TRATAMENTO DA HIPERACTIVIDADE VESICAL DE CAUSA

Transcription

Carlos Manuel Pires Martins da Silva
TRATAMENTO DA HIPERACTIVIDADE VESICAL DE
CAUSA NEUROGÉNICA E NÃO NEUROGÉNICA
PELA DESSENSIBILIZAÇÃO VESICAL
Dissertação de candidatura ao grau de Doutor apresentada
à Faculdade de Medicina da Universidade do Porto
Porto, 2008
Artigo 48º, § 3º
“A Faculdade não responde pelas doutrinas expendidas na dissertação”
(Regulamento da Faculdade de Medicina do Porto, Decreto-Lei nº 19337
de 29 de Janeiro de 1931)
Tratamento da hiperactividade vesical pela dessensibilização vesical
Corpo Catedrático da Faculdade de Medicina do Porto
Professores Efectivos
Doutor Manuel Maria Paula Barbosa
Doutor Manuel Alberto Coimbra Sobrinho Simões
Doutor Jorge Manuel Mergulhão Castro Tavares
Doutora Maria Isabel Amorim de Azevedo
Doutora Maria Amélia Duarte Ferreira
Doutor José Agostinho Marques Lopes
Doutor Patrício Manuel Vieira Araújo Soares Silva
Doutor Daniel Filipe Lima Moura
Doutor Belmiro dos Santos Patrício
Doutor Alberto Manuel Barros da Silva
Doutor José Manuel Lopes Teixeira Amarante
Doutor José Henrique Dias Pinto de Barros
Doutora Maria Fátima Machado Henriques Carneiro
Doutora Isabel Maria Amorim Pereira Ramos
Doutora Deolinda Maria Valente Alves Lima Teixeira
Doutora Maria Dulce Cordeiro Madeira
Doutor Cassiano Pena de Abreu e Lima
Doutor Altamiro Manuel Rodrigues Costa Pereira
Doutor Rui Manuel Almeida Mota Cardoso
Doutor António Carlos Freitas Ribeiro Saraiva
Doutor Álvaro Jerónimo Leal Machado de Aguiar
Doutor António José Pacheco Palha
III
Carlos Martins da Silva
Doutor José Luís Medina Vieira
Doutor José Carlos Neves da Cunha Areias
Doutor Manuel Jesus Falcão Pestana Vasconcelos
Doutor João Francisco Montenegro Andrade Lima Bernardes
Doutora Maria Leonor Martins Soares David
Doutor Fernando Manuel Mendes Falcão dos Reis
Doutor Rui Manuel Lopes Nunes
Doutor Amadeu Pinto de Araújo Pimenta
Professores Jubilados ou Aposentados
Doutor Abel José Sampaio da Costa Tavares
Doutor Alexandre Alberto Guerra Sousa Pinto
Doutor Amândio Gomes Sampaio Tavares
Doutor António Augusto Lopes Vaz
Doutor António Carvalho Almeida Coimbra
Doutor António Fernandes da Fonseca
Doutor António Fernandes Oliveira Barbosa Ribeiro Braga
Doutor António Germano Pina Silva Leal
Doutor António Luís Tomé da Rocha Ribeiro
Doutor António Manuel Sampaio de Araújo Teixeira
Doutor Artur Manuel Giesteira de Almeida
Doutor Cândido Alves Hipólito Reis
Doutor Carlos Rodrigo Magalhães Ramalhão
Doutor Daniel Santos Pinto Serrão
Doutor Eduardo Jorge Cunha Rodrigues Pereira
Doutor Fernando de Carvalho Cerqueira Magro Ferreira
Doutor Fernando Tavarela Veloso
IV
Doutor Francisco José Zarco Carneiro Chaves
Doutor Francisco de Sousa Lé
Doutor Henrique José Ferreira Gonçalves Lecour de Menezes
Doutor João Silva Carvalho
Doutor Joaquim Germano Pinto Machado Correia da Silva
Doutor Joaquim Oliveira Costa Maia
Doutor José Augusto Fleming Torrinha
Doutor José Carvalho de Oliveira
Doutor José Fernando Barros Castro Correia
Doutor José Manuel Costa Mesquita Guimarães
Doutor Levi Eugénio Ribeiro Guerra
Doutor Luís Alberto Martins Gomes de Almeida
Doutor Manuel Augusto Cardoso de Oliveira
Doutor Manuel Machado Rodrigues Gomes
Doutor Manuel Teixeira Amarante Júnior
Doutora Maria da Conceição Fernandes Marques Magalhães
Doutor Mário José Cerqueira Gomes Braga
Doutor Serafim Correia Pinto Guimarães
Doutor Valdemar Miguel Botelho dos Santos Cardoso
Doutor Walter Friedrich Alfred Osswald
Ao Professor Doutor Francisco Cruz
VII
À minha família
IX
Prefácio
O prazer está no caminho e não apenas no objectivo…
Ao longo da nossa vida profissional cruzamo-nos, por vezes, com pessoas que nos fazem ver a caminhada sob um outro olhar. Tenho a consciência que o meu caminho profissional seria diferente, não fora o caso de o
Professor Doutor Francisco Cruz, na altura recentemente doutorado, ter sido
nomeado orientador do meu Internato Complementar de Urologia. O seu
entusiasmo contagiante pela investigação fez-me interessar pela mesma e
assim enriquecer a minha formação científica e médica. Este trabalho é fruto
da sua instigação e do seu constante encorajamento.
Ao Professor Doutor António Avelino, co-orientador neste trabalho,
agradeço a disponibilidade e a colaboração permanentes vindas do “outro
lado” – o laboratório. Estas reflectiram-se na extrapolação para a clínica dos
seus resultados experimentais e na sua colaboração prática, nomeadamente
no manuseamento e preparação extemporânea das soluções de resiniferatoxina e no processamento das amostras de biopsias vesicais.
Aos colegas do Serviço de Urologia que me ajudaram nos vários projectos, nomeadamente na referenciação, selecção e observação de doentes,
tornando mais fácil o percurso, o meu obrigado.
XI
Nesta dissertação, encontram-se os resultados deste trabalho de
investigação, sob a forma de cinco publicações. A estas, adicionaram-se
dois capítulos, um de introdução e outro de considerações finais em que se
correlacionam e discutem os resultados.
XII
Em obediência ao disposto no Decreto-Lei nº 388/70, Artigo 8º, parágrafo 2, esclareço que efectuei o planeamento e execução das experiências,
observação do material e análise dos resultados e redigi as primeiras versões
das seguintes publicações, que fazem parte integrante desta dissertação:
I - Silva C, Rio Me, Cruz F. Desensitization of bladder sensory fibers by
intravesical resiniferatoxin, a capsaicin analog: long-term results for
the treatment of detrusor hyperreflexia. European Urology 38: 444452, 2000.
II - Silva C, Ribeiro MJ, Cruz F. The effect of intravesical resiniferatoxin in
patients with idiopathic detrusor instability suggests that involuntary
detrusor contractions are triggered by C-fiber input. Journal of Urology 168: 575-579, 2002.
III - Silva C, Silva J, Ribeiro MJ, Avelino A, Cruz F. Urodynamic effect of
intravesical resiniferatoxin in patients with neurogenic detrusor overactivity of spinal origin: results of double-blind randomized placebo-controlled trial. European Urology 48: 650-655, 2005.
IV - Silva C, Silva J, Castro H, Reis F, Dinis P, Avelino A, Cruz F. Bladder
sensory desensitization decreases urinary urgency. BMC Urology 7:
9, 2007.
V - Silva C, Avelino A, Souto-Moura C, Cruz F. A light- and electron-microscopic histopathological study of human bladder mucosa after
intravesical resiniferatoxin application. British Journal of Urology International 88: 355-360, 2001.
A reprodução destas publicações foi feita com autorização das respectivas editoras.
XIII
ABREVIATURAS UTILIZADAS NA “INTRODUÇÃO”,
“CONSIDERAÇÕES FINAIS” E “RESUMO E CONCLUSÕES”
AMPc
“Cyclic adenosine monophosphate”
Monofosfato de adenosina cíclico
ATP
“Adenosine triphosphate”
Trifosfato de adenosina
CGRP
“Calcitonin gene-related peptide”
Peptídeo relacionado com o gene da calcitonina
ERK
“Extracellular signal regulated kinase”
Cínase regulada por sinais extracelulares
GMPc “Cyclic guanosine monophosphate”
Monofosfato de guanosina cíclico
HBP Hiperplasia benigna da próstata
ICS “International Continence Society”
MAPK “Mitogen activated protein kinase”
Cínase activada por mitogénios
NGF “Nerve growth factor”
Factor de crescimento nervoso
NK Neurocininas
OAB
“Overactive bladder”
Síndrome da bexiga hiperactiva
XV
XVI
PKC
Proteína cínase C
mRNA
“Messenger ribonucleic acid”
Ácido ribonucleico mensageiro
RTX
Resiniferatoxina
SBH
Síndrome da bexiga hiperactiva
SNC
Sistema nervoso central
SP substância P
TRPV1 “Transient receptor potential vanilloid type 1”
Potencial de receptor temporário de tipo vanilóide, tipo 1
et al. et alii
INDICE
INTRODUÇÃO............................................................................................... 1
1- Síndrome da bexiga hiperactiva.............................................................. 3
1.1 - Definição ........................................................................................ 3
1.2 - Síndrome da bexiga hiperactiva e hiperactividade do detrusor . ... 6
1.3 - Prevalência...................................................................................... 7
1.4 - História natural................................................................................ 9
1.5 - Repercussão na qualidade de vida................................................. 9
1.6 - Repercussão económica............................................................... 11
2 - Terapêutica do síndrome da bexiga hiperactiva.................................... 13
2.1 - Fármacos anticolinérgicos............................................................ 13
2.2 - Toxina botulínica............................................................................ 18
2.3 - Outros fármacos em investigação................................................. 20
3 - Razão para o tratamento do síndrome da bexiga hiperactiva
com vanilóides....................................................................................... 24
3.1 - Receptor vanilóide e agonistas .................................................... 24
3.2 - Experiência prévia com capsaicina............................................... 26
3.3 - Resiniferatoxina como agente dessensibilizante.......................... 28
OBJECTIVOS............................................................................................... 31
XVII
PUBLICAÇÕES........................................................................................... 37
I - Desensitization of bladder sensory fibers by intravesical
resiniferatoxin, a capsaicin analog: long-term results for the
treatment of detrusor hyperreflexia........................................................ 39
II - Urodynamic effect of intravesical resiniferatoxin in patients with
neurogenic detrusor overactivity of spinal origin: results of a
double-blind randomized placebo-controlled trial................................. 51
III - The effect of intravesical resiniferatoxin in patients with idiopathic
detrusor instability suggests that involuntary detrusor contractions
are triggered by C-fiber input................................................................. 59
IV - Bladder sensory desensitization decreases urinary urgency................. 67
IV - A light and electron-microscopic histopathological study of human
bladder mucosa after intravesical resiniferatoxin application................ 75
CONSIDERAÇÕES FINAIS......................................................................... 83
1 - A resiniferatoxina na hiperactividade do detrusor............................ 85
2 - Modo de administração da resiniferatoxina..................................... 87
3 - Local de actuação dos vanilóides.................................................... 88
4 - Dessensibilização vesical e imperiosidade...................................... 90
5 - Segurança da resiniferatoxina.......................................................... 92
CONCLUSÕES............................................................................................ 95
BIBLIOGRAFIA............................................................................................ 99
RESUMO.................................................................................................... 121
SUMMARY . .............................................................................................. 125
XVIII
INTRODUÇÃO
1- SÍNDROME DA BEXIGA HIPERACTIVA
1.1- Definição
De acordo com a terminologia recentemente adoptada pela International Continence Society (ICS), o síndrome da bexiga hiperactiva (SBH) é um
quadro clínico caracterizado por imperiosidade, com ou sem incontinência
urinária, geralmente associada a polaquiúria e noctúria, após exclusão de
patologia infecciosa ou outra que justifiquem aqueles sintomas (Abrams et
al., 2002). Esta nova definição, em que o sintoma central é a imperiosidade,
veio substituir a definição anterior introduzida em 1997. Esta determinava
o SBH como um quadro clínico caracterizado pela presença de polaquiúria, imperiosidade e incontinência por imperiosidade, que poderiam ocorrer associados ou isoladamente (Abrams e Wein, 1997; Milson et al., 2001;
Abrams, 2003). Tal como é afirmado na definição, o SBH é um diagnóstico
de exclusão. É necessário excluir outras doenças que causam os mesmos
sintomas, como por exemplo a infecção urinária, a neoplasia vesical, a litíase, a cistite intersticial e a diabetes melllitus, antes de estabelecer o diagnóstico de SBH (Abrams et al., 2002). Os quadros clínicos designados como
“Síndrome de polaquiúria-imperiosidade” ou “Síndrome de imperiosidade”
(“Urgency-frequency syndrome” ou “Urge syndrome” na literatura anglosaxónica, respectivamente) devem ser considerados como equivalentes de
SBH (Abrams et al., 2002).
A actual definição do SBH, sendo de índole clínica, veio facilitar a realização e comparação de estudos sobre a prevalência, o impacto na qualidade
de vida e na produtividade laboral e a eficácia das diversas terapêuticas. De
facto, as definições anteriores incluíam parâmetros urodinâmicos (Abrams et
al.,1988; Wein e Rovner, 2002), que dificultavam aqueles estudos, nomeadamente os epidemiológicos.
A designação “Síndrome da bexiga hiperactiva” apareceu, pela primeira
vez, num relatório da ICS em 2002 (Abrams et al., 2002), com o objectivo de
normalizar a terminologia da função e das disfunções do aparelho urinário
inferior. De facto, o termo já era usado na prática clínica, embora incorrectamente, com o mesmo significado que “hiperactividade do detrusor” ou
“detrusor hiperactivo”. No entanto, a utilização indiferente destes termos
não é correcta, devendo os últimos ser apenas utilizados após o achado de
contracções involuntárias do detrusor durante a fase de enchimento de uma
cistomanometria (Abrams e Wein, 1997; Abrams, 2003).
A imperiosidade é definida pela ICS como uma vontade súbita, forte e
inadiável de urinar (Abrams et al., 2002). Trata-se de uma sensação anormal
que traduz uma alteração da sensibilidade vesical durante a fase de enchimento da bexiga. É frequentemente difícil de caracterizar e definir pelos doentes (Chapple et al., 2005a) e exige do clínico um esforço suplementar para
a diferenciar da vontade muito forte de urinar, que é uma sensação normal.
A imperiosidade, como sintoma central da SBH, induz o aparecimento
dos outros sintomas, ao reduzir o tempo disponível entre o início da vontade
miccional e a micção (Chapple et al., 2005a). A imperiosidade é despertada
por volumes de enchimento vesical geralmente inferiores aos valores que
despertam a vontade miccional normal em indivíduos saudáveis. Por outro
lado, os doentes tendem a urinar pequenos volumes de urina de maneira a
evitar o aparecimento daquela sensação. Assim, associados à imperiosidade
surgem a polaquiúria e a noctúria.
As definições de polaquiúria e de noctúria actualmente recomendadas
pela ICS são pouco precisas. De acordo com aquela sociedade, deve considerar-se que um doente tem polaquiúria sempre que ache que urina durante
o dia mais frequentemente que o habitual (Abrams et al., 2002). A definição
anterior, em contrapartida, definia polaquiúria se o número de micções fosse
superior a 8 (Swithinbank e Abrams, 2001). Como se compreende, a definição actual, além de não ser objectiva, está sujeita a uma variação interpessoal significativa.
Pela actual definição de noctúria, considera-se que este sintoma está
presente quando um indivíduo acorda pelo menos uma vez para urinar (Abrams et al., 2002). Tendo em consideração que cerca de 25-30% da população
em geral refere ter uma micção durante a noite (Irwin et al., 2006), seria talvez
mais prudente considerar que existe noctúria apenas quando o doente acorda duas ou mais vezes para urinar.
A incontinência urinária está relativamente desvalorizada na definição
actual de SBH por se ter entendido que o seu aparecimento depende de
factores não urológicos tais como a facilidade de locomoção e o grau de
acessibilidade a instalações sanitárias. Facilmente se compreende que num
doente com dificuldades na marcha ou na ausência de um local adequado
para urinar, a imperiosidade, ainda que ligeira, pode despertar a perda involuntária de urina. Pelo contrário, uma imperiosidade intensa em cenários de
acesso fácil a instalações sanitárias pode não causar incontinência urinária.
O SBH com incontinência urinária é designado na literatura anglo-saxónica como “Overactive bladder wet” (SBH “molhado”) e o SBH sem incontinência urinária como “Overactive bladder dry” (SBH “seco”) (Stewart et al.,
2003; Abrams, 2003).
1.2 - Síndrome da bexiga hiperactiva e hiperactividade do detrusor
O SBH é um quadro clínico que não deve ser confundido com a hiperactividade do detrusor. Esta é definida como o aparecimento num estudo
urodinâmico de contracções involuntárias do detrusor, espontâneas ou provocadas, durante a fase de enchimento vesical. É, portanto, um diagnóstico
urodinâmico (Abrams et al., 2002). No entanto, a hiperactividade do detrusor
é um achado bastante frequente nos estudos urodinâmicos de doentes com
SBH (Hashim e Abrams, 2006), de tal modo que a hiperactividade do detrusor
é frequentemente considerada como a marca urodinâmica daquele síndrome.
As contracções involuntárias do detrusor, quer fásicas quer terminais,
são frequentemente observadas em doentes com lesões neurológicas. Esta
hiperactividade do detrusor deve denominar-se por hiperactividade neurogénica do detrusor, terminologia que veio substituir a designação “hiperreflexia do detrusor” (Abrams et al., 2002). As doenças ou lesões neurológicas
mais frequentemente diagnosticadas em doentes com SBH, de etiologia
neurogénica, são os traumatismos vértebro-medulares, a esclerose múltipla,
os acidentes vasculares cerebrais, os mielomeningocelos, a doença de Parkinson e as mielites. Nos doentes com SBH devido a causa neurológica a
associação entre os sintomas e a hiperactividade do detrusor é praticamente
constante (Wein, 1998). Excluem-se obviamente os doentes nos quais as
vias neurológicas sensitivas estão lesadas, como por exemplo em casos de
lesão completa da medula espinal, e nos quais a percepção do sintoma imperiosidade pode estar impedida (Chapple et al., 2005a).
Nos casos em que não se identifica uma doença neurológica, como
causa subjacente para a hiperactividade do detrusor, a ICS recomenda a designação hiperactividade idiopática do detrusor, em vez de “instabilidade
do detrusor” (Abrams et al., 2002).
A associação entre os sintomas e a hiperactividade do detrusor é menos
constante nos doentes sem patologia neurológica associada. A associação é
também menos frequente quando não ocorre incontinência urinária. A hiperactividade do detrusor está presente em 90% dos homens com SBH “molhado” e em 58% das mulheres com os mesmos sintomas (Hashim e Abrams, 2006). Nos doentes com SBH “seco”, a hiperactividade do detrusor está
presente apenas em 69% e 44% dos homens e mulheres, respectivamente
(Hashim e Abrams, 2006). A razão pela qual a prevalência da hiperactividade
do detrusor é maior no género masculino é desconhecida.
Apesar da associação entre SBH e a hiperactividade do detrusor, deve
notar-se que esta pode surgir em indivíduos assintomáticos (Heslington e
Hilton, 1996).
Será, portanto, de concluir que ou a imperiosidade tem outras causas
ou a sensibilidade dos actuais estudos urodinâmicos é ainda baixa, sendo
incapazes de detectar, por exemplo, as contracções segmentares da bexiga.
Estas podem ser detectadas num elevado número de indivíduos com imperiosidade, mas requerem instrumentação sofisticada (Drake et al., 2005).
1.3 - Prevalência
Com base em definições anteriores do SBH, efectuaram-se dois estudos epidemiológicos, o NOBLE – “National Overactive Bladder Evaluation”
- nos Estados Unidos (Stewart et al., 2001) e o SIFO – “Swedish Institute for
Opinion Research” - na União Europeia (Milson et al., 2001). O primeiro usou
como critério de SBH a ocorrência de 4 ou mais episódios de imperiosidade
nas 4 semanas prévias, associada ou a polaquiúria (mais de 8 micções por
dia) ou a outras estratégias de adaptação pelo doente para diminuir ou prevenir a imperiosidade (limitação da ingestão de líquidos, restrição de viagens,
micção temporizada, necessidade de localizar as instalações sanitárias em
novos locais). No estudo SIFO, a definição foi a introduzida pela ICS em
1997, já descrita atrás (Abrams e Wein, 1997). Destes estudos, concluiu-se
que o SBH afectava globalmente 17% da população adulta, que a prevalência aumentava com a idade e atingia igualmente ambos os sexos (Stewart et
al., 2001; Milson et al., 2001). A incontinência urinária por imperiosidade, de
acordo com estes estudos, seria contudo mais frequente nas mulheres do
que nos homens (Stewart et al., 2003).
A mudança da definição impulsionou novos estudos epidemiológicos,
cujos resultados foram divulgados recentemente à comunidade científica
(Irwin et al., 2006). O estudo EPIC realizado através de entrevistas telefónicas a 19165 indivíduos de ambos os géneros, com idade superior a 18 anos,
decorreu em 4 países da União Europeia (Alemanha, Itália, Reino Unido e
Suécia) e no Canadá. A prevalência do SBH foi de 11,8%, um pouco menor
do que a encontrada nos estudos anteriores. Os restantes resultados epidemiológicos foram sobreponíveis. A prevalência do SBH era igual nos dois
géneros (11% dos homens e 13% das mulheres) e aumentava com a idade
(Irwin et al., 2006). A incontinência urinária ocorria em 49% das mulheres
com SBH, mas só em 30% as perdas de urina estavam associadas à imperiosidade. A incontinência urinária identificou-se em 29% dos homens com
SBH, estando as perdas de urina associadas à imperiosidade em 17,5%
(Irwin et al., 2006). Em 2007, foi publicado o estudo referente à prevalência
do SBH na Finlândia (Tikkinen et al., 2007). A menor prevalência encontrada,
6,5% nos homens e 9,3 % nas mulheres, pode ser atribuída quer aos critérios metodológicos adoptados quer a factores culturais.
Em conclusão, e tendo em conta o envelhecimento da população, os
estudos disponíveis mostram que o SBH tem uma elevada prevalência na
população em geral, afectando milhões de pessoas em todo o mundo.
