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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 -
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 -
The Journal of the Association of... Apr 2024The isometric handgrip (IHG) test is commonly used to detect sympathetic autonomic dysfunction. Tamsulosin, approved for the management of symptomatic benign prostatic... (Observational Study)
Observational Study
Effect of α-blockers on Handgrip Test Response of Diastolic Blood Pressure in Hypertensive, Benign Hypertrophy of Prostate Patients in a Therapeutics Clinic, Kolkata: A Cross-sectional Study.
BACKGROUND
The isometric handgrip (IHG) test is commonly used to detect sympathetic autonomic dysfunction. Tamsulosin, approved for the management of symptomatic benign prostatic hyperplasia (BPH), acts as an antagonist for α1-adrenergic receptors (α1-AR), whereas prazosin, an α receptor blocker, being less selective than tamsulosin, is used as an antihypertensive agent clinically. Our objective was to investigate if there is a distinction in blood pressure (BP) increase during IHG exercise between individuals with essential hypertension taking tamsulosin compared to those taking prazosin.
MATERIALS AND METHODS
A cross-sectional observational study was performed on 50 subjects receiving tablet prazosin and 47 subjects receiving tamsulosin, who were asked to undergo an IHG test. Pre- and posttest BP was recorded for both the groups, and the difference in diastolic BP (DBP) (delta DBP) was compared between the groups and to their respective baseline values.
RESULTS
Post-IHG test, mean DBP was found to be 93.98 ± 9.13 mm Hg in the prazosin group and 101.00 ± 12.05 mm Hg in the tamsulosin group, respectively. The change of delta DBP in the tamsulosin group was significant, but the prazosin group showed an insignificant rise in DBP.
CONCLUSION
Prazosin, being less selective than tamsulosin in terms of α1 receptor antagonism, showed suppression of BP during IHG. Tamsulosin demonstrates high selectivity for prostatic receptors while showing minimal affinity for vascular receptors. As a result, its impact on BP is expected to be minimal.
Topics: Humans; Male; Cross-Sectional Studies; Prostatic Hyperplasia; Prazosin; Tamsulosin; Middle Aged; Adrenergic alpha-1 Receptor Antagonists; Blood Pressure; Hypertension; Hand Strength; Aged; Antihypertensive Agents; India
PubMed: 38881078
DOI: 10.59556/japi.72.0501 -
Alcohol, Clinical & Experimental... Mar 2024Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly...
BACKGROUND
Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly improves alcohol drinking outcomes in individuals with alcohol withdrawal symptoms (AW), but effects on liver enzymes are unknown. We assessed the effects of prazosin treatment on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) in individuals with AUD.
METHODS
Participants (N=100) with AUD were enrolled in a 12-week randomized controlled trial and received either placebo or 16 mg/day of prazosin. Whole blood was drawn from 92 participants to measure liver enzyme levels every 4 weeks, and severity of AW was assessed weekly. Analysis predicting liver function outcomes used linear mixed effects models.
RESULTS
Controlling for alcohol consumption, a significant AW × treatment effect was seen for ALT (p < 0.05), AST (p < 0.05) and GGT (p < 0.01). Additionally, AST (b = 0.2, p < 0.01), ALT (b = 0.2, p < 0.05), and GGT (b = 0.3, p < 0.01) were elevated in individuals with higher AW in the placebo but not in the prazosin group (AST: p > 0.66; ALT: p > 0.65). Only in the prazosin group were lower GGT levels associated with higher withdrawal severity (b = -0.16, p < 0.05).
CONCLUSIONS
We found an interaction of alcohol withdrawal symptoms and prazosin treatment on liver enzyme levels, which were not influenced by week in the trial or the amount of alcohol consumed. Together, these findings suggest that prazosin treatment reduces liver enzymes over the course of AUD treatment among individuals with significant AW, though replication to establish clinical utility is needed.
