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Estrogens and dementia: a clinical and epidemiological update
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
Estrogen interactions with cholinergic systems of the brain may be particularly relevant to Alzheimer’s disease. Profound cholinergic deficits occur in Alzheimer’s disease, and reductions in central acetylcholine transmission clearly affect learning and memory2, 94. In the United States, the only drug approved by the Food and Drug Administration for Alzheimer’s disease symptoms is tacrine, a centrally active anticholinesterase that retards the inactivation of acetylcholine. Several large randomized trials have shown significant, but modest, cognitive benefits for Alzheimer’s disease patients able to tolerate the drug. A recent retrospective analysis of data from one such large tacrine intervention trial95 found that women using oral estrogen replacement at entry and subsequently randomized to tacrine performed significantly better on the primary cognitive outcome measure than women receiving placebo96. Women in the tacrine arm who were not taking estrogens performed comparably with those in the placebo group. The number of estrogen users in this trial was quite small and estrogen use was not randomized, but these observational findings support the contention that some estrogen effects in Alzheimer’s disease may be mediated through the cholinergic system. Future randomized controlled trials should specifically consider additive or synergistic effects of estrogen and an agent that boosts central cholinergic activity
Cholinergic Agonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar
As discussed above, cholinergic agonists are useful in many therapeutic conditions and as insecticides as well. But various side effects limit their use. Scientists have been working to develop new molecules to minimize or avoid these side effects. ACh, a direct acting agonist, has few clinical applications as it is rapidly hydrolyzed. Long-acting synthetic cholinergic agonists are preferred for clinical use (Ebert, 2013). Tacrine (Kromer and Eltze, 1991) is a ChE-blocking drug, and it was approved in 1993 by the FDA for the treatment of Alzheimer’s disease. It has to be given four times a day due to short half-life of only 1.4–3.6 h. Donepezil, approved in 1996, has more selective mode of action, fewer side effects and long t1/2 (70 h), and makes unit dose enough in a day (Mehta et al., 2012). Important advances are again required for the successful treatment of CNS problems such as Alzheimer’s disease. Novel muscarinics provide leads for new classes of muscarinics. Many compounds are still in trials and which might be a novel substitutes for conventional cholinergic agonists in the near future. Safety and prolong the effectiveness of such compounds require sufficient time, in-depth clinical studies, and evaluation, but it can be a start for the development of safe cholinergic agonists.
Psychopharmacology EMIs
Published in Michael Reilly, Bangaru Raju, Extended Matching Items for the MRCPsych Part 1, 2018
Choline.Donepezil.Galanthamine.Ginkgo biloba.Lecithin.Nicotinic acid.Physostigmine.Rivastigmine.Tacrine.Tyrosine.
Design, synthesis and evaluation of OA-tacrine hybrids as cholinesterase inhibitors with low neurotoxicity and hepatotoxicity against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Huali Yang, Hongwei Jia, Minghui Deng, Kaicheng Zhang, Yaoyang Liu, Yang Liu, Maosheng Cheng, Wei Xiao
As mentioned above, hepatotoxicity is a major side effect for tacrine. Considering hepatoprotective efficacy of OA, the strategy adopted for the design of OA-tacrine hybrids in this work. To further investigate the hepatotoxicity of hybrids, AnnexinV/PI double staining method was used to evaluate the effects of compounds B4 and D4 on cell apoptosis at the concentration of 50 μM. As shown in Figure 6, the percentage of apoptotic cells increased from 4.34% (control group) to 18.90% (Tacrine group). Compared with the tacrine-treated group, the groups treated compounds B4 and D4 (7.69% and 8.18%, respectively) showed significantly reduced percentages of apoptotic cells. This result indicated that compounds B4 and D4 have been proposed as potential inhibitors of cholinesterase with low hepatotoxicity.
Polymer drug conjugates containing memantine, tacrine and cinnamic acid: promising nanotherapeutics for the treatment of Alzheimer’s disease
Published in Journal of Microencapsulation, 2023
Tobeka Naki, William Morwa Reagile Matshe, Mohammed Olusegun Balogun, Suprakas Sinha Ray, Samuel Ayodele Egieyeh, Blessing Atim Aderibigbe
Tacrine was the first drug approved for the treatment of AD but was withdrawn due to hepatotoxicity (Ríos et al. 2019). Nonetheless, tacrine derivatives have been reported to display promising biological outcomes (Romero and Marco-Contelles 2017, Romero et al. 2013). Tacrine increases cerebral blood flow and blocks the release of Beta-amyloid precursor protein, making it a promising drug that can be further modified (Nordberg 1996, Harkins et al. 1997, Summers 2022). Memantine is also approved for the treatment of moderate to severe AD (Tariot et al. 2004). It is a moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist (Tariot et al. 2004). It prevents pathologically high levels of glutamate that are in control of neuronal dysfunction (Danysz and Parsons 2003). Different therapeutics have been developed for the management of AD.
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
The major issue of clinical use of tacrine is hepatotoxicity which led to its withdrawal from the clinical practice in 200347–49. However, as it was demonstrated in several cases, modification of tacrine structure or its hybridisation could change its toxicity profile leading to safer tacrine derivatives50. Owing to the fact that our newly synthesised compounds are tacrine-like derivatives, the cytotoxic effect of selected candidates 7, 15, 20, 21, 23, and 25 on human hepatocellular carcinoma cell line (HepG2) was determined. Obtained results (Table 4) were then compared with that of the reference compounds. In general, the hepatotoxic effect of selected compounds showed a very similar pattern as in vitro neurotoxicity. Similarly, and as before, compounds 23 and 15 could be considered as relatively non-hepatotoxic agents.