1.4 - História natural
Para um melhor conhecimento da evolução e da história natural do SBH
são necessários estudos epidemiológicos de longa duração, infelizmente
ainda não disponíveis (Toozs-Hobson e Latthe, 2007). Contudo, os estudos
disponíveis sugerem que a hiperactividade do detrusor e os sintomas urinários têm tendência a persistir num número elevado de doentes (Garnett e
Abrams, 2003). No caso particular dos doentes neurológicos, a hiperactividade do detrusor, se ocorrer no contexto de dissinergia vésico-esfincteriana
e causar pressões intravesicais persistentemente acima de 40 cmH20, pode
pôr em risco a função renal (McGuire et al., 1981). Nestes casos, a introdução precoce da terapêutica é determinante para a diminuição das repercussões no alto aparelho urinário, nomeadamente a insuficiência renal (Foley et
al., 1997). Mais ainda, a história natural da hiperactividade do detrusor neurogénica e a sua repercussão sintomática são significativamente alteradas
por factores não urológicos como a história natural da patologia neurológica
subjacente (Denys et al., 2006).
1.5 - Repercussão na qualidade de vida As repercussões do SBH na qualidade de vida dos doentes são significativas e verificam-se a vários níveis, nomeadamente físico (limitação ou impedimento de algumas actividades físicas, uso de roupa interior e de roupa
de cama especiais, precauções especiais com o vestuário, restrição de líquidos), psicológico (sensação de culpa e depressão, distúrbios do sono, perda
de auto-estima, receio de se tornar um encargo para terceiros, e medo de
não conseguir “controlar” a bexiga e de cheirar a urina), profissional (absentismo, diminuição da produtividade), social (redução dos contactos sociais,
necessidade de planeamento das deslocações tendo em conta a proximidade de instalações sanitárias) e sexual (restrição de contactos íntimos e sexuais) (Milson et al., 2001; Stewart et al., 2001; Kelleher et al., 2002; Stewart et
al., 2003; Tubaro, 2004; Irwin et al., 2005).
Em mulheres jovens (20-45 anos) com SBH, utilizando um questionário
padronizado e validado, o Questionário de Impacto da Incontinência (IIQ),
para avaliação de vários domínios da qualidade de vida, verificou-se que as
mulheres com imperiosidade urinária marcada, mas sem incontinência, referiram como ponto mais negativo, na sua qualidade de vida, a interferência
na capacidade de mobilidade pela necessidade de terem que recorrer frequentemente a instalações sanitárias, para evitar uma perda de urina. Como
seria de esperar, as mulheres com incontinência por imperiosidade sofrem
uma interferência mais marcada na sua qualidade de vida (Liberman et al.,
2001; Van der Vaart et al., 2002; Chiaffarino et al., 2003), para o que contribui
certamente o sentimento de vergonha associado à perda de urina, particularmente se em público (Van der Vaart et al., 2002). Verificou-se, ainda, que
a interferência na qualidade de vida era mais significativa nas mulheres com
SBH do que nas mulheres com incontinência urinária de esforço (Kelleher et
al., 1997a; McGhan, 2001; Van der Vaart et al., 2002; Chiaffarino et al., 2003).
Este facto é resultado, seguramente, da imprevisibilidade da imperiosidade,
em contraste com a possibilidade de previsão e prevenção da incontinência
associada aos esforços.
A deterioração na qualidade de vida é significativamente maior no SBH
do que noutras doenças crónicas, como a hipertensão arterial e a diabetes mellitus. Analisando a repercussão na qualidade de vida destas doenças
através da forma reduzida do Questionário de Percepção do Estado de Saúde (“Medical Outcomes Study: 36-Item Short Form Health Survey” ou MOS
SF-36), encontrou-se no SBH uma maior limitação nos domínios relaciona-
10
dos com o desempenho por razões físicas e emocionais, com as actividades
sociais e sexuais, bem como com a vitalidade e a percepção de bem estar
geral (Milson et al., 2000; McGhan et al., 2001; Kelleher et al., 2002). A incidência de depressão associada ao SBH é elevada (13% nos homens e 17%
nas mulheres com SBH “seco”, e 16% nos homens e 17% nas mulheres
com SBH “molhado”). A incidência da depressão é semelhante à observada
em outras doenças crónicas, como a artrite reumatóide, diabetes mellitus e
hipertensão arterial (Abrams et al., 2000).
No caso particular dos doentes com hiperactividade neurogénica do
detrusor, os sintomas urinários, como por exemplo a incontinência urinária,
podem interferir mais na qualidade de vida do que as restrições e limitações
físicas impostas pela doença neurológica subjacente (Denys et al., 2006).
Ainda neste grupo particular de doentes, a qualidade de vida é afectada de
uma maneira única, não observada noutras formas de hiperactividade do
detrusor. Na verdade, nestes doentes verifica-se um maior risco de deterioração do alto aparelho urinário (Foley et al., 1997).
1.6 - Repercussão económica
A repercussão económica do SBH é elevada, sendo comparável à de
outras doenças crónicas, como a asma e a osteoporose. Por exemplo, a
soma total dos custos associados ao SBH, nos Estados Unidos, no ano 2000
foi calculado em mais de 7 500 milhões de euros, ou seja, cerca de 222 euros por doente (Hu et al., 2004; Hu e Wagner, 2005). Como seria de esperar,
os custos agravam-se na presença de incontinência urinária (Ekelund et al.,
1993; Hu et al., 2004). Os custos do SBH resultam dos actos de diagnóstico e de terapêutica, dos gastos nas fraldas, do absentismo, da falta de
produtividade e do tratamento de complicações indirectas como infecções
11
urinárias, lesões dérmicas e fracturas ósseas causadas por quedas. Estas
são particularmente frequentes em doentes idosos com imperiosidade e incontinência urinária (Wagner e Hu, 1998; Brown et al., 2000; Yoshimura e
Chancellor, 2002). O maior número de consultas a que recorrem os doentes
com SBH, as doenças associadas como a depressão e a maior taxa de internamentos hospitalares e em lares contribuem, também, para os custos
elevados da doença (Jones e Perese, 2003).
Setenta e cinco por cento dos doentes com SBH afirmam que a doença
interfere na sua rotina diária (Irwin et al., 2005). Os doentes com incontinência por imperiosidade têm maiores limitações laborais, que se reflectem em
menor produtividade (por ex. interrupção de reuniões), na escolha de um
local de trabalho mais perto da residência e na tendência para uma reforma
antecipada (Irwin et al., 2005).
12
2 – TERAPÊUTICA DO SÍNDROME DA BEXIGA HIPERACTIVA
2.1 – Fármacos anticolinérgicos
Os anticolinérgicos ou antimuscarínicos são, actualmente, o tratamento
farmacológico de primeira linha da SBH (Lu e Chancellor, 2004; Andersson et
al., 2005; Silva e Cruz, 2008). São várias as razões que sustentam a utilização
destes fármacos.
A acetilcolina é o neurotransmissor mais importante para a contracção
muscular do detrusor normal (Chess-Williams et al., 2001). As células musculares lisas do detrusor possuem receptores muscarínicos M2 e M3 (ChessWilliams, 2002). Estes últimos, apesar de ocorrerem em menor número, são os
principais receptores envolvidos na contracção muscular induzida pela acetilcolina (Chess-Williams et al., 2001). Após a ligação à acetilcolina, os receptores M3 activam o sistema de segundos mensageiros que envolve a hidrólise
dos fosfoinositóis, resultando na acumulação de cálcio intracelular e posterior
contracção do detrusor (Brading et al., 1999). Os receptores M2, quando estimulados pela acetilcolina, inibem a cascata da adenilcíclase e contribuem para
a contracção do detrusor, de um modo indirecto, ao reverterem o relaxamento
mediado pelos receptores adrenérgicos (Hedge et al., 1997). No entanto, em
modelos experimentais de hipertrofia do detrusor verificou-se que estes podem contribuir directamente para a contracção muscular através da activação
da PKC (proteína cínase C) (Braverman e Ruggieri, 2003). Estes achados experimentais já foram confirmados na bexiga humana, nomeadamente de doentes
com hiperactividade neurogénica do detrusor (Pontari et al., 2004).
13
Os receptores muscarínicos foram também identificados na mucosa
vesical, quer no urotélio (Tyagi et al., 2006; Mansfield et al., 2007) quer nas
células intersticiais (Mukerji et al., 2006a). Nestas últimas, os receptores M2
e M3 estão significativamente aumentados em doentes com hiperactividade
idiopática do detrusor (Mukerji et al., 2006a). A importância deste achado
assenta no facto de as células intersticiais poderem representar um marcapasso (“pacemaker”) vesical capaz de gerar actividade contráctil no detrusor.
Contudo, estes achados devem ser vistos com cautela, uma vez que outro
estudo recente mostrou uma diminuição, em vez dum aumento, do mRNA
que traduz o receptor M3 na mucosa dos doentes com SBH (Mansfield et al.,
2007).
Além da acção motora, isto é, abolição das contracções provocadas
pela acetilcolina no músculo liso, novas acções dos antimuscarínicos têm
sido postuladas durante a fase de preenchimento vesical (Yokoyama et al.,
2005, 2007). A hipótese de que os anticolinérgicos actuam, nesta fase do
ciclo miccional, por acção directa no braço sensitivo é apoiada pela recente
demonstração da existência de receptores muscarínicos nas fibras sensitivas, nomeadamente nas fibras C, e no urotélio (De Wachter e Wyndaele,
2003; Kim et al., 2005; Mukerji et al., 2006a; Trevisani et al., 2007). Curiosamente verificou-se que as fibras sensitivas que inervam a mucosa e o músculo detrusor estão aumentados em modelos animais de hiperactividade vesical (Dikson et al., 2006). Verificou-se ainda uma expressão aumentada das
fibras parassimpáticas em contacto muito próximo com as fibras sensitivas
na mucosa vesical de ratos com cistite crónica (Dikson et al., 2006), um achado que apoia estruturalmente a hipótese de que as fibras parassimpáticas
podem ter um papel na sensibilização das fibras aferentes em quadros de
hiperactividade vesical. Assim, a origem da acetilcolina capaz de activar os
14
receptores muscarínicos, presentes no urotélio e nas fibras sensitivas, pode
ser dupla. Uma é o urotélio (Yoshida et al., 2006), outra poderá ser o parassimpático que inerva a mucosa. Hedlund et alii demonstraram recentemente
que os efeitos dos anticolinérgicos na capacidade vesical eram idênticos
em animais intactos e em animais tratados com resiniferatoxina sistémica e
assim desprovidos de fibras sensitivas de tipo C, sugerindo eventualmente
a participação de outras fibras nervosas sensitivas (Aδ) no mecanismo de
acção dos antimuscarínicos (Hedlund et al., 2007).
Os anticolinérgicos disponíveis no mercado são a oxibutinina, tolterodina, cloreto de tróspio, propiverina e a solifenacina. Embora pertençam ao
mesmo grupo terapêutico, há diferenças reconhecidas entre eles, quando
comparados em relação à eficácia clínica, mas sobretudo em relação aos
efeitos laterais (Chapple et al., 2005b; Jonas, 2007). A oxibutinina de libertação imediata, o primeiro anticolinérgico disponível no mercado, apesar de
eficaz, apresenta como grande inconveniente a taxa elevada de efeitos laterais, particularmente a xerostomia (Anderson et al., 1999). O desenvolvimento de novas formulações galénicas da oxibutinina, como as transdérmicas
e as orais de libertação prolongada parecem diminuir significativamente os
efeitos secundários (Anderson et al., 1999; Dmochowski et al., 2003). A tolterodina, particularmente a formulação galénica de libertação prolongada,
tem uma eficácia semelhante à da oxibutinina, mas com menos efeitos laterais, devido à sua maior afinidade para a bexiga (Van Kerrebroeck et al.,
2001). O cloreto de tróspio, quando comparado com a oxibutinina, tem menor incidência de efeitos laterais e maior aderência ao tratamento (Halaska et
al., 2003). Tem ainda a particularidade de, por ser quimicamente uma amina
quaternária, não atravessar a barreira hemato-encefálica. Assim, tem menos
efeitos adversos anticolinérgicos no SNC, facto a considerar em doentes
idosos. A solifenacina foi o primeiro anticolinérgico, com selectividade para
15
os receptores M3, a ser lançado no mercado, em 2004. Quando comparado
com o placebo e com a tolterodina demonstrou maior eficácia na redução
dos sintomas da SBH, particularmente a imperiosidade (Chapple et al., 2004)
e na melhoria da qualidade de vida dos doentes (Kelleher et al., 2005). A propiverina, um fármaco com acção anticolinérgica e bloqueadora de canais de
cálcio (Stöhrer et al., 2007), foi recentemente introduzido no mercado, mas
são escassos os estudos comparativos, de longa duração, disponíveis com
este fármaco.
É provável que o número de fármacos anticolinérgicos aumente significativamente nos próximos anos, tendo em conta os investimentos da indústria farmacêutica nesta linha de investigação. São exemplos disso a darifenacina e a fesoterodina. A darifenacina, em ensaios clínicos comparados com
placebo, demonstrou uma taxa de abandono da terapêutica de apenas 2%
(Chapple et al., 2005c). Os primeiros resultados de ensaios clínicos com a fesoterodina foram recentemente apresentados, com resultados sobreponíveis
aos dos outros anticolinérgicos (Chapple et al., 2007).
Apesar do que atrás ficou dito, a utilidade clínica dos fármacos antagonistas dos receptores muscarínicos foi recentemente questionada numa
extensa metanálise (Herbison et al., 2003). Na verdade, quando se analisam
os resultados dos vários ensaios clínicos verifica-se que a melhoria dos sintomas induzida pelos anticolinérgicos em 65% dos doentes com SBH (Andersson et al., 2005; Chapple et al., 2005b; MacDiarmid, 2007) é pequena,
quando analisada em termos absolutos (Herbison et al., 2003). Por exemplo,
a diminuição média da frequência urinária de 10 para 8 episódios por dia, a
diminuição média dos episódios de imperiosidade de 8 para 6 por dia e a
diminuição média do número de pensos de protecção de 2 para 1,5 por dia
(Chapple et al., 2005c; Van Kerrebroeck et al., 2001), embora possam ser
16
significativos em termos estatísticos, são de difícil percepção para o doente.
Assim sendo, o significado clínico destes valores é discutível. Esta controvérsia é ainda agravada pelo facto dos ensaios clínicos não reflectirem, como se
sabe, a realidade da prática clínica (Jonas, 2007; Hampel, 2007).
A metanálise de Herbison reconheceu ainda que, em muitos ensaios, o
braço tratado activamente podia ser mais facilmente reconhecido pela elevada incidência de efeitos laterais, nomeadamente a xerostomia, do que pela
melhoria dos sintomas urinários (Herbison et al., 2003).
A elevada percentagem dos efeitos laterais associados aos anticolinérgicos resulta da ubiquidade dos receptores muscarínicos no corpo humano.
Os subtipos M2 e M3 podem ser encontrados nas glândulas salivares, no
tracto gastrointestinal, no músculo ciliar, no músculo cardíaco e no SNC,
onde estão envolvidos em acções tais como a secreção salivar e sudorípara,
a capacidade de concentração e a memorização (Low et al., 1992; Proctor e
Carpenter, 2006; McQuail e Burk, 2006). O seu bloqueio causa por isso numerosos efeitos laterais. Para além da referida xerostomia, os antimuscarínicos causam obstipação, dispepsia, arritmias cardíacas (taquicardia, prolongamento do intervalo QT), dificuldade na acomodação visual e efeitos a nível
central, como menor capacidade de concentração, menor capacidade de
memorização, insónias e tonturas (Andersson, 2004; Chapple et al., 2005b;
McQuail e Burk, 2006; Giramonti et al., 2007). Estes efeitos contribuem, seguramente, para a menor adesão dos doentes à terapêutica prolongada com
estes fármacos (Kelleher et al., 1997b; Silva e Cruz, 2008). Apesar de estarem
publicadas taxas de persistência da medicação de cerca de 70 % ao fim de
12 meses em ensaios clínicos (Kreder et al., 2002), na prática clínica esta
taxa diminui drasticamente para cerca de 20% ao fim de um ano de medicação (Chui et al., 2004; Yu et al., 2005; Silva e Cruz, 2008). Para esta baixa
17
taxa de persistência da medicação contribuem a relativa falta de eficácia, os
efeitos laterais, as expectativas, demasiado altas, dos doentes em relação
à medicação e a perda de motivação dos doentes quando enfrentam uma
doença crónica (Fantl et al., 1996; Kelleher et al., 1997 b; Milson et al., 2001,
Hampel, 2007).
Tendo em conta o panorama atrás exposto, não é de estranhar o aparecimento de linhas de investigação de novos tratamentos do SBH, particularmente úteis para doentes refractários aos anticolinérgicos, isto é, que não
respondem sintomaticamente ou que desenvolvem efeitos laterais insuportáveis (Ouslander, 2004; Cruz e Silva, 2006).
2.2 - Toxina botulínica
A injecção no detrusor de toxina botulínica do serótipo A é o tratamento
mais frequentemente oferecido aos doentes com formas de SBH refractárias
aos anticolinérgicos, embora não seja ainda uma medicação aprovada (Cruz
e Silva, 2004, 2006; Silva e Cruz, 2004; Dmochowski e Sand, 2007). A toxina botulínica impede a libertação de neurotransmissores das terminações
nervosas para a fenda sináptica (Jankovic e Brin, 1997; Apostolidis et al.,
2006a). Estudos recentes indicam que a toxina botulínica bloqueia não só a
libertação de acetilcolina das fibras parassimpáticas, mas também a libertação de neurotransmissores das fibras sensitivas da bexiga (Duggan et al.,
2002; Rapp et al., 2006).
O maior estudo realizado até agora com a toxina botulínica incluiu 200
doentes com hiperactividade neurogénica do detrusor, causada por traumatismo vértebro-medular, esclerose múltipla, espinha bífida e mielomeningocelo (Reitz et al., 2004). Aos 3 meses, o volume de enchimento vesical, que
18
despertava a primeira contracção do detrusor, aumentou em média 64%, a
capacidade cistométrica máxima aumentou em média 54% e os valores da
pressão máxima do detrusor diminuíram para metade. Em termos clínicos,
73% dos doentes ficaram continentes, nos intervalos das algaliações intermitentes, e os restantes referiram diminuição do volume e da frequência das
perdas de urina. Mais ainda, a medicação anticolinérgica pôde ser suspensa
em 30 % dos doentes e diminuída nos restantes.
No SBH causado por hiperactividade idiopática do detrusor, o maior
estudo, realizado por Schmid et alii, que incluiu 100 doentes, verificou aos 6
meses de avaliação uma diminuição da imperiosidade e da incontinência e
uma melhoria urodinâmica em 86% dos doentes (Schmid et al., 2006). Estes
autores usaram 100 U para diminuir o risco de retenção urinária subsequente
à paralisia do detrusor e assim evitar a necessidade de algaliação intermitente que dificilmente é bem aceite neste grupo de doentes. Mesmo assim,
4% dos doentes tiveram retenção urinária (Schmid et al., 2006). Note-se que
doses superiores a 100 U, ensaiadas nestes doentes, causaram uma taxa de
retenção urinária em cerca de um terço dos doentes (Kuo, 2004; Popat et al.,
2005; Sahai et al., 2007).
Para além do risco de retenção urinária em doentes que até ao momento
do tratamento não realizavam algaliação intermitente, a injecção intravesical
de toxina botulínica tem outros inconvenientes. O mais difícil de ultrapassar
é a necessidade de ser injectado, sob controlo cistoscópico, numa sala operatória sob sedação ou anestesia. Mais ainda, a necessidade de repetição
do tratamento, em média ao fim de 9 meses, acentua este inconveniente e
agrava os custos desta opção terapêutica (Grosse et al., 2005). Deve ser ainda mencionado que a injecção de toxina botulínica pode despertar sintomas
de botulismo, incluindo fraqueza muscular de longa duração, disfagia e as-
19
tenia acentuada (Wyndaele e Van Dromme, 2002). Estes efeitos devem-se à
difusão da toxina para além do local da administração e ainda que raros são
mais prováveis em doentes com distonia ou espasticidade, em crianças, em
doentes idosos com função respiratória comprometida e em doentes com
alterações da transmissão neuromuscular, como a miastenia gravis.
Assim, apesar da eficácia demonstrada nos casos de SBH refractários,
os factos atrás descritos fazem prever que a injecção intravesical de toxina
botulínica dificilmente se venha a tornar uma terapêutica de primeira linha
nos doentes com SBH.
2.3 - Outros fármacos em investigação
Os avanços no conhecimento dos mecanismos envolvidos na SBH fazem pressupor que brevemente novas terapêuticas surjam. De facto, foram
identificados novos receptores, neurotransmissores e vias de sinalização intracelular envolvidos no controlo da micção, localizados quer no SNC quer
no sistema nervoso periférico e no tracto urinário inferior.
Os receptores purinérgicos surgiram como potenciais alvos terapêuticos, após a demonstração que ratinhos com delecção do gene para o receptor P2X3 tinham uma diminuição significativa das contracções do detrusor
(Cockayne et al., 2000). No entanto, ainda não estão disponíveis antagonistas dos receptores purinérgicos.
Dois tipos de receptores adrenérgicos, α e ß, estão identificados na bexiga. Enquanto os primeiros predominam no colo vesical e a sua estimulação
induz a sua contracção, os segundos predominam no resto da bexiga e a sua
20
estimulação induz o relaxamento do detrusor (Levin et al., 1988; Yamaguchi e
Chapple, 2007). O papel funcional dos receptores α localizados no detrusor,
nomeadamente os α1D, é hoje reconhecido como sendo limitado, não sendo
de prever o desenvolvimento de fármacos antagonistas destes receptores
com utilidade clínica (Michel e Vrydag, 2006). Dois fármacos agonistas ß,
YM-178 e GW-427353, estão actualmente em avaliação. Os resultados preliminares dos ensaios clínicos indicam que o primeiro induz uma melhoria da
imperiosidade, da incontinência por imperiosidade e da polaquiúria (Takasu
et al., 2007).
As neurocininas (NKs) pertencem a uma família de neuropeptídeos que
estão envolvidos na modulação dos reflexos miccionais ao nível central e periférico (Lecci e Maggi, 2001; Sellers et al., 2006). Estão presentes em maior
quantidade nas terminações nervosas sensitivas da bexiga de doentes com
SBH do que de indivíduos normais (Smet et al., 1997). Em vários modelos
experimentais de hiperactividade vesical, os antagonistas dos receptores
das neurocininas aumentaram a capacidade cistométrica máxima (Lecci e
Maggi, 2001). Recentemente, um ensaio clínico controlado com placebo demonstrou que um antagonista selectivo de elevada afinidade para o receptor
NK1 era superior ao placebo na diminuição da imperiosidade e da frequência
urinária (Green et al., 2006). Dado que na bexiga humana os receptores predominantes são os NK2 (Sellers et al., 2006), o mecanismo provável de acção
deste fármaco será ao nível da medula espinal, onde poderá interromper o
afluxo sensitivo entre os aferentes primários e os neurónios sensitivos de
segunda ordem.
