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Journal of Pharmacological and... 2024The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological...
The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of "non-QT" cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human.
Topics: Dogs; Animals; Humans; Drug Evaluation, Preclinical; Hemodynamics; Heart Rate; Pharmaceutical Preparations; Heart Ventricles; Hydrochlorothiazide; Blood Pressure
PubMed: 38479593
DOI: 10.1016/j.vascn.2024.107497 -
Medical Oncology (Northwood, London,... Mar 2024Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to...
Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Haloperidol; Chlorpromazine; Antipsychotic Agents; Prazosin; Hep G2 Cells; Antineoplastic Agents; Apoptosis; Cell Line, Tumor
PubMed: 38472423
DOI: 10.1007/s12032-024-02323-7 -
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