Development of therapeutic agents for urinary incontinence by in vivo analysis of dru-receptor binding characteritics

抗胆碱能药物如丙哌维林和奥昔布宁（Oxy）广泛用于治疗排尿和急迫性尿失禁。然而，这些药物的使用通常受到全身副作用的限制，例如已知在口服给药时经常发生的口干，以及作用持续时间短。为了开发DI治疗中的有效药物，我们表征了丙哌维林和奥昔布宁口服给药后以及经皮应用Oxy（MM-801）后大鼠组织中的毒蕈碱受体结合。【实验一】：口服奥昔布宁后，大鼠膀胱、前列腺、颌下腺、心脏和大脑皮质中特异性结合（-）-[^3H]QNB的表观解离常数（Kd）与对照组相比显著增加。此外，在这些大鼠的颌下腺中，<max>（-）-[^3 H]QNB结合的最大结合位点（B_）数量减少。同样，口头广告 ...更多信息 丙哌维林使大鼠膀胱等组织中（-）-[^3H] QNB结合的Kd值显著增加，前列腺、心脏和颌下腺的Kd值增加更明显。另一方面，与奥昔布宁不同，丙哌维林口服给药导致<max>颌下腺中（-）-[^3 H] QNB结合的B_值几乎没有降低。总之，本研究表明，奥昔布宁和丙哌维林，口服给药后，显着结合组织，如膀胱中的毒蕈碱受体，奥昔布宁似乎表现出长期结合唾液腺中的毒蕈碱受体。【实验二】：与对照组相比，Oxy灌胃后大鼠膀胱、颌下腺、心脏和结肠中[N-甲基-^3 H]东莨菪碱（NMS）特异性结合的解离常数（Kd）显著增加，而最大结合位点数（B_<max>）仅在颌下腺和心脏中减少。口服Oxy后1和3小时各组织的K_d值明显增加，而12和24小时则无明显变化，而<max>颌下腺和心脏的B_值则明显降低，并可维持至少24小时。经皮给药MM-801 2-48小时后，膀胱[^3H] NMS结合的K_d值明显增加，大鼠颌下腺、心脏和结肠的B_值几乎没有降低<max>。随着MM-801作用时间的延长，K_d值的增加幅度增大，在12 h时达到最大值。这些数据表明，经皮给药的Oxy（MM-801）与大鼠膀胱中的毒蕈碱受体显著结合，并且与颌下腺中受体的结合很容易通过该TTS逆转，而不是通过经口给药逆转。本研究可能提供了一个合理的有效性透皮应用氧在治疗DI。少

Anticholinergic agents such as propiverine and oxybutynin (Oxy) are widely used for the treatment of micturition and urge urinary incontinence. However, the use of these drugs is often limited by systemic side effects such as dry mouth known to occur frequently when they were orally administered, and also by short-duration of action. To develop effective agents in the therapy of DI, we characterized muscarinic receptor binding in rat tissues after the oral administration of propiverine and oxybutynin and after the transdermal application of Oxy (MM-801).[Experiment I] : Oral administration of oxybutynin caused a significant increase in the apparent dissociation constant (K_d) for specific (-)-[^3H]QNB binding in the rat bladder, prostate, submaxillary gland, heart and cerebral cortex, compared with each of the control values. Also, in the submaxillary gland of these rats, there was a reduction in the maximal number of binding sites (B_<max>) for (-)-[^3H]QNB binding. Similarly, oral ad … More ministration of propiverine brought about a significant increase in the K_d values for (-)-[^3H] QNB binding in rat tissues including the bladder, and greater increase in K_d values was seen in the rat prostate, heart and submaxillary gland. On the other hand, oral administration of propiverine, unlike oxybutynin, resulted in very little reduction in the B_<max> valules for (-)-[^3H] QNB binding in the submaxillary gland. In conclusion, the present study has shown that oxybutynin and propiverine, after oral administration, bind significantly to muscarinic receptors in tissues such as the bladder and that oxybutynin appears to exhibit long-term binding to muscarinic receptors in the salivary gland.[Experiment II] : Following the oral administration of Oxy, there was a significant increase in dissociation constant (K_d) for specific [N-methyl-^3H] scopolamine (NMS) binding in urinary bladder, submaxillary gland, heart and colon of rats compared with the value of control rats, and a concomitant reduction of maximal number of binding sites (B_<max>) only in submaxillary gland and heart. Such increase in K_d value in each tissue was seen at 1 and 3 hr after oral administration of Oxy, but not at 12 and 24 hr. In contrast, a significant reduction of B_<max> value in submaxillary gland and heart was maintained for at least 24 hr. Transdermal application of MM-801 for 2-48 hr caused a significant increase in K_d value for [^3H] NMS binding in bladder, submaxillary gland, heart and colon of rats, and there was little reduction of B_<max> value in each tissue. The increment of K_d value increased with the application time of MM-801, being maximal at 12 hr later. These data suggest that the transdermally administered Oxy (MM-801) binds significantly to the muscarinic receptor in urinary bladder of rats and the binding to the receptor in submaxillary gland is easily reversible by this TTS but not by the oral administration. The present study may provide a rationale for the usefulness of transdermal application of Oxy in the therapy of DI. Less