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PubMed2004

Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies.

Capsaicin and other naturally occurring pungent molecules have been used for centuries as topical analgesics and rubefactants to treat a variety of chronically painful conditions. Recently, instillations of high-concentration capsaicin and resiniferatoxin solutions have been found to be useful for the management of persistent bladder pain or overactive bladder. However, only within the last 7 years has it been appreciated that the selective action of these compounds on a subset of sensory nerve fibres is mediated by agonist activity at a ligand-gated ion channel called the transient receptor potential vanilloid receptor 1 (TRPV1). Accordingly, this discovery has fueled intensive research and drug development efforts, mainly in a search for novel analgesic or anti-inflammatory therapies. Two different, but non-mutually exclusive, strategies are being pursued: optimisation of TRPV1 agonist-based therapies, which can functionally inactivate nociceptive nerve fibres, and identification of receptor antagonists, which would prevent nociceptive fibres from being activated by ongoing inflammatory stimuli. Available information on TRPV1 agonists in development and their biological rationale will be summarised in this review.

Capsaicin↗

PubMed2004

Chronic pain syndromes of gynecologic origin.

Women seek gynecologic medical attention for 2 main reasons--abnormal bleeding and pelvic pain. Gynecologists are often more comfortable with the diagnosis and management of abnormal bleeding than with the diagnosis and management of pelvic pain. One reason is that chronic pelvic pain can result from a variety of abdominal and pelvic causes, including endometriosis, pelvic inflammatory disease, adhesions and urogenital causes, such as vulvodynia, and from bladder complaints, including overactive bladder, urinary tract infection and interstitial cystitis (IC). The symptoms of IC--chronic pelvic pain with urinary urgency, frequency and nocturia--are all too frequently attributed to these other causes of chronic pelvic pain, in large part because gynecologists rarely consider the bladder as a source of pelvic pain. In addition, IC can masquerade as, and coexist with, other causes of pelvic pain, particularly endometriosis. Early diagnosis and treatment of IC can reduce the occurrence of unnecessary procedures and treatments and can improve the patient's prognosis and quality of life. Bladder-origin pelvic pain should be considered in all women who present with these symptoms.

Chronic Disease↗

PubMed2005

Posterior tibial nerve stimulation: is the once-a-week protocol the best option?

AIM: Aim of our study was to compare the results of posterior tibial nerve stimulation (PTNS) performed weekly with those of PTNS performed 3 times per week in patients with overactive bladder syndrome. METHODS: Thirty-five patients (28 females, 7 males) with overactive bladder syndrome not responding to antimuscarinic therapy were enrolled in a prospective study. A total of 17 out of 35 patients were randomly assigned to group A and treated with a PTNS protocol based on weekly stimulation sessions; 18 out of 35 patients were randomly assigned to group B and treated with a PTNS protocol based on stimulation sessions performed 3 times per week. All subjects were evaluated by means of 24 h bladder diaries, quality of life questionnaires (I-QoL, SF36) and urodynamic evaluation before and after treatment. Patients were asked after each stimulation session to give their opinion on the efficacy of the treatment. We have considered ''success'' those patients who presented a reduction >50% of the micturition episodes/24 h (ME/24) or (if incontinent) of the incontinence episodes/24 h (IE/24). Results before and after treatments in both groups were collected and statistically compared. RESULTS: As a whole, 11/17 patients (63%) in group A and 12/18 patients (67%) in group B were considered ''success''; 4/11 (36%) incontinent patients in group A and 5/11 (45%) incontinent patients in group B were completely cured after treatment. In both groups, patients reported subjective improvement after 6-8 stimulation sessions. CONCLUSIONS: Our findings seem to show that the periodicity of stimulation does not effect the results of PTNS treatment. The advantage of more frequent stimulation sessions is to achieve earlier a clinical improvement.

Electric Stimulation Therapy↗

PubMed1990

[Two cases of neurogenic bladder due to HTLV-1 associated myelopathy (HAM)].

