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Aging Cell Aug 2022Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being,... (Review)
Review
Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age-related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant-based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non-interventional studies have connected high-quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha-ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.
Topics: Aging; Caloric Restriction; DNA Methylation; Epigenesis, Genetic; Humans; Life Style
PubMed: 35778957
DOI: 10.1111/acel.13664 -
Journal of Clinical Hypertension... Sep 2011KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically,... (Review)
Review
KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 hours) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. • Furosemide usage, the most widely used diuretic in the loop diuretic class, can be complicated by extremely erratic absorption, with a bioavailability range of 12% to 112%. • Chlorthalidone, at a dose of 25 mg, is comparatively more potent than 50 mg of hydrochlorothiazide, particularly as related to overnight blood pressure reduction. • In ALLHAT, there was no difference among chlorthalidone, amlodipine, lisinopril, and doxazosin for the primary outcome or mortality. • Secondary outcomes were similar except for a 38% higher rate of heart failure with amlodipine; a 10% higher rate of combined cardiovascular disease, a 15% higher rate of stroke, and a 19% higher rate of heart failure with lisinopril; and a 20% higher rate of cardiovascular disease, a 20% higher rate of stroke (40% higher rate in blacks), and an 80% higher rate of heart failure with doxazosin, compared with chlorthalidone. • The ACCOMPLISH study may affect future practice guidelines as a result of its findings favoring the amlodipine/benazepril combination; however, the generalizability to patient populations with a lesser cardiovascular risk profile remains in question and the dose of hydrochlorothiazide was only 12.5 mg to 25 mg daily, which was a dose lower than that used in placebo-controlled trials using hydrochlorothiazide. • Certain low-renin patient groups (eg, blacks, the elderly, and diabetics) as well as those who manifest the metabolic syndrome are commonly more responsive to thiazide-type diuretic therapy. • Diuretics can be successfully combined with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, centrally acting agents, and even calcium channel blockers. • Although thiazide-type diuretics are among the best-tolerated antihypertensive agents in terms of symptomatic adverse effects, diuretic-related adverse side effects include those with established mechanisms (eg, such as electrolyte changes and/or metabolic abnormalities) and other side effects, which are less well understood mechanistically (eg, impotence), although the latter is not universally accepted as a diuretic-related side effect. • Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. • Thiazide-induced hyperuricemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion, but does not necessarily contraindicate using a thiazide, especially if a uric acid-lowering drug such as allopurinol is being used. • Adverse interactions include the blunting of thiazide effects by nonsteroidal anti-inflammatory drugs and the potential to increase fatigue, lethargy, and increase in glucose when combined with β-blockers. • Thiazide-type diuretics are useful first-line agents in the treatment of hypertension because they have been proven to reduce cardiovascular mortality and morbidity in systolic and diastolic forms of hypertension and do so at low cost. • Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (eg, heart failure and significant fluid retention with vasodilator drugs, such as minoxidil) or with advanced renal failure and can be combined with thiazide-type diuretics.
Topics: Antihypertensive Agents; Humans; Hypertension; Hyperuricemia; Hypokalemia; Risk Management; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome
PubMed: 21896142
DOI: 10.1111/j.1751-7176.2011.00512.x -
Lancet (London, England) Nov 2015Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by... (Comparative Study)
Comparative Study Randomized Controlled Trial
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
BACKGROUND
Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.
METHODS
In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081.
FINDINGS
Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.
INTERPRETATION
Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.
FUNDING
The British Heart Foundation and National Institute for Health Research.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-1 Receptor Antagonists; Aged; Bisoprolol; Cross-Over Studies; Double-Blind Method; Doxazosin; Female; Humans; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome
PubMed: 26414968
DOI: 10.1016/S0140-6736(15)00257-3 -
The New England Journal of Medicine Dec 2003Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown.
METHODS
We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia.
RESULTS
The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone.
CONCLUSIONS
Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.
Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Analysis of Variance; Disease Progression; Double-Blind Method; Doxazosin; Drug Therapy, Combination; Enzyme Inhibitors; Finasteride; Humans; Male; Middle Aged; Prostatic Hyperplasia; Severity of Illness Index
PubMed: 14681504
DOI: 10.1056/NEJMoa030656 -
Drug Design, Development and Therapy 2021To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism.