A neutralização do factor de crescimento nervoso (NGF) ou o bloqueio
dos seus receptores de alta afinidade tornaram-se, também, um alvo de in-
21
vestigação. De facto, em estudos experimentais, o NGF aumenta a actividade contráctil da bexiga (Lamb et al., 2004). Além disso, a concentração de
NGF na urina de doentes com SBH é cerca de dez vezes maior do que nos
controlos (Kim et al., 2006).
Os canais de potássio estão também envolvidos na regulação da actividade contráctil da bexiga (Gopalakrishnan e Shieh, 2004). No entanto, a
toxicidade cardíaca associada aos abridores de canais de potássio tem sido
um obstáculo à sua aplicação clínica (Darblade et al., 2006).
A aplicação clínica dos fármacos inibidores das fosfodiesterases está
actualmente a ser investigada, particularmente na hiperactividade vesical
associada à HBP, onde os resultados preliminares indicam que induzem
predominantemente uma melhoria dos sintomas de armazenamento vesical
(Andersson et al., 2007). Como se sabe, as fosfodiesterases promovem a
inactivação dos nucleotídeos cíclicos, GMPc e AMPc, e os inibidores daquelas enzimas aumentam a sua concentração intracelular. O AMPc está
implicado no relaxamento do músculo liso da uretra e da próstata e o GMPc
no da bexiga (Andersson et al., 2007).
Quanto às vias de sinalização intracelular, a via da Rho-cínase pode induzir contracção do músculo liso quando sobreexposto a neurotransmissores adrenérgicos como a noradrenalina. Em estudos experimentais os inibidores da Rho-cínase suprimiram a hiperactividade vesical que ocorre em
ratos espontaneamente hipertensivos, caracterizados por apresentarem um
tónus simpático exagerado (Rajasekaran et al., 2005).
22
A via de sinalização das ERKs (Cínases regulada por sinais extracelulares) poderá, também, constituir um alvo terapêutico a explorar no futuro.
Esta via de sinalização intracelular pertence à família das cínases activadas
por mitogénios (MAPK) (Boulton et al.,1991). Verificou-se uma fosforilação
aumentada das ERKs na medula espinal de ratos espinalizados, que, se inibida, diminui a hiperactividade vesical (Cruz et al., 2006).
23
3 - RAZÃO PARA O TRATAMENTO DO SBH COM VANILÓIDES
Do exposto anteriormente, resulta que o tratamento de primeira linha
para a SBH, os antimuscarínicos, está longe de ser ideal e as terapêuticas
alternativas têm inconvenientes significativos. Neste contexto, a dessensibilização vesical surge como linha a explorar.
3.1- Receptor vanilóide e agonistas
A capsaicina e a resiniferatoxina (RTX), as duas moléculas mais conhecidas da família dos compostos vanilóides, são substâncias neurotóxicas que
bloqueiam especificamente o afluxo sensitivo conduzido pelas fibras aferentes do tipo C. Estas fibras expressam o receptor TRPV1 (receptor de potencial
temporário de tipo vanilóide, tipo 1), o único alvo conhecido da capsaicina
e do RTX (Szallasi e Blumberg, 1999). Este receptor foi identificado em 1994
por autorradiografia (Szallasi et al., 1994) e posteriormente clonado no rato
(Caterina et al., 1997) e no Homem (Hayes et al., 2000). A ligação dos vanilóides a este receptor inicia uma cadeia de reacções no neurónio, inicialmente
uma excitação provocada pelo influxo de cálcio e posteriormente a dessensibilização, em que a fibra nervosa se torna refractária a novos estímulos
(Cruz et al., 1996; Szallazi e Blumberg, 1999). Embora os mecanismos não
sejam completamente conhecidos, esta incapacidade da fibra nervosa para
responder a novos estímulos, durante longos períodos, pode ser explicada
em parte por um conjunto de alterações como as concentrações elevadas
de cálcio intracelular, a desfosforilação da proteína TRPV1 pela calcineurina,
24
uma fosfatase dependente de cálcio e calmodulina (Novakova-Tousova et
al., 2007), as alterações funcionais induzidas nos organelos intracelulares
(retículo endoplasmático e mitocôndrias) e no núcleo (Olah et al., 2001), a
alteração das propriedades eléctricas da membrana neuronal (Caudle et al.,
2003), a diminuição da expressão do receptor TRPV1 na superfície neuronal
(Avelino et al., 2002), o bloqueio do transporte intra-axonal de NGF e a consequente deplecção de neuropeptídeos (Szallazi e Blumberg, 1999).
O primeiro impulso para o interesse clínico da dessensibilização na hiperactividade vesical, através da aplicação intravesical de agonistas do receptor vanilóide TRPV1, proveio da descoberta de um reflexo miccional espinal,
mediado pelas fibras C e sensível aos vanilóides. A primeira demonstração
ocorreu no gato (de Groat et al., 1990; de Groat, 1997). Nos gatos normais,
as contracções reflexas do detrusor não eram alteradas pela capsaicina indicando que o reflexo miccional mediado pelas fibras C não estava envolvido.
Pelo contrário, em gatos cronicamente espinalizados, aquelas contracções
eram completamente suprimidas pelo vanilóide (de Groat et al., 1990; de
Groat, 1997), demonstrando a emergência do reflexo espinal mediado pelas
fibras C.
Outros estudos clínicos e experimentais sugeriram que aquele reflexo
espinal poderia ter um papel importante na hiperactividade não neurogénica
do detrusor. É o caso de estudos em modelos animais de obstrução infravesical crónica, nos quais a estimulação do nervo pélvico provoca uma resposta parassimpática precoce, que precede a resposta parassimpática normal
(Steers e de Groat, 1988). Esta diferença no tempo de latência na resposta
à estimulação do nervo pélvico confirma a existência de dois reflexos miccionais: um reflexo miccional espinal curto e um reflexo miccional supra-espinal longo (Steers e de Groat, 1988). Estes dados vieram a ser observados
25
também no Homem. Em doentes com hiperactividade vesical associada a
hiperplasia benigna da próstata (HBP), verificou-se, após anestesia local da
uretra prostática com lidocaína, que bloqueia preferencialmente as fibras C,
um aumento do volume vesical que desperta a primeira sensação de micção
e da capacidade cistométrica máxima (Yokoyama et al., 1994). No mesmo
tipo de doentes, Chai et alii (Chai et al., 1998) avaliaram o teste de água gelada. Como se sabe, as contracções do detrusor induzidas pelo frio dependem
de vias neuronais espinais, iniciadas pelas fibras C, e este teste é geralmente
negativo em adultos sem patologia neurológica (Geirsson et al.,1993). Em
71% dos doentes, avaliados por Chai et alii, este teste era positivo. O papel
das fibras C nos sintomas do tracto urinário inferior associados a HBP foi
ainda corroborado num estudo clínico recente com 12 doentes submetidos
a dessensibilização intravesical com RTX que induziu uma melhoria clínica
significativa dos sintomas urinários de armazenamento (Dinis et al., 2004).
A participação das fibras C na hiperactividade do detrusor é ainda sugerida
pelo aumento de fibras sensitivas peptidérgicas (Smet et al., 1997) e imunorreactivas para o TRPV1 (Apostolidis et al., 2005a) na mucosa vesical de
doentes com hiperactividade idiopática e neurogénica do detrusor.
3.2 - Experiência prévia com capsaicina
A capsaicina foi a primeira neurotoxina a ser usada clinicamente para
dessensibilizar as fibras sensitivas vesicais. O contacto do homem com a
capsaicina não se iniciou com a sua aplicação intravesical. A capsaicina é
extraída de plantas do género Capsicum (malaguetas) e condimenta diariamente a dieta de milhões de pessoas, sendo responsável pela típica sensação de ardor associada à sua utilização (Szallasi e Blumberg, 1999). Várias
alusões históricas referem que foi usada com fins terapêuticos, embora de
26
um modo empírico, como por exemplo no tratamento de odontalgias (Szallasi e Blumberg, 1999).
Mais de uma centena de doentes com o síndrome da bexiga hiperactiva
de causa neurogénica foram tratados com capsaicina intravesical, em sete
ensaios clínicos não controlados (Fowler et al., 1992, 1994; Geirsson et al.,
1995; Das et al., 1996; Igawa et al., 1996; Cruz et al., 1997a; De Ridder et al.,
1997) e num controlado com placebo (de Séze et al., 1998). A metodologia
usada foi semelhante em todos os estudos, consistindo numa instilação intravesical, durante 30 minutos, de uma solução alcoólica a 30%, contendo
1-2 mM de capsaicina. O volume da solução era de 100 a 125 ml (ou metade
da capacidade vesical, se menor que esse valor). Os melhores resultados
foram obtidos em doentes com lesões medulares incompletas causadas
por esclerose múltipla, traumatismos ou doenças infecciosas medulares,
que ainda mantinham algum grau de sensibilidade vesical e que mantinham
micções voluntárias. Após um período inicial de agravamento dos sintomas,
com a duração de duas semanas, 70 a 90% dos doentes referiram continência total ou uma melhoria significativa (Fowler et al., 1994; Cruz et al., 1997a;
De Ridder et al., 1997). Além disso, a capsaicina também reduziu o número
de micções e o número de episódios de imperiosidade (Fowler et al., 1994;
Cruz et al., 1997a; De Ridder et al., 1997). Os estudos urodinâmicos demonstraram que a capsaicina intravesical aumentava a capacidade da bexiga em
70 a 90% dos doentes, sendo esse aumento de 47 a 156% em relação aos
valores pré-tratamento. Os efeitos da capsaicina intravesical permaneciam
por longos períodos de tempo, excedendo 6 a 9 meses em muitos casos
(Fowler et al., 1994; Cruz et al., 1997a; De Ridder et al., 1997).
A dor suprapúbica associada à instilação de capsaicina foi frequentemente referida pelos doentes com sensibilidade vesical preservada. Esta dor
27
iniciava-se imediatamente após a instilação da capsaicina e frequentemente
exigia a administração de medicação analgésica. Nalguns casos foi mesmo
necessário interromper o tratamento. A capsaicina despertou, ainda, episódios de disreflexia autonómica em doentes com lesões espinais altas (Geirsson et al., 1995; Cruz et al., 1997a).
Do exposto, rapidamente se concluiu que a capsaicina, apesar da eficácia, estava longe de ser o fármaco ideal para induzir a dessensibilização
vesical.
3.3 - Resiniferatoxina como agente dessensibilizante
O RTX é extraído do cacto Euphorbia resinifera frequente no Norte de
África (Szallazi e Blumberg, 1999). Avelino et alii demonstraram em estudos
experimentais que a aplicação tópica de RTX, em doses extremamente baixas, dessensibilizava os aferentes vesicais sem induzir a excitação nóxica
inicial característica da capsaicina (Avelino et al.,1999). Para isso, contribuem
as diferentes correntes eléctricas induzidas nos neurónios aferentes primários pela capsaicina e pelo RTX. Ao abrir lentamente o canal do receptor, o
RTX induz correntes lentas e prolongadas. Pelo contrário, a capsaicina abre
rapidamente o canal, o que leva a uma maior entrada de cálcio para o neurónio, gerando potenciais de acção rápidos e de curta duração (Liu e Simon
1996; Szallasi e Blumberg, 1999). Estas diferenças electrofisiológicas podem
explicar, em parte, a menor irritabilidade e a maior potência dessensibilizante
do RTX em relação à capsaicina. Tal como a capsaicina, o RTX reduzia a
imunorreactividade vesical para SP, CGRP e TRPV1 e aumentava o volume vesical que despertava uma micção reflexa em animais (Avelino e Cruz,
28
2000; Avelino et al., 2002). Estes efeitos eram prolongados, mas reversíveis
(Avelino e Cruz, 2000; Avelino et al., 2002).
A resiniferatoxina é um análogo mais potente da capsaicina e compartilha com esta um anel aromático homovanílico, facto que induziu à designação genérica destas substâncias como vanilóides (Szallasi e Blumberg,
1996). É uma molécula altamente lipofílica, sendo difícil manter-se numa
solução aquosa, o que dificulta o armazenamento de uma solução estável
(Szallasi e Blumberg, 1992).
O facto da resiniferatoxina dessensibilizar os neurónios sensitivos sem
causar excitação neuronal inicial significativa (Avelino et al., 1999) tornou o
RTX no fármaco apropriado para a dessensibilização de aferentes primários
vesicais no Homem. A administração tópica do látex da Euphorbia fora usada empiricamente durante séculos para tratamento de dores articulares, sem
efeitos tóxicos conhecidos (Appendino e Szallasi, 1997). Mais recentemente,
estudos de toxicidade sugeriram que o RTX era inócuo para o Homem quando aplicado por via intravesical (Afferon Corporation, USA; Icos Lilly, USA;
dados não publicados).
29
OBJECTIVOS
31
Da revisão acabada de efectuar, torna-se evidente que o desenvolvimento de novos fármacos para o tratamento da SBH é uma necessidade
premente. Tendo em conta os vários indícios de que as fibras aferentes primárias de tipo C poderão estar implicadas na génese da SBH, a dessensibilização das fibras C surge como um paradigma terapêutico a necessitar de
exploração.
No presente trabalho, propusemo-nos esclarecer os seguintes aspectos:
a) avaliar o potencial terapêutico da dessensibilização vesical na hiperactividade do detrusor neurogénica;
b) avaliar o potencial terapêutico da dessensibilização vesical na hiperactividade do detrusor não neurogénica;
c) avaliar os efeitos da terapêutica dessensibilizante no sintoma principal do SBH, a imperiosidade;
d) esclarecer o papel das fibras sensitivas C na fisiopatologia do
SBH;
e) avaliar o perfil de segurança das substâncias dessensibilizantes.
Os trabalhos efectuados deram origem a cinco publicações integradas
na presente dissertação. As publicações estão organizadas de acordo com
os objectivos propostos e não necessariamente por ordem cronológica.
33
Utilizámos, como ferramenta farmacológica de investigação, a resiniferatoxina, tendo em conta os conhecimentos acumulados acerca dos mecanismos de acção deste vanilóide em diversos estudos experimentais (Ishisuka et al., 1995; Avelino et al., 1999) e clínicos prévios (Cruz et al., 1997b).
Na primeira publicação, investigámos os resultados clínicos e urodinâmicos, num estudo clínico aberto, da instilação intravesical da resiniferatoxina em doentes com hiperactividade neurogénica do detrusor. Avaliou-se
também o grau de desconforto ou dor associado à instilação intravesical da
substância.
Na segunda publicação, avaliámos os efeitos urodinâmicos e clínicos da
resiniferatoxina em doentes com hiperactividade neurogénica do detrusor,
num estudo controlado com placebo, randomizado, paralelo e com ocultação dupla.
Na terceira publicação, investigámos o papel das fibras C na hiperactividade idiopática do detrusor. Num estudo clínico aberto, avaliámos ainda
a eficácia da terapêutica intravesical com resiniferatoxina nesta disfunção
miccional.
Na quarta publicação, e perante a hipótese de as fibras C estarem envolvidas no afluxo sensitivo anormal proveniente da bexiga ou no processamento anómalo da informação sensitiva, estudámos o papel das fibras C
na génese da imperiosidade. Num estudo clínico controlado com placebo,
comparámos, ainda, as alterações induzidas pela resiniferatoxina na qualidade de vida dos doentes com SBH.
34
Na quinta publicação, decidimos avaliar o perfil de segurança do uso de
resiniferatoxina com fins terapêuticos no Homem, apesar de não haver relatos de toxicidade em trabalhos experimentais e haver alguma experiência de
uso humano em patologia não urológica. Para este trabalho, recorremos ao
estudo por microscopia óptica e electrónica da mucosa vesical em doentes
previamente submetidos a instilação de resiniferatoxina.
35
PUBLICAÇÕES
37
PUBLICAÇÃO I
Desensitization of bladder sensory fibers by intravesical resiniferatoxin, a capsaicin analog: long-term results for the treatment of
detrusor hyperreflexia
39
Neurourology
European
Urology
Eur Urol 2000;38:444–452
Accepted after revision: October 19, 1999
Desensitization of Bladder Sensory Fibers by
Intravesical Resiniferatoxin, a Capsaicin Analog:
Long-Term Results for the Treatment of
Detrusor Hyperreflexia
Carlos Silva a, Maria-Edite Rio b, Francisco Cruz a, c
a Departments of Urology and bNeurology, Hospital S. João and c Institute of Histology and Embryology of the
Faculty of Medicine and IBMC of the University of Porto, Porto, Portugal
Key Words
Resiniferatoxin · Capsaicin · Bladder · Detrusor hyperreflexia · Desensitization
Abstract
Objectives: To assess the pungency and the desensitizing effects of intravesical resiniferatoxin,
an ultrapotent capsaicin analog, in patients with detrusor hyperreflexia.
Methods: Fourteen patients with detrusor hyperreflexia were instilled during 30 min, without
any form of local anesthesia, with 100 ml (or the bladder capacity if lower than that volume) of
50 or 100 nM resiniferatoxin solutions in 10% alcohol in saline. Patients were evaluated by voiding chart and urodynamic tests (volume to first contraction, maximal cystometric capacity, maximal detrusor pressure, icewater test) at 14, 30, 60, and 90 days and every 3 months thereafter
Results: Resiniferatoxin instillation did not evoke pain or temporary worsening of urinary symptoms. Treatment improved or abolished incontinence in 9 out of 12 incontinent patients. Mean urinary frequency decreased from 14.2 B 6.4 to 10.3 B 3.2 at 3 months (p = 0.01). At this time point,
mean maximal cystometric capacity increased from 182.3 B 119.8 to 330.0 B 201.6 ml (p = 0.01) and
the ice water test, positive in 13 cases, became negative in 8 of them. Maximal detrusor pressure
was not modified by the treatment. The effect was long-lasting, reaching 12 months in 7 cases.
Conclusions: The absence of irritative symptoms during bladder instillation of resiniferatoxin
and the rapid onset of desensitization make this vanilloid superior to capsaicin for the treatment
of detrusor hyperreflexia.
Copyright © 2000 S. Karger AG, Basel
Introduction
Detrusor hyperreflexia is a major cause for urinary frequency, urgency and incontinence in patients with spinal
cord lesions disconnecting sacral spinal cord segments from
Fax +41 61 306 12 34
E-Mail [email protected]
www.karger.com
� 2000 S. Karger AG, Basel
0302–2838/../....–.... $17.50/0
Accessible online at:
www.karger.com/journals/eur
the pons [1]. In addition to compromising the social integration of spinal patients, detrusor hyperreflexia may occur
in a set of detrusor sphincter dyssynergia. In consequence,
high residual urine volumes and extreme voiding pressures
may ensue, seriously jeopardizing the integrity of the upper
Prof. Francisco Cruz
Department of Urology, Hospital de S. João
P–4200 Porto (Portugal)
Tel. +351 2 5091468, Fax +351 2 5505728
41
Table 1. Clinical and urodynamic detaisl of 14 cases treated with intravesical RTX
Case No.
Sex
Age
Diagnosis
Performance
status
Continence
Frequency,
times/day
VFC,
ml
MCC,
ml
MDP,
cm H2O
RTX dose
nM
1
2
3
4
5
6
7
8
9
10
11
12
13
14
M
M
F
F
M
F
M
M
F
F
M
M
M
M
35
34
37
26
50
65
70
47
47
25
30
37
44
27
extradural abcess
multiple sclerosis
spinal injury
multiple sclerosis
myelitis
stroke
spinal injury
spinal injury
multiple sclerosis
spinal injury
spinal injury
multiple sclerosis
spinal injury
spinal injury
walkers
whell-chair
walkers
bed-bound
walkers
walk normal
whell-chair
whell-chair
walk normal
whell-chair
whell-chair
walk normal
walkers
walkers
continent
continent
pads
pads
urosheath
pads
urosheath
urosheath
pads
pads
urosheath
pads
pads
urosheath
17
26
10
–
11
18
ISC
ISC
19
–
ISC
8
14
5
256
56
20
17
256
145
391
52
130
76
24
149
140
56
309
63
51
18
268
156
414
200
209
80
338
212
170
65
55
21
64
61
99
38
50
48
92
182
74
108
108
118
50
50
100
100
100
50
50
50
100
50
100
100
50 + 100
100
VFC = Volume to first contraction; ISC = intermittent self-catherization.
urinary tract [1]. Most spinal hyperreflexic patients are currently managed with anticholinergic or smooth muscle relaxant drugs and clean intermittent catheterization. However, in many patients these measures do not avoid frequent
voidings and nonvoluntary urine loss or give rise to unacceptable side effects [1].
Experimental studies have suggested that desensitization
of bladder afferent fibers of the C type, by turning them less
reactive to natural stimuli, can be an advantageous treatment of detrusor hyperreflexia. In fact, systemic administration of capsaicin proved capable of suppressing detrusor
contractions in chronic spinal cats but had no effect on detrusor activity in intact animals [2]. This may be due to the
fact that the sensory fibers that trigger the micturition reflex
in intact and chronically spinalized cats are substantially
different. Whereas in the former, micturition is under the
control of a long reflex initiated in sensory fibers of the Aδ
type, in the latter, micturition is controlled by a short sacral
reflex triggered by sensory fibers of the C type that are
highly sensitive to capsaicin [3]. These bladder afferents also occur in humans where they contribute to pain perception and micturition control [4]. Their desensitization by intravesical capsaicin has indeed been shown to be effective
in decreasing frequency, urgency or incontinence in spinal
patients [5–10]. Unfortunately, capsaicin pungency seen in
patients with preserved bladder sensation constitutes a
drawback preventing its wide clinical application. It occurs
immediately after the contact of capsaicin with the bladder
mucosa as an intense burning pain in the lower abdomen before desensitization takes place [5–9]. Local anesthesia of
the bladder mucosa decreased but did not abolish capsaicin
pungency [7, 8]. In addition, neuronal excitation may produce severe episodes of autonomic dysreflexia in susceptible patients [6].
