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Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent

A muscarinic, agonist technology, used in drug combinations, animal repellents, botanical equipment and methods, etc., can solve problems such as insufficient response

Inactive Publication Date: 2012-08-15
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current medical therapies for OAB using antimuscarinic agents are often suboptimal, as many patients do not demonstrate an adequate response to current therapies, and / or cannot tolerate the substantial side effects, such as oral dry

Method used

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  • Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent
  • Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent
  • Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0425] Materials and methods

[0426] The following materials and methods were used in Examples 1-3. Male mature Sprague-Dawley rats were used. Use CO 2 After gas euthanasia, the entire bladder was removed. A longitudinal strip (approximately 6 mm × 3 mm) of the outer triangular portion of the detrusor muscle was prepared. Place each strip in an atmosphere containing oxygen (95% O2 + 5% CO 2) in a heated (37°C) organ bath (25 mL) of Krebs solution. One end of the strip was fixed to an organ bath and the other end was connected to an isometric transducer (AD Instruments) under a resting tension of 10 mN. The responses of the prepared samples were recorded at a sampling frequency of 10 Hz using a multi-channel data acquisition system (PowerLab, AD Instruments), and measured using analysis software (Chart, AD Instruments). After an equilibration time of at least 60 min, an electric field stimulus (EFS) at 60 Hz; duration, 0.3 ms; 3 s; 90 V was applied to each tissue strip...

Embodiment 2

[0431] β 3 Combination therapy of the AR agonist CL316243 with an antimuscarinic agent selected from tolterodine, oxybutynin and darfinacin

[0432] When administered alone, CL316243, tolterodine, oxybutynin, and darfenacin all inhibited EFS-induced isolated detrusor contractions. Table 5 shows the concentration of each compound that induced 25% inhibition. These values ​​are used in the isobologram analysis below.

[0433] Table 5. Inhibition of Detrusor Contraction by CL316243, Tolterodine, Oxybutynin, and Darfinacine

[0434]

[0435] In the combination therapy, CL316243 was administered with tolterodine, oxybutynin and darfinacin at a fixed weight ratio, and the results of the isobologram analysis are shown in Figure 2. Fig. 2 shows CL316243 and tolterodine (1:2, Figure 2A ) or oxybutynin (1:10, Figure 2B ) show a synergistic effect. On the other hand, CL316243 and darfenazine (1:2, Figure 2C ) shows simple addition (ie, no synergy).

[0436] While not ...

Embodiment 3

[0441] β 3 - Combination of AR agonist compound 12 with tolterodine or darfinacine

[0442] In this example, different β 3 -AR agonists to study beta 3 -Synergistic effect of combination therapy of an AR agonist and an antimuscarinic agent.

[0443] β as described in Table 3 above 3 IC of -AR agonist compound 12 inhibits EFS-induced isolated detrusor contraction 25 The value is 275 nM. Thus, compound 12 was more potent than CL316243 in inhibiting EFS-induced contraction of rat bladder strips (IC 25 2.86 nM, see Table 5) was 100-fold lower. This is consistent with the effect of compound 12 on rat β 3 The low potency activity of -AR is consistent.

[0444] In the combination study, compound 12 was administered with tolterodine or darfenacin at a fixed weight ratio of 50:1. The results of isobologram analysis are shown in Fig.3. Figure 3 shows that compound 12 has a M of about 1 2 / M 3 The 50:1 combination of tolterodine ( Figure 3A ) have a synergistic effect...

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Abstract

Described herein is an improved method of treating overactive bladder, wherein the method comprises administering to a patient in need thereof a beta 3 adrenergic receptor agonist, an antimuscarinic agent, and an optional selective M2 antagonist. Such combination therapy provides improved efficacy and / or reduced side effects.

Description

Background technique [0001] The function of the lower urinary tract is to store and periodically excrete urine. This requires the coordination of the storage and voiding reflexes, involving various input and output neural pathways, leading to the modulation of central and peripheral mechanisms of action and the resulting synergy of the sympathetic and parasympathetic components of the autonomic and bodily motor pathways regulation. These can approximately regulate the contraction state of bladder (detrusor) and urethral smooth muscles and striated muscles of the urethral sphincter. [0002] Overactive bladder is characterized by symptoms of urinary urgency (with or without urge incontinence), usually associated with frequency and nocturia. In the United States and Europe, the prevalence of OAB is estimated to be 16 to 17% among women and men over the age of 18 years. Overactive bladder is most commonly classified as an idiopathic condition, but can also be secondary to neur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N57/00
CPCA61K31/137A61K31/221A61K31/4025A61K45/06A61P13/10A61K2300/00A61K31/426A61K31/517A61K31/41A61K31/40
Inventor H.纳加布库罗S.D.埃蒙森M.S.辛哈罗伊W.S.丹尼T.L.弗伦克尔
Owner SCHERING AG
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