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Biomedical subjects

M B Chancellor

Publications and source records attributed to M B Chancellor.

At least 37 records · Page 2Linked to original sources
PubMed2001

A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate.

BACKGROUND: Oxybutynin chloride and tolterodine tartrate are anticholinergic agents used to suppress involuntary bladder contractions in urinary incontinence. They act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. The same types of muscarinic receptors are found in the salivary glands; thus anticholinergic agents may decrease saliva production and cause dry mouth, a commonly cited reason for discontinuation of therapy. OBJECTIVE: The primary objective of this study was to compare saliva output, which is an objective measure of dry mouth, in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo. METHODS: This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4-period crossover study. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. Saliva output was measured objectively before dosing with each treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing. RESULTS: Thirty-six healthy adult volunteers (22 women and 14 men) participated in the study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. There were no significant differences in predose saliva output between the 4 study groups. With placebo, saliva output increased throughout the day. Saliva output was maintained at predose levels throughout the day with extended-release oxybutynin. Two hours after dosing with tolterodine and immediate-release oxybutynin, saliva output decreased nearly 0.5 g in specimens collected over 2 minutes. All 3 active treatments were associated with lower saliva output compared with placebo. Extended-release oxybutynin and tolterodine were similar with respect to area under the saliva concentration-time curve but were associated with significantly greater saliva output than was immediate-release oxybutynin (P < 0.01). There were no serious adverse events (AEs) in this study. AEs were similar between treatments, although the incidence of headache was higher in the active-treatment groups than with placebo. CONCLUSIONS: Objective assessment of saliva output in healthy adult volunteers indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediate-release oxybutynin, suggesting that they may yield lower levels of dry mouth.

Adult↗
PubMed2001

Gene therapy strategies for urological dysfunction.

Novel molecular techniques such as conventional and ex vivo gene therapy, and tissue engineering have only recently been introduced to the field of urology. The lower urinary tract is ideally suited for minimally invasive therapy, and also ex vivo approaches would limit the risk of systemic side effects. Muscle-derived stem cells have been used successfully to treat stress incontinence, and rats with diabetic bladder dysfunction benefited from nerve growth factor (NGF)-based gene therapy. Nitric oxide synthase and capase-7 might provide suitable gene therapy targets for erectile dysfunction and benign prostatic hyperplasia, respectively.

Animals↗
PubMed2001

Effect of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride.

UNLABELLED: Aims : Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL [(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined. METHODS: This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for approximately 16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations. RESULTS: Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P = 0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P = 0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy. CONCLUSIONS: Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.

Administration, Oral↗
PubMed2001

Neural control of the urethra.

Coordination between the urinary bladder and the urethra is mediated by multiple reflex pathways organized in the brain and spinal cord. Some reflexes promote urine storage; whereas other reflexes facilitate voiding. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter (EUS) and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes are dependent upon interneuronal circuitry in the spinal cord. During voiding the spinal storage reflexes are inhibited by supraspinal mechanisms which originate in the pontine micturition center. Glutamatergic, serotonergic and alpha, adrenergic excitatory transmission as well as GABAergic/glycinergic inhibitory transmission have been implicated in the central control of sphincter reflexes. During voiding, a parasympathetic nitrergic inhibitory input to the urethral smooth is activated. This reflex mechanism which is triggered by bladder afferents persists in paraplegic rats and therefore must be mediated at least in part by spinal interneuronal circuitry. In female rats, the parasympathetic nitrergic pathway is prominent; but in male rats it is obscured by a dominant parasympathetic cholinergic excitatory input to the urethral smooth muscle. The function of the cholinergic pathway in voiding is uncertain. Stimulation of urethral afferents can also influence bladder activity. Contraction of the external urethral sphincter activates afferents that inhibit reflex bladder contractions; whereas infusion of fluid through the urethra facilitates bladder contractions. These reflexes are also organized in the spinal cord and presumably play a role in urine storage and elimination. Alterations in primitive bladder-to-urethra and urethra-to-bladder reflex mechanisms may contribute to neurogenic bladder dysfunction.

Afferent Pathways↗
PubMed2001

Autologous primary muscle-derived cells transfer into the lower urinary tract.

