Current Medicinal Chemistry - Volume 10, Issue 5, 2003

The development of an increasing number of antiretroviral agents has dramatically reduced HIV-associated morbidity and mortality. However, most of these drugs have been approved through clinical trials where only surrogate markers for clinical endpoints have been used. Ideally, a surrogate marker should be biologically plausible, predictive of disease progression and measurable by standardized assays. Historically, a number of candidate markers have been explored for monitoring the course of HIV infection and response to treatment. While the level of plasma HIV RNA and the absolute numbers of peripheral CD4+ T cells have eventually become the reference markers in clinical practice, several additional parameters are still being evaluated to improve our knowledge of the virus-host interaction, discriminate between apparently equivalent stages and further refine antiretroviral treatment. Advances in molecular methods and growing elucidation of HIV dynamics in vivo have made it possible to consider several molecular virologic parameters as candidate markers for treatment response, including intracellular levels of different HIV RNA species and amount of integrated and unintegrated HIV DNA. Much effort has been recently devoted to the definition of immunological parameters as prognostic markers. The abnormal activation induced by HIV on the immune system represents a major pathogenetic feature of HIV infection. Immune activation may be evaluated by the analysis of activation markers expressed on the cell membrane and by the quantification of soluble plasma molecules released by activated cells. Such markers of immune activation have an important prognostic significance in terms of disease progression and might be suitable for the monitoring and prognosis of antiretroviral therapies. In the late years, the possibility of extending potent antiretroviral therapies to developing countries has raised the need of simple, reliable and cost-effective tests to measure prognostic markers for disease evolution and assessment of therapy efficacy. This review summarizes the benefits and limits of reference and candidate surrogate markers and their integration for optimal antiretroviral therapy.

The development of small molecule kinase inhibitors as potential cancer therapeutics is an area of intense interest, and a subset of these agents target cyclindependent kinase (CDK) activity. Ten distinct CDKs (1-9, 11), when paired with their cyclin activators, are integral to such diverse processes as cell cycle control, neuronal development, and transcriptional regulation. Mutation and / or aberrant expression of certain CDKs and their regulatory counterparts are associated with uncontrolled proliferation and tumorigenesis. As such, CDK selective inhibitors (CDKIs) that attenuate or prevent tumor growth have been developed. Recently, interest in the therapeutic potential of CDKIs has expanded to include neurodegenerative diseases, where dysregulated CDK activity has been linked to the pathogenesis of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke. Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors. To date, CDKIs have shown promise as neuroprotective agents in the research laboratory and, in the future, may prove useful in the neurology clinic.

The importance of lipophilicity for pharmacological and toxicological potency of xenobiotics has been recognized for a century. The reference lipophilicity scale is defined by the logarithm of partition coefficient, log P, determined in the loctanol- water partition system. The tediousness of determinations and limited interlaboratory reproducibility of log P, on one hand, and the observations of linear relationship between log P and chromatographic retention parameters, on the other hand, gave rise to the substitution of the former by the readily available chromatographic data. Since its introduction, the reversed-phase high - performance liquid chromatography (HPLC), which has been viewed in terms of partition of a solute between a polar, aqueous mobile phase and a nonpolar stationary phase appeared especially suitable for lipophilicity (hydrophobicity) determination. The method got wide acceptance and has officially been recommended by the OECD. Fundamental relationships between chromatographic parameters are reviewed from the point of view of convenient and reliable lipophilicity measurements. The advantages and disadvantages of the stationary phase materials, which are presently employed for the determination of lipophilicity as well as those of specific HPLC systems and procedures, are critically reported. The literature on the application of chromatographic and electrochromatographic methods for assessment of lipophilicity of xenobiotics is reviewed. A separate paragraph is devoted to interpretation of retention parameters from HPLC systems comprising biomacromolecules. Role of lipophilicity in drug-biomacromolecule interactions is discussed in terms of quantitative structure-retention relationships (QSRR). Finally, reports are analyzed on systemic information which can be extracted by multivariate methods of data processing, like principal component analysis (PCA), from sets of lipophilicity parameters determined in diverse HPLC systems.

Anthracycline antibiotics are of particular value in the therapy of malignant diseases and exert profound effects not only on tumor cells but also on cells in the cardiovascular system. These quinone drugs affect vascular tone by a multitude of mechanisms, including acute modulation of Ca2+ homeostasis, altered expression of membrane proteins and enzymes that are involved in the control of smooth muscle contraction, and generation of autoregulatory mediators, such as nitric oxide and endothelin. Anthracyclines interfere with blood coagulation-fibrinolysis balance due to its effects on the production of prostacyclin, plasminogen activator and plasminogen activator inhibitor in the endothelium. Moreover, anthracyclines are thought to be the modulators of angiogenesis. The intensity and quality of anthracycline actions on blood vessel function are highly variable and may depend not only on the chemical structure of anthracycline but also on the type of blood vessel as well as the metabolic and redox status of the vascular tissue. Vascular actions of anthracyclines are possibly involved in both beneficial as well as toxic and undesirable side-effects such as tumor progress. Further investigations are required to clarify the relation between specific modifications of vascular cell function and clinical events observed during antineoplastic therapy with anthracyclines.