Resiniferatoxin (RTX), an extract of the Euphorbia
plant, contains, like capsaicin, an homovanillyl ring in its
molecule [11] and competes for the same membrane receptor in type C afferent fibers [12, 13]. Preliminary pharmacological studies have estimated that RTX is 1,000 to 10,000fold more potent than capsaicin to induce desensitization of
bladder sensory fibers in the rat but only 3 times more potent to excite them [11, 14]. Therefore, at an experimental
level, desensitization could be obtained at very low RTX
concentrations which were only scarcely irritant to bladder
sensory fibers [15–18]. Recently, we extended intravesical
application of RTX to patients with detrusor hyperreflexia
[19]. In a small pilot study, RTX instillation, carried out
without any form of local anesthesia, did not evoke any significant discomfort [19]. The ensuing desensitization,
which lasted for several months, was effective in reducing
the frequency and duration of episodes of urinary incontinence and to markedly increase bladder capacity [19]. In the
present work, we update our preliminary study, describing
several patients followed for more than one year and submitted to repeated instillation.
Desensitization of Bladder Sensory Fibers
by Intravesical Resiniferatoxin
Eur Urol 2000;38:444–452
42
445
Materials and Methods
The present study comprises 14 patients with bladder hyperreflexia, 9 males and 5 females, with a mean age of 41 years (range 25–70
years). Bladder hyperreflexia was due to spinal cord injury in 7 patients, multiple sclerosis in 4 cases, spinal extradural abscess (1),
transverse myelitis (1) and cerebrovascular accident (1). Eight cases
had received intravesical capsaicin previously (cases 1–6, 9 and 12)
and were considered for RTX instillation after their clinical and urodynamic condition had receded to precapsaicin levels. Table 1 gives
details of individual disability. One case was bedridden, 3 cases
walked normally or with minimal difficulty, 5 used walkers and 5 were
wheelchair-bound. Twelve patients filled a voiding chart where daily
micturitions (or intermittent bladder catheterizations) and episodes of
incontinence were recorded for at least 3 consecutive days. Nine of
these patients had perurethra micturitions whereas the other 3 emptied
their bladders by intermittent catheterization. Cases 4 and 10 were permanently on pads and were unable to accurately record the number of
reflex micturitions at baseline. Twelve cases were incontinent and
used either pads (cases 3, 4, 6, 9–11) or urosheath devices to collect
urine (cases 5, 7, 8, 12–14). Following clinical evaluation, all patients
were screened by hematological and biochemical blood tests, microbiological urinary investigation and ultrasonographic or radiologic evaluation of the urinary system. Fill cystometry was performed with Dantec instruments, with a two-way 8-F catheter inserted in the urethra for
saline infusion at 50 ml/min (except case 4 infused at 5 ml/min), and
simultaneous recording of bladder pressure. The volumes of first detrusor contraction (FDC), maximal cystometric capacity (MCC) and
maximal detrusor pressure (MDP) were determined in all patients. After cystometry, the ice water test was performed by rapid infusion of
50 ml of saline at 0°C, or half of the previously determined MCC if
lower than that volume, during a period of 20 s. The test was considered positive if an involuntary detrusor contraction exceeding 15 cm
of water occurred in the next 60 s. The following exclusion criteria to
initiate the RTX treatment were observed: age less than 18 years, pregnancy, cardiovascular, renal, hepatic or psychiatric disorders, malignant diseases, clinically significant abnormal laboratory values, gross
abnormalities of the upper urinary tract, concomitant bladder diseases,
duration of urinary symptoms less than 12 months or treatments influencing bladder performance. An exception was considered in patients
on anticholinergic medication as long as the daily dose was unchanged
throughout the study (cases 7 and 10). RTX was obtained from
Afferon (USA) and its solutions prepared in our hospital. All patients
gave written informed consent approved by the Ethics Committee of
the Hospital São João.
Immediately before treatment, patients were clean catheterized
with a three-way 20-F indwelling Foley catheter to allow RTX infusion and simultaneous recording of the bladder pressure. The bladder
was emptied and the balloon was inflated to 10 ml and maintained
gently pulled against the bladder neck to reduce leakage of RTX solution to the urethra. Treatment consisted of one single instillation of
100 ml (or a volume equivalent to MCC) of 50 or 100 nM RTX solutions of 10% alcohol in saline which were left inside the bladder during 30 min. RTX was then evacuated, the bladder was rinsed with normal saline and an ice water test performed as above before the Foley
catheter was removed. Vital signs were recorded immediately before,
during and at the end of treatment. In addition, patients were asked to
estimate discomfort felt during RTX instillation in a visual analog
scale in which 0 was no discomfort and 10 was pain felt during capsaicin instillation in cases submitted to this treatment, or a very intense
446
Eur Urol 2000;38:444–452
pain in the other cases. The first 5 patients were kept in the ward for
24 h. All the others were sent home immediately after conclusion of
the treatment.
All patients were followed at days 14, 30, 60 and 90 after treatment. At each time point, patients were clinically reevaluated, a micturition chart (as defined above) was collected and a filling cystometry and an ice water test were repeated. In addition, at the first 4 visits,
blood and urine samples were collected for biochemical and microbiological tests, respectively. After this initial period, patients were followed up every 3 months until clinical and urodynamic measurements
had returned to baseline levels. At each of these visits, patients were
clinically reevaluated, a micturition chart (as defined above) was collected and a filling cystometry was obtained.
Successive treatments followed the same method used in the initial
procedure and were performed at patient request, after confirmation
that urinary frequency, incontinence and MCC had returned to baseline values. Follow-up visits were done at 30 days, 90 days and every
3 months thereafter. At each of these time points, a micturition chart
was collected and cystometry was repeated.
Prophylactic antibiotics were administered after RTX instillation
and after every urodynamic study. The mean values of urinary frequency, volume to FDC, MCC and MDP, determined before and after
treatment, were compared by a paired t test for means.
Results
General Considerations
A total of 24 instillations of 50 or 100 nM solutions, either as a first or as a subsequent treatment, were carried out.
In general, a sharp rise in detrusor pressure followed by series of phasic contractions occurred within a few minutes
after the beginning of treatment and remained throughout it,
although becoming gradually more spaced near the end
(fig. 1). During phasic contractions, patients noticed an
urge sensation to urinate which subsided as soon as detrusor
pressure returned to normal values. In addition, patients
with preserved bladder sensation felt inching or a warm
sensation in the lower abdomen during the initial minutes of
RTX administration which waned thereafter. Patients did
not complain of severe discomfort or overt pain during RTX
instillation, or asked for any kind of analgesic medication
despite of the fact that the entire procedure was carried out
without any form of local anesthesia. Blood pressure and
heart rate remained stable during treatments. Accordingly,
in the visual analog scale (fig. 2) most patients scored the
discomfort produced by first or subsequent treatments below 3, whether they had received intravesical capsaicin on a
previous occasion or not. The only exception occurred at
the second treatment of patient 13 who felt a brief burning
pain in the lower abdomen rated at 8 accompanied by a sudden rise of blood pressure and heart rate (fig. 2). Reinstillation was carried out with 100 nM RTX instead of the initial
Silva/Rio/Cruz
43
Fig. 1. Phasic detrusor contractions record-
ed during the 30 min of a solution of 100 nM
RTX remaining in the bladder (case 14, first
treatment).
50 nM solution. However, a third instillation of a 100 nM
solution in this patient, 9 months later, was uneventful. Intravesical instillation of RTX did not cause hematuria or
any other recognizable side effect. Some symptomatic urinary tract infections occurred but were controlled after appropriate antibiotherapy.
Clinical and Urodynamic Findings during the First
90 Days
Intravesical instillation of RTX brought clinical improvement in 11 patients either due to a decrease of urinary
frequency, or to a decrease in the severity of urinary incontinence or both. As a rule, clinical improvement was accompanied by progress of the urodynamic findings. The effects of the 50 or 100 nM solution instillations were very
similar and therefore the results of both treatments will be
presented together.
The mean urinary frequency of the 9 patients who registered their perurethra micturitions in the voiding chart was
14.2 B 6.4 at baseline (fig. 3). RTX administration decreased urinary frequency without evoking any transient period of symptom worsening. At day 14, the mean urinary
frequency was 9.7 B 4.1 (p = 0.009) and did not change appreciably up to the visit after 90 days at which the mean urinary frequency was 10.3 B 3.2 (p = 0.01) (fig. 3). Case 10,
who did not fill the voiding chart at baseline, recovered control over micturition and emptied her bladder 4 times a day.
44
Fig. 2. Discomfort score on a 10-point analog scale for the 14 pa-
tients and 24 instillations. 0 = No discomfort, 10 = overt pain, felt during a previous capsaicin instillation of 1 mM for cases 1–6, 9 and 12
or under a nonspecified situation for the other cases.
In patients on intermittent catheterization, RTX instillation
had no effect on the number of daily procedures.
The number of daily episodes of urinary incontincence
that occurred in 12 patients was reduced in 4 patients and
suppressed during long periods of time in 5 cases. In 8 patients with more than 1 episode of incontinence per day, the
number of leaking episodes decreased from 3.6 at baseline
to 2.0 after 14 days and 1.5 after 90 days.
The mean MCC of the 14 patients was 182.3 B 119.8 ml
at baseline, increased to 276 B 172.9 ml at day 14 (p = 0.05)
Eur Urol 2000;38:444–452
447
Fig. 3. a Mean frequency, (b) mean MCC,
(c) mean volume for FDC and mean (d)
MDP during the initial 90-day period of observation after the first RTX instillation.
Mean frequency and FDC were calculated
from the 9 cases with spontaneous perurethra
micturitions. Mean MCC and MDP were calculated from the 14 cases.
a
b
c
d
Fig. 4. a Mean MCC and (b) frequency
after a single RTX instillation in 7 cases in
whom treatment lasted 1 year. MCC was calculated from 7 cases, whereas for frequency,
only data from 4 cases were used since the
other 3 performed intermittent self-catheterization.
a
and reached the highest value, 330.0 B 201.6 ml, by day 90
(p = 0.01) (fig. 3). The mean bladder volume at which FDC
occurred increased in the 9 patients with spontaneous micturitions from 134.2 B 83.1 ml at baseline to 186.4B112.6
ml (p = 0.05) at day 14 and remained above pretreatment
levels up to the visit at 90 days (fig. 3). The MDP in the 14
patients was 79.8 B 41.4 cm H2O at baseline and did not decrease after RTX instillation (fig. 3). The ice water test was
positive in 13 cases at baseline. Immediately after RTX instillation, the ice water test became negative in 4 of those
cases and in an additional 2 at 14 days. At 90 days, the test
was negative in 8 cases.
Three patients (cases 4, 5 and 7) did not achieve any clinical improvement from RTX instillation. Cases 4 and 5 had
448
Eur Urol 2000;38:444–452
b
been previously treated with 1 mM capsaicin, also without
success.
Duration of the RTX Effect
The clinical improvement in the 11 patients who responded favorably to RTX during the initial 90-day period
was long-lasting. In 7 patients (cases 1–3, 6, 10, 11 and 14),
the clinical effect lasted 12 or more months. The evolution
of the mean MCC and urinary frequency of those patients
during 12 months is shown in figure 4. The mean MCC was
151.7 B 122.5 ml at baseline, increased to 341.7B187.5 ml
at day 90 (p = 0.03), and reached its maximum, 360.5 B
163.6 ml, after 6 months (p = 0.02). At 12 months, it was
still above baseline level (262.4B111.7 ml, p = 0.01). Only
Silva/Rio/Cruz
45
Fig. 5. Changes of (a) mean frequency and
(b) MCC 30 days after 8 RTX reinstillations.
a
4 patients in this cohort had spontaneous micturitions. Their
mean urinary frequency decreased from 14.5 B 9.1 at baseline to 9.2 B 3.8 after 90 days (p = 0.07 and was still below
the initial value after 12 months (7.7 B 2.0, p = 0.08). In
cases 13, 9 and 12, the clinical response lasted 3, 6 and 9
months, respectively. Patient 8 was lost to follow-up after
the end of the initial phase.
Clinical and Urodynamic Findings at Reinstillation
Ten reinstillations were accomplished in 9 cases [cases
1–3, 5, 6, 9, 12, 13 (twice) and 14]. After treatment, patients
5 and 6 refused to adhere to the scheduled follow-up and
were lost to the study. Nevertheless, both gave their subjective impression of the second instillation. Case 5, who did
not obtain clinical improvment from the first instillation,
again denied any subjective improvement. Case 6 believed
to have obtained only a very marginal one. The following
results were therefore calculated from 8 reinstillations in 7
patients.
The mean frequency decreased from 10.2 B 2.9 to
8.6 B1.7 at 30 days (p = 0.009) and MCC increased from
195 B 109.6 to 334.7 B 151.4 (p = 0.006) (fig. 5). Incontinence episodes were present at the time of the second instillation in 6 patients, improved in 2 and disappeared in 4 of
them. At the time of completion of the manuscript, the effect of the second RTX treatment already exceeded 6
months in some patients (cases 1, 3, 9 and 13).
Discussion
Clinical and Urodynamic Changes
The present study showed that intravesical administration of RTX decreased urinary frequency and incontinence
in patients with detrusor hyperreflexia of the spinal origin.
46
b
Clinical improvement was accompanied by an increase in
bladder capacity at involuntary FDC and at MCC, and the
disappearance of cold-induced detrusor contractions. These
findings were long-lasting, persisted between 6 and 12
months in most patients, and could be extended to a similar
period of time by repeated instillations, fully confirming
our first report on the subject [19].
In terms of clinical or urodynamic effects, RTX administration reproduced the results previously obtained by capsaicin instillation. In fact, decreased urinary frequency, decreased or fully suppressed urinary incontinence and
increased bladder capacity were common findings in up to
80% of the patients with detrusor hyperreflexia following
capsaicin treatment [5, 8, 9]. Furthermore, intravesical capsaicin concealed the ice water test in some patients [6]. The
only lack of coincidence between capsaicin and RTX effects might occur with MDP since some capsaicin studies
have reported a significant decrease of this parameter [5, 9]
while RTX did not interfere with it. It should, however, be
stressed that the only study in which capsaicin was compared with the vehicle solution (30% alcohol) did not find
any effect of the neurotoxin on MDP either [10]. Therefore,
the only real difference between RTX and capsaicin at the
clinical or urodynamic level amounts to their relative potency. RTX exerted its effects in 50–100 nM solutions
whereas capsaicin required 1–2 nM, that is, several thousand times more concentrated solutions, to be effective.
Drug Pungency
The most important finding of the present work concerns
the low pungency of RTX. Upon its intravesical application, itching or a warm sensation in the lower abdomen
were the only sensations felt by patients, the intensity of
which was low taking into consideration that in a scale of
ten, most patients scored the discomfort produced by treat-
Eur Urol 2000;38:444–452
449
ments below 3. Blood pressure and heart rate were not altered by RTX instillation and there was no temporary worsening of the urinary symptoms. This contrasts sharply with
the extreme pungency of capsaicin seen in most clinical trials. Its manifestations included an intense burning sensation
in patients retaining some form of bladder sensation [5,
7–9] or life-threatening episodes of autonomic dysreflexia
in cases of complete spinal cord transection at a high thoracic or cervical level [6]. Moreover, intravesical capsaicin
typically exacerbated urinary frequency, urgence and urge
incontinence during the first 1–2 weeks after treatment [5,
7, 9].
The large therapeutic window of RTX was immediately
recognized after the preliminary pharmacological demonstration that its potency to induce desensitization or irritation was extremely different. RTX was several thousand
times more potent than capsaicin in desensitizing primary
afferents but only 3–4 times more potent to induce neurogenic inflammation [11]. or to evoke the pressor reflex in
the perfused rabbit ear assay [14] and it was even equipotent to capsaicin in inducing nociception in the eye-wiping
assay [11]. This raised the possibility of desensitizing sensory fibers with very low RTX concentrations, so low that
no significant acute irritative effects would be evoked. At
the experimental level, this possibility was demonstrated in
what concerns bladder sensory fibers. The saturating concentration of RTX to induce complete densitization of the
rat bladder sensory fibers was 100 nM, that is, 10,000 times
lower than the 1 mM dose of capsaicin required to achieve
the same goal [17, 18]. However, the intensity of the spinal
c-fos expression immediately after 100 nM RTX instillation
was only one fourth of that induced by 1 mM capsaicin in
the deep spinal horn and only one tenth in the superficial
dorsal horn [18]. The reduced c-fos expression induced by
RTX in the latter spinal region is particular striking since it
indicates that less noxious input reached a spinal area where
most nociceptive specific sensory neurons are located [20].
Susceptibility of Different Types of Bladder Afferents to
Drug Pungency
Despite the reduced RTX pungency reported by patients,
the 50 or 100 nM RTX solutions used were still irritant to
bladder sensory fibers, as shown by the strong phasic detrusor contractions triggered during the initial period of instillation which mimicked those seen during capsaicin applications [5, 7, 21]. Detrusor hyperactivity occurring during
capsaicin or RTX instillation may involve stimulation of
bladder wall neurokinin receptors of the NK2 subtype by
neuropeptides released from nerve terminals [16, 22]. As a
matter of fact, the selective nonpeptidic antagonist of the
450
Eur Urol 2000;38:444–452
NK2 receptor SR 48968 can suppress contractions triggered
by both vanilloids in the rat urinary bladder [16, 22]. It is also interesting that in this species, capsaicin or RTX induced
a similar release of SP and CGRP from nerve terminals immediately after their intravesical administration, as deduced
from the reversible reduction of the density of immunoreactive nerve fibers in the mucosa and muscular layer to less
that 20% of controls [23]. If excitation of NK2 receptors is,
however, the sole explanation for pungency, it remains unexplained why a similar rate of neuropeptide release induces bladder pain in the case of capsaicin, but not RTX.
The apparent contradiction between low pungency and
the occurrence of strong detrusor contractions during RTX
instillation may rather suggest that this vanilloid can act as
an irritant only on certain subsets of bladder C-afferent
fibers. According to physiological studies, about 70% of
bladder sensory fibers have a low threshold for response
and encode intravesical pressure in the physiologic range
which indicates a preferential role in micturition control
[24]. The remaining 30% are high-threshold fibers which
respond to high intravesical pressures usually in the noxious
range, a characteristic suggesting their specific involvement
in bladder nociception [24]. In awake animals, instillation
of 100 µM capsaicin could apparently excite both types, as
shown by the simultaneous occurrence of an intense licking
of the lower abdomen indicative of bladder pain and a reduction of bladder capacity by more than 75% [16]. On the
contrary, 100 nM RTX may only irritate the low-threshold
subset since it decreased bladder capacity without evoking
pain behavior [16]. The same seems to occur in the human
bladder where low concentrations (0.1 µM) of capsaicin only facilitated detrusor contractions whereas higher concentrations (1 µM or higher) also evoked a burning sensation in
the lower abdomen [4]. Like very low capsaicin concentrations, RTX in the concentrations used here may, therefore,
be sufficient to excite the low-threshold fibers and trigger
detrusor contractions but insufficient to irritate high-threshold C-fibers and generate pain sensations.
Vanilloid Receptor: Single or Multiple Subtypes?
It is commonly believed that RTX or capsaicin exert
their biological actions due to the presence of an homovanillyl ring in their molecules [11–15]. This common
moiety would allow the specific recognition of a binding
site first visualized by [3H]RTX autoradiography in unmyelinated primary afferents [12]. This binding site was recently cloned as the VR1 vanilloid receptor and further
characterized as a nonselective calcium channel [13]. It is,
however, difficult to reconcile the different exciting and desensitizing properties of both compounds on the basis of a
Silva/Rio/Cruz
47
single receptor model. In contrast to a single receptor model, two receptors with different affinities for RTX and capsaicin and unequal distribution in bladder C-afferent subsets
would fit nicely. Recent experimental work carried out in
rat dorsal good ganglion cells in culture has brought additional evidence for the existence of two vanilloid receptor
subclasses. One had high affinity for RTX and generated a
weak calcium inflow whereas the other showed high affinity for capsaicin and evoked a robust calcium uptake into the
neuron [25]. Desensitization induced by RTX was preferentially inhibited by ruthenium red, whereas desensitization
induced by capsaicin was antagonized by capsazepine [25].
Further studies will be necessary to elucidate the distribution of both subtypes in bladder sensory fibers.
Clinical Implications
The ideal vanilloid to be used in clinical practice should
have a potent desensitizing activity and a weak pungent effect. In addition, it should be safe for human application.
Concerning the former aspect, there is no doubt that, in contrast to capsaicin, RTX seems to approach that goal. In respect of safety RTX application in our patients was not
associated with any clinical or biochemical side effect. Desensitization, although long-lasting, was reversible, indicating the absence of neuronal death among bladder afferents.
In addition, no pathological changes were found by cystoscopies and in random cold bladder biopsies performed in
some patients that received RTX for longer periods of time
(data not published). Finally, 50–100 nM concentrations
were chosen taking into consideration the relative potency
of RTX and capsaicin in experimental assays in the rat [17,
18, 26]. They seem, however, to approach the ideal RTX
dose to be used in hyperreflexia. As a matter of fact, lower
doses as 10 nM used in another clinical study induced a
short-lasting improvement which did not exceed 2 weeks
[27]. On the other hand, higher concentrations, as
10,000 nM, recently assayed by the same group gave rise to
a prolonged state of bladder areflexia during which patients
needed to empty their bladders by clean intermittent
catheterization [28].
Conclusions
The present results with intravesical RTX constitute the
largest experience reported with this substance as a desensitizing treatment for detrusor hyperreflexia. Its high clinical
efficacy combined with a low pungency and absence of other side effects make RTX an ideal substitute for capsaicin,
the first vanilloid employed to desensitize human bladder
sensory fibers.
Acknowledgment
We would like to thank Professor António Coimbra for the critical
review of the manuscript.
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49
PUBLICAÇÃO II
Urodynamic effect of intravesical resiniferatoxin in patients with
neurogenic detrusor overactivity of spinal origin: results of double-blind randomized placebo-controlled trial
51
European
Urology
European Urology 48 (2005) 650–655
Neurourology
Urodynamic Effect of Intravesical Resiniferatoxin in
Patients with Neurogenic Detrusor Overactivity of
Spinal Origin: Results of a Double-Blind Randomized
Placebo-Controlled Trial
Carlos Silvaa, João Silvaa, Maria-José Ribeiroa, António Avelinob, Francisco Cruza,b,*
a
Department of Urology, Hospital S. João, 4200-319 Porto, Portugal
Faculty of Medicine of Porto, Institute of Histology and Embryology, IBMC of the University of Porto, 4200-319 Porto, Portugal
b
Accepted 19 April 2005
Available online 12 May 2005
Abstract
Objectives: To access by a placebo-controlled randomized clinical trial the effect of intravesical resiniferatoxin on
the urodynamic parameters of patients with neurogenic detrusor overactivity (NDO) of spinal origin.