The goal of these experiments was to establish the basic methodology for future clinical applications of muscle-derived cells (MDC) tissue engineering and gene transfer for the treatment of urological dysfunction. Primary MDC isolated via preplating techniques from adult female SD rats were transduced with retrovirus encoding the expression of beta-galactosidase reporter gene. The MDC were injected into the right and left lateral walls of the bladder and proximal urethra of the autologous animals (n = 6) with a 10 microl Hamilton micro syringe. The amount of injected MDC ranged from 1 to 2 x 10(6) cells. The injected tissue was harvested after 7, 14, and 28 days, sectioned and examined histologically for beta-galactosidase and immunohistochemically for fast myosin heavy chain specific to skeletal muscle. The tissues were also stained for anti-CD4 and anti-CD8 antibodies to assess for cellular immune reaction. We have detected a large number of autologous MDC expressing beta-galactosidase and positively stained for fast myosin heavy chain in the bladder and urethral wall. Many injected myoblasts and myotubes were also seen in the bladder and urethral wall at each time point. Staining of lymphocytes with anti-CD4 and anti-CD8 antibodies was negative after MDC injection at each time point. We have demonstrated the long-term survival of autologous MDC and MDC mediated gene transfer into the bladder and urethral wall. Autologous MDC and MDC mediated gene transfer may be a promising treatment to augment bladder and urethral sphincter function.

Animals↗
PubMed2001

Gene therapy and tissue engineering for urologic dysfunction: status and prospects.

This article reviews the recent advances in gene therapy and tissue engineering for urologic dysfunction. Although the number of gene therapy-based clinical trials has increased dramatically in the field of urologic oncology, such trials are still few within the neurourologic field. Recently, new biologic approaches employing growth factors have been utilized to treat various pathological conditions. Among them, transfer of genes such as those encoding growth factors represents a promising way to deliver therapeutic proteins to malfunctioning tissues, which leads to the improvement of organ function. Tissue engineering, which may eventually be combined with gene therapy, also offers the potential to create new functional genitourinary tissue for regeneration and replacement of tissue lost as a consequence of disease. Thus, both tissue engineering and gene therapy may hold promising new solutions in the urologic field.

Animals↗
PubMed2001

Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adenovirus-transduced myoblast vectors.

BACKGROUND AND PURPOSE: Nitric oxide (NO) has been recognized as an important transmitter for genitourinary tract function. This transmitter mediates smooth muscle relaxation and is essential for erection. The objective of our research was to determine whether overexpression of nitric oxide synthase (NOS) in the corpus cavernosum of the penis would correct erectile dysfunction. MATERIALS AND METHODS: We introduced the inducible form of the enzyme NOS (iNOS) into the corpus cavernosum of adult (250-300 g) male Sprague-Dawley rats by injecting a solution of plasmid, adenovirus, or adenovirus-transduced myoblast cells (adeno-myoblast) (N = 3-5 each group). We also injected plasmid, adenovirus, and adeno-myoblast encoding the expression of the beta-gatactosidase reporter gene. RESULTS: We noted expression of beta-galactosidase throughout the corpora cavernosum after injection of each of the three solutions. Staining was greatest for adeno-myoblast followed by adenovirus and then plasmid. The basal intracavernous pressure (ICP) of iNOS-treated animals (adenovirus and adenovirus-transduced myoblast) increased to 55 +/- 23 cm H(2)O v 5 +/- 6 H(2)O in naive animals (P = 0.001). Stimulation of the cavernous nerve (15 Hz, 1.5 msec, 10-40 V, 1 min) resulted in a twofold increase in ICP (adenovirus and adeno-myoblast) from the basal level of the iNOS-treated animals. Direct in situ measurement of NO demonstrated release of 1 to 1.3 microM NO in the adeno-myoblast-treated penis. CONCLUSION: Myoblast-mediated gene therapy was more successful in delivering iNOS into the corpus cavernosum than were the direct adenovirus or plasmid transfection methods. Gene therapy of NOS may open new avenues of treatment for erectile dysfunction. Control of NOS expression would be necessary to prevent priapism.

Adenoviridae↗
PubMed2001

Efficacy of sacral nerve stimulation for urinary retention: results 18 months after implantation.

