Several recent reports have indicated an increased prevalence of gallstones in association with p... more Several recent reports have indicated an increased prevalence of gallstones in association with pregnancy. If these reports are true, the early puerperium should be a favorable time to detect the disease in its initial stages and follow its natural course. Accordingly, the gallbladder was examined by ultrasound in 980 women during the immediate postpartum period and in 150 nulliparous, age-matched healthy volunteers. Gallstones were detected in 12.2% of the puerperal women and in 1.3% of the control group. In 70 patients who had stones in a functioning gallbladder, 22 (31%) had had attacks of biliary colic. The history of pain was more common in patients with stones greater than 10 mm in diameter. Forty-one women with small stones (< 10 mm) were followed clinically and ultrasonographically for between 6 and 24 (mean = 8.7) mo. All remained pain-free, and in twelve subjects (29%) the stones disappeared. Gallbladder bile was examined in 11 normal volunteers (controls) immediately after delivery and in 19 women with small stones 39 +/- 6 days postpartum. Bile was saturated with cholesterol in the controls and was unsaturated in patients with gallstones. We conclude that in our population pregnancy is a very important pathogenetic factor favoring gallstone formation. Attacks of biliary colic appear early and frequently in young Chilean women with this disease. Unexplained disappearance of small stones frequently occurs: in some cases it is likely to be the result of spontaneous dissolution because bile becomes unsaturated within a few weeks of delivery.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
During the last few years, vanilloid substances and botulinum-A toxin were extensively investigat... more During the last few years, vanilloid substances and botulinum-A toxin were extensively investigated as new therapies for overactive bladder. Intravesical administration of capsaicin or resiniferatoxin-2 members of the vanilloid family-has been shown to increase bladder capacity and decrease urge incontinence in patients with neurogenic, as well as nonneurogenic, forms of detrusor overactivity. In addition, vanilloids have been shown also to reduce bladder pain in patients with hypersensitive disorders. Vanilloids are exogenous ligands of vanilloid receptor type 1 (VR1), an ion channel present in the membrane of type C primary afferent nerve fibers. This receptor, which plays a key role in pain perception and control of the micturition reflex, may be upregulated by nerve growth factor (NGF), a neurotrophic molecule detected in high concentrations in overactive detrusor tissue. Vanilloids, by reducing uptake of NGF through sensory neurons, may counteract VR1 upregulation. Intravesical injections of botulinum-A toxin, a neurotoxin produced by Clostridium botulinum, were shown to increase bladder capacity and to decrease urge incontinence episodes in patients with neurogenic detrusor overactivity. Botulinum-A toxin impedes the release of acetylcholine from cholinergic nerve endings at the neuromuscular junction, leading to paralysis of the detrusor smooth muscle. UROLOGY 63 (Suppl 3A): 65-73, 2004.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
Objectives: To evaluate the effect of bladder C-fiber desensitization on BPH-associated storage L... more Objectives: To evaluate the effect of bladder C-fiber desensitization on BPH-associated storage LUTS. Methods: Twelve patients with predominant BPH-associated storage LUTS gave written informed consent to enter the study. IPSS and QoL scores, micturition chart, uroflowmetry, cystometry and post-void residual (PVR) were obtained at baseline and at 1, 3 and 6 months after a single intravesical administration of 50 nM resiniferatoxin (RTX) solution. Results: Mean IPSS score decreased from 20:1 AE 6:0 to 10:5 AE 4:4 at 1 month ( p ¼ 0:0001), to 10:3 AE 4:4 at 3 months ( p ¼ 0:00001) and to 9:8 AE 5:7 at 6 months ( p ¼ 0:00001). Mean QoL score decreased from 4:5 AE 1 to 2:5 AE 1 at 1 month ( p ¼ 0:0001), to 2:3 AE 1 at 3 months ( p ¼ 0:0004) and to 2:6 AE 1:2 at 6 months ( p ¼ 0:0003). Mean urinary frequency decreased from 15:2 AE 8:5 to 10:8 AE 7:3 at 1 month ( p ¼ 0:0002), to 10:2 AE 4:9 at 3 months ( p ¼ 0:002) and to 11:7 AE 9:2 at 6 months ( p ¼ 0:005). Urge incontinence, which was present in six cases, disappeared in 4 patients and decreased to less than half in the other two. Mean first desire to void and maximal cystometric capacity increased significantly after RTX whereas uroflowmetry and PVR were not altered. Conclusions: Intravesical desensitization of bladder C fibres with intravesical RTX might be useful in the treatment of patients with predominant BPH associated storage LUTS. #
Background: Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involut... more Background: Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involution and improve LUTS and urinary flow in patients with Benign Prostatic Enlargement (BPE). However, the duration of these effects is unknown. The objective of this work was to determine the duration of prostate volume reduction after one single intraprostatic injection of 200U of Botulinum Toxin Type-A.
