Life sciences
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Cannabimimetics (commonly referred to as synthetic cannabinoids), a group of compounds encompassing a wide range of chemical structures, have been developed by scientists with the hope of achieving selectivity toward one or the other of the cannabinoid receptors CB1 and CB2. The goal was to have compounds that could possess high therapeutic activity without many side effects. However, underground laboratories have used the information generated by the scientific community to develop these compounds for illicit use as marijuana substitutes. This chapter reviews the different classes of these "synthetic cannabinoids" with particular emphasis on the methods used for their identification in the herbal products with which they are mixed and identification of their metabolites in biological specimens.
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The endogenous cannabinoid anandamide (AEA) exerts the majority of its effects at CB1 and CB2 receptors and is degraded by fatty acid amide hydrolase (FAAH). FAAH KO mice and animals treated with FAAH inhibitors are impaired in their ability to hydrolyze AEA and other non-cannabinoid lipid signaling molecules, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). AEA and these other substrates activate non-cannabinoid receptor systems, including TRPV1 and PPAR-α receptors. ⋯ Indeed, pharmacological and genetic FAAH disruption in mice enhances nicotine reward and withdrawal. However, in rats, pharmacological blockade of FAAH significantly inhibits nicotine reward and has no effect in nicotine withdrawal. Studies suggest that non-cannabinoid mechanisms may play a role in these species differences.
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Morphine sulfate and other opiate/narcotic analgesics are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance. This complex pathophysiological cycle contributes significantly to decreased quality of life in the growing population of subjects with chronic pain due to oversedation, reduced physical activity, respiratory depression, constipation, potential for addiction, and other side-effects. ⋯ To this end, several antioxidant synthetic enzymes (synzymes) have been developed to effectively prevent the formation of PN (superoxide dismutase mimetics, SODms) or to decompose PN once it is formed (PN decomposition catalysts). The objectives of this mini-review written on PN and morphine antinociceptive tolerance are to 1) summarize recent advances made in the development of novel synzymes as therapeutics, 2) discuss the importance of nitroxidative stress in opiate anatinociceptive tolerance and 3) argue that PN is a rational target for therapeutic intervention in pain management. These concepts provide a pharmacological basis for developing inhibitors of PN biosynthesis as novel non-narcotic analgesics, thus addressing a large and currently unmet medical need with major socioeconomic consequences.
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This article reviews the importance of the renin-angiotensin-aldosterone system (RAAS) in the cardiometabolic continuum; presents the pros and cons of dual RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); and examines the theoretical and practical benefits supporting the use of direct renin inhibitors (DRIs) in combination with ACEIs or ARBs. ⋯ It is possible that aliskiren plus either an ACEI or ARB may provide greater RAAS blockade than monotherapy with ACEIs or ARBs, and lead to additive improvement in BP and clinically important outcomes.
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Of all the molecules reported to have toxicological effects, BMAA (beta-methylamino alanine) stands out as having the most checkered past. In the late 1960's it was reported to be a toxic component of the cycad flour consumed by Chamorros on Guam which caused the high incidence of amyotrophic lateral sclerosis (ALS) in Guam, that was associated with a Parkinson's disease-like dementia complex (ALS-PDC). However, because ALS-PDC is a slow onset disease, manifesting itself as long as 30 years following exposure to the putative neurotoxin, and only acute toxic effects of BMAA were observed in animal studies, interest in BMAA waned. ⋯ Also, reports that BMAA can be incorporated into plant and animal proteins, a heretofore unrecognized dietary source of BMAA, further solidified this new hypothesis. However, once again this hypothesis has its detractors and it remains controversial. This manuscript critically evaluates in vivo studies directed at establishing an animal model of BMAA-induced ALS-PDC and their implications for this hypothesis.