Case-1 (24-year-old female) had complained of slowly progressive urinary incontinence (since 14 years old) and gait disturbance (since 18 years old). A marked pyramidal disorder was observed, and anti-HTLV-1 antibody (1:640) was present in her peripheral blood. She was diagnosed as having HTLV-1 associated myelopathy (HAM). Repeated urodynamic studies (UDS) revealed exacerbation of overactive bladder and detrusor-sphincter dyssynergia (DSD) with the progress of the disease. Case-2 (48-year-old male) had complained of gait disturbance (since 32 years old) and progressive urinary hesitancy (since 46 years old). Physical examination revealed a marked pyramidal disorder. Anti-HTLV-1 antibody (1:200) and ATL-like cells were present in his peripheral blood. He was diagnosed as having HAM. The voiding cystourethrography demonstrated an abnormal change of the bladder wall. UDS revealed overactive bladder and marked DSD. Medications based on adrenocortical steroids and urological cares have improved urinary disturbance, in both cases.

Adrenal Cortex Hormones↗

PubMed2004

Nocturia in older people: a review of causes, consequences, assessment and management.

Nocturia is common in older people and it may be bothersome for both patients and carers. It is most commonly related to bladder storage difficulties and nocturnal polyuria. The former results most frequently from an uninhibited overactive bladder. The latter occurs as a consequence of age-associated changes in the circadian rhythm of urine excretion. The management of an overactive bladder includes both behavioural and drug treatment. The management options for nocturnal polyuria include an afternoon diuretic and desmopressin, but caution is required, particularly with the latter, as it can cause significant hyponatraemia.

Adult↗

PubMed2006

[Pittsburgh experience with botulinum toxin A injection].

We report one institution's six-year experience using botulinum toxin A (BONT-A) in the bladder and urethra in 110 patients for a variety of lower urinary tract dysfunction. 110 patients (age 19-82) were injected with BONT-A into the bladder (n=42) or urethra (n=68), 35 M, 75 F. Voiding dysfunction included: neurogenic detrusor overactivity and/or detrusor sphincter dyssynergia, overactive bladder (OAB), benign prostatic hyperplasia (BPH), bladder neck obstruction (BNO) and interstitial cystitis (IC). Currently, 27 patients have undergone further injections (up to 6) at intervals > 6 months. All the patients with bladder BONT-A injection had preoperative evidence of involuntary detrusor contractions during urodynamic testing. Analysis of the 110 patients indicates that 67.3% reported a decrease or absence of incontinence. Diaries indicate a decrease in both day and night voiding symptoms. Efficacy occurred within 7 days and lasted for at least 6 months. Condition specific QOL symptom scores also demonstrated improvement. There have been no long-term complications. Two MS women with mild baseline stress urinary incontinence reported increased leakage with stress after BONT-A external sphincter injection. One MS woman who had a bladder injection had an increased residual urine from 78 to 155 ml. She did not have to perform intermittent catheterization. BONT-A injection is a safe and promising treatment modality for a variety of lower urinary tract dysfunctions for both skeletal and smooth muscle dysfunction. In our series, BONT-A is equally effective in women as it is in men. Bladder injections with BONT-A are effective for not only neurogenic detrusor overactivity but also overactive bladder. BONT-A can even be considered for IC.

Adult↗

PubMed2004

Increased expression of neuronal nitric oxide synthase in bladder afferent cells in the lumbosacral dorsal root ganglia after chronic bladder outflow obstruction.

