Electromotive Administration Research Articles

Intravesical electromotive administration of botulinum toxin type A in improving the bladder and bowel functions: Evidence for novel mechanism of action

Objective: To examine the hypothesis that what is the concomitant mechanism of action botulinum toxin type A (BoNTA) administration by intravesical electromotive into the bladder resulting in bladder function improvement. We also tried to confirm the possibility of retrograde trans-axonal transportation of toxin. Design: Animal study. Setting: Ten male rabbits were divided into two groups. Participants: Group 1 (G1) (n = 5) (BoNTA/EMDA), and group 2 (G2) (n = 5) the control group. Interventions: Animals in G1received 10 IU/Kg of intravesical BoNTA through a specific catheter for electromotive drug administration (BoNTA/EMDA). About 0.1–0.15 ml of toxin was diluted in 1 ml of distilled water. The maximum frequency of the device for drug solution delivery was set at 4 mA for 15 min. In G2 as the control group, the same procedure was performed to deliver normal saline to the bladder. Outcome measures: Multiple biopsies were taken from bladder’s contiguous structures one month postoperatively. The immunohistochemical (IHC) evaluation was performed with anti-clostridium botulinum toxoid type A mouse IgM monoclonal antibody. Results: In specimens of G1, BoNTA penetrated through muscular layers of the bladder wall and the staining was uniform in the urothelium, interstitium, and muscular layers. Positive IHC staining showed that BoNTA was traced in the upper and lower spinal cord in addition to pelvic nerve, sacral nerve plexus, intestine wall, and pelvic floor muscle. In G2, all the specimens were intact in IHC staining. Conclusions: The presence of BoNTA in lower and upper spinal cord suggests the possibility of retrograde trans-axonal transfer of toxin to lower and upper neural pathways which may result in simultaneous improvement in bladder and bowel functions.

Symptoms-modifying effects of electromotive administration of glucosamine sulphate among patients with knee osteoarthritis.

Background:Most trials on symptom-modifying effects of glucosamine are limited to administration through oral route with dearth of empirical data on the use of electromotive force.Objective:The study determined the effects of glucosamine sulphate (GS) iontophoresis (IoT) on radiographic parameters of patients with knee osteoarthritis (OA).Methods:Fifty-three patients were randomly assigned to three groups. About 1 g each of GS was administered using IoT and cross-friction massage (CFM) for participants in groups 1 (IoT) and 2 (CFM), respectively. Group 3 ((Combined therapy) CoT) received 1 g of GS using both IoT and CFM. Interventions were twice a week for 12 weeks. Analysis of variance (ANOVA) was used to analyze the data ().Results:After 12 weeks, the medial joint space width (JSW) of the CFM group was significantly higher than that of IoT and CoT groups ( and ). Lateral JSW of IoT group was significantly higher than both CFM () and CoT groups (). There were significant decreases in pain intensities; increase in knee flexion and physical functions across the groups (; , respectively).Conclusion:It was concluded that there were significant decreases in the degenerative changes at the knee joint.

Endocavitary prophylaxis of superficial urothelial bladder tumours: new compounds

Bladder urothelial carcinoma is the fourth most frequent cancer among European men, accounting for about 7% of the total cancers. Transurethral resection (TUR) is usually indicated as the standard treatment for non-muscle invasive bladder cancer (NMIBC). However, TUR is unable to guarantee a complete eradication of Ta, T1 tumors with a recurrence rate ranging from 50 to 70%, and a progression rate to muscle invasive disease ranging from 10 to 15%. METHODS. The European Association of Urology guidelines recommend adjuvant intravesical chemotherapy after definitive diagnosis of intermediate/high risk NMIBC to reduce both recurrence and progression of the disease. To provide a comprehensive review of intravesical treatment options for NMIBC, we performed a search of the PubMed database for articles between 1980 and 2009 that reported on intravesical agents for treating this disease. RESULTS. A critical analysis of the findings resulting from large multicenter trials, phase I, II, III studies for pertinent novel agents and from review articles was carried out. We focused on the following issues: 1) the role of the treatment with Bacillus Calmette-Guérin (BCG) and the need of maintaining the drug schedule (with or without interferon- alpha); 2) the correct timing of adjuvant immuno- and chemotherapy; 3) the use of the novel chemotherapeutic agents; 4) the use of the novel technique of chemotherapeutic agents administration, with a particular interest on electromotive administration of mitomycin.