PURPOSE: We investigate the efficacy of sacral neurostimulation in patients with idiopathic urinary retention in a prospective, randomized multicenter trial. MATERIALS AND METHODS: A total of 177 patients with urinary retention refractory to standard therapy were enrolled in the study. Greater than 50% improvement in baseline voiding symptoms during a 3 to 7-day percutaneous test stimulation qualified a patient for surgical implantation of an InterStim parallel system. Of the patients who qualified for implantation 37 were randomly assigned to a treatment and 31 to a control group. Patients in the treatment group underwent early surgical implantation of the sacral nerve stimulation system, while implantation was delayed in the control group for 6 months. Followup evaluations, including voiding diary analysis and temporary deactivation of the stimulator at 6 months, were conducted at 1, 3, 6, 12 and 18 months after implantation in the treatment group, and after 3 and 6 months in the control group. RESULTS: Compared to the control group, patients implanted with the InterStim system had statistically and clinically significant reductions in the catheter volume per catheterization (p <0.0001). Of the patients treated with implants 69% eliminated catheterization at 6 months and an additional 14% had a 50% or greater reduction in catheter volume per catheterization. Therefore, successful results were achieved in 83% of the implant group with retention compared to 9% of the control group at 6 months. Temporary inactivation of sacral nerve stimulation therapy resulted in a significant increase in residual volumes (p <0.0001) but effectiveness of sacral nerve stimulation was sustained through 18 months after implant. CONCLUSIONS: Results of this prospective, randomized clinical study demonstrate that sacral nerve stimulation is effective for restoring voiding in patients with retention who are refractory to other forms of treatment.

Adult↗
PubMed2001

Persistence and survival of autologous muscle derived cells versus bovine collagen as potential treatment of stress urinary incontinence.

PURPOSE: We explored the use of autologous muscle derived cells as a method of treating stress urinary incontinence. We determined whether urethral muscle derived cell injection is feasible and compared it with bovine collagen injection. MATERIALS AND METHODS: Muscle derived cells isolated from female Sprague-Dawley rats were first transduced with retrovirus carrying the transgene for beta-galactosidase. We injected approximately 1 to 1.5 x 106 cells into the bladder wall and proximal urethra of 6 autologous animals. Tissue was harvested after 3 and 30 days, sectioned, stained for fast myosin heavy chain and assayed for beta-galactosidase. To compare muscle derived cell and bovine collagen injections 100 microl. of commercially available bovine collagen were also injected in Sprague-Dawley female rats. Tissue was harvested in 3 animals each after 3 and 30 days, sectioned and stained for trichrome. Subsequently, 3 adult SCID mice were used to compare the level of transgene expression at each time point after injecting 1.5 x 106 cells per injection, which were transduced with adenovirus carrying the transgene for beta-galactosidase. RESULTS: A large number of cells expressing beta-galactosidase were observed in the bladder and urethral wall 3 and 30 days after autologous cell injection in Sprague-Dawley rats. The persistence of primary muscle derived cells at 3 days was similar to that of collagen. However, at 30 days there was significant cell persistence while only a minimal amount of injected bovine collagen was detectable. Approximately 88% of the beta-galactosidase expression at day 3 remained at day 30 in SCID mice. CONCLUSIONS: We present 2 new findings important for the emerging field of urological tissue engineering, including the feasibility of injecting autologous skeletal muscle derived cells into the lower urinary tract and the greater persistence of such injected cells versus injected bovine collagen. Therefore, autologous muscle derived cell injection may be an attractive alternative treatment option for stress urinary incontinence.

Animals↗
PubMed2001

Analysis of the afferent limb of the vesicovascular reflex using neurotoxins, resiniferatoxin and capsaicin.

The afferent limb of the vesicovascular reflex (VV-R) evoked by distension or contraction of the urinary bladder (UB) was studied in urethane-anesthetized female rats by examining the changes in VV-R after administration of C-fiber afferent neurotoxins [capsaicin and resiniferatoxin (RTX)]. Systemic arterial blood pressure increased parallel (5.1 to 53.7 mmHg) with graded increases in UB pressure (20 to 80 cm H(2)O) or during UB contractions. The arterial pressor response to UB distension was significantly reduced (60-85%) by acute or chronic (4 days earlier) intravesical administration of RTX (100-1,000 nM) or by capsaicin (125 mg/kg sc) pretreatment (4 days earlier). Chronic neurotoxin treatments also increased the volume threshold (>100%) for eliciting micturition in anesthetized rats but did not change voiding pressure. Acute RTX treatment (10-50 nM) did not alter the arterial pressor response during reflex UB contractions, whereas higher concentrations of RTX (100-1,000 nM) blocked reflex bladder contractions. It is concluded that VV-R is triggered primarily by distension- and contraction-sensitive C-fiber afferents located, respectively, near the luminal surface and deeper in the muscle layers of the bladder.

Administration, Intravesical↗
PubMed2001

Feasibility of a temporary urethral stent through the striated sphincter in patients in the early phase (6 months) of spinal cord injury.

