuppressive agent, tacrolimus , is administered to patients after hematopoietic stem cells transplantation from non-relatives for a long period, it should be confirmed whether interactions related to combination therapy with MCFG appear.In this study, we measured the blood level of MCFG in 29 patients with hematological diseases, and analyzed the data. We report findings regarding administration to patients with liver/kidney hypofunction and combination therapy with FK-506. MATERIALS AND METHODS SubjectsThe subjects were 29 patients who were admitted to the First Department of Internal Medicine (Department of Hematology) in Nagano Red Cross Hospital between February 2003 and October 2004. Written informed consent regarding the measurement of the blood MCFG level was obtained from the patients or their families. As a rule, blood was collected 3 d or more after the start of administration, when MCFG reached a steady state, to obtain a trough value. If necessary, blood was collected in accordance with the general condition.Informed Consent In obtaining informed consent from the patients or their families, we paid attention to protect the patients' rights according to the Helsinki declaration. In addition, it was explained that blood samples were not used for purposes other than this study. The Ethics Committee in our hospital approved this study.Preparation of the Solutions A standard solution of MCFG and a solution containing an internal standard substance (IS), FR195743, were supplied by Fujisawa Pharmaceutical Co., Ltd. MCFG was dissolved in ethanol at a concentration of 100 mg/ml, and the standard stock solution thus prepared was stored at Ϫ20°C. The IS was dissolved in 0.02 mol/l potassium dihydogenphosphate/acetonitrile (50/50, v/v) at a concentration of 100 mg/ml, and the IS stock solution thus prepared was stored at 4°C. The standard stock solution was diluted with ethanol to make standard working solutions at a concentration of 25, 10, 2.5, 1, 0.25, and 0.05 mg/ml, respectively. The IS stock solution was diluted with ...
Background/purpose Chemotherapy is important for cancer treatment, but patients’ physical and mental stress may lead to unfavorable pain control, an increase in the risk of relapse, and a reduction in the quality of life (QOL). Recently, aromatherapy has been performed in addition to palliative care in many countries, such as Japan and the United States, but scientific evidence remains insufficient. To investigate the usefulness of aromatherapy as complementary and alternative medicine, we evaluated its influence on the immune and autonomic nervous systems. Methods We instructed healthy volunteers to inhale aroma oil at bedtime for 6 weeks, and measured changes in the salivary level of secretory immunoglobulin A (s-IgA). Furthermore, blood was collected in addition to saliva in some healthy volunteers, and the blood level of noradrenaline (NA) was measured to examine its relationship to changes in the salivary s-IgA level. Results Aromatherapy with lavender and grapefruit oils significantly increased the salivary s-IgA level: lavender oil increased 3.5-fold ( p = 0.03), and grapefruit oil increased 2.55-fold ( p = 0.04). On lavender oil inhalation, there was a weak, positive correlation between changes in the salivary s-IgA level and those in the blood NA level (R 2 = 0.24). Conclusion The results showed that aromatherapy with lavender and grapefruit oils reduced stress by acting on the immune and autonomic nervous systems in healthy volunteers. In the future, its clinical usefulness must be investigated through similar examination in patients in whom the stress level may be high.
Voriconazole, (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol, is a widespectrum triazole antifungal agent (Fig. 1a). It selectively inhibits cytochrome P450 (CYP) dependent 14a-demethylase, which is a key enzyme in the fungal sterol biosynthesis pathway, specifically the conversion of lanosterol to ergosterol within the membrane component. Compared with other azole compounds, voriconazole shows a broader-spectrum antifungal activity, and it therefore can be used to treat severe or serious fungal infections, e.g., Candida spp., Aspergillus spp., Cryptococcus spp.2-4) Voriconazole is metabolized hepatically, primarily via the CYP isoenzymes CYP2C9, CYP2C19 and CYP 3A4. 4,5) The metabolites of voriconazole do not have antifungal activity. The CYP2C19 isozyme, which acts in the major metabolic pathway for voriconazole, exhibits significant genetic polymorphism, and consequently a number of poor metabolizers (PMs) are found. Potent interactions with voriconazole by CYP isozymes also affect the plasma levels of voriconazole. 5,6) The PMs are found with much higher frequency (18 to 23%) in the Japanese population than in North American and European white populations (3 to 5%). 7,8) Since the PMs result in increased plasma levels of voriconazole, 5,6) it is important to determine the concentration of voriconazole in human plasma to avoid side effects of voriconazole treatment, such as photopsia, skin rashes, liver dysfunction and so on. Studies concerning the safety, tolerability and pharmacokinetics of intravenous and/or oral dosing regimens of voriconazole demonstrated that voriconazole was generally safe and well tolerated, and it exhibited nonlinear pharmacokinetics. 9,10) Therapeutic monitoring of voriconazole in plasma, therefore, might be warranted in some patients who are at higher risk, especially due to PMs of the CYP2C19 genotype.Several methods including high-performance liquid chromatography (HPLC) combined with mass spectrometry, 11) or with UV detection, [12][13][14][15][16] and bioassay, 16) have been reported to determine voriconazole in biological fluids. The previously reported HPLC-UV methods are clinically useful, but sample pretreatment methods such as solid phase extraction 13) or a solvent extraction 15,16) followed by evaporation under nitrogen stream are required for the assay. Such tedious procedures are undesirable for many clinical applications, whereas an on-line HPLC method with direct plasma injection would be much more convenient. Therefore, there have been developed two methods; one is size exclusion chromatography coupled with a reversed-phase HPLC system with column-switching, 12) and another is a direct plasma injection HPLC micro method using an internal surface reversed-phase column. 14)In this paper, we describe a simple column-switching HPLC system with a direct plasma injection that does not involve any complicated pretreatment. We have used this system to study the pharmacokinetics of voriconazole in healthy volunteers following a sin...
We previously reported that a 150 mg or higher daily dose is necessary for treatment of pulmonary aspergillosis with micafungin (MCFG) alone in patients with blood diseases. Since a delay in the treatment of pulmonary aspergillosis has a major influence on patient survival, clarification of the effective blood concentration of MCFG enables rapid treatment. Establishment of an appropriate dose is also useful for reducing the risk of adverse effects, such as MCFG-induced impairment of liver function. Aiming for the rapid and safe treatment of pulmonary aspergillosis, we established new clinical diagnostic criteria of mycosis and MCFG therapeutic effect judgment criteria, and investigated the effective blood concentration of MCFG for mycosis. The blood trough level of MCFG in patients with blood diseases at each clinical improvement rating of pulmonary aspergillosis was 5.23؎2.44 m mg/ml in markedly improved cases, 4.08؎2.63 m mg/ml in improved cases, and 3.45؎1.63 m mg/ml in successfully prevented cases, showing no significant difference among the 3 groups. Based on this finding, it is advisable to target a 5 m mg/ml or higher blood trough level of MCFG in establishing the dose for aspergillosis in patients with blood diseases.
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