In this study the desensitizing power of increasing concentrations of resiniferatoxin applied top... more In this study the desensitizing power of increasing concentrations of resiniferatoxin applied topically to the bladder mucosa, and the irritating properties of the most effective desensitizing dose, were determined with the aid of the spinal expression of the proto-oncogene c-fos. Desensitization was assessed by the decrease in the number of Fos-immunoreactive spinal neurons induced by the intravesical instillation of 1% acetic acid, when the latter was preceded by resiniferatoxin in concentrations between 1 and 1000 nM. Irritation, as shown by the noxious excitation of vesical sensory innervation, was measured by the c-fos response evoked by a single application of resiniferatoxin. As to the desensitizing power, resiniferatoxin produced a dose-dependent effect with a maximum at 100 nM, which decreased Fos-immunoreactive cell numbers to less than 10% of controls. No further decrease of c-fos activation occurred at 1000 nM. As to the irritating power, the saturation dose of resiniferatoxin (100 nM) produced a very weak c-fos activation in lumbosacral spinal cord segments. These data show that in an effective desensitizing concentration, resiniferatoxin is virtually devoid of nociceptive effects, in agreement with current clinical observations.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
urethane anaesthesia, a needle was inserted in the bladder dome and saline infused at 6 mL/h for ... more urethane anaesthesia, a needle was inserted in the bladder dome and saline infused at 6 mL/h for 2 h. Finally the animals were perfusion-fixed through the ascending aorta with 4% paraformaldehyde. Transverse sections cut from L6 spinal cord segments were immunoreacted for Fos protein and positive cells in the dorsal horn counted. In a further set of equal groups the bladders were prepared in the same way under urethane anaesthesia and after 30-min of stabilization, saline was infused at 6 mL/h and the volume evoking reflex micturition determined.
Naunyn-schmiedebergs Archives of Pharmacology, 2006
The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by cap... more The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by capsaicin, heat, protons and endogenous ligands such as anandamide. It is largely expressed in the urinary tract of mammals. Structures in which the receptor expression is firmly established include sensory fibers and urothelial cells, although the presence of TRPV1 in other cell types has been reported. As in other systems, pain perception was the first role attributed to TRPV1 in the urinary tract. However, it is now increasingly clear that TRPV1 also regulates the frequency of bladder reflex contractions, either through direct excitation of sensory fibers or through urothelial-sensory fiber cross talk involving the release of neuromediators from the epithelial cells. In addition, the recent identification of the receptor in urothelial and prostatic cancer cells raise the exciting hypothesis that TRPV1 is involved in cell differentiation. Desensitization of the receptor by capsaicin and resiniferatoxin has been investigated for therapeutic purposes. For the moment, lower urinary tract dysfunctions in which some benefit was obtained include painful bladder syndrome and overactive bladder of neurogenic and non-neurogenic origin. However, desensitization may become obsolete when non-toxic, potent TRPV1 antagonists become available.
