Eiseki Usami

Inhibition of Tumor Necrosis Factor-alpha and Interleukin-1-beta Production by Beta-adrenoceptor Agonists from Lipopolysaccharide-stimulated Human Peripheral Blood Mononuclear Cells.

The effects of beta-adrenoceptor agonists (beta-agonists) on the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-8 (IL-8) by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) were investigated. The beta-agonists, procaterol, clenbuterol, fenoterol and terbutaline, inhibited TNF-alpha and IL-1 beta production in a concentration-dependent manner, whereas they had no effect on IL-8 production. TNF-alpha production was inhibited more potently than IL-1 beta. Dibutyryl cyclic AMP (dbcAMP) also inhibited the production of TNF-alpha and IL-1 beta, but not IL-8. TNF-alpha production was almost completely inhibited by dbcAMP, whereas IL-1 beta production appeared to be partially refractory even at the highest concentration examined. Both procaterol and theophylline elevated cAMP levels in LPS-stimulated PBMCs, but the effect of procaterol was limited. The inhibition of TNF-alpha and IL-1 beta production by procaterol was additively potentiated with theophylline. dl-Propranolol, a beta-adrenoceptor antagonist, abrogated the inhibition of TNF-alpha and IL-1 beta production by procaterol. These results indicate that beta-agonists inhibit the production of proinflammatory cytokines, such as TNF-alpha and IL-1 beta, by elevating intracellular cAMP levels. These properties of beta-agonists might be beneficial in the treatment of allergic inflammation.

Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells.

1. The effects of cAMP-phosphodiesterase (PDE) isozyme inhibitors on the production of tumor necrosis factor alpha (TNF-alpha), and interleukins 1 beta 8 (IL-1 beta and IL-8) by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) were evaluated. In addition, we investigated the effects of dibutyryl cAMP (dbcAMP) and beta-adrenergic receptor agonist on the production of these cytokines. 2. Type IV PDE inhibitors were more effective at inhibiting the production of TNF-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. In contrast, these agents had no effect on IL-8 production. 3. Increasing concentrations of dbcAMP progressively reduced the production of TNF-alpha and IL-1 beta but not IL-8. 4. The addition of beta-agonist increased the inhibitory effect of PDE inhibitors tested on the production of TNF-alpha and IL-1 beta. 5. Type IV PDE inhibitors could be potent pharmacological agents for the treatment of diseases in which TNF-alpha and IL-1 beta are important etiological factors.

Immunomodulatory Action of Levofloxacin on Cytokine Production by Human Peripheral Blood Mononuclear Cells

Levofloxacin (LVFX), the bacteriologically active isomer of ofloxacin, is a fluorinated quinolone. LVFX suppressed the proliferative activity of peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA). LVFX increased interleukin-2 (IL-2) production by PBMC stimulated with PHA in a dose-dependent manner, with more than 10 micrograms/ml of LVFX causing a significant increase. The granulocyte-macrophage colony-stimulating factor and soluble IL-2 receptor production by PHA-stimulated PBMC was suppressed at high concentrations of LVFX. Interleukin-1 beta production by lipopolysaccharide-stimulated PBMC was suppressed in a concentration-dependent manner by LVFX, and tumor necrosis factor-alpha production was suppressed at only the highest concentration. In contrast, interleukin-8 production was little affected by LVFX. These results show that LVFX has an immunomodulatory action on cytokines production by PBMC independent of its antimicrobial activity.

Modulation of Th1- and Th2-Like Cytokine Production from mitogen-stimulated Human Peripheral Blood Mononuclear Cells by Phosphodiesterase Inhibitors.

1. Effects of phosphodiesterase (PDE) inhibitors on the production of IFN-gamma, IL-2, IL-4 and IL-5 by phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMC) were investigated. In addition, we investigated the effects of dibutyrylcyclic AMP (dbcAMP) and a beta-adrenoceptor agonist on production of these cytokines. 2. Type IV, type III and nonselective PDE inhibitors were effective at inhibiting the production of IFN-gamma and IL-2 production in a dose-dependent manner. In contrast, IL-4 and IL-5 production was inhibited by only the highest concentration of type IV inhibitor, and other agents had no effect on the production. 3. Similarly, dbcAMP inhibited the production of IFN-gamma and IL-2 more potently than IL-4 and IL-5. 4. The addition of a beta-adrenoceptor agonist increased the inhibitory effect of PDE inhibitors tested on the production of IFN-gamma and IL-2. 5. These results indicate that PDE inhibitors or cAMP-elevating agents modulate Th1 cytokine more effectively than Th2 cytokine production.