Methods: Twenty eight patients with spinal NDO were randomised to receive intravesically 50 nM resiniferatoxin
dissolved in 10% ethanol in saline (RTX group) or only the vehicle solution (placebo group). Filling cystometries
were obtained in each patient at 1 month and 1 week before and at 1 and 3 months after treatment. In a visual analog
scale patients were asked to estimate the discomfort induced by treatment. Patients were also persuaded to fill a
micturition chart during the 3 days preceding each cystometry.
Results: The RTX and placebo groups were homogeneous in what respects the volume to first involuntary detrusor
contraction (FDC, 143 � 95 ml and 115 � 58 ml, respectively, p = 0.3) and maximal cystometric capacity (MCC,
189 � 99 ml and 198 � 111 ml, respectively, p = 0.8). At the end of the study, mean FDC and MCC in the RTX
group, 184 � 93 ml and 314 � 135 ml, respectively were significantly higher than in the placebo group,
115 � 61 ml (p = 0.03) and 204 � 92 ml (p = 0.02). In the visual analogue scale discomfort caused by treatment
was similar. Only 10 patients in the RTX group and 6 patients in the placebo group completed adequately the
micturition chart. Mean frequency and urinary incontinence decreased significantly only in the RTX group.
Conclusions: Intravesical RTX is effective in increasing bladder capacity in spinal NDO patients. Such increment
might contribute to decrease urinary frequency and incontinence of these patients.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Resiniferatoxin; Neurogenic bladder; Neurogenic detrusor overactivity; Desensitization
1. Introduction
Resiniferatoxin (RTX) and capsaicin, two natural
occurring vanilloid compounds, share a unique property,
the capacity to excite and then to desensitize type C
primary afferent fibers [1]. Both actions require the
activation of a non-selective calcium channel abundantly expressed in those sensory fibers, the so called
* Corresponding author. Tel. +351 2 5091468; Fax: +351 2 5505728.
E-mail address: [email protected] (F. Cruz).
transient receptor potential vanilloid 1 (TRPV1), previously known as vanilloid receptor type 1 (VR1) [2].
Excitation is the consequence of TRPV1 opening which
generates spike-like calcium currents [1]. The transient
high intracellular calcium causes desensitization, a still
imprecise phenomenon that includes neuropeptide
release, block of sensory transmission and eventually
neuronal degeneration [1,3]. Regardless of the evident
similarities between the two molecules, as shown by the
occurrence of an identical homovanillyl ring in both
[1,3], RTX is several thousands times more potent in
0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2005.04.012
53
C. Silva et al. / European Urology 48 (2005) 650–655
desensitization than capsaicin but only a few hundreds
more in excitation [1]. As a result, in studies conducted
in the rat bladder, complete C-fiber desensitization could
be obtained with RTX in concentrations so low that
preliminary excitation was negligible [4].
As predicted by experimental studies [4], pilot, nonplacebo controlled trials carried out with spinal NDO
patients [5–10] showed that intravesical RTX in concentrations ranging from 10 nM up to 1000 nM caused
a very modest bladder C-fiber excitation. Abdominal
pain was minimal and episodes of autonomic dysreflexia were not reported [5–10]. Nevertheless, RTX in
concentration of 50 nM or higher induced a longlasting desensitization that, likewise observed with
capsaicin, delayed involuntary detrusor contractions,
increased bladder capacity and improved urinary
symptoms in NDO patients [5,7–10]. A recent prospective double-blinded, dose escalating clinical trial
conducted in spinal NDO patients confirmed the low
exciting effect of RTX on bladder C-fibers [11]. Surprisingly, however, this study could not demonstrate a
clear superiority of RTX, whatever the concentration
used, 5 to 1000 nM, to increase bladder capacity in
NDO patients [11]. Unfortunately, the discrepancy
between this and previous open labelled studies were
never solved by a new placebo controlled randomised
clinical trial. The reported difficulties in the preparation of RTX solutions might have contributed to the
lack of new studies. In fact, this compound is unstable
and adheres to plastics [12]. At this moment, these
inconveniences can only be overtaken by preparing
RTX solutions immediately before intravesical administration [13], a contingency that many centres might
not be prepared to face.
To decide whether or not bladder desensitization by
intravesical RTX delays involuntary detrusor contractions and increases bladder capacity in NDO patients
we conducted a double blind placebo controlled study
in which 50 nM RTX was compared against the vehicle
solution, 10% ethanol in saline. As primary endpoints
we investigated the effect of RTX on the volume to first
involuntary detrusor contraction (FDC) and on maximal cystometric capacity (MCC). As secondary endpoints we investigated the discomfort brought about by
RTX instillation and the effect of this compound on
urinary frequency and daily number of episodes of
urinary incontinence.
2. Material and methods
Twenty-eight patients with NDO of spinal origin, 15 males and
13 females with a mean age of 38 years (range 20–69) gave written
54
651
informed consent approved by the Ethics Committee of our institution to participate in this study. The following exclusion criteria to
initiate the RTX treatment were observed: age less than 18 years,
pregnancy, known cardiovascular, renal, hepatic or psychiatric
disorders, malignant diseases, duration of NDO less than 12 months
and concomitant bladder diseases and/or treatments influencing
bladder performance. An exception was considered in patients on
anticholinergic medication as long as the pre-treatment daily dose
was unchanged throughout the study. Spinal NDO was due to spinal
cord injury (11), multiple sclerosis (8), transverse myelitis (5),
myelomeningocele (2), vascular malformation (1) and idiopathic
spinal atrophy (1). Hematological and biochemical blood tests, and
kidney and bladder ultrasound were normal in all patients.
Two cystometrograms were obtained in each patient 1 month and
1 week before treatment at a filling speed of saline of 50 ml/minute.
(The study was already under way when ICS recommended the use of
20 ml/minute as the ideal filling speed for cystometries in NDO
patients. Due to such contingency we could not adopt the new ICS
directives.) The infused volume at which detrusor pressure first rose
15 cm of water above the baseline was taken as the volume to first
detrusor contraction (FDC). Maximal cystometric capacity (MCC)
was recorded at the moment patients felt bladder discomfort and
asked to stop saline infusion or a detrusor contraction leading to urine
leakage per urethra occurred. Patients were also asked to fill a
micturition chart of at least three consecutive days registering
micturitions and episodes of urinary incontinence. Patients were
then blindly randomised to be instilled with 100 ml of a 50 nM RTX
solution (RTX group) or with 100 ml of the vehicle solution, 10%
ethanol in saline (placebo group). RTX was obtained from Sigma and
a 10 mM stock solution in pure ethanol prepared and kept in the dark
at 4 8C in a glass container. For each instillation 100 ml of a 50 nM
solution using 10% ethanol in saline as vehicle was prepared by
adding 0.5 ml of the stock solution to 90 ml of saline and 9.5 ml of
pure ethanol. Both RTX and ethanol solutions were prepared by one
of the authors (AA) and sent blindly to the other investigators
responsible for their application. Instillation, which lasted 30 minutes, was carried out within 30–60 minutes after preparation to
minimise RTX absorption by plastic devices. Details of the instillation method were given elsewhere [7]. For short, patients were clean
catheterized with a three-way 20 F indwelling Foley catheter to allow
solution infusion and simultaneous recording of the bladder pressure.
Vital signs were recorded immediately before, during and at the end
of treatment. In addition, patients were asked to estimate discomfort
felt during instillation in a visual analog scale in which 0 was no
discomfort and 10 was an excruciating pain requiring analgesic
treatment or solution evacuation. At the end of the treatment the
solution was evacuated and the bladder was gently rinsed with normal
saline. Then, the Foley catheter was removed and patients sent home.
Filling cystometries were repeated at 1 and 3 months after
treatment, as described above, and FDC and MCC recorded. In
addition, at these time points patients were again asked to bring a
micturition chart of at least the preceding three days. Only after the
last visit was the code broken and investigators informed if the
patient had received RTX or its vehicle solution. Oral ciprofloxacin
was administered for urinary infection prophylaxis after solution
instillation and after every urodynamic study, wether performed
before or after treatment.
For statistical comparisons FDC and MCC of each patient
before and after instillation was calculated as the average of the
values recorded in the two cystometrograms obtained before and
after the treatment. This was decided in order to minimize the
variation of FDC and MCC in neurogenic patients upon repeated
652
urodynamic testings. The daily frequency and urinary incontinence
before and after treatment was calculated by counting the episodes
in the micturition charts and dividing the sum obtained before and
after instillation by the registered number of days. A two-tailed,
two sample Student t-test assuming unequal variance was used to
compare mean FDC, MCC, pain score, frequency and incontinence
between RTX and placebo groups at baseline and at the end of the
study. An one-tailed paired t-test for means was applied to compare
the differences between mean frequency and incontinence inside
each group before and after treatment since the number of patients
that completed micturition chart was low. In both tests a p < 0.05
was considered statistically significant.
3. Results
RTX and placebo groups were homogeneous in
what concerns gender, age, FDC and MCC (see
Table 1). Mean FDC was 143 � 95 ml in the RTX
group and 115 � 58 ml in the placebo group (p = 0.3).
Mean MCC was 189 � 99 and 198 � 111 ml in the
RTX and in the placebo group, respectively (p = 0.8).
Ten patients in the RTX group and 6 patients in the
placebo group completed adequately two micturition
charts before and two after bladder instillation. In these
patients mean frequency and urinary incontinence at
baseline were also similar (Table 1). The origin of
NDO in the two groups was equilibrated. The RTX
group included 5 patients with spinal cord injury (2
complete at T10 and L1 and 3 incomplete), 4 with
multiple sclerosis, 3 with transverse myelitis, 1 with
vascular malformation and 1 with idiopathic spinal
atrophy. Two patients of the RTX group were under
oral anti-cholinergic medication. The placebo group
included 6 patients with spinal cord injury (2 complete
at C6 and L1 and 4 incomplete), 4 with multiple
sclerosis, 2 with transverse myelitis and 2 with myelomeningocele. Three patients of the placebo group
were taking anti-cholinergic medication. Due to the
fact that a large collection of diseases was present in
both groups, each one represented by only a few cases,
no further effort was made to analyse the effect of RTX
and placebo by disease type.
At the end of the study mean FDC in the placebo
group, 115 � 61 ml, had not changed but had increased
29%, to 184 � 93 ml, in the RTX group (Fig. 1). The
Fig. 1. Mean volume to first involuntary detrusor contraction (FDC) and
maximal cystometric capacity (MCC) at the end of the study in the RTX and
placebo group.
difference between mean FDC of the two groups at the
end of the study was statistically significant (p = 0.03).
In what concerns mean MCC at the end of the study, it
showed a 3% increase in the placebo group, to
204 � 92 ml, and a 66% increase, to 314 � 135 ml
in the RTX group (Fig. 1). The difference between
mean MCC of the two groups at the end of the study
was statistically significant (p = 0.02). We, thereafter,
analysed wether the increment of FDC and MCC
occurred in the first, second or in both cystometries
performed after treatment. At 1 and 3 months the
average FDC was 184 � 140 ml and 180 � 63 ml
whereas MCC was 271 � 146 ml and 354 � 164 ml,
respectively. As the differences between 1 and 3
months were not statistically significant it seems reasonable to assume that RTX-induced urodynamic
improvement was already present at 1 month followup and was sustained at 3 months.
In the 0–10 points visual analogue scale the mean
discomfort caused by 50 nM RTX instillation was
slightly higher, (2.0 � 2.5), than that caused by 10%
ethanol in saline (0.6 � 0.8). However this difference
was not statistically significant (p = 0.08). No other
side effects were reported after RTX instillation,
Table 1
Characteristics of the patients in the RTX and placebo group
RTX
Placebo
N
Gender
Age
FDC (ml)
MCC (ml)
Frequency
Incontinence
14
14
7M, 7F
8M, 6F
40 � 14
37 � 13
p = 0.6
143 � 95
115 � 58
p = 0.3
189 � 99
198 � 111
p = 0.8
9.5 � 2.5
10 � 2
p = 0.6
4 � 4.5
1.8 � 2.5
p = 0.2
55
namely no cases of autonomic dysreflexia, hematuria
or persistent infections occurred. In the RTX group,
mean frequency decreased from 9.5 � 2.5 times per
day to 7.6 � 2.1 times per day (p = 0.01). Daily incontinence also decreased significantly from 4.5 � 4.5
times per day to 1.6 � 1.4 times per day (p = 0.03).
In contrast, in the placebo group, both daily frequency
(10 � 2 before and 9.6 � 2.6 after, p = 0.6) and incontinence (1.8 � 2.5 before and 1.0 � 1.4 after, p = 0.3)
were not altered by 10% ethanol instillation. However,
due to the small number of cases that filled the micturition chart in each arm, the differences between mean
urinary frequency and incontinence at the end of the
study were not statistically significant.
4. Discussion
The present placebo-controlled randomized clinical
trial demonstrates that intravesical instillation of
50 nM RTX dissolved in 10% ethanol in saline
increases bladder volumes for FDC and for MCC in
NDO patients. The average increase of the latter
urodynamic parameter was particularly impressive,
125 ml per patient. Such increase may, theoretically,
contribute to decrease daily urinary frequency and
incontinence in NDO patients. If one estimates the
volume of urine produced hourly by one adult between
50 and 100 ml, the variation in MCC observed in this
study after RTX may offer to NDO patients an extra
period of 1–2 hours to safely accommodate urine. Such
effect was clearly suggested by the decrease of frequency and incontinence in the RTX but not in the
placebo group, despite the small number of patients
that were able to fill a micturition chart in both arms.
The results of our study corroborate the findings of
several non-controlled RTX trials previously carried
out in NDO patients. In our initial experience with 50–
100 nM, RTX was instilled in 21 patients, the majority
of whom had partial spinal cord lesions or mild to
moderate forms of multiple sclerosis. Urodynamic
improvement was found in 85% and clinical improvement in 80% of them [5,7]. More recently, Giannantoni
et al. [8] instilled 100 nM RTX in 12 patients with
spinal cord injuries at levels ranging between C5 and
T11 that were refractory to anticholinergics. A significant increase in the mean MCC and a clinical
improvement in 90% of the patients was reported
[8]. De Seze et al. [10] instilled 100 nM RTX in 21
NDO cases resistant to anticholinergics, 12 with spinal
cord injuries at a non-specified level and 9 with multiple sclerosis. Urodynamic improvement occurred in
60% and clinical improvement in 80% of them. Kuo [9]
56
653
instilled a much higher concentration of RTX, 10 mM,
in 20 NDO cases resistant to anti-cholinergic agents.
The majority of Kuo’s patients had high, complete
spinal cord lesions. Urodynamic improvement
occurred in 75% and clinical improvement in 60%
of them [9]. Thus, it is surprising why the placebocontrolled study of Kim et al. [11] did not report
significant differences in the urodynamic parameters
between the placebo and the RTX arms. At this
moment, the hypothesis forwarded by these authors
[11] to explain the lack of efficacy of RTX, the low
number of patients enrolled, is probably correct. The
study was designed in a dose-escalating placebo controlled form. Each dose-testing group had only 4
patients, a number eventually to low to surpass the
notorious variability in urodynamic findings among
NDO patients. In addition, as authors were unaware
of RTX absorption by plastics, the amount of RTX
actually delivered to patients might have been erratic
[11].
The ideal patient for RTX treatment is still undetermined. However, like with anti-muscarinic drugs, it
might be expected that patients with partial lesions at
low spinal cord levels and multiple sclerosis patients
might respond better than patients with complete cervical cord transections. In addition, when selecting a
patient to RTX instillation one should be aware that all
the studies conducted up to now showed that desensitization does not decrease maximal detrusor pressure
[7–9]. This is not surprising since RTX does not
desensitize parasympathetic bladder nerve fibers
[14], nor bind muscarinic receptors essential to bladder
smooth muscle contraction [15]. Thus, in patients with
NDO and high intravesical pressure at risk of upper
urinary tract deterioration, RTX alone will not confer
adequate renal protection. If anti-cholinergic drugs are
not effective to decrease detrusor pressure, these type
of patients should be better managed by botulinum
toxin [16,17]. The bladder injections of this neurotoxin, in contrast with RTX, induces a long-lasting
detrusor paralysis that convert the overactive bladder
into a flaccid reservoir which can then be emptied at
regular intervals by clean intermittent catheterization
[16,17].
TRPV1 receptors that mediate the effect of intravesical RTX in NDO patients are most probably
located in the thin sensory fibers that form dense
networks under or between urothelial cells and line
smooth muscle detrusor cells [18,19]. In fact, the
density of TRPV1 immunoreactive (IR) fibers is
increased in NDO cases and is brought back to normal
in patients that exhibited good clinical response to RTX
instillation [12]. It is still unclear why the bladders of
654
NDO patients exhibit TRPV1 hyper-innervation.
Nevertheless, as TRPV1 sensory nerves are dependent
upon the trophic action of nerve growth factor (NGF),
the well-known increase of this neurotrophin in the
bladder after spinal cord transection [20,21] may promote their sprouting. On the other hand, as RTX
decreases NGF in bladder sensory nerves [22], it is
possible that intravesical instillation of this compound
counteracts the trophic effect of the NGF excess and
contributes to restore the normal density of TRPV1-IR
bladder nerves.
TRPV1 was already shown to occur in urothelial
cells of rodents [23] and humans [24,25]. In rodents,
TRPV1 excitation was shown to increase ATP release
from urothelial cells [23], a neurotransmitter that excite
sub-urothelial P2X3 sensory fibers. Although this
fibers were shown to be essential to initiate the micturition reflex in rodents [26], a similar mechanism has
not yet been demonstrated in humans. In fact, TRPV1IR was demonstrated in human urothelial cells [24,25],
but the functional meaning of such finding was not yet
made clear. Thus, the possible contribution of TRPV1
receptors occurring in urothelial cells to the final
clinical effect of intravesical RTX in NDO patients
requires further investigation.
Like in the previous non-controlled studies, in the
present work RTX was applied into the bladder dissolved in 10% ethanol in saline in spite of the fact that
the compound is soluble in pure saline. The objective
underlying the use of ethanol was to dissolve the mucin
coat that shields the most superficial urothelial cells
and to increase RTX penetration into the bladder wall.
However, in a recent study, ethanol was also shown to
excite TRPV1 and to increase its response to capsaicin
[27]. Thus, in addition to increase RTX penetration,
ethanol might also have enhanced the TRPV1 response
to RTX. Such effect of ethanol on TRPV1 could argue
against the instillation of 10% ethanol in the placebo
group, regardless of being the vehicle solution for RTX
preparation. However, a desensitizing effect of ethanol
on the TRPV1 receptor was not demonstrated [27]. If
such effect will be demonstrated in the future it must be
very weak since no urodynamic or clinical changes
were found in the placebo group of our study.
In conclusion, this placebo controlled randomized
clinical trial shows that intravesical RTX increases
bladder capacity in spinal NDO patients. As a consequence of this effect, an improvement of urinary
symptoms might be legitimately expected. To further
expand RTX as a therapeutic option in NDO patients it
is now essential to find stable formulations ready to
administer in medical centres in which RTX manipulation, essential to instil fresh prepared solutions, is
not possible. In addition, it would facilitate placebocontrolled studies to determine the individual susceptibility of neurologic diseases to RTX.
References
[1] Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and
mechanisms. Pharmacol Rev 1999;51:159–212.
[2] Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD,
Julius D. The capsaicin receptor: a heat-activated ion channel in the
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[3] Cruz F. Vanilloid receptor and detrusor instability. Urology 2002;
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[4] Avelino A, Cruz F, Coimbra A. Intravesical resiniferatoxin desensitizes rat bladder sensory fiberswithout causing intense noxious excitation. A c-fos study. Eur J Pharmacol 1999;378:17–22.
[5] Cruz F, Guimarães M, Silva C, Reis M. Supression of bladder
hyperreflexia by intravesical resiniferatoxin. Lancet 1997;350:640–1.
[6] Lazzeri M, Beneforti P, Turini D. Urodynamic effects of intravesical
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[10] de Sèze M, Wiart L, de Sèze MP, Soyeur L, Dosque JP, Blajezewski S,
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et al. Intravesical resiniferatoxin for refractory detrusor hyperreflexia:
a multicenter, blinded, randomized, placebo-controlled trial. J Spinal
Cord Med 2003;26(4):358–63.
[12] Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A,
Jacques TS, et al. Parallel changes in bladder suburothelial
vaniloid receptor TRPV1 and pan-neuronal marker PGP9.5
immunoreactivity in patients with neurogenic detrusor overactivity
after intravesical resiniferatoxin treatment. BJU Int 2004;93(6):
770–6.
[13] Silva C, Cruz F. Intravesical pharmacological treatment. In: Corcos J,
Schick E, editors. Neurogenic bladders – adults and children. London:
Martin Dunitz Ldt; 2004. p. 507–17.
[14] Avelino A, Cruz F. Peptide immunoreactivity and ultrastructure of rat
urinary bladder nerve fibers after topical desensitization by capsaicin
or resiniferatoxin. Autonomic Neuroscience Basic and clinical 2000;
86:37–46.
[15] Chapple CR, Yamanishi T, Chess-Williams R. Muscarinic receptor
subtype and management of the overactive bladder. Urology 2002;
60(5):82–8.
[16] Reitz A, Stohrer M, Kramer G, Del Popolo G, Chartier-Kastler E,
Pannek J, et al. European experience of 200 cases treated with
botulinum-A toxin injections into the detrusor muscle for urinary
incontinence due to neurogenic detrusor overactivity. Eur Urol 2004;
45:510–5.
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[17] Giannantoni A, Di Stasi SM, Stephen RL, Bini V, Constantini E,
Porena M. Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic detrusor overactivity: a prospective randomized
study. J Urol 2004;172(1):240–3.
[18] Yiangou Y, Facer P, Ford A, Brady C, Wiseman O, Fowler CJ, et al.
Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human
urinary bladder. BJU Int 2001;87:774–9.
[19] Avelino A, Cruz C, Nagy I, Cruz F. Vanilloid receptor type 1
expression in the rat urinary tract. Neuroscience 2002;109:787–98.
[20] Seki S, Sasaki K, Fraser MO, Igawa Y, Nishizawa O, Chancellor MB,
et al. Immunoneutralization of nerve growth factor in lumbosacral
spinal cord reduces bladder hyperreflexia in spinal cord injured rats. J
Urol 2002;168:2269–74.
[21] Vizzard MA. Changes in urinary bladder neurotrophic factor mRNA
and NGF protein following urinary bladder dysfunction. Exp Neurol
2000;161:273–84.
