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Lijecnicki Vjesnik 2011Studies were identified on internet by searching on address: http://www.ncbi.nlm.nih.gov/pubmed/ with criteria that studies should be placebo-controlled and randomized... (Review)
Review
Studies were identified on internet by searching on address: http://www.ncbi.nlm.nih.gov/pubmed/ with criteria that studies should be placebo-controlled and randomized in trials of alpha-blockers in chronic category III prostatitis evaluated by symptom-score NIH-CPSI. From 13 clinical studies three were excluded because of not using NIH-CPSI, three were in Chinese language and two were congress abstracts. Analysed were five studies with four or five Jadad scale including 563 patients. Alpha-blockers alfuzosin, terazosin, tamsulosin and doxazosin have been used through 6 weeks and 6 months. Better results were accomplished by less selective alpha-blockers alfuzosin, terazosin and doxazosin through 3-6 months in patients having higher NIH-CPSI score and higher voiding score.
Topics: Adrenergic alpha-Antagonists; Chronic Disease; Humans; Male; Prostatitis
PubMed: 21888082
DOI: No ID Found -
British Journal of Pharmacology May 2007Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting...
BACKGROUND AND PURPOSE
Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA-8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed.
EXPERIMENTAL APPROACH
Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA-8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA-8159 (30 mg kg(-1)) and terazosin (5 mg kg(-1)) to male Sprague-Dawley rats.
KEY RESULTS
After simultaneous i.v. and p.o. administration of terazosin and DA-8159, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA-8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA-8159 and terazosin compared with each drug alone.
CONCLUSIONS AND IMPLICATIONS
The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA-8159, since both DA-8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Dexamethasone; Drug Interactions; Male; Membrane Proteins; Microsomes, Liver; Prazosin; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Troleandomycin
PubMed: 17351661
DOI: 10.1038/sj.bjp.0707192 -
European Journal of Pharmacology Jan 20226-nitrodopamine (6-ND) is released from rat isolated vas deferens and modulates electrical-field stimulation (EFS) contractions of the rat isolated epididymal vas...
6-nitrodopamine (6-ND) is released from rat isolated vas deferens and modulates electrical-field stimulation (EFS) contractions of the rat isolated epididymal vas deferens (RIEVD) via a specific receptor which is blocked by tricyclic antidepressants. Here, the effects of selective α-adrenergic receptor antagonists on RIEVD contractions induced by 6-ND, dopamine, noradrenaline, adrenaline and EFS were investigated. Doxazosin and tamsulosin (3-10 nM) caused significant rightward shifts of the concentration-response curve to 6-ND, but had no effect on dopamine-, noradrenaline- and adrenaline-induced contractions. Alfuzosin (10 nM) produced rightward shifts on concentration-response curves to all catecholamines. Silodosin (10 nM) and terazosin (100 nM) displaced to the right the noradrenaline, dopamine and adrenaline curves, but higher concentrations of both antagonists (100 and 300 nM, respectively) were required to displace the 6-ND curves. The EFS-induced contractions were significantly inhibited only at the concentrations that the α-adrenergic receptor antagonists caused rightward shifts on the 6-ND concentration-response curves. The inhibition of EFS-induced contractions by doxazosin (10 nM), tamsulosin (10 nM), alfuzosin (10 nM), silodosin (100 nM) and terazosin (300 nM), were not observed in RIEVD obtained from animals chronically treated with L-NAME. This work demonstrates that α-adrenoceptor antagonists act as 6-ND receptor antagonists in RIEVD, opening the possibility that many actions previously attributed to noradrenaline could be due to 6-ND antagonism. In addition, blockade of the 6-ND receptors by both tricyclic antidepressants and α-adrenergic receptor antagonists may represent the common mechanism of action responsible for their therapeutic use in the treatment of premature ejaculation.
Topics: Animals; Male; Vas Deferens
PubMed: 34951979
DOI: 10.1016/j.ejphar.2021.174716 -
World Journal of Cardiology May 2015New uses of cardiovascular drugs with proven experience are emerging, including for treating cancer. Quinazoline is a compound made up of two fused six member simple... (Review)
Review
New uses of cardiovascular drugs with proven experience are emerging, including for treating cancer. Quinazoline is a compound made up of two fused six member simple aromatic rings, benzene and pyrimidine rings, with several biological effects. Cardiologists first used quinazoline-based α1-adrenoceptor antagonists prazosin, doxazosin, and terazosin; currently available data support their use as safe, well tolerated, and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects. Recent findings highlight the anticancer effects of quinazoline-based α1-adrenoceptor antagonists, indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia.
