Doxazosin and erlotinib have anticancer effects in the endometrial cancer cell and important roles in ERα and Wnt/ß-catenin signaling pathways.

ERα and Wnt/ß-catenin pathways are critical for the progression of most endometrial cancers. We aimed to investigate the cytotoxic and apoptotic effects of tamoxifen and quinazoline derivative drugs of doxazosin and erlotinib, and their roles in ERα and Wnt/ß-catenin signaling pathways in human endometrial cancer RL 95-2 cell. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay and xCELLigence systems were performed to evaluate cytotoxicity. Furthermore, apoptotic induction was tested by Annexin V analysis. Caspase-3 and -9 activity and changes in the mitochondrial membrane potential were evaluated. The level of reactive oxygen species was measured by incubating with dichlorofluorescein diacetate. Protein ratios of p-ERα/ERα, GSK3ß/p-GSK3ß, and p-ß-catenin/ß-catenin and expression levels of ESR1, EGFR, c-Myc genes were evaluated to elucidate mechanisms in signaling pathways. We found that the tested drugs showed cytotoxic and apoptotic effects in the cells. Doxazosin significantly reduced ESR1 expression, slightly reduced the p-ß-catenin/ß-catenin ratio and c-Myc expression. Erlotinib significantly increased c-Myc expression while significantly decreasing the p-ß-catenin/ß-catenin and p-ERα/ERα ratio, and ESR1 expression. However, we observed that the cells develop resistance to erlotinib over a certain concentration, suggesting that ERα, ESR1, EGFR, and c-Myc may be a new target for overcoming drug resistance in the treatment of endometrial cancer. We also observed that erlotinib and doxazosin play an important role in the ERα signaling pathway and can act as potent inhibitors of PKA and/or tyrosine kinase in the Wnt/ß-catenin signaling pathway in RL 95-2 cell. In conclusion, doxazosin and erlotinib may have a possible therapeutic potential in human endometrial cancer.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.

AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3- ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS: Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.

Management of Insomnia and Anxiety in Myasthenia Gravis.

Myasthenia gravis is a neuroimmunological disorder leading to skeletal muscle weakness. Common symptoms of the disease, such as anxiety, depression, and insomnia, can cause significant distress in patients. Unfortunately, selecting an appropriate medication for treatment of psychiatric comorbidities can prove to be challenging for providers given the unique pharmacologic constraints that myasthenia gravis presents. The authors present the following clinical vignette and accompanying discussion in an attempt to highlight the special considerations that must be taken into account when treating anxiety and insomnia in patients with myasthenia gravis, as well as to provide an overview of available medication options through the lens of existing constraints.

A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco-deprived and -satiated smokers.

OBJECTIVE: To test the effects of doxazosin, an α1 antagonist, on cognitive functioning during tobacco withdrawal in smokers. METHODS: Participants (n = 35) were randomly assigned to receive placebo, 4-mg/day, or 8-mg/day doxazosin. They completed a continuous performance task and self-reported their withdrawal symptoms at baseline and twice following a medication titration period: once in a tobacco-deprived state and again in a nondeprived state. Ability to resist smoking was assessed using a laboratory smoking-lapse paradigm. RESULTS: Participants showed poorer cognitive performance on most measures taken from the continuous performance task when tobacco deprived. Eight-mg/day doxazosin improved inhibitory control during the nondeprivation session but did not affect sustained attention or reaction time. Participants receiving doxazosin reported fewer withdrawal symptoms during deprivation than those on placebo. Those showing the greatest improvement of inhibitory control under doxazosin were better able to resist smoking (i.e., latency to smoke) during a smoking lapse task. Self-reported withdrawal symptoms also were negatively associated with time to smoking. CONCLUSIONS: Doxazosin reduced symptoms of tobacco withdrawal according to self-report and cognitive assessment and improved inhibitory control above predrug levels. This research identifies potential mechanisms by which doxazosin might improve smoking outcomes.

The effects of alpha 1-adrenoceptor blockade and angiotensin converting enzyme inhibition on central and brachial blood pressure and vascular reactivity: the doxazosin-ramipril study.