PubMed: 38258493
DOI: 10.1111/acer.15263 -
Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing.Drug Metabolism and Pharmacokinetics Aug 2023The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial...
The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.8, 50 mM phosphate). The solid form of the residual particles was identified by Raman spectroscopy. In the pH range below 6.5, the equilibrium solubility in phosphate buffer was lower than that in the unbuffered solutions (pH adjusted by HCl and NaOH). Raman spectra showed that the residual solid was a phosphate salt of PRZ. In the pH range above 6.5, the pH-solubility profiles in the phosphate buffer solutions and the unbuffered solutions were the same. The residual solid was a PRZ freebase (PRZ-FB). In the dissolution test, PRZ-HCl particles first changed to a phosphate salt within 5 min, then gradually changed to PRZ-FB after several hours. Since the intestinal fluid is buffered by the bicarbonate system in vivo, the dissolution behavior in vivo may not be properly evaluated using a phosphate buffer solution. For drugs with a low phosphate solubility product, it is necessary to consider this aspect.
Topics: Buffers; Hydrogen-Ion Concentration; Solubility; Bicarbonates; Phosphates
PubMed: 37393739
DOI: 10.1016/j.dmpk.2023.100519 -
Medical Oncology (Northwood, London,... Mar 2024Psychosocial stress promotes cancer pathogenesis involving angiogenesis through alterations in neuroendocrine-immune functions that may involve adrenoceptor...
Estrogen-receptor status determines differential regulation of α1- and α2-adrenoceptor-mediated cell survival, angiogenesis, and intracellular signaling responses in breast cancer cell lines.
Psychosocial stress promotes cancer pathogenesis involving angiogenesis through alterations in neuroendocrine-immune functions that may involve adrenoceptor (AR)-dependent signaling mechanisms in the brain, lymphoid organs, and cancerous cells. Various concentrations of α- and α- AR-specific agonists and antagonists were incubated in vitro with estrogen receptor-positive (ER +) MCF-7, and ER (-) MDA MB-231 cells to examine the secretions of VEGF-A, VEGF-C, and nitric oxide (NO), and expression of signaling molecules- p-ERK, p-CREB, and p-Akt on the proliferation of breast cancer cell lines. Cellular proliferation, VEGF-A and NO secretion, expression of p-ERK, p-CREB, and p-Akt were enhanced in MCF-7 cells treated with α-AR agonist while VEGF-C secretion alone was enhanced in MDA MB-231 cells. Treatment of MCF-7 and MDA MB-231 cells with α- AR agonist similarly enhanced proliferation and decreased NO production and p-CREB expression while VEGF-C secretion was decreased in MCF-7 cells and p-Akt expression was decreased in MDA MB-231 cells. α-AR inhibition reversed cellular proliferation and VEGF-A secretion by MCF-7 cells while α-AR inhibition reversed the proliferation of MCF-7 and MDA MB-231 cells and VEGF-C secretion by MCF-7 cells. Taken together, breast cancer pathogenesis may be influenced by distinct α-AR-mediated signaling mechanisms on angiogenesis and lymphangiogenesis that are dependent on estrogen receptor status.
Topics: Humans; Female; Breast Neoplasms; MCF-7 Cells; Vascular Endothelial Growth Factor C; Proto-Oncogene Proteins c-akt; Vascular Endothelial Growth Factor A; Cell Survival; Angiogenesis; Cell Proliferation; Estrogens; Receptors, Estrogen; Receptors, Adrenergic; Cell Line, Tumor
PubMed: 38526769
DOI: 10.1007/s12032-024-02322-8 -
ACS Chemical Neuroscience May 2024The compound -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast...
The compound -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.
Topics: Animals; Antidepressive Agents; Benzamides; Mice; Male; Dopamine Antagonists; Dopamine; Hindlimb Suspension; Organoselenium Compounds
PubMed: 38639539
DOI: 10.1021/acschemneuro.4c00092 -
Journal of Ethnopharmacology Mar 2024Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this...
