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The Limbic System
Published in Jay A. Goldstein, Chronic Fatigue Syndromes, 2020
Hippocampus. Although the hippocampus receives afferents from numerous structures, its efferents are generally considered to be in the fornix, which terminates in the mammillary body. There are also direct hippocampal efferents to the amygdala and septum. Via the fornix, there are indirect projections to the medial preoptic area, the anterior hypothalamus, the lateral hypothalamic area, the ventral tegmental area, and the central gray matter of the midbrain.12 The mammillary body has diffuse projections in the brain. Hippocampal efferents are said to reach widespread areas of the cerebral cortex and amygdala in the rhesus monkey. These fibers cross to the contralateral limbic zone through commissures, as is true for those of the amygdala and piriform cortex. Mirror images of unilateral limbic lesions have been reported in the contralateral hemisphere. Although the hippocampus has been implicated in emotion and neuro-immune-endocrine regulation, its main function is in the making of memories, and in this mode virtually its entire sensory input is paralimbic. Because of this connection, there is a distinct motivational component to learning. Anxiety may be mediated in the dorsal hippocampus through the septo-hippocampal circuit, since both diazepam and tandospirone, a 5HT 1A agonist, have anti-anxiety effects when injected into the dorsal hippocampus.13 The hippo-campus may also be involved in depression, particularly in elderly depressed patients, in whom magnetic resonance imaging (MM) revealed significantly shortened Ti spin lattice relaxation times.14
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Tandospirone is also partially metabolized by CYP2D6 while CYP3A4 is the major catalyst for this novel antipsychotic (Natsui et al. 2007). M4 (hydroxylation of the pyrimidine ring) is the major metabolite formed with CYP2D6 while M2 (hydroxylation of the norbornan ring) and 1-PP (oxidative cleavage of the butyl chain) predominated with CYP3A4 (Natsui et al. 2007). TZB-30878, a novel 5-HT1A agonist/5-HT3 antagonist, is currently under development for the treatment of irritable bowel syndrome. It is mainly metabolized by CYP3A, with minor contribution from CYP2D6 (Minato et al. 2008). The use of recombinant human CYP enzymes suggested that CYP3A4 is the major enzyme involved in the oxidative metabolism of CJ-036878 (a novel and potent antagonist of the N-methyl-D-aspartate receptor), with minor contributions from CYP1A2, 2C19, and 2D6 (Nishida et al. 2007).
Hereditary Spastic Paraparesis and Other Hereditary Myelopathies
Published in Anand D. Pandyan, Hermie J. Hermens, Bernard A. Conway, Neurological Rehabilitation, 2018
Jon Marsden, Lisa Bunn, Amanda Denton, Krishnan Padmakumari Sivaraman Nair
Recommendations for the symptomatic treatments of spasticity, Parkinsonism, dystonia, and cramps have been outlined and include benzodiazepines, baclofen, and carbamazepine.115,116 A case study has described the use of botulinum toxin injections for lower limb spasticity and cramps that produced no side effects although the clinical benefits were not described.117 In contrast botulinum toxin injections for associated cervical dystonia have been associated with dysphagia.118 A double-bind randomised controlled trial119 of the antibiotics sulfamethoxazole and trimethoprim (co-trimoxazole) have not supported the improvements in spasticity and rigidity described by earlier smaller trials.120,121 Some people with SCA3 can show levadopa-responsive dystonia and therefore patients should undergo a levadopa trial if dystonia is present. SCAs involving Parkinsonian features, such as SCA2 and 3 (MJD), often respond to dopaminergic therapy, such as levodopa122–125 and dopaminergic drugs can also be helpful in ameliorating restless legs to aid uninterrupted sleep.125–127 Amantadine is sometimes used to treat dystonia and bradykinesia.125,128 Those experiencing muscle cramps, most commonly encountered in SCA3, can trial magnesium, chinine, quinine, or mexiletine drug therapies.129 As with other SCAs and cerebellar disorders the pharmacological management of ataxia is limited.115,130 Tandospirone may improve symptoms of ataxia, depression, and insomnia.116
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
Several additional 5-HT1A partial agonists are currently under development for the treatment of anxiety disorders. The azapirone gepirone was demonstrated to improve symptoms in patients with co-morbid GAD and panic disorder with agoraphobia in an open study [86]. However, no RCTs have been conducted to assess its efficacy in any anxiety disorder. In patients with MDD and a high level of anxiety symptoms, augmentation of SSRI treatment with azapirone tandospirone improved both depressive and anxiety symptoms [87]. A multicentre RCT conducted in China compared 60 mg vs. 30 mg/day of tandospirone in patients with GAD over 6 weeks [88]. However, the lack of a placebo group in this study makes overall interpretation of the efficacy of tandospirone challenging. The higher tandospirone dosage was associated with a greater HAM-A decrease but no difference in overall response rate. An additional 5-HT1A partial agonist with 5-HT2 antagonist actions (FKW00GA) is under development with reported efficacy in phase 2 trials in GAD [89]. To date, the results of these trials have not been published.