We aimed to study whether inhibition of the renin-angiotensin-aldosterone system has effects on vascular structure and function beyond the effects on blood pressure reduction alone. Patients with mild-to-moderate hypertension (n = 61, age 54 ± 12 years, 34% women) received the angiotensin converting enzyme inhibitor ramipril 10 mg or the alpha 1-adrenoceptor blocker doxazosin 8 mg double-blind for 12 weeks. Aortic blood pressure, pulse wave velocity, and augmentation index were assessed by applanation tonometry. Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation and by pulse wave analysis with beta 2-adrenoceptor agonist stimulation. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and iontophoresis. Treatment with doxazosin or ramipril reduced aortic and brachial blood pressures (all P < 0.001), with greater reductions in aortic than brachial systolic blood pressures (P = 0.021) and aortic/brachial pulse pressure ratio (P = 0.005). Compared to doxazosin, ramipril reduced carotid-femoral and carotid-radial pulse wave velocity (both P < 0.05). Forearm endothelial dependent and independent vasodilatation, assessed by post-ischemic flow mediated vasodilatation and glyceryl trinitrate, and by pulse wave analysis remained unchanged by both doxazosin and ramipril. In addition, skin microvascular endothelial dependent (acetylcholine) and independent vasodilatation (sodium nitroprusside) remained unchanged. In conclusion, ramipril reduced indices of aortic stiffness, suggesting that angiotensin converting enzyme inhibitor therapy may have effects beyond blood pressure reduction. However, treatment did not appear to influence endothelial function. Evidence of endothelial dysfunction and its possible improvement by antihypertensive treatment might require more advanced hypertension.This study is registered at ClinicalTrials.gov (NCT02901977) and at EudraCT (# 2007-000631-25).

Effects of the inverse alpha-agonist doxazosin in allergic rhinitis.

BACKGROUND: We examined the paradoxical hypothesis that the alpha-receptor inverse agonist doxazosin might produce beneficial effects in allergic rhinitis. OBJECTIVES: To evaluate single and chronic dosing effects of doxazosin on nasal airflow and symptoms in allergic rhinitis. METHODS: Fifteen patients randomized to receive 3-5 weeks of oral doxazosin 4 mg daily or placebo in crossover fashion. Measurements were taken at baseline and after first and last doses. RESULTS: There was a fall in peak nasal inspiratory flow (PNIF) between baseline vs. first dose of doxazosin: mean difference -19 L/min (95% CI -35 to -2) P = 0.03, with recovery between first and last doses: 21 L/min (95% CI 7-34) P = 0.006. Nasal visual analogue scale (VAS) and blockage scores were worse between baseline vs. first dose of doxazosin: mean difference VAS -10 mm (95% CI -18 to -2) P = 0.02, blockage -0.7 (95% CI -1.3 to -0.1) P = 0.02, with recovery between first and last doses: VAS 15 mm (95% CI 4-25) P = 0.009, blockage 1.1 (95% CI 0.5-1.6) P = 0.001. The oxymetazoline dose-response for PNIF was blunted after single vs chronic dosing with doxazosin: mean difference -17 L/min (95% CI -30 to -4) P = 0.01. Heart rate and diastolic blood pressure showed the same pattern. There was a significant difference between doxazosin and placebo for nasal blockage score and heart rate after single but not chronic dosing. CONCLUSIONS: There was a disconnect between single and chronic dosing effects of doxazosin for nasal symptoms, oxymetazoline response and cardiovascular outcomes, in turn suggesting alpha-1 receptor up-regulation.

The new insight of prostate-specific antigen reduction during finasteride therapy in aging men.