Nitric oxide (NO), a neurotransmitter in autonomic reflex pathways, plays a role in functional neuroregulation of the lower urinary tract. Upregulation of the levels of neuronal nitric oxide synthase (nNOS), the enzyme system responsible for NO synthesis, has been documented in the peripheral, spinal and supraspinal segments of the micturition reflex in diseases such as cystitis, bladder/sphincter dyssynergia following spinal cord injury and bladder overactivity after cerebral infarction. These observations suggest that NO might play a role in the development of bladder overactivity. In this study, nNOS-immunoreactivity (IR) was evaluated in bladder afferent and spinal neurons following bladder outflow obstruction (BOO) in male and female rats. Chronic BOO was induced by placing lumen reducing ligatures around the proximal urethra. Six weeks following the obstructive or sham surgery, bladder function was evaluated by awake cystometry. Bladder afferent neurons in L1, L2, L6 and S1 dorsal root ganglia (DRG) were identified by retrograde neuronal labeling with injection of Fast Blue into the bladder smooth muscle. A differential distribution of nNOS-IR was subsequently evaluated in bladder afferent neurons in the DRG and in the associated spinal cord segments. The percentage of bladder afferent neurons expressing nNOS-IR was increased in L6 (1.8-fold in males and 1.9-fold in females) and S1 (2.8-fold in males and 5.3-fold in females) DRG. In contrast, no changes in nNOS-IR in neurons or fiber distribution were observed in any spinal cord segments examined.

Animals↗

PubMed1997

The influence of colonic enema irrigation on urodynamic findings in patients with neurogenic bladder dysfunction.

OBJECTIVE: To evaluate whether colonic enema irrigation influences the urodynamic characteristics of patients with spina bifida, an overactive bladder and detrusor sphincter dyssynergia (DSD). PATIENTS AND METHODS: Since 1991, 83 patients with spina bifida at our institution have treated their bowel dysfunction by colonic irrigation every 24-48 h. In 12 patients (seven boys and five girls, mean age 7.7 years, range 0.7-13.8) with an overactive bladder and DSD, urodynamic studies of the bladder before and after enema treatment were available with no intercurrent changes in urological therapy. RESULTS: There were no significant changes overall in bladder capacity, leak-point pressure, bladder compliance and bladder instability in the selected group of children. CONCLUSION: Although enema therapy for bowel treatment in patients with spina bifida gave good results for faecal incontinence, with good patient compliance, no favourable effect on bladder function should be expected in most patients with a high-risk urinary tract dysfunction. Further study is needed to determine factors in patients who will benefit urologically from enema treatment.

Child↗

PubMed2004

Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence.

The lower urinary tract constitutes a functional unit controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. In the adult, micturition is controlled by a spinobulbospinal reflex, which is under suprapontine control. Several central nervous system transmitters can modulate voiding, as well as, potentially, drugs affecting voiding; for example, noradrenaline, GABA, or dopamine receptors and mechanisms may be therapeutically useful. Peripherally, lower urinary tract function is dependent on the concerted action of the smooth and striated muscles of the urinary bladder, urethra, and periurethral region. Various neurotransmitters, including acetylcholine, noradrenaline, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in this neural regulation. Muscarinic receptors mediate normal bladder contraction as well as at least the main part of contraction in the overactive bladder. Disorders of micturition can roughly be classified as disturbances of storage or disturbances of emptying. Failure to store urine may lead to various forms of incontinence, the main forms of which are urge and stress incontinence. The etiology and pathophysiology of these disorders remain incompletely known, which is reflected in the fact that current drug treatment includes a relatively small number of more or less well-documented alternatives. Antimuscarinics are the main-stay of pharmacological treatment of the overactive bladder syndrome, which is characterized by urgency, frequency, and urge incontinence. Accepted drug treatments of stress incontinence are currently scarce, but new alternatives are emerging. New targets for control of micturition are being defined, but further research is needed to advance the pharmacological treatment of micturition disorders.

Animals↗

PubMed2006

The impact of detrusor overactivity on the management of stress urinary incontinence in women.

The presence of overactive bladder symptoms, urodynamic detrusor overactivity, and urge incontinence can complicate the diagnosis and management of stress urinary incontinence in women. The exact pathophysiology of mixed incontinence is not well characterized; in some patients, the stress and urge etiology may be pathologically linked. The role of urodynamics in evaluating patients with mixed incontinence remains controversial. Conservative therapies, such as bladder training, pelvic floor exercise, biofeedback, and electrical stimulation, offer moderate success in women with mixed incontinence. Surgery (colposuspension, bladder neck pubovaginal slings, and midurethral slings) offers excellent subjective and objective cure rates in patients with mixed incontinence. Preoperative detrusor overactivity is cured consistently 50%of the time with colposuspension and slings. Overall, the presence of preoperative detrusor overactivity does not appear to significantly worsen the outcome of conservative and surgical treatments for stress urinary incontinence in women.