Electromotive Administration of Topical Medications in Clinical Physiotherapy Practice: A Review

Oral and injection routes of drug administration has adverse effect in the body system, hence, there is paradigm shift in route of drug administration to the use of electromotive force via the skin where applicable; and this by passes the first pass effect metabolism. Both iontophoresis and ultra-sonophoresis are examples of procedures for the electromotive administration of drugs. Potential serious side-effects are eliminated because transdermal routes of drug administration are known to possess little or no side effects. Iontophoresis is the introduction of medicinal ions into the body using Direct Current. It is a painless, sterile and non invasive technique with minimal adverse reactions in the gastro-intestinal system. The dose depends on current and time of treatment and a typical dosage is 40 mA-min. This review revealed that Iontophoresis is being used to subdue inflammation using topical Non-steroidal anti-inflammatory drugs, administer antibiotics to combat infection, manage bicep brachii spasticity of stroke survivours, promote wound healing, reduce bacteria colonization, combat fungal infection; and has produced analgesic effects in several studies. Also, the reviewed showed that ultrasonophoresis is relevant in clinical physiotherapy practice.

Comparison of transdermal electromotive administration of verapamil and dexamethasone versus intra‐lesional injection for Peyronie's disease

To compare the efficacy of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone for the treatment of Peyronie's disease. Patients with Peyronie's disease of less than 2-year duration were randomized into two groups of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone. During the 6-week therapy period, a single weekly dose of 10mg verapamil and 4mg dexamethasone solution was administered to 30 patients in each group either by transdermal electromotive method or via the conventional injection method by a syringe connected to a 25 G needle. Evaluations of plaque length, width, and volume, penile curvature, erectile dysfunction and penile deviations were carried out before and after 1 and 3months of the interventions. Erectile pain was reduced in the electromotive group from a mean of 5.1-1.0 in scale of 10 and from 5.4 to 3.6 in the injection group (p=0.006). Regarding plaque length, plaque width, penile curvature plaque volume and erectile dysfunction, the electromotive administration group showed better results which, however, were not statistically significant. (p>0.05). Transdermal electromotive drug administration yielded comparable results as against current conventional intra-lesional injection technique and fared better in controlling erectile pain.

Electromotive administration of mitomycin

In the September, 2011, issue of The Lancet Oncology, Savino Di Stasi and colleagues1 report the feasibility and safety of intravesical electromotive drug administration (EMDA) of mitomycin in non-muscle-invasive bladder cancer before transurethral resection of bladder tumours (TURBT). Their results were excellent; they showed that intravesical EDMA before TURBT reduces recurrence rates and enhances the disease-free interval compared with intravesical passive diffusion of mitomycin after TURBT and TURBT alone.

Concentration-depth profiles of mitomycin-C in the human bladder wall after passive diffusion, thermochemotherapy, and electromotive drug administration.

4568 Background: Device-assisted intravesical mitomycin-C (MMC), including electromotive administration (EMDA) and thermochemotherapy (TC), shows promise and offers the prospect of greater efficacy than passive diffusion (PD). Integration of drug delivery with tissue pharmacodynamic data provides a means to rational design of intravesical treatments. We compared concentration-depth profiles of MMC in the bladder wall after PD, TC and EMDA. Methods: During each experiment, 3 full thickness sections of viable human bladder wall were placed between the two chambers of individual diffusion cells, with urothelium exposed to donor compartments containing 40 mg of MMC in 100 ml water and with serosa-facing receptor compartments containing 100 ml of 0.9% NaCl solutions. Fifteen paired experiments were conducted over a 30-min period. In TC experiments, the two chamber cells were placed in a 37°C incubator with the donor compartments filled with heated MMC solutions at 44°C. In EMDA experiments an anode was placed in the donor compartment and a cathode in the receptor compartment. The electrodes were connected to the current generator and experiments were performed with pulsed direct current of 23 mA. No electric current or TC were applied in PD control experiments. Bladder wall sections were cut serially into 40-mm slices parallel to the urothelium, the tissues were homogenized and analyzed by high-performance liquid chromatography for MMC concentration. Results: Concentration-depth profiles of MMC in bladder wall tissues following PD, TC or EMDA are reported below (Table). Data are expressed as μ g of MMC/mg of wet tissue, the means ± standard error of the mean (SEM) of 15 replicates per experimental group. Conclusions: EMDA significantly enhances MMC transport into all of the layers of the bladder wall, compared to both PD and TC. The latter had no effect whatsoever on MMC transport into bladder wall tissues compared to PD. PD TC EMDA p value Urothelium (80-200 μ m) 53.057 ± 8.240 58.270 ± 8.820 207.991 ± 23.440 <0.001 Lamina propria(200-1,200 μ m) 18.095 ± 2.139 20.935 ± 3.205 85.339 ± 5.882 <0.001 Muscle layer(1,200-4,000 μ m) 2.120 ± 0.326 2.424 ± 0.297 24.888 ± 3.645 <0.001 No significant financial relationships to disclose.

