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A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x₁ and x₂: one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.
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Benign prostatic hyperplasia (BPH) is very common in older men, causing symptoms that can markedly impair quality of life. Surgical treatment, typically transurethral resection of the prostate (TURP), is highly effective but can be costly and is associated with the risk for significant morbidity. Medical treatments for BPH are targeted toward reducing bladder outlet obstruction either by androgen blockade to reduce prostatic volume or alpha-adrenergic blockade to relax the smooth muscle tone of the prostate. In recent years, understanding of the sympathetic innervation of the prostate has improved. This has been paralleled by the development of alpha-adrenergic blocking agents, from nonselective alpha-antagonists, to selective alpha1-antagonists, to the more selective alpha1A-antagonists. It is anticipated that more specific agents will optimize the therapeutic effectiveness of alpha-adrenergic blockade in the prostate while reducing the side effects associated with alpha-adrenergic blockade in other areas of the body, such as the vascular system. This article reviews the evolution of alpha-blockade therapy in management of BPH, focusing on tamsulosin, an agent targeted toward the alpha1A-adrenoceptor that predominates in the prostate. Clinical trials in Europe and the United States have provided evidence that tamsulosin is effective at doses of 0.4 and 0.8 mg/day. At both doses, tamsulosin is associated with significant improvements in the American Urological Association symptom score and the mean and peak urinary flow rates as compared with placebo. This once-daily alpha1A-adrenergic antagonist is well-tolerated, with a minimal potential for the side effects associated with alphas-blocker therapy.
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Benign Prostatic Hyperplasia (BPH) usually occurs in males 45-50 old and progressively involves 75% of the male population over 75 years of age. The clinical manifestations of BPH are related primarily to bladder outlet obstructions resulting from enlargement (mechanical component) of the prostate gland, and from extrinsic and intrinsic sympathetic activation of alpha-adrenoceptors (dynamic component) present in the prostatic muscle tissue, prostatic urethra, bladder base and neck. Several drugs have been employed in the last decades: LHRH analogs (Leuprorelin and Goserelin) which can reduce the testicular production of androgens with reduction in prostate size; Serenoa repens for its anti-androgenic and anti-estrogenic activities; Finasteride (5-alpha-reductase inhibitor) which blocks the conversion of testosterone into the more active dihydrotestosterone. Finally, the alpha 1 blocking agents (Terazosin, Doxazosin, Tamsulosin) that improve urinary symptoms by acting on dynamic component. Clinical improvements derive from their antagonist action on alpha 1 adrenergic receptors which mediate contraction of the prostate gland, proximal urethra, bladder base and neck, with the consequent reduction of urethral pressure, bladder outlet resistance, and increase of urinary flow. Due to its pharmacodynamic and pharmacokinetic properties, as well as the clinical results obtained, Terazosin, alpha 1 blocker, appears to be particularly useful in the treatment of patients with mild- to moderate symptomatic BPH.
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Patients on AB/AM combination therapy remained on alpha blockers for longer than those on alpha blocker monotherapy (p = 0.04); 92.4% were persistent at 3 months versus 89.0%, and at 1 year 50.8% were persistent versus 49.6%, respectively. The highest number of days on therapy was reported for tamsulosin plus solifenacin. As confirmed by multivariate analysis, patients with the highest adherence to AM medication (= 80%) persisted on alpha blockers for longer than those with the lowest (< 50%) adherence (p < 0.05).
