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PubMedDate not supplied

Some actions of chandonium iodide, a new short-acting muscle relaxant, in anaesthetized cats and on isolated muscle preparations.

1. The actions of the new skeletal muscle relaxant chandonium (HS310) on the cardiovascular, respiratory and skeletal muscle systems of the cat under chloralose anaesthesia and on chick and rat isolated skeletal muscle preparations have been described. 2. In the cat chandonium exhibited a potent, competitive, non-depolarizing neuromuscular blocking action that was rapid in onset and of short duration. It possessed a selective atropine-like action at the cardiac vagus neuro-effector junction but little or no ganglion blocking activity. Neither adrenergic neurone noralpha-adrenoceptor blocking properties were evident. 3. Unlike tubocurarine, chandonium was without effect on the airways system of the anaesthetized cat. 4. Chandonium possessed weak anticholinesterase action. It is conceivable that this effect may contribute to its short duration of action. 5. The results from these studies suggest that chandonium may have possible clinical applications as a short-acting muscle relaxant.

Acetylcholine↗
PubMed1992

Finasteride in the treatment of benign prostatic hyperplasia. A urodynamic evaluation.

A group of 69 men with bladder outflow obstruction due to benign prostatic hyperplasia (BPH) were treated in a double-blind, placebo-controlled study with finasteride (Proscar, MK-906), a 5-alpha reductase inhibitor, 5 mg or 10 mg/day or placebo for 3 months; subsequently, 20 patients received finasteride 5 mg/day for a further 9 months in an open extension study. In treated patients dihydrotestosterone declined by over 60%, remaining unchanged with placebo. Symptom scores fell significantly in all 3 groups. Mean maximum flow rates fell slightly in placebo-treated patients but improved by 1.5 ml/s in the 10 mg group and by 3.3 ml/s in the 5 mg group. After 1 year's treatment, the reduction in symptom score and increase in flow rate were well maintained; the mean prostate volume was reduced by 14% and prostatic specific antigen declined by 28%. It was concluded that finasteride shows some efficacy in the treatment of BPH, with minimal toxicity, but 12 months of therapy or longer may be necessary to achieve maximal effect.

Aged↗
PubMed2005

Selecting therapy for maintaining sexual function in patients with benign prostatic hyperplasia.

In the first of these mini-reviews the selection of therapy for the maintenance of sexual function in patients with BPH is outlined, along with an explanation of how altered regulation of neurotransmitters, especially noradrenaline, may underlie the syndrome of LUTS and sexual dysfunction. Other mini-reviews outline the current status of robotic surgery to treat renal and adrenal disorders, and its future applications, and the potential use of the nitric oxide/cGMP pathway as a potential target to treat BOO associated with benign prostatic enlargement. Finally, the capacity to be creative in academic departments is extolled as a core property of academicians, and its surfacing described as having the potential to revitalize individuals and departments.

5-alpha Reductase Inhibitors↗
PubMed2005

Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies.

OBJECTIVE: To report additional analyses of efficacy over the initial 2 years and during a 2-year open-label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5alpha-reductase, was shown to be effective and well tolerated. PATIENTS AND METHODS: All patients in the placebo and active groups were eligible for entry into the 2-year open-label extension, with all receiving dutasteride 0.5 mg daily. Mean changes from baseline were calculated for the American Urologic Association Symptom Index (AUA-SI) score at each scheduled time in the double-blind and open-label phase. The additional analyses included a breakdown of the AUA-SI score, including stratifying patients by symptom severity, assessment by baseline age and prostate volume, and the evaluation of symptoms responders. RESULTS: There was a clinically meaningful improvement in AUA-SI in patients on dutasteride in the double-blind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA-SI score and individual question scores than those on dutasteride in the open-label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4-year duration of the study. CONCLUSION: In men with symptomatic benign prostatic hyperplasia, long-term (4-year) treatment with the dual isozyme 5alpha-reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement.

5-alpha Reductase Inhibitors↗
PubMed2006

Long-term therapy with the dual 5alpha-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia.

OBJECTIVE: To examine the long-term (4-year) safety and tolerability of dutasteride in the treatment of symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Patients who completed the double-blind phase of three dutasteride Phase III studies were eligible to enter a 2-year open-label extension, during which all patients received dutasteride 0.5 mg. Safety was assessed, including adverse-event reporting, clinical laboratory assessments, yearly physical examinations, and vital sign assessments. RESULTS: In all, 2340 patients entered the open-label phase, 1188 of whom previously received dutasteride during the double-blind phase of the study. The most common drug-related adverse events (occurring in > or = 1%) were effects on sexual function, which decreased with a longer duration of therapy. Gynaecomastia was reported in a small percentage of men throughout the 4-year study period. The incidence of individual sexual functional adverse events that led to withdrawal was < or = 1% (0.3-1.0%) during the 4-year study period. Dutasteride had no relevant effects on vital signs or clinical laboratory variables. CONCLUSION: These data show that dutasteride is well tolerated during long-term use for the treatment of symptomatic BPH.

