Current Drug Discovery Technologies - Volume 10, Issue 3, 2013

Biomedical animal models predict clinical efficacy with varying degrees of success. An important feature of in vivo modeling is matching the age of the animals used in preclinical research to the age of peak incidence for a disease state in humans. However, growth and development are highly variable between mammalian species, and age matching is always based on assumptions about the nature of development. We propose that researchers commonly make the assumption that developmental sequences are highly conserved between mammalian species – an assumption that we argue is often incorrect. We instead argue that development is often a modular process. Consideration of the modular nature of development highlights the difficulty in matching animal ages to human ages in a one-to-one scalar manner. We illustrate this with a discussion of the problem of age matching rodents to humans for neuroprotection experiments, and argue that researchers should pay deliberate attention to the modularity of developmental processes in order to optimally match ages between species in biomedical research.

A new paradigm is emerging in modern drug discovery. It is a fusion of traditional and modern medicine, phenotypic and targeted drug discovery, or systems and reductionist thinking. This is exemplified by using a combination of network medicine and high throughput screening. It blends the use of physiologically relevant biological systems with the high throughput and statistical robustness of modern assay technologies. The basic principles of network theory and tools of network medicine are described. Scale-free networks and their organizing principles are discussed. They are emergent properties of living, autopoietic systems. This includes networks of people who do high throughput screening (HTS), and microscopic networks of ions, metabolites, DNA, RNA, proteins, lipids, carbohydrates, viruses, bacteria, fungi, human cells and tissues. Databases have been constructed based on the metabolome, genome, transcriptome, proteome, lipidome, glycocode, virome, bacteriome and many others. Modern HTS can be used to examine the interactions of many parts of the complex human network. High content screening (HCS) can look at perturbations that occur when test compounds are added to single cells. Allo-network drugs can have effects far beyond a single protein and can be transmitted to other cells. Interactions and hidden connections can be revealed, with the goal of developing new drugs that have few, if any harmful side effects and are effective against multi-drug resistant cancer cells or bacteria.

Over forty years ago, biochemist Lauro Galzigna conducted an in-vitro experiment showing that the antipsychotic chlorpromazine reacted with the putative psychotogen adrenochrome to form a polymer resembling melanin. The field of psychopharmacology has essentially ignored that simple but illustrative experiment in the intervening time. The present study reproduces principle elements of Galzigna’s experiment and expands the scope to include the antipsychotic medications olanzapine and minocycline. The rate of reaction was slow, with maximal yield of black polymer being achieved by 4, 10 and 7 days with chlorpromazine, olanzapine and minocycline, respectively. Changing the pH was most informative for chlorpromazine and minocycline reactions, where yield increased sharply between pH 6.1 and 6.9, and decreased slightly between pH 6.9 and 7.8, consistent with reaction profiles expected for aromatic substitution. Preincubation of olanzapine with iodine doubled the polymer yield, facilitated by the addition of iodine to the aromatic ring and presumably followed by its departure as a “leaving group”. Increasing the salt concentration 1.5-fold depressed yields for all three drugs, most likely via ionic shielding of charged functional groups, diminishing reactivity. The results are discussed in regards to the mechanism of action of antipsychotic medications, casting doubt on commonly held theories. The time course of the chemical reactions presented here and the concentrations required, are much more consistent with clinical results than are models concerning receptor-mediated mechanisms. Furthermore, minocycline was effective in this model, but does not appear to have affinity for the primary receptor families thought by many to mediate antipsychotic efficacy.

Lipid metabolism plays a critical role in health, and there are a variety of methodologies available to investigators to determine how rates of metabolic processes respond to drugs and other interventions aimed at altering lipid metabolism. Commonly the abundance of lipids in the body is measured (e.g., plasma lipoprotein concentrations), but this static measure offers only a limited view on the dynamics and complexity of lipid metabolism as it pertains to health and disease. The synthesis and clearance rates of lipoproteins provide critical information pertaining to cardiovascular disease, and the mobilization of triglyceride and fatty acids and partitioning between metabolic fates affects the body composition and other aspects of health. Various techniques are available to measure the kinetics of lipid metabolism including stable isotope approaches, radio-isotope approaches, and non-isotopic approaches. The focus of this review is to describe various techniques for evaluating lipid kinetics in animal models and humans using isotopes as well as other techniques, and recent advances are highlighted.

