Udo Jonas

Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder.

OBJECTIVES To evaluate the efficacy and tolerability of a new extended-release (ER), once-daily, capsule formulation of tolterodine, relative to placebo and the existing immediate-release (IR), twice-daily, tablet formulation, for treatment of the overactive bladder. METHODS This was a double-blind, multicenter, randomized, placebo-controlled trial. One thousand five hundred twenty-nine patients (81% women) with urinary frequency (eight or more micturitions every 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral therapy with tolterodine ER 4 mg once daily (n = 507), tolterodine IR 2 mg twice daily (n = 514), or placebo (n = 508) for 12 weeks. Efficacy was assessed at the end of the treatment period on the basis of the micturition diary variables. Tolerability and safety were assessed by evaluating the adverse events, electrocardiogram parameters, laboratory values, and treatment withdrawals. RESULTS Tolterodine ER 4 mg once daily (P = 0.0001) and tolterodine IR 2 mg twice daily (P = 0.0005) both significantly reduced the mean number of urge incontinence episodes per week compared with placebo. The median reduction in these episodes as a percentage of the baseline values was 71% for tolterodine ER, 60% for tolterodine IR, and 33% for placebo. The ER formulation was 18% more effective than the IR formulation (P <0.05). Treatment with both formulations of tolterodine was also associated with statistically significant improvements in all other micturition diary variables compared with placebo. For both formulations, the mean decreases in micturition frequency (P <0.0079) and pad usage (P <0.0145) were significant, and the mean volume voided per micturition increased (P = 0.0001). The rate of dry mouth (of any severity) was 23% for tolterodine ER, 30% for tolterodine IR, and 8% for placebo. The overall dry mouth rate for patients taking tolterodine ER was 23% lower than for tolterodine IR (P <0.02), and the rate of severe dry mouth in the ER group was only 1.8%. The rates of withdrawal were comparable for the two active groups and the placebo group. No safety concerns were noted. CONCLUSIONS Tolterodine ER 4 mg once daily is effective and well tolerated in the treatment of overactive bladder with no safety concerns. Tolterodine ER demonstrated an improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth compared with the existing IR twice-daily formulation.

Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention☆

Many patients have chronic, debilitating symptoms of voiding dysfunction that are refractory to conventional medical or surgical therapies. This multicenter, prospective study evaluated the long-term effectiveness of sacral nerve stimulation using the implantable Medtronic InterStim therapy for urinary control in patients with otherwise intractable complaints of urinary urge incontinence, urgency-frequency, or retention. Each patient first underwent temporary, percutaneous sacral nerve test stimulation. If at least a 50% reduction in target symptoms was documented for at least 3 days, patients received a permanent Medtronic InterStim sacral nerve stimulation system that includes a surgically implanted lead and neurostimulator. Regular follow-up was conducted with outcome data. We report here on patients who have been observed from 1.5 to 3 years postimplantation. The results demonstrate that after 3 years, 59% of 41 urinary urge incontinent patients showed greater than 50% reduction in leaking episodes per day with 46% of patients being completely dry. After 2 years, 56% of the urgency-frequency patients showed greater than 50% reduction in voids per day. After 1. 5 years, 70% of 42 retention patients showed greater than 50% reduction in catheter volume per catheterization. We conclude that the Medtronic InterStim therapy for urinary control system is an effective therapy with sustained clinical benefit for patients with intractable symptoms of urinary urge incontinence, urgency-frequency, or retention.

CHARACTERIZATION AND FUNCTIONAL RELEVANCE OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES OF THE HUMAN PROSTATE

PURPOSE Current pharmacological concepts in the treatment of benign prostatic hyperplasia are aimed at the static and dynamic component of the disease. Mainly alpha-blocking agents are used to reduce the adrenergic tone of prostatic myocytes, thus, increasing urine flow through the prostatic urethra by reducing urethral resistance. With the introduction of the phosphodiesterase (PDE) 5 inhibitor sildenafil the concept of PDE inhibition has gained tremendous interest in the field of urology. We characterized PDE isoenzymes from human prostatic tissue by molecular biology and protein chemistry, and investigated the effects of various PDE inhibitors compared with standard pharmacological agents on adrenergic tension in isolated human prostatic strips. MATERIALS AND METHODS PDE isoenzymes were characterized by reverse transcriptase-polymerase chain reaction and anion exchange chromatography. Using the organ bath technique we determined the relaxing effects of the PDE inhibitors papaverine, vinpocetine (Biomol GmbH, Hamburg, Germany), erythro-9-[2-hydrox-3-nonyl]adenine hydrochloride (Tocris Cookson, Ltd., Bristol, United Kingdom) rolipram (Schering AG, Berlin, Germany), zaprinast (Rhône-Poulenc Rorer, Ltd., Dagenham, United Kingdom) and sildenafil (Pfizer, Ltd., Sandwich, United Kingdom), the adenylate cyclase activating agent forskolin (ICN Biomedicals, Aurora, Ohio) and the nitric oxide donor sodium nitroprusside on adrenergic tension in prostatic strips isolated from the transition zone. RESULTS Reverse transcriptase-polymerase chain reaction revealed messenger RNA transcripts encoding for PDE 1, 2, 4, 5, 7, 8, 9 and 10 in the various anatomical regions of the human prostate, including the peripheral, central and transition zones. Except for complementary DNA encoding for PDE 1C, complementary DNA fragments encoding for PDE 1A, 1B, 2A, 4A, 4B, 4C, 4D, 5A, 7A, 8A, 9A and 10A were found at almost even ratios in the different histological regions of the prostate. The hydrolytic activities of PDE 4 and 5 were present in the cytosolic fraction of prostatic tissue, whereas in the particulate fraction only the hydrolytic activity of PDE 4 was detected. Adrenergic tension in prostatic strip preparations was reversed by forskolin, sodium nitroprusside, and inhibitors of PDE 4 and 5. CONCLUSIONS Our results demonstrate the presence and functional relevance of PDE isoenzymes 4 and 5 in human prostatic tissue. These studies support the possible use of inhibitors of PDE 4 and 5 for treating urinary obstruction secondary to benign prostatic hyperplasia.