ETHNOPHARMACOLOGICAL RELEVANCE
Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain.
AIM OF THE STUDY
To assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (K) mechanisms in its anti-nociceptive effects.
MATERIAL AND METHODS
We employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1-, α2- and β-adrenergic, potassium adenosine triphosphate (K), opioidergic and serotonergic systems, respectively.
RESULTS
MO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception.
CONCLUSIONS
MO contains biologically active compounds with potential anti-nociceptive properties that modulate K opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.
Topics: Rats; Animals; Oils, Volatile; Melissa; Plant Extracts; Chronic Pain; Metergoline; Plants, Medicinal; Formaldehyde; Yohimbine; Adrenergic Agents; Acetates; Adenosine Triphosphate; Naloxone; Potassium; Prazosin
PubMed: 38030022
DOI: 10.1016/j.jep.2023.117500 -
Fundamental & Clinical Pharmacology Dec 2023RS17053 is classed as an α -adrenoceptor selective antagonist.
BACKGROUND
RS17053 is classed as an α -adrenoceptor selective antagonist.
OBJECTIVES
We have examined its profile of action at all subtypes of α -adrenoceptor.
METHODS
Noradrenaline (NA) evoked contractions of rat vas deferens involve α -adrenoceptors in phasic contractions and α -adrenoceptors in tonic contractions. Contractions of rat aorta to NA involve α - and α -adrenoceptors.
RESULTS
RS17053 (10 M) shifted NA potency and virtually abolished tonic contractions to NA, with little or limited effect on phasic contractions. The α -adrenoceptor antagonist BMY7378 (3 × 10 M) significantly inhibited the remaining phasic component of the contractions, and the α -adrenoceptor antagonist RS100329 (10 M) inhibited further the residual tonic contraction. Hence, RS17053 shows high selectivity for α -adrenoceptors over α -adrenoceptors in rat vas deferens. However, RS17053 (10 M) produced a large shift in the potency of NA in rat aorta, with a pK of 6.82. Large shifts of NA potency in rat aorta involve α -adrenoceptor blockade.
CONCLUSION
Results in rat vas deferens demonstrate low potency of RS17053 at α -adrenoceptors, but results from rat aorta can only be explained as demonstrating α -adrenoceptor antagonism by RS17053. RS17053 may be a useful pharmacological tool when reclassified as a mainly α - and to a lesser extent α -adrenoceptor antagonist with little effect at α -adrenoceptors.
Topics: Male; Rats; Animals; Prazosin; Vas Deferens; Receptors, Adrenergic, alpha-1; Norepinephrine; Aorta
PubMed: 37392126
DOI: 10.1111/fcp.12930 -
Research Square May 2024Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and...
Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and to better understand individual and sex differences in neurobiological mechanisms related to BD, the use of outbred rat strains would be valuable. Here, we developed a novel BD model where after 3+ months of intermittent access to 20% alcohol Wistar rats drank, twice a week, with two 5-minute intake (what we called Two-shot) separated by a 10-minute break. Our findings showed during Two-Shot that most animals reached ≥ 80mg% BAC levels (when briefly food-restricted). However, when increasing alcohol concentrations from 20% to 30%, 40%, or 50%, rats titrated to similar intake levels, suggesting rapid sensing of alcohol effects even when front-loading. Two-Shot drinking was reduced in both sexes by naltrexone (1mg/kg), validating intake suppression by a clinical therapeutic agent. Further, both propranolol (β adrenergic receptor antagonist) and prazosin (α1 adrenergic receptor antagonist) reduced female but not male BD at the lower dose. Thus, our results provide a novel model for BD in outbred rats and suggest that female binging is more sensitive to adrenergic modulation than males, perhaps providing a novel sex-related therapy.
PubMed: 38853968
DOI: 10.21203/rs.3.rs-4402198/v1