Tolterodine is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin. Results of randomised double-blind ...placebo-controlled studies indicate that tolterodine 4 mg/day (administered as immediate-release tablets 2mg twice daily or extended-release capsules 4mg daily) is superior to placebo in improving micturition diary variables in patients with overactive bladder. Moreover, tolterodine 2mg twice daily is as effective as oxybutynin 5mg 3 times daily. Maximum treatment effects with both drugs occurred after 5 to 8 weeks of treatment and improvements were maintained during long term treatment for up to 24 months. In a pooled analysis of four 12-week studies, equivalent and significant reductions in micturition frequency (-2.3 and -2.0 vs -1.4, p < 0.001) and the incidence of urge incontinence episodes (-1.6 and -1.8 vs -1.1, p < 0.05) were reported for tolterodine 2mg twice daily and oxybutynin 5mg 3 times daily compared with placebo. Functional bladder capacity was also significantly increased. Improvements in patient perceptions of their urgency symptoms and of problems caused by their bladder condition were significantly greater during treatment with tolterodine than with placebo. Tolterodine was generally well tolerated in clinical trials of up to 24 months' duration. Dry mouth was the most frequent adverse event. The incidence (40 vs 78%, p < 0.001) and intensity of this event was lower with tolterodine 2mg twice daily than oxybutynin 5mg 3 times daily. Additionally, a 23% lower incidence of dry mouth was reported with once daily extended-release tolterodine capsules than with twice daily immediate-release tablets (p < 0.02). The incidence of adverse CNS events with tolterodine was low and similar to that of placebo. Tolterodine was well tolerated in elderly patients and no serious tolerability concerns were identified.
Tolterodine is the first antimuscarinic agent to specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as valuable treatment for the symptoms of overactive bladder.
Pindolol‐insensitive
3
H‐5‐hydroxytryptamine (
3
H‐5‐HT) binding to rat hypothalamic membranes was pharmacologically and functionally characterized to resolve whether this procedure selectively ...labels 5‐HT
7
receptors.
Consistent with a previous report, 3 μ
M
and not 100 n
M
pindolol was required to occupy fully 5‐HT
1A
and 5‐HT
1B
receptors. Remaining
3
H‐5‐HT binding was saturable (
K
D
, 1.59±0.21 n
M
; B
max
, 53.8±3.1 fmol.mg protein
−1
).
Displacement of
3
H‐5‐HT with metergoline and 5‐CT revealed shallow Hill slopes (<0.5) but seven other compounds had slopes >0.8 and p
K
i
values and the rank order of affinity were significantly correlated (
r
=0.81 and 0.93, respectively) with published
3
H‐5‐HT binding to rat recombinant 5‐HT
7
receptors.
In the presence of pindolol, 5‐HT‐enhanced accumulation of
32
P‐cyclic AMP was unaffected by the 5‐HT
4
antagonist RS39604 (0.1 μ
M
) or the 5‐ht
6
antagonist Ro 04–6790 (1 μ
M
) but significantly attenuated by mesulergine (250 n
M
), ritanserin (450 n
M
) or methiothepin (200 n
M
) which have high affinity for the 5‐HT
7
receptor.
Intracerebroventricular pretreatment with the serotonergic neurotoxin 5,7‐dihydroxytryptamine, 5,7‐DHT, elevated the
3
H‐5‐HT B
max
2 fold, indicating that the hypothalamic 5‐HT
7
receptor is post‐synaptic to 5‐HT nerve terminals and regulated by synaptic 5‐HT levels.
These results suggest that, in the presence of 3 μ
M
pindolol,
3
H‐5‐HT selectively labels hypothalamic binding sites consistent with functional 5‐HT
7
receptors.
British Journal of Pharmacology
(1999)
127
, 236–242; doi:
10.1038/sj.bjp.0702503
Azimilide Clemett, D; Markham, A
Drugs (New York, N.Y.),
02/2000, Letnik:
59, Številka:
2
Journal Article
Recenzirano
Azimilide is a potassium channel antagonist that, in contrast to existing class III antiarrhythmic agents, blocks both the rapidly (I(Kr)) and slowly (I(Ks)) activating components of the delayed ...rectifier potassium current. In animal and clinical studies, azimilide prolonged repolarisation by increasing the action potential duration and effective refractory period. In animal models, azimilide was effective in terminating both atrial and ventricular arrhythmias. Azimilide also demonstrated antifibrillatory efficacy in a canine model of sudden cardiac death. In patients with a history of atrial fibrillation/flutter, oral azimilide controlled arrhythmias more effectively than placebo in a 6-month randomised double-blind study. At a dosage of 125 mg once daily, azimilide significantly increased the time to first symptomatic recurrence of atrial fibrillation/flutter. However, no significant difference between placebo and azimilide was found in another study. Oral azimilide 100 mg once daily demonstrated clinically significant treatment effects in patients with paroxysmal supraventricular tachycardia. In clinical trials, azimilide was generally well tolerated and headache was the most commonly occurring adverse event. Azimilide is associated with a low incidence of proarrhythmic events, such as torsades de pointes, and few serious adverse events have been reported.
