Tesis doctoral de Carolina Salcedo Roca
The study is focused on the pharmacological characterization of a new drug forthe treatment of urgency urinary incontinence, a pathology considered to be due to a hyperactivity of the bladder and known as overactive bladder (oab). This is a common clinical problem which may originate from dysfunction of the peripheral or central nervous pathways, the urotehlium, the smooth muscle and other tissue components. When conscious control of the parasympathetic micturition reflex is altered, symptoms of oab arise, creating a serious health problem commonly giving rise to severe psychological and social problems. Worldwide, there are only seven clinically available drugs, all non-selective or poorly selective antimuscarinics, for the treatment of oab: oxybutynin (oxy), tolterodine (tol), propiverine, fesoterodine, trospium, darifenacin (dar) and solifenacin (sol). All have demonstrated efficacy for the treatment of oab symptoms but their pharmacokinetic and adverse event profiles differ and provide the need for new, safer treatments. The main objective of this investigation was to characterize the pharmacology of svt-40776, a novel substituted quinuclidine derivative, as a potential new drug aimed at treating oab. We postulated that a m2 sparing muscarinic antagonist would be predictive of a safe cardiovascular profile. In addition, we wished to prove that m2 antagonism is not a requirement to achieve the effectiveness of the classical non-selective muscarinic antagonists. the affinity and selectivity of svt-40776 for the human m3 mach receptor subtype was determined by [3h]nms receptor binding competition in cho cell membranes expressing human muscarinic receptors. Svt-40776 showed the highest affinity (ki= 0.19 nm) and selectivity (203-fold vs. M2) for the human m3 receptor subtype, in comparison with other muscarinic antagonists. Svt-40776 was a reversible antagonist. In functional studies using isolated mice bladder svt-40776 showed the ability to induce a rightward parallel shift in the cumulative agonist concentration-response curves, obtaining a pa2 of 9.5. Antagonist activities of tol, sol and dar were 8.4, 8.6 and 8.7, respectively. In isolated mice atria preparations (m2 mediated effect), cch curves were surmountably antagonized by all the compounds. The rank order of antagonist activities (pa2) was tol (8.5), sol (7.8), dar (7.3) and svt-40776 (7.3). Svt-40776 exhibited the highest bladder vs. Atria selectivity (199-fold), therefore predicting a safer cardiovascular profile than the other antagonists tested. In the ex vivo isolated tissue functional studies (obtaining the sample 3h post-oral dosing), svt-40776 inhibited cch-induced bladder contractions in a concentration-dependent manner after oral administration in mice. The pa2-ed was 0.72mg/kg in bladder and 40.3mg/kg in atria, giving a 58-fold ratio between muscarinic cardiac effects vs. Bladder effects, which compared favorably with tol (0.21-fold), sol (1.5-fold) and dar (2.4-fold). guinea pig was used for in vivo studies, as m3:m2 receptor population proportion (1:3) was more similar to human (1:3) compared to rat (1:9) (fetscher et al., 2002) and also due to the similarity of its urethra morphology and functionality to human urethra (walters et al., 2006). As a general conclusion, svt-40776 did inhibit micturition contractions in the two models used, the isovolumetric and the cystometric, without affecting arterial pressure (map) and/or heart rate (hr). Thus, for binding affinities the order (greater to lesser affinity) is svt-40776>dar>tol>sol, whereas for functional in vivo potency the order is svt-40776>dar > sol> tol. therefore, the present study has shown that svt-40776, is the most potent and selective m3 vs. M2 muscarinic receptor antagonist described so far for the treatment of overactive bladder. Its activity profile confirms the hypothesis that m2 receptor is not necessary for achieve effective bladder modulation. The compound has successfully completed phase i clinical trials and is currently undergoing phase ii clinical trials for the treatment of overactive bladder.
Datos académicos de la tesis doctoral «The pharmacology of svt-40776, a new muscarinic antagonist for the treatment of urinary incontinence«
- Título de la tesis: The pharmacology of svt-40776, a new muscarinic antagonist for the treatment of urinary incontinence
- Autor: Carolina Salcedo Roca
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 05/12/2008
Dirección y tribunal
- Director de la tesis
- Andres Fernandez Garcia
- Tribunal
- Presidente del tribunal: dolors Balsa lópez
- María isabel Loza garcia (vocal)
- (vocal)
- (vocal)