Female↗

PubMed1992

[Results in treatment of urinary incontinence in the elderly].

The diagnosis and treatment of urinary incontinence in the elderly out-clinic patients were reviewed. Sixty-three patients (24 males and 39 females) over 60 years old, who consulted our clinic complaining urinary incontinence, were subjected to the present study. The patients' ages ranged from 60 to 91, with the mean age of 72.9 years old. The types of the incontinence were urge in 44 cases (69.8%), stress in 10 (15.9%), outflow in 5 (7.9%) and mixture of urge and stress in 4 (6.4%). Urge incontinence resulted from unstable bladder in 63.6% and from neurogenic bladder (overactive detrusor) in 36.4%. Cerebrovascular diseases were the most common cause of the neurogenic bladder. Fifty-four patients (85.7%) were out-patients and 9 (14.3%) were hospitalized for other diseases. Thirteen patients (20.6%) with dementia were included. Diagnosis was made on the basis of a detailed questionnaire, physical examination and voiding chart, and confirmed by urodynamic study. Treatment was positively made by means of drug therapy, operation, clean intermittent catheterization and/or behavior training. As results, incontinence disappeared in 52.4% (frequency of incontinence/day: 5.0 +/- 2.6 times/day to 0), was fairly improved in 30.2% (5.1 +/- 2.3 to 1.2 +/- 0.8), was slightly improved in 7.9% (3.4 +/- 1.4 to 2.4 +/- 1.4) and unchanged in 9.5% (8.2 +/- 2.3 to 8.3 +/- 2.2). Severe neurogenic bladder (overactive), dementia and physical disability were proposed to be important factors responsible for treatment failure. Aggressive therapy should be tried to treat the urinary incontinence in the elderly, since favourable results can be expected in most of the cases.

Aged↗

PubMed2001

Tolterodine: an overview.

Tolterodine has emerged as a new anticholinergic drug to treat detrusor instability in recent years. This substance and its major metabolite DD01 exhibit a favourable effect-to-side-effect ratio for the bladder. Several clinical studies demonstrated the drug's efficacy in reducing the symptoms of an overactive bladder (urgency, urge incontinence and high micturition frequency) and in increasing functional bladder volume. With a clinical effectiveness comparable to oxybutynin, the side effect-profile measures up favourably to oxybutynin. Consequently, though some limitations need to be addressed, tolterodine can be regarded as the drug of first choice to treat overactive bladders in a variety of patient groups: the young (and otherwise healthy), the elderly, as well as in patients with renal and hepatic insufficiency. A new extended release formula of tolterodine has been launched that may improve patients' compliance.

Animals↗

PubMed2003

Pharmacological effects of darifenacin on human isolated urinary bladder.

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl(2)- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA(2 )values) at the muscarinic M(3) receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10(-6) mol/l, did not inhibit the KCl- and CaCl(2)-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10(-5) mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10(-9)-10(-6) mol/l), propiverine (10(-8)- 10(-5) mol/l), oxybutynin (10(-8)-10(-5) mol/l) and atropine (10(-9)-10(-6) mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca(2+) channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M(3) receptor and support its use as a treatment for overactive bladder.

Aged↗

PubMed2006

Comparison of efficacy of oxybutynin and tolterodine for prevention of catheter related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study.

