Research Article: Effect of co-administration of BRL-37344 and tadalafil on reduction of overactive bladder symptoms after induction of detrusor overactivity in mice1

Date Published: February 28, 2019

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em

Author(s): Marcos Fiuza de Carvalho, Thuliermes Lopes Pamplona, Márcio Alencar Barreira, Francisco Vagnaldo Jacuru Fechine, Lúcio Flávio Gonzaga-Silva, Ricardo Reges Maia de Oliveira.


To evaluate the impact of the combination of BRL 37344 and tadalafil (TDF)
on the reduction of overactive bladder (OB) symptoms.

Thirty mice were randomized into 5 groups (G) of 6 animals each. L-NAME was
used to induce DO. G1: Control; G2: L-NAME; G3: L-NAME + TDF; G4: L-NAME +
BRL 37344; G5: L-NAME + TDF + BRL 37344. After 30 days of treatment, the
animals were submitted to cystometry to evaluate non-voiding contractions
(NVC), threshold pressure (TP), baseline pressure (BP), frequency of
micturition (FM) and threshold volume (TV). Differences between the groups
were analyzed with ANOVA followed by the Tukey test.

NVC increased in G2 (4.33±2.58) in relation to G1 (1.50±0.55). NVC decreased
in G3 (2.00±1.10), G4 (1.50±1.52) and G5 (2.00±1.26) compared to G2
(p<0.05). FM decreased in G3 (0.97±0.71), G4 (0.92±0.38) and G5 (1.05±0.44) compared to G2 (p<0.05). However, the combination of TDF and BRL37344 was not more effective at increasing NVC and improving FM than either drug alone. The five groups did not differ significantly with regard to TV. The combination of BRL 37344 and TDF produced no measurable additive effect on reduction of OB symptoms.

Partial Text

Overactive bladder (OB) is a highly prevalent symptom condition that affects
millions of US men and women. Costs for the management of OB continue to rise and
represents a significant public health burden to the USA1. A Brazilian study showed a high prevalence of OB (18.9%), leading to
impaired quality of life and sexual function2. The gold standard treatment of this pathology is the use of medications
with anti-muscarinic action3. However, some patients discontinue treatment because they do not present a
good response and do not tolerate adverse effects (dry mouth, constipation, blurred
vision)4. The limitations of anti-muscarinic therapy indicate the need for effective
and well tolerated options in the treatment of detrusor overactivity (DO).

The experimental study was performed at the Laboratory of Experimental Surgery,
Universidade Federal do Ceará (UFC) after approval by the Ethics and Animal Research
Committee (protocol 05/14).

The cystometric findings are summarized in Table

In vivo animal cystometry represents an accepted methodology for the study of lower
urinary tract physiology. Mice are technically more difficult to use, but the same
approach as in rats can be used. Suprapubic voiding cystometry using a simple and
reliable urine collection method under urethane anesthesia is feasible in mice,
permitting the integration of voided volumes with pressure and time data. The
inclusion of volume and flow data enhances the usefulness of the mouse model for in
vivo assessment of DO. Available disease models in rodents have limited
translational value, but despite many limitations, rodent cystometry may give
important information on bladder physiology and pharmacology17.

The combination of BRL 37344 and tadalafil produced no measurable additive effect on
reduction of OB symptoms after induction of DO.