5-alpha Reductase Inhibitors↗
PubMed2006

Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice.

OBJECTIVE: To assess the improvements in symptoms, quality of life (QoL), discomfort and satisfaction in patients with symptomatic benign prostatic hyperplasia (BPH) treated with dutasteride in clinical practice. PATIENTS AND METHODS: In a prospective, multicentre open-label study, we evaluated the efficacy and safety in clinical practice of dutasteride, 0.5 mg/day for 24 weeks, in patients with symptomatic BPH. The primary endpoint was the proportion of patients achieving at least a 3-point decrease from baseline in the International Prostate Symptom Score (IPSS) after 24 weeks of treatment. The secondary endpoints included changes from baseline in measures of QoL (IPSS item 8 and BPH Impact Index score, BII), and patient discomfort and satisfaction (visual analogue scales, VAS) at 12 and 24 weeks. RESULTS: Of the 366 patients assessed, 72.5% achieved at least a 3-point reduction in IPSS at 24 weeks; the IPSS decreased from 15.3 at baseline to 10.2 at 12 weeks, and to 9.1 at 24 weeks. There were significant (P < 0.001) decreases in all the individual IPSS items at 12 and 24 weeks, with more marked improvements in voiding symptoms than storage symptoms. There were also significant (P < 0.001) improvements in the BII and VAS scores for patient discomfort and satisfaction at both times. CONCLUSIONS: Dutasteride treatment for 24 weeks significantly improved BPH symptoms, QoL and patient discomfort and satisfaction, and was well tolerated in clinical practice.

Azasteroids↗
PubMed1984

Diazotization and thiocyanate differentiate agonists from antagonists for the high- and low-affinity receptors of gamma-aminobutyric acid.

The differentiation of high- and low-affinity postsynaptic gamma-aminobutyric acid (GABA) receptors was examined in a washed cortical membrane preparation of the rat. The selective elimination of the high- and low-affinity GABA sites by the chaotropic anion thiocyanate and diazotization by p-diazobenzenesulfonic acid (DSA), respectively, offered two model systems for the separate sites. The [3H]GABA displacing potencies of some GABA agonists [GABA, 4,5,6,7-tetrahydro- isoxazole [4,5c]pyridine-3-ol (THIP), and muscimol] and antagonists [bicuculline methiodide (BCM), 3-alpha-hydroxy-16-imino-5 beta-17-aza-androstan-11-one (R-5135), and d-tubocurarine] and their slope factors were examined in these model systems and in control membranes. The displacing potency of the agonists was increased in the DSA-pretreated membranes and decreased in the presence of thiocyanate. The displacing potency of the antagonists was shifted in an opposite manner. The chaotropic effect of thiocyanate was reversible and not additive with the inhibitory effect of diazotization on the specific binding of GABA. Inhibition of specific GABA binding by pyridoxal-5-phosphate (PLP) could not be protected by GABA antagonists (BCM and R-5135) but only by agonists. The results can be interpreted in the framework of a dual (agonist-antagonist) receptor model, postulating a hydrophobic accessory site at the low-affinity GABA receptor. The effect of thiocyanate on the GABA receptor may result in the exposure of the hydrophobic accessory sites.

Androstanes↗
PubMed1985

t-[3H]butylbicycloorthobenzoate: new radioligand probe for the gamma-aminobutyric acid-regulated chloride ionophore.

t-[3H]Butylbicycloorthobenzoate [( 3H]TBOB; 22 Ci/mmol) was prepared by reductive dechlorination of its 4-chlorophenyl analog with tritium gas. This new radioligand binds reversibly to fresh washed rat brain P2 membranes in 500 mM NaCl plus 50 mM sodium-potassium phosphate buffer (pH 7.4) at 25 degrees C, with 80-90% specific relative to total binding, a KD of 61 +/- 15 nM, and a Bmax of 1.6 +/- 0.5 pmol/mg of protein. [3H]TBOB association with its binding site(s) is monophasic, but its dissociation is biphasic. The binding characteristics of [3H]TBOB are essentially identical to those of t-[35S]butylbicyclophosphorothionate [( 35S]TBPS) with respect to pH dependence, stimulation by anions, regional distribution in the brain, and pharmacological profile. Saturation analyses and dissociation studies further indicate that TBOB and TBPS have a common binding site. However, binding of the two radioligands differs in respect to temperature effects. In contrast to [35S]TBPS, which exhibits negligible binding at 0 degrees C, [3H]TBOB binds to rat brain membranes at 0, 25, and 37 degrees C with similar KD values. [3H]TBOB with its long radioactive half-life and temperature-independent KD is a valuable supplement to [35S]TBPS in further biochemical and pharmacological characterization of the gamma-aminobutyric acid receptor-ionophore complex.

