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Nature Chemical Biology Jan 2015Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely...
Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Apoptosis; Cells, Cultured; Cytokines; HSP90 Heat-Shock Proteins; Infarction, Middle Cerebral Artery; Mice; Models, Molecular; Phosphoglycerate Kinase; Prazosin; Protein Conformation; Rats; Sepsis; Stress, Physiological; Stroke
PubMed: 25383758
DOI: 10.1038/nchembio.1657 -
The American Journal of Managed Care Apr 2006Benign prostatic hyperplasia (BPH) is extremely common in the aging man and may cause significant lower urinary tract symptoms (LUTS) necessitating treatment. Drug... (Review)
Review
Benign prostatic hyperplasia (BPH) is extremely common in the aging man and may cause significant lower urinary tract symptoms (LUTS) necessitating treatment. Drug treatment is the mainstay of treatment for symptomatic BPH and is directed at relaxing prostatic smooth muscle, reducing prostate volume, or a combination of these effects. The most commonly used drugs for this indication are alpha1-adrenergic receptor antagonists, which relax prostatic smooth muscle, and 5-alpha-reductase inhibitors, which reduce prostatic androgen levels and consequently prostate size. Invasive interventions include the gold standard, transurethral resection of the prostate (TURP), and several minimally invasive surgical options. Although effective in alleviating symptoms, TURP carries a higher risk of morbidity and complications, including sexual side effects (mainly ejaculatory dysfunction), than medical therapy or minimally invasive techniques. Treatment for BPH, whether medical or surgical, must take patients' comorbid conditions into consideration so that LUTS may be effectively relieved, with the smallest risk of exacerbating any concomitant conditions.
Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Azasteroids; Cardiovascular Diseases; Comorbidity; Doxazosin; Drug Therapy, Combination; Dutasteride; Enzyme Inhibitors; Erectile Dysfunction; Finasteride; Global Health; Humans; Male; Prazosin; Prostatic Hyperplasia; Quinazolines; Sulfonamides; Tamsulosin; Transurethral Resection of Prostate; Treatment Outcome
PubMed: 16613527
DOI: No ID Found -
British Journal of Clinical Pharmacology Jan 1998A radioreceptor assay has been developed for alpha1-adrenoceptor subtypes and applied to a pharmacokinetic analysis of tamsulosin and terazosin. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
AIMS
A radioreceptor assay has been developed for alpha1-adrenoceptor subtypes and applied to a pharmacokinetic analysis of tamsulosin and terazosin.
METHODS
Young, male, healthy volunteers received 0.4 mg tamsulosin (as Omnic modified release capsules) or 5 mg terazosin (as Flotrin tablets) in a randomized, cross-over design. Before and after 1, 3, 5, 7, 10 and 23.5 h plasma was analyzed by radioreceptor assay using cloned human alpha1A-, alpha1B- and alpha1D-adrenoceptors and specific h.p.l.c. analysis.
RESULTS
Following ingestion of tamsulosin median peak plasma levels of 16 ng ml(-1) were reached after 5 h and declined to 2 ng ml(-1) at 23.5 h. The time course in the radioreceptor assay was similar, and at most time points binding to alpha1A-adrenoceptors was significantly greater than to alpha1B- and alpha1D-adrenoceptors. Following ingestion of terazosin median peak plasma levels of 91 ng ml(-1) were reached after 1 h and declined to 11 ng ml(-1) at 23.5 h. In the radioreceptor assay binding also peaked at 1 h and declined thereafter, but even after 23.5 h considerable binding activity remained detectable at all three subtypes. At most time points binding to the alpha1A- and alpha1D-adrenoceptor was significantly greater than to the alpha1B-adrenoceptor.
CONCLUSIONS
We conclude that alpha1-adrenoceptor antagonist pharmacokinetics can be monitored by radioreceptor assays in a subtype-selective manner. Tamsulosin and terazosin exhibit subtype selective receptor binding ex vivo. The discordance between terazosin blood levels as determined by h.p.l.c. and radioreceptor assay at late time points indicates the possible involvement of metabolites in in vivo terazosin effects.
