Patients were evaluated by dy namic retinal vessel analysis, autonomic function

Despite MAPK 検定 this low tissue plasma ratio, the concentration reached a value above the reported CDK5 p25 and casein kinase 1 inhibitory IC50 values for more than 6 hours. Discussion Recently, the tri substituted purine CR8 was introduced as a selective second generation CDK inhibitor analogue of roscovitine, In vitro studies have shown that CR8 is 2 4 fold more potent as a CDK inhibitor and 50 100 fold more cytotoxic in tumor cell lines, How ever, this enhanced in vitro activity of CR8 needs to be confirmed in vivo in animal models prior to further de velopment toward clinical trials in patients. The future investigation and development of this purine requires an accurate analytical method for the quantitative deter mination of its pharmacokinetics pattern.<br><br> In the present investigation we have developed and validated a new analytical method for the determination of CR8 in plasma and tissue samples. Our data showed that the method is selective and accurate. The acceptance criteria for the method validation are well in accordance with internationally accepted criteria, Moreover, the volume required for the analysis is only 50 ul of plasma, MK-1775 溶解度 a favorable factor when considering plasma sampling from small laboratory animals. The present method was employed for studying the pharmacokinetics and biodistribution of the drug in mice. It is of great importance to use a single, suitable analytical method for both pre clinical and clinical stud ies of newly introduced drugs, such as CDK inhibitors, that are promising for the treatment of several diseases including cancer.<br><br> One important factor is that the present method does not require work up procedures, a favorable factor for clinical studies where large numbers of samples are generated and speed of analysis is important. The pharmacokinetics profile constitutes a set of critical factors, strongly influencing whether CR8 should enter preclinical and clinical trials as an anti tumor agent. ms-275 分子量 Good oral absorption and appropriate bio logical half life allowing enough exposure to the drug to produce pharmacological activity and anti tumor effect, and sufficient elimination allowing minimal tox icity, are indeed crucial for further development of an anti cancer drug.<br><br> Roscovitine, which was introduced as one of the earli est CDK inhibitors, is at the present time undergoing phase II clinical trials in advanced non small cell lung cancer and nasopharyngeal cancers, Roscovitine was shown to have good oral bioavailability and low systemic toxicity profile, However, the anti tumor re sponses observed were modest, most probably a conse quence of the drugs short half life and rapid metabolism to inactive metabolites, Generally, exposure to the drugs is an important factor in the exertion of their anti tumor activity.<br><br> It has been shown that the optimum ef fect of roscovitine and the closely related analogue, N N1, on tumor cell lines occurs after 8 16 hours of exposure, The systemic exposure to roscovitine in adult animals and humans did not allow a plasma concentration to be maintained above the reported anti tumor IC50 for more than 1 2 hours, even when the max imum tolerated doses were administered, The only exception was in young rats, most probably due to im mature metabolism, The present results showed that the systemic exposure expressed as plasma AUC of CR8 was, for 10 hours, far higher than the anti tumor IC50 values found in vitro, Thus, second generation an alogues of roscovitine might, in addition to increased cell potency, solve the problem of insufficient exposure observed in roscovitine.