Androstanes↗
PubMed1985

Differential degradation of different benzodiazepine binding proteins by incubation of membranes from cerebellum or hippocampus with trypsin.

When rat brain membranes were incubated with [3H]flunitrazepam in the presence of UV light, predominantly one protein (P51) was irreversibly labeled in cerebellum and at least two proteins (P51 and P55) were labeled in hippocampus. On digestion of membranes with increasing concentrations of trypsin up to 40% of radioactivity irreversibly bound to proteins was removed from the membranes. In addition, P51 was nearly completely degraded to a peptide with apparent molecular weight 39,000 and this peptide was further degraded to a peptide with apparent molecular weight 25,000. In contrast, protein P55 was only partially degraded by trypsin and yielded two proteolytic peptides with apparent molecular weights 42,000 and 45,000 which seemed to be rather stable against further attack by trypsin. Membranes treated with trypsin still had the capacity to bind [3H]-flunitrazepam reversibly with an affinity similar to that of membranes not previously treated with trypsin. When these membranes were irradiated with UV light, the same proteolytic peptides were detected as in membranes first photolabeled and then digested with trypsin. These results suggest a close association between reversible and irreversible benzodiazepine binding sites and indicate that membrane-associated proteins P51 and P55 are differentially protected against degradation by trypsin.

Affinity Labels↗
PubMed1985

Modulation of [3H]diazepam binding in rat cortical membranes by GABAA agonists.

GABAA receptor agonists modulate [3H]diazepam binding in rat cortical membranes with different efficacies. At 23 degrees C, the relative potencies for enhancement of [3H]diazepam binding by agonists parallel their potencies in inhibiting [3H]gamma-aminobutyric acid [( 3H]GABA) binding. The agonist concentrations needed for enhancement of [3H]diazepam binding are up to 35 times higher than for [3H]GABA binding and correspond closely to the concentrations required for displacement of [3H]bicuculline methochloride (BMC) binding. The maximum enhancement of [3H]diazepam varied among agonists: muscimol = GABA greater than isoguvacine greater than 3-aminopropane sulphonic acid (3APS) = imidazoleacetic acid (IAA) greater than 4,5,6,7-tetrahydroisoxazolo (4,5,6)-pyridin-3-ol (THIP) = taurine greater than piperidine 4-sulphonic acid (P4S). At 37 degrees C, the potencies of agonists remained unchanged, but isoguvacine, 3 APS, and THIP acquired efficacies similar to GABA, whereas IAA, taurine, and P4S maintained their partial agonist profiles. At both temperatures the agonist-induced enhancement of [3H]diazepam binding was reversible by bicuculline methobromide and by the steroid GABA antagonist RU 5135. These results stress the importance of studying receptor-receptor interaction under near-physiological conditions and offer an in vitro assay that may predict the agonist status of putative GABA receptor ligands.

Androstanes↗
PubMed1988

Kinetic modulation by GABAergic agents of high- and low-affinity binding of [3H]methyl beta-carboline-3-carboxylate.

The kinetics of dissociation of [3H]methyl beta-carboline-3-carboxylate (beta-CCM) binding was studied in a synaptosomal membrane preparation of rat cerebral cortex. Dissociation was biphasic: a faster phase (10-30% contribution) was followed by a slower phase. Picrotoxin pretreatment at 22 degrees C enhanced the equilibrium binding of [3H]beta-CCM. The half-life of the slower phase of beta-CCM dissociation (t1/2II) was increased by 60 muM picrotoxin from 1.7 min to 3.3 min. The dissociation of [3H]beta-CCM was identical when initiated by an excess of either diazepam or beta-CCM. Quasi-equilibrium Scatchard analysis of [3H]beta-CCM binding was performed by a kinetic separation of the rapid and slow phases of dissociation. The slow and rapid phases represented beta-CCM binding sites of high and low affinity, respectively. The dissociation of [3H]beta-CCM (control t1/2II = 2.0 min) was decelerated by the gamma-aminobutyric acid (GABA) antagonist 3-alpha-hydroxy-16-imino-5 beta-17-aza-androstan-11-one (R 5135) (t1/2II = 2.5 min) and accelerated by GABA (t1/2II = 1.6 min). GABA inhibited both high- and low-affinity beta-CCM bindings.