We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of... more We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of noxious bladder input and bladder overactivity associated with cystitis. Spinal c-fos expression triggered by innocuous bladder distention (10 cm water) was studied in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Bladder reflex activity was studied using urethane anesthesia in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Inflammatory changes in the bladder of transient receptor potential vanilloid subfamily 1 +/+ and -/- mice were identical. Bladder distention in sham inflamed +/+ mice induced a mean +/- SD of 4 +/- 2 Fos cells per section. Bladder distention after lipopolysaccharide inflammation increased Fos cells to 34 +/- 5 (p <0.001). The number of Fos cells after bladder distention in sham and lipopolysaccharide inflamed -/- mice was similar (2 +/- 1 and 2 +/- 1, respectively, p >0.05). During saline infusion of sham inflamed bladders in +/+ mice 0.46 +/- 0.14 contractions per minute were documented. In lipopolysaccharide inflamed +/+ mice that frequency was increased to 1.13 +/- 0.12 contractions per minute (p <0.001). In sham and lipopolysaccharide inflamed -/- mice bladder frequency was similar (0.47 +/- 0.08 and 0.61 +/- 0.10, respectively, p >0.05). Our data demonstrate that transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity associated with cystitis.
Activation of the c-fos proto-oncogene following mechanical or chemical noxious stimulation of th... more Activation of the c-fos proto-oncogene following mechanical or chemical noxious stimulation of the urinary bladder was studied at T12-L2 and L5-S1, the spinal cord segments of projection of the hypogastric nerve (HGN) and pelvic nerve (PN) fibers, respectively. In intact adult rats, c-fos expression was found at T12-L2 only in lamina I. At L5-S1, Fos cells occurred in lamina I, the intermediolateral gray matter (ILG), and the dorsal commissure (DCM). These two areas contained the highest number of immunoreactive cells. Although more Fos cells were induced by mechanical than by chemical stimulation, the distribution of the reactive neurons was similar after both types of stimuli. In adult rats that had been treated neonatally with capsaicin, there was a marked fall in c-fos activation by mechanical or chemical noxious stimuli in all immunoreactive areas. The loss of Fos cells was more pronounced in ILG and DCM at L5-S1 (95%) than in lamina I at the two spinal domains (70%). The confinement of c-fos activation to lamina I at T12-L2, the spinal cord domain of the HGN, suggests that the input carried from the bladder by this nerve is preferentially used for pain perception. The same function is expected for noxious input reaching lamina I at L5-S1, the spinal cord territory of termination of the PN. However, the striking number of Fos cells in ILG and DCM supports the important role played by this nerve in the control of the micturition reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
Objectives: To determine the distribution of sensory fibers immunoreactive to the pain receptor T... more Objectives: To determine the distribution of sensory fibers immunoreactive to the pain receptor TRPV1 in the human prostate. Methods: Eight prostates were harvested from cadaver transplant donors and immediately immersion fixed. Longitudinal and transverse 20 mm sections were cut on a cryostat and immunoreacted with two anti-human TPRV1 antibodies. Results: TRPV1-immunoreactive nerve fibers were distributed throughout the prostatic urethral mucosa, verumontanum, ejaculatory ducts and periurethral prostatic acini. In the urethral mucosa, TRPV1-immunoreactive fibers penetrated the epithelial layer up to its surface. In the transitional and peripheral zones of the gland no TRPV1immunoreactive nerve fibers were detected. Conclusions: The existence of a rich TRPV1 sensory innervation in the human prostate may open new therapeutic perspectives for the treatment of pain in patients with chronic prostatitis (Chronic Pelvic Pain Syndrome). #
Activation of the protooncogene c-los at spinal cord segments T12-L2 and L5-$1 was used to study ... more Activation of the protooncogene c-los at spinal cord segments T12-L2 and L5-$1 was used to study the effects of topical administration of capsaicin on bladder primary afferents coursing in the hypogastric (HGN) or pelvic (PN) nerves of adult rats. Two hours after capsaicin instillation in the bladder numerous Fos cells occurred in lamina I at T12-L2 and in lamina I, intermediolateral gray matter (ILG) and dorsal commissure (DCM) at L5-S1. Twenty-four hours later, the Fos immunoreaction had disappeared from the spinal cord. At this time, instillation of 1% acetic acid into the bladder of capsaicin-treated rats induced considerably fewer Fos cells than in animals that had been instilled only with the vehicle solution for capsaicin. The difference in the average number of Fos cells was statistically significant in lamina I, ILG and DCM at L5-S1 but not in lamina I at T12-L2. Thus, intravesical capsaicin at the doses used excites bladder primary afferents coursing in the HGN and PN, but only desensitizes those coursing in the PN. It is suggested that this may depend on the differential occurrence of capsaicin receptors in the two nerves.