PURPOSE
To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism.
METHODS
In vivo, a mouse liver fibrosis model was induced by the intraperitoneal injection of carbon tetrachloride (CCl). Doxazosin was administered at doses of 2.5, 5 and 10 mg/(kg*day) by gavage. After 20 weeks, blood and liver tissues were collected for serological and histological analysis, respectively. Blood analysis, hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry and immunofluorescence staining were used to measure the extent of liver fibrosis in model and control mice. In vitro, the human HSC cell line LX-2 was cultured and treated with different doses of doxazosin for the indicated times. The effects of doxazosin on LX-2 cell proliferation and migration were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The number of autophagosomes in LX-2 cells was observed by transmission electron microscopy (TEM). Infection with green fluorescent protein (GFP)-LC3B adenovirus, GFP-red fluorescent protein (RFP)-LC3B adenovirus and mCherry-EGFP-LC3 adeno-associated virus was performed to examine changes in autophagic flux in vitro and in vivo. Cell apoptosis was measured by flow cytometry in vitro and by TUNEL assays both in vitro and in vivo. Immunoblotting was performed to evaluate the expression levels of proteins related to fibrosis, autophagy, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR).
RESULTS
Doxazosin inhibited HSC proliferation and migration. HSC activation was attenuated by doxazosin in a concentration-dependent manner in vivo and in vitro. Doxazosin also blocked autophagic flux and induced apoptosis in HSCs. In addition, the PI3K/Akt/mTOR pathway was activated by doxazosin and regulated fibrosis, autophagy and apoptosis in HSCs.
CONCLUSION
The study confirmed that doxazosin could inhibit autophagy by activating the PI3K/Akt/mTOR signaling pathway and attenuate liver fibrosis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Apoptosis; Autophagy; Carbon Tetrachloride; Cell Line; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Doxazosin; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34456560
DOI: 10.2147/DDDT.S317701 -
The Journal of Clinical Endocrinology... Jul 2020Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
OBJECTIVE
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
DESIGN
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898).
SETTING
Multicenter study including 9 centers in The Netherlands.
PATIENTS
134 patients with nonmetastatic PPGL.
INTERVENTION
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
MAIN OUTCOME MEASURES
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
RESULTS
Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
CONCLUSIONS
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Blood Pressure; Doxazosin; Female; Humans; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Treatment Outcome
PubMed: 31714582
DOI: 10.1210/clinem/dgz188 -
International Journal of Environmental... Dec 2022Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and... (Meta-Analysis)
Meta-Analysis Review
Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and meta-analysis of the effects of different pharmacological placebo-controlled randomized clinical trials, covering the period up to 1 December 2022, was performed. Searches were conducted in PubMed, Embase, Web of Science, PsychInfo, Cinahl, and Google Scholar, resulting in the identification of 1762 articles, of which 14 met the inclusion criteria: pharmacological intervention of nightmares, based on a placebo-controlled randomized trial published in a European language, reporting outcomes either/or in terms of nightmare frequency, nightmare distress, or nightmare intensity, and reporting sufficient information enabling calculation of effect sizes. Most studies involved the effect of the α-adrenergic antagonist prazosin in samples of veterans or soldiers suffering from posttraumatic stress disorder. Other medications used were hydroxyzine, clonazepam, cyproheptadine, nabilone, and doxazosin. The vast majority of studies were conducted in the USA. The studies comprised a total of 830 participants. The Clinician-Administered PTSD Scale was the most frequently used outcome measure. The results showed an overall effect size of Hedges' = 0.50 (0.42 after adjustment for publication bias). The synthetic cannabinoid nabilone (one study) showed the highest effect size ( = 1.86), followed by the histamine H-antagonist hydroxyzine (one study), and prazosin (10 studies), with effect sizes of = 1.17 and = 0.54, respectively. Findings and limitations are discussed, and recommendations for future studies are provided.
Topics: Humans; Dreams; Randomized Controlled Trials as Topic; Prazosin; Adrenergic alpha-1 Receptor Antagonists; Stress Disorders, Post-Traumatic; Hydroxyzine
PubMed: 36613097
DOI: 10.3390/ijerph20010777