Die behandeling van VIGS - Geneesmiddels en vaksiene - Wat hou die toekoms in?

The developing epidemic of acquired immunodeficiency syndrome (AIDS) has prompted a broadly based research effort to find drugs and vaccines for preventing and treating this disease. Compounds such as zidovudine (AZT), ampligen and the broad spectrum of pyrimidine dideaxynucleosides have yielded some promise for the treatment of AIDS in terms of better quality of life for sufferers, but no cure is in sight yet. Also the quest for therapeutic and preventative vaccines has also been ongoing for several years. The latest development of the Salk vaccine has led to wild speculation in the lay press of a cure for AIDS. However, some seemingly insurmountable practical and moral-ethical problems beset both the development of AIDS chemotherapy and an AIDS vaccine. The most vexing of these problems is the lack of a suitable animal model for testing and the consequent questions of whether uninfected or HIV-infected but symptom-free volunteers can or should be used in testing potentially lethal compounds or vaccines

Modularity in Protein Complex and Drug Interactions Reveals New Polypharmacological Properties

Recent studies have highlighted the importance of interconnectivity in a large range of molecular and human disease-related systems. Network medicine has emerged as a new paradigm to deal with complex diseases. Connections between protein complexes and key diseases have been suggested for decades. However, it was not until recently that protein complexes were identified and classified in sufficient amounts to carry out a large-scale analysis of the human protein complex system. We here present the first systematic and comprehensive set of relationships between protein complexes and associated drugs and analyzed their topological features. The network structure is characterized by a high modularity, both in the bipartite graph and in its projections, indicating that its topology is highly distinct from a random network and that it contains a rich and heterogeneous internal modular structure. To unravel the relationships between modules of protein complexes, drugs and diseases, we investigated in depth the origins of this modular structure in examples of particular diseases. This analysis unveils new associations between diseases and protein complexes and highlights the potential role of polypharmacological drugs, which target multiple cellular functions to combat complex diseases driven by gain-of-function mutations

Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage-Gated Calcium Channel Blockers

Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca2+ overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca2+ overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall, 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP1-01, 7a) had the most favorable pharmacological profile with an IC50 value of 86 μM for LTCC inhibition and significant reduction of hydrogen peroxide-induced cell death. In general, the triquinylamines were more active as LTCC blockers than the oxa-pentacycloundecylamines. The aza-pentacycloundecylamines were potent LTCC inhibitors, with 8-hydroxy-N-phenylethyl-8,11-azapentacyclo[5.4.0.02,6.03,10.05,9]undecane (8b) also able to offer significant protection in the cell viability assays

Brain uptake kinetics of nicotine and cotinine after chronic nicotine exposure

ABSTRACT Blood-brain barrier (BBB) nicotine transfer has been well documented in view of the fact that this alkaloid is a cerebral blood flow marker. However, limited data are available that describe BBB penetration of the major tobacco alkaloids after chronic nicotine exposure. This question needs to be addressed, given long-term nicotine exposure alters both BBB function and morphology. In contrast to nicotine, it has been reported that cotinine (the major nicotine metabolite) does not penetrate the BBB, yet cotinine brain distribution has been well documented after nicotine exposure. Surprisingly, therefore, the literature indirectly suggests that central nervous system cotinine distribution occurs secondarily to nicotine brain metabolism. The aims of the current report are to define BBB transfer of nicotine and cotinine in naive and nicotine-exposed animals. Using an in situ brain perfusion model, we assessed the BBB uptake of 3 H]cotinine BBB transfer is not altered by chronic nicotine exposure. To our knowledge, this is the first report detailing the uptake of nicotine and cotinine after chronic nicotine exposure and quantifying the rate of BBB penetration by cotinine

Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study

Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using 23I]iodobenzamide (IBZM)and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 9mTc-HMPAO thexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the BZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders in humans undergoing chronic HP treatment