BACKGROUND: Bladder discomfort related to intraoperative catheterization of urinary bladder is a distressing symptom and more so in patients awakening from anaesthesia. These symptoms are similar to symptoms of overactive bladder. Muscarinic receptor antagonists have been reported to be effective in the treatment of overactive bladder. This study was therefore undertaken to evaluate the efficacy of oxybutynin and tolterodine in preventing catheter related bladder discomfort. METHODS: Two hundred and thirty-four consecutive adult patients, ASA I and II, of either sex, undergoing elective percutaneous nephrolithotomy surgery requiring urinary bladder catheterization were randomized into three equal groups of 78 each. Group C (control) received placebo, Group O (oxybutynin) received oxybutynin 5 mg and Group T (tolterodine) received tolterodine 2 mg orally 1 h before surgery. After induction of anaesthesia patients were catheterized with a 16 Fr Foley's catheter and the balloon was inflated with 10 ml distilled water. The bladder discomfort was assessed at 0, 1, 2 and 6 h after patient's arrival in the post-anaesthesia care unit. Severity of bladder discomfort was graded as mild, moderate and severe. RESULTS: Incidence of bladder discomfort observed in the control group was higher, i.e. 58% (45/78), compared with oxybutynin and tolterodine groups where it was 35% (28/78) and 33% (26/78), respectively (P<0.05). Significant reduction in the severity of bladder discomfort was also observed after oxybutynin and tolterodine therapy compared with control (P<0.05). CONCLUSION: Pretreatment with either oxybutynin or tolterodine reduces the incidence and severity of catheter related bladder discomfort.

Adult↗

PubMed2001

The effect of tolterodine on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive containing ethinyl estradiol and levonorgestrel.

BACKGROUND: Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. Given the prevalence pattern of overactive bladder and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. Based on a search of MEDLINE from 1990 to 2001, there have been no studies of whether concomitant use of these agents entails a risk of drug-drug interaction or conception. OBJECTIVE: This study investigated the effects of tolterodine on the pharmacokinetics and pharmacodynamics of a low-dose combination oral contraceptive (ethinyl estradiol 30 microg/levonorgestrel 150 microg). METHODS: This was an open-label, randomized, 2-period crossover study in healthy women. Oral contraception was given for 21 days either alone or in combination with oral tolterodine 2 mg BID (on days 1-14) over two 28-day contraceptive cycles. Pharmacokinetic assessments were performed on day 14 based on plasma levels of ethinyl estradiol and levonorgestrel up to 24 hours after dosing and serum tolterodine levels at 1 to 3 hours after dosing. The potential for pharmacodynamic interaction was assessed in terms of the risk of failure of suppression of ovulation based on serum levels of estradiol and progesterone measured throughout each cycle. RESULTS: Twenty-four healthy women (age, 23-41 years [mean, 30 years]; height, 155-178 cm [mean, 167 cm]; body weight, 51-75 kg [mean, 64 kg]) participated in the study. There was no evidence of a pharmacokinetic interaction between tolterodine and the steroid hormones in the oral contraceptive used, nor did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Serum levels of estradiol and progesterone indicated suppression of ovulation in both treatment periods. CONCLUSION: In this selected population. coadministration of tolterodine did not affect the contraceptive efficacy of a low-dose combination oral contraceptive containing ethinyl estradiol and levonorgestrel.

Adult↗

PubMed2004

Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder.

INTRODUCTION: Endoscopical injections of Botulinum toxin type A into the detrusor muscle are gaining clinical acceptance in the treatment of neurogenic detrusor overactivity. Structural effects of Botulinum toxin type A are only known from studies on striated muscles, where a widespread nerve sprouting occurs temporarily. The aim of this study was to evaluate the ultrastructural effects of Botulinum toxin type A injections on the human detrusor. MATERIAL AND METHODS: 30 detrusor biopsies were obtained from 24 patients with neurogenic detrusor overactivity. Patients were divided into two groups: Group I included 13 biopsies from patients before the first Botulinum toxin type A injection. Group II included 6 biopsies from patients within 3 months after the first injection and 11 biopsies at the time of decreasing efficacy of Botulinum toxin type A. The biopsies were processed by standard procedure for detailed electron microscopic study and evaluated by 2 examiners without prior knowledge of clinical/urodynamic data. RESULTS: No statistically significant detrusor changes have been found concerning muscle cell fascicle structure (p = 0.445), width of intercellular space (p = 0.482) and number/kind of muscle cell junctions (p = 0.443). A median of 70% of intrinsic axon terminals presented with signs of degeneration in group I, a median of 66% in group II (p = 0.840). Out of 309 evaluated axon terminals in both groups, 1 sprouting axon was found in group I, 3 sprouting axons in group II (p = 0.864). Specimen from group I and group II showed only limited collagen deposits within the detrusor. No changes in the ultrastructure of the detrusor have been observed in those biopsies obtained before and after the Botulinum toxin type A injection of the same patient. CONCLUSION: This study verifies our earlier report of severe intrinsic axon degeneration in the detrusor of patients with neurogenic detrusor overactivity. It also shows nearly no structural differences of the detrusor before and after Botulinum toxin type A injections. Contrary to reports of striated muscle, axonal sprouting within the detrusor was very limited after Botulinum toxin type A injections indicating pathophysiologically different reactions to the toxin either between striated muscle and smooth muscle or between different treated diseases.

