Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

[Transarterial "pile-up" infusion therapy of cisplatin and lipiodol emulsion in hepatic malignancies without TAE (transcatheter arterial embolization)].

We developed a modified transcatheter arterial infusion method using anticancer agents to treat hepatic malignancies; intermittent injections of iodized oil, lipiodol, containing adriamycin or epirubicin during the arterial infusion of cisplatin (75-200 mg/body) in order to achieve a higher concentration and longer retention of these anticancer agents in the tumor tissue. Fourteen patients with hepatocellular carcinoma (HCC) and five patients with metastatic liver cancer were treated with this "pile-up" arterial infusion therapy by anticancer agents without gelatin sponge TAE. In HCC patients, 50% or greater reduction in tumor size was obtained in 7 of 14 patients (50%). Serum AFP levels decreased by more than 75% in 6 of 7 patients in whom pretreatment serum levels of AFP were more than 200 ng/ml. The one-year and two-year survival rates were estimated at 55% and 27.5%, respectively, by the Kaplan-Meier method. Significant reduction in tumor size was not observed in 5 cases with metastatic liver cancer. Concerning the adverse effects, alimentary symptoms and fever were noted for a few days in many cases, but they were temporary and tolerable in almost all of the patients. Severe adverse changes in laboratory data were not observed. Thus this "pile-up" infusion therapy of anticancer agents without TAE may be a useful therapy for HCC.

[Kinetic estimation of infused Lipiodol within a hepatoma using a CT dynamic study].

Distribution of Lipiodol within hepatic tumor was evaluated using serial computed tomography. Imagistic Lipiodol transition into the tumor via hepatic artery was slower than that of water soluble contrast medium, spreading to central part first and turn to peripheral part of the tumor. This method was thought to be useful to clarify Lipiodol distribution in hepatic tumor and to decide the method or necessity of additional trans-arterial therapy.

Intra-arterial injection of adriamycin/mitomycin C lipiodol suspension in liver metastases.

Intra-arterial injection of a suspension of adriamycin and/or mitomycin C in Lipiodol was performed in 17 patients with hepatic metastases, which at angiography were poorly vascularized. Accumulation of Lipiodol in the tumors was demonstrated at computed tomography (CT) in 15 of 17 patients examined within one week. Follow-up with CT showed that Lipiodol remained in the tumor during the first month in 94 per cent, after 2 months in 31 per cent, and after 3 months in 17 per cent. In the non-tumor part of the liver Lipiodol disappeared earlier, and one month after injection it could no longer be traced on CT. In 8/17 cases (47%) CT, after intra-arterial injection of Lipiodol, gave superior information compared with CT after intravenous contrast enhancement. Tumor response was achieved in 9 of 16 cases. Particularly in metastases originating from cancer of the colon and stomach response was observed with a decrease in tumor size in 8 of 10 patients.