Published papers

Oral fluoroquinolones are widely known to form chelate complexes with metal-containing drugs, resulting in inhibition of their intestinal absorption. However, for intestinal sterilization, the concomitant regimen may be a selective and effective strategy due to decreased absorption of fluoroquinolones result in the retainment of antibiotics at the intestine if the mixture still perpetuated antibacterial activity. Therefore, to clarify whether the mixture of fluoroquinolones and sucralfate affects their antibacterial activity or not, we conducted in vitro study. According from the checkerboard study using a microdilution method with Mueller-Hinton broth, the antibacterial activity of these fluoroquinolones-sucralfate mixtures equaled to the parent fluoroquinolones even in the presence of sucralfate at the molar ratio of [sucralfate: fluoroquinolone] was less than 166, and the minimal inhibitory concentrations for clinical isolated Escherichia coli and Pseudomonas aeruginosa strains were independent of the existence of sucralfate. These data imply that the chelated forms of each fluoroquinolone retain antibacterial activity even in the presence of the recommended therapeutic doses of sucralfate in clinical practice.

We performed a prospective study to assess the optimal blood concentration of tacrolimus in Japanese patients with rheumatoid arthritis (RA). The dose of tacrolimus (1-3mg/day) was administered orally once daily after the evening meal, and the blood concentration of tacrolimus 12 hr after administration was quantified. A total of 23 patients were enrolled. Clinical efficacy was assessed using the Disease Activity Score in 28 joints and European League Against Rheumatism (EULAR) response criteria at each outpatient visit during months 1-6. The ratio of patients who showed a moderate or good response was 47.8% (11/23). The mean blood concentrations of tacrolimus in EULAR responders and EULAR non-responders were 5.5±3.6 (mean±S.D.) and 3.1±1.9 ng/ml, respectively (p=0.069). Interestingly, although tacrolimus had lower mean blood concentrations (<5 ng/ml) compared with transplant fields (10-20 ng/ml), six (35.3%) of 17 patients showed sufficient response to tacrolimus. In addition, in five patients, tacrolimus was co-administered with methotrexate (MTX). On the other hand, the mean blood concentrations of tacrolimus in patients who did or did not develop adverse events were 4.8±4.4 (n=8) and 4.0±2.1 (n=15) ng/ml, respectively (p=0.624). We failed to clear the optimal blood concentration of tacrolimus in RA patients, but one of the most remarkable findings was the observation that patients in whom tacrolimus was combined with MTX reached a positive response at much lower tacrolimus concentrations compared to patients not co-treated with MTX.

Infections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (≥38.0°C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.

We performed a retrospective study to examine the preventive effects of newquinolones for endogenous infection in patients receiving various allogeneic hematopoietic stem cell transplantation including bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT). Forty-nine patients were enrolled. Ciprofloxacin or norfloxacin was orally administered for intestinal sterilization from day -14 until engraftment. As a result, the period from transplantation until engraftment was significantly longer in CBT group than in BMT group. The febrile index (the ratio of the febrile (≥38.0°C) period during neutropenia (≤500 cells/mm3) and C-reactive protein (CRP)-positive index (the ratio of CRP-positive (≥2.0 mg/dl) period during neutropenia) were comparable among the three groups. In addition, no gram-negative bacteria in stool was isolated in the three groups; that is, an endogenous infection of gram-negative bacteria, a potential pathogen, was well controlled by newquinolones. We should be careful when interpreting the results of this small study; however, newquinolones are clinically effective for endogenous infection of gram-negative bacteria in patients receiving not only BMT, but also PBSCT and CBT.

Monitoring the adverse reaction patterns specific to individual patients is important to avoid subsequent reactions. Gynecologic cancer chemotherapy is often implemented repeatedly with an altered protocol during prolonged terms. The purpose of this study was to develop and assess the efficacy of a worksheet that pharmacists can use to analyze adverse reaction patterns in individual patients with gynecologic chemotherapy. The worksheet which we developed consisted of multiple sections. One section is for necessary drug information for the proper use of antineoplastic agents. Another section is for the following items recorded by the pharmacists: a) patients' basic information such as stage of disease and protocol, b) state of implementation and break of chemotherapy and supportive therapy on calendar, and c) laboratory data and symptoms. We arranged the last item below the calendar and enabled pharmacists to easily assess individual adverse reactions coupled with the treatment course. Reviews of the developed worksheet indicated that the worksheet led to the convenient detection of individual adverse reaction patterns and effective prevention of additional adverse reactions. This monitoring sheet covering long-term chemotherapy which was designed to predict individual adverse reaction patterns will improve the individualization and safety of gynecologic chemotherapy.

