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The Primary Care Companion For CNS... Mar 2024
Topics: Humans; Dreams; Prazosin; Clinical Trials as Topic
PubMed: 38442072
DOI: 10.4088/PCC.23cr03638 -
Toxicology and Applied Pharmacology Mar 2024Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore,...
Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D/D receptor antagonist, 5 mg/kg), SCH-23390 (D receptor antagonist, 0.05 mg/kg), prazosin (α adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective β-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D, α and β-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.
Topics: Mice; Animals; Propranolol; Quality of Life; Analgesics; Pain; Norepinephrine; Yohimbine; Adrenergic alpha-1 Receptor Antagonists; Dopamine; Sulpiride; Receptors, Adrenergic, alpha-2
PubMed: 38437958
DOI: 10.1016/j.taap.2024.116881 -
Toxicology Letters Apr 2024Drug transporters are among the factors that determine the pharmacokinetic profiles after drug administration. In this study, we investigated the roles of drug...
Drug transporters are among the factors that determine the pharmacokinetic profiles after drug administration. In this study, we investigated the roles of drug transporters involved in transport of SN-38, which is an active metabolite of irinotecan, in the intestine under inflammatory conditions in vitro and determined their functional consequences. The expression alterations of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 2B1 were determined at the mRNA and protein levels, and the subsequent functional alterations were evaluated via an accumulation study with the representative transporter substrates [prazosin and dibromofluorescein (DBF)] and SN-38. We also determined the cytotoxicity of SN-38 under inflammatory conditions. Decreased BCRP expression and increased OATP2B1 expression were observed under inflammatory conditions in vitro, which led to altered accumulation profiles of prazosin, DBF, and SN-38, and the subsequent cytotoxic profiles of SN-38. Treatment with rifampin or novobiocin supported the significant roles of BCRP and OATP2B1 in the transport and cytotoxic profile of SN-38. Collectively, these results suggest that BCRP and OATP2B1 are involved in the increased cytotoxicity of SN-38 under inflammatory conditions in vitro. Further comprehensive research is warranted to completely understand SN-38-induced gastrointestinal cytotoxicity and aid in the successful treatment of cancer with irinotecan.
Topics: Humans; Female; Irinotecan; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins; Organic Anion Transporters; Antineoplastic Agents; Membrane Transport Proteins; Prazosin; Breast Neoplasms
PubMed: 38423481
DOI: 10.1016/j.toxlet.2024.02.011 -
Basic & Clinical Pharmacology &... May 2024Although α-adrenoceptor (α-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still...
Although α-adrenoceptor (α-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α-AR antagonists against SSE was due to the involvement of α-AR subtypes. Our results further suggested that α-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.
Topics: Male; Rats; Animals; Tamsulosin; Adrenergic alpha-1 Receptor Antagonists; Ejaculatory Dysfunction; Sulfonamides; Prazosin; Receptors, Adrenergic, alpha-1; Adrenergic alpha-Antagonists; Naphthalenes; Piperazines
PubMed: 38409579
DOI: 10.1111/bcpt.13993 -
Child and Adolescent Psychiatric... Apr 2024Trauma exposure significantly impacts sleep in children. Nightmares are common. Evidence-based therapies are superior to medications but may not always be available in... (Review)
Review
Trauma exposure significantly impacts sleep in children. Nightmares are common. Evidence-based therapies are superior to medications but may not always be available in acute settings. No FDA-approved medications exist for the treatment of trauma-related sleep disturbances in youth. The evidence-base for the use of medications is largely based on case reports, retrospective chart reviews, clinical opinion, and adult studies. This evidence is reviewed for a number of medications, including prazosin, trazodone, alpha-2 agonists, quetiapine, and others.
Topics: Adult; Child; Humans; Adolescent; Retrospective Studies; Transients and Migrants; Stress Disorders, Post-Traumatic; Sleep; Prazosin; Sleep Wake Disorders
PubMed: 38395505
DOI: 10.1016/j.chc.2023.08.001 -
Proceedings of the National Academy of... Feb 2024The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding...
The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
Topics: Humans; Animals; Phosphoglycerate Kinase; Prazosin; Parkinson Disease; Glycolysis
PubMed: 38377207
DOI: 10.1073/pnas.2318956121 -
Purinergic Signalling Feb 2024Stimulation of sympathetic nerves in the vas deferens yields biphasic contractions consisting of a rapid transient component resulting from activation of P2X1 receptors...