Neuromodulation of voiding dysfunction and pelvic pain

SummaryNeuromodulation of sacral roots provides an alternative mode of therapy for patients presenting with voiding dysfunctions and chronic pelvic pain. Physiologically, this is accomplished by intervention in the neuronal pathways of micturition via sacral nerve-root electrical stimulation. Preoperative evaluation using temporary percutaneous sacral root stimulation selects the patients who are most likely to benefit from permanent electrode implantation. To date, no evidence of peripheral nerve damage has been recorded. Our experience with >1500 percutaneous tests and 150 permanent foramen implant procedures documents the safety and efficacy of this technique.

Age and Bladder Outlet Obstruction Are Independently Associated with Detrusor Overactivity in Patients with Benign Prostatic Hyperplasia

BACKGROUND Detrusor overactivity is one known cause of lower urinary tract symptoms and has been linked to bladder storage symptoms (urgency, frequency, or urge incontinence). OBJECTIVE To determine clinical and urodynamic parameters associated with detrusor overactivity in patients with suspected benign prostatic hyperplasia. DESIGN, SETTING, AND PARTICIPANTS During 1993-2003, urodynamic investigations were performed in patients aged 40 yr or older and with lower urinary tract symptoms, benign prostatic enlargement, and/or suspicion of bladder outlet obstruction (maximum flow rate < 15 ml/s or postvoid residual urine > 50 ml). MEASUREMENTS Detrusor overactivity was defined according to the new International Continence Society classification (2002) as involuntary detrusor contractions during cystometry, which may be spontaneous or provoked, regardless of amplitude. The Schäfer algorithm was used to determine bladder outlet obstruction. RESULTS In total, 1418 men were investigated (median age: 63 yr) of whom 864 men (60.9%) had detrusor overactivity. In univariate analysis, men with detrusor overactivity were significantly older, more obstructed, had larger prostates, higher irritative International Prostate Symptoms Score subscores, a lower voiding volume at free uroflowmetry, and a lower bladder capacity at cystometry. The prevalence of detrusor overactivity rose continuously with increasing bladder outlet obstruction grade. Multivariate analysis showed that only age and bladder outlet obstruction grade were independently associated with detrusor overactivity. After age adjustment, the odds ratios of detrusor overactivity compared to Schäfer class 0 were 1.2 for class I, 1.4 for class II, 1.9 for class III, 2.5 for class IV, 3.4 for class V, and 4.7 for class VI. CONCLUSIONS In patients with clinical benign prostatic hyperplasia, detrusor overactivity is independently associated with age and bladder outlet obstruction. The probability of detrusor overactivity rises with increasing age and bladder outlet obstruction grade.

Long–Term Effectiveness of Sacral Nerve Stimulation for Refractory Urge Incontinence

Objectives: To evaluate the long–term efficacy of sacral nerve stimulation for refractory urinary urge incontinence. Study Design and Methods: Urge incontinent patients qualified for surgical implantation of a neurostimulator system after trial screening with percutaneous test stimulation. Surgical implantation of the InterStim System (Medtronic Inc., Minneapolis, Minn., USA) was performed in cases where a >50% reduction in incontinence symptoms was documented during the 3– to 7–day test stimulation period. The InterStim System consists of an implantable pulse generator, a transforamenally placed quadripolar lead, and an extension that connects these two devices for unilateral stimulation of the S3 or S4 sacral nerve. Efficacy for 96 implanted patients was based on urinary symptom changes as quantified in voiding diaries collected at baseline and annually after surgical implantation. Results: As compared to baseline, the group of 96 implanted patients demonstrated significant reductions in urge incontinent symptoms at an average of 30.8±14.8 (range 12–60) months with respect to the number of urge incontinent episodes per day, severity of leaking, and the number of absorbent pads/diapers replaced per day due to incontinence (all p<0.0001, respectively). Gender, pretreatment variables, and age were not found to be relevant factors that affected these results. 11 of the 96 patients underwent device explant due to lack of efficacy, pain or bowel dysfunction. These data were conservatively included in the efficacy results. No permanent injuries associated with the devices or therapy were reported. Conclusion: Sacral nerve stimulation is an effective treatment for refractory urge incontinence with sustained long–term benefit through an average of 30.8 months.