OBJECTIVE: To evaluate the effect of finasteride on prostate-specific antigen (PSA) in Chinese population. MATERIALS AND METHODS: From Feb 2011 to Jan 2012, 83 benign prostatic hyperplasia (BPH) patients with prostate volume (PV) >30 mL were enrolled in our study. All the patients were older than 50 years and all of them received combined therapy (finasteride + doxazosin). All the patients were required for 1-year follow-up. PSA level and PV was measured at the start, 6 and 12 months, respectively. RESULTS: 79 patients completed the follow up. PSA level reduced by approximately 40 % during finasteride therapy. We defined baseline PSA as PSA1, PSA at 6 months as PSA2, PSA at 12 months as PSA3. PSA1 was significantly correlated with PSA2/PSA1 and PSA3/PSA1. However, prostate volume was not correlated with PSA1. We divided the patients into three groups according to PSA level. Groups 1, 2, 3 represented the patients with PSA less than 2 ng/mL, between 2 and 4 ng/mL and greater than 4 ng/mL, respectively. Both the PSA2/PSA1 and the PSA3/PSA1 had significant difference among three groups. Furthermore, group 1 and group 2 both showed the fairly large data variance. CONCLUSIONS: When baseline PSA level was greater than 4 ng/mL, the doubling rule could be used for screening. When baseline PSA level was less than 4 ng/Ml, the doubling rule might not be an accurate predictor. We can use the PSA rise from nadir or proPSA to predict prostate cancer.

Doxazosin oral intake therapy to relieve stent - related urinary symptoms and pain: a prospective, randomized, controlled study.

OBJECTIVE: To assess the impact of Doxazosin Oral Intake Therapy on urinary symptoms and pain in patients with indwelling ureteral stents Patients and Methods: A total of 239 patients with ureteral stone-related hydronephrosis who underwent a double-J stent insertion after ureteroscopic lithotripsy were enrolled. Patients were randomized to receive doxazosin cotrolled release 4 mg once daily for 4 weeks or matching placebo. Patients completed the brief-form Chinese version Ureteric Stent Symptom Questionnaire (USSQ) and quality of life (QoL) score 2 weeks and 4 weeks after stent placement and 4 weeks after stent withdrawal. The analgesic use was also recorded during the stenting period. RESULTS: Patients in Doxazosin Oral Intake Therapy group, in the first 2 weeks and second 2 weeks with the stent in situ, expressed significant lower daytime frequency (p=0.028 and p=0.038), nocturia (p=0.021 and p=0.008) and urgency (p=0.012 and p=0.014), respectively. Similarly, flank pain score, QoL score and analgesic use were also significant less in the stenting period. There was no significant difference in scores of urinary symptoms, pain and QoL during the post-stent period between two cohorts. CONCLUSIONS: Doxazosin Oral Intake Therapy reduced stent-related urinary symptoms, pain and the negative impact on QoL.

Enantioselective pharmacokinetics of doxazosin and pharmacokinetic interaction between the isomers in rats.

In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high-pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (-)-(R)-doxazosin 3.0 mg/kg, (+)-(S)-doxazosin 3.0 mg/kg, and rac-doxazosin 6.0 mg/kg. AUC values of (+)-(S)-doxazosin were always larger than those of (-)-(R)-doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (Cmax ) value of (-)-(R)-doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the Cmax value of (+)-(S)-doxazosin did not change significantly. The area under the curve (AUC) and Cmax values for (+)-(S)-doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (-)-(R)-doxazosin increases (+)-(S)-doxazosin exposure probably by inhibiting the elimination of (+)-(S)-doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer-enantiomer interaction occurs after rac-administration.

5α-Reductase inhibitor is less effective in men with small prostate volume and low serum prostatic specific antigen level.

BACKGROUND/PURPOSE: Large total prostate volumes (TPVs) or high serum prostate-specific antigen (PSA) levels indicate high-risk clinical progression of benign prostatic hyperplasia. This prospective study investigated the treatment outcome of combined 5α-reductase inhibitor and α-blocker in patients with and without large TPVs or high PSA levels. METHODS: Men aged ≥ 45 years with International Prostate Symptom scores (IPSS) ≥ 8, TPV ≥ 20 mL, and maximum flow rate ≤ 15 mL/s received a combination therapy (dutasteride plus doxaben) for 2 years. Patients with baseline PSA ≥ 4 ng/mL underwent prostatic biopsy for excluding malignancy. The changes in the parameters from baseline to 24 months after combination therapy were compared in those with and without TPV ≥ 40 mL or PSA levels ≥ 1.5 ng/mL. RESULTS: A total of 285 patients (mean age 72 ± 9 years) completed the study. Combination therapy resulted in significant continuous improvement in IPSS, quality of life index, maximum flow rate, and postvoid residual (all p < 0.0001) regardless of baseline TPV or PSA levels. However, only patients with baseline TPV ≥ 40 mL had significant improvements in IPSS-storage subscore, voided volume, reduction in TPV, transitional zone index, and PSA levels. In addition, patients with baseline TPV < 40 mL and PSA < 1.5 ng/mL had neither a reduction in TPV nor a decrease in serum PSA level. CONCLUSION: A high TPV indicates more outlet resistance, whereas elevated serum PSA level reflects glandular proliferation. Thus, patients with TPV<40 mL and low PSA levels has less benefit from 5α-reductase inhibitor therapy. The therapeutic effect of combined treatment may arise mainly from the α-blocker in these patients.

Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy.

PURPOSE: We examined the effects of doxazosin, finasteride and combined therapy in men with lower urinary tract symptoms associated with benign prostatic hyperplasia on sexual function, as assessed by the Brief Male Sexual Function Inventory during 4 years. MATERIALS AND METHODS: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in sexual function was a secondary outcome. We analyzed the records of 2,783 men enrolled in the study who completed the inventory at baseline and at least once during followup. RESULTS: In men enrolled in MTOPS sexual function decreased with time. Men assigned to finasteride and combined therapy experienced overall statistically significant but slight worsening of ejaculatory function compared with men on placebo. Men assigned to combined therapy also experienced significant worsening in erectile function and sexual problem assessment. There was no significant difference in changes in any inventory domain in men assigned to doxazosin alone compared to placebo. CONCLUSIONS: This study significantly extends understanding of the effects of long-term treatment with these drugs on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Treatment with finasteride or combined therapy was associated with worsening sexual function while treatment with doxazosin alone was associated with minimal negative impact, if any. Physicians should discuss with their patients the possible long-term effects of these drugs for lower urinary tract symptoms associated with benign prostatic hyperplasia on sexual function.

(-)Doxazosin is a necessary component for the hypotensive effect of (±)doxazosin during long-term administration in conscious rats.

AIM: Doxazosin is a racemic mixture of (-)doxazosin and (+)doxazosin that is currently used as an add-on therapy for hypertension. In this study we investigated the contribution of each enantiomer to the hypotensive action of long-term administration of (±)doxazosin in conscious rats. METHODS: Blood pressure of conscious SD rats was measured using a volume pressure recording system. The rats were orally administered (-)doxazosin, (+)doxazosin, or (±)doxazosin (8 mg·kg(-1)·d(-1)) for 12 weeks. Plasma concentrations of the agents were analyzed with HPLC. The effect of the agents on α1-adrenoceptor was examined in isolated rat caudal artery preparations. RESULTS: Treatment of conscious rats with a single dose of (±)doxazosin (8 mg/kg) did not affected DBP and MBP, but significantly decreased SBP by 11.9% 4 h after the administration. Long-term treatment of conscious rats with (±)doxazosin significantly decreased SBP, DBP and MBP with a maximal decrease of SBP by 29.3% 8 h after the last administration. The rank order of the hypotensive actions caused by long-term treatment in conscious rats was (±)doxazosin>(+)doxazosin>>(-)doxazosin. However, the pKB values for inhibiting NA-induced contraction of isolated rat caudal artery were (+)doxazosin (8.995)>(±)doxazosin (8.694)>(-)doxazosin (8.032). The plasma concentrations of (-)doxazosin, (+)doxazosin, and (±)doxazosin were 18.26±3.55, 177.11±20.66, and 113.18±13.21 ng/mL, respectively, 8 h after the last administration of these agents. CONCLUSION: Long-term treatment with (±)doxazosin produces potent hypotensive action in conscious rats that seems to result from synergic interaction of the two enantiomers.

Comparison of the efficacy of isosorbide mononitrate and doxazosin in the treatment of lower urinary tract symptoms and benign prostatic hyperplasia: a randomized clinical trial.