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Reversal of left ventricular (LV) hypertrophy is an important goal of antihypertensive therapy. This phase 3b study compared the ability of the angiotensin receptor blocker olmesartan medoxomil with the calcium channel blocker amlodipine besylate to induce regression of LV hypertrophy and vascular hypertrophy after achieving blood pressure (BP) goal. After a washout phase, 102 patients with hypertension and LV hypertrophy were randomized to olmesartan medoxomil 20 mg/day, up titrated to 40 mg/day, or amlodipine 5 mg/day, up titrated to 10 mg/day, for up to 4 weeks until a BP goal of <140/90 mm Hg (<130/85 mm Hg for diabetes) was achieved (hydrochlorothiazide 25 mg/day and terazosin 1 to 5 mg/day 2 times/day could be added if needed). Upon achieving the BP goal or by week 8, and again at weeks 26 and 52, assessments of LV mass and compliance and arterial structure and function were performed by echocardiography, Doppler flow, and arterial ultrasonography, respectively. There was no statistically significant percent change in LV mass at 52 weeks in either treatment group (11.6% with olmesartan medoxomil vs 2.9% with amlodipine) and no statistically significant difference between treatment groups. There were no significant changes in LV compliance or carotid or femoral artery wall-to-lumen ratios in either treatment group at 52 weeks. In conclusion, there did not appear to be a clinically significant BP-independent effect with olmesartan medoxomil or amlodipine on LV mass decrease, diastolic function or vascular structure, and compliance in patients with hypertension and LV hypertrophy.
The cultured prostatic cells demonstrated hill and valley morphology, which is a hallmark of smooth muscle cells in vitro, and stained positively for desmin. In addition, electron microscopic examination of ultrastructural morphology revealed myofilaments. Confluent cultures of prostatic smooth muscle cells showed a clear, dose-dependent contractile response to phenylephrine. Furthermore, contraction of the prostatic smooth muscle cells by 10(-6) mol/L phenylephrine was completely inhibited by pretreatment with 10(-6) mol/L terazosin.
Benign prostatic hyperplasia (BPH) can have a profound affect on a patient's quality of life and sexual function and is considered by patients to be one of the most important aspects affected by the disease. Different treatments can produce a variable response in terms of the patient's quality of life, including sexual activity and satisfaction. Varying rates of erectile dysfunction (ED) and retrograde ejaculation following surgery for BPH have been reported. In general, the incidence of these side-effects is less after minimally invasive therapies, such as interstitial laser coagulation and transurethral microwave therapy, but the data available are limited. The lowest rates of sexual dysfunction are reported with medical therapies. The 5alpha-reductase inhibitor, finasteride, can result in ED in 5-9% of patients and ejaculation disorders in 0.8-2.0%. With the exception of tamsulosin, alpha(1) blockers are associated with a low rate of sexual dysfunction. No cases of ED have been reported with alfuzosin and abnormal ejaculation with terazosin or alfuzosin is negligible. Indeed, early research suggests a beneficial effect of alpha(1) blockers on sexual function. In addition to information on the efficacy of a particular therapy, patients should be informed of side effects, in particular those relating to sexual function, in order that they can make informed treatment decisions.Prostate Cancer and Prostatic Diseases (2001) 4, S12-S16
Meal ingestion stimulates an increase in small intestinal water and electrolyte absorption. Endogenous norepinephrine may at least partially mediate this meal-stimulated proabsorptive response. Luminally administered alpha 1-adrenergic agonists such as norepinephrine and phenylephrine cause significant small bowel absorption, which can be prevented by the selective alpha 1-adrenergic antagonist terazosin. This study tested two hypotheses: (1) a meal stimulates ileal water, electrolyte, and glucose absorption; and (2) meal-stimulated ileal absorption is mediated via alpha 1-adrenergic receptor activation. Absorption studies (N = 27) were performed on dogs with 25-cm ileal Thirty-Vella fistulas (TVF). Perfusion with [14C]PEG was used to calculate absorption of water, electrolytes, and glucose from the TVF. Three groups were randomly studied over 4 hr: (1) terazosin alone, (2) meal alone, and (3) terazosin plus meal. Terazosin (10(-4) M) was administered to the TVF in groups 1 and 3 following the first hour. A 480-kcal mixed canine meal was ingested at the end of the second hour in groups 2 and 3. Ileal water, electrolyte, and glucose absorption increased significantly in response to meal ingestion (P < 0.05). Luminal terazosin did not significantly alter basal or meal-stimulated ileal absorption. In conclusion, meal ingestion stimulates ileal absorption of water, electrolytes, and glucose. Neither basal nor meal-stimulated ileal absorption is altered by alpha 1-adrenergic receptor blockade. These data suggest that nonadrenergic neural pathways or humoral factors are the likely mediators of meal-induced intestinal absorption.
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Terazosin is a new long-acting, selective alpha 1-adrenergic antagonist. Its pharmacokinetic and pharmacodynamic profiles are similar to those of prazosin, but terazosin has a half-life three to four times longer. This allows once daily dosing of terazosin and a potential advantage in ensuring patient compliance to treatment. Terazosin has been evaluated alone and in combination with other drugs for the treatment of mild to moderate hypertension. Terazosin has been shown to have favorable lipid and side effect profiles. Unlike prazosin, the drug is available (but not yet marketed) in parenteral form. Its gradual onset of action with intravenous use would limit its potential application in hypertensive emergencies. Other possible uses for terazosin might include treatment of congestive heart failure and Raynaud's phenomenon, but definitive studies are needed.
Indirect comparison of data derived from the placebo-controlled studies involving 6,333 patients and the data derived from the direct comparative studies involving 507 patients demonstrate that all alpha1-adrenoceptor antagonists (alfuzosin, terazosin, doxazosin and tamsulosin) produce comparable improvements in LUTS and urinary flow. Total symptom score is in general improved by 30-40% and Qmax by 16-25%. The difference between currently available alpha1-adrenoceptor antagonists is related to their side effect profile. Alfuzosin (especially the sustained release formulation) and tamsulosin (modified release formulation 0.4 mg) seem to be better tolerated than terazosin and doxazosin. The percentage of patients that withdrew due to bothersome side effects with alfuzosin and tamsulosin 0.4 mg was comparable to that with placebo (about 4-10%) whereas in the terazosin and doxazosin studies an additional 4-10% of patients dropped out because they did not tolerate the therapy. Tamsulosin has less effect on blood pressure than alfuzosin (especially in elderly patients) and causes less symptomatic orthostatic hypotension during orthostatic stress testing than terazosin.
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A total of 1,229 subjects with clinical benign prostatic hyperplasia (BPH) were randomized to 1 year of placebo, finasteride, terazosin or drug combination. The primary outcome measures were American Urological Association (AUA) symptom score and peak flow rate. Relevant secondary outcome measures were symptom problem score, BPH impact score and global rating of improvement.
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Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala terazosin delivered before conditioning enhanced short- and long-term memory. Terazosin delivered after conditioning did not affect consolidation. In vitro, terazosin impaired lateral amygdala inhibitory postsynaptic currents leading to facilitation of excitatory postsynaptic currents and long-term potentiation. Since alpha1 blockers are prescribed for hypertension and post-traumatic stress disorder, these results may have important clinical implications.
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Finasteride, which inhibits the enzyme 5 alpha-reductase, reduces prostate size and relieves the symptoms of benign prostatic hyperplasia (BPH) in men with enlarged prostates. alpha 1 -Adrenoceptor antagonists, such as doxazosin and terazosin, are also effective in the treatment of BPH. Previous clinical studies in which finasteride had little or no effect alone, have shown little or no additive effect with alpha 1 -adrenoceptor antagonists. The Medical Therapy of Prostatic Symptoms study showed a considerable benefit with finasteride alone and an additive effect when administered with doxazosin. One interpretation of these results is that if finasteride is effective alone in BPH, the combination with an alpha 1 -adrenoceptor antagonist will give an additive effect.