Flavonoids are a group of low-molecular-weight polyphenolic compounds of plant origin. They exhibit a variety of biological activities such as anti-inflammatory, antioxidant, antiviral, and antitumor etc. Baicalein, is a bioactive flavone constituent of Scutellariae radix with a wide range of beneficial activities. But the poor solubility and dissolution rate limit its oral intestinal absorption and bioavailability. The aim of this study was to develop an amphiphilic phytophospholipid complex in order to enhance the delivery of poorly soluble drug (baicalein). The baicalein-phospholipid complex (Ba-PLc) was prepared and evaluated for various physico-chemical parameters like drug loading, infrared absorption (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffractometry (X-RPD), scanning electron microscopy (SEM), aqueous/ n-octanol solubility and dissolution study. In the SEM, phospholipid complex (Ba-PLc) was found fluffy and porous with rough surface morphology. FT-IR, DSC and X-RPD data confirmed the formation of phospholipid complex. The water/ n-octanol solubility of baicalein was improved significantly in the complex. Improved dissolution was shown by the phospholipid complex. The results of the study concluded that the phospholipid complex may be considered as a promising drug delivery system for improving the absorption and overall bioavailability of the baicalein molecule.

Major recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) are associated with significant psychosocial morbidity and excess premature mortality primarily attributable to suicide and coronary heart disease. Limited efficacy and adverse side-effects associated with psychotropic medications used in the treatment of MDD and BD highlight the urgent need to develop safe and efficacious treatments or treatment adjuncts. A body of evidence now indicates that long-chain omega-3 (LCn-3) fatty acid deficiency is a feature associated with MDD and BD. The etiology of LCn-3 deficits in MDD and BD patients may be attributable to both genetic and environmental factors. Dietary LCn-3 supplementation is safe and well-tolerated with chronic administration and corrects LCn-3 deficiency in MDD and BD patients. LCn-3 supplementation has been found to augment the therapeutic efficacy of psychotropic medications in the treatment of mood symptoms and to reduce suicidality. Preliminary studies also suggest that LCn-3 supplementation is efficacious as monotherapy in the treatment and prevention of psychopathology in children and adolescents. LCn-3 supplementation is also associated with reduced risk for developing coronary heart disease. The overall cost-benefit ratio associated with LCn-3 supplementation provides a strong rationale to diagnose and treat LCn-3 deficiency in MDD and BD patients, and to prevent LCn-3 deficiency in subjects at high risk for developing these disorders.

A growing body of evidence suggests that omega (ω)-3 polyunsaturated fatty acids (PUFAs) are clinically useful in patients with psychiatric disorders. In the present review, we summarize the findings of randomized, placebocontrolled clinical trials that have focused on the potential therapeutic utility of ω-3 PUFAs in patients with mental illnesses. We searched the PubMed database for placebo-controlled clinical trials using the keywords “PUFAs”, “omega-3”, “eicosapentaenoic acid”, and “docosahexaenoic acid” in combination with the following terms: “anxiety disorders”, “mood disorders”, “autism”, “attention-deficit hyperactivity disorder” (ADHD), “personality disorders”, and “schizophrenia”. The literature review indicated that personality disorders, autism, and anxiety disorders have been investigated less frequently than mood disorders, schizophrenia, and ADHD. Although no definite conclusions can be drawn on the therapeutic efficacy of ω-3 PUFAs in the majority of the psychiatric illnesses examined here, the evidence suggests that these molecules have a potential preventive role in people at extremely high risk for developing psychosis. Future studies in the field should examine ω-PUFAs turnover in neural membranes. Moreover, special attention should be paid to potential confounds, such as smoking and dietary habits.