Drugs online research references
J Med Chem. 2000 Jul 13;43(14):2703-18.
In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.
Barrow JC, Nantermet PG, Selnick HG, Glass KL, Rittle KE, Gilbert KF, Steele TG, Homnick CF, Freidinger RM, Ransom RW, Kling P, Reiss D, Broten TP, Schorn TW, Chang RS, O'Malley SS, Olah TV, Ellis JD, Barrish A, Kassahun K, Leppert P, Nagarathnam D, Forray C.
Departments of Medicinal Chemistry, Pharmacology, and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10893308&dopt=Abstract
smail.umaryland.edu
Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both drugs, already in clinical use and with established adverse-effect profiles, against prostatic tumors for the treatment of advanced prostate cancer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10969806&dopt=Abstract
Pharmacotherapy. 2000 Sep;20(9):1055-9.
Retrospective evaluation of a potential interaction between azithromycine and warfarin in patients stabilized on warfarin.
Beckey NP, Parra D, Colon A.
Department of Veterans Affairs Medical Center, West Palm Beach, Florida 33410, USA.
STUDY OBJECTIVE: To investigate a potential interaction between azithromycin and warfarin. DESIGN: Retrospective case-control study. SETTING: Veterans Affairs medical center. PATIENTS: Fifty-two patients stable on anticoagulation therapy. INTERVENTION: Patients who received a prescription for azithromycin and warfarin at any time since the hospital was opened, June 1, 1995, to July 22, 1999, were identified through a computerized report generated from the pharmacy prescription package. MEASUREMENTS AND MAIN RESULTS: Patients having a stable international normalized ratio (INR; defined as a therapeutic INR +/- 0.2) for at least two consecutive visits before receiving an azithromycin prescription were reviewed. Changes in INR from before and after addition of azithromycin were compared with changes in a control group. Controls were identified from a computer-generated report of patients who received a prescription for terazosin and warfarin at any time since the hospital was opened to July 22, 1999 (terazosin was chosen as it has no known interaction with warfarin). These patients also had a stable INR for at least two consecutive visits before receiving the terazosin prescription. In patients with INRs on record within 14 days after starting azithromycin or terazosin (9 patients/group), the average change in INR was 0.18 +/- 0.48 in the azithromycin group and 0.07 +/- 0.49 in the terazosin group (p=0.60). For patients with an INR on record within 30 days after starting azithromycin or terazosin (26 patients/group), the average change in INR was 0.25 +/- 0.67 in the azithromycin group and 0.05 +/- 0.55 in the terazosin group (p=0.18). CONCLUSION: An interaction between azithromycin and warfarin was not observed in this retrospective review of patients with a stable INR receiving the combination.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10999497&dopt=Abstract
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