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Tedizolid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Tedizolid has been observed to weakly and reversibly inhibit monoamine oxidase in vitro (Flanagan et al., 2013; Merck, 2014). When this interaction was assessed in a mouse head twitch model, no increased head twitch response occurred at tedizolid doses equivalent to approximately 25-fold human therapeutic dose concentrations. In contrast, head twitch response increased significantly in mice administered fluoxe- tine and human-equivalent linezolid dose concentrations (Flanagan et al., 2013). Similarly, lack of clinical adrenergic findings with tedizolid was described in a placebo-controlled crossover study of healthy individuals. No meaningful increases in blood pressure or heart rate were seen on tedizolid co-administration with pseudoephedrine (Flanagan et al., 2013). When tedizolid was co-administered with tyramine, a ≥ 30-mmHg increase in systolic blood pressure was achievable, but only at an elevated median tyramine dose of 325 mg (compared with 425 mg placebo). On tyramine challenge, palpitations were reported in 72.4% (21/29) and 46.4% (13/28) of patients receiving tedizolid and placebo, respectively (Merck, 2014).
Effects of Antidepressants on Specific Neurotransmitters: Are Such Effects Relevant to Therapeutic Actions?
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
In addition to changes in the major excitatory neurotransmitter glutamate there is also evidence that antidepressants modulate the action of the principal inhibitory transmitter, gamma-amino butyric acid (GABA). Over 20 years ago it was shown that the concentration of GABA in the cerebrospinal fluid and plasma from depressed patients is reduced [49,83a]. Experimental studies have also shown that different classes of antidepressants, including ECT, increased the density of GABA-B receptors in the frontal cortex and hippocampus of rat brain [58,84]. Other experimental studies in which several GABAmimetic drugs were tested also showed that they had a similar behavioral profile in the olfactory bulbectomized rat model of depression to standard antidepressants [106]. The possible mechanism whereby antidepressants modulate GABA-B receptor activity is uncertain, but there is evidence that GABA-B receptors may act as heteroceptors on serotonergic terminals in limbic regions of the rat brain [41]. Thus it was shown that the GABamimetic drug progabide increased the head-twitch response induced by serotonin in rodents; the density of cortical 5HT2 receptors was also shown to be increased under these conditions. Thus, it would appear that the functional changes in the GABAergic system are closely interrelated to those in the serotonergic and noradrenergic systems.
Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems
Published in Drug Metabolism Reviews, 2018
William E. Fantegrossi, Catheryn D. Wilson, Michael D. Berquist
A useful behavioral assay sensitive to 5-HT2AR agonists is the head-twitch response (HTR) (reviewed in Martin et al. 1963; Gonzalez-Maeso and Sealfon 2009). Synthetic cannabinoids can inhibit DOI-induced head twitches. For example, Darmani (2001) reported that pretreatment with structurally distinct classical synthetic cannabinoids HU-210, CP 55,940, or WIN 55,212–2 dose dependently attenuated DOI-induced head twitches in mice. At the time of the writing of this review, synthetic cannabinoids have not been reported to elicit head twitches, however, there is evidence presented in the literature that demonstrates head twitch behavior can be induced by the CB1R antagonist/inverse agonist, rimonabant (Darmani and Pandya 2000). Rimonabant can induce head twitching behavior in drug-naïve rodents, which can be attenuated by the selective 5-HT2AR antagonist, SR46349B (Darmani and Pandya 2000; Darmani 2001; Janoyan et al. 2002). Additionally, DOI-induced head twitch behavior is inhibited when indirect-acting cannabinoid agonists, such as AM404 and URB597 are administered (Egashira et al. 2011). Taken together, these in vivo data imply that 5-HT2AR agonists and antagonists produce the opposite psychosis-like effects observed in HTR compared with the cannabinoid receptor agonists and antagonists. The interaction between CB1R signaling an 5-HT2AR expressions and function is an active area of research which may help to further identify the mechanisms of cannabinoid-induced psychosis in the future.
New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Anna Stankiewicz, Katarzyna Kaczorowska, Ryszard Bugno, Aneta Kozioł, Maria H. Paluchowska, Grzegorz Burnat, Barbara Chruścicka, Paulina Chorobik, Piotr Brański, Joanna M. Wierońska, Beata Duszyńska, Andrzej Pilc, Andrzej J. Bojarski
The experiments were performed according to the procedure described in our previous studies75,80. Briefly, to habituate mice to the experimental environment, each animal was transferred to a 12 cm (diameter) × 20 cm (height) glass cage lined with sawdust 30 min before treatment. Test compounds were administered intraperitoneally (i.p.) at doses of 2.5, 5, and 10 mg/kg body weight 60 min before the test was performed. The head twitch response (HTR) in mice was induced by DOI (2.5 mg/kg, i.p.). Immediately after treatment, the number of head twitches was counted during a 20 min session. Haloperidol and clozapine were used as the reference compounds at active doses of 0.2 and 5 mg/kg, respectively.