Current Medicinal Chemistry - Volume 13, Issue 22, 2006

There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid β (Aβ) in the pathogenic cascade of Alzheimer's disease (AD). Different Aβ assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Aβ oligomers might be involved in AD pathogenesis at a very early stage of th Read More

A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules that modulate the formation of protein-protein complexes. Although the feasibility of this approach has been demonstrated in principle by recent results, many of the smallmolecule modulators known to date have not been found by rational design approaches. In large part this is d Read More

The approach of chemical genetics has been widely used to study biological systems and to discover new drugs, signaling pathways and targets. The current review focuses on the development and utilization of a cell- and caspase-based apoptosis induction assay for the discovery of apoptosis inducers. We began with the development of a cell based phenotypic assay, which was used for the identification of small molecules tha Read More

The structural and functional aspects of cytochrome P450 (CYP) enzymes are reviewed in the light of current developments in X-ray crystallography and other physical evidence, together with recent findings on the regulation of, and polymorphisms in, the human drug-metabolizing CYPs. It is emphasized that the crystal structures of eukaryotic CYPs are particuarly useful for constructing homology models of the human enzym Read More

Approximately 40%-60% of developing drugs failed during the clinical trials because of ADME/Tox deficiencies. Virtual screening should not be restricted to optimize binding affinity and improve selectivity; and the pharmacokinetic properties should also be included as important filters in virtual screening. Here, the current development in theoretical models to predict drug absorption-related properties, such as intestinal a Read More

Rimonabant (SR141716, Acomplia®) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its Read More

Breathing is generated and controlled by a brainstem neuronal network. Both intrinsic and synaptic interactions are involved in respiratory rhythm generation and their contribution is state-dependent, changing with hypoxia and the neuromodulatory state. Cellular mechanisms involved in acute or chronic pathological conditions are still unknown. A dysfunction in the neuronal network that controls breathing may be involved in se Read More

Breakdown of glucose under physiological conditions gives rise to glucose degradation products (GDPs). GDPs are also formed during heat sterilization of glucose-containing peritoneal dialysis fluids (PDfluids). In PD-fluids GDPs have been shown in many different in vitro assays to be responsible for adverse effects such as growth inhibition, and impaired leukocyte function and impaired wound healing of peritoneal me Read More

Cyclosporin-A (CsA) is a potent and selective immunosupressive agent that, due to its mechanism of action, may be used to inhibit both the inflammatory reaction and the synthesis of nitric oxide (NO), a wellknown neurotoxic agent. By these means CsA may diminish overproduction of free radicals and secondarily, lipid peroxidation (LP), both observed after acute spinal cord (SC) injury. Studies performed on reliable exp Read More

Histamine plays a prominent and diverse role in the pathophysiology of allergic disease and therapeutic intervention is therefore typically focused on blocking the effects of this biogenic amine. A new antihistamine, levocetirizine, is the R-enantiomer of cetirizine dihydrochloride and like its parent compound undergoes minimal hepatic metabolism. Levocetirizine has pharmacodynamically and pharmacokinetically favourable Read More

Thrombolysis has become an approved therapy for acute stroke. However, many stroke patients do not benefit from such treatment, since the presently used criteria are very restrictive, notably with respect to the accepted time window. Even so, a significant rate of intracranial hemorrhage still occurs. Conventional cerebral computed tomography (CT) without contrast has been proposed as a selection tool for acute stroke p Read More