PubMed: 26015856
DOI: 10.4330/wjc.v7.i5.238 -
Journal of Controlled Release :... Aug 2022Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro...
Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro and exposure to pigmented eye in vivo has been shown, there is a discrepancy between rapid drug release from melanin particles in vitro and the long in vivo retention in the pigmented tissues. We investigated mechanisms and kinetics of pigment-related drug retention experimentally using isolated melanin particles from porcine retinal pigment epithelium and choroid, isolated porcine eye melanosomes, and re-pigmented ARPE-19 cells in a dynamic flow system. The experimental studies were supplemented with kinetic simulations. Affinity and capacity of levofloxacin, terazosin, papaverine, and timolol binding to melanin revealed K values of ≈ 50-150 μM and B ≈ 40-112 nmol.mg. The drugs were released from melanin in <1 h (timolol) or in 6-12 h (other drugs). The drugs were released slower from the melanosomes than from melanin; the experimental differences ranged from 1.2-fold (papaverine) to 7.4-fold (timolol). Kinetic simulations supported the role of the melanosomal membrane in slowing down the release of melanin binders. In release studies from the pigmented ARPE-19 cells, drugs were released from the cellular melanin to the extracellular space in ≈ 1 day (timolol) and ≈ 11 days (levofloxacin), i.e., much slower than the release from melanin or melanosomes. Simulations of drug release from pigmented cells in the flow system matched the experimental data and enabled further sensitivity analyses. The simulations demonstrated a significant prolongation of drug retention in the cells as a function of decreasing drug permeability in the melanosomal membranes and increasing melanin content in the cells. Overall, we report the impact of cellular factors in prolonging drug retention and release from melanin-containing cells. These data and simulations will facilitate the design of melanin binding drugs with prolonged ocular actions.
Topics: Animals; Computer Simulation; Levofloxacin; Melanins; Papaverine; Retinal Pigment Epithelium; Swine; Timolol
PubMed: 35738465
DOI: 10.1016/j.jconrel.2022.05.059 -
Anticancer Research Nov 2013Certain α1-adrenoreceptor antagonists induce significant apoptosis and impair tumor vascularity without affecting cellular proliferation, effects specific to the... (Review)
Review
Certain α1-adrenoreceptor antagonists induce significant apoptosis and impair tumor vascularity without affecting cellular proliferation, effects specific to the quinazoline structure. These anticancer effects have been attributed to both induction of classical apoptosis and reversal of anoikis resistance via disruption of integrin-mediated cell survival pathways. Recent drug optimization efforts have generated several novel compounds with quinazoline-derived chemical structure that exert potent anti-tumor activity via anoikis. Results from pre-clinical and clinical studies implicate a potential value of quinazoline-based analogues in prostate cancer prevention and therapy. A retrospective study of a large patient cohort at our center, revealed that treatment with α1-andrenoreceptor antagonists significantly reduced the risk of developing prostate cancer, indicating a potential chemopreventative mechanism for these FDA-approved agents. In the present review we discuss the current understanding of the signaling mechanisms reversing anoikis resistance by the quinazoline-based compounds in prostate tumors, towards enabling identification of novel therapeutic targets for the treatment of metastatic castration-resistant prostate cancer (CRPC).
Topics: Animals; Humans; Male; Prostatic Neoplasms; Quinazolines
PubMed: 24222103
DOI: No ID Found -
Toxins Apr 2021Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial...
Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups ( = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α-adrenergic agonist) was compared between the two groups before and after TE (α-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC = 1.74 × 10 M; Exp EC = 1.079 × 10 M, = 0.046). TE treatment resulted in a significant dose-dependent increase in EC in both exposure and control groups ( < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, = 0.36; TE 100 nM, < 0.001; TE 300 nM, < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Arteries; Ergot Alkaloids; Ergotism; Female; Hindlimb; Muscle, Smooth, Vascular; Prazosin; Receptors, Adrenergic, alpha-1; Sheep, Domestic; Signal Transduction; Vasoconstriction; Vasoconstrictor Agents
PubMed: 33924041
DOI: 10.3390/toxins13040291 -
Parkinsonism & Related Disorders Jan 2022Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD.