Early outcomes, associated factors and predictive values of clinical outcomes of tandospirone in generalized anxiety disorder: a post-hoc analysis of a randomized, controlled, multicenter clinical trial
Published in Current Medical Research and Opinion, 2023
Yi Fu, Jian Lin Ji, Shen Xun Shi, Hai Yin Zhang, Guo Zhen Lin, Ying Li Zhang, Xiuli Li, Wen Yuan Wu
At present, GAD treatment is mainly based on medication. Commonly used anxiolytic drugs in the clinic include anxiolytics (benzodiazepines and 5-HT1A receptor partial agonists) and antidepressants with anxiolytic effects. 5-HT1A receptor partial agonists mainly produce anxiolytic effects by regulating 5-HT function. Tandospirone is a representative 5-HT1A receptor partial agonist. In vitro and in vivo studies have shown that tandospirone is mainly metabolized by cytochrome P450 (CYP) 3A4. In vivo, tandospirone is metabolized to 1-(2-pyrimidine) -piperazine by CYP3A4. Trials have demonstrated the anxiolytic effects of tandospirone7,8. The currently approved indications of tandospirone in China are anxiety caused by various neuroses, including GAD, essential hypertension, peptic ulcer and other physical diseases. The recommended dose of tandospirone is 30-60 mg/d9. Several national and international guidelines have recommended 5-HT1A receptor partial agonists for the first-line treatment of anxiety disorders, especially GAD10–12. Tandospirone is highly effective and safe, and represents a more promising drug for clinical application compared with traditional anti-anxiety drugs13–15.
Novel investigational therapeutics for generalized anxiety disorder (GAD)
Published in Expert Opinion on Investigational Drugs, 2019
Bella Schanzer, Ana Maria Rivas-Grajales, Aamir Khan, Sanjay J Mathew
Tandospirone is a novel nonbenzodiazepine anxiolytic derivative of azapirone that is a strong and selective agonist of serotonin 5HT1A receptor. Tandospirone received regulatory approval in China and Japan for GAD in 2003 and 1996, respectively. 5HT1 receptors have long been a focus of study in the mediation of anxiety. Tandospirone is a partial agonist of the 5-HT1A receptor and likely functions through the development of a continuous water channel by mobilizing nearby amino acid residues. It is also highly potent as compared to other partial agonists, such as buspirone or ipsapirone, with a Ki value of 27 ± 5 nM. In addition, it is highly selective to the 5-HT1A receptor, in contrast to the other azapirones that also have a moderate-to-high affinity for the dopamine D2 receptor and alpha1-adrenergic receptors. In addition, it is characterized as a full agonist at the 5-HT1A autoreceptors in the raphe nuclei as well as a partial agonist at postsynaptic 5-HT1A receptors in the forebrain area [57]. It is currently the focus of a Phase IV trial to determine the optimal dose for treatment.Agomelatine is a selective agonist of melatonergic receptors that are found throughout the central and peripheral nervous systems. It has also been found to activate GABA neurons thereby modulating the GABAergic pathway. It is believed that this is potentiated by agomelatine’s antagonism of 5HT2C receptors that are located in the hippocampus, amygdala, and cerebral cortex. Therefore, in addition to being useful for depression, which is what it has been approved for in some countries, there is evidence to support its use in the treatment of comorbid depression and anxiety [58].Vortioxetine is an atypical antidepressant that mediates its response through inhibition of the serotonin transporter (SERT) by binding with high affinity to the transporter leading to selective blockade of serotonin reuptake and by direct modulation of 5-HT receptor activity. Its activity at the 5-HT receptors depends on which receptor subtype as it acts as a weak antagonist at 5-HT3 and 5-HT7 and 5-HT1D but as a partial agonist at 5-HT1B and a full agonist at 5-HT1A. The multi-receptor activity may account for its broad clinical response including both antidepressant and anxiolytic effects [59].