[22] Avelino A, Cruz C, Cruz F. Nerve growth factor regulates galanin and
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[23] Birder LA, Kanai AJ, de Groat WC, Kiss S, Nealen ML, Burke NE,
et al. Vanilloid receptor expression suggestsa sensory role for urinary
bladder epithelial cells. Proc Natl Acad Sci USA 2001;98:13396–401.
[24] Lazzeri M, Vannucchi MG, Zardo C, Spinelli M, Beneforti P, Turini D,
et al. Immunohistochemical evidence of vanilloid receptor 1 in normal
human urinary bladder. Eur Urol 2004;46(6):792–8.
[25] Apostolidis A, Brady CM, Yiangou Y, Davis J, Fowler CJ, Anand P.
Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin. Urology 2005;65(2):
400–5.
[26] Cockayne DA, Hamilton SG, Zhu OM, Dunn PM, Zhong Y, Novakovic S, et al. Urinary bladder hyporeflexia and reduced pain-related
behaviour in P2X3-deficient mice. Nature 2000;407(6807):1011–115.
[27] Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi
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vanilloid receptor-1. Nat Neurosci 2002;5(6):546–51.
PUBLICAÇÃO III
The effect of intravesical resiniferatoxin in patients with idiopathic
detrusor instability suggests that involuntary detrusor contractions are triggered by C-fiber input
59
0022-5347/02/1682-0575/0
THE JOURNAL OF UROLOGY®
Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 168, 575–579, August 2002
Printed in U.S.A.
THE EFFECT OF INTRAVESICAL RESINIFERATOXIN IN PATIENTS
WITH IDIOPATHIC DETRUSOR INSTABILITY SUGGESTS THAT
INVOLUNTARY DETRUSOR CONTRACTIONS ARE TRIGGERED BY
C-FIBER INPUT
CARLOS SILVA,* MARIA JOSÉ RIBEIRO
AND
FRANCISCO CRUZ
From the Department of Urology, Hospital São João and Institute of Histology and Embryology, Faculty of Medicine of Porto and
Institute of Biologia Molecular Celular, University of Porto, Porto, Portugal
ABSTRACT
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in
patients with idiopathic detrusor instability.
Materials and Methods: Filling cystometry and a voiding chart were done in 13 patients with
idiopathic detrusor instability. The first detrusor contraction, maximal cystometric capacity,
daily frequency and the number of episodes of urinary incontinence were determined. A 50 nM.
solution of resiniferatoxin, a specific C-fiber neurotoxin, was then instilled in the bladder for 30
minutes. Patients were reevaluated 30 and 90 days later.
Results: Resiniferatoxin instillation delayed or suppressed involuntary detrusor contractions
during filling cystometry. The mean first detrusor contraction plus or minus standard deviation
increased from 170 � 109 ml. at baseline to 440 � 130 ml. (p � 0.0001) at 30 days and to 391 �
165 ml. (p � 0.008) at 90 days. Mean maximal cystometric capacity increased from 291 � 160 to
472 � 139 ml. (p � 0.01) at 30 days and to 413 � 153 ml. (p � 0.1) at 90 days. The mean number
of episodes of urinary incontinence daily decreased from 4.3 � 2.7 to 0.9 � 2.7 (p � 0.001) at 30
days and to 0.7 � 0.9 (p � 0.009) at 90 days. Mean frequency daily also decreased from 12 � 3.2
to 9.7 � 3.2 (p � 0.003) and to 9.9 � 3.5 (p � 0.001) times at the same time points, respectively.
Conclusions: C-fiber input seems to have an important role in the generation of involuntary
detrusor contractions and lower urinary tract symptoms in patients with idiopathic detrusor
instability. Substances that block C-fiber input may represent a new strategy for treating this
bladder dysfunction.
KEY WORDS: bladder, urodynamics, nerve fibers, urinary incontinence
Detrusor instability, which is a leading cause of lower
urinary tract symptoms, is characterized on urodynamics by
involuntary detrusor contractions during bladder filling in
otherwise normal individuals.1 Despite considerable efforts
to clarify the origin of such abnormal detrusor activity the
pathological mechanisms underlying detrusor instability remain unknown. Evidence to date is balanced between a neurogenic2, 3 and a myogenic4 cause, the former implicating
enhanced bladder C-fiber sensory input2 or the emergence of
an abnormal atropine resistant parasympathetic transmission.3 The lack of a consistent explanation of involuntary
detrusor contractions may be the reason why first line therapy to decrease lower urinary tract symptoms in these patients remains essentially limited to anti-muscarinic drugs
despite the intense side effects evoked during prolonged administration.5
The participation of bladder C-fibers in involuntary detrusor contractions was first noted in spinal cord injured patients. Spinal cord lesions interrupt the neuronal pathways
connecting the sacral spinal cord and the pontine micturition
center, inactivating the supraspinal reflex that controls voiding in normal adults.2 As a result, voiding is left under the
control of an involuntary sacral reflex that is usually inactive
in normal adults.2 This change is accompanied by a change in
the sensory input that initiates reflex activity. The supraspiAccepted for publication March 22, 2002.
Supported by the Portuguese government through Fundação
Ciência Tecnologia Project POCTI/FEDER32466/NSE/00.
* Current address: Department of Urology, Hospital São Mareos,
Braga, Portugal.
nal reflex is exclusively stimulated by sensory input conveyed in thin myelinated A�-fibers running in the pelvic
nerves, whereas the sacral reflex only depends on that conveyed
by unmyelinated C-fibers.2 This was the rationale for the therapeutic application of intravesical capsaicin6 and resiniferatoxin7 in patients with spinal detrusor hyperreflexia. Due to
their ability to blockade specifically C-fiber input these substances attenuate or suppress involuntary detrusor activity.
Lately evidence has also suggested that involuntary detrusor contractions in patients with detrusor instability
also depend on a C-fiber initiated micturition reflex. Intravesical lidocaine decreased involuntary contractions in patients with idiopathic detrusor instability.8 Because lidocaine more effectively anesthetizes C-fibers than A�-fibers,
the contribution of a C-fiber input to abnormal detrusor
activity was strongly suggested.8 The high density of
C-fiber staining for substance P and calcitonin generelated peptide in the bladder mucosa of patients with
idiopathic detrusor instability may provide a rational explanation for enhanced bladder C-fiber input in this disease.9 The high incidence of cold evoked detrusor contraction, a C-fiber mediated micturion reflex not involved in
normal voiding, in patients with detrusor instability and
bladder outlet obstruction pointed in the same direction.10
Animal models of chronic bladder outlet obstruction also
implied the participation of C-fiber input in the origin of
detrusor instability.11 Gradual filling of overactive but not
of normal bladders caused a premature C-fiber initiated
parasympathetic efferent discharge in the pelvic nerve
575
61
576
EFFECT OF RESINIFERATOXIN ON DETRUSOR INSTABILITY
that preceded the normal A�-dependent outflow.11 Interestingly the sprouting of bladder C-fiber terminals around
sacral parasympathetic motor neurons innervating the
bladder also occurred in these animals.11
In the current study we evaluated the hypothesis that a
micturition reflex triggered by bladder C-fiber input underlies involuntary detrusor contractions in patients with idiopathic detrusor instability. To test it we induced specific
blockade of bladder C-fiber input with intravesical resiniferatoxin. Concentrations were used that abolished involuntary detrusor contractions in patients with spinal detrusor
hyperreflexia7 but had no effect on bladder capacity in normal subjects.12 We investigate whether an intravesical resiniferatoxin solution delays or abolishes involuntary detrusor
contractions and whether intravesical resiniferatoxin improves lower urinary tract symptoms. Preliminary data were
presented in abstract form.13
MATERIALS AND METHODS
Two men and 11 women 24 to 70 years old (mean age 50)
with more than a 1-year history of lower urinary tract symptoms and urodynamically proved idiopathic detrusor instability provided written informed consent approved by the
ethics committee at our institution to participate in this
study (see table). Clinical history, physical examination including neurological assessment and ultrasound of the whole
urinary tract were done in all patients before entering the
study to diagnose concomitant neurological or bladder disease that could influence bladder function. In addition, patients with cardiovascular, renal, hepatic, psychiatric or malignant disorders and pregnancy patients were excluded from
analysis. Hematological or biochemical blood tests were normal in the 13 patients and all had negative microbiological
urinary investigations. Patient 4, who was on anticholinergics at a dose that could influence bladder performance (5
mg. oxybutinin 3 times daily) was included in the study
because the daily oxybutinin dose remained unchanged
throughout the study.
Filling cystometry was performed in all patients with a
Dantec instrument (Dantec, Skovlunde, Denmark). A 2-way
8Fr catheter was inserted in the urethra for saline infusion
at 50 ml. per minute and simultaneous recording of bladder
pressure. Volume at the first detrusor contraction above 15
cm. water and at maximal cystometric capacity was determined (see table). In addition, all patients completed a voiding chart, in which voiding and incontinence episodes were
recorded for at least 3 consecutive days.
A 10 mM. stock solution of resiniferatoxin in pure ethanol
was prepared and maintained in the dark at 4C in a glass
container. For each instillation 100 ml. 50 nM. solution of
10% ethanol in saline as vehicle was prepared by adding 0.5
ml. stock solution to 90 ml. saline and 9.5 ml. pure ethanol.
This solution was prepared immediately before each instillation to decrease the contact of resiniferatoxin with plastic
containers.
Patients underwent clean catheterization with a 3-way
20Fr indwelling Foley catheter to allow resiniferatoxin infusion and simultaneous bladder pressure recording. The bladder was emptied. A balloon was inflated to 10 ml. and maintained with gentle pulling against the bladder neck to
decrease resiniferatoxin solution leakage into the urethra.
Bladder instillation of 100 ml. 50 nM. resiniferatoxin solution
was then done for 30 minutes. Vital signs were recorded
immediately before, during and at the end of instillation. In
addition, patients were asked to estimate the discomfort
experienced during resiniferatoxin instillation on a visual
analog scale of 0 —no discomfort to 10 —intense pain requiring analgesic treatment or bladder emptying. At the end
resiniferatoxin was evacuated, the bladder was rinsed with
normal saline, the Foley catheter was removed and the patients were discharged home.
All patients were followed at 30 days after treatment. At
this point they were clinically reevaluated, a voiding chart
was obtained and filing cystometry was repeated. Patients 1
to 8 and 12 agreed to complete a similar protocol at 90 days.
Patient 11 agreed to complete a voiding chart at this date but
refused urodynamic testing. Prophylactic antibiotics were
administered after resiniferatoxin instillation and after each
urodynamic study.
The table shows first detrusor contraction, maximal cystometric capacity, the number of incontinence episodes daily
and daily frequency in each patient at baseline, and at 30 and
90 days. The number of incontinence episodes and frequency
were determined by counting those reported in the voiding
chart and dividing the sum by the number of days. In addition, mean volume at the first detrusor contraction, mean
maximal cystometric capacity, mean daily frequency, and the
mean number of incontinence episodes at baseline, and at 30
and 90 days plus or minus standard deviation were calculated and compared by the 2-tailed paired t test for means.
RESULTS
General considerations. Before resiniferatoxin instillation
the mean volume at the first detrusor contraction and mean
maximal cystometric capacity were 170 � 109 and 291 � 160
ml., respectively. Except for patient 2 all reported episodes of
urinary incontinence (mean 4.3 � 2.7 episodes daily at baseline) (see table). Mean urinary frequency at the same time
point was 12 � 3.2 times daily.
Generally resiniferatoxin evoked a series of phasic detrusor contractions that started shortly after the beginning of
instillation and remained throughout it, although it became
gradually more spaced toward the end. During phasic contractions patients noticed the urge sensation to urinate,
Urodynamic and clinical details on 13 patients at baseline, and 30 and 90 days after 50 nm. resiniferatoxin
Pt.—Age—Sex
No.
1 —44 —F
2 —49 —M
3 —30 —F
4 —70 —M
5 —24 —F
6 —58 —F
7 —64 —F
8 —42 —F
9 —55 —F
10 —76 —F
11 —52 —F
12 —64 —F
13 —28 —F
62
Vol. at First Detrusor
Contraction (ml.)
Max. Cystometric Capacity
(ml.)
Daily Urinary Frequency
Daily Urinary Incontinence
Episodes
0 Days
30 Days
90 Days
0 Days
30 Days
90 Days
0 Days
30 Days
90 Days
0 Days
30 Days
90 Days
70
300
100
150
333
135
37
65
44
194
356
225
203
295
420
364
460
492
483
534
476
525
251
326
351
750
184
394
563
618
364
528
439
283
—
—
—
146
—
184
350
654
170
350
173
405
141
76
238
506
279
273
297
422
364
460
664
556
534
476
525
262
484
351
750
195
483
563
620
364
538
443
283
—
—
—
231
—
14
15
12
11
10
9.3
18
13
11
11
9
17
7
11
9
14
8
8
8
15
6
9
9
8
16
6
12
10
7
8
8
8
16
6
—
—
8
16
—
7.5
—
8
3
1.5
3
4
7.8
1.8
8
0.9
2.3
3.7
2.5
—
0
0
0.8
0.7
0.6
0
1.2
2
0.4
2.3
0.7
1.25
—
0
0
0.6
1.5
0.4
0
—
—
0.1
2.5
—
577
FIG. 1. Filling cystometry in patient 6 at baseline (A) and 30 days after 50 nM. resiniferatoxin instillation (B). Volume at first detrusor
contraction increased from 135 to 483 ml. Pdet, detrusor pressure. Pves, vesical pressure. Pabd, abdominal pressure. Vinfus, infusion volume.
which subsided as soon as detrusor pressure returned to
normal. In addition, patients experienced iching or a warm
sensation in the lower abdomen during the initial minutes of
resiniferatoxin administration, which waned thereafter.
Patients did not complain of severe discomfort or overt
pain during resiniferatoxin instillation and they did not ask
for any type of analgesic medication, although the whole
procedure was performed without local anesthesia. Average
discomfort score on the visual analog scale was 3, the minimum score was 0 in 3 patients and the maximum was 8 in 1.
Blood pressure and heart rate remained stable during resiniferatoxin instillation in all cases.
Urodynamic and clinical findings. Resiniferatoxin delayed
or suppressed involuntary detrusor contractions during filling cystometry (fig. 1). Consequently the volume of bladder
filling at which the first detrusor contraction occurred was
increased in 12 patients (92%) at 30 days and was still above
baseline in 8 of the 9 (88%) who underwent cystometry at
that date (see table). Mean volume at the first detrusor
contraction was 440 � 130 ml. (p � 0.0001) at 30 days and
391 � 165 ml. (p � 0.008) at 90 days (fig. 2). Maximal
cystometric capacity was also increased in 11 patients at 30
days but it was almost at baseline in 5 of the 9 who underwent cystometry at 90 days (see table). Mean maximal cystometric capacity was 472 � 139 ml. (p � 0.01) at 30 days and
413 � 153 ml. (p � 0.1) at 90 days (fig. 2).
Intravesical instillation of resiniferatoxin improved urinary incontinence in 11 (91%) patients of the 12 (91%) with
incontinence. In 3 cases (25%) complete continence was
achieved, in 6 (50%) the average number of incontinence
episodes daily decreased more than 50% and in 2 (17%) this
improvement did not achieve 50% (see table). The mean
number of incontinence episodes daily was 0.9 � 2.7 (p �
0.001) at 30 days and 0.7 � 0.9 (p � 0.009) at 90 days (fig. 3).
Mean urinary frequency also decreased. It was 9.7 � 3.2
times daily at 30 days (p � 0.003) and 9.9 � 3.5 at 90 days
(p � 0.001, fig. 3).
root ganglion neurons that give rise to type C primary afferent fibers.14 –16 Accordingly in bladder tissue vanilloid receptor type 1 immunohystochemical staining was confined to
unmyelinated nerve fibers.17, 18 Therefore, the principal finding of the current study (the increment of bladder volume at
the first detrusor contraction) should be attributable to the
effect of resiniferatoxin on vanilloid receptor type 1 receptors
in bladder C-fibers.
FIG. 2. Mean volume at first detrusor contraction (FDC) and maximal cystometric capacity (MCC) at baseline, and 30 and 90 days
after 50 nM. resiniferatoxin.
DISCUSSION
Resiniferatoxin is an extract of the dry latex of Euphorbia
resinifera, a cactus-like plant that is abundant in northern
Africa and shares with capsaicin a homovanillic ring. Previous studies have shown that resiniferatoxin is a strong agonist of vanilloid receptor type 1, an ion channel present in
rats14, 15 and humans.16 Using in situ hybridization techniques vanilloid receptor type 1 gene expression in peripheral tissues was shown to be restricted to the small dorsal
FIG. 3. Mean daily frequency and number of episodes of urinary
incontinence at baseline, and 30 and 90 days after 50 nM. resiniferatoxin.
63
578
Resiniferatoxin inactivates C-fibers after initial and brief
excitation.15 After resiniferatoxin binding vanilloid receptor
type 1 channels open, allowing a massive inflow of calcium
and other ions into C-fibers. Ion overload may generate action potentials, and the release of substance P and calcitonin
gene-related peptide from peripheral nerve endings,15 which
contribute to the painful or itch sensations and detrusor
contractions felt by patients during resiniferatoxin instillation.7 A period of decreased bioelectrical activity of C-fibers
usually known as desensitization then succeeds.14, 15 It has
not yet been determined whether desensitization of bladder
C-fibers is a functional state18 or if it involves the degeneration of nerve terminals in the bladder wall.6 However, whatever the mechanisms desensitization caused by resiniferatoxin decreases sensory input conveyed in bladder C-fibers
and decreases the number of spinal neurons that become
excited by bladder stimuli.19 Therefore, the potential of intravesical resiniferatoxin to suppress involuntary detrusor
contractions in patients with idiopathic detrusor instability
strongly suggests that the C-fiber rather than the A�-fiber
input triggers the abnormal detrusor activity associated with
this bladder dysfunction.
In normal adults C-fiber input does not have a significant
role in voiding control.2, 12 Desensitization of bladder C-fibers
in normal adult cats2 and humans12 does not change filling
cystometry or bladder capacity. Therefore, understanding
why C-fiber input becomes preponderant in the voiding control of patients with idiopathic detrusor instability may contribute to elucidating the physiopathology of this disorder.
The emergence of a strong C-fiber micturition reflex was first
identified in chronic spinal cord injured mammals, including
humans.2, 6 In this case the preponderance of the C-fiber
reflex was explained by abolition of the A�-fiber reflex caused
by interruption of the neuronal pathways connecting the
sacral spinal cord to the pontine micturition center.2 However, this mechanism was unlikely in our patients, who were
neurologically normal. Another possibility may be the increase in C-fiber input that reaches the spinal cord after
C-fiber sensitization by neurotrophic factors produced in excess in the bladder, namely nerve growth factor (NGF).11 In
fact, smooth muscle of unstable obstructed bladders has been
shown to produce high amounts of NGF.11 Interestingly inactivation of this neurotrophic factor could abolish bladder
instability.11 Therefore, studies designed to measure NGF
and other trophic factors in the bladder of patients with
idiopathic and other types of detrusor instability may be
worthwhile in the future.
Although the current study suggests the involvement of
bladder C-fibers in idiopathic detrusor instability, it cannot
be ignored that other abnormalities have already been identified in patients with this disease. Recently it was shown
that the density of a ligand-gated purinergic receptor subtype
is increased in the detrusor muscle of female patients with
idiopathic detrusor instability, which could explain the emergence of atropine resistant, parasympathetic induced detrusor contractions.3 On the other hand, spontaneous tetanic
contractions have been identified in detrusor strips from
patients with detrusor instability, a finding that presupposes
facilitated electrical coupling of smooth muscle cells.4 Such a
finding that supports a myogenic origin of the disease4 was
tentatively explained by an increased number of ultra close
junctions linking myocites.20 However, these data and our
findings are not mutually exclusive, but rather may be complementary. Bladder C-fibers are numerous in the detrusor
layer, where they lie in intimate contact with smooth muscle
cells.18 Thus, any spontaneous activity of the muscle cells is
prone to excite C-fibers, which eventually become more excitable by an excess of neurotrophic factors. This situation
can generate a parasympathetic outflow leading to the contraction of detrusor smooth muscle cells, which is eventually
facilitated by the surplus of ligand-gated purinergic receptor
64
subtypes3 and by the abnormal electrical coupling provided
by the ultra close junctions.20 By inactivating C-fibers resiniferatoxin would interrupt this circuit.
Another important finding in the current study was the
long lasting decrease in lower urinary tract symptoms,
namely urinary incontinence, reported by our patients after
intravesical resiniferatoxin. To our knowledge the reason for
the prolonged effect of resiniferatoxin is still unknown but it
may involve long lasting down-regulation of C-fiber receptors
and neuropeptides, such as substance P or calcitonin generelated peptide,18 and even C-fiber loss.6 Whatever the mechanisms involved, our clinical findings may expand the indications of human bladder desensitization, which has been
limited to date to detrusor hyperreflexia. In this condition
intravesical capsaicin6 or resiniferatoxin7 has been assayed
with the latter substance preferable due to decreased pungency7 and lack of toxicity to the human bladder mucosa.21
However, before recommending intravesical resiniferatoxin
for treating idiopathic detrusor instability it may be prudent
to wait for a large, placebo controlled trial.
CONCLUSIONS
This study suggests that involuntary detrusor contractions
are triggered by bladder sensory input conveyed in C-fibers.
These primary afferents may be a new target for the medical
treatment of idiopathic detrusor instability.
Dr. Antonio Avelino prepared resiniferatoxin solutions and
Prof. Antonio Coimbra critically read the manuscript.
REFERENCES
1. Abrams, P., Blaivas, J. G., Stanton, S. L. and Andersen, J. T.:
Standardisation of terminology of lower urinary tract function.
Neurourol Urodynam, 7: 403, 1988
2. de Groat, W. C.: A neurologic basis for the overactive bladder.