Stimulation of sympathetic nerves in the vas deferens yields biphasic contractions consisting of a rapid transient component resulting from activation of P2X1 receptors by ATP and a secondary sustained component mediated by activation of α-adrenoceptors by noradrenaline. Noradrenaline can also potentiate the ATP-dependent contractions of the vas deferens, but the mechanisms underlying this effect are unclear. The purpose of the present study was to investigate the mechanisms underlying potentiation of transient contractions of the vas deferens induced by activation of α-adrenoceptors. Contractions of the mouse vas deferens were induced by electric field stimulation (EFS). Delivery of brief (1s duration) pulses (4 Hz) yielded transient contractions that were inhibited tetrodotoxin (100 nM) and guanethidine (10 µM). α,β-meATP (10 µM), a P2X1R desensitising agent, reduced the amplitude of these responses by 65% and prazosin (100 nM), an α-adrenoceptor antagonist, decreased mean contraction amplitude by 69%. Stimulation of α-adrenoceptors with phenylephrine (3 µM) enhanced EFS and ATP-induced contractions and these effects were mimicked by the phorbol ester PDBu (1 µM), which activates PKC. The PKC inhibitor GF109203X (1 µM) prevented the stimulatory effects of PDBu on ATP-induced contractions of the vas deferens but only reduced the stimulatory effects of phenylephrine by 40%. PDBu increased the amplitude of ATP-induced currents recorded from freshly isolated vas deferens myocytes and HEK-293 cells expressing human P2X1Rs by 93%. This study indicates that: (1) potentiation of ATP-evoked contractions of the mouse vas deferens by α-adrenoceptor activation were not fully blocked by the PKC inhibitor GF109203X and (2) that the stimulatory effect of PKC on ATP-induced contractions of the vas deferens is associated with enhanced P2X1R currents in vas deferens myocytes.
PubMed: 38374492
DOI: 10.1007/s11302-024-09993-y -
Sleep Medicine Clinics Mar 2024Trauma-associated sleep disorder (TASD) is a recently described parasomnia that develops following a traumatic event. It consists of trauma-related nightmares,... (Review)
Review
Trauma-associated sleep disorder (TASD) is a recently described parasomnia that develops following a traumatic event. It consists of trauma-related nightmares, disruptive nocturnal behaviors, and autonomic disturbances, and shares similarities with post-traumatic stress disorder and rapid eye movement behavior disorder. The underlying pathophysiology of TASD and how it relates to other parasomnias are still not entirely understood; proposed treatment is similarly nebulous, with prazosin at the forefront along with management of comorbid sleep disorders. The purpose of this article is to characterize and highlight the clinical features of this condition.
Topics: Humans; Polysomnography; Sleep Wake Disorders; Parasomnias; Stress Disorders, Post-Traumatic; Dreams
PubMed: 38368073
DOI: 10.1016/j.jsmc.2023.10.005 -
European Journal of Pharmacology Apr 2024Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells...
Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 μg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.
Topics: Mice; Humans; Animals; Muscle, Smooth, Vascular; Pulse Wave Analysis; Mice, Knockout; Mice, Inbred C57BL; Aortic Aneurysm, Abdominal; Apoptosis; Inflammation; Angiotensin II; Disease Models, Animal; Myocytes, Smooth Muscle; Kruppel-Like Transcription Factors; Prazosin
PubMed: 38331337
DOI: 10.1016/j.ejphar.2024.176397 -
Neuropharmacology Apr 2024Sleep is an instinct behavior, and its significance and functions are still an enigma. It is expressed throughout one's life and its loss affects psycho-somatic and...
Sleep is an instinct behavior, and its significance and functions are still an enigma. It is expressed throughout one's life and its loss affects psycho-somatic and physiological processes. We had proposed that it might maintain a fundamental property of the neurons and the brain. In that context, it was shown that sleep, rapid eye movement sleep (REMS) in particular, by regulating noradrenaline (NA), maintains the brain excitability. It was also reported that sleep-loss affected memory, reaction time and decision-making ability among others. However, as there was lack of clarity on the cause-and-effect relationship as to how the sleep-loss could affect these basic behaviors, their association was questioned and it was difficult to propose a cure or at least ways and means to ameliorate the symptoms. Also, we wanted to conduct the studies in a simpler model system so that conducting future molecular studies might be easier. Hence, using zebrafish as a model we evaluated if sleep-loss affected the basic decision-making ability, a cognitive process and if the effect was induced by NA. Indeed, our findings confirmed that upon sleep-deprivation, the cognitive decision-making ability of the prey zebrafish was compromised to protect itself by running away from the reach of the exposed predator Tiger Oscar (TO) fish. Also, we observed that upon sleep-loss the axonal arborization of the prey zebrafish brain was reduced. Interestingly, the effects were prevented by prazosin (PRZ), an α1-adrenoceptor (AR) antagonist and when the zebrafish recovered from the lost sleep.
Topics: Animals; Norepinephrine; Zebrafish; Sleep Deprivation; Sleep; Neurons; Receptors, Adrenergic, alpha-1
PubMed: 38331315
DOI: 10.1016/j.neuropharm.2024.109861