Intravesical Electromotive Botulinum Toxin-A Administration: an Experimental Study

Purpose The method of Intravesical Electromotive Drug Administration (EMDA) has been applied for the treatment of enormous urological pathologies. However, there is no clinical or experimental report of intravesical botulinum toxin-A (BTX-A) administration in the literature. In this study, an animal model was designed to evaluate the depth of BTX-A penetration and its distribution pattern through rabbit bladder wall layers by the application of EMDA. Material and Methods Ten male healthy New Zealand white rabbits were selected, anesthetized and then, catheterized with a specific catheter containing a conducting electrode. The bladder was washed out with normal saline twice or more until the catheter output became clear. The animals were allocated into two groups, the EMDA group (I), a current generator delivered a total of 2 to 2.4 mA at the frequency of 2.5 kHz for 15 min to the fully distended bladder containing 10 IU/kg BTX-A (Dysport®, Ipsen Limited, UK) and two 2 cm × 2 cm dispersive pads, attached bilaterally parallel to midline at the level of distended bladder. In group II, electrical current with same characteristics was applied to the bladder filled with normal saline solution. For each bladder, three full- thickness from dome, posterior and anterior bladder were obtained and submitted for immunohistochemical staining with primary monoclonal antibody in a dilution of 4:100. The negative controls were processed similarly except the primary antibody was eliminated from the protocol. Results Immunohistochemical staining in EMDA group detected BTX-A at the level of eurothelium, interstitial and muscularis layers in the dome, posterior and anterior walls. In control group, all layers were intact. Conclusions In this study, intravesical electromotive BTX-A administration showed deep and homogenous penetration of the toxin throughout the urinary bladder layers.

Retrograde Dissemination Through Sacral Neural Pathways: Mechanism of Action for Botulinum Toxin Type A in Concomitant Neuropathic Bladder and Bowel Dysfunction

Purpose In our two previous studies with intravesical botulinum toxin type A (BTX-A) injection and electromotive BTX-A administration in children with myelomeningocele and neurogenic detrusor overactivity, notable improvement in concomitant bowel dysfunction occurred. The exact mechanism for this observation is still unclear but the effect of toxin on common neural pathways for urinary and bowel function and the diffusion of toxin to bladder's contiguous structures are existing hypotheses. This experimental model aimed at determining the validity of current hypotheses. Material and Methods Ten male white New Zealand rabbits were divided in two equal groups: the first group received intravesical 10 IU/kg BTX-A through a specific catheter for electromotive drug administration. A maximum current of 4 mA for 15 min was delivered to the drug solution. In another group, the electrical current with similar characteristics was delivered to the saline-filled bladder. Then, biopsies from the bladder wall and bladder's contiguous structures including intestinal wall lying posterior to the bladder, pelvic floor muscles, sacral neural plexus, and anal sphincter were taken and then submitted for immunohistochemical analysis. Results Botulinum toxin penetrated through muscularis layer of the bladder wall in BTX-A group. The toxin was not present in pelvic floor muscles, intestinal wall, and anal sphincter. The toxin was detected in sacral neural plexus in BTX-A group. Conclusions Botulinum toxin type A acts on neuromuscular junction. Current study suggests that retrograde dissemination of toxin through upper neural pathways which also control bowel motor function can justify simultaneously improved bladder and bowel function.

