Benign prostatic hyperplasia
Several disorders Wachs mol BPH the human upper and lower urinary tract, such as urinary stone disease, lower urinary tract symptoms LUTS due to benign prostatic hyperplasia BPH and detrusor overactivity, can Wachs mol BPH therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively. In order to ensure a drug effect without significant Wachs mol BPH events, a certain degree of tissue selectivity is mandatory.
The treatment of said conditions aims to focus on orally available drugs acting via intracellular signalling pathways. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an Wachs mol BPH mediator in the control of the outflow region bladder, urethra.
The use of phosphodiesterase PDE inhibitors, such Wachs mol BPH sildenafil, tadalafil, vardenafil, avanafil or udenafil, known to Wachs mol BPH the degradation of the second messenger cyclic GMP, offers great opportunities in the treatment of lower urinary tract dysfunction.
PDE Wachs mol BPH are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio.
The purpose of this review is to focus on the potential use and clinical significance of PDE inhibitors in the treatment of storage and voiding dysfunctions of the lower urinary tract. The strategy of Wachs mol BPH the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction LUTD.
Cyclic nucleotides are synthesized from the corresponding nucleoside triphosphates by the activity of adenylyl and guanylyl cyclases. Cyclic nucleotides are degraded by phosphodiesterase PDE isoenzymes, a heterogeneous group of hydrolytic enzymes. Some of these isoenzyme families consist Wachs mol BPH more Wachs mol BPH one gene and some genes are alternatively spliced so that more than 50 isoenzymes or variants have been identified.
Some PDE genes are also variably expressed in different tissues [ 34 ]. Since the distribution and functional significance of PDE isoenzymes can vary in different tissues, isoenzyme-selective inhibitors have the potential to exert specific effects on the target tissue.
The activities of PDE4 and Wachs mol BPH were isolated using anion exchange chromatography from cytosolic supernatants prepared from tissue specimens taken from the transition zone of the prostate. PDE4 was also detected in the microsomal fraction of prostate tissue Wachs mol BPH 8 ]. Later, immunohistochemistry revealed the distribution of PDE4 and PDE5 in stromal and glandular areas of the transition zone [ 9 ].
Interestingly, Wachs mol BPH contraction of isolated prostate tissue brought about by the vasoconstrictor peptide endothelin 1 ET-1 was also counteracted by rolipram, tadalafil, sildenafil and vardenafil, with rolipram and tadalafil being most effective [ 11 ]. In experiments using a model of cultured human prostate smooth muscle cells, the number of cells showing constriction in response to ET-1 was significantly reduced by the non-specific PDE inhibitor theophylline, PDE5 inhibitor sildenafil and the adenylyl cyclase activator forskolin [ Wachs mol BPH ].
Another hypothesis postulates that the abnormal growth pattern of smooth muscle, connective and glandular Wachs mol BPH in prostatic stromal and glandular compartments, respectively, seen in conjunction with BPH might be induced by hypoxia resulting from an age-related impairment in local blood flow. Consequently, a key role of urogenital ageing and subsequent alterations in the blood supply to the Wachs mol BPH has been suggested in the development of BPH.
This issue is addressed in more detail at the end of the following section. The basic research efforts outlined above have provided the basis for the development and introduction of new therapeutic modalities into the management of lower urinary tract dysfunction LUTDsome of which might soon be offered to patients.
BPH represents a major health care problem in westernized countries. Symptoms and signs of BPH comprise storage and voiding dysfunction, as well as benign prostatic enlargement BPE with variable degrees of benign prostatic obstruction BPO [ 13 ]. Major symptoms include urinary frequency, nocturia and slow stream. Later, larger randomized, double-blind trials, of which some were placebo-controlled, were conducted enrolling patients presenting with LUTS with or without erectile dysfunction ED Table 2.
The duration of Wachs mol BPH trials was 8—12 weeks. A significant reduction of bladder storage and voiding symptoms during treatment was also noted while PVR and Q max did not change significantly.
From this finding, it was concluded that extraprostatic pathophysiological mechanisms related to an impairment in the activity of the nitric oxide NO system might also be involved in the onset of LUTS. Although some studies showed an increase in Q max with an increased dose of a PDE5 inhibitor, this observation was not significantly different from Wachs mol BPH placebo group [ 20 — 24 ]. This might be due to the fact that baseline values measured were already close to normal at the time patients were enrolled into the Wachs mol BPH [ 24 ].