OBJECTIVE: To assess the feasibility of a temporary urethral stent through the striated sphincter in patients in the early phase (before 6 months) of spinal cord injury (SCI) in a department of neurological rehabilitation. METHODS: Fourteen consecutive men with SCI with urinary retention within 6 months after SCI were prospectively treated. Thirteen patients were tetraplegic (C2 to C7) and 1 was paraplegic. All patients were managed with indwelling catheters (10) or intermittent catheterization (4). The Nissenkorn polyurethane urethral stent was inserted across the external sphincter under local anesthesia for an anticipated 4-month duration. RESULTS: No perioperative complications were encountered. Hospital mean stay at the urological department was 1.9 days (range 1-4 days). All patients had good emptying of the bladder (residual urine less than 100 ml) and were free of all types of catheterization. Five stents had to be repositioned in the first 2 weeks, 1 was removed for obstruction at 2.5 months. There was no lithiasis, no upper urinary tract alteration, no symptomatic infection nor local discomfort during follow-up. At a mean of 3.7 months after implantation, 10/14 (71.5%) patients chose sphincterotomy by permanent urethral stent and 4 had stent removal for learning of self-intermittent catheterization (3) and indwelling catheter (1). CONCLUSIONS: The temporary sphincter stent is a new, feasible and reversible technique to manage neuropathic bladder dysfunction in the early phase after SCI. A randomized study on intermittent catheterization should be conducted. It should consider patients' and nursing caregivers' evaluations.

Adult↗
PubMed2001

The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor.

PURPOSE: Interstitial cystitis, a chronic disease of the bladder, is characterized by urinary frequency, urgency and suprapubic pain. Nerve growth factor is a substance that may sensitize afferent nerves and induce bladder hyperactivity. It is often increased in the urine of patients with interstitial cystitis. We evaluated the role of Adelta and C fiber afferents in the type of bladder hyperactivity induced by the intravesical administration of nerve growth factor. MATERIALS AND METHODS: A total of 22 Wistar and 8 Sprague-Dawley adult female rats were anesthetized with 1.2 gm/kg urethane given subcutaneously. A transurethral catheter was inserted into the bladder. Some animals were pretreated with 125 mg/kg capsaicin injected subcutaneously 4 days before nerve growth factor administration. Cystometry was performed by slowly filling the bladder at a rate of 0.04 ml per minute for 15 minutes with a volume of up to 0.6 ml. Parameters measured included volume threshold and pressure threshold for inducing the micturition reflex, compliance, bladder contraction amplitude, number of contractions and the inter-contraction interval. Nerve growth factor (0.5 ml of 20 microg/ml in 10% dimethyl sulfoxide) or a vehicle solution (0.5 ml of 10% dimethyl sulfoxide) was infused into the bladder through a transurethral catheter and retained for 1 hour. RESULTS: In Wistar rats nerve growth factor increased the mean number of contractions by 111% versus controls (5.7 versus 2.7, p <0.05), and decreased the mean volume threshold by 41% (0.244 versus 0.412 ml, p <0.05). This effect of nerve growth factor was not detected in Sprague-Dawley rats. Capsaicin pretreatment increased the volume threshold by 59% but did not change nerve growth factor induced bladder hyperactivity. CONCLUSIONS: The intravesical application of nerve growth factor acutely induced bladder hyperactivity in Wistar but not in Sprague-Dawley rats. Because the C fiber afferent neurotoxin capsaicin did not change the effect of nerve growth factor, we believe that Adelta afferent neurons have a major role in nerve growth factor induced bladder hyperactivity.

Administration, Intravesical↗
PubMed2001

Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction.

PURPOSE: Botulinum toxin injection into the external urinary sphincter in spinal cord injured men with detrusor-sphincter dyssynergia has been reported. We expand the clinical use of botulinum toxin for a variety of bladder outlet obstructions and to decrease outlet resistance in patients with acontractile detrusor but who wish to void by the Valsalva maneuver. MATERIALS AND METHODS: Prospective treatment was performed for voiding dysfunction in 8 men and 13 women 34 to 74 years old. The reasons for voiding dysfunction included neurogenic detrusor-sphincter dyssynergia in 12 cases, pelvic floor spasticity in 8 and acontractile detrusor in 1 patient with multiple sclerosis who wished to void by the Valsalva maneuver. Using a rigid cystoscope and a collagen injection needle, a total of 80 to 100 units of botulinum A toxin (Botox) were injected into the external sphincter at the 3, 6, 9 and 12 o'clock positions. RESULTS: Preoperatively 19 of 21 patients were on indwelling or intermittent catheterization. After botulinum A injection all but 1 patient were able to void without catheterization. No acute complications, such as general paralysis or respiratory depression, occurred and none of the patients had dribbling or stress urinary incontinence. Postoperative post-void residual decreased by 71% and voiding pressures decreased on average 38%. Of the 21 patients 14 (67%) reported significant subjective improvement in voiding. Followup ranges from 3 to 16 months, with a maximum of 3 botulinum A injections in some patients. CONCLUSIONS: Urethral sphincter botulinum injection should be considered for complex voiding dysfunction. Encouraging improvement without complications were seen in most of our patients. We have expanded the use of botulinum toxin to treat pelvic floor spasticity and also women.