Endocavitary Prophylaxis of Superficial Urothelial Bladder Tumours: New Compounds

Bladder urothelial carcinoma is the fourth most frequent cancer among European men, accounting for about 7% of the total cancers. Transurethral resection (TUR) is usually indicated as the standard treatment for non-muscle invasive bladder cancer (NMIBC). However, TUR is unable to guarantee a complete eradication of Ta, T1 tumors with a recurrence rate ranging from 50 to 70%, and a progression rate to muscle invasive disease ranging from 10 to 15%. Methods The European Association of Urology guidelines recommend adjuvant intravesical chemotherapy after definitive diagnosis of intermediate/high risk NMIBC to reduce both recurrence and progression of the disease. To provide a comprehensive review of intravesical treatment options for NMIBC, we performed a search of the PubMed database for articles between 1980 and 2009 that reported on intravesical agents for treating this disease. Results A critical analysis of the findings resulting from large multicenter trials, phase I, II, III studies for pertinent novel agents and from review articles was carried out. We focused on the following issues: 1) the role of the treatment with Bacillus Calmette-Guérin (BCG) and the need of maintaining the drug schedule (with or without interferon-alpha); 2) the correct timing of adjuvant immuno- and chemotherapy; 3) the use of the novel chemotherapeutic agents; 4) the use of the novel technique of chemotherapeutic agents administration, with a particular interest on electromotive administration of mitomycin.

The effectiveness of transdermal electromotive administration with verapamil and dexamethasone in the treatment of Peyronie’s disease

To determine the effectiveness of transdermal electromotive administration (TEA) of verapamil and dexamethasone in the treatment of Peyronie's disease (PD). Totally, 51 patients with PD were prospectively included in the study. All patients were evaluated by history, subjective score scales, physical examination, photographs, and penile USG, before and after therapy. All patients were treated with TEA of the combination of verapamil and dexamethasone. The treatment plan included a total of 20 sessions (at 3-day intervals for a period of 2 months), each with a duration of 20 min. At the end of the study, improvements in penile plaques, penile deviation, pain on erection, and erectile dysfunction were determined. The findings in 41 of the 51 patients were eligible to present. Median patient age was 52 years. Median duration of disease at presentation was 8 months. Remarkable reduction in palpable plaques and in penile angulation was observed in 10 patients (24%) and 11 (26%) patients, respectively. There were significant decreases in median plaque volume from 72 mm(2) to 45 mm(2) (P < 0.001), and in median penile angulation from 25 degrees to 15 degrees (P < 0.001). Impaired sexual activity and pain on erection had completely resolved in 11 (55%) patients and in 16 (80%), respectively. The results of our study have shown that TEA of the combination of verapamil and dexamethasone is a more effective therapy for improving subjective symptoms rather than objective symptoms. Therefore, we think that this treatment can be individualized according to the clinical features of PD patients.

Daily Intravesical Instillation of 1 mg Nociceptin/Orphanin FQ for the Control of Neurogenic Detrusor Overactivity: A Multicenter, Placebo Controlled, Randomized Exploratory Study

We studied the feasibility, safety and efficacy of daily intravesical instillation of 1 mg of the endogenous peptide nociceptin/orphanin FQ in a selected group of patients who perform clean intermittent self-catheterization for neurogenic detrusor overactivity incontinence. A total of 18 patients with neurogenic detrusor overactivity incontinence and on clean intermittent self-catheterization were prospectively randomized to receive 1 mg nociceptin/orphanin FQ in 10 cc saline (9) or placebo (saline) solution (9) at the first morning catheterization for 10 days. All patients completed a voiding diary using a frequency/volume chart according to International Continence Society guidelines, and reported daily incontinence frequency. Mean changes in incontinence episode frequency and voiding diary mean bladder capacity from baseline throughout treatment were the primary outcome variables. Urodynamic parameters (cystomanometric bladder capacity, maximum bladder pressure) were also recorded at baseline and during the study. The 2 groups were well balanced and all patients completed the study. The urodynamic parameters recorded during the study showed an increase in cystomanometric bladder capacity and a decrease in maximum bladder pressure compared to baseline only in patients assigned to the nociceptin/orphanin FQ group. Mean daily urine leakage episodes during nociceptin/orphanin FQ treatment were 0.94 vs a pretreatment baseline of 2.18 (p < 0.05), while no significant changes were reported in the placebo group (2.06 vs 2.43 baseline). The total mean voiding diary bladder capacity increased from 171 +/- 70 to 294 +/- 107 ml in patients receiving nociceptin/orphanin FQ, while voiding diary mean bladder capacity remained unchanged in patients receiving placebo (from 182 +/- 55 to 178 +/- 23 ml). No significant problems related to feasibility of the procedure as well as significant side effects were reported by patients. This study showed that intravesical nociceptin/orphanin FQ but not placebo inhibited the micturition reflex in patients with neurogenic detrusor overactivity incontinence, and demonstrated the clinical efficacy of nociceptin/orphanin FQ during 10 days of treatment. These findings support the use of nociceptin/orphanin FQ peptide receptor agonists as an innovative therapeutic approach for controlling detrusor overactivity incontinence.