Androstanes↗
PubMed1988

GABAA receptor populations bind agonists and antagonists differentially and with opposite affinities.

Pretreatment of synaptosomal membranes with a diazo-coupling reagent and the presence of Cl- ions were used to differentiate high- and low-affinity populations of postsynaptic gamma-aminobutyric acid (GABAA) receptors. The super-low-affinity GABAA receptors were characterized by the enhancing effect of GABA on [3H]diazepam binding. The GABA antagonists 2-(3-carboxypropyl)-3-amino-4-methyl-6-phenylpyridazinium chloride (SR 95103) and 3-alpha-hydroxy-16-imino-5 beta-17-aza-androstan-11-one (R 5135) shifted and suppressed the dose-response curve of GABA on diazepam binding. SR 95103 displaced the lower affinity [3H]GABA binding with higher potency. Dissociation of the binding of the antagonist 2-(3-carboxypropyl)-3-amino-6-p-methoxyphenylpyridazinium bromide ([3H]SR 95531) was polyphasic. Displacing potencies of SR 95531 and GABA were examined on the major (85%) rapid and minor slower phases of dissociation separated kinetically. The slower phase corresponded to higher affinity binding of SR 95531 which was displaced by GABA with about 10 times less potency. Photoaffinity labeling with muscimol decreased the number of [3H]muscimol binding sites by 27%. It decreased the displacing potency of GABA by 72%, but not that of bicuculline methiodide. These findings can be explained by a preferential binding of antagonists to hydrophobic accessory sites around low-affinity GABAA receptors.

Affinity Labels↗
PubMed1985

Antagonism of inhibitory amino acids by the steroid derivative RU5135.

The steroid derivative RU5135 has been tested for its ability to antagonize glycine and the gamma-aminobutyric acid (GABA) analogue muscimol on isolated preparations of rat optic nerve and cuneate nucleus, respectively. On the cuneate nucleus, RU5135 antagonized muscimol in a competitive manner with a pA2 value of 8.31. RU5135 shared a common site of action with bicuculline that was separate from the picrotoxin site. On the optic nerve, RU5135 antagonized glycine with a pA2 of 7.67. It shared a common site of action with strychnine.

Amino Acids↗
PubMed1994

In vitro potency and mode of action of ANQ9040: a novel fast acting muscle relaxant.

1. The in vitro potency and mode of action of the novel, rapid-onset steroidal relaxant ANQ9040 were characterized in the rat isolated phrenic nerve hemidiaphragm. 2. At 32 degrees C, ANQ9040 antagonized neurally evoked contractures with EC50s of 21.5 microM for unitary twitches; 14.4 microM for 2 Hz 'trains of four'; and 7.5 microM for 50 Hz (2 s) tetanic stimulus trains. 3. (+)-Tubocurarine was 22-24 times more potent than ANQ9040 in comparative organ bath experiments. 4. Intracellular recording from endplates revealed that ANQ9040 (0.53-10.0 microM) dose-dependently and reversibly decreased the amplitude of miniature-endplate potentials (IC50 of circa 0.95 microM) without changing transmembrane potential. 5. Surmountable antagonism of subthreshold responses to exogenous (ionophoretic) acetylcholine provided evidence for a non-depolarizing and competitive blockade of post-junctional nicotinic receptors. 6. Sucrose gap recordings of phrenic nerve action potentials revealed that, at concentrations up to 32 microM, ANQ9040 produced no tonic or frequency-dependent antagonism of axonic Na+ channels. 7. We conclude that ANQ9040 is a relatively low-affinity, non-depolarizing, nicotinic antagonist. The in vitro results are discussed in relation to factors impinging on relaxant kinetics and current models for frequency-dependent fade.

Action Potentials↗
PubMed1990

Cortisone: a potent GABAA antagonist in the guinea-pig isolated ileum.

In the guinea-pig isolated ileum, cortisone at 0.001-10 nM induced a non-competitive, dose-dependent antagonism of GABAA-receptor-mediated contractile responses to applied GABA, depressing the maximum contractile response to GABA (100 microM), without affecting contractile responses to acetylcholine or cholinergic twitch contractions. At higher concentrations (greater than 10 nM), cortisone depressed contractile responses to acetylcholine (10-100 nM) and cholinergic twitch responses to transmural stimulation. Cortisone is thus the most potent non-competitive antagonist at GABAA-receptor complexes in the guinea-pig ileum. From molecular modelling, sterically there appeared little difference between cortisone and cortisol, the latter being an enhancer of GABAA-receptor-mediated action in the ileum. However, there were significant differences in electrostatic potentials between the two steroids, due to the different levels of oxidation at C11 which may contribute to such opposing actions.

Androstanes↗