OBJECTIVE: We aimed to compare the efficacy of isosorbide mononitrate and doxazosin in the treatment of lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: 80 patients with LUTS were included in this randomized clinical study. All patients were evaluated with uroflowmetry, post-void residual (PVR) urine, prostate volume, International Prostate Symptom Score (IPSS), serum PSA, urinalysis and culture. 40 patients were prescribed doxazosin for 4 weeks, another 40 were prescribed isosorbide mononitrate for 4 weeks. Urologic re-evaluation was done at the end of the study. RESULTS: 74 patients completed the study. The mean age of patients was 59.6 ± 0.7 years, the mean PSA value was 1.7 ± 0.1 ng/ml and the mean prostate volume was 41.9 ± 1.7 ml. Doxazosin markedly improved IPSS (from 16.2 ± 0.7 to 9.5 ± 0.5), maximum urinary flow rate (from 10.9 ± 0.7 to 12.8 ± 0.6 ml/s) and PVR urine (from 68.1 ± 9.4 to 39.0 ± 4.4 ml) (p < 0.0001, p < 0.0001, p = 0.0004, respectively). Isosorbide only improved IPSS (from 16.5 ± 0.9 to 14.6 ± 0.8) (p = 0.032). CONCLUSIONS: Daily administration of isosorbide does not seem to be an alternative to α-blocker therapy. Controlled, randomized novel studies are required to establish that whether nitric oxide donors are an effective alternative in LUTS treatment.

The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Comparison of 7 α(1)-adrenoceptor antagonists in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia:a short-term crossover study.

A crossover study was conducted to identify the best α1-adrenoceptor (α1AR) antagonist for individual patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). One hundred thirteen patients (mean age 70.8 years) were enrolled. All patients met BPH clinical study guidelines. Seven agents were utilized:tamsulosin 0.2mg, silodosin 8mg, urapidil 60mg, naftopidil 50mg, prazosin 1mg, terazosin 2mg, and doxazosin 1mg. Patients were initially prescribed tamsulosin or silodosin for a week and then urapidil for a week. Two weeks later, they were prescribed the better of the 2 agents for a week and a new agent for the next week. This cycle was repeated until all 7 agents were tested. Efficacy was evaluated with the International Prostate Symptom Score. The agent rankings were doxazosin (25 [22%]), silodosin (22 [19%]), urapidil (19 [17%]), naftopidil (17 [15%]), terazosin (12 [11%]), tamsulosin (11 [10%]), prazosin (7 [6%]). Only 12 patients (11%) changed agents after the crossover study was completed. The major reason was adverse events (83%). We found that each of the 7 α1AR antagonists has its own supporters. Further, the one-week crossover study was useful in identifying the best agent for the treatment of each individual with LUTS.

Dual silencing of Hsp27 and c-FLIP enhances doxazosin-induced apoptosis in PC-3 prostate cancer cells.

We evaluated effect of dual gene silencing of Hsp27 and c-FLIP in doxazosin-induced apoptosis of PC-3 cell. After transfection using Hsp27 and c-FLIP siRNA mixture (dual silencing), doxazosin treatment was done at the concentrations of 1, 10, and 25 µ M. We checked apoptosis of PC-3 cells with and TUNEL staining. We also checked interaction between Hsp27 and C-FLIP in the process of apoptosis inhibition. Spontaneous apoptotic index was 5% under single gene silencing of Hsp27 and c-FLIP and 7% under dual silencing of Hsp27 and c-FLIP. When doxazosin treatment was added, apoptotic indices increased in a dose-dependent manner (1, 10, and 25 µ M): nonsilencing 10, 27, and 52%; Hsp27-silencing: 14, 35, and 68%; c-FLIP silencing: 21, 46, and 78%; dual silencing: 38, 76, and 92%. While c-FLIP gene expression decreased in Hsp27- silenced cells, Hsp27 gene expression showed markedly decreased pattern in the cells of c-FLIP silencing. The knockout of c-FLIP and Hsp27 genes together enhances apoptosis even under 1 µ M, rather than low concentration, of doxazosin in PC-3 cells. This finding suggests a new strategy of multiple knockout of antiapoptotic and survival factors in the treatment of late-stage prostate cancer refractory to conventional therapy.

