Current pharmaceutical design
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Human African trypanosomiasis or sleeping sickness is resurgent [1,2]. The disease is caused by subspecies of the parasitic haemoflagellate, Trypanosoma brucei. Infection starts with the bite of an infected tsetse fly (Glossina spp.). ⋯ The fourth, eflornithine, is effective against late stage disease caused by T. b. gambiense, but is ineffective against T. b. rhodesiense. Another drug, nifurtimox is licensed for South American trypanosomiasis but also been used in trials against melarsoprol-refractory late sage disease. This review focuses on what is known about modes of action of current drugs and discusses targets for future drug development.
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Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. ⋯ The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.
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The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection. Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition. ⋯ Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review. Although a "magical bullet" for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, "tailored" according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.
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Fever above 38 degrees C that occurs in patients with acute neurosurgical diseases appears to worsen secondary brain injury and ultimate neurologic outcomes. Laboratory investigations are quite clear regarding the adverse effects of fever in terms not only of functional outcomes, but also histologic and neurochemical injury. ⋯ The ability to eliminate fever in most of these patients during the first five to seven days after their injury would seem desirable. Based on a phase-I trial, it appears that intravascular cooling is a promising new method for avoiding fever in the neurosurgical ICU.
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There are approximately 500 species of predatory cone snails within the genus Conus. They comprise what is arguably the largest single genus of marine animals alive today. It has been estimated that the venom of each Conus species has between 50 and 200 components. ⋯ Conus libraries represent a rich pharmacopoeia and the potential to "therapeutically mine" such a resource appears limitless. The paucity of synthetic methodologies necessary to achieve the regioisomeric folding patterns present in these native peptides precludes access to synthetic conotoxin libraries, further validating the overall "mining" strategy. In this article, we will present a pragmatic overview of the molecular diversity as well as the neurobiological mechanisms that define each major class of conotoxin.