Combination of muscarinic receptor antagonists and beta- 3 adrenoceptor agonists for treating overactive bladder
A receptor antagonist and bladder overuse technology, applied in the direction of drug combinations, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of high incidence and insufficient treatment of urgency
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Embodiment 1
[0150] Example 1. Drug Interaction Studies Using Healthy Human Subjects
[0151] Drug interaction studies were conducted in healthy human volunteers using repeated oral doses of solaburone and oxybutynin administered alone and in combination with each other to evaluate the effects on pharmacokinetic and pharmacodynamic parameters. Effect, as measured by post-void residual volume (PVR). PVR is measured at steady state in subjects treated with each agent alone as well as in combination.
[0152] The study was a two-cohort randomized, open-label, repeat-dose, 3-way crossover study in healthy adult subjects. Two marketed formulations of oxybutynin were used in this study: i) Ditropan which is immediate release (IR) oxybutynin; and ii) Ditropan It is an extended release (XL) oxybutynin. The total daily dose administered was 20 mg. Solaburone is given as a tablet. Details of the Solaburone tablet composition used are given in Table 1 (Composition A).
[0153] The first cohort...
Embodiment 2
[0176] Example 2. Effect of Combination of Beta-Adrenergic Receptor Agonist and Antimuscarinic Agent on Rat Bladder Contractility
[0177] Stimulation of bladder efferent nerves results in the release of acetylcholine (ACh), which in turn stimulates post-junctional muscarinic (M3) receptors on bladder smooth muscle, causing contractions and subsequent urination. M2 receptors are functionally expressed in human bladder smooth muscle and also play a role in bladder contractility, however, most likely indirectly by enhancing M3-mediated contraction and inhibiting β-adrenergic receptor-mediated relaxation. Play a role. Antimuscarinic drugs are thought to work primarily by blocking the M3 receptor, thus inhibiting the contractions associated with overactive bladder.
[0178] Another approach to treating overactive bladder involves targeting the beta3-adrenergic receptors that are also located on the smooth muscle of the bladder. Post-junction stimulation of β3-adrenoceptors resul...
Embodiment 3
[0187] Example 3. Effect of Combinations of Various β-Adrenergic Receptor Agonists and Antimuscarinic Agents on EFS (Electric Field Stimulation) Induced Bladder Contraction in Rats
[0188] In this study, various combinations of β3-adrenergic receptor agonists and antimuscarinic agents were tested in isolated rat bladder muscle strips.
[0189] Bladder smooth muscle strips were obtained from female rats (Sprague-Dawley strain, body weight 240-360 g). Two muscle strips were prepared per bladder and placed in a 5 ml organ bath containing Krebs-Henseleit solution (maintained at 37°C, pH 7.4, with 95% O 2 / 5% CO 2Inflatable) connected to the tension sensor. Prazosin (1 μM) was added to Krebs solution to block α1-adrenergic receptors. The muscle strips were equilibrated at a resting tension of 1.0 g for at least 60 min, during which time the tissue was washed every 15 min. Then, each muscle strip was exposed to 80 mM KCl to verify its viability. After another washout period of...
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