Topics: Administration, Oral; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Animals; Chromatography, High Pressure Liquid; Cloning, Molecular; Cross-Over Studies; Humans; Male; Placebos; Prazosin; Radioligand Assay; Rats; Receptors, Adrenergic, alpha-1; Single-Blind Method; Substrate Specificity; Sulfonamides; Tamsulosin; Transfection
PubMed: 9489594
DOI: 10.1046/j.1365-2125.1998.00636.x -
International Braz J Urol : Official... 2013To evaluate the effects of terazosin and tolterodine on ureteral stent discomfort. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the effects of terazosin and tolterodine on ureteral stent discomfort.
MATERIALS AND METHODS
Of 163 patients assessed for eligibility, 104 patients were randomly assigned to receive placebo, 2 mg of terazosin twice daily, 2 mg of tolterodine daily, or both terazosin plus tolterodine during the stenting period. Prior to stenting and at stent removal, the International Prostate Symptom Score (IPSS), the IPSS quality of life (QoL) subscore and the Visual Analog Scale for Pain were determined. The patients also reported their analgesic use during the stenting period.
RESULTS
Ninety-four patients completed the study. We noted significant decreases in the total IPSS scores (p = 0.002), irritative subscore (p = 0.039), QoL (p = 0.001), flank pain (p = 0.013), voiding pain (p = 0.01) and amount of analgesics used (p = 0.02) in the groups. However, neither the obstructive subscore nor the suprapubic pain improved significantly (p = 0.251 and p = 0.522, respectively). The patients receiving terazosin plus tolterodine experienced significant reductions in the total IPSS, irritative symptoms, QoL, flank pain, voiding pain and decreased analgesics use compared with those patients receiving placebo. However, compared with placebo, terazosin monotherapy did not affect pain levels, and tolterodine monotherapy did not improve QoL, flank pain or analgesics use.
CONCLUSIONS
Terazosin plus tolterodine improves ureteral stent-related complications, including irritative symptoms, the amount of analgesics used, QoL, flank pain and voiding pain but does not decrease obstructive symptoms or suprapubic pain. This trial was registered at www.clinicaltrials.gov as NCT01530243.
Topics: Adolescent; Adult; Benzhydryl Compounds; Cresols; Device Removal; Double-Blind Method; Female; Flank Pain; Humans; Male; Middle Aged; Phenylpropanolamine; Prazosin; Prospective Studies; Quality of Life; Stents; Surveys and Questionnaires; Time Factors; Tolterodine Tartrate; Treatment Outcome; Ureter; Urological Agents; Visual Analog Scale; Young Adult
PubMed: 24456787
DOI: 10.1590/S1677-5538.IBJU.2013.06.09 -
International Journal of Environmental... Jun 2022Pneumoconiosis remains one of the most serious global occupational diseases. However, effective treatments are lacking, and early detection is crucial for disease...
Pneumoconiosis remains one of the most serious global occupational diseases. However, effective treatments are lacking, and early detection is crucial for disease prevention. This study aimed to explore serum biomarkers of occupational coal workers' pneumoconiosis (CWP) by high-throughput metabolomics, combining with machine learning strategy for precision screening. A case-control study was conducted in Beijing, China, involving 150 pneumoconiosis patients with different stages and 120 healthy controls. Metabolomics found a total of 68 differential metabolites between the CWP group and the control group. Then, potential biomarkers of CWP were screened from these differential metabolites by three machine learning methods. The four most important differential metabolites were identified as benzamide, terazosin, propylparaben and N-methyl-2-pyrrolidone. However, after adjusting for the influence of confounding factors, including age, smoking, drinking and chronic diseases, only one metabolite, propylparaben, was significantly correlated with CWP. The more severe CWP was, the higher the content of propylparaben in serum. Moreover, the receiver operating characteristic curve (ROC) of propylparaben showed good sensitivity and specificity as a biomarker of CWP. Therefore, it was demonstrated that the serum metabolite profiles in CWP patients changed significantly and that the serum metabolites represented by propylparaben were good biomarkers of CWP.
Topics: Anthracosis; Biomarkers; Case-Control Studies; Coal; Coal Mining; Humans; Machine Learning; Metabolomics; Pneumoconiosis
PubMed: 35742299
DOI: 10.3390/ijerph19127051 -
Hypertension (Dallas, Tex. : 1979) Apr 2008Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study...
Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 muL/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY ( approximately 40 bpm), while lowering MAP to a greater extent in SHR (-22+/-4 mm Hg) than WKY (-4+/-3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R.
Topics: Adrenergic alpha-Antagonists; Agouti-Related Protein; Animals; Antihypertensive Agents; Blood Pressure; Eating; Female; Heart Rate; Hypertension, Renal; Hypothalamus; Male; Melanocortins; Melanocyte-Stimulating Hormones; Neuropeptide Y; Prazosin; Pro-Opiomelanocortin; Propranolol; RNA, Messenger; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Leptin; Sympathetic Nervous System
PubMed: 18285617
DOI: 10.1161/HYPERTENSIONAHA.107.100636 -
Clinical Cardiology Nov 1990The sympathetic nervous system plays a major role in the pathogenesis of essential hypertension and is mediated by the alpha and beta receptors. The alpha receptor is... (Review)
Review
The sympathetic nervous system plays a major role in the pathogenesis of essential hypertension and is mediated by the alpha and beta receptors. The alpha receptor is divided into two types, alpha 1 and alpha 2, based on response to epinephrine and norepinephrine. alpha 1-Adrenergic receptors have a high affinity for drugs such as prazosin, doxazosin, and terazosin, which act to reduce blood pressure by selective blockade of the receptor. These agents provide a rational approach to the treatment of hypertension by correcting elevated total peripheral resistance, the fundamental hemodynamic abnormality in essential hypertension. In contrast, early alpha-adrenergic receptor blockers nonselectively blocked both alpha 1 and alpha 2 receptors and were unsuitable as antihypertensive agents because they induced tachycardia and patients developed a tolerance to them rapidly. alpha 1-Adrenergic blockers also have beneficial effects on plasma lipoproteins, tending to decrease levels of triglycerides and cholesterol and increase levels of high-density lipoprotein (HDL) cholesterol and the HDL cholesterol/total cholesterol ratio. beta-Adrenergic blockers, such as propranolol and atenolol, have been shown to have an adverse effect on the lipid profile by tending to increase levels of triglycerides and decrease HDL cholesterol. A number of mechanisms contribute to these effects, in particular, adrenergic modulation of lipoprotein lipase and the triglyceride secretion rate. Doxazosin has been shown to increase the activity of LDL receptors, which may be partly responsible for its beneficial effect on plasma lipids and lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adrenergic alpha-Antagonists; Humans; Hypertension; Lipoproteins
PubMed: 1980236
DOI: 10.1002/clc.4960131104 -
Journal of Andrology 1991The rationale for using alpha blockade to treat benign prostatic hyperplasia (BPH) is based on the physiology and pharmacology of prostate smooth muscle. Approximately... (Review)
Review
The rationale for using alpha blockade to treat benign prostatic hyperplasia (BPH) is based on the physiology and pharmacology of prostate smooth muscle. Approximately 20% of the area density of the prostate adenoma is smooth muscle. In vitro isometric tension studies have demonstrated that the contractile properties of the human prostate adenoma are mediated primarily by alpha 1 adrenoceptors. Alpha blockers presumably decrease the resistance along the prostatic urethra by relaxing the smooth muscle component of the prostate. Over the past 14 years, at least 16 clinical trials have confirmed the efficacy of alpha blockade in the treatment of BPH. The primary advantage of terazosin over all other commercially available alpha blockers is that its longer half-life allows for a once-daily dosage regimen. Two Phase II studies conducted in the United States, a multicenter dose titration randomized withdrawal study and the author's personal experience with terazosin, are summarized in this report. Overall, the peak urinary flow rate increased 50% and the mean urinary flow rate increased 46% following terazosin therapy. The mean obstructive and irritative scores improved 67% and 35%, respectively. The adverse reactions occurring with an incidence greater than 5% included headache (10%), asthenia (7%), and dizziness (14%). All adverse events were reversible on termination of therapy. The preliminary experiences with alpha blockers for the treatment of BPH has been very encouraging. Yet, the definitive role of alpha blockade in BPH awaits the reporting of multicenter, randomized placebo-controlled studies.
