Drugs online research references
Eur J Pharmacol. 2002 Jun 7;445(1-2):125-31.
Characterization of some novel alpha 1-adrenoceptor antagonists in human hyperplastic prostate.
Chueh SC, Chern JW, Choong CM, Guh JH, Teng CM.
Department of Urology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Sect. 1, Taipei, Taiwan.
We synthesized some quinazoline-based compounds, such as FH-71 (ethyl 4-(3-(4-(2-methoxyphenyl)piperazinyl)aminoquinazolin-2-carboxylate), EW-65 (4-(3-(4-(2-methoxyphenyl)piperazinyl)propyl)aminoquinazolin-2-carboxamide) and EW-154 (2-(4-(4-(2-methoxyphenyl)piperazinyl)butyl)amino-4-cyclohexylamino-quinazolin), and then characterized their pharmacological properties in several tissues. All of these compounds produced potent inhibition of phenylephrine but not high K(+) or U46619 (11 alpha,9 alpha-epoxymethano-15S-hydroxy-prosta-5Z,13E-dienoic acid)-induced contractions in rat aorta, suggesting alpha(1)-adrenoceptor antagonist properties. With rat vasa deferentia and spleens as the functional alpha(1A)- and alpha(1B)-adrenoceptor models, respectively, FH-71 exhibited greater antagonistic potency in rat vas deferens, EW-154 in rat spleen, and EW-65 had similar effects in both tissues. The potency ratios of terazosin, FH-71, EW-65 and EW-154 against phenylephrine-induced contractions in rat vas deferens/spleen were 1, 19.04, 0.39 and 0.09, respectively. The results suggest that FH-71 is a selective alpha(1A)-adrenoceptor antagonist, whereas EW-154 exhibits more antagonistic selectivity against alpha(1B)-adrenoceptors. FH-71 also showed a greater potency than EW-65 and EW-154 against phenylephrine-induced contraction in human hyperplastic prostate. The pA(2) values were 8.34, 7.44 and 7.05, respectively. Furthermore, FH-71 and EW-65 were not cytotoxic whereas EW-154 (all in 10 microM) had a massive toxic effect (more than 80%) in human prostatic smooth muscle cells. These data show FH-71 to be a potent and selective alpha(1A)-adrenoceptor antagonist with activity in human hyperplastic prostate.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12065203&dopt=Abstract
J Urol. 1999 Jun;161(6):2002-8.
Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia.
Chon JK, Borkowski A, Partin AW, Isaacs JT, Jacobs SC, Kyprianou N.
Division of Urology, University of Maryland School of Medicine, Baltimore, USA.
PURPOSE: Recent evidence indicated that an alpha 1 blocker, doxazosin, induces prostate apoptosis in patients with benign prostatic hyperplasia (BPH). In this study, to determine whether this apoptotic response was mediated by alpha 1 adrenoceptor-dependent mechanism or was specific to doxazosin, we examined the effect of another alpha 1 blocker, terazosin, in addition to doxazosin, on the dynamics of prostate cell growth. MATERIALS AND METHODS: Cell proliferation and apoptosis were evaluated in BPH patients, an untreated (control) group (n = 31), and men treated with terazosin (n = 42) and doxazosin (n = 61) for the relief of the obstructive symptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8 mg./day) treatment varied from 1 week to 3 years. Ki-67 immunostaining and the TUNEL assay were used to evaluate the proliferative and apoptotic indices, respectively, in both the epithelial and stromal components of prostate (biopsy and prostatectomy) specimens. The smooth muscle cell content of the prostatic stroma was identified on the basis of smooth muscle alpha-actin immunoreactivity. RESULTS: A significant induction of apoptosis was observed in both the prostatic epithelial and stromal cells within the first month of terazosin and doxazosin therapy, as compared with untreated controls (p < 0.05). Furthermore, the marked induction of prostatic stroma apoptosis in response to both alpha 1 adrenoceptor antagonists was paralleled by a significant decrease in the smooth muscle alpha-actin expression. This loss of prostatic smooth muscle cells correlated with morphological stromal regression (as detected by trichrome staining) and BPH symptom improvement. Neither terazosin nor doxazosin therapy resulted in significant changes in prostate cell proliferation. CONCLUSIONS: These findings demonstrate that alpha-blockers as a class may regulate prostate growth by inducing apoptosis in both the epithelial and stromal cells, with little effect on cell proliferation. Apoptosis-mediated prostate stromal regression appears as a molecular mechanism underlying the therapeutic response to alpha 1 blockade in the treatment of BPH.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10332490&dopt=Abstract
central.murdoch.edu.au
AIMS: To determine whether postjunctional alpha1- and alpha2-adrenoceptors mediate vasoconstrictor responses in the cutaneous vasculature of the human forearm. METHODS: Drugs were administered transdermally by iontophoresis in the forearm of 20 healthy participants. Phenylephrine and clonidine were administered at sites pretreated with the relevant antagonist (terazosin and rauwolscine), and at additional untreated sites and sites pretreated with saline. To enhance the contrast between sites, the forearm was heated to 42 degrees C before flow was measured with the laser Doppler technique. RESULTS: After the iontophoresis of phenylephrine, blood flow at the site pretreated with terazosin was 24+/-37% (+/-95% confidence interval) greater than flow at the reference site, whereas flow was 53+/-24% lower than reference flow at the previously untreated site and 77+/-10% lower than reference flow at the site pretreated with saline (P<0.001). After the iontophoresis of clonidine, blood flow at the site pretreated with rauwolscine was 25+/-21% greater than flow at the reference site, whereas flow was 56+/-15% lower than reference flow at the previously untreated site and 72+/-8% lower than reference flow at the site pretreated with saline (P<0.001). The saline pretreatment enhanced vasoconstriction to phenylephrine (P<0.05) and clonidine (P=0.05). CONCLUSIONS: Pre-treatment with the appropriate antagonist blocked vasoconstrictor responses to phenylephrine and clonidine, consistent with the presence of both alpha-adrenoceptor subtypes in cutaneous vessels of the human forearm. In addition, iontophoretic pretreatment with saline facilitated vasoconstrictor responses, suggesting that a nonspecific effect of iontophoresis may enhance drug penetration through the stratum corneum.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12100224&dopt=Abstract
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