Current pharmaceutical design
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The circadian clock is a biological system that allows organisms to adapt to temporal constraints of the environment. It governs all body functions. The circadian clock has an endogenous period and entrains to the external day by the means of timing cues, also called "zeitgebers". ⋯ Circadian desynchrony may be a factor in many diseases. This review presents literature in which the impact of circadian desynchrony on disease development - with a special focus on critical illness - has been addressed. The treatment options that have so far been investigated are also presented.
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Pomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. ⋯ Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson's disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer's disease psychosis.
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Review
Is time to change to halogenated drugs in cardiac surgery, what do we have to do with propofol?
There is initial evidence, at least in cardiac surgery, that total intra-venous anesthesia (usually a propofol-based total intravenous anesthesia) is associated with an increased mortality when compared to an anesthetic plan including a halogenated anesthetics. The cardiac protective properties of halogenated agents (desflurane, isoflurane and sevoflurane) have not been confirmed in non-cardiac surgery and mixed results exist for patients admitted in postoperative intensive care units. This article summarizes the papers with the most impressive findings in favor of halogenated anesthetics, but it recognizes that, at the same time, there is no evidence based medicine against the use of propofol, highlighting the need for large randomized trials that should focus on survival.
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New designer drugs (synthetic cannabinoids and synthetic cathinones) are new "legal highs" that are sold online for recreational public or private use. Synthetic cannabinoids are psychoactive herbal and chemical products that mimic the effects of cannabis when used. These drugs are available on the Internet or in head shops as incense or air fresheners to circumvent the law. ⋯ The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the availability via the Internet are the main features that attract users, but the number of intoxicated people presenting with emergencies is increasing. There is evidence that negative health and social consequences may affect recreational and chronic users. The addictive potential of designer drugs is not negligible.
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The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. ⋯ We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler's virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.