METHODS
We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events.
RESULTS
Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of βATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01).
CONCLUSIONS
This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.
Topics: Adenosine Triphosphate; Dizziness; Humans; Parkinson Disease; Pilot Projects; Prazosin
PubMed: 34894470
DOI: 10.1016/j.parkreldis.2021.11.022 -
The Cochrane Database of Systematic... Sep 2011Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate which can result in bothersome lower urinary tract symptoms. The treatment goal for men... (Review)
Review
BACKGROUND
Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate which can result in bothersome lower urinary tract symptoms. The treatment goal for men with BPH is to relieve these bothersome symptoms.
OBJECTIVES
This systematic review assessed the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH.
SEARCH STRATEGY
Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library), by checking bibliographies, and by contacting manufacturers and researchers.
SELECTION CRITERIA
Trials were eligible if they (1) randomized men with BPH to receive tamsulosin in comparison with placebo, other BPH medications or surgical interventions and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements, and (3) had a treatment duration of 30 days or longer. Eligibility was assessed by at least two independent observers.
DATA COLLECTION AND ANALYSIS
Information on patients, interventions, and outcomes were extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of tamsulosin with placebo, medical or surgical interventions was the change in urologic symptom scale scores. Secondary outcomes included changes in urinary flow measures (peak urine flow rate). The main outcome measure for adverse effects was the number of men reporting adverse effects.
MAIN RESULTS
Fourteen studies involving 4122 subjects met inclusion criteria. Study duration ranged from 4 to 26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = -1.49 to -0.72; 12% improvement) and -1.6 points (95% CI = -2.3 to -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 mL/sec (95% CI = 0.59 to 1.51) and 1.1 mL/sec (95% CI= 0.65 to 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg to 0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon® in improving symptoms and flow rates though the doses of all alpha-antagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin.
AUTHORS' CONCLUSIONS
Tamsulosin provided a small to moderate improvement in urinary symptoms and flow compared to men receiving placebo in men with BPH. Effectiveness was similar to other alpha antagonists and increased only slightly with higher doses. Long term effectiveness and ability to reduce complications due to BPH progression could not be determined. Adverse effects were generally mild but their frequency, including withdrawals, increased substantially with the higher doses that are generally available for treatment.
Topics: Adrenergic alpha-Antagonists; Humans; Male; Middle Aged; Prostatic Hyperplasia; Randomized Controlled Trials as Topic; Sulfonamides; Urinary Bladder Neck Obstruction; Urinary Retention
PubMed: 21901681
DOI: 10.1002/14651858.CD002081.pub2 -
British Journal of Clinical Pharmacology Apr 2007To assess the mechanistic relationship between doxazosin (alpha(1)-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Q(max), the... (Review)
Review
AIMS
To assess the mechanistic relationship between doxazosin (alpha(1)-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Q(max), the maximum urinary flow rate) and to compare the mean receptor occupancy ratio at clinical doses of doxazosin, tamsulosin, terazosin and prazosin in benign prostatic hyperplasia (BPH).
METHODS
A ternary complex model, which described the mechanism of alpha(1)-receptor antagonists, was fitted to the pharmacological effects and receptor occupancy ratio data for doxazosin (standard tablet). In addition, mean receptor occupancy was calculated for other alpha(1)-receptor antagonists and the optimal receptor occupancy was evaluated. The clinical pharmacological effects of the controlled release formulation of doxazosin (doxazosin GITS) were estimated based on the receptor occupancy.
RESULTS
The mechanistic based model was able to describe the pharmacological effects of doxazosin. Regardless of the plasma concentrations or clinical dose of each drug, the results suggest that receptor occupancy is useful to assess quantitatively and compare the pharmacological effects of drugs with similar mechanisms of action. The clinical dosage for doxazosin GITS was estimated to be at least 8 mg and the stable pharmacological effect is expected based on the estimated receptor occupancy.
CONCLUSIONS
A model for Q(max) improvement in BPH based on the receptor occupancy theory was able to describe the clinical effects of the alpha(1)-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of alpha(1)-receptor antagonists.
Topics: Adrenergic alpha-Antagonists; Doxazosin; Humans; Male; Prostatic Hyperplasia; Receptors, Adrenergic; Urination
PubMed: 17052252
DOI: 10.1111/j.1365-2125.2006.02783.x