All studies listed, except the one conducted by Guven et al. Improvement Wachs mol BPH IPSS was significant in all treatment arms but most pronounced with the drug combinations. PVR, Q maxfrequency and nocturia were significantly improved with alfuzosin only and the combination Wachs mol BPH [ 2526 ].
Both drug regimens improved Q max and decreased PVR. However, no significant differences between tamsulosin only vs. At study end point, IPSS scores had improved significantly when compared with baseline values [ 28 ]. A very recent study conducted by Tuncel et al.
The authors found that the improvements in IPSS, Q max and PRV were significantly more pronounced in those patients who had received the combination therapy than in those who were Wachs mol BPH sildenafil citrate only. However, treatment with the drug combination did not enhance the improvements in IPSS and Wachs mol BPH symptoms seen in the tamsulosin group [ 29 ].
Some studies focused in particular on the urodynamic effects of PDE5 inhibitors on voiding function, including Q max and detrusor pressure at maximum urinary flow, in men with BPO. However, these improvements were not significant [ 3031 ]. A single dose of the PDE5 inhibitor 50 mg or mg resulted in an improvement in Q max in the patients. Q ave and the mean voided volumes of the patients also increased while no significant differences were registered in Q maxQ ave and voided volumes of the control group before and after placebo administration [ 3233 ].
It should be taken into consideration that the study design, and especially the small number of patients, made it rather difficult to Wachs mol BPH firm conclusions from these observations. It was shown by means of transrectal contrast-enhanced colour Doppler ultrasonography that perfusion of the transition zone of the prostate was significantly lower and mean flow Wachs mol BPH index significantly higher in men with BPH than in healthy controls.
Thus, it seems likely that the regular administration of a PDE5 inhibitor may, to a certain degree, overcome ischaemia due to vascular damage and normalize local blood flow patterns [ 34 — 36 ]. Anticholinergic drugs m-cholinoceptor antagonists are currently the therapy of choice to treat urgency and urgency incontinence, lately known as Wachs mol BPH overactive bladder syndrome OAB [ 37 ]. Wachs mol BPH, up until now, anticholinergic drugs acting exclusively on detrusor smooth muscle are not available.
Moreover, the unstable detrusor seems to be regulated in part by non-cholinergic mechanisms. This might explain the side effects and limited clinical efficacy of anticholinergic drugs [ 38 ]. Important central or peripheral non-cholinergic mechanisms known to be involved in the control of micturition involve purinergic, gamma aminobutyric acid GABAglutamatergic, opioid and serotoninergic receptors. Positive signals for drugs acting at other sites, such as the vitamin D analogue Wachs mol BPH and the neurokinin-1 receptor antagonist aprepitant, have also been found.
Although positive proof-of-principle studies are available for some of these therapeutic approaches, there is not sufficient information for proper clinical assessment and none of the strategies has so far been approved for treatment of OAB [ 3940 ]. However, the specific modulation of intracellular second messenger pathways may offer a promising possibility to achieve selective modulation of function of the urinary bladder, especially with regard to the contraction and relaxation of detrusor smooth muscle.
It was also described that the tension of human isolated detrusor strip preparations contracted by the muscarinic agonist carbachol was reversed by the non-specific PDE inhibitor papaverine and the PDE1 inhibitor vinpocetine. It was concluded from these findings that the cAMP pathway and PDE1 might be of significance in the control of detrusor smooth muscle.
This hypothesis is supported by the observation that the PDE4 inhibitor rolipram effectively inhibited the phasic myogenic contractile activity of human isolated detrusor smooth muscle.
It was proposed that PDE4 is involved in the control of the phasic myogenic activity of the human bladder and that inhibitors of PDE4 might represent an alternative strategy for the treatment of the OAB [ 44 ].
The reversal by sildenafil of the tonic contraction induced by the muscarinic agonist carbachol of human isolated detrusor strip preparations remained unaltered in the presence of the NO donor sodium nitroprusside but was significantly attenuated by the guanylyl cyclase inhibitor ODQ and adenylyl cyclase inhibitor MDl Studies on the expression and activity of PDE5 in the human Wachs mol BPH demonstrated that the enzyme is expressed in muscle fibres and the vascular endothelium [ 4748 ].
