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Introduction
Published in Shein-Chung Chow, Innovative Statistics in Regulatory Science, 2019
Table 1.5 presents the results first reported in Leber (1989), which was again used by Temple (1983) and Temple and Ellenberg (2000) to illustrate the issues and difficulties in evaluating and interpreting active-controlled trials. All six trials compare nomifensine (a test antidepressant) to imipramine (a standard tricyclic antidepressant) concurrently with placebo. The common baseline means and 4-week adjusted group means based on the Hamilton depression scale are given in Table 1.5. Except for trial V311(2), based on the Hamilton depression scale, both nomifensine and imipramine showed more than 50% mean reduction. However, magnitudes of average reduction on the Hamilton depression scale at 4 weeks for the placebo are almost the same as the other two active treatments for all five trials. Therefore, these five trials do not have assay sensitivity. It should be noted that trial V311(2) is the smallest trial, with a total sample size only of 22 patients. However, it was the only trial in Table 1.5 that demonstrates that both nomifensine and imipramine are better than placebo in the sense of both comparative clinical significance and statistical significance.
Parkinson’s Disease and Aging: Presynaptic Nigrostriatal Function
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
Nomifensine demonstrates high affinity and specificity for catecholamine (including both dopamine and noradrenaline) reuptake sites. Following the administration of [11C]nomifensine, the uptake of radioactivity has been shown to be high in the striatum where there is a high density of dopamine terminals, and much lower in cerebellum, which is almost devoid of dopaminergic innervation.40 The specificity of [11C]nomifensine for dopamine reuptake sites in the striatum is confirmed by,the blockade of nomifensine uptake by mazindol, which also acts at the same site.
Special Problems with Biological Fluids
Published in Joseph Chamberlain, The Analysis of Drugs in Biological Fluids, 2018
Even using chromatographic methods, the analyst needs to be aware of the presence of labile conjugates that could revert to parent drug if over enthusiastic methods are used for preliminary extraction. Thus, at least two separate chromatographic methods for the determination of nomifensine in human plasma were published213,214 before it was pointed out that the circulating form of the drug was the labile conjugate and the true levels of unchanged nomifensine were only one-hundredth, if that, of the previously reported concentrations following therapeutic doses.184 As elaborated in later chapters, it is important to consider the possibility of the interference by metabolites in particular methods of analysis.
Machine learning-based prediction of drug approvals using molecular, physicochemical, clinical trial, and patent-related features
Published in Expert Opinion on Drug Discovery, 2022
ChEMBL database provides extensive data about drugs including withdrawal information at https://www.ebi.ac.uk/chembl/g/#browse/drugs. We downloaded the dataset of withdrawn drugs in ChEMBL v30. Among the total of 65 withdrawn drugs in this list, 12 of them were found in the ‘nervous system diseases’ group as their intended indication. We decided to focus on these drugs in our use-case study. These drugs are presented in Table S11, together with the reasons behind their withdrawal after their regulatory approval, such as cardiotoxicity, hepatotoxicity and neurotoxicity. Upon testing the drugs provided in Table S11 in our ‘Nervous System Diseases’ prediction model (using the data from phase III trials dating before their initial approval), we found that 8 out of 12 drugs (66%) are predicted as unapproved, correctly. The prediction scores (which can also be read as the probability for approval) produced by the model for these drugs vary between 0.33 and 0.48, given the threshold of approval used in our study: 0.5 (these scores are produced using ‘predict_proba’ function in the Python Scikit-learn package). For example, DrugApp successfully predicted that Nomifensine, an antidepressant that was withdrawn from the market due to hematological toxicity and hepatotoxicity, would be ‘unapproved.’ These results indicate that our approach is promising in terms of revealing drugs to be withdrawn from the market sometime after their phase III approval, and has a potential to prevent large-scale losses in terms of both health and economy, by providing an early warning at the end of phase III trials.
Current and emerging drug therapies for the treatment of depression in adults with epilepsy
Published in Expert Opinion on Pharmacotherapy, 2019
There are only two published randomized controlled trials for depression in epilepsy. One published over three decades ago and compares nomifensine, amitriptyline and placebo in 45 individuals with epilepsy and depression over a period of 12 weeks [20]. Response rates in the region of 43% for amitriptyline and 79% for nomifensine were reported but remission rates are not presented. The other study assesses the antidepressant effect of a traditional Chinese medicine remedy, Xylaria Nigripes, as compared to placebo in a 12-week, randomized, double-blind, controlled study in 104 people [21]. Treatment with Xylaria Nigripes seems associated with a significant reduction in mean HDRS scores but neither response rates nor remission rates are provided. The Cochrane Review [19] has also identified two additional randomized, controlled studies in Chinese journals. One compares paroxetine with doxepin in 67 individuals with epilepsy and depression [22] while the other is a controlled trial of venlafaxine versus no treatment in 64 individuals [23]. A response rates of 82% for paroxetine and of 71% for doxepin at 8 weeks is reported [22] while the other study reports a response rates of 69% for venlafaxine at 8 weeks [23] but neither present data on remission rates.
Antidepressants with different mechanisms of action show different chronopharmacological profiles in the tail suspension test in mice
Published in Chronobiology International, 2019
Hiroshi Kawai, Reiko Iwadate, Takuya Ishibashi, Naomi Kudo, Yoichi Kawashima, Atsushi Mitsumoto
Antidepressant activity is influenced by circadian rhythm. Several antidepressants show diurnal activity in clinical settings and animal models. Lofepramine and clomipramine most effectively ameliorate depression when they are administered at midnight (00:00 h) and midday (12:20 h), respectively (Nagayama 1999; Nagayama et al. 1991; Philipp and Marneros 1978). The sedation and xerostomia caused by amitriptyline administration are more severe following morning than evening treatments (Nakano and Hollister 1983). On the other hand, the effects of fluoxetine do not differ between morning and evening administration (Usher et al. 1991). Timing for the maximal efficacy differs among the drugs. In animal studies, amitriptyline and fluvoxamine were most effective in the early dark phase (Ushijima et al. 2005), whereas nomifensine, milnacipran, and imipramine worked best in the light phase (Borsini et al. 1990; Kawai et al. 2018a, 2018b). A behavioral test suggested that the serotonergic and noradrenergic activities of milnacipran may contribute toward its overall antidepressant activity in the morning and evening, respectively (Kawai et al. 2018a). The dosing time-dependent antidepressant activity of these drugs could be explained by the circadian fluctuation of monoaminergic neuron activity (Kawai et al. 2018a; Ushijima et al. 2005). Earlier results suggested that the chronopharmacological profiles of antidepressants depend on their modes of action. To the best of our knowledge, however, no study to date has yet compared the chronopharmacological profiles of various antidepressants administered under the same experimental conditions.