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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 -
Endocrine Dec 2021To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery.
PURPOSE
To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery.
METHODS
A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale.
RESULTS
One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm.
CONCLUSION
Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.
Topics: Adrenal Gland Neoplasms; Humans; Phenoxybenzamine; Pheochromocytoma; Retrospective Studies; Treatment Outcome
PubMed: 34373995
DOI: 10.1007/s12020-021-02843-6 -
ELife Nov 2021Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical...
BACKGROUND
Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials.
METHODS
Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO.
RESULTS
Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy.
CONCLUSIONS
We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness.
FUNDING
GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.
Topics: Adverse Drug Reaction Reporting Systems; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bayes Theorem; COVID-19; Calcium Channel Blockers; Data Mining; Drug-Related Side Effects and Adverse Reactions; Fibrinolytic Agents; Humans; Hypertension; Pharmacovigilance; SARS-CoV-2
PubMed: 34812146
DOI: 10.7554/eLife.70734 -
World Journal of Surgical Oncology Jun 2023Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of...
BACKGROUND
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of catecholamines. Patients may develop cardiovascular complications in the perioperative phase due to the massive release of catecholamines, particularly during anesthetic induction and surgical manipulation of the tumor. The aim of this retrospective study was to evaluate the risk factors involved in perioperative hemodynamic instability in patients who underwent surgery for chromaffin tumors.
METHODS
Forty patients (median age 55 [36.50-64.50]) undergone surgery for PHEO/abdominal PGL from January 2011 to December 2016 at the AOU Careggi (Florence, Italy) were retrospectively evaluated. Systolic, diastolic, and mean blood pressure were considered at baseline and during surgery. Patients with blood pressure steadily < 140/90 mmHg before surgery were considered "adequately prepared". A preoperative therapy with doxazosin, a selective alpha-1 blocker, was started in all patients for at least 14 days prior to the surgery. The presence of hemodynamic instability was reported.
RESULTS
Comparing males and females, a significant difference in doxazosin daily dose (p = 0.018), systolic blood pressure (p = 0.048), and in the proportion of adequately prepared patients (p = 0.031) emerged. A positive correlation between preoperative daily dose of doxazosin, tumor size (B = 0.60, p < 0.001), and urinary normetanephrine levels (B = 0.64, p < 0.001) was also observed. Hemodynamic instability occurred in 30.0% of patients. The absence of adequate preparation (p = 0.012) before surgery, urinary normetanephrine levels (NMNur p = 0.039), and surgery time (minutes) (p = 0.021) resulted as risk factors of hemodynamic instability in our series. The use of intraoperative drugs was higher in patients with hemodynamic instability (p < 0.001). A pre-surgical SBP level of > 133 mmHg (OR = 6 CI95% 1.37-26.20, p = 0.017) and an intraoperative SBP and MBP levels of > 127 mmHg (OR = 28.80 CI95% 2.23-371.0, p = 0.010) and > 90 mmHg (OR = 18.90 CI95% 1.82-196.0, p = 0.014), respectively, were identified as effective thresholds to recognize patients at higher risk of HI.
CONCLUSIONS
A preoperative therapy with alpha-blockers is useful, but not sufficient to avoid surgical risks. Patients with higher pre-surgical levels of NMNur, pre-surgical SBP > 133 mmHg, and/or intraoperative SBP > 127 mmHg and MBP > 90 mmHg, should be carefully monitored. A multidisciplinary approach is indispensable to optimize the management of PHEOs/abdominal PGLs in order to reduce surgical complications.
Topics: Male; Female; Humans; Middle Aged; Pheochromocytoma; Retrospective Studies; Doxazosin; Normetanephrine; Paraganglioma; Hemodynamics; Adrenal Gland Neoplasms; Catecholamines; Vascular Diseases
PubMed: 37370080
DOI: 10.1186/s12957-023-03072-z -
BioMed Research International 2018Regulation of the mechanisms of fibrosis is an important goal in the treatment of liver cirrhosis. One mechanism is the participation of hepatic stellate cells in...
Regulation of the mechanisms of fibrosis is an important goal in the treatment of liver cirrhosis. One mechanism is the participation of hepatic stellate cells in fibrogenesis when activated by catecholamines. Consequently, / adrenoblockers are proposed as an alternative treatment for chronic liver lesions such as fibrosis and/or cirrhosis and for possible liver regeneration. We herein analyzed the effect of doxazosin and carvedilol treatments during the regeneration of tissue in a hamster model of liver cirrhosis. Tissue samples were examined by H&E and PAS to evaluate tissue damage and with Sirius red to assess collagen fiber content. ALT, AST, albumin, and total proteins were examined by spectrophotometry. Determination of the levels of -SMA and TGF- in hepatic tissue was examined by Western blot and of the expression of TIMP-2, MMP-13, -FP, HGF, CK-7, and c-Myc was examined by qPCR. Treatment with doxazosin or carvedilol prompted histological recovery and reduced collagen fibers in the livers of cirrhotic hamsters. The expression of TIMP-2 decreased and that of MMP-13 increases in animals treated with adrenoblockers with respect to the group with cirrhosis. Additionally, the concentration of -SMA and TGF- declined with both drugs with respect to placebo p<0.05. On the other hand, each drug treatment led to a distinct scenario for cell proliferation markers. Whereas doxazosin produced no irregularities in -FP, Ki-67, and c-Myc expression, carvedilol induced an increment in the expression of these markers with respect to the intact. Hence, doxazosin and carvedilol are potential treatments for the regression of hepatic cirrhosis in hamsters in relation to the decrease of collagen in the hepatic parenchyma. However, at regeneration level we observed that doxazosin caused slight morphological changes in hepatocytes, such as its balonization without affecting the hepatic function, and on the other hand, carvedilol elicited a slight irregular expression of cell proliferation markers.