Adolescent↗

PubMed2003

Pharmacological effects of KRP-197 on the human isolated urinary bladder.

KRP-197, 4-(2-methylimidazol-l-yl)-2,2-diphenylbutyramide, is a newly synthesized antimuscarinic drug, developed for the treatment for overactive bladder. For evaluation of pharmacological characteristics of KRP-197, we investigated whether it influenced both prejunctional and postjunctional muscarinic receptors on the isolated human detrusor smooth muscles as compared with the effects of atropine, oxybutynin, and propiverine. Using the muscle bath technique, we investigated the effects of various antimuscarinic drugs on the contractions induced by carbachol, KCl, CaCl(2), and electrical field stimulation. Furthermore, using high-performance liquid chromatography with a microdialysis technique, we measured the acetylcholine release from the muscle strips during electrical field stimulation. The effects of various antimuscarinic drugs on acetylcholine releases were also evaluated. Pretreatment with various antimuscarinic drugs caused parallel shifts to the right in carbachol-induced concentration-response curves. The rank order of pA(2) values was KRP-197 > or = atropine > oxybutynin > propiverine. Atropine and KRP-197 did not cause significant inhibition of KCl- and CaCl(2)-induced contractions. All drugs caused concentration-dependent inhibitions in electrical field stimulation-induced contractions. Pretreatment with atropine and propiverine did not cause significant changes in electrical field stimulation-induced acetylcholine release. However, KRP-197, and oxybutynin caused significant decreases in acetylcholine release. The present study demonstrates that KRP-197 has an inhibitory effect on postjunctional muscarinic receptors as well as on prejunctional muscarinic receptors to modulate acetylcholine release in human detrusor smooth muscles. The findings suggest the usefulness of KRP-197 as a therapeutic drug for an overactive bladder with symptoms of frequency, urgency, and urge incontinence.

Aged↗

PubMed1999

Pharmacological effects of tolterodine on human isolated urinary bladder.

Tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine+ ++, is an antimuscarinic drug developed for the treatment of overactive bladder with symptoms of frequency, urgency and urge incontinence. We investigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropa namine, on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation in human isolated urinary bladder smooth muscles, using the muscle bath technique. Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome region of the bladder. Carbachol (10(-9)-10(-2) M) caused concentration-dependent contraction of human detrusor smooth muscles. Tolterodine (10(-9)-10(-6) M), DD 01 (10(-9)-10(-6) M), oxybutynin (10(-8)-10(-6) M), propiverine (10(-8)-10(-6) M), atropine (10(-9)-10(-6) M), pirenzepine (10(-8)-10(-5) M), methoctramine (10(-8)-10(-5) M) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (10(-9)-10(-6) M) caused typical shifts to the right of the concentration-response curves for carbachol, except for higher concentrations (10(-5) M) of oxybutynin and propiverine, which caused a decrease of about 30% of the maximum contractile responses to carbachol. All the slopes of the regression lines of Schild plots were close to unity, and the rank order of pA2 values was: atropine = DD 01 = tolