Drugs online research references
J Pharmacol Exp Ther. 1997 Jun;281(3):1272-83.
Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part I.
Leonardi A, Hieble JP, Guarneri L, Naselsky DP, Poggesi E, Sironi G, Sulpizio AC, Testa R.
Pharmaceutical R&D Division, Recordati S.p.A., Milano, Italy.
Alpha adrenoceptor antagonists have been convincingly shown to be beneficial in reducing both subjective and objective indices of urethral obstruction in benign prostatic hyperplasia. Rec 15/2739 (SB 216469) is a novel alpha-1 adrenoceptor (alpha-1 AR) antagonist currently being developed for benign prostatic hyperplasia. When evaluated in radioligand binding assays with expressed animal or human alpha-1 ARs, Rec 15/2739 shows marked to moderate selectivity for the alpha-1a AR subtype. Its affinity for the recombinant alpha-2 AR subtypes or native dopaminergic D2 receptor was about 100-fold lower than that for alpha-1a AR subtype. In canine tissues, Rec 15/2739 was 20-fold more potent as an inhibitor of [3H]prazosin binding to prostate vis-a-vis aorta. Functional studies in isolated rabbit tissues also confirmed the uroselectivity of Rec 15/2739, with substantially higher affinity (Kb = 2-3 nM) being observed in urethra and prostate, compared with ear artery and aorta (Kb = 20-100 nM). The in vitro selectivity observed with Rec 15/2739 was confirmed in vivo in the anesthetized dog, comparing potency against norepinephrine- or hypogastric nerve stimulation-induced urethral contraction with its ability to reduce diastolic blood pressure. In this model, Rec 15/2739 had greater selectivity than any other alpha-1 AR antagonist examined, including terazosin and tamsulosin. Based on the low potency of prazosin and some of its structural analogs in the rabbit and dog lower urinary tract tissues, it appears that norepinephrine contracts these tissues via activation of the alpha-1L AR. Hence this alpha-1 AR subtype, rather than the alpha-1A AR, may mediate the contraction in vivo.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9190863&dopt=Abstract
Urology. 1997 Jul;50(1):55-61.
Urodynamic and clinical effects of noninvasive and minimally invasive treatments in elderly men with lower urinary tract symptoms stratified according to the grade of obstruction.
Witjes WP, Robertson A, Rosier PF, Neal DE, Debruyne FM, de la Rosette JJ.
Department of Urology, University Hospital Nijmegen, The Netherlands.
OBJECTIVES: We investigated the symptomatic and urodynamic effects of several noninvasive and minimally invasive treatment modalities to quantify these effects and to compare subjective and objective results within groups with various degrees of obstruction. METHODS: In a prospective study at one center, 487 patients who completed a full screening program including urodynamic investigation started treatment with watchful waiting, terazosin, transurethral microwave thermotherapy, or laser treatment of the prostate; they were re-evaluated symptomatically and urodynamically after 6 months of therapy. The symptomatic and urodynamic results of 87 patients from another center who underwent transurethral resection of the prostate and who had their second urodynamic evaluation 6 months after surgery were also included. RESULTS: In patients without bladder outlet obstruction (BOO), improvement in maximum flow and symptom scores with little change in the degree of obstruction was most apparent, whereas a decrease of detrusor pressure at maximum flow was observed mainly in patients with BOO. The urodynamic effect but not the symptomatic effect of treatments depended on the initial grade of BOO. Urodynamic changes were more marked in the minimally invasive treatment groups compared with the noninvasive treatment groups. CONCLUSIONS: In symptomatic patients with benign prostatic hyperplasia, symptomatic improvement in the short term does not seem to depend on changes in urodynamic parameters. Future well-controlled studies focusing on the durability of symptomatic and urodynamic effects will be needed to illustrate the relative potential of urodynamic and other clinical parameters to predict a favorable response to current and innovative treatments.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9218019&dopt=Abstract
J Pharmacol Exp Ther. 1997 Jul;282(1):228-35.
Comparative alpha-1 adrenoceptor subtype selectivity and functional uroselectivity of alpha-1 adrenoceptor antagonists.
Martin DJ, Lluel P, Guillot E, Coste A, Jammes D, Angel I.
Synthelabo Recherche, Department of Internal Medicine, Rueil-Malmaison, France.
We investigated the relevance of selectivity for a given alpha-1-adrenoceptor subtype for in vivo uroselectivity of several alpha-1-adrenoceptor antagonists (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin and 5-Me-urapidil). Comparison of the affinities of these alpha-1-adrenoceptor antagonists at the cloned alpha-1a, alpha-1b and alpha-1d-adrenoceptor subtypes revealed that tamsulosin and 5-Me-urapidil showed selectivity for the alpha-1a subtype. No significant correlations were found between the affinities for alpha-1b or alpha-1d-adrenoceptors and the pK(B) values obtained against phenylephrine-induced contraction of the rabbit prostate in vitro. In contrast, the antagonist potencies in rabbit prostate were correlated (r = 0.89, P < .05) with the pKi values for the alpha-1a-adrenoceptor subtype. However, the pK(B) values were consistently smaller (by 0.6 to 1.9 log unit) than the pKi values for the alpha-1a-adrenoceptor subtype, a result that suggests that the alpha-1-adrenoceptor mediating urethral contractions does not have all the characteristics of the alpha-1a-adrenoceptor. The simultaneous measurement of urethral and arterial pressures in the same conscious male rat allows evaluation of the functional uroselectivity of these antagonists based on their respective effects on both pressures. Dose ranges were selected according to effects on urethral pressure and most antagonists were found effective within the 3 to 100 microg/kg i.v. range. Alfuzosin markedly decreased urethral pressure and either did not decrease blood pressure (10-30 microg/kg) or slightly decreased it at the highest dose tested (100 microg/kg). Doxazosin did not produce sustained reductions in urethral pressure until a dose of 30 microg/kg. Blood pressure was not reduced until 100 microg/kg. Prazosin reduced urethral pressure and blood pressure within the same dose-range whereas terazosin did not decrease urethral pressure at doses that significantly decreased blood pressure (30 and 100 microg/kg). 5-Me-urapidil, an alpha-1a-selective compound did not significantly modify urethral and blood pressure whereas tamsulosin, another alpha-1a-selective compound reduced urethral pressure and blood pressure within the same dose range. In conclusion, in the conscious male rat the functional uroselectivity is not correlated with a selective affinity for the alpha-1a-adrenoceptor subtype.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9223558&dopt=Abstract
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