OBJECTIVETo evaluate the short-term surgical complications and results of a tension-free vaginal ... more OBJECTIVETo evaluate the short-term surgical complications and results of a tension-free vaginal tape (TVT) system (TVT-SecurTM, Gynecare, Ethicon, Somerville, NJ, USA) in the treatment of female stress urinary incontinence (SUI).To evaluate the short-term surgical complications and results of a tension-free vaginal tape (TVT) system (TVT-SecurTM, Gynecare, Ethicon, Somerville, NJ, USA) in the treatment of female stress urinary incontinence (SUI).PATIENTS AND METHODSTVT-Secur was applied to 107 women with SUI through a vaginal incision and left abutting the urethra. Postoperative pain, complications, de novo lower urinary tract symptoms, incontinence cure rate and the King’s Health Questionnaire (KHQ) score were evaluated.TVT-Secur was applied to 107 women with SUI through a vaginal incision and left abutting the urethra. Postoperative pain, complications, de novo lower urinary tract symptoms, incontinence cure rate and the King’s Health Questionnaire (KHQ) score were evaluated.RESULTSThe operative duration was 12 min; the mean pain score was 2.3 and only one patient had transient voiding difficulties. After a mean follow-up of 15 months, 71% of the patients were dry and 14% improved. The KHQ scores decreased significantly for most subscores. Urgency appeared de novo in six patients (5.6%), and vaginal erosion required one TVT-Secur explantation.The operative duration was 12 min; the mean pain score was 2.3 and only one patient had transient voiding difficulties. After a mean follow-up of 15 months, 71% of the patients were dry and 14% improved. The KHQ scores decreased significantly for most subscores. Urgency appeared de novo in six patients (5.6%), and vaginal erosion required one TVT-Secur explantation.CONCLUSIONThis study shows that TVT-Secur is a simple and safe treatment for female SUI, but before recommending this sling as a first choice for treating SUI, TVT-Secur must pass the test of time and comparative studies with conventional slings.This study shows that TVT-Secur is a simple and safe treatment for female SUI, but before recommending this sling as a first choice for treating SUI, TVT-Secur must pass the test of time and comparative studies with conventional slings.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
The effects of the local anesthetic lidocaine on the noxious excitation and subsequent desensitiz... more The effects of the local anesthetic lidocaine on the noxious excitation and subsequent desensitization of bladder sensory fibers, produced by intravesical capsaicin, were evaluated through c-fos activation in the spinal cord. Noxious excitation was demonstrated by counting Fos-immunoreactive (IR) cells occurring in the rat spinal cord 2 hours after intravesical administration of 1 mM. capsaicin, preceded or not by 2% lidocaine. Desensitization was studied by comparing the number of Fos-IR cells induced by 1% acetic acid in rats treated 24 hours before with 1 mM. intravesical capsaicin preceded or not by 2% lidocaine. Lidocaine instilled previously markedly reduced the number of Fos-IR spinal cells responding to capsaicin-induced bladder afferent excitation. Numbers of Fos-IR cells induced by acetic acid instillation in bladders desensitized by capsaicin administrated 24 hours before were not changed by lidocaine application prior to capsaicin. These findings suggest that local anesthetic pretreatment of the bladder with lidocaine reduces the capsaicin-induced noxious excitation of the sensory fibers without decreasing their subsequent desensitization.
