Kazuyoshi Nakazawa

A Randomized Controlled Trial of Sublingual Immunotherapy for Japanese Cedar Pollinosis

Background: Japanese cedar pollen represents an important and unique allergen. Sublingual immunotherapy (SLIT) has been suggested to be a highly effective route of desensitization against a variety of allergens. However, little information is available about its use in cedar pollen allergy. Methods: A blinded randomized, placebo-controlled trial employing SLIT for cedar pollinosis was conducted over a period of 6 months. Sixty-seven subjects were enrolled and the symptom scores during the pollen season were evaluated by a symptom diary, measurement of cedar-specific IgE and IgG4, and determination of Cry j-specific Th2 clones before SLIT and before and after the pollen season. Results: No major adverse effects were observed in either group. The serum-specific IgG4 activity increased significantly after SLIT in the active group. The active group also exhibited significantly lower symptom scores compared to the placebo. The specific Th2 clone sizes were not significantly different between the groups before the pollen season. However, an increase in the clone size was observed after the pollen season in the placebo group, but not in the active group. Conclusion: Use of SLIT for Japanese cedar pollinosis was found to be safe and associated with an increase in cedar-specific IgG4 levels. Such therapy inhibited the increase in Cry j-specific Th2 clone size induced by pollen exposure. Finally, use of SLIT resulted in significant improvement of the clinical symptoms of cedar pollinosis in this patient population. These observations suggest that SLIT may offer another safe approach to the management of cedar pollinosis.

Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation.

The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.

The Leaching of Diethylhexyl Phthalate from the Administration Set into the Intravenous Cyclosporine Solutions.

We investigated the leaching of diethylhexyl phthalate (DEHP, a plasticizer of polyvinyl chloride) from a polyvinyl chloride container or an administration set into intravenous cyclosporine solutions. The concentration of DEHP was measured by high-performance liquid chromatography. A linear relation was found between the amount of DEHP dissolved from the administration set into the aqueous solution and the concentration of polyoxyethylated castor oil within the range of 2.5-12.5mg/ml. The amount of DEHP dissolved from the polyvinyl chloride bag into solutions increased with time, and after 24 hours at initial cyclosporine concentration of 1.0mg/ml, 76.7μg/ml of DEHP was found in the solution.When the cyclosporine solution was passed through the administration set with 100cm in length at a flow rate 0.58ml/min and with the initial cyclosporine concentration of 500μg/ml, the concentration of DEHP in the solution was incresed to as much as about 5.8μg/ml in 30 min, and the same level continued till 180min.

The loss of diazepam from solutions into the administration set.

The mechanism of diazepam loss into the administration set was investigated in equilibrium and kinetic studies.A linear relation was found between the absorbed amount of diazepam by the administration set and the equilibrium concentration within the range of 4.0-20.0μg/ml at 30°C.This result suggests that diazepam loss into the administration set occurs through a mechanism of partition and diffusion similarly to isosorbide dinitrate or nitroglycerin.When the diazepam solution was passed through the administration set at a flow rate of 1.08ml/min, initial concentration 50μg/ml and the length of administration set 100cm, the diazepam concentration was reduced to 62.6% in 10 min, and gradually returned to the initial level with time.it was found that the factors effecting the loss of diazepam were the kind of containers, the length of administration set and the flow rate of intravenous solutions.