Yasunori Yamashita

Structural significance of azaheterocyclic amines related to Parkinson's disease for dopamine transporter

We have evaluated the neuronal uptake of 12 neutral and quaternary azaheterocyclic amines that are possible candidates for idiopathic Parkinsons disease via dopamine transporter of striatal synaptosomes. The double-reciprocal plots for dopamine transporter obtained from Wistar rat and C57BL/6 mouse synaptosomes with N-methyl-4-phenylpyridinium cation (MPP+) as a substrate were identical to each other. Neutral beta-carbolines and tetrahydroisoquinolines were unfavorable substrates for dopamine transporter. The quarternization of these compounds strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Although catechol tetrahydroisoquinolines were weak substrates, their quarternization reduced their original properties as substrates for dopamine transporter. These results provide both topographic and electrogenic information of azaheterocyclic amines for the dopamine transporter-mediated influx. The intramolecular distance between the N-atom and the centroid of the benzene ring could be an important factor for the recognition of binding site of dopamine transporter, and an adequate net charge similar to dopamine would be further required for translocation into the cells.

The Evaluation of Transdermal Nitrate Tape Preparations on their Side Effects for Skin Irritation, Efficacies and Costs. The Determination of Water Permeability and Exfoliation of Stratum Corneum.

In recent years, transdermal tape preparations have been widely used for numerous patients. A major problem related to the use of such tape is skin irritation. This adverse event is considered to be due to the impermeability of water through the tape material during adhesion and the occurrence of skin, eruption after its removal. As a result, the water permeability of the tape materials and the amounts of stratum comeum stripped from the skin were studied on five transdermal nitrate tape preparations. The water permeability of the preparation, in which the polyester membrane was used for the backing body, depends on the membrane thickness: a thinner membrane has a higher water permeability. The highest permeability was detected in the Antup® preparation. On the other hand, the amount of stratum comeum stripped from the skin was significantly lower when the new Frandol tape S® preparation was applied. According to these results and other drug information such as the cost of the preparation, we evaluated the quality of these products based on decision analysis criteria. This evaluation thus accurately indicated the effectiveness, safety and cost of the product. As a result, the highest score was obtained by the new Frandol tape S® preparation among the five tested products. This product showed the lowest amount of stratum comeum and the low incidence of side effects. In other words, new Frandol tape S® appears to be the most cost-beneficial transdermal nitrate tape preparation. The method used in this study was thus shown to be useful for the selection of the safest and most effective transdermal tape preparation.