Oral anticancer agent medication adherence by outpatients

In the present study, medication adherence and factors affecting adherence were examined in patients taking oral anticancer agents. In June 2013, 172 outpatients who had been prescribed oral anticancer agents by Ogaki Municipal Hospital (Ogaki, Gifu, Japan) completed a questionnaire survey, with answers rated on a five-point Likert scale. The factors that affect medication adherence were evaluated using a customer satisfaction (CS) analysis. For patients with good and insufficient adherence to medication, the median ages were 66 years (range, 21–85 years) and 73 years (range, 30–90 years), respectively (P=0.0004), while the median dosing time was 131 days (range, 3–3,585 days) and 219 days (24–3,465 days), respectively (P=0.0447). In 36.0% (62 out of 172) of the cases, there was insufficient medication adherence; 64.5% of those cases (40 out of 62) showed good medication compliance (4–5 point rating score). However, these patients did not fully understand the effects or side-effects of the drugs, giving a score of three points or less. The percentage of patients with good medication compliance was 87.2% (150 out of 172). Through the CS analysis, three items, the interest in the drug, the desire to consult about the drug and the condition of the patient, were extracted as items for improvement. Overall, the medication compliance of the patients taking the oral anticancer agents was good, but the medication adherence was insufficient. To improve medication adherence, a better understanding of the effectiveness and necessity of drugs and their side-effects is required. In addition, the interest of patients in their medication should be encouraged and intervention should be tailored to the condition of the patient. These steps should lead to improved medication adherence.

Evaluation of hypokalemia and potassium supplementation during administration of liposomal‑amphotericin B

Patients prescribed liposomal-amphotericin B (L-AMB) frequently require supplemental potassium to prevent hypokalemia. The aim of this retrospective study was to examine the appropriate potassium supplementation conditions to treat hypokalemia induced by L-AMB. The subjects were 100 hematological patients who received L-AMB for the first time between April 2012 and March 2013. A total of seven patients were excluded. Of the remaining 93 patients, 48 (51.6%) were assigned to the group receiving supplemental potassium (supplementation group), and 45 (48.4%) were assigned to the group without potassium supplementation (non-supplementation group). Hypokalemia greater than grade 3 was exhibited by 50 of the 93 (53.8%) patients. Multivariate analysis revealed that the minimum serum potassium levels during L-AMB administration (≤2.98 mEq/l) were an independent factor significantly contributing to the effectiveness of potassium supplementation [odds ratio (OR), 3.62; 95% confidence interval (CI), 1.44–9.59; P<0.01]. In addition, multivariate analysis revealed that the serum potassium levels (≥2.83 mEq/l) prior to the potassium supplementation were an independent factor significantly contributing to the development of proper potassium supplementation (OR, 14.21; 95% CI, 1.95–310.72; P=0.02), and no significant difference was observed in the dosage of the potassium supplementation administered to the patients who recovered from hypokalemia and those who did not. In conclusion, it is necessary to begin potassium supplementation prior to the reduction of the serum potassium levels to <2.83 mEq/l. Potassium supplementation at an early stage of L-AMB treatment is important to prevent severe electrolyte abnormalities.

Pharmaceutical Care for Patients Undergoing S-1 Plus Cisplatin Therapy for Unresectable Recurrent Gastric Cancer

We examined the adverse gastrointestinal events associated with tegafur/gimeracil/oteracil potassium (S-1) plus cisplatin therapy for unresectable recurrent gastric cancer and risk factors for discontinuing therapy due to adverse events. A total of 65 subjects who had received S-1 plus cisplatin therapy for gastric cancer at Ogaki Municipal Hospital were examined. We found that the risk factors for discontinuation of the therapy due to adverse events were serum albumin (Alb) level less than 3.5 g/dL (odds ratio [OR]: 321.14, P = .0015), creatinine clearance (CrCl) rate less than 78 mL/min (OR: 35.23, P = .0123), and performance status (PS) more than 1 (OR:12.62, P = .0243). Moreover, grade 3 or 4 nonhematological toxicities (including malaise and anorexia) were significantly higher in subjects with Alb less than 3.5 g/dL and CrCl less than 78 mL/min (P < .01). In conclusion, we should pay attention to the safety and continuity of S-1 plus cisplatin therapy in cases where the Alb level is <3.5 g/dL, CrCl level is <78 mL/min, and PS level is >1. Pharmacists should consider reducing the treatment dosage and providing nutritional support in such cases.