Several recent reports have indicated an increased prevalence of gallstones in association with p... more Several recent reports have indicated an increased prevalence of gallstones in association with pregnancy. If these reports are true, the early puerperium should be a favorable time to detect the disease in its initial stages and follow its natural course. Accordingly, the gallbladder was examined by ultrasound in 980 women during the immediate postpartum period and in 150 nulliparous, age-matched healthy volunteers. Gallstones were detected in 12.2% of the puerperal women and in 1.3% of the control group. In 70 patients who had stones in a functioning gallbladder, 22 (31%) had had attacks of biliary colic. The history of pain was more common in patients with stones greater than 10 mm in diameter. Forty-one women with small stones (< 10 mm) were followed clinically and ultrasonographically for between 6 and 24 (mean = 8.7) mo. All remained pain-free, and in twelve subjects (29%) the stones disappeared. Gallbladder bile was examined in 11 normal volunteers (controls) immediately after delivery and in 19 women with small stones 39 +/- 6 days postpartum. Bile was saturated with cholesterol in the controls and was unsaturated in patients with gallstones. We conclude that in our population pregnancy is a very important pathogenetic factor favoring gallstone formation. Attacks of biliary colic appear early and frequently in young Chilean women with this disease. Unexplained disappearance of small stones frequently occurs: in some cases it is likely to be the result of spontaneous dissolution because bile becomes unsaturated within a few weeks of delivery.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
During the last few years, vanilloid substances and botulinum-A toxin were extensively investigat... more During the last few years, vanilloid substances and botulinum-A toxin were extensively investigated as new therapies for overactive bladder. Intravesical administration of capsaicin or resiniferatoxin-2 members of the vanilloid family-has been shown to increase bladder capacity and decrease urge incontinence in patients with neurogenic, as well as nonneurogenic, forms of detrusor overactivity. In addition, vanilloids have been shown also to reduce bladder pain in patients with hypersensitive disorders. Vanilloids are exogenous ligands of vanilloid receptor type 1 (VR1), an ion channel present in the membrane of type C primary afferent nerve fibers. This receptor, which plays a key role in pain perception and control of the micturition reflex, may be upregulated by nerve growth factor (NGF), a neurotrophic molecule detected in high concentrations in overactive detrusor tissue. Vanilloids, by reducing uptake of NGF through sensory neurons, may counteract VR1 upregulation. Intravesical injections of botulinum-A toxin, a neurotoxin produced by Clostridium botulinum, were shown to increase bladder capacity and to decrease urge incontinence episodes in patients with neurogenic detrusor overactivity. Botulinum-A toxin impedes the release of acetylcholine from cholinergic nerve endings at the neuromuscular junction, leading to paralysis of the detrusor smooth muscle. UROLOGY 63 (Suppl 3A): 65-73, 2004.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
Objectives: To evaluate the effect of bladder C-fiber desensitization on BPH-associated storage L... more Objectives: To evaluate the effect of bladder C-fiber desensitization on BPH-associated storage LUTS. Methods: Twelve patients with predominant BPH-associated storage LUTS gave written informed consent to enter the study. IPSS and QoL scores, micturition chart, uroflowmetry, cystometry and post-void residual (PVR) were obtained at baseline and at 1, 3 and 6 months after a single intravesical administration of 50 nM resiniferatoxin (RTX) solution. Results: Mean IPSS score decreased from 20:1 AE 6:0 to 10:5 AE 4:4 at 1 month ( p ¼ 0:0001), to 10:3 AE 4:4 at 3 months ( p ¼ 0:00001) and to 9:8 AE 5:7 at 6 months ( p ¼ 0:00001). Mean QoL score decreased from 4:5 AE 1 to 2:5 AE 1 at 1 month ( p ¼ 0:0001), to 2:3 AE 1 at 3 months ( p ¼ 0:0004) and to 2:6 AE 1:2 at 6 months ( p ¼ 0:0003). Mean urinary frequency decreased from 15:2 AE 8:5 to 10:8 AE 7:3 at 1 month ( p ¼ 0:0002), to 10:2 AE 4:9 at 3 months ( p ¼ 0:002) and to 11:7 AE 9:2 at 6 months ( p ¼ 0:005). Urge incontinence, which was present in six cases, disappeared in 4 patients and decreased to less than half in the other two. Mean first desire to void and maximal cystometric capacity increased significantly after RTX whereas uroflowmetry and PVR were not altered. Conclusions: Intravesical desensitization of bladder C fibres with intravesical RTX might be useful in the treatment of patients with predominant BPH associated storage LUTS. #
Background: Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involut... more Background: Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involution and improve LUTS and urinary flow in patients with Benign Prostatic Enlargement (BPE). However, the duration of these effects is unknown. The objective of this work was to determine the duration of prostate volume reduction after one single intraprostatic injection of 200U of Botulinum Toxin Type-A.