[Results of open multicenter study of the safety of doxazosin in combination with indigal in men with stages I-II prostatic adenoma].

The article presents a method of conservative treatment of men with I-II stage prostatic adenoma using a combination of doxazosin and indigal, which has antioxidant, antiproliferative and anti-inflammatory properties, that allowed improving urodynamic parameters and reducing the progression prostate adenoma, minimizing the adverse effects of treatment.

[Combined treatment of patients with lower urinary tract symptoms and erectile dysfunction].

In men of middle and older age group, urination disorders and erectile dysfunction are often combined. The role of phosphodiesterase type 5 inhibitors in the treatment of these patients remains uninvestigated. Prospective study included 38 patients with urination disorders and erectile dysfunction. The average age of the patients was 63.6 +/- 5.3 years. During first three months of observation, all patients have received alpha-adrenoblocker doxazosin at a dose of 4 mg once daily per os, the next three months--phosphodiesterase type 5 inhibitor udenafil at a dose of 50 mg once daily per os was added to doxazosin. 3 months after treatment, majority of patients reported improvement of urination. The statistically significant changes in BP and heart rate were not recorded, indicating a satisfactory tolerability and safety of doxazosin. Against the background of combined treatment during next 3 months, progressive improvement of erectile function (IIEF score 12.8 +/- 3.4 vs 18.4 +/- 3.7; p < 0.05), and regression of urination disorders, according to IPSS score (13.4 +/- 1.2 vs 11.2 +/- 1.7; p < 0.05) were observed. Uroflowmetric indicators were not significantly changed. Based on experimental and clinical studies, it was suggested that the dysregulation of NO--cGMP system, pathological activation of Rho-kinase pathways, hyperactivity of autonomic innervation, atherosclerosis and impaired blood flow in the pelvic organs are the common pathophysiological mechanisms for LUTS and erectile dysfunction. The clinical efficacy of phosphodiesterase type 5 inhibitors in the treatment of patients with these diseases is explained by its effects on these mechanisms.

[Features of neurohumoral regulation in children with combined dysfunction of the pelvic organs].

During examination of 165 children aged 5 to 15 years (primarily identified during planned monitoring in Petrozavodsk children's institutions) with dysfunctional urination and encopresis without organic lesion of the central nervous system, autonomic dysfunction syndrome (ADS) was revealed. According to the results of urological examination, which was supplemented with the registration of spontaneous voiding rate and counting the radial pulse, overactive bladder syndrome and insufficient relaxation of the pelvic floor muscles during urination and defecation were detected; relationship between the number of heart rate (as a marker of sympathetic nervous system activity) and the effective volume was identified. It was revealed that the children with ADS in the presence of tachycardia show intermittent decrease of effective amounts of urination, and have residual urine. The standard course of treatment using colon hydrotherapy and biofeedback to activate cystic and obturator reflex caused a positive but short-term therapeutic effect; clinically and statistically significant increase in the effective volume of the bladder was not achieved, despite the reduction in residual urine volume. During the course of treatment using methods of biofeedback, bladder volume remained almost unchanged and tachycardia persisted, indicating the continued oppression of the sympathetic activity. The course of treatment using nootropic drug picamilon and alpha-adrenoblocker doxazosin with peripheral actions allowed to restore the reservoir and evacuation functions of the bladder, to achieve a regular bowel movement without encopresis. It was revealed that the combined dysfunction of pelvic organs occur in children with high activity of the sympathetic division of the ANS, which has a direct impact on the accumulation phase of voiding cycle and relaxation of the pelvic floor muscles.

[Experience of the use of silodosin in acute urinary retention caused by benign prostatic hyperplasia].

For the treatment of acute urinary retention (AUR) as one of the most serious complications of adenoma of the prostate (BPH), alpha-adrenoblockers are widely used. The article presents an experience of the use of the new uroselective alpha-adrenoblocker silodosin approved for the treatment of patients with urination disorders caused by BPH. Its pharmacological profile has a number of advantages, including the highest uroselectiveness at the present day, immediate action, the potential for the use of standard dose of 8 mg 1 time a day, which does not require a correction depending on the age, and the possibility of the simultaneous application with antihypertensive drugs.