These results have been interpreted in terms that PDE5 is involved in mediating bladder smooth muscle relaxation and controlling tissue proliferation. Wachs mol BPH from a direct effect on the smooth muscle of the detrusor, there are also hints Wachs mol BPH PDE5 inhibitors may act in a way to help prevent deleterious alterations of the histological structure of the urinary bladder that may lead to disturbances in urine storage and voiding.
A link between structural and functional changes and the activity of mitochondrial key enzymes, such as the citrate synthase, malate dehydrogenase, succinate cytochrome c reductase, NADH cytochrome c reductase and cytochrome c oxidase, has been demonstrated [ 5253 ]. However, so far, no evidence has been presented that sildenafil or other PDE5 inhibitors can modify the activity of the mitochondrial energy supply, namely the citric acid cycle and electron transport chain.
Recently, the acute effects of the PDE5 inhibitor vardenafil Wachs mol BPH investigated in a single centre, randomized, double-blind, placebo-controlled trial in a group of 25 spinal cord injured males with micturition disorders who were on oxybutynin treatment. Following a baseline urodynamic evaluation, another urodynamic test was performed 1—3 h after the administration of 20 mg vardenafil or placebo.
Primary endpoints were changes in maximum detrusor pressure during voiding, maximum cystometric capacity and bladder volume at first overactivity sensation. Vardenafil administration significantly decreased maximum detrusor pressure, considerably improved cystometric capacity and increased volume at first sensation [ 55 ]. In an attempt to assess the role of PDE5 inhibitors in the recovery of urinary continence after bilateral nerve sparing radical Wachs mol BPH, 39 patients were assigned after surgery to three treatment arms in a double-blind fashion: vardenafil on demand, Wachs mol BPH daily at bed-time nightly or placebo.
Bother scores measure the distress associated with post-prostatectomy urinary dysfunctions while the UF domain reflects dryness rather than general voiding function in the patients. The improvement in UF and UB at month 1 and month 12 was significant in the vardenafil treatment groups.
Administration of the drug once Wachs mol BPH at bed-time resulted in greater UF after 3, 6 and 9 months and less UB after Wachs mol BPH months. The improvements in maximal recovery were also more pronounced. Patients who had received vardenafil daily at bed-time experienced less bother after 3 months and 6 months than those who were subjected to on-demand use [ 56 ]. Based on the knowledge of the mechanisms controlling the male and female urinary tract, the use of selective PDE inhibitors has been suggested as a logical approach for the treatment of various urological diseases.
Due to the unending challenge to conceive first-line treatments demonstrating advanced efficacy over the previous options, the strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunctions.
The authors would like to thank Mrs Nicola Jane Hitchcock-van Dornick Hannover, Germany for editing the linguistic style of the manuscript. National Center for Biotechnology InformationU. Br J Clin Pharmacol. Wachs mol BPH Ückert 1, 2 and Matthias Oelke 1. Author information Article notes Wachs mol BPH and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Several disorders of Wachs mol BPH human upper and lower urinary tract, such as urinary stone Wachs mol BPH, lower urinary tract symptoms LUTS due to benign prostatic hyperplasia BPH and detrusor overactivity, can be therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively.
Open in a separate window. PDE inhibitors and the overactive bladder OAB Findings from basic research studies Anticholinergic drugs m-cholinoceptor antagonists are currently the therapy of choice to treat urgency and urgency incontinence, lately known as the overactive bladder syndrome OAB [ 37 ]. Conclusions Based on Wachs mol BPH knowledge of the mechanisms controlling the male and female urinary tract, the use of selective PDE inhibitors has been suggested as a logical approach for the treatment of various urological diseases.
Acknowledgments The authors would like to thank Mrs Nicola Jane Hitchcock-van Dornick Hannover, Germany for editing Wachs mol BPH linguistic style of the manuscript. Competing interests There are no competing interests to declare. Cyclic GMP phosphodiesterase and smooth muscle function. Circ Res.
Cyclic nucleotide phosphodiesterase activity, expression, and targeting cells in the cardiovascular system. Mol Pharmacol. Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol. An update on Wachs mol BPH nucleotide phosphodiesterase PDE inhibitors: phosphodiesterases Wachs mol BPH drug selectivity.