Costas Giaginis

Alternative Measures of Lipophilicity: From Octanol–Water Partitioning to IAM Retention

This review describes lipophilicity parameters currently used in drug design and QSAR studies. After a short historical overview, the complex nature of lipophilicity as the outcome of polar/nonpolar inter- and intramolecular interactions is analysed and considered as the background for the discussion of the different lipophilicity descriptors. The first part focuses on octanol-water partitioning of neutral and ionisable compounds, evaluates the efficiency of predictions and provides a short description of the experimental methods for the determination of distribution coefficients. A next part is dedicated to reversed-phase chromatographic techniques, HPLC and TLC in lipophilicity assessment. The two methods are evaluated for their efficiency to simulate octanol-water and the progress achieved in the refinement of suitable chromatographic conditions, in particular in the field of HPLC, is outlined. Liposomes as direct models of biological membranes are examined and phospolipophilicity is compared to the traditional lipophilicity concept. Difficulties associated with liposome-water partitioning are discussed. The last part focuses on Immobilised Artificial Membrane (IAM) chromatography as an alternative which combines membrane simulation with rapid measurements. IAM chromatographic retention is compared to octanol-water and liposome-water partitioning as well as to reversed-phase retention and its potential to predict biopartitioning and biological activities is discussed.

Current State of the Art in HPLC Methodology for Lipophilicity Assessment of Basic Drugs. A Review

Abstract HPLC provides a users friendly, rapid, and compound sparing methodology, which is successfully applied to determine drug lipophilicity. Under suitable chromatographic conditions isocratic and extrapolated retention factors correlate well with octanol‐water partition or distribution coefficients. The present review provides an overview of the stationary and mobile phases, which are preferably used for lipophilicity assessment mainly in the case of basic compounds. Difficulties raised by the interference of silanophilic interactions in the partition mechanism, and the ways proposed to face this problem are discussed. Attention has been given to the extrapolation procedure and the standardization of conditions to obtain 1∶1 correlation between extrapolated retention factors and logP or logD. Other chromatographic indices encoding information on the lipophilic behavior are briefly presented. A separate section refers to recent advances in IAM Chromatography, its similarities/dissimilarities with reversed phase HPLC and the octanol-water system, as well as its potential to mimic specific interactions with phospholipids.

Peroxisome proliferator-activated receptors (PPARs) in the control of bone metabolism

Peroxisome proliferator‐activated receptors (PPARs) are ligand‐activated nuclear transcription factors that regulate the storage and catabolism of dietary fats. PPARs constitute molecular targets for the treatment of human metabolic disorders, and also play a crucial role in inflammatory‐related disease and cancer. Recent evidence has revealed the presence of three different PPAR isotypes (α, β/δ, and γ) in different cells of the bone tissue, as well as the possible role of PPAR ligands in bone turnover. In the present review, the latest knowledge of the expression of PPARs in bone tissue and the diverse effects of PPAR ligands on bone metabolism is summarized. PPARs, especially of the γ isotype, could be targets for the treatment of diverse bone diseases such as osteoporosis and osteopenia related to either diabetes or aging.

Direct injection liquid chromatography/positive ion electrospray ionization mass spectrometric quantification of methotrexate, folinic acid, folic acid and ondansetron in human serum

A rapid liquid chromatography/positive ion electrospray mass spectrometric assay (LC/ESI-MS) was developed for the quantitation of methotrexate, folinic acid, folic acid and ondansetron in human serum. The assay was based on 100microL serum samples, following acetonitrile precipitation of proteins and filtration that enabled direct injection into the LC/MS system. All analytes and the internal standard, alfuzosin, were separated by using a Zorbax Eclipse XDB-C(8) analytical column (2.1mmx150.0mm i.d., particle size 3.5microm) with isocratic elution. The mobile phase was composed of a mixture of water/acetonitrile containing 0.1%, v/v formic acid (75:25, v/v), pumped at a flow rate of 0.15mLmin(-1). Quantitation of the analytes was performed with selected ion monitoring (SIM) in positive ionization mode using electrospray ionization interface. The assay was found to be linear in the concentration range of 0.01-25.00microgmL(-1) for methotrexate and 0.01-5.00microgmL(-1) for folic acid, folinic acid and ondansetron. Intermediate precision was found to be less than 4.2% over the tested concentration ranges. A run time of less than 7.0min for each sample made it possible to analyze a large number of human serum samples per day. The method can be used to quantify methotrexate, folinic acid, folic acid and ondansetron in human serum covering a variety of clinical studies and it was applied to the analysis of human serum samples obtained from children with acute lymphoblastic leukemia.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands as potential therapeutic agents to treat arthritis

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has already been considered as an attractive molecular target for the treatment of human metabolic disorders. Pleiotropic functions beyond this limit, such as anti-inflammatory and anti-proliferative effects against several pathological states, including atherosclerosis, osteoporosis and cancer, are currently being explored. Several natural and synthetic PPAR-gamma ligands have been the focus of extensive research effort as potent anti-inflammatory agents in diverse disease states. In the last decade, accumulative experimental evidence has further suggested that PPAR-gamma is involved in several inflammatory signaling pathways associated with arthritis. PPAR-gamma appears to be expressed by major cell populations in joints, such as chondrocytes, synoviocytes, fibroblasts and endothelial cells. PPAR-gamma ligands have also been shown to inhibit major inflammatory signaling pathways, reducing the synthesis of cartilage catabolic factors responsible for articular cartilage degradation in arthritis. In the present review the crucial role of PPAR-gamma ligands in arthritis and the underlying mechanisms participating in essential inflammatory signaling pathways are summarized. Taking into consideration the data so far, PPAR-gamma ligands seem to represent potential therapeutic agents in the aim to reduce mainly the inflammation implicated in arthritis. However, the precise molecular mechanisms through which PPAR-gamma ligands exert their actions are strongly recommended to be clarified, as both receptor-dependent and -independent actions were shown to be elicited.

