Futoshi Yamazaki

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.

Comparison of Lipiodol Water‐m‐Oil‐m‐Water Emulsion and Oil‐in‐Water Emulsion: Acute Toxicity and Deposition in Liver after Hepatic Arterial Administration in Rats

Lipiodol is an oily contrast medium widely used as an embolizing material for transcatheter arterial embolization (TAE) therapy, an effective method for treating unresectable hepatocellular carcinoma. We investigated the acute toxicity and deposition in the liver of lipiodol water-in-oil-in-water (w/o/w) emulsion encapsulating epirubicin hydrochloride after hepatic arterial administration to rats, and compared results with those of the oil-in-water (o/w) emulsion conventionally used for TAE therapy. Deposition was detected by means of an X-ray CT scanner. It was, therefore, suggested that the dose of the emulsions would be controllable by monitoring them during the surgical operation. The concentration of epirubicin hydrochloride in the liver was increased and its residence was prolonged by encapsulating it in the w/o/w emulsion membranes. The toxic effects of epirubicin hydrochloride and lipiodol on the normal hepatic cells were reduced, resulting in a decrease in both glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activity. Consequently, an enhanced therapeutic effect of w/o/w emulsion would be expected compared with the conventional o/w emulsion, owing to the sustained release of the agent and the targeting property of lipiodol to the malignant cells. It was concluded that the w/o/w emulsion is a suitable formulation for chemoembolization therapy.

The Prescription Plan of Intravenous Hyperalimentation for HPN(IV) : A Long-term Test on the Residual Ratio of Insulin in Single and Twin Bags Prepared for TPN

We herein report a case in which insulin was added to a high-calorie infusion preparation administered for 7 days to patients with HPN. In our previous study, the residual ratio of insulin was measured based on the formula ; Hicaliq® solution-No.2 (700mL) +Proteamin® 12X (200mL) + 10% NaCl (20mL). As a result, the residual ratio decreased daily until the 7th day.In the present study, the residual ratio of insulin was measured in the infusion bags and the drip solution of other high-calorie infusion solutions ; Unicaliq® N and Aminotripa® No.2.The residual ratio of insulin in the drip solution of Unicaliq® N began to decrease gradually from the 3rd day, and it decreased to approximately 71 % on the 7th day. In contrast, there were no successive decreases in residual ratio of insulin during the 7day period in either the infusion bags or drip solution of Aminotripa® No.2.The residual ratio was constant at approximately 85%. In other words, with Unicaliq® N, as with Hicaliq® solution-No.2, the residual ratio of insulin decreased due to a decrease in the daily insulin titer. Based on these findings as determined using the above formulas, the control of blood sugar level may be hindered on the 5th day and thereafter. Conversely, with Aminotripa® No.2, the residual ratio of insulin did not decrease for 7days.Therefore, Aminotripa® No.2 seems to be the most appropriate formula among the three evaluated ones for the high-calorie infusion in patients undergoing HPN, when the stability of insulin is regarded as important.

Appropriate Medication according to the Research of Medicinal History.

After tracking the of medicinal treatments administered to hopitalized patients under pharmaceutical care at a surgery ward for a one year period from November 1994 to October 1995, we analyzed the risk of interaction with other drugs. Based on the results of our data, we made the following conclusions:(1) We concluded that multiple combination medicinal therapy tended to a patients QOL (quality of life), in addition to the effects by frequent injections and high dosages of many other drugs, and such treatment also incresed the possibility of a crisis due to drug interaction.Therefore, when any prescribed drugs are suspected to be ineffective the doctor should immediately determine whether or not they are appropriate.(2) As for drug interaction, the details of the results of our analysis were sent to the doctors in writing in order to heighten therefore, whenever drugs were used in combination by the doctors, their awareness, the safety of their combined use should be carefully checked to avoid any dangerows combinations.As a result, we were able to reduce the adverse effects of inappropriate drug combinations and their harmful in teractions.