In this study the desensitizing power of increasing concentrations of resiniferatoxin applied top... more In this study the desensitizing power of increasing concentrations of resiniferatoxin applied topically to the bladder mucosa, and the irritating properties of the most effective desensitizing dose, were determined with the aid of the spinal expression of the proto-oncogene c-fos. Desensitization was assessed by the decrease in the number of Fos-immunoreactive spinal neurons induced by the intravesical instillation of 1% acetic acid, when the latter was preceded by resiniferatoxin in concentrations between 1 and 1000 nM. Irritation, as shown by the noxious excitation of vesical sensory innervation, was measured by the c-fos response evoked by a single application of resiniferatoxin. As to the desensitizing power, resiniferatoxin produced a dose-dependent effect with a maximum at 100 nM, which decreased Fos-immunoreactive cell numbers to less than 10% of controls. No further decrease of c-fos activation occurred at 1000 nM. As to the irritating power, the saturation dose of resiniferatoxin (100 nM) produced a very weak c-fos activation in lumbosacral spinal cord segments. These data show that in an effective desensitizing concentration, resiniferatoxin is virtually devoid of nociceptive effects, in agreement with current clinical observations.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
urethane anaesthesia, a needle was inserted in the bladder dome and saline infused at 6 mL/h for ... more urethane anaesthesia, a needle was inserted in the bladder dome and saline infused at 6 mL/h for 2 h. Finally the animals were perfusion-fixed through the ascending aorta with 4% paraformaldehyde. Transverse sections cut from L6 spinal cord segments were immunoreacted for Fos protein and positive cells in the dorsal horn counted. In a further set of equal groups the bladders were prepared in the same way under urethane anaesthesia and after 30-min of stabilization, saline was infused at 6 mL/h and the volume evoking reflex micturition determined.
Naunyn-schmiedebergs Archives of Pharmacology, 2006
The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by cap... more The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by capsaicin, heat, protons and endogenous ligands such as anandamide. It is largely expressed in the urinary tract of mammals. Structures in which the receptor expression is firmly established include sensory fibers and urothelial cells, although the presence of TRPV1 in other cell types has been reported. As in other systems, pain perception was the first role attributed to TRPV1 in the urinary tract. However, it is now increasingly clear that TRPV1 also regulates the frequency of bladder reflex contractions, either through direct excitation of sensory fibers or through urothelial-sensory fiber cross talk involving the release of neuromediators from the epithelial cells. In addition, the recent identification of the receptor in urothelial and prostatic cancer cells raise the exciting hypothesis that TRPV1 is involved in cell differentiation. Desensitization of the receptor by capsaicin and resiniferatoxin has been investigated for therapeutic purposes. For the moment, lower urinary tract dysfunctions in which some benefit was obtained include painful bladder syndrome and overactive bladder of neurogenic and non-neurogenic origin. However, desensitization may become obsolete when non-toxic, potent TRPV1 antagonists become available.