Topics: Animals; Antigens, Differentiation; Carvedilol; Cell Proliferation; Cricetinae; Disease Models, Animal; Doxazosin; Gene Expression Regulation; Liver Cirrhosis; Liver Regeneration; Male; Mesocricetus
PubMed: 30643808
DOI: 10.1155/2018/4706976 -
The Cochrane Database of Systematic... Oct 2010Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH.
OBJECTIVES
To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS).
SEARCH STRATEGY
We searched The Cochrane Library (which includes CDSR (Cochrane Database of Systematic Reviews), DARE (Database of Abstracts of Reviews of Effects), HTA (Heath Technology Assessments), and CENTRAL (Cochrane Central Register of Controlled Trials, and which includes EMBASE and MEDLINE), LILACS (Latin American and Caribbean Center on Health Sciences Information) and Google Scholar for randomized, controlled trials (RCTs). We also handsearched systematic reviews, references, and clinical-practice guidelines.
SELECTION CRITERIA
Randomized trials in the English language with placebo and/or active arms with a duration of at least 6 months.
DATA COLLECTION AND ANALYSIS
JT extracted the data, which included patient characteristics, outcomes, and harms. Our primary outcome was change in a validated, urinary symptom-scale score, such as the AUA/IPSS. A clinically meaningful change was defined as 4 points. We also categorized outcomes by trial lengths of ≤ 1 year (short term) and > 1 year (long term).
MAIN RESULTS
Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, ≥ 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more likely than finasteride to improve peak urine flow and nocturia, versus finasteride. Versus tamsulosin, peak urine flow and QoL improved equally well versus finasteride. However, finasteride was associated with a lower risk of surgical intervention compared to doxazosin, but not to terazosin, while finasteride and doxazosin were no different for risk of acute urinary retention. Two small trials reported no difference in urinary symptom scores between finasteride and tamsulosin. Finasteride + doxazosin and doxazosin monotherapy improved urinary symptoms equally well (≥ 4 point improvement).For finasteride, there was an increased risk of ejaculation disorder, impotence, and lowered libido, versus placebo. Versus doxazosin, finasteride had a lower risk of asthenia, dizziness, and postural hypotension, and versus terazosin, finasteride had a significant, lower risk of asthenia, dizziness, and postural hypotension.
AUTHORS' CONCLUSIONS
Finasteride improves long-term urinary symptoms versus placebo, but is less effective than doxazosin. Long-term combination therapy with alpha blockers (doxazosin, terazosin) improves symptoms significantly better than finasteride monotherapy. Finasteride + doxazosin improves symptoms equally - and clinically - to doxazosin alone. In comparison to doxazosin, finasteride + doxazosin appears to improve urinary symptoms only in men with medium (25 to < 40 mL) or large prostates (≥ 40 mL), but not in men with small prostates (25 mL).Comparing short to long-term therapy, finasteride does not improve symptoms significantly better than placebo at the short term, but in the long term it does, although the magnitude of differences was very small (from < 1.0 point to 2.2 points). Doxazosin improves symptoms better than finasteride both short and long term, with the magnitude of differences ∼2.0 points and 1.0 point, respectively. Finasteride + doxazosin improves scores versus finasteride alone at both short and long term, with mean differences ∼2.0 points for both time points. Finasteride + doxazosin versus doxazosin improves scores equally for short and long term.Drug-related adverse effects for finasteride are rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo. Versus doxazosin, which has higher rates of dizziness, postural hypotension, and asthenia, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder. Finasteride significantly reduces asthenia, postural hypotension, and dizziness versus terazosin. Finasteride significantly lowers the risk of asthenia, dizziness, ejaculation disorder, and postural hypotension, versus finasteride + terazosin.
Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Disease Progression; Doxazosin; Drug Therapy, Combination; Enzyme Inhibitors; Finasteride; Humans; Male; Prostatic Hyperplasia; Prostatism; Randomized Controlled Trials as Topic
PubMed: 20927745
DOI: 10.1002/14651858.CD006015.pub3 -
Acta Neurobiologiae Experimentalis 1996We review the crucial role of the two neurotransmitters norepinephrine (NE) and GABA in eliciting GnRH pulse. NE acts via an alpha l-receptor mechanism and also GABA... (Review)
Review
We review the crucial role of the two neurotransmitters norepinephrine (NE) and GABA in eliciting GnRH pulse. NE acts via an alpha l-receptor mechanism and also GABA acts at the alpha-subtype of the GABA receptor. The function of NE appears to be induction of phasic activation of GnRH neurons and GABA inhibits GnRH neurons tonically until they are all ready for phasic activation. By an unknown mechanism preoptic GABA release in dramatically reduced which causes simultaneous desinhibition of the GnRH neurons. Hence they release their product into the portal vessels simultaneously which is the appropriate signal for the pituitary ganodotrophs. The action of norepinephrine and GABA is most likely exerted at the perikarya level of the GnRH neurons since the alpha l-adreno receptor blocker doxazosin and GABA inhibit GnRH secretion only when applied into the medial preoptic/anterior hypothalamic area (where in the rat brain the GnRH perikarya are located). Utilizing a quantitative reverse transcription polymerase chain reaction, we demonstrate furthermore that GnRH receptors are present in the mediobasal hypothalamus as well as in the preoptic area of rats. Their function appears to serve autoinhibitory purposes since Buserelin added to medium significantly decreased GnRH release. Simultaneously, the release of GABA was increased and that of glutamate decreased. We conclude from these experiments that GABAergic and glutamatergic neurons in the hypothalamus may also be GnRH-receptive.
Topics: Animals; Brain Chemistry; Gonadotropin-Releasing Hormone; Humans; Rats
PubMed: 8917899
DOI: 10.55782/ane-1996-1176 -
Pharmacology Research & Perspectives Aug 2020α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and...
α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1-adrenoceptor subtype affinity and selectivity. [3H]prazosin whole-cell binding was conducted in CHO cells stably expressing either the full-length human α1A, α1B, or α1D-adrenoceptor. As expected, doxazosin was a high-affinity nonselective α1-antagonist although other compounds (eg, cyclazosin, 3-MPPI, and ARC239) had higher affinities. Several highly α1A-selective antagonists were confirmed (SNAP5089 had over 1700-fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B-selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two-component-binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high-affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D-adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1-adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1-adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α-blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.
Topics: Adrenergic alpha-Antagonists; Animals; Antidepressive Agents; Antipsychotic Agents; CHO Cells; Cricetulus; Humans; Receptors, Adrenergic, alpha-1
PubMed: 32608144
DOI: 10.1002/prp2.602 -
The American Journal of Managed Care Apr 2006Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract... (Review)
Review
Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract symptoms (LUTS), occurs in about one quarter of men in their 50s, one third of men in their 60s, and about half of all men 80 years or older. Although effective treatments for LUTS/BPH are available, this condition often occurs in the context of common, age-related comorbidities such as cardiovascular disease, hypertension, and erectile dysfunction. Alpha1-selective adrenergic receptor (a1-AR) antagonists (eg, alfuzosin, doxazosin, tamsulosin, terazosin) remain the cornerstone of therapy for LUTS/BPH. In addition, 5-alpha-reductase inhibitors (ie, dutasteride, finasteride) have been associated with improvements in LUTS/BPH in men with larger prostates, especially when used in combination with a1-AR antagonists. Although all these drugs have been shown to be beneficial for the treatment of BPH, there are differences in side-effect profiles. When selecting an appropriate course of therapy, these side effects and any impact they may have on existing comorbid conditions must be considered.
Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Age Distribution; Aged; Aged, 80 and over; Cardiovascular Diseases; Comorbidity; Diabetes Complications; Enzyme Inhibitors; Erectile Dysfunction; Global Health; Humans; Male; Metabolic Syndrome; Middle Aged; Prevalence; Prostatic Hyperplasia; Risk Factors
PubMed: 16613526
DOI: No ID Found -
Journal of Clinical Hypertension... Dec 2005Alpha1-adrenergic-blocking drugs are effective in reducing blood pressure and do so in a fashion comparable to most other antihypertensive drug classes. These compounds... (Review)
Review
Alpha1-adrenergic-blocking drugs are effective in reducing blood pressure and do so in a fashion comparable to most other antihypertensive drug classes. These compounds are most effective in patients in the upright position, reducing systolic and diastolic pressures by 8%-10%. Alpha1-adrenergic-blocking drugs incrementally reduce blood pressure when combined with most drug classes and are the only antihypertensive drug class to improve plasma lipid profiles. Alpha1-adrenergic-blocking drugs are also accepted as important elements of the treatment plan for symptomatic benign prostatic hypertrophy. Dose escalation of an alpha1-adrenergic-blocking drug can trigger renal Na+ retention, and the ensuing volume expansion can attenuate its blood pressure-lowering effect. Orthostatic hypotension can occur with these compounds, particularly when a patient is volume-contracted. Dizziness, headache, and drowsiness are common side effects with alpha1-adrenergic blockers. A modest decline in the use of doxazosin and other alpha1-adrenergic-blocking drugs has occurred coincident to the early termination of the doxazosin treatment arm in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Blood Pressure; Humans; Hypertension; Hypotension, Orthostatic; Lipids; Treatment Outcome
PubMed: 16330901
DOI: 10.1111/j.1524-6175.2005.05300.x