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Between 1987 and 1995, 743 patients with clinically localized prostate cancer were treated with 3D-CRT. A total of 275 (37%) patients developed Grade 2 acute urinary symptoms as defined by the RTOG morbidity scoring system. Terazosin hydrochloride (THC), a selective alpha-1 adrenoceptor blocking agent, was given to 119 (43%) patients for treatment of their urinary symptoms, whereas nonsteroidal anti-inflammatory medications (NSAID) were administered to 71 patients (26%). Thirty-one patients (11%) were treated with other medications, and 54 (20%) did not seek pharmacologic intervention for their urinary symptoms. Patients were monitored weekly to assess changes in urinary urgency, frequency, and nocturia.
Thirteen patients with essential hypertension were treated with an alpha 1-adrenoceptor antagonist, terazosin (1 to 4 mg/day) for 12 months. To assess the mechanism of its antihypertensive effect, the hemodynamic and endocrinological responses to terazosin were determined before, 3, and 12 months after the administration of terazosin. Blood pressure significantly decreased within 2 weeks after the start of terazosin and its effect was sustained throughout the 12 month period. Pulse rate did not change except slight increase in the third month. The hemodynamic studies revealed that total peripheral resistance significantly decreased and cardiac output slightly increased, indicating that the antihypertensive effect of terazosin is mainly produced by its vasodilation. Blood volume and plasma volume did not change. Although plasma renin activity remained the same, plasma aldosterone significantly decreased in response to terazosin. Plasma noradrenaline increased in the third month, but returned to the baseline level in the twelfth month. Thus, terazosin monotherapy lowered blood pressure throughout one year without drug tolerance including volume expansion and/or accentuation of renin-angiotensin-aldosterone system or sympathetic function.
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In all, 4571 cases and an equal number of controls were identified. Current use of alpha-blockers (prazosin, doxazosin, indoramin, terazosin, alfuzosin and tamsulosin) was compared with non-use of alpha-blockers. Current use of alpha-blockers on the index date was associated with an increased risk of hip/femur fracture [adjusted odds ratio (OR) 1.9, 95% confidence interval (CI): 1.1-3.0] in the overall analysis. The effect was particularly strong for first prescriptions within a treatment episode (adjusted OR 5.1, 95% CI: 1.0-31.7) and during the first month of treatment (adjusted OR 4.1, 95% CI: 0.7-23.9). Stratification according to indication of use showed that current use of alpha-blockers was not associated with hip/femur fracture in men with a diagnosis of benign prostatic hyperplasia (adjusted OR 1.0, 95% CI: 0.4-2.5), but was associated in men who used alpha-blockers for cardiovascular disease (adjusted OR 2.8, 95% CI: 1.4-5.4).
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In the present study the alpha 1 selective agonist phenylephrine (PE), the alpha 2 selective agonist clonidine (CLO) and the non-selective endogenous catecholamine norepinephrine (NE) and dopamine (DA) were injected directly into the blood supply of the paravertebral sympathetic ganglia (PSG) of anesthetized open-chest dogs. Intra-arterial injection of all agonists produced dose-dependent decreases in mean arterial pressure (MAP) and femoral vascular resistance (FVR) but had no effect on heart rate. Their potency order was CLO greater than NE greater than PE greater than DA. Intravenous injections of the medium dose for NE and PE produced significant increases in MAP, while the medium dose of CLO injected iv produced a small decrease in MAP. The ganglionic blocking agent, hexamethonium (10 mg/kg iv) completely eliminated the hypotensive response to all agonists. Intra-arterial administration of the alpha 1 selective antagonist terazosin (0.5 mg) significantly reduced the decrease in MAP produced by the ganglionic actions of PE, but had no significant effect on the response to CLO. In contrast, the alpha 2 selective antagonist rauwolscine (100 micrograms) significantly reduced the decreases in MAP produced by ia CLO, but not that produced by ia PE. However, both antagonists inhibited the hypotensive effect of NE and DA. These findings suggest that both subtypes of alpha-adrenoceptors, alpha 1 and alpha 2, are present in the PSG and that both subtypes are inhibitory since their activation results in reduced transmission of impulses through the ganglia.