Exemestane is an orally active irreversible steroidal aromatase inactivator that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with ...advanced breast cancer. In clinical trials, tumour responses were elicited by exemestane regardless of disease site, importantly, in patients with visceral disease. In patients with disease refractory to tamoxifen, once daily exemestane 25 mg produced objective response rates of 15 to 28% that were sustained for a median duration of 69 to 76 weeks. In a large comparative study, exemestane and megestrol showed similar clinical efficacy according to objective response and overall success rates. However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol. Additionally, a significant survival advantage for exemestane over megestrol was reported. Exemestane retains efficacy in patients refractory to multiple hormonal therapies. In patients whose disease had progressed after tamoxifen and megestrol, objective response rates of 11 and 13% were reported, and responses were similar regardless of whether megestrol resistance was de novo or acquired. Objective responses also occurred in studies that explored sequential use of exemestane after failure of aminoglutethimide (26% with exemestane 200 mg/day) or other nonsteroidal aromatase inhibitors (6.6% with exemestane 25 mg/day). Additionally, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment. As first-line treatment, once daily exemestane 25 mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20 mg. Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600 mg. At the 25 mg recommended once daily dosage, the most commonly occurring adverse events were nausea, hot flushes, fatigue, increased sweating and dizziness. Weight gain occurred in significantly more patients receiving megestrol than among those treated with exemestane. Androgenic events have been reported in a small number of patients receiving once daily exemestane 200 mg, but were rarely reported at the recommended dosage.
Exemestane is effective in postmenopausal patients with tamoxifen-refractory advanced breast cancer, prolonging time to disease progression and treatment failure and improving survival compared with megestrol treatment. Moreover, exemestane has an acceptable tolerability profile and a convenient once daily oral dosage regimen. Available data indicate that exemestane maintains its efficacy in patients with visceral metastases and does not show cross-resistance with nonsteroidal aromatase inhibitors. Preliminary data indicate that exemestane is also effective as first-line therapy for advanced breast cancer.
5-HT
2C receptor mRNA has a widespread distribution in the human and rat CNS but the absence of a specific high affinity ligand has made autoradiographic localisation of the receptor difficult. By ...raising polyclonal antibodies against the rat 5-HT
2C receptor protein this study reports the immunohistochemical distribution of this receptor in the rat CNS. A sephadex purified 5-HT
2C antiserum visualised a single immunopositive band (54 kDa) in Western blots of membranes prepared from several rat brain regions and caused intense membrane immunofluorescence in HEK 293 cells transfected with h5-HT
2C cDNA, which were both attenuated by incubation with the antigenic peptide sequence (200–300 μM). 5-HT
2C-like immunoreactivity was located on neurones throughout the CNS. The most abundant 5-HT
2C-like immunoreactive cell bodies were in the anterior olfactory nucleus, medial and intercalated amygdaloid nuclei, hippocampus layers CA1 to CA3, laterodorsal and lateral geniculate thalamic nuclei, caudate-putamen and several areas of the cortex (including piriform and frontal), consistent with this receptor being located postsynaptic to serotonergic neurones. Immunopositive neurones were also found in the dorsal raphé, suggesting that 5-HT
2C receptors may be on some serotonergic neurones. The overall distribution of 5-HT
2C-like immunoreactivity complements previous findings with conventional radioligands and agrees well with reported levels of 5-HT
2C receptor mRNA.
Pindolol‐insensitive 3H‐5‐hydroxytryptamine (3H‐5‐HT) binding to rat hypothalamic membranes was pharmacologically and functionally characterized to resolve whether this procedure selectively labels ...5‐HT7 receptors.
Consistent with a previous report, 3 μM and not 100 nM pindolol was required to occupy fully 5‐HT1A and 5‐HT1B receptors. Remaining 3H‐5‐HT binding was saturable (KD, 1.59±0.21 nM; Bmax, 53.8±3.1 fmol.mg protein−1).
Displacement of 3H‐5‐HT with metergoline and 5‐CT revealed shallow Hill slopes (<0.5) but seven other compounds had slopes >0.8 and pKi values and the rank order of affinity were significantly correlated (r=0.81 and 0.93, respectively) with published 3H‐5‐HT binding to rat recombinant 5‐HT7 receptors.
In the presence of pindolol, 5‐HT‐enhanced accumulation of 32P‐cyclic AMP was unaffected by the 5‐HT4 antagonist RS39604 (0.1 μM) or the 5‐ht6 antagonist Ro 04–6790 (1 μM) but significantly attenuated by mesulergine (250 nM), ritanserin (450 nM) or methiothepin (200 nM) which have high affinity for the 5‐HT7 receptor.
Intracerebroventricular pretreatment with the serotonergic neurotoxin 5,7‐dihydroxytryptamine, 5,7‐DHT, elevated the 3H‐5‐HT Bmax 2 fold, indicating that the hypothalamic 5‐HT7 receptor is post‐synaptic to 5‐HT nerve terminals and regulated by synaptic 5‐HT levels.
These results suggest that, in the presence of 3 μM pindolol, 3H‐5‐HT selectively labels hypothalamic binding sites consistent with functional 5‐HT7 receptors.
British Journal of Pharmacology (1999) 127, 236–242; doi:10.1038/sj.bjp.0702503
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