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JAMA Neurology Apr 2021Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely... (Observational Study)
Observational Study
IMPORTANCE
Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases.
OBJECTIVE
To determine whether use of terazosin, doxazosin, and alfuzosin is associated with a decreased risk of developing PD.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used active comparator control and propensity score-matched data from Danish nationwide health registries, including the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Civil Registration System, from January 1996 to December 2017 and data from the Truven Health Analytics MarketScan database from January 2001 to December 2017. Men without PD who newly initiated terazosin/doxazosin/alfuzosin therapy or tamsulosin therapy, which is used for a similar indication (benign prostatic hyperplasia or unspecified urinary problems) but does not enhance glycolysis, and had at least 1 year of follow-up after medication start were included. In Denmark, the database included all residents, while the Truven database is a compilation of insurance claims across the US. Data were analyzed from February 2019 to July 2020.
EXPOSURES
Patients who used terazosin/doxazosin/alfuzosin vs tamsulosin. Additional dose-response analyses were carried out.
MAIN OUTCOMES AND MEASURES
Differences in the hazard of developing PD identified by diagnoses or use of PD-specific medications between patients who ever used terazosin/doxazosin/alfuzosin or tamsulosin.
RESULTS
A cohort of 52 365 propensity score-matched pairs of terazosin/doxazosin/alfuzosin and tamsulosin users were identified in the Danish registries, of which all were male and the mean (SD) age was 67.9 (10.4) years, and 94 883 propensity score-matched pairs were identified in the Truven database, of which all were male and the mean (SD) age was 63.8 (11.1) years. Patients in the Danish cohort who used terazosin/doxazosin/alfuzosin had a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), and patients in the Truven cohort had an HR of 0.63 (95% CI, 0.58-0.69). There was a dose-response association with short-duration, medium-duration, and long-duration use of terazosin/doxazosin/alfuzosin users having a decreasing HR in both the Danish cohort (short: HR, 0.95; 95% CI, 0.84-1.07; medium: HR, 0.88; 95% CI, 0.77-1.01; long: HR, 0.79; 95% CI, 0.66-0.95) and Truven cohort (short: HR, 0.70; 95% CI, 0.64-0.76; medium: HR, 0.58; 95% CI, 0.52-0.64; long: HR, 0.46; 95% CI, 0.36-0.57).
CONCLUSIONS AND RELEVANCE
These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Cohort Studies; Databases, Factual; Denmark; Doxazosin; Female; Follow-Up Studies; Glycolysis; Humans; Male; Middle Aged; Parkinson Disease; Prazosin; Quinazolines; Registries; Risk Factors; Tamsulosin; United States
PubMed: 33523098
DOI: 10.1001/jamaneurol.2020.5157 -
NPJ Parkinson's Disease Mar 2023Terazosin is an α-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent...
Terazosin is an α-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
PubMed: 36864060
DOI: 10.1038/s41531-023-00477-1 -
Minerva Urology and Nephrology Aug 2023Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and...
BACKGROUND
Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and sexual AEs associated with ABs based on Eudra-Vigilance reported AEs.
METHODS
Eudra-Vigilance (EV) database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of sexual and neuro-vascular AEs for tamsulosin, alfuzosin, silodosin, prazosin and doxazosin per category and severity until July 30, 2022. Pooled Relative Risk (PRR) was used to compare data between drugs.
RESULTS
Overall the number of AEs were 2842 for Alfuzosin, 11,086 for tamsulosin, 792 for terazosin, 572 for prazosin and 4641 for doxazosin. Different percentages of AEs were obtained for each drug and in different age groups according to EV sub-groups (≤65, 65-85, ≥85). On PRR analysis, the risk of ejaculatory disorders for Silodosin (11%) is 18.5 times higher (PRR 18.5 95%CI; 10.7-31.8; P<0.05) when compared to alfuzosin and the risk of orthostatic hypotension is 2 times lower (PRR=1,84 95%CI 1.32-2.57; P<0.05).
CONCLUSIONS
Real life data is consistent with registry studies regarding side effects related to alpha-blockers. Alfuzosin is safer in terms of ejaculatory disorders while silodosin and tamsulosin in terms of orthostatic hypotension. Clinicians should consider these data when prescribing ABs especially in younger and older patients.
Topics: Humans; Doxazosin; Tamsulosin; Hypotension, Orthostatic; Adrenergic alpha-Antagonists; Prazosin; Urogenital Diseases
PubMed: 37067186
DOI: 10.23736/S2724-6051.23.05225-4 -
Urology Journal Apr 2021The present study aims to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (LUTS), the urine flow, and blood... (Comparative Study)
Comparative Study Randomized Controlled Trial
A Randomized Crossover Pilot Study Examining the Effect of Carvedilol and Terazosin plus Enalapril on Urinary Symptoms of Patients with Hypertension and Benign Prostatic Hyperplasia.