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The authors concluded that treatment with terazosin was associated with greater peak urinary flow rate and lower symptom score than treatment with placebo. There was no variability of efficacy of terazosin as a result of prostrate volume, and measurement of prostrate volume was not essential before initiation of therapy.
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BPH is common in older men; more than 90% of men aged 70 and older suffer from BPH. (1,2) BPH has substantial negative effect on quality of life, with symptoms that interfere with activities of daily living. (3) The symptoms of BPH are primarily due to bladder outlet obstruction and are caused by dynamic prostatic smooth muscle tone and static prostatic obstruction. (4,5) The smooth muscle tone is dependent on the degree of the alpha-1 adrenergic receptors present in the bladder neck, prostrate capsule, and prostrate gland. The blockade of alpha-1 receptors with drugs such as terazosin reduces bladder outlet obstruction by reducing the smooth muscle tone. STUDY SELECTION AND DATA SOURCES: Selected studies were all RCTs of terazosin with two primary end points, namely, changes in the peak urinary flow rates and urinary symptom scores from baseline. Nine studies were selected using a Medline search, the details of which were not provided. The studies were conducted in North America and Europe between 1992 and 1996. Two of the studies included unpublished data that were obtained from Abbott Laboratories, which is the manufacturer of terazosin (Hytrin). The company also provided data on the other seven studies.
Male patients over the age of 50 years were recruited from clinics over 3 months and divided into two groups: 18 study patients taking α(1)-adrenoreceptor antagonists (Flomax, Uroxatral, Cardura and Hytrin) and 31 control patients who had never been on them. Those with conditions known to affect pupil diameter were excluded. Pre-dilation pupil diameters were recorded using a pupillometer in mesopic and scotopic conditions. Right eyes were dilated with phenylephrine and tropicamide, and the left eye served as an undilated control. Following dilation, pupil diameters were measured in both lighting conditions.
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In benign prostatic hyperplasia (BPH) there will be a sudden impact on overall quality of life of patient. This disease occurs normally at the age of 40 or above and also is associated with sexual dysfunction. Thus, there is a need of update on current medications of this disease. The presented review provides information on medications available for BPH. Phytotherapies with some improvements in BPH are also included. Relevant articles were identified through a search of the English-language literature indexed on MEDLINE, PUBMED, Sciencedirect and the proceedings of scientific meetings. The search terms were BPH, medications for BPH, drugs for BPH, combination therapies for BPH, Phytotherapies for BPH, Ayurveda and BPH, BPH treatments in Ayurveda. Medications including watchful waitings, Alpha one adrenoreceptor blockers, 5-alpha reductase inhibitors, combination therapies including tamsulosin-dutasteride, doxazosin-finasteride, terazosin-finasteride, tolterodine-tamsulosin and rofecoxib-finasteride were found. Herbal remedies such as Cernilton, Saxifraga stolonifera, Zi-Shen Pill (ZSP), Orbignya speciosa, Phellodendron amurense, Ganoderma lucidum, Serenoa Repens, pumpkin extract and Lepidium meyenii (Red Maca) have some improvements on BPH are included. Other than these discussions on Ayurvedic medications, TURP and minimally invasive therapies (MITs) are also included. Recent advancements in terms of newly synthesized molecules are also discussed. Specific alpha one adrenoreceptor blockers such as tamsulosin and alfuzosin will remain preferred choice of urologists for symptom relief. Medications with combination therapies are still needs more investigation to establish as preference in initial stage for fast symptom relief reduced prostate growth and obviously reduce need for BPH-related surgery. Due to lack of proper evidence Phytotherapies are not gaining much advantage. MITs and TURP are expensive and are rarely supported by healthcare systems.
In normal rats intracerebroventricular administration of 8 nmol. kg.-1 prazosin (Pfizer Central Research, Sandwich, United Kingdom) or terazosin (Abbott Laboratories, Abbott Park, Illinois) (nonsubtype selective) caused no change in cystometric parameters. At 24 or 80 nmol. kg.-1 the 2 drugs significantly decreased voiding pressure and increased bladder capacity, voided volume and post-void residual urine volume. Administering vehicle had no effect. In rats with outlet obstruction the drug effects were significantly more pronounced than in normal animals (p <0.05), and urinary retention was produced in 50% of rats receiving prazosin. In normal rats the selective alpha1A-adrenoceptor antagonists KMD 3213 (0.8, 8 and 24 nmol. kg.-1) dose dependently depressed voiding pressure, and increased bladder capacity and voided volume, whereas BMY 7378 (selective for alpha1D-adrenoceptors) and A322312 (selective for alpha1B-adrenoceptors) at doses up to 80 nmol. kg.-1 had no effect.
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Comparative morphometrical study of the renal glomerular system was carried out in hypertensive NISAG rats treated with hypotensive drugs during the prepubertal period. Blockade of the renin-angiotensin system with enalapril or losartan during the critical period of ontogeny (the 2nd month of life) produced a long-term hypotensive and renoprotective effect. Treatment with alpha-adrenoblocker terazosin during this period of ontogeny produced a less pronounced hypotensive effect, though with renoprotection. Corinfar (Ca2+ channel blocker) was least effective.
Some α1 -adrenoceptor antagonists possess anti-cancer actions that are independent of α1 -adrenoceptors and the aim of these studies was to assess the relative cytotoxic potencies of α1 -adrenoceptor antagonists and the mechanisms involved in these actions.
Parotid gland swelling is a less frequently reported side effect of clozapine and has no licensed treatment. A 58-year-old man treated with clozapine for treatment-resistant schizophrenia developed bilateral painful parotid swellings and hypersalivation. Initial trials of dose alteration and antihypersalivatory medication had limited success. A combination of benzatropine and terazosin was successful in treating the parotid hyperplasia. Clozapine was the probable cause of parotid swelling in our case, as established using the Naranjo adverse drug reaction probability scale and World Health Organization causality categories. Literature for treatments of clozapine-induced parotid gland swellings was reviewed. None of the published articles suggested a treatment regimen for clozapine-induced parotid hyperplasia. Most reports only highlighted the occurrence of salivary gland swelling with clozapine. Others mentioned management strategies, which included spontaneous resolution, or resolution on discontinuing clozapine. One report, a trial with benzatropine and ipratropium, had variable success. In this case the re-emergence of parotid swelling when terazosin and benzatropine doses were missed followed by a quick resolution upon recompliance, goes some way in proving that this combination is indeed effective. The combination of terazosin and benzatropine appears to have a role in treating parotid gland swellings induced by clozapine.
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)
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This analysis examines the relative effectiveness of current medical therapies for BPH in preventing AUR, AUR-related catheterisation and surgery in real-life clinical practice.
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The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched.
Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist.
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In diabetic rats the intravesical pressure thresholds for inducing urethral relaxation and the lowest urethral pressure (UPP nadir) during urethral relaxation were significantly higher by 142% and 86%, respectively, than in normal rats, while baseline UPPs were not significantly different. The mean rate of high frequency oscillations of urethral striated muscle in diabetic rats was also significantly lower by 23% than in normal rats. After alpha-bungarotoxin treatment (333 mug/kg intravenously) to eliminate striated muscle sphincter contractions the SD of baseline UPPs was significantly larger by 93% than in normal rats. Intravenous administration of terazosin (0.4 mg/kg), an alpha1-adrenoceptor antagonist, significantly decreased the UPP nadir, intravesical pressure thresholds inducing urethral relaxation and the SD by 41%, 87% and 138%, respectively, in diabetic rats but not in normal rats. In the 2 groups of animals after alpha-bungarotoxin treatment urethral relaxation during a reflex bladder contraction was inhibited by Nomega-nitro-L-arginine (40 mg/kg intravenously), a nitric oxide synthase inhibitor.