Urology, suppl., 50: 36, 1997
3. O’Reilly, B., Kosaka, A. H., Knight, G. F., Chang, T. K., Ford,
A. P., Rymer, J. M. et al: P2X receptors and their role in female
idiopathic detrusor instability. J Urol, 167: 157, 2002
4. Brading, A. F.: A myogenic basis for the overactive bladder.
5. Chapple, C. R.: Muscarinic receptor antagonists in the treatment
of overactive bladder. Urology, suppl., 55: 33, 2000
6. Fowler, C. J.: Intravesical treatment of overactive bladder.
7. Silva, C., Rio, M. E. and Cruz, F.: Desensitization of bladder
sensory fibres by intravesical resiniferatoxin, a capsaicin analogue: long-term results for the treatment of detrusor hyperreflexia. Eur Urol, 38: 444, 2000
8. Yokoyama, O., Komatsu, K., Kodama, K., Yotsuyanagi, S.,
Niikura, S. and Namiki, M.: Diagnostic value of intravesical
lidocaine for overactive bladder. J Urol, 164: 340, 2000
9. Chai, T. C., Gray, M. L. and Steers, W.: The incidence of a
positive ice water test in bladder outlet obstructed patients:
evidence for bladder neural plasticity. J Urol, 160: 34, 1998
10. Smet, P. J., Moore, K. H. and Jonavicius, J.: Distribution and
colocalization of calcitonin gene-related peptide, tachykinins,
and vasoactive intestinal peptide in normal and idiopathic
unstable human urinary bladder. Lab Invest, 77: 37, 1997
11. Steers, W. D.: Rat overview and innervation. Neurourol Urodyn,
13: 97, 1994
12. Lazzeri, M., Beneforti, P. and Turini, D.: Urodynamic effects of
intravesical resiniferatoxin in humans: preliminary results in
stable and unstable detrusor. J Urol, 158: 2093, 1997
13. Cruz, F. and Silva, C.: Can desensitization of bladder sensory
fibers relieve urinary symptoms in patients with detrusor
instability? Preliminary report with intravesical resiniferatoxin. Neurourol Urodyn, 19: 379, 2000
14. Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A.,
Levine, J. D. and Julius, D.: The capsaicin receptor: a heatactivated ion channel in the pain pathway. Nature, 389: 816,
1997
15. Szallasi, A. and Blumberg, P. M.: Vanilloid (Capsaicin) receptors
and mechanisms. Pharmacol Rev, 51: 159, 1999
16. Hayes, P., Meadows, H. J., Gunthorpe, M. J., Harries, M. H.,
Duckworth, D. M., Cairns, W. et al: Cloning and functional
expression of a human orthologue of rat vanilloid receptor-1.
Pain, 88: 205, 2000
17. Yiangou, Y., Facer, P., Ford, A., Brady, C., Wiseman, O., Fowler,
C. J., et al: Capsaicin receptor VR1 and ATP-gated ion channel
P2X3 in human urinary bladder. BJU Int, 87: 774, 2001
18. Avelino, A., Cruz, C., Nagy, I., Cruz, F.: Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience, 109: 787, 2002
19. Avelino, A., Cruz, F. and Coimbra, A.: Intravesical resiniferatoxin
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desensitizes rat bladder sensory fibres without causing intense
noxious excitation. A c-fos study. Eur J Pharmacol, 378: 17, 1999
20. Tse, V., Wills, E., Szonyi, G. and Khadra, M. H.: The application
of ultrastructural studies in the diagnosis of bladder dysfunction in a clinical setting. J Urol, 163: 535, 2000
21. Silva, C., Avelino, A., Souto-Moura, C. and Cruz, F.: A light- and
electron-microscope histopathological study of the human
bladder mucosa after intravesical resiniferatoxin application.
BJU Int, 88: 355, 2001
65
PUBLICAÇÃO IV
Bladder sensory desensitization decreases urinary urgency
67
BMC Urology
BioMed Central
Open Access
Research article
Bladder sensory desensitization decreases urinary urgency
Carlos Silva1, João Silva1, Helder Castro1, Frederico Reis1, Paulo Dinis1,
António Avelino2 and Francisco Cruz*1,2
Address: 1Department of Urology, Hospital S. João and Faculty of Medicine of Porto, Porto, Portugal and 2Department of Histology and
Embryology, Faculty of Medicine of Porto and IBMC of the University of Porto, Porto, Portugal
Email: Carlos Silva - [email protected]; João Silva - [email protected]; Helder Castro - [email protected];
Frederico Reis - [email protected]; Paulo Dinis - [email protected]; António Avelino - [email protected];
Francisco Cruz* - [email protected]
* Corresponding author
Published: 11 June 2007
BMC Urology 2007, 7:9
doi:10.1186/1471-2490-7-9
Received: 1 April 2007
Accepted: 11 June 2007
This article is available from: http://www.biomedcentral.com/1471-2490/7/9
© 2007 Silva et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: Bladder desensitization has been investigated as an alternative treatment for refractory detrusor
overactivity. Most open and controlled clinical trials conducted with intravesical RTX showed that desensitization
delays the appearance of involuntary detrusor contractions during bladder filling and decreases the number of
episodes of urgency incontinence.
Urgency is being recognised as the fundamental symptom of overactive bladder (OAB), a symptomatic complex
which recent epidemiological studies have shown to affect more than 10% of the Western population. As antimuscarinic drugs, the first line treatment for OAB, are far from being able to fully control urgency, the
opportunity to test other therapeutic approaches is created. The present work was, therefore, designed as an
exploratory investigation to evaluate the effect of bladder desensitization on urinary urgency.
Methods: Twenty-three OAB patients with refractory urgency entered, after given informed consent, a 30 days
run-in period in which medications influencing the bladder function were interrupted. At the end of this period
patients filled a seven-day voiding chart where they scored, using a 0–4 scale, the bladder sensations felt before
each voiding. Then, patients were instilled with 100 ml of 10% ethanol in saline (vehicle solution) and 30 days later
a second seven-day voiding chart was collected. Finally, patients were instilled with 100 ml of 50 nM RTX in 10%
ethanol in saline. At 1 and 3 months additional voiding charts were collected.
At the end of the vehicle and 3 months period patients were asked to give their subjective impression about the
outcome of the treatment and about the willingness to repeat the previous instillation.
Results: At the end of the run-in period the mean number of episodes of urgency per week was 71 ± 12 (mean
± SEM). After vehicle instillation, the mean number of episodes of urgency was 56 ± 11, but only 4 patients (17%)
considered that their urinary condition had improved enough to repeat the treatment. At 1 and 3 months after
RTX the number of episodes of urgency decreased to 39 ± 9 (p = 0.002) and 37 ± 6 (p = 0.02), respectively (p
indicates statistical differences against vehicle). The percentage of patients with subjective improvement after RTX
and willing to repeat the instillation at a later occasion was 69%.
Conclusion: In OAB patients with refractory urgency bladder desensitization should be further investigated as
an alternative to the standard management. Additionally, the specific effect of RTX on TRPV1 receptors suggests
that urothelium and sub-urothelial C-fibers play an important role to the generation of urgency sensation.
Page 1 of 6
(page number not for citation purposes)
69
Background
Resiniferatoxin (RTX), the ultrapotent capsaicin analogue,
was shown to desensitize TRPV1, a non-specific calcium
channel, which is abundantly expressed in neuronal and
non-neuronal bladder structures, including type C-sensory fibers [1], urothelial cells [2,3] and possibly interstitial cells [4]. Following desensitization, TRPV1 becomes
less responsive to further activation by RTX or similar
compounds and its expression is strongly reduced, both in
the urothelium [3] and in sensory nerve fibers [5]. In addition, experimental studies have shown that desensitization reduces bladder response to distension, as shown by
the increase of the volume threshold to reflex voiding [6]
and decreased activation of sensory driven spinal cord
genes as c-fos [7].
Urgency is being recognised as the fundamental symptom
of overactive bladder (OAB), a symptomatic complex
which recent epidemiological studies have shown to affect
more than 10% of the Western population [8]. Unfortunately, anti-muscarinic drugs, the first line treatment for
OAB, although providing some improvement, are far
from being able to fully control this bothersome lower
urinary tract symptom [9]. This creates the opportunity to
test other therapies that, if promising, can be offered as
second line options.
Bladder desensitization has been exploited in the last decade as an alternative treatment for refractory detrusor
overactivity [10,11]. Most open [12-15] and controlled
[16-18] clinical trials conducted so far showed that the
number of episodes of urgency incontinence in patients
with detrusor overactivity was decreased by intravesical
RTX at the same time at which the compound delayed the
appearance of involuntary detrusor contractions during
bladder filling and increased bladder capacity. Furthermore, in a controlled study, the global urinary condition
improved in 62% of detrusor overactivity (DO) patients
treated with intravesical RTX but only in 21% of those that
received the vehicle solution alone [18]. The effect of RTX
on urgency was also reported in OAB patients without
DO. In a small open label study RTX showed a trend to
decrease the number of episodes of urinary urgency [19].
The present work was designed to further explore the
effect of bladder desensitization on urinary urgency. As a
primary objective it was investigated if intravesical RTX
could reduce the number of episodes of urinary urgency.
As a secondary objective the effect of bladder desensitization on urgency incontinence and urinary frequency was
also analysed. This study was presented in part in abstract
form [20].
http://www.biomedcentral.com/1471-2490/7/9
Methods
Twenty-three patients (7 males and 16 females with a
mean age of 50 years, range 21–77) with OAB refractory
to antimuscarinics were enrolled during 2005. All patients
had at least 7 urgency episodes per week. Six patients had
a neurogenic cause for OAB symptoms whereas the
remaining patients were idiopathic. All gave written
informed consent approved by the Ethics Committee of
our Institution to receive intravesical RTX. The following
exclusion criteria to enter the study were observed: age less
than 18 years, pregnancy, known cardiovascular, renal,
hepatic or psychiatric disorders, malignant diseases, duration of the OAB syndrome less than 12 months and concomitant bladder diseases, namely lower urinary tract
symptoms suggestive of bladder outlet obstruction and/or
treatments influencing bladder performance. In addition,
patients were excluded in the presence of abnormal haematological and biochemical blood tests, abnormal kidney and bladder ultrasound and a positive urine culture.
The design of the study was the following. At the first visit
the patients were enrolled in the study and entered a runin period of 30 days during which anti-muscarinic drugs
or other drugs that could affect bladder function were
stopped. Patients filled a voiding chart of the last 7 days of
this period. At the second visit the voiding chart was collected and patients were instilled during 30 minutes with
100 ml of the vehicle used to prepare the RTX solution,
10% ethanol in saline. The patients were then sent home
for another 30 days. In the last seven days of this period
patients filled another voiding chart. At the third visit the
voiding chart corresponding to the vehicle period was collected and 100 ml of a 50 nM RTX solution were slowly
instilled into the bladder by gravity and left in contact
with the mucosa during 30 minutes. If detrusor contractions occurred, the solution could freely reflux into the
container and then return into the bladder once the contractions wanned. The patients were sent home at the end
of the treatment. Two additional visits were scheduled at
1 and 3 months after RTX instillation. At the end of each
period, 7 day voiding charts were collected. At the end of
the vehicle and 3 months period patients were asked to
give their subjective impression about the outcome of the
treatment and about the willingness to repeat the previous
instillation. During the duration of the study no urodynamic studies were performed as the definitions of
urgency and OAB are purely clinic.
A validated scale to assess urinary urgency is not yet available in the Portuguese language. In addition, the distinction between the words urge and urgency, possible in the
English language, has no equivalent in Portuguese. Therefore, the suggestion for describing urgency according to
the circumstances during which it was experienced and by
the impact it had on concomitant activity being carried by
Page 2 of 6
70
the patients was followed to build up a scale easily understandable by the patients [21]. The options are listed
below and the system score was taught to the patients at
the first visit. Only options 3 and 4 were considered as
equivalents of urgency. Option 2 was used to refer urge.
0 – "I voided because it was convenient although I did not
feel a bladder sensation".
1 – "I voided because I had the sensation that my bladder
was becoming full and the opportunity to void was convenient".
2 – "I voided because I had the sensation that my bladder
was extremely full. I looked for a convenient place to void
without feeling any eminent risk of urine leakage".
3 – "I voided because I had a sudden strong desire to void
which I felt that could cause an urine leakage. I immediately interrupted what I was doing and looked for a convenient place where I started voiding in time".
4 – "I had a sudden strong desire to void that I felt that
could cause urine leakage. Although I immediately looked
for a convenient place to void, I had a leak before starting
voiding".
RTX was obtained from Sigma and a 10 mM stock solution in pure ethanol was prepared and kept in the dark at
4°C in a glass container. For each instillation 100 ml of a
50 nM solution using 10% ethanol in saline as vehicle was
prepared by one of the authors by adding 0.5 ml of the
stock solution to 90 ml of saline and 9.5 ml of pure ethanol. Instillation was carried out within 30–60 minutes
after preparation to minimise RTX absorption by plastic
devices. Instillations of the vehicle solution and of the
RTX solution were carried on without any form of analgesia or bladder anesthesia. Oral ciprofloxacin was administered for urinary infection prophylaxis at each instillation.
Urgency events, which corresponded to micturitions
scored as 3 or 4, were counted for each patient at the end
of the run-in period, vehicle period and at 1 and 3 months
after RTX instillation. The number of patients in whom
the number of urgency episodes decreased 25% or more
after vehicle instillation and RTX was counted. Patients
who considered to have had a subjective improvement at
the same time points and would repeat instillations if necessary at a later occasion were also counted. The number
of micturitions per week was obtained from the micturition charts. Data are presented as mean values per week ±
standard error of the mean (SEM). Those at the vehicle
period and at 1 and 3 months after RTX instillation were
compared by a two-tailed paired t-test for means. Percentage of patients with t25% improvement in urgency epi-
sodes and with subjective improvement after vehicle and
RTX treatment was compared by a z-test. A p < 0.05 was
considered statistically significant.
Results
At the end of the run-in period the mean number of episodes of urgency per week, that is micturition events preceded by sensations scored as 3 or 4, was 71 ± 12. The
average number of episodes of urgency after vehicle instillation was 56 ± 11. Nine patients (39%) had a decrease in
the number of episodes of urgency equal or superior to
25%. However, only 4 patients (17%) considered that
their urinary condition had improved enough to repeat
the treatment. The average number of urgency episodes at
1 and 3 months after RTX instillation was 39 ± 9 (p =
0.002 against vehicle) and 37 ± 6 (p = 0.02 against vehicle), respectively (Fig. 1). After RTX a 25% or more
decrease over the number of episodes of urgency counted
at the end of the vehicle period occurred in 14 patients
representing an increase in the percentage of RTX
responders to 60%. However this variation should be
taken as a trend since it did not achieve statistical significance (p = 0.2). The percentage of patients with subjective
improvement after RTX and willing to repeat the instillation at a later occasion increased to 69%. (p = 0.001, Fig.
2).
The episodes of urgency associated with incontinence
were evaluated separately. At baseline the mean number
was 21 ± 5. They decreased to 12 ± 4 after placebo instillation. At 1 and 3 months after RTX the episodes of
urgency incontinence further decreased to 8 ± 3 and 9 ± 3,
respectively. However, these values were not statistically
different from those after vehicle instillation (p = 0.05 and
p = 0.1, respectively).
p = 0.02
100
p = 0.002
80
60
40
20
Run-in
Vehicle
RTX 1 month
RTX 3 months
Figure
Number
the
after
instillation
50 1nM
of episodes
RTX
of the
instillation
of
vehicle
urgency
solution
at theand
run-in
at 1period,
and 3 months
after
Number of episodes of urgency at the run-in period, after
the instillation of the vehicle solution and at 1 and 3 months
after 50 nM RTX instillation.
Page 3 of 6
71
Discussion
p = 0.001
p = 0.2
80
60
Vehicle
40
RTX
20
0
% of patients with ≥25% decrease
on urgency
% of patients with subjective
improvement
Figure
Percentage
number
patients
the
RTX
instillation
instillation
2of
with
episodes
ofsubjective
patients
if (blue
necessary,
ofbars)
with
urgency
improvement
after
a 25%
per
vehicle
orweek
more
and
(red
and
willing
decrease
bars)
percentage
toorrepeat
on
50the
nM
of
Percentage of patients with a 25% or more decrease on the
number of episodes of urgency per week and percentage of
patients with subjective improvement and willing to repeat
the instillation if necessary, after vehicle (red bars) or 50 nM
RTX instillation (blue bars).
The number of micturitions per week, which was 95 ± 11
at the run-in period, decreased to 87 ± 10 after the vehicle
instillation. A further decrease to 75 ± 8 at 1 month (p =
0.02 against vehicle) and to 75 ± 7 at 3 months (p = 0.03
against vehicle) was observed after the RTX instillation
(Fig 3).
RTX instillation was associated with a slight discomfort,
described by patients as an itch sensation or urgency to
urinate. In no case was analgesic medication required or
instillation interrupted. After RTX treatment none of the
patients reported difficulties in emptying the bladder.
110
p = 0.03
10 0
p = 0.02
90
The most important finding of the present study was the
decrease of the number of episodes of urinary urgency
induced by bladder desensitization. Urinary frequency
also decreased and urgency incontinence showed a strong
trend to a reduction. These objective changes were accompanied by a subjective improvement in more than two
thirds of the patients. In addition, this study further confirmed the reports of good tolerability of RTX instillation
in low concentrations [13,16]. In spite of the fact that no
bladder anaesthesia was performed, all our patients carried out the 30 minutes RTX instillation to the end without difficulty.
This study was exploratory and was not designed as a randomized double arm placebo controlled trial due to the
limitations in recruiting patients for an off-license treatment in one single center. Nevertheless mean episodes of
urgency and micturition occurring 1 and 3 months after
RTX instillation were significantly less than those after the
simple instillation of the vehicle solution. In addition,
RTX brought a 25% improvement in the number of episodes of urgency over the vehicle period to 60% of the
patients whereas vehicle application alone had caused a
similar improvement rate over the run-in period in only
39% of the patients.
Due to the lack of validated scales to quantify urgency in
the Portuguese language we had to build-up a scale to
assess this symptom. As the words urge and urgency have
no equivalent in the Portuguese language we preferred a
scale which evaluated the circumstances in which urgency
occurred and its impact on the patients' daily activities,
rather than its intensity. Although our option might be
object of criticism, actually, the best mean to evaluate and
measure urgency is not yet established and is under
intense controversy. Researchers exist who prefer scales in
which different degrees of urgency intensity are contemplated [22,23]. However others only recognise the necessity of distinguishing urgency form urge and consider that
urgency, being a sudden and compelling desire to urinate,
does not have degree of severity [24].
80
70
60
Run-in
Vehicle
1 mo nth
3 mo nth
Figure
Number
period,
and
3 months
after
3of micturition
the
after
instillation
50 nM
episodes
RTX
of the
instillation
per
vehicle
weeksolution
at the run-in
and at 1
Number of micturition episodes per week at the run-in
period, after the instillation of the vehicle solution and at 1
and 3 months after 50 nM RTX instillation.
The reason for the improvement associated with RTX
should be explained by its specific affinity to TRPV1
[25,26]. This receptor was recently found to be over
expressed in the trigone of patients with urgency [27]. In
C-fibers RTX binding to TRPV1 causes a massive inflow of
calcium and other ions into the fiber, generating action
potentials and releasing neuropeptides from peripheral
nerve endings [25,26], both events contributing to itch or
urgency sensations reported by some patients in the
present and in previous studies in which RTX instillation
was carried out [14,16]. A transient reduction of bladder
sensory input conveyed to the central nervous system in C
Page 4 of 6
72
fibers then follows [7]. The interruption of C-fiber influx
may thus have contributed to the symptomatic improvement observed after RTX instillation in our patients.
It is probable that part of sensory input conveyed in C fibers is not initiated by a direct stimulation of peripheral
nerve endings but results from their activation by neurotransmitters and neurotrophic factors released from the
urothelium [28]. RTX binding to TRPV1 present in urothelial cells may, therefore, have contributed to urgency
improvement by disrupting the cross-talk between
urothelial cells and suburothelial C-fibers. Inflow currents
occur in human urothelial cells after TRPV1 activation
suggesting that the receptor in the urothelium retains
properties similar to those described in sensory neurons
[29]. Likewise RTX application is followed by a reduction
in urothelial TRPV1 expression [3]. Thus, RTX treatment
might have reduced the potential of urothelial cells to
release compounds which are known to excite suburothelial sensory fibres [2]. One of these compounds
might be nerve growth factor (NGF) [30]. Although it is
unclear at the moment if TRPV1 excitation enhances NGF
release from urothelium, this neurotrophin was shown to
induce bladder overactivity in experimental animals [31]
and was found in high amounts in the urine of OAB
patients [32].
It is also possible that RTX has prevented the ATP released
from urothelial cells [2] and consequently the activation
of sub-urothelial C-fibers expressing P2X3 receptors [15].
It is known that TRPV1 is involved in ATP release from the
urothelium in response to stretch stimuli [33]. In addition, animal studies demonstrated that P2X3 receptors are
essential for the generation of bladder contractions and
noxious sensations [34]. As a matter of fact, knocking-out
P2X3 in mice renders the bladder hypoactive and the animals less reactive to pain [34]. Intravesical RTX decreases
both TRPV1 in urothelial cells [3] and the number of suburothelial P2X3 expressing fibers in the human bladder
[15].
In our study the instillation of 10% ethanol in saline
alone caused a marked improvement in the number of
urgency episodes when compared to the run-in phase. It
seems, however, improbable that such effect was due to a
desensitizing action of ethanol on TRPV1 receptors. In
fact, although ethanol was found to bind TRPV1, it does
not cause its desensitization [35]. In addition, in a recent
clinical trial with patients with neurogenic detrusor overactivity 10% ethanol in saline alone did not cause any variation on urodynamic parameters in contrast with the
solution containing RTX 50 nM that significantly
increased the bladder volume to first involuntary detrusor
contraction and maximal cystometric capacity [16]. Similar findings were reported by Kuo et al. In 54 patiens with
refractory DO, 21% of the patients treated with 10% ethanol improved at 3 months, a number considerably
smaller that the 62% that improved after RTX 10 nM, four
weekly instillations [18]. Thus, the improvement induced
by 10% ethanol instillation in the present study should be
taken as part of a placebo effect, a commonly recognized
phenomenon in clinical trials involving OAB patients
[36].
Conclusion
This exploratory study indicates that desensitization may
be useful to treat patients with urinary urgency, particularly if refractory to the standard management. This finding also has important pathophysiological implications as
it indicates that C-fiber input plays an important role to
the generation of the urgency sensation. Since at present
RTX is the only compound with desensitizing effect suitable for human use, a randomised placebo controlled
study is justified to further investigate the role of desensitization in the treatment of urgency. The dose for intravesical RTX used in the present work should be considered
as indicative in future studies. In fact, all studies in which
RTX was used to treat OAB symptoms [14,18,19], including the present one, used RTX concentrations of 50 nM or
lower. In addition, urodynamics studies should be
included in future studies. Although it was not the case of
this study, urodynamics might elucidate if urgency in
patients with or without detrusor overactivity have the
same origin.