PURPOSE
The present study aims to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (LUTS), the urine flow, and blood pressure (BP) in patients with moderate hypertension (HTN) and benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS
In this randomized crossover trial, a total of 40 men with HTN and LUTS symptoms were enrolled. The first group was treated with carvedilol, and the second one received terazosin plus enalapril. After eight weeks of treatment, the patients experienced a one-month washout period, and the treatments changed and continued for eight weeks. To diagnose BPH in the study, the international prostate symptom score (IPSS) questionnaire was used. Moreover, the prostate-specific antigen (PSA), the post-void residual (PVR) urine volume, and the maximum urinary flow rate (Q-max using the uroflowmetry test) were measured.
RESULTS
Effect assessment results in this crossover trial illustrated neither carryover effects nor significant treatment effects on all primary outcomes (P > 0.05). Moreover, the results for the period effect indicated a significant reduction in BP (systolic and diastolic), PVR, and IPSS, yet a significant raise in Qmax.
CONCLUSION
The effects of carvedilol are similar to those of the combination of terazosin and enalapril in patients with moderate HTN and BPH in controlling LUTS. Carvedilol could be used as an appropriative drug in patients with moderate HTN and cardiac problems with LUTS of BPH. Further studies are recommended to be conducted to investigate and compare the efficacy of carvedilol with that of other alpha-blockers with a larger sample size and over a longer period of time.
Topics: Adrenergic alpha-1 Receptor Antagonists; Aged; Antihypertensive Agents; Carvedilol; Cross-Over Studies; Drug Therapy, Combination; Enalapril; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Prazosin; Prostatic Hyperplasia; Single-Blind Method
PubMed: 33840085
DOI: 10.22037/uj.v18i.5678 -
Frontiers in Chemistry 2022Nitrogen-containing heterocyclic compounds have shown promising therapeutic effects in a variety of inflammatory and neurodegenerative diseases. Recently, terazosin...
Nitrogen-containing heterocyclic compounds have shown promising therapeutic effects in a variety of inflammatory and neurodegenerative diseases. Recently, terazosin (TZ), a heterocyclic compound with a quinazoline core, was found to combine with phosphoglycerol kinase 1 (Pgk1) and protect neurons by enhancing Pgk1 activity and promoting glycolysis, thereby slowing, or preventing the neurodegeneration of PD. These findings indicated that terazosin analogs have bright prospects for the development of PD therapeutics. In this study, a series of terazosin analogs were designed and synthesized for neuroprotective effects by targeting Pgk1. Among them, compound was obtained with the best Pgk1 agonistic activity and neuroprotective activity. Further study indicates that it can increase intracellular ATP content and reduce ROS levels by stimulating the activity of Pgk1, thereby playing a role in protecting nerve cells. In conclusion, this study provides a new strategy and reference for the development of neuroprotective drugs.
PubMed: 35958233
DOI: 10.3389/fchem.2022.906974 -
Annals of Medicine and Surgery (2012) Feb 2024Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal... (Review)
Review
Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal protein in the brain, namely, the Lewy body causes disturbances in typical neural functioning, leading to a range of cognitive, motor, and mental symptoms that have a substantial influence on the overall well-being and quality of life of affected individuals. There is no definitive cure for the disease; however, several nonpharmacological and pharmacological modalities have been tried with questionable efficacies. The aim of this study is to figure out the role of different interventional strategies in the disease. Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated. Talking about nonpharmacological measures, exercise, physical therapy, multicomponent therapy, occupational therapy, psychobehavioral modification, transcranial stimulation, and deep brain stimulation have been used with variable efficacies. Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out. However, there drugs are still in the different phases of clinical trials and are not commonly used in clinical practice. With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures.
PubMed: 38333295
DOI: 10.1097/MS9.0000000000001664 -
International Journal of Molecular... Aug 2016This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to... (Review)
Review
This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antineoplastic Agents; Doxazosin; Female; Humans; Male; Prazosin; Prostatic Neoplasms
PubMed: 27537875
DOI: 10.3390/ijms17081339 -
Expert Opinion on Pharmacotherapy Jun 2004Prostate cancer is the second most common cause of cancer death in men in the US. Patients with prostate cancer are initially treated with surgical resection, radiation... (Review)
Review
Prostate cancer is the second most common cause of cancer death in men in the US. Patients with prostate cancer are initially treated with surgical resection, radiation or antiandrogen therapy. After an initial remission, however, the majority of prostate tumours evolve into a highly aggressive, metastatic androgen-independent state, for which successful therapy has not yet been established. During the past few years, new perspectives have emerged towards the development of preventive and therapeutic approaches for prostate cancer. Quinazoline-based alpha(1)-blockers have been shown to have antitumour efficacy against prostate cancer cells in inducing apoptosis and anoikis via an alpha(1)-adrenoceptor-independent mechanism. Specifically, doxazosin and terazosin can induce apoptosis, inhibit invasion and migration of prostate cancer and endothelial cells, and reduce their adhesion potential to extracellular matrix components, thus enhancing their susceptibility to anoikis. This review discusses recent evidence suggesting the apoptotic efficacy of quinazoline-based alpha(1)-adrenoceptor antagonists, doxazosin and terazosin and speculates on the therapeutic promise of these drugs as novel antitumour agents against prostate cancer. From a drug discovery perspective, separation of the effect of doxazosin on apoptosis in prostate cancer cells from its original pharmacological activity in normal prostate cells, will provide a molecular basis in developing a novel class of apoptosis-inducing agents through lead optimisation.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Angiogenesis Inhibitors; Anoikis; Doxazosin; Humans; Male; Prazosin; Prostatic Neoplasms; Quinazolines; Sulfonamides; Tamsulosin
PubMed: 15163273
DOI: 10.1517/14656566.5.6.1279 -
Antibiotics (Basel, Switzerland) Jan 2022Antimicrobial resistance is among the world's most urgent public health problems. Diminishing of the virulence of bacteria is a promising approach to decrease the...
