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Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Common NMDA receptor antagonists include amantadine,27 ketamine, methoxetamine, phencyclidine (PCP), nitrous oxide, dextromethorphan and dextrorphan, memantine, ethanol, riluzole (used in ALS),28 xenon, HU-211 (also a cannabinoid), lead (Pb2+),29 conantokins, and huperzine A. Dual opioid and NMDA receptor antagonists include ketobemidone, methadone, dextropropoxyphene, tramadol, kratom alkaloids, and ibogaines.
Marine Drugs: A Source of Medicines for Neuroinflammatory Disorders
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Arunachalam Muthuraman, Narahari Rishitha, Nallapilai Paramakrishnan
Stroke is the fourth leading directly to death in the world. Multiple etio-logical factors are employed in the progress of stroke. The symptoms of stroke are originated by abnormal functions of the neurovascular system (Jean-Louis et al., 2008). The initial events of stroke originate from vascular segments, the narrow or blocking of the cerebral vascular system are making the ischemic environments to the specific area of the brain (Moskowitz et al., 2010). The hypoxic and ischemic events activate the abnormal cellular metabolic activity and activate the inflammatory signals via stimulation of mitochondrial, nuclear, and endoplasmic reticulum in the affected area of the brain (Nathan and Ding, 2010). Myeloid cells, i.e., macrophages, monocytes, eosinophils, basophils, neutrophils, erythrocytes, and megakaryocytes are playing an important role in the management of neuron functions. In addition, T-cells, B-cells, and natural killer cells are also contributed to the regulation of neuronal cell function. Further, the myeloid and lymphoid cells contribute to the formation of dendritic cells (Graf and Enver, 2009). Dendritic cell functions are essential for the maintaining of both adaptive and innate immunity for a healthy brain. Furthermore, dendritic cells have a unique ability to stimulate memory and naïve T-cells which is required to clear the misfolding proteins(Joffre et al., 2012). In a stroke, the chronic neuroinflammation of regional brain tissue is clearing macrophages and migratory dendritic cells which lead to the loss of neuronal regulatory functions. The various conventional anti-inflammatory, anti-thrombotic agents and phytomedicines are showed the ameliorative effect in stroke patients (Reagan-Shaw et al., 2008). Even, it also causes the potential adverse effects due to too complex mechanism and involvement of multiple pathways of neurodegeneration. The marine drugs, i.e., CEP-1347, xyloketalB, and polyphenolic compounds of Ecklonia cava are attenuated the stroke symptoms via multiple pharmacological actions like anti-oxidant, anti-inflammatory, immunosuppressive, and neuroprotective actions (Carlsson et al., 2009; Gong et al., 2018; Kim et al., 2012). Xyloketal B is an important potent medicine to treat neuroinflammation (Gong et al., 2018). Further, it also ameliorates the stroke symptoms via inhibition of ROS, toll-like receptor-4, and nuclear factor kappa-B activity (Choi and Choi, 2015; Pan et al., 2017). Currently, various marine drugs are under the preclinical screening stage to explore their improvement of neurovascular functions. Such agents are waixenicin, bryostatin-1, ilimaquinone, 5,8-diepi-ilimaquinone, 4,5-diepi-dactylospongiaquinone, JBIR-59, JBIR-124, conantokin-G, x-conotoxin (Choi and Choi, 2015; Pan et al., 2017; Safaeinejad et al., 2018). Therefore, marine drugs have a promising role in the management of neurovascular disorders including stroke symptoms.
Identifying molecular mechanisms of acute to chronic pain transition and potential drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Kannan Aravagiri, Adam Ali, Hank C Wang, Kenneth D Candido, Nebojsa Nick Knezevic
Unlike chronic pain formation in the periphery, the transition from acute to chronic pain in the CNS mainly occurs with the activation of NMDA/AMPA receptors by excitatory neurotransmitters. As a result, these receptors have been known targets for the possible prevention of chronic pain. Ketamine, one of the most commonly used NMDA antagonists, has shown some promise in reducing morphine usage, especially with regard to postoperative ketamine infusions [53]. Furthermore, it was found that NMDA receptor inhibition with low-dose ketamine can reduce the effects of opioid-induced hyperalgesia [54,55]. Other NMDA antagonists, including dizocilpine, norketamine, conantokin G, and traxoprodil, are currently being studied through intrathecal preparations in animal models for the prevention of hypersensitivity and secondary hyperalgesia involving inflammatory processes and nerve injury [22,56]. With regard to AMPA, studies done on AMPA-specific antagonists in intrathecal preparations reveal decreased secondary hyperalgesia [57]. These diverse options of NMDA and AMPA receptor inhibitors offer the possibility of providing some form of chronic pain prevention, but there have yet to be any human trials.
Advances in venom peptide drug discovery: where are we at and where are we heading?
Published in Expert Opinion on Drug Discovery, 2021
Taylor B. Smallwood, Richard J. Clark
The clinical development pipeline is the final stage peptide candidates must face, which sees many drugs discontinued as new therapeutic drugs must achieve very high standards to be accepted for the market. Not specific to just venom-derived peptides, factors including adverse effects, lack of efficacy and dose-limiting toxicity are often responsible for the discontinuation of many clinical trials [4]. Several venom-derived peptides have been discontinued at different stages, including ximelagatran (Phase 2, hepatic toxicity), MSI-78 (Phase III, lack of efficacy), leconotide (Phase I/IIa company went bankrupt), Xen2174 (Phase IIb, dose-limiting toxicity), Vc1.1 (Phase IIa, lack of efficacy), contulakin (Phase Ia, financial issues) and conantokin (Phase II, financial issues). This illustrates how difficult it can be to move from preclinical animal studies to actions in humans free from adverse effects.