Evaluation of the role and usefulness of a pharmacist outpatient service for patients undergoing monotherapy with oral anti-cancer agents

Introduction When rapid feedback to physicians must be provided, e.g. monitoring therapy with the oral anticoagulant warfarin or providing therapeutic support for patients undergoing cancer chemotherapy, the involvement of pharmacists is required for outpatients. We launched a pharmacist outpatient service for patients with cancer taking oral anti-cancer agents. We evaluated the role and usefulness of the pharmacist outpatient service for these patients undergoing oral monotherapy with anti-cancer agents. Methods Data regarding prescription recommendations were collected from the drug management guidance records of 154 patients who consulted the pharmacist outpatient service between July 2013 and September 2015. In addition, the rates of prescription recommendation adherence were calculated. Between April and August 2015, a self-reported questionnaire was administered to 47 patients undergoing therapy with oral anti-cancer agents who were visiting the pharmacist outpatient service at the Ogaki Municipal Hospital (Ogaki, Japan). Results Prescription recommendations were given to 235 cases. The total rate of adherence to the prescription recommendations was 94.9% (223/235 cases). The majority of prescription recommendations regarding supportive care were those for moisturizing agents (20.9%), analgesics (20.9%), steroid ointments (12.7%), and antihypertensive agents (10.8%). When continued guidance was provided, significant changes were observed for survey items 3 (knowing the side effects of the medication), 8 (worrying about side effects), and 12 (interest in prescribed medicine) (p = 0.0049, p < 0.0001, and p = 0.0164, respectively). Conclusion Our study showed that continued pharmaceutical intervention resulted in a deeper understanding of the medications’ side effects, and it reduced anxiety levels in patients undergoing monotherapy with oral anti-cancer agents.

Analysis of the incidence of tumor lysis syndrome in patients with hematological malignancies treated with rasburicase

The purpose of this study was to assess the incidence of tumor lysis syndrome (TLS) in patients with hematological malignancies treated with rasburicase, and to evaluate the dose and duration of rasburicase administration. A total of 52 patients were enrolled. The background of the patients, incidence of TLS and laboratory data were retrospectively examined; in addition, the dose and duration of rasburicase administration and the factors affecting the onset of TLS were evaluated and compared among TLS risk categories. During the study period, 2 (3.8%) of the patients developed clinical TLS and 24 (46.2%) developed laboratory TLS (LTLS). Although the LTLS rate was very high, there were no life-threatening cases of TLS. The median daily dose of rasburicase administered to all patients was 7.5 mg/day (interquartile range, 7.5-9.0 mg/day), and the daily weight-based dose was 0.147 mg/kg/day (range, 0.126-0.178 mg/kg/day). The administration duration was 3 days (interquartile range, 3-4 days). Additionally, there was no significant association between TLS risk classification and daily rasburicase administration dose, duration, or post-administration laboratory data. The factors affecting the onset of TLS included serum uric acid level, as well as serum creatinine and phosphate levels. Rasburicase was highly effective in the prevention and management of hyperuricemia, even at a low-dose (7.5 mg/day) and a duration that was 3 days shorter compared with that recommended by the manufacturer. Therefore, clinicians should administer rasburicase based on their clinical judgment, taking into consideration the cost-effectiveness of this therapy.

Usefulness of a pharmacist outpatient service for S‑1 adjuvant chemotherapy in patients with gastric cancer

S-1 adjuvant chemotherapy is an outpatient treatment for gastric cancer. To evaluate the role of the pharmacist outpatient service in increasing medication adherence and reducing adverse events associated with S-1, the present study retrospectively analyzed prescription recommendations from pharmacists to physicians and the persistence rate of S-1 adjuvant chemotherapy use in patients with gastric cancer. A total of 40 subjects who utilized the pharmacist outpatient service between November 2014 and March 2016 comprised the pharmacist group; and 94 patients who underwent S-1 adjuvant chemotherapy for gastric cancer between September 2012 and October 2014, but not as pharmacist outpatients, comprised the control group. Data on the prescription recommendations, persistence rate of S-1 adjuvant chemotherapy for 1 year and relative dose intensity were collected. The number of interventions and consultations for the pharmacist outpatient group were 40 and 644, respectively. Prescription recommendations regarding dosage, drug administration interval, and supportive therapy were provided in 62, 15 and 132 cases, respectively. The prescription proposal acceptance rate was 92.5%. The persistence rate of S-1 adjuvant chemotherapy for 1 year was significantly higher in the pharmacist group (82.5%) compared with the control group (39.4%; P<0.0001). The discontinuation rate due to adverse events was significantly lower in the pharmacist group (7.5%) compared with the control group (31.9%; P=0.0015). In subjects who completed S-1 adjuvant chemotherapy, the relative dose intensities in the control and pharmacist groups were 82.9 and 84.7%, respectively. In conclusion, the continued pharmaceutical intervention ensured a high persistence rate of S-1 adjuvant chemotherapy.