Antimicrobial resistance is among the world's most urgent public health problems. Diminishing of the virulence of bacteria is a promising approach to decrease the development of bacterial resistance. Quorum sensing (QS) systems orchestrate the bacterial virulence in inducer-receptors manner. Bacteria can spy on the cells of the host by sensing adrenergic hormones and other neurotransmitters, and in turn, these neurotransmitters can induce bacterial pathogenesis. In this direction, -adrenergic blockers were proposed as an anti-virulence agents through inhibiting the bacterial espionage. The current study aimed to explore the -blockers' anti-QS activities. Within comprehensive in silico investigation, the binding affinities of seven -adrenoreceptor blockers were evaluated towards structurally different QS receptors. From the best docked -blockers into QS receptors, terazosin was nominated to be subjected for further in vivo and in vitro anti-QS and anti-virulence activities against and . Terazosin showed a significant ability to diminish the QS-controlled pigment production in Moreover, Terazosin decreased the biofilm formation and down-regulated its QS-encoding genes. Terazosin protected mice from the pathogenesis. In conclusion, -adrenergic blockers are proposed as promising anti-virulence agents as they hinder QS receptors and inhibit bacterial espionage.
PubMed: 35203781
DOI: 10.3390/antibiotics11020178 -
Therapeutic Advances in Urology 2019Benign prostatic hyperplasia (BPH), a common urological disease in aging men, frequently produces lower urinary tract symptoms (LUTS). Clinical studies have shown that...
BACKGROUND
Benign prostatic hyperplasia (BPH), a common urological disease in aging men, frequently produces lower urinary tract symptoms (LUTS). Clinical studies have shown that terazosin relaxes the smooth muscle of the prostate and bladder, facilitates bladder emptying, improves LUTS, increases maximum urinary flow, and reduces the residual volume of urine. D-004, a lipid extract of the fruit of the Cuban royal palm (), presents a similar efficacy to Saw palmetto. Clinical studies have demonstrated its efficacy and safety in short- and medium-term trials in patients with BPH. The objective of this study was to compare the efficacy and tolerability of D-004 with terazosin for 6 months on LUTS in patients with BPH.
METHODS
The present phase III study had an open, randomized, comparative design, with two parallel groups who received D-004 (320 mg/day) or terazosin (5 mg/day) for 6 months. The study included men at least 50 years of age, with evidence of the LUTS of moderate intensity according to the International Symptoms of the Prostate (IPSS). The effects on the IPSS Scale was the primary efficacy variable. The effects on the size of the prostate and the residual volume were secondary variables. The subjective self-perception of symptom relief at trial completion was a collateral outcome. Analysis was done by intention-to-treat.
RESULTS
The study included 100 men with a diagnosis of BPH, confirmed by digital rectal examination and ultrasonography, and moderate LUTS (IPSS score >7, <19). Baseline characteristics were similar in both groups. Nine patients did not continue the study: one from group D-004 (due to protocol violation) and eight from the terazosin group (six due to adverse events and two due to protocol violation; < 0.01). D-004 and terazosin significantly reduced the IPSS scores at the end of the 6 months of therapy by 74.2% and 66.1%, respectively, with respect to baseline values. Comparisons between groups performed showed that, at the end of the treatment, D-004 was more effective ( < 0.05) than terazosin in reducing the IPSS score. Although the average size of the prostate was reduced in both groups, this reduction reached statistical significance only for D-004. On the other hand, postvoid residual volume was significantly and similarly reduced in both groups. Both treatments were safe, while D-004 was better tolerated than terazosin.
CONCLUSIONS
D-004 administered at a dose of 320 mg/day for 6 months showed comparable efficacy with terazosin (5 mg/day) in reducing the LUTS (IPSS score), producing a significant decrease in prostate volume and postvoid residual volume. Both treatments were safe, with better tolerability for D-004 as compared with terazosin.
PubMed: 31217822
DOI: 10.1177/1756287219854923