Drugs online research references
Expert Opin Investig Drugs. 1999 Dec;8(12):2073-2094.
Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia.
Forray C, Noble SA.
Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.
Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of 'prostatism' that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of alpha1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The alpha1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an alpha1-subtype selective drug. The blockade of alpha1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic alpha1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective alpha1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three alpha1-adrenoceptors led to the identification of the alpha1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective alpha1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner from the pharmacodynamic properties of compounds without alpha1A-subtype selectivity. Clinical experience with tamsulosin, an alpha1A/alpha1D selective drug, has failed to demonstrate a significant improvement in efficacy beyond that demonstrated for non-subtype selective alpha1-blockers, and gives support to the notion that alpha1A-selective antagonists might achieve greater efficacy for the treatment of BPH. Given the demonstrated uroselectivity of alpha1A-selective antagonists in preclinical models, it is anticipated that third generation alpha1-blockers will exhibit improved urinary flow efficacy and be better tolerated than tamsulosin. The extent to which the improvement in urinary flow will translate to the relief of symptoms of prostatism, however, remains to be demonstrated in randomised placebo-controlled clinical trials of alpha1A-selective antagonists.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11139841&dopt=Abstract [PubMed - as supplied by publisher]
Acta Physiol Scand. 2000 Nov;170(3):191-9.
The vagal cardiac accelerator system in the reflex control of heart rate in conscious dogs.
Roossien A, Brunsting JR, Zaagsma J, Zijlstra WG, Muntinga JH.
Department of Medical Physiology, University of Groningen, Groningen, The Netherlands.
The reactions of the vagal cardioaccelerator (VCA) system to changes in mean arterial pressure (MAP) were studied in five beta-adrenoceptor blocked conscious dogs. An increase in MAP was obtained by administration of vasopressin or methoxamine, a decrease by doxazosin or nitroprusside. In the first series of experiments the MAP changes were induced after muscarinic receptor blockade, in a second series both before and after muscarinic blockade. Prior to these experiments, the maximum VCA activity, defined as the difference between maximum heart rate after muscarinic blockade and the rate after additional nicotinic blockade, was determined. We hypothesized that this quantity, as a measure of VCA activity, depends on the prevailing vagal tone. In the first series of experiments, a rise in MAP evoked an increase in heart rate, a fall in MAP indicated decrease. In the second series, when prior to muscarinic blockade the vagal tone was reflexly raised, the subsequent VCA reflex response to the rise in MAP was attenuated. Prior to the muscarinic blockade the vagal tone was reflexly lowered, the VCA reflex response was enhanced. Direct chronotropic effects of MAP-varying drugs were ruled out by the absence of a heart-rate response in experiments on vagotomized animals. We concluded that the vagal cardioaccelerator system is involved in the reflex control of heart rate. Both the VCA reflex response to changes in systemic blood pressure and the maximum VCA activity however, are determined by the prevailing vagal tone.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167304&dopt=Abstract
med.uib.no
Angiotensin-converting enzyme inhibitors are renoprotective in diabetes mellitus through their intrarenal hemodynamic effects. Alpha-1 blockade has variable pre- and postglomerular vasodilatory effects dependent upon the stimulation of the sympathetic nervous system. We tested the hypothesis that the two different classes of drugs have similar renal hemodynamic effects when the patients are examined in an upright position where the sympathetic nervous system is activated. Mean blood pressure (MAP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined in 28 hypertensive type-1 diabetic patients with variable degree of nephropathy treated for a mean period of 7.6 +/- 0.4 months with captopril (n = 13) or doxazosin (n = 15). Average treatment doses were 112 +/- 7 mg/day in the captopril group and 8 +/- 1 mg/day in the doxazosin group. Sitting MAP decreased from 118 +/- 3 to 106 +/- 4 mm Hg after captopril (p < 0.05), and from 117 +/- 4 to 110 +/- 3 mm Hg after doxazosin (p = 0.07). GFR and ERPF were unchanged in both groups. The filtration fraction (FF) decreased from 0.27 +/- 0.02 to 0.25 +/- 0.02 after captopril (p < 0.05) and from 0.26 +/- 0.01 to 0.25 +/- 0.01 after doxazosin (p = 0.08). Calculation of 95% confidence intervals of the difference between the post-treatment values as well as the difference between pre- and post-treatment values of MAP, GFR, ERPF and FF of the two drugs indicates no difference in renal hemodynamic response between the drugs. In conclusion, captopril and doxazosin have similar renal hemodynamic responses when the patients are examined in a situation where the sympathetic nervous system is stimulated, and this suggests that doxazosin has a renoprotective effect beyond the blood pressure-lowering effect.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11174009&dopt=Abstract
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