List of abbreviations
ATP – adenosine triphosphate
DO – detrusor overactivity
NGF – Nerve Growth Factor
OAB – Overactive bladder
P2X3 – P2X family of ATP-gated ion channels, subtype 3
RTX – Resiniferatoxin
TRPV1 – Transient receptor potential vanilloid subfamily
1
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
CS designed the study, was involved in clinical assessment
of patients, analysed the data and wrote the manuscript.
CS, JS, HC, FR and PD selected, treated and followed the
patients.
AA prepared the resiniferatoxin solutions.
FC participated in the design of the study and its coordination, analysed the data and wrote the manuscript.
Page 5 of 6
73
All the authors read and approved the manuscript.
Acknowledgements
We thank Dr. Célia Duarte Cruz for the statistical analysis. This work was
funded by the Portuguese government through Fundação Ciência Tecnologia, project POCI/SAU-NEU/55983/2004.
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Pre-publication history
The pre-publication history for this paper can be accessed
here:
http://www.biomedcentral.com/1471-2490/7/9/prepub
Page 6 of 6
74
PUBLICAÇÃO V
A light- and electron-microscopic histopathological study of human bladder mucosa after intravesical resiniferatoxin application
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CONSIDERAÇÕES FINAIS
83
A Resiniferatoxina na hiperactividade do detrusor
O presente trabalho demonstrou que a dessensibilização intravesical
com RTX induz uma melhoria clínica e urodinâmica significativa em doentes
com hiperactividade do detrusor, neurogénica (Publicação I) e não neurogénica (Publicação III). Estes efeitos foram, na maior parte dos doentes, de
longa duração, entre 6 e 12 meses (Publicação I). Mais ainda, nos doentes
submetidos a novo tratamento verificou-se uma replicação dos resultados
obtidos com a instilação inicial (Publicação I).
Os resultados observados nos doentes neurogénicos foram reproduzidos noutros ensaios abertos (Giannantoni et al., 2002; Kuo, 2003, 2005; de
Séze et al., 2004). Estes resultados vieram a ser confirmados num estudo
controlado com placebo, com nível de evidência superior na escala do Centro
de Oxford para a Medicina baseada na evidência. De facto, este estudo demonstrou uma maior eficácia urodinâmica e clínica da instilação intravesical
de RTX do que a solução veículo em doentes neurogénicos (Publicação III).
A melhoria clínica e urodinâmica em doentes com hiperactividade do detrusor não neurogénica (Publicação III) não foi por nós objecto de confirmação, através de um estudo controlado com placebo. No entanto, os nossos
resultados foram confirmados num estudo com tais características que incluiu
54 doentes (Kuo et al., 2006). Três meses após a instilação, a percentagem de
doentes com melhoria clínica era significativamente maior no grupo submetido a instilação de RTX (61%) do que no grupo controlo (21%). Seis meses
após a instilação, 50% dos doentes submetidos a RTX mantinham-se com
melhoria clínica enquanto esta percentagem era de 10% no grupo controlo.
85
Em conclusão, o RTX é eficaz no tratamento da hiperactividade do detrusor quer idiopática quer neurogénica. Estes resultados poderão ser ainda
mais relevantes se se considerar que os doentes seleccionados e incluídos
nos vários ensaios clínicos eram refractários à terapêutica de primeira linha.
Por esta mesma razão, os resultados obtidos com o RTX não se devem comparar com os resultados obtidos com anticolinérgicos em ensaios clínicos.
A instilação intravesical de RTX é bem tolerada, não sendo necessária a
administração prévia de medicação analgésica ou anestésica (Publicação I,
II, III, IV). Não ocorreu nenhum caso de disreflexia autónoma nem foi preciso
interromper a instilação de RTX. Mais ainda, o desconforto sentido pelos
doentes com a instilação da solução de RTX não foi significativamente diferente do sentido com a instilação da solução veículo (Publicação II). Estes
resultados clínicos confirmam no Homem os achados de estudos experimentais prévios. Nestes, verificou-se que a dessensibilização com RTX não
era precedida por uma irritação sensitiva marcada, sugerindo o favorecimento da aplicação clínica do RTX em detrimento da capsaicina (Avelino et al.,
1999, 2002). A ausência de dor, de desconforto significativo ou de episódios
de disreflexia autónoma associados à instilação de RTX contrasta com o
observado durante a instilação de capsaicina, a primeira neurotoxina a ser
utilizada no Homem, como agente dessensibilizante das fibras C (Fowler et
al., 1994; Das et al., 1996; Cruz et al., 1997a; De Ridder et al., 1997). A inocuidade da instilação de RTX foi também observada por outros investigadores
(Giannatoni et al., 2002, 2004; de Séze et al., 2004; Palma et al., 2004).
Embora se tivesse postulado a existência de dois subtipos de receptores com diferentes afinidades para a capsaicina e para o RTX para justificar
as diferenças observadas na capacidade irritativa e dessensibilizante das
duas substâncias (Publicação I), tal hipótese não se confirmou. Mais prova-
86
velmente, a menor pungência do RTX em relação à capsaicina advém do tipo
de correntes electrofisiológicas induzidas nos neurónios por cada uma das
substâncias, mais lentas e duradouras no caso do RTX (Liu e Simon, 1996;
Szallasi e Blumberg, 1999).
Modo de administração da resiniferatoxina
A maior parte dos investigadores usou o método instituído por Fowler
et alii, aquando dos primeiros estudos com capsaicina no Homem (Fowler et
al., 1992). Consiste na instilação intravesical de 100-125 ml de uma solução
alcoólica a 30%, contendo 1-2 mmol/l de capsaicina, usando para tal uma
sonda de Foley. A solução permanece em contacto com a mucosa vesical
durante 30 minutos.
Por extrapolação de estudos experimentais com RTX em que a dose
100 nM se revelou a dose ideal para a dessensibilização vesical (Avelino et
al., 1999) e tendo em conta que a dose de capsaicina utilizada no homem,
1-2 mmol/l, foi a mesma que induziu maior dessensibilização no rato (Cruz et
al., 1996), optou-se por 100 ml de uma solução de RTX, 50-100 nM, que se
deixou em contacto com a mucosa vesical durante 30 minutos.
Este método de administração não foi seguido por outros investigadores. Kuo optou por usar doses menores (10 nM) em 4 instilações semanais,
com o objectivo de minimizar ainda mais o desconforto provocado pelas
contracções do detrusor, que doses de 50-100 nM normalmente despertam
(kuo, 2005). Lazzeri et alii usaram doses muito maiores que provocaram retenção urinária transitória em doentes com patologia neurológica (Lazzeri
et al., 1998). Contudo, estas doses elevadas não foram utilizadas por mais
nenhum grupo de investigadores pelo que a ocorrência de retenção urinária
após RTX requer confirmação.
87
Como atrás foi dito, a molécula do RTX é altamente lipofílica, sendo
difícil manter-se numa solução aquosa (Szallasi e Blumberg, 1992; Szallasi e
Fowler, 2002). Daí a necessidade de usar uma solução alcoólica. Além disso,
o RTX adere a material plástico, perdendo cerca de metade da sua actividade por cada hora em contacto com aquele material (Brady et al., 2004). Estas
características tornam necessário a preparação extemporânea das soluções
e têm dificultado a preparação de uma solução estável para uso clínico em
larga escala. Podem, ainda, explicar em parte a falta de eficácia do RTX em
alguns estudos (Kim et al., 2003; Rios et al., 2007).
Local de actuação dos vanilóides
O efeito dessensibilizante do RTX depende da sua ligação ao receptor
TRPV1 (Tominaga e Caterina, 2004). Na bexiga, este receptor foi identificado
em primeiro lugar nas fibras sensitivas C (Yiangou et al., 2001; Avelino et al.,
2002). Daí que se tenha deduzido que a melhoria da hiperactividade do detrusor, neurogénica (Publicações I e II) e idiopática (Publicação III), era devida
à dessensibilização daquelas fibras sensitivas. Tal veio a ser demonstrado,
mais tarde, uma vez que a instilação de RTX diminuía a expressão dos receptores TRV1 nas fibras nervosas vesicais (Avelino et al., 2002; Brady et al.,
2004). Note-se que o número de fibras que expressam o TRPV1 está aumentado em doentes com hiperactividade neurogénica e idiopática do detrusor
(Brady et al., 2004; Apostolidis et al., 2005a).
A actuação do RTX nas fibras vesicais de tipo C é também sugerida
pela negativação do teste da água gelada num número significativo de doentes com hiperactividade neurogénica do detrusor (Publicação I). Como se
88
sabe, as contracções despertadas pela água gelada são iniciadas em fibras
sensitivas do tipo C e foram demonstradas quer em doentes neurogénicos
(Geirsson et al., 1993; Mukerji et al., 2006b) quer em idiopáticos (Al-Hayek et
al., 2006). A negativação deste teste nestes doentes foi também confirmada
por outro grupo de investigadores (Shin et al., 2005).
Destes dados concluiu-se que as fibras C estariam envolvidas na fisiopatologia da hiperactividade do detrusor. Sai, assim, reforçada a tese da
teoria sensitiva na hiperactividade do detrusor e do SBH em geral.
Dada a identificação recente do receptor TRPV1 em estruturas não neuronais, como o urotélio (Birder et al., 2001; Lazzeri et al., 2004; Apostolidis et
al., 2005b) e as células intersticiais (Ost et al., 2002), e tendo em conta a actuação do RTX nesses receptores, não podemos, consequentemente, excluir
um eventual papel fisiopatológico dessas estruturas na hiperactividade do
detrusor. Apostolidis et alii verificaram uma diminuição da imunorreactividade para o TRPV1 nas células uroteliais após instilação intravesical de RTX em
doentes neurogénicos (Apostolidis et al., 2005b). Liu e Kuo verificaram uma
melhor resposta clínica à instilação de RTX em doentes com hiperactividade
idiopática do detrusor com hiperexpressão do receptor TRPV1 no urotélio e
na submucosa (Liu e Kuo, 2007). Charrua et alii demonstraram a funcionalidade do TRPV1 no urotélio do Homem (Charrua et al., 2006). Note-se que o
receptor TRPV1 tem um papel relevante na libertação de neurotransmissores pelo urotélio, como, por exemplo, o ATP (Birder et al., 2001). As células
intersticiais podem também desempenhar um papel no processamento da
informação sensitiva vesical. Estão localizadas no suburotélio em contacto
próximo com as fibras sensitivas e sabe-se hoje que podem responder a
estímulos externos, como o ATP e pH ácido (Fry et al., 2007).
89
Estes dados morfológicos e funcionais sugerem, portanto, que, para
além das fibras C, o urotélio e as células intersticiais poderão também ser
um alvo importante da actuação do RTX.
Dessensibilização vesical e imperiosidade
Estudos recentes em fase aberta demonstraram que a instilação intravesical desta neurotoxina em doentes com hiperactividade do detrusor diminuía a imperiosidade e o número de episódios de incontinência por imperiosidade (Publicação I, Publicação II, Palma et al., 2004). Mais recentemente,
Apostolidis et alii (Apostolidis et al., 2006b) verificaram o mesmo efeito em
doentes com SBH, mas sem hiperactividade do detrusor.
Sendo recentes as modificações introduzidas no conceito da SBH, que
catapultaram a imperiosidade para o centro do complexo sintomático, não
é de estranhar a escassez de estudos que avaliem especificamente o efeito
do tratamento neste sintoma, mesmo com a terapêutica de primeira linha, os
anticolinérgicos. Alguns destes estudos com anticolinérgicos parecem demonstrar efeitos benéficos na imperiosidade (Freeman et al., 2003; Chapple
et al., 2004, 2005d).
Contudo, não há ainda nenhum instrumento universalmente aceite para
medir especificamente a imperiosidade e avaliar as alterações induzidas pelas terapêuticas, sendo tema de controvérsia (Brubaker et al., 2006).
Cardozo et alii utilizaram, como instrumento de aferição da imperiosidade, o tempo de latência ou de aviso (“warning time”) definido como o tempo
entre a primeira sensação de imperiosidade e a micção (Cardozo e Dixon,
90
2005). Neste estudo demonstraram, de uma forma indirecta, um efeito significativo da darifenacina na imperiosidade, ao verificarem que a darifenacina
aumentou, em média, o tempo de latência em 1,8 minutos (Cardozo e Dixon,
2005). Contudo, como se compreende, este parâmetro, embora pretenda ser
objectivo, é de difícil percepção e de complexa avaliação pelo doente.
Dado não existir uma escala própria, em português, para avaliar a imperiosidade, decidimos criar uma escala de fácil compreensão pelo doente, em
que a mesma é avaliada tendo em conta as circunstâncias em que ocorre e
as repercussões que tem nas tarefas habituais do doente (Publicação IV).
Neste trabalho demonstrámos que a dessensibilização do braço sensitivo da inervação vesical com RTX, em doentes com síndrome da bexiga
hiperactiva, diminui o número de episódios de imperiosidade, associada ou
não a incontinência urinária (Publicação IV). Embora não tenha sido um estudo randomizado, procurou-se ter um controlo com placebo, dado haver
a percepção que o efeito placebo poderia ser relevante aquando do tratamento da imperiosidade. Assim, o desenho do estudo incluiu uma avaliação
basal, uma avaliação após a solução veículo, entendida como placebo, e
avaliações após RTX.
Para além de sugerir que o TRPV1 pode ser um alvo para o tratamento da imperiosidade, o efeito positivo do RTX na imperiosidade sugere que
o TRPV1 pode estar envolvido na sua génese. Estudos recentes parecem
confirmar esta hipótese. Liu et alii encontraram um aumento da expressão
do mRNA TRPV1 na mucosa do trígono de doentes com imperiosidade (Liu
et al., 2007). Noutro estudo, Liu e Kuo verificaram haver correlação entre
a expressão aumentada do TRPV1, na mucosa dos doentes, e a taxa de
resposta sintomática após RTX (Liu e Kuo, 2007). Além disso, em estudos
experimentais, Charrua et alii, após provocação de inflamação vesical em
91
ratinhos com delecção do gene TRPV1 e ratinhos normais, verificaram que
nos animais com delecção do gene a inflamação não aumentou a expressão
da proteína Fos na medula espinal, significando que não houve resposta ao
estímulo nóxico, ao contrário do que aconteceu em animais normais com
inflamação vesical (Charrua et al., 2007).
Em conclusão, a dessensibilização vesical poderá vir a ser uma das terapêuticas mais eficazes para o tratamento da imperiosidade associada ao
SBH.
Segurança da resiniferatoxina
Muito se tem debatido acerca da neurotoxicidade da resiniferatoxina,
particularmente se induz ou não degeneração das fibras nervosas, quando
aplicada por via intravesical. Em estudos de microscopia electrónica, 24 horas após instilação intravesical de RTX em ratos, não se verificou degeneração de estruturas nervosas (Avelino e Cruz, 2000; Avelino et al., 2002). Pelo
contrário, após administração sistémica da neurotoxina verifica-se ocorrência destas lesões nervosas (Avelino e Cruz, 2000). Estes estudos experimentais sugerem que, com as doses utilizadas por via intravesical, a probabilidade de ocorrer lesão neurológica irreversível é muito pequena.
Além das lesões neurológicas, o potencial carcinogénico dos vanilóides
foi outra preocupação inicial dos investigadores. Isto deve-se ao facto do RTX
ser estruturalmente semelhante aos ésteres de forbol que são substâncias
usadas como promotoras de tumores em trabalhos experimentais (Szallasi
e Blumberg, 1999). Contudo, em estudos experimentais, verificou-se que o
RTX não tem a capacidade de induzir respostas celulares características dos
92
ésteres de forbol e não promove a formação de tumores (Zur Hausen et al.,
1979). Este facto deve-se à ausência na molécula do RTX do radical livre OH
na posição C20, sendo substituído pelo anel aromático homovanílico (Szallasi e Blumberg, 1999)
Neste trabalho (Publicação V), demonstrámos que a instilação intravesical de RTX, em doentes com hiperactividade do detrusor neurogénica,
não causou alterações na morfologia do urotélio, da membrana basal e da
camada de mucina. Mais ainda, não induziu lesões detectáveis por microscopia electrónica nas fibras amielínicas presentes na mucosa vesical. Notese que este método tinha identificado lesões de degenerescência neuronal
após administração de vanilóides por via sistémica (Avelino e Cruz, 2000).
Outros trabalhos anteriores, com capsaicina, suportam as nossas observações. Dasgupta et alii verificaram a ausência de lesões na mucosa vesical em
doentes submetidos a várias instilações de capsaicina, nos 5 anos prévios
(Dasgupta et al., 1998).
93
CONCLUSÕES
95
Deste trabalho de investigação, podem deduzir-se as seguintes conclusões:
- A dessensibilização vesical é uma terapêutica eficaz na hiperactividade do detrusor de causa neurogénica e não neurogénica;
- A dessensibilização vesical diminui a imperiosidade nos doentes
com síndrome da bexiga hiperactiva;
- A resiniferatoxina é o agente dessensibilizante de eleição, na medida em que é inócuo e é seguro, quando instilado por via intravesical,
e o seu modo de administração é fácil;
- A solução de resiniferatoxina para instilação intravesical apresenta
como inconveniente actual a necessidade de ser preparada extemporaneamente, devido à instabilidade da molécula numa solução
aquosa;
- A longa duração dos efeitos obtidos, com uma instilação de resiniferatoxina, favorece a sua aplicação no síndrome da bexiga hiperactiva, uma doença crónica em que o número de doentes que
persistem na terapêutica de primeira linha é reduzido;
- O receptor TRPV1 e as estruturas na bexiga que o expressam, as
fibras sensitivas vesicais do tipo C, as células uroteliais e as células
intersticiais, estão envolvidos na génese da hiperactividade do detrusor e da imperiosidade.
97
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RESUMO
121
O síndrome da bexiga hiperactiva (SBH) é um quadro clínico com elevada prevalência na população em geral, caracterizado por imperiosidade, com
ou sem incontinência urinária, geralmente associada a polaquiúria e noctúria,
cuja etiologia não está ainda esclarecida. A hiperactividade do detrusor é o
achado urodinâmico mais frequente nos doentes com SBH.
A terapêutica de primeira linha da SBH, os antimuscarínicos, está longe
de ser a ideal, devido à eficácia limitada e aos efeitos laterais. Estes factos
repercutem-se na baixa adesão à terapêutica.
Neste trabalho, procurou-se esclarecer o potencial terapêutico da dessensibilização vesical no SBH associado a hiperactividade do detrusor de
causa neurogénica e não neurogénica, dado os indícios de que os receptores TRPV1 (potencial de receptor temporário de tipo vanilóide, tipo 1), localizados nas fibras aferentes primárias de tipo C, no urotélio e nas células intersticiais, poderiam estar implicados na génese do SBH. Avaliou-se,
ainda, os efeitos da terapêutica dessensibilizante no sintoma principal da
SBH, a imperiosidade. Noutra vertente do trabalho, procurou-se determinar
o papel do receptor TRPV1 na génese da hiperactividade do detrusor e da
imperiosidade. Com recurso a estudos de microscopia óptica e electrónica,
avaliou-se também a segurança da instilação intravesical da resiniferatoxina,
o agente dessensibilizante escolhido para este trabalho.
123
Deste trabalho, foram deduzidas as seguintes conclusões:
- A dessensibilização intravesical do receptor TRPV1 induz uma melhoria clínica e urodinâmica significativa em doentes com hiperactividade do detrusor, de causa neurogénica e não neurogénica. Estes
efeitos, obtidos com uma única instilação, são de longa duração,
entre 6 e 12 meses;
- A dessensibilização intravesical do TRPV1 em doentes com o síndrome da bexiga hiperactiva diminui o número de episódios de imperiosidade, associada ou não a incontinência urinária;
- O receptor TRPV1 e as estruturas vesicais onde ele é expresso, a
saber, as fibras C, o urotélio e as células intersticiais, estão envolvidos na fisiopatologia da hiperactividade do detrusor e na génese da
imperiosidade;
- A instilação intravesical de resiniferatoxina não é tóxica, não se tendo observado alterações na morfologia da mucosa vesical. Além
disso, é bem tolerada, não sendo necessária a administração prévia
de medicação analgésica ou anestésica, podendo ser feita em regime ambulatório;
- Terapêuticas direccionadas para a inactivação ou modulação do
eixo sensitivo podem ser uma opção eficaz em doentes com SBH.
A resiniferatoxina é actualmente o agente dessensibilizante de eleição.
124
SUMMARY
125
Overactive bladder (OAB), a syndrome with elevated prevalence in the
general population, is characterized by urgency, with or without urinary incontinence and often associated with frequency and nocturia. Its causes are
not completely known and detrusor overactivity is considered its urodynamic
landmark.
Anticholinergic drugs, the current standard treatment of OAB, are far
from being considered ideal, given their limited efficacy and side effects.
These facts are responsible for the low persistence on medication for OAB
patients.
In this research project, we have attempted to clarify the potential therapeutic value of bladder desensitization on patients with neurogenic or idiopathic detrusor overactivity, given the hypothesis that TRPV1 receptor (transient
receptor potential vanilloid type 1), located in type C afferent fibers, urothelial cells and interstitial cells, could be involved in OAB physiopathology. We
have also evaluated the effects of bladder desensitization in urgency, the
principal symptom of OAB.
A further aim of this project was to clarify the role of the TRPV1 receptor
on the ethiology of detrusor overactivity and urgency. The safety of intravesical treatment with resiniferatoxin (RTX), the chosen desensitizing agent,
was also evaluated through the study of bladder biopsies by way of light and
electron microscopy.
127
In the study, the following conclusions were obtained:
- Bladder desensitization with RTX is effective in increasing bladder
capacity and decreasing urinary frequency and incontinence in
patients with neurogenic or idiopathic detrusor overactivity. These
effects are long lasting, between 6 and 12 months.
- Bladder desensitization decreases the number of episodes of urinary urgency in overactive bladder patients.
- The TRPV1 receptor and bladder structures where TRPV1 is located, that is, C fibers, urothelium and interstitial cells, are involved in
the pathophysiology of detrusor overactivity and the generation of
urgency.
- The instillation of resiniferatoxin is well tolerated without any administration of analgesic or anaesthetic drugs and can be carried out in
an outpatient clinic. It is also non toxic as no morphologic changes
in the bladder mucosa were observed.
-
Treatment directed towards inactivation or modulation of the afferent axis might be an effective option to offer to overactive bladder
patients. The absence of irritative symptoms during bladder instillation of resiniferatoxin and the rapid onset of desensitization makes,
at the moment, this vanilloid the ideal drug to administer to OAB
patients.
128

TRATAMENTO DA HIPERACTIVIDADE VESICAL DE CAUSA

Transcription

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