role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase [CdK] inhibitor - Roscovitine

Pharmacokinetics, pharmacodynamics and pharmacogenetics play an important role in drug discovery and contribute to treatment success. This is an essential issue in cancer treatment due to its high toxicity. During the last decade, cyclin-dependent kinase inhibitors were recognized as a new class of compounds that was introduced for the treatment of several diseases including cancer. Cyclin-dependent kinases [Cdks] play a key role in the regulation of cell cycle progression and ribonucleic acid transcription. Deregulation of Cdks has been associated with several malignancies, neurodegenerative disorders, viral and protozoa infections, glomerulonephritis and inflammatory diseases. [R]-roscovitine is a synthetic tri-substituted purine that inhibits selectively Cdk1, 2, 5, 7 and 9. Roscovitine has shown promising cytotoxicity in cell lines and tumor xenografts. In this paper, we present several aspects of pharmacokinetics [PK] and pharmacodynamics [PD] of roscovitine. We present also some of our investigations including bioanalysis, haematotoxicity, age dependent kinetics, PK and effects on Cdks in the brain. Unfavourable kinetic parameters in combination with poor distribution to the bone marrow compartment could explain the absence of myelosuppression in vivo despite the efficacy in vitro. Higher plasma and brain exposure and longer elimination half-life found in rat pups compared to adult rats may indicate plasma and brain exposure and longer elimination half-life found in rat pups compared to adult rats may indicate that roscovitine can be a potential candidate for the treatment of brain tumours in children. Cdk5 inhibition and Erk1/2 activation that was detected in brain in rat pups may suggest the use of roscovitine in neurodegenerative diseases. Early pharmacokinetic/ pharmacodynamic studies are important issues in drug discovery and may affect further development of promising drug candidates

Testicular tumours: Does color doppler has a role?

The aim of this work was to assess the role of high-resolution ultrasonography [US] and color Doppler ultrasonography [CDS] in the diagnosis and evaluation of testicular tumors and the ability of each modality to add important information aiming to reach a precise diagnosis and hence a prompt management. The study was conducted on six patients with painless testicular swellings. It was concluded that gray scale along with the clinical and physical findings help to establish a specific diagnosis in almost all cases. CDS does not add any clinically important information and does not help in establishing a definite diagnosis of testicular tumors due to the great overlap between the findings in cases of testicular tumors and those of inflamed and normal tests. However, CDS seems to be more helpful in depicting the infiltrative lesions, such as lymphoma and leukemia, which increases the diagnostic confidence of the examiner