Toshiya Nakao

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.