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Special Consideration of Drug Disposition
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
The incidence of adverse drug reactions is, among other things, an age-dependent phenomena. Among patients of advanced age (70-79 years), there is a seven-fold greater occurrence of adverse drug reactions than in a patient population which is 50 years younger. Although the aging process per se is still poorly understood, it is reasonable to suggest that aging brings about a general deterioration of many physiological functions. In the same instance of renal function, mean glomerular filtration rates decrease by one-half, renal blood flow is reduced by a similar amount, and tubular excretory capacity falls also–perhaps by 40% between the second and eighth decennium. Other changes are also taking place: hepatic microsomal enzyme activity is gradually diminished; cardiac output is lessened; intestinal absorption is impaired; and the relative fat burden is elevated while lean muscle is reduced.
Psychobiology of insomnia
Published in Philip N. Murphy, The Routledge International Handbook of Psychobiology, 2018
Ximena Omlin, Kai Spiegelhalder, Leonie Maurer, Simon D. Kyle
Genes are thought to play an important role in insomnia etiology [27]. Results from twin studies estimate a heritability for insomnia of 22% to 59% in adults and a wider range 14% to 71% in children [27]. Furthermore, insomnia heritability appears to be stable across time in adults and recent evidence suggests that insomnia symptoms are more heritable in females (~59%) than males (~38%) [28]. In order to identify specific genes linked to insomnia a number of candidate gene studies have focused on genes involved in the generation of circadian rhythms, the so-called clock genes (i.e., PER; CLOCK), and those that are associated with the serotoninergic system (5-HTTLPR) [29]. Several genome wide association studies (GWAS) have identified new target genes associated with insomnia/sleep-related phenotypes [30–33], and follow-up replication studies have found support for a role of CACNA1C, ABCC9 [34] and RBFOX3 loci [35]. However, the marked heterogeneity of investigated sleep phenotypes to date limits understanding about genetic variants associated with insomnia disorder specifically and therefore future studies need to adopt a more consistent phenotyping approach [29].
Sleep deprivation therapy: A rapid-acting antidepressant
Published in S.R. Pandi-Perumal, Meera Narasimhan, Milton Kramer, Sleep and Psychosomatic Medicine, 2017
The results showed a significant and marked loss in rhythmicity in the top-ranked cyclic genes in MDD patients compared to controls and provided the first direct evidence of dysregulation in clock gene expression across six brain regions. The findings were independent of medication and cause of death. Dysregulated genes included the core circadian clock genes (i.e., BMAL1, PER1, PER2, PER3, Rev-Erbα, DBP, DEC1, and DEC2), which are essential to modulating virtually all rhythms throughout the body.84
Pers reverse angiotensin II -induced vascular smooth muscle cell proliferation by targeting cyclin E expression via inhibition of the MAPK signaling pathway
Published in Chronobiology International, 2023
Wan Jin, Yu Tian, Yanyun Ding, Deixi Zhou, Long Li, Meng Yuan, Yuanzhu Wu, Mingqi Ye, Jiajie Luan, Kui Yang
Although we observed similar regulatory trends of Per1 and Per2 after Ang II stimulation, as well as a phase shift between mRNA and protein expression, there were slight differences in the time-dependent regulation of Per1 and Per2 at specific time points. We propose two possible reasons for these results. Firstly, existing literature has demonstrated that the timing of peak and trough in the periodic oscillations of Pers gene expression in in vitro experiments is time-dependent, with a constant anti-phase difference between limbs. The exact timing of phase and oscillations of the core clock, and their correlation with functional output oscillations, may vary from cell to cell, tissue to tissue, and from in vitro to in vivo. Secondly, Per1 and Per2 may play distinct roles in circadian oscillation. Ogawa et al. suggested that Per1 is part of a morning oscillator tracking dawn, while Per2 is part of an evening oscillator tracking dusk (Steinlechner et al. 2002). Furthermore, Riddle et al. demonstrated differential localization between Per1 and Per2 in the brain’s master circadian clock. The central SCN exhibited the highest abundance of PER1 protein, while higher expression of PER2 protein was observed in the rostral, dorsal, and caudal aspects compared to PER1 (Riddle et al. 2017). Therefore, the differences in PER1 and PER2 expression at certain time points may arise from variations in their functions and structures.
Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma
Published in Chronobiology International, 2023
Lei Qian, Xiaochen Ding, Xiaoyan Fan, Shisen Li, Yihuan Qiao, Xiaoqun Zhang, Jipeng Li
PER1 is a crucial gene of the central circadian clock that regulates the expression of numerous other circadian clock genes in the circadian clock network, including PER2, DEC1, CRY1, NPAS2, and PER3 (Shearman et al. 2000; Siepka et al. 2007; Zhao et al. 2016). Disturbances in circadian rhythms mediated by PER1 can dysregulate the balance between apoptosis and proliferation, eventually leading to carcinogenesis (Sato et al. 2011; Yang et al. 2009). Moreover, silencing PER1 interferes with the circadian rhythm of PER1-HK2 and promotes trastuzumab resistance. In addition, efficacy of trastuzumab in STAD was shown to be significantly improved upon inhibition of glycolysis and PER1 following treatment with a combination of metformin and trastuzumab at zeitgeber time 6 (Wang et al. 2022). These findings suggest that further investigation of circadian rhythm mediation by the circadian clock gene PER1 can provide new insights on valid targets for preventing and treating cancer.
Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats
Published in Stress, 2023
Hershel Raff, Breanna L. Glaeser, Aniko Szabo, Christopher M. Olsen, Carol A. Everson
Another interesting sexually dimorphic finding (i.e., in males only) was the consistent, large sleep-restriction-induced decrease in the expression of Gilz and Per1 mRNAs in the male hypothalamic PVN during abstinence without a change in Nr3C1 or Nr3c2 (glucocorticoid or mineralocorticoid receptor) mRNAs. This did not occur in the females. The expression of Gilz and Per1 are well known downstream biomarkers of glucocorticoid activity (Ayyar et al., 2015; Gehrand et al., 2022; George et al., 2017). Of relevance to this study of sleep restriction in rats during opioid abstinence is the decrease in PVN Per1 (Period Circadian Regulator 1) mRNA expression. Per1 expression is altered with both sleep restriction (Li et al., 2022) and opioid abstinence (Li et al., 2009) although we not aware of a study evaluating their interaction. Furthermore, the importance of the sex differences in molecular clock gene expression in the hypothalamus with respect to both diurnal rhythmicity and stress responses has been established (Chun et al., 2015, 2018). Therefore, it is possible that expression of these glucocorticoid sensitive Gilz and Per1 genes may be involved in the transduction or a reflection of the interactive effects of opioid abstinence and sleep restriction.