We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of... more We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of noxious bladder input and bladder overactivity associated with cystitis. Spinal c-fos expression triggered by innocuous bladder distention (10 cm water) was studied in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Bladder reflex activity was studied using urethane anesthesia in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Inflammatory changes in the bladder of transient receptor potential vanilloid subfamily 1 +/+ and -/- mice were identical. Bladder distention in sham inflamed +/+ mice induced a mean +/- SD of 4 +/- 2 Fos cells per section. Bladder distention after lipopolysaccharide inflammation increased Fos cells to 34 +/- 5 (p <0.001). The number of Fos cells after bladder distention in sham and lipopolysaccharide inflamed -/- mice was similar (2 +/- 1 and 2 +/- 1, respectively, p >0.05). During saline infusion of sham inflamed bladders in +/+ mice 0.46 +/- 0.14 contractions per minute were documented. In lipopolysaccharide inflamed +/+ mice that frequency was increased to 1.13 +/- 0.12 contractions per minute (p <0.001). In sham and lipopolysaccharide inflamed -/- mice bladder frequency was similar (0.47 +/- 0.08 and 0.61 +/- 0.10, respectively, p >0.05). Our data demonstrate that transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity associated with cystitis.
Activation of the c-fos proto-oncogene following mechanical or chemical noxious stimulation of th... more Activation of the c-fos proto-oncogene following mechanical or chemical noxious stimulation of the urinary bladder was studied at T12-L2 and L5-S1, the spinal cord segments of projection of the hypogastric nerve (HGN) and pelvic nerve (PN) fibers, respectively. In intact adult rats, c-fos expression was found at T12-L2 only in lamina I. At L5-S1, Fos cells occurred in lamina I, the intermediolateral gray matter (ILG), and the dorsal commissure (DCM). These two areas contained the highest number of immunoreactive cells. Although more Fos cells were induced by mechanical than by chemical stimulation, the distribution of the reactive neurons was similar after both types of stimuli. In adult rats that had been treated neonatally with capsaicin, there was a marked fall in c-fos activation by mechanical or chemical noxious stimuli in all immunoreactive areas. The loss of Fos cells was more pronounced in ILG and DCM at L5-S1 (95%) than in lamina I at the two spinal domains (70%). The confinement of c-fos activation to lamina I at T12-L2, the spinal cord domain of the HGN, suggests that the input carried from the bladder by this nerve is preferentially used for pain perception. The same function is expected for noxious input reaching lamina I at L5-S1, the spinal cord territory of termination of the PN. However, the striking number of Fos cells in ILG and DCM supports the important role played by this nerve in the control of the micturition reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
Objectives: To determine the distribution of sensory fibers immunoreactive to the pain receptor T... more Objectives: To determine the distribution of sensory fibers immunoreactive to the pain receptor TRPV1 in the human prostate. Methods: Eight prostates were harvested from cadaver transplant donors and immediately immersion fixed. Longitudinal and transverse 20 mm sections were cut on a cryostat and immunoreacted with two anti-human TPRV1 antibodies. Results: TRPV1-immunoreactive nerve fibers were distributed throughout the prostatic urethral mucosa, verumontanum, ejaculatory ducts and periurethral prostatic acini. In the urethral mucosa, TRPV1-immunoreactive fibers penetrated the epithelial layer up to its surface. In the transitional and peripheral zones of the gland no TRPV1immunoreactive nerve fibers were detected. Conclusions: The existence of a rich TRPV1 sensory innervation in the human prostate may open new therapeutic perspectives for the treatment of pain in patients with chronic prostatitis (Chronic Pelvic Pain Syndrome). #
Activation of the protooncogene c-los at spinal cord segments T12-L2 and L5-$1 was used to study ... more Activation of the protooncogene c-los at spinal cord segments T12-L2 and L5-$1 was used to study the effects of topical administration of capsaicin on bladder primary afferents coursing in the hypogastric (HGN) or pelvic (PN) nerves of adult rats. Two hours after capsaicin instillation in the bladder numerous Fos cells occurred in lamina I at T12-L2 and in lamina I, intermediolateral gray matter (ILG) and dorsal commissure (DCM) at L5-S1. Twenty-four hours later, the Fos immunoreaction had disappeared from the spinal cord. At this time, instillation of 1% acetic acid into the bladder of capsaicin-treated rats induced considerably fewer Fos cells than in animals that had been instilled only with the vehicle solution for capsaicin. The difference in the average number of Fos cells was statistically significant in lamina I, ILG and DCM at L5-S1 but not in lamina I at T12-L2. Thus, intravesical capsaicin at the doses used excites bladder primary afferents coursing in the HGN and PN, but only desensitizes those coursing in the PN. It is suggested that this may depend on the differential occurrence of capsaicin receptors in the two nerves.
OBJECTIVETo evaluate the short-term surgical complications and results of a tension-free vaginal ... more OBJECTIVETo evaluate the short-term surgical complications and results of a tension-free vaginal tape (TVT) system (TVT-SecurTM, Gynecare, Ethicon, Somerville, NJ, USA) in the treatment of female stress urinary incontinence (SUI).To evaluate the short-term surgical complications and results of a tension-free vaginal tape (TVT) system (TVT-SecurTM, Gynecare, Ethicon, Somerville, NJ, USA) in the treatment of female stress urinary incontinence (SUI).PATIENTS AND METHODSTVT-Secur was applied to 107 women with SUI through a vaginal incision and left abutting the urethra. Postoperative pain, complications, de novo lower urinary tract symptoms, incontinence cure rate and the King’s Health Questionnaire (KHQ) score were evaluated.TVT-Secur was applied to 107 women with SUI through a vaginal incision and left abutting the urethra. Postoperative pain, complications, de novo lower urinary tract symptoms, incontinence cure rate and the King’s Health Questionnaire (KHQ) score were evaluated.RESULTSThe operative duration was 12 min; the mean pain score was 2.3 and only one patient had transient voiding difficulties. After a mean follow-up of 15 months, 71% of the patients were dry and 14% improved. The KHQ scores decreased significantly for most subscores. Urgency appeared de novo in six patients (5.6%), and vaginal erosion required one TVT-Secur explantation.The operative duration was 12 min; the mean pain score was 2.3 and only one patient had transient voiding difficulties. After a mean follow-up of 15 months, 71% of the patients were dry and 14% improved. The KHQ scores decreased significantly for most subscores. Urgency appeared de novo in six patients (5.6%), and vaginal erosion required one TVT-Secur explantation.CONCLUSIONThis study shows that TVT-Secur is a simple and safe treatment for female SUI, but before recommending this sling as a first choice for treating SUI, TVT-Secur must pass the test of time and comparative studies with conventional slings.This study shows that TVT-Secur is a simple and safe treatment for female SUI, but before recommending this sling as a first choice for treating SUI, TVT-Secur must pass the test of time and comparative studies with conventional slings.
Recent experimental studies have identified a category of unmyelinated type C bladder afferent fi... more Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.
Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patie... more Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity in patients with idiopathic detrusor instability.
The effects of the local anesthetic lidocaine on the noxious excitation and subsequent desensitiz... more The effects of the local anesthetic lidocaine on the noxious excitation and subsequent desensitization of bladder sensory fibers, produced by intravesical capsaicin, were evaluated through c-fos activation in the spinal cord. Noxious excitation was demonstrated by counting Fos-immunoreactive (IR) cells occurring in the rat spinal cord 2 hours after intravesical administration of 1 mM. capsaicin, preceded or not by 2% lidocaine. Desensitization was studied by comparing the number of Fos-IR cells induced by 1% acetic acid in rats treated 24 hours before with 1 mM. intravesical capsaicin preceded or not by 2% lidocaine. Lidocaine instilled previously markedly reduced the number of Fos-IR spinal cells responding to capsaicin-induced bladder afferent excitation. Numbers of Fos-IR cells induced by acetic acid instillation in bladders desensitized by capsaicin administrated 24 hours before were not changed by lidocaine application prior to capsaicin. These findings suggest that local anesthetic pretreatment of the bladder with lidocaine reduces the capsaicin-induced noxious excitation of the sensory fibers without decreasing their subsequent desensitization.
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