Electrostatic interactions and ionization effect in immobilized artificial membrane retention: A comparative study with octanol–water partitioning

The present study is a continuation of our efforts to investigate the effect of electrostatic interactions and ionization on immobilized artificial membrane (IAM) retention. The previous set of neutral and basic drugs was extended to include acids and ampholytes and analogous buffer conditions in the mobile phase were used, namely morpholinepropanesulfonic acid and phosphate buffer saline, adjusted at pH 7.4. The important contribution of electrostatic forces in IAM retention of positively charged species was further justified by the results of the present study, while analogous electrostatic interactions for ionized acidic drugs were not found to affect significantly the affinity for the IAM stationary phase. The critical role of shielding or exposure of the charged centers on the IAM surface, as a result of the effect of the aqueous component of the mobile phase, was evaluated by the use of water instead of buffer for a number of drugs. Measurements at pH 5.0 demonstrated the effect of ionization in IAM retention despite the partial compensation by electrostatic interactions in the case of protonated basic drugs. Silanophilic interactions were also found to play a potential role as secondary interactions in IAM retention. IAM chromatographic indices were compared to octanol-water distribution coefficients and the corresponding relationships established. Finally, solvation analysis was applied in the aim to gain insight in the balance of forces between IAM retention and octanol-water partitioning. The results showed that apart from electrostatic interactions, there is no significant differentiation between the two systems.

Peroxisome proliferator-activated receptor-gamma ligands as investigational modulators of angiogenesis.

PPAR-γ ligands constitute important insulin sensitizers that have already been approved for the treatment of human metabolic disorders. They also exert pleiotropic effects on cell proliferation and cancer and are now being explored in preclinical studies. Angiogenesis constitutes a multifaceted process that is implicated in tumor development and other benign disease states that are associated with diabetes. Recent data have further extended the crucial role of PPAR-γ ligands as potential angiogenesis modulators, in vitro and in vivo. This review summarizes the latest knowledge of the role of PPAR-γ ligands in angiogenesis that are related to both malignant and non-malignant disease states. Taking into careful consideration the data so far, PPAR-γ could be considered as a therapeutic target for diverse disease states in which excessive angiogenesis is implicated, including cancer and diabetes complications.

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Ligands: Novel Pharmacological Agents in the Treatment of Ischemia Reperfusion Injury

Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands constitute important insulin sensitizers that have already been used for the treatment of human metabolic disorders, exerting also pleiotropic effects on inflammatory related diseases and cancer. Ischemia-reperfusion injury that is mainly associated with organ transplantation constitutes a serious complication with a great relevance in clinical practice. Accumulating experimental data have recently revealed that natural and synthetic PPAR-γ ligands exert beneficial effects against ischemia-reperfusion injury. The present review summarizes the available information on the role of PPAR-γ ligands in ischemia-reperfusion injury amongst the different organ systems. Taking into consideration the data so far, PPAR-γ ligands seem to represent potential therapeutic agents in the aim to reduce or even prevent injury associated with ischemia-reperfusion.

Peroxisome Proliferator-Activated Receptor-gamma Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-gamma ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-gamma ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-gamma ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-gamma may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-gamma ligands can enhance angiogenic phenotype in tumoral cells.

Application of quantitative structure-activity relationships for modeling drug and chemical transport across the human placenta barrier: a multivariate data analysis approach.

Pharmacological agents and environmental pollutants can transfer from mother to fetus across the placental barrier, leading to reproductive toxic effects. Ex vivo human placental perfusion constitutes the most widely used method to study placental transfer and metabolism of drugs and chemicals. The aim of the present study was to evaluate whether quantitative structure–activity relationship (QSAR) methodology could serve as an effective alternative tool to estimate drugs and chemicals transport across the human placental barrier on the basis of easily interpretable molecular, physicochemical and structural properties. Multivariate data analysis (MVDA) was applied to a set of 88 structurally diverse drugs and chemicals to model placental transfer expressed by clearance index values compiled from literature sources. An adequate and robust QSAR model (r2 = 0.73, Q2 = 0.71, RMSEE = 0.15) was established, providing an informative illustration of the contributing physicochemical, molecular and structural properties of the compounds in placental transfer process. Descriptors reflecting the polarity of compounds proved to be the most important with a negative sign. Lipophilicity and, at a lower extent, molecular size parameters exerted positive contribution in the model. Thus, QSAR analysis may be considered as a promising alternative tool to support high‐throughput screening of drugs and chemicals in respect to their transport across placental barrier. Copyright