Topics: Adrenergic alpha-Antagonists; Humans; Male; Prostatic Hyperplasia
PubMed: 1722795
DOI: No ID Found -
Journal of Korean Medical Science Jun 2008The aim of this study was to compare the impacts of terazosin and tamsulosin, on prostate activity, i.e., serum prostate-specific antigen, total prostate volume (TPV),... (Comparative Study)
Comparative Study
The aim of this study was to compare the impacts of terazosin and tamsulosin, on prostate activity, i.e., serum prostate-specific antigen, total prostate volume (TPV), and transition zone volume (TZV). A total of 90 patients who presented with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), ranging in age from 52 to 83 yr (median 65 yr), were included in the study. Patients were given 0.2 mg tamsulosin, 2 mg terazosin, or 4 mg terazosin once daily for an average of 14 months (range, 6-56 months). Subjective (International Prostate Symptom Scores, I-PSS) and objective (maximal flow rate and post-void residual) parameters were assessed both at baseline and at treatment cessation. Serum prostate-specific antigen (PSA) levels were found to be unaffected by treatment (1.2 and 1.3 ng/mL). In total patients, multivariate analysis showed that baseline TPV was the only independent predictor of treatment-related TPV reduction. Moreover, baseline TPV > or =30 g was found to be associated with a higher likelihood of TPV reduction (odds ratio [OR], 3.939; 95% confidence interval [CI], 1.506-10.304; p=0.005), and a baseline TZV of > or =10 g was associated with a 7.1-times greater chance of TZV reduction (OR, 7.100; 95% CI, 2.428-20.763; p<0.001). The same model showed that patients on 2 mg terazosin had a 10.8-fold greater likelihood (OR, 10.770; 95% CI, 1.409-82.323; p=0.022) and that those on 4 mg terazosin had a 9.0-fold greater likelihood (OR, 9.001; 95% CI, 1.724-46.995; p=0.009) of a TZV reduction than those on 0.2 mg tamsulosin. In addition, symptoms improved regardless of prostate activity after taking alpha1-blockers. Our findings suggest that terazosin reduces TZV and demonstrate that the relief of symptoms associated with BPH may not be due to a prostate activity reduction induced by apoptosis in the prostate gland.
Topics: Adrenergic alpha-Antagonists; Aged; Aged, 80 and over; Humans; Logistic Models; Male; Middle Aged; Prazosin; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Retrospective Studies; Sulfonamides; Tamsulosin; Treatment Outcome
PubMed: 18583890
DOI: 10.3346/jkms.2008.23.3.509 -
Journal of Pharmacological Sciences 2010alpha(1)-Adrenoceptor antagonists are the mainstay of medical treatment of male voiding dysfunction which typically is attributed to benign prostatic hyperplasia. While... (Review)
Review
The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: alpha-blockers in the treatment of male voiding dysfunction - how do they work and why do they differ in tolerability?
alpha(1)-Adrenoceptor antagonists are the mainstay of medical treatment of male voiding dysfunction which typically is attributed to benign prostatic hyperplasia. While original concepts have assumed that they relieve voiding dysfunction by relaxing prostatic smooth muscle, newer data indicate that their therapeutic effects at least partly occur independent of prostatic relaxation, perhaps involving direct effects on blood vessels, urothelium, afferent nerves, and/or smooth muscle of the urinary bladder. The adverse event profiles differ among alpha(1)-adrenoceptor antagonists, with tamsulosin having a particularly good cardiovascular tolerability. While this was originally attributed to its selectivity for alpha(1A)-adrenoceptors, it appears that alfuzosin which lacks subtype-selectivity, has a very similar tolerability. In contrast, doxazosin and terazosin, which are chemically and pharmacologically more closely related to alfuzosin than to tamsulosin, appear to have more side effects attributable to the cardiovascular system. More recent data indicate that tolerability differences between alpha(1)-adrenoceptor antagonists may at least partly relate to pharmacokinetic rather than to pharmacodynamic differences. Taken together, these data emphasize the idea that concepts about drug efficacy and tolerability despite being highly plausible may not necessarily be true and always require thorough experimental testing.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Humans; Male; Muscle Relaxation; Muscle, Smooth; Prostatic Hyperplasia; Receptors, Adrenergic, alpha-1; Urination Disorders
PubMed: 20134112
DOI: 10.1254/jphs.09r15fm