Efficacy and safety of two doses of tolterodine versus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and urgency : urodynamic evaluation

SummaryTolterodine is a new competitive muscarinic receptor antagonist developed for the treatment of the unstable bladder. A total of 242 patients were enrolled in a multicenter, multinational, randomized, double-blind, placebo-controlled study conducted over a period of 4 weeks in patients with detrusor overactivity and symptoms of frequency, urgency, and urge incontinence. The objective of the study was to compare the efficacy and safety of tolterodine given at 1 or 2 mg b.i.d. versus placebo. At week 4 a statistically significant increase in the volume at first contraction (p = 0.030) and maximal cystometric capacity (p = 0.034) was only in the tolterodine 2 mg b.i.d. group. Tolterodine was safe and generally well tolerated. The incidence of dry mouth, as the most commonly reported adverse event, was only 9% and of mild to moderate intensity.

THE EFFECT OF THE SPECIFIC PHOSPHODIESTERASE (PDE) INHIBITORS ON HUMAN AND RABBIT CAVERNOUS TISSUE IN VITRO AND IN VIVO

PURPOSE Phosphodiesterases (PDE) are key enzymes in the regulation of the smooth muscle tone. Experimental studies showed PDE III and V-isoenzymes to play an important role in the smooth muscle tone regulation of corpus cavernosum. Recently, a specific PDE III-inhibitor (milrinone) and a PDE V-inhibitor (sildenafil) were introduced in clinical studies. An experimental study was done to examine a potential role of PDE-inhibitors in the treatment of erectile dysfunction. MATERIALS AND METHODS In the organ bath, strips from human and rabbit corpus cavernosum were precontracted and increasing doses of PDE inhibitors were added. In patients with erectile dysfunction as well as in rabbits, intracavernous injections of milrinone were done. RESULTS PDE-inhibitors dose-dependently relaxed human and rabbit corpus cavernosum strips. In the precontracted human cavernous tissue, milrinone and sildenafil were equally potent and efficacious in vitro. In the rabbit, milrinone induced slight tumescence but dramatic circulatory side effects. In patients, penile tumescences as well as full erections were observed. CONCLUSIONS Milrinone strongly relaxes human cavernous smooth muscle cells but it exhibits low relaxant effects in the rabbit cavernous tissue. In human tissue, sildenafil was equieffective with milrinone in vitro. In vivo, milrinone induced a good erectile response in humans but a poor erectile effect in rabbits. Our results support a possible potential for selective PDE-III and -V inhibitors in the treatment of impotence and give further evidence that the rabbit is an animal model of limited value to study the effects of drugs on cavernous smooth muscle tone regulation in vivo.

Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours

The proto-oncogene c-kit and its ligand stemcell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit protein and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens of nonseminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growthstimulatory effect of high concentrations of SCF on nonseminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.

Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside.

Abstract Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence. However, muscarinergic receptor blockers with adequate selectivity for detrusor smooth muscle are not available. Also, in contrast to the normal detrusor, the unstable detrusor neurotransmission seems to be at least partially regulated by non-cholinergic (NANC) pathways. These factors may explain the common side effects and the limited clinical efficacy of these compounds. Specific modulation of intracellular second messenger pathways offers the possibility of organ selective manipulation of tissue function, specifically contraction and relaxation of smooth musculature. Because of their central role in the intracellular regulation of smooth muscle tone phosphodiesterases (PDEs) are an attractive pharmacological targets. The PDE 5 specific inhibitor sildenafil (Viagra) has revolutionized the treatment of patients with erectile dysfunction. Numerous other PDE inhibitors are currently under investigation for the treatment of various disorders. We investigated the role of PDEs in human detrusor smooth muscle. Our data demonstrate the presence of five PDE isoenzymes in human detrusor and suggest, for the first time, that the cAMP pathway and the calcium/calmodulin-stimulated PDE (PDE 1) are of functional importance in the intracellular regulation in this tissue in vitro. In addition, initial clinical data with the PDE 1 inhibitor vinpocetine in patients not responding to standard anticholinergic therapy indicate a possible role for vinpocetine in the treatment of urgency, urge incontinence and, possibly, low compliance bladder and interstitial cystitis. The results of a larger randomized, double-blind, placebo-controlled, multicenter trial with vinpocetine show a tendency in favor of vinpocetine over placebo; however, statistically significant results were documented for one parameter only. This might be due to the rather low dosage chosen and the small sample size. Further studies are necessary and currently underway to delineate the optimal dosage, indications and patient population. Modulation of intracellular key enzymes effecting second messenger metabolism, i.e. isoenzyme-selective PDE inhibition is a novel approach which possibly avoids the limitations of anticholinergic therapy in patients with lower urinary tract dysfunction.