MP-03.10: The effect of transdermal electromotive administration (EMDA) of verapamil on the serum levels of transforming growth factor-beta (TGF-beta), metalloproteinase 1 (MMP1) and their inhibitors (TIMPs) in Peyronie’s disease

Verapamil, a calcium antagonist, is reported to suppress the activity of TGF-β and increase collagenase. The activity of collagens depends on the activity of inhibitors of metalloproteinase (TIMPs). In this study, we investigated the levels of TGF-β, MMP1 and TIMPs (TIMP1 and TIMP2) in the serum and blood from corpora cavernosa of patients with Peyronie’s disease and how these are affected by the EMDA.

A PROSPECTIVE, RANDOMIZED STUDY USING TRANSDERMAL ELECTROMOTIVE ADMINISTRATION OF VERAPAMIL AND DEXAMETHASONE FOR PEYRONIE’S DISEASE

Uncontrolled studies with intraplaque electromotive administration of verapamil and dexamethasone have demonstrated objective improvements in Peyronie's disease. We performed a prospective controlled study to assess the efficacy of intraplaque electromotive verapamil/dexamethasone vs electromotive lidocaine. Patients with Peyronie's disease were randomized into a study group (47 patients) and a control group (49 patients). For each treatment session an electrode receptacle was sited over the plaque and filled with either 5 mg verapamil and 8 mg dexamethasone (study group) or 2% lidocaine (control group), and a 2.4 mA electric current was applied for 20 minutes. All patients were scheduled for 4 sessions per week for 6 weeks. Assessment before and after treatment included measurements of plaque volume and penile curvature, and pain on erection (from questionnaire). A total of 37 patients in the study group and 36 in the control group completed treatment courses. In the study group there were significant decreases in median plaque volume from 824 to 348 mm, and in penile curvature from 43 to 21 degrees. In the control group median volume and curvature were unchanged. The difference in results after treatment between the 2 groups was also significant. Significant pain relief occurred in both groups, transient in the control group and permanent in the study group. All patients experienced temporary erythema at the electrode site. There were no other side effects. Intraplaque electromotive verapamil and dexamethasone induce substantial objective improvement in Peyronie's disease compared to electromotive lidocaine administration.

740 Prospective, randomized study using transdermal electromotive administration of verapamil and dexamethasone for Peyronie's disease

740 Prospective, randomized study using transdermal electromotive administration of verapamil and dexamethasone for Peyronie's disease

Intravesical Electromotive Mitomycin C Versus Passive Transport Mitomycin C for High Risk Superficial Bladder Cancer: A Prospective Randomized Study

In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment. Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed. The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p = 0.036) and 58% versus 31% (p = 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p = 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC (43 vs 8 ng/ml), consistent with bladder content absorption. Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer.

The stability of lidocaine and epinephrine solutions exposed to electric current and comparative administration rates of the two drugs into pig bladder wall.

Intravesical electromotive administration of local anesthetics is clinically successful but electrochemistry, cost and effectiveness limit the choice of drugs to diluted lidocaine HCl 4% mixed with epinephrine. These studies address the stability of lidocaine and epinephrine both over time and when exposed to electric current, i.e. transport rates with passive diffusion and electromotive administration. The drug mixture used was 50 ml lidocaine 4%, 50 ml H2O and 1 ml epinephrine 1/1000. For stability, the solution was placed either in bowls for 7 days or in a two chamber cell with the donor compartment (drugs) separated from the receptor compartment (NaCl solution) by a viable pig bladder wall. This was subjected to 30 mA for 45 min. Stability was measured with mass spectrometry. The cell was also used to determine transport rates with passive diffusion and currents of 20 mA and 30 mA, over 20, 30 and 45 min. Drug measurements in both compartments and bladder were made with HPLC. Lidocaine remained stable throughout the 7 days, epinephrine on day 1 only and both drugs were stable with 30 mA for 45 min. Comparing 20 mA and 30 mA with passive diffusion, there were significant differences in 6/6 donor compartment lidocaine levels, 4/6 receptor compartment levels and 6/6 bladder tissue levels and also in 6/6 epinephrine donor levels and 6/6 tissue levels. The combination lidocaine and epinephrine remains stable for 1 day and when exposed to 30 mA for 45 min. Electric current accelerates the transport of lidocaine and epinephrine.