Adult↗
PubMed2001

Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain.

PURPOSE: Refractory genitourinary pain is a common but difficult condition to treat. Examples of chronic genitourinary pain include orchalgia, interstitial cystitis, pain after bladder suspension surgery, nonbacterial prostatitis, and genital pain related to lumbosacral neuropathy. We report our experience with oral gabapentin treatment for this condition. Gabapentin is an anticonvulsant with unclear but therapeutic effects on neurologic pain. MATERIALS AND METHODS: Twenty-one patients referred with refractory genitourinary pain were treated with oral gabapentin. There were 9 men and 12 women. In the male patients, the location of pain was testicle (4), bladder (2), penis (1), or prostate (2). In female patients, the pain was located in the urethra (4), bladder (6), vulva (1), or vagina (1). The dose of gabapentin was titrated from 300 up to 2,100 mg/day. Subjective pain severity and 10-cm visual pain scale was used before and 6 months after therapy. RESULTS: The mean dose of gabapentin was 1,200 mg/day (range 300-2,100 mg). Ten of 21 patients reported subjective improvement of their pain. The remaining patients did not perceive any improvement. Gabapentin was well tolerated; only 4 patients dropped out due to side effects. The most common adverse effects were dizziness and drowsiness. Five of 8 patients with interstitial cystitis reported improvement. CONCLUSIONS: Although only 10 of 21 patients improved with gabapentin, this cohort included only patients with refractory genitourinary pain that failed a wide range of prior treatments. Gabapentin belongs in the armaterium of the urologist who treats genitourinary pain.

Acetates↗
PubMed2001

Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: potential treatment for diabetic bladder dysfunction.

PURPOSE: Diabetic cystopathy resulting from sensory neuropathy may potentially be treated by direct gene therapy. It has been suggested that nerve growth factor (NGF) has an ameliorative effect in preventing the death in diabetes of afferent dorsal root ganglion neurons, which control bladder function. We investigated NGF gene transfer to the bladder and bladder afferent pathways for treating diabetic cystopathy. We used replication competent and replication defective herpes simplex virus type 1 (HSV-1) vectors that express a functionally active form of the beta-subunit of mouse NGF (beta-NGF) to examine the level and duration of therapeutic gene expression after administration of the vectors. MATERIALS AND METHODS: NGF expression during acute (3 days) and latent (21 days) infections was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical testing after the injection of 1 x 106 to 1 x 108 pfu HSV-NGF expression vectors into the bladder wall of adult rats. RESULTS: HSV vectors with the strong human cytomegalovirus immediate early promoter used to drive beta-NGF gene expression exhibited increased NGF 3 days after infection in the bladder and L6 to S1 dorsal root ganglia, where bladder afferent neurons are located. ELISA analysis revealed that NGF in the bladder tissue and dorsal root ganglia was increased 7 to 9 and 2 to 4-fold, respectively, over the control vector. Increased NGF expression in L6 to S1 dorsal root ganglia neurons was also detected by immunohistochemical staining with antiNGF antibodies. Extended NGF expression was detected by ELISA 21 days after injection. Replication defective vectors containing HSV-1 latency promoter (LAP-2) driving NGF expressed NGF in the bladder and dorsal root ganglia 21 days after bladder injection. ELISA analysis confirmed an approximate 2 to 3-fold increase of NGF expression in the bladder and L6 to S1 dorsal root ganglia. CONCLUSIONS: The NGF gene may be transferred and expressed in the bladder and bladder afferent pathways using HSV vectors. To our knowledge our study represents the first demonstration of the effectiveness of gene therapy for altering neurotrophic expression in visceral sensory neurons. This technique of gene transfer may be useful for treating certain types of neurogenic bladder dysfunction, such as diabetic cystopathy, in which decreased NGF transport may be a causative factor.

Animals↗