We performed a retrospective study to examine the protective effect of low-dose dexamethasone (DEX) on delayed adverse events induced by carboplatin (CBDCA)-based combination chemotherapy in patients with thoracic tumors. Low-dose DEX (4-8 mg/day) was administered on day 1 and after, in addition to a serotonin 5-HT3 receptor antagonist. The acute adverse events (day 1) were well controlled in the patients with or without co-treatment of DEX. On the other hand, the delayed nausea, emesis, anorexia, and fatigue after day 2 failed to be controlled by 5-HT3 antagonist alone. Co-treatment with DEX significantly suppressed the grade of the delayed adverse events during days 2-10. The mean ratio of complete protection during days 2-10 were significantly higher in the DEX-treated group compared with the non-DEX-treated group. These results reveal that low-dose DEX is a clinically effective treatment for the prevention of delayed adverse events induced by CBDCA-based combination chemotherapy.

The purpose of this study was to assess patient participation in cancer therapy and the sharing of patient information among the medical care team (physicians, nurses, pharmacists, and especially patients). We monitored the side effects of cancer chemotherapy with patients, and developed two support tools: One scored the points of subjective symptoms (fatigue, anorexia, nausea, etc) by patients, and the other recorded objective symptoms (clinical examination data) by pharmacists. It is most important that they attend each patient at their bedside. At this time, the trial was evaluated by questionnaire survey by inpatients receiving cancer chemotherapy (n=15). As a result, all patients (15/15) responded that this trial was necessary. This trial addressed the following: 1) increased communication between patients and medical staff concerning side effects (14/15), 2) increased interest in side effects (10/15), 3) when a patient tells medical staff about side effects, they act on it (10/15). None of the patients felt inconvenienced by scoring every day (0/15), or anxiety about side effects (0/15). Furthermore, all patients (15/15) responded that “participation of pharmacists in cancer chemotherapy” was necessary. This trial revealed no problems and suggested that patients related to the center of medical care. We should be careful in interpreting results of this small sized trial; however, the following conclusions should be reached: 1) introduction of monitoring side effects of cancer chemotherapy with patients, 2) develop communication among the medical care team.

The proclamation of April 2002 of a Ministry of Health, Labor and Welfare ordinance has enabled doctors to prescribe drugs for an outpatient without a limit on the length of prescription terms except for a few drugs. There is a concern that the prescription-term deregulation could cause careless drug therapy management in order to extend the interval between patient hospital visits. The purpose of this study is to make pre- and post-deregulation comparisons of two items, prescription terms and implementation of clinical examination that complied with package-insert precautions, and to discuss the approaches to increase safety. Prescription terms have lengthened progressively. In the pre-regulation period of January to March 2002, the mean prescription term was 19.9 days; in the post-regulation period of July to September 2002, it was 24.9 days; and in July to September 2003, 28.6 days. Even for anti-tumor agents, there were prescriptions over 90 days after deregulation. There was no significant difference between the pre- and post-deregulation compliance ratios for the package-insert precautions in eight drugs of investigated nine. However, one case had a delay in detection of liver dysfunction, which was caused by deviation from the once-a-month testing indicated in the package-insert precautions for prolonged prescription terms. The evidence suggested that the deregulation led to negligent drug therapy management. To assure safe therapy, the following should be addressed: first, sufficient function of a computerized prescriber order entry system and second, creation of a new framework with pharmacists' active involvement such as collaborative therapy management with physicians.

The purpose of this study was to assess the impact by switching co-administered triazole antifungal agent from fluconazole (FCZ) to voriconazole (VCZ) on the blood concentration of tacrolimus (FK506) in patients receiving allogeneic hematopoietic stem cell transplantation. We performed a retrospective study presented as case reports. The blood concentration of FK506 was increased after the switch from FCZ to VCZ, resulting in increase of the concentration/dose (C/D) ratio of FK506. Thus, the mean C/D ratios of FK506 with oral administration was surprisingly increased over 4.5-fold after the switch. Therefore, it was necessary to reduce the FK506 dose when co-administered FCZ is switched to VCZ. We should be careful when interpreting the results of these case reports; however, in some patients, it is recommended that the dose of FK506 be reduced to one-fifth after the switch.