Intravesical bacillus Calmette-Guerin vs passive diffusion and electromotive administration of mitomycin C in patients with carcinoma in situ of the bladder: a randomised cross over study

Intravesical bacillus Calmette-Guerin vs passive diffusion and electromotive administration of mitomycin C in patients with carcinoma in situ of the bladder: a randomised cross over study

INTRAVESICAL OXYBUTYNIN: MODE OF ACTION ASSESSED BY PASSIVE DIFFUSION AND ELECTROMOTIVE ADMINISTRATION WITH PHARMACOKINETICS OF OXYBUTYNIN AND N-DESETHYL OXYBUTYNIN

A proportion of patients with detrusor hyperreflexia who are unresponsive to oral oxybutynin often benefit from intravesical oxybutynin instillation. To our knowledge the precise mode of action of this method is obscure. In 12 patients with detrusor hyperreflexia who were previously unresponsive to oral and intravesical passive diffusion of 5 mg. oxybutynin we administered 5 mg. oxybutynin orally as well as increased doses of 15 mg. oxybutynin intravesically with passive diffusion and with 15 mA. associated electric current. Each administration mode per patient was associated with an 8-hour urodynamic monitoring session during which oxybutynin and N-desethyl oxybutynin plasma levels, and intravesical oxybutynin uptake were measured. A dose of 5 mg. oxybutynin orally induced no urodynamic improvement with an area under the plasma concentration time curve of combined N-desethyl oxybutynin plus oxybutynin of 16,297 ng./8 hours and an area under the curve ratio of N-desethyl oxybutynin-to-oxybutynin of 11:1. Passive diffusion oxybutynin resulted in 12 mg. oxybutynin intravesical uptake and significant improvement in 3 of 8 urodynamic measurements, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was only 2,123 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was 1.1:1.0. Electromotive administration of oxybutynin resulted in almost complete intravesical uptake of the 15 mg. dose, significant improvement in all 8 urodynamic measurements and an increased oxybutynin level versus oral and passive diffusion, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was 4,574 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was inverted at 1.0:1.4. The oral dose of 5 mg. oxybutynin caused anticholinergic side effects in 8 of the 12 patients. Neither intravesical passive diffusion nor electromotive administration caused side effects with an uptake of 12 and 15 mg., respectively. A large proportion of intravesical oxybutynin is sequestered, probably in the urothelium. Intravesical oxybutynin administration confers therapeutic benefits via localized direct action within the bladder wall.

INTRAVESICAL ELECTROMOTIVE ADMINISTRATION OF OXYBUTYNIN IN PATIENTS WITH DETRUSOR HYPERREFLEXIA UNRESPONSIVE TO STANDARD ANTICHOLINERGIC REGIMENS

About 15% to 20% of patients with detrusor hyperreflexia do not benefit from oral oxybutynin regimens, frequently because of unpleasant side effects. Several reports indicate that intravesical oxybutynin is effective in many of these patients but there are some who still fail to respond. A select group of 10 adults with detrusor hyperreflexia unresponsive to standard oral and intravesical oxybutynin regimens were treated at weekly intervals with 5 mg. oxybutynin orally, or 5 mg. oxybutynin in 100 ml. intravesically for 60 minutes of passive diffusion and for 30 minutes with 5 mA. electrical current. Each treatment (plus oral placebo and 2 intravesical controls) was associated with an 8-hour, full urodynamic monitoring session, and periodic blood and bladder content sampling. There was no significant objective improvement with oral or intravesical passive diffusion oxybutynin. Conversely there was significant improvement in 5 of 6 objective urodynamic measurements with intravesical electromotive oxybutynin. Plasma profiles were a single peak and decay following oral oxybutynin and 2 distinct peaks with intravesical passive diffusion and electromotive oxybutynin. Area under the curve for intravesical passive diffusion were 709 ng. per 8 hours versus oral 1,485 (p <0.05) versus intravesical electromotive 2,781 (p <0.001). Bladder content samples confirmed oxybutynin absorption. Oral oxybutynin caused anticholinergic side effects in 7 of 10 patients. There were no side effects with intravesical passive diffusion or electromotive administrations. Accelerated intravesical administration results in greater bioavailability and increased objective benefits without side effects in previously unresponsive patients compared with oral and intravesical passive diffusion oxybutynin administration.