Tag Archive for: detrusor overactivity

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Article of the Month: Have TRP channels fulfilled their promise in LUTS?

Every Month the Editor-in-Chief selects the Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Month heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Wouter Everaerts, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶ and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.

Editorial: TRP channel – a reality that still requires many years of scientific efforts

Seventeen years have elapsed since the capsaicin receptor was first cloned by Caterina et al. [1] and the excellent review with an unusual provocative title by Deruyver et al. [2] was written. The capsaicin channel, re-named transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1), is now commonly referred to as the founding member of the TRP family, as it currently includes 28 related channels, a number difficult to foresee in those early years [3].

TRP channels have been extensively studied in the lower urinary tract (LUT) with the aim of clarifying their role in micturition control and in the generation of LUTS. It is well accepted that TRP receptors have neuronal and non-neuronal expression [3, 4]. TRPV1 is fundamental to bladder hyperactivity and pain associated with LUT inflammation [3], while TRPV4 may participate in the generation of the normal sensation to void [5]. Another group of TRP receptors may even participate in bladder oncogenesis, which seems to be a role of TRPV2 [3]. The main substance of all this information is not a myth; rather it represents a large body of very solid scientific data.

There are certainly still many obscure areas. The distribution of TRP receptors in the bladder is certainly one of them. However, I disagree that a substantial part of available technical and financial resources have been allocated to study this matter. One should not forget that other matters, like the role of many TRP channels for bladder function, remain elusive. Broadly speaking, in my opinion, future key studies should tackle three very relevant but still unclear points. The importance of most TRP channels for bladder function is difficult to predict at the moment [3]. Just as an example, TRPA1 and TRPM8, which are sensitive to cold temperatures, are expressed in the bladder. However, the bladder, as all internal organs, is conserved at very constant physiological temperatures, making it difficult to understand the relevance of cold receptors to its function. Then, we need to find what the endogenous agonists for TRP receptors are in the LUT. Anandamide has been largely explored as an endogenous agonist for TRPV1 in the bladder [6], a fruitful observation as drugs able to manipulate endogenous levels of anandamide are currently being explored in clinical trials. The same holds true for the other members of the TRP family. TRPA1 may respond to infections due to its capacity to react to hydrogen sulphide [3]. But for the large majority of the TRP family endogenous agonists remain unknown. Finally, TRP antagonists that are simultaneously effective and safe must be generated. Most available TRPV1 antagonists, produced to date, although able to control bladder dysfunction in models of cystitis and spinal cord injury [3], cause hyperthermia and have been associated with an enlargement of ischaemic areas of the heart after coronary artery obstruction [3]. TRPV4 antagonists look very promising for controlling frequency but a compound safe for human use is still eagerly awaited [2]. Eventually the combination of antagonists for more than one of these receptors may prove effective at very low doses, so low that they do not generate serious adverse effects [7].

In conclusion, TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful. And that may take more time than we anticipate at the moment.

 

Francisco Cruz
Department of Urology, Al. Hernani Monteiro, Porto, Portugal

 

References

 

1 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JDJulius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 81624

 

 

3 Avelino A, Charrua A, Frias B et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf) 2013; 207: 110122

 

4 Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001; 98: 13396401

 

5 Gevaert T, Vriens J, Segal A et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 345362

 

 

Video: TRP channel modulators as pharmacological treatments for LUTS – myth or reality?

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.

Article of the Week: The botulinum toxin benefit for overactive bladder

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying blog written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

 

Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB)

Amar Mohee, Ayisha Khan, Neil Harris, Ian Eardley

Read the full article
OBJECTIVES

• To assess the long-term compliance with repeated injections of intravesical botulinum toxin (BT) in a ‘real-life’ mixed population of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity.

• To identify the reasons why patients discontinued BT therapy and to explore the outcomes of those patients who did discontinue treatment.

PATIENTS AND METHODS

• Retrospective evaluation of the case notes of a series of patients who had received intravesical BT treatment at a large UK teaching hospital.

• No antibiotic prophylaxis was given for the procedure.

RESULTS

•Over a period of 7 years, 268 patients were initiated on intravesical BT treatment for overactive bladder (OAB) at our institution, with 137 followed up for ≥36 months, with 80 patients having ≥60 months follow-up after their first injection.

• Almost two-thirds of patients (61.3%) had discontinued intravesical BT therapy at 36 months, with a 63.8% discontinuation rate at 60 months.

• The main reasons for discontinuation were tolerability issues, mainly urinary tract infections and the need for clean intermittent self-catheterisation. Primary and secondary losses of efficacy were of secondary importance.

• Most of the patients that discontinued have remained under urology care and now receive alternative methods of treatment.

CONCLUSIONS

• Intravesical BT therapy is an effective short-term treatment for OAB.

• With time, two-thirds of patients discontinued treatment usually because of the tolerability issues associated with treatment.

 

Read Previous Articles of the Week

Editorial: Is botulinum toxin not the solution to OAB after all?

Dirk De Ridder
Department of Urology, University Hospital Leuven, Belgium

The article by Mohee et al. highlights a problem that is often neglected: the outomes we see in clinical trials do not predict the success of the therapy in real life. We know this from anticholinergics: the study results are good, but the performance in real life is much poorer. Only 20-40% will continue to take the medication.

For botulinum toxin in OAB it is surprising to see that even in experienced hands only 38.7% of patients continued with the treatment at 36 months. The reasons to abandon the treatment were retention, the need for CISC and urinary tract infections. Moreover, 8.6% of the patients had no response at all after the initial injection.

Of course infections could have been avoided by using prophylactic antibiotics, but the other issues remain. How to explain the primary failures? How to manage the risk of CISC?

Given the fact that most patients abandoned the treatment within the first 3 years, more research would be needed on how to increase the treatment adherence of the patients after the initial injection.

This challenging article also stresses the fact that in a time where only RCTs stand a good chance of being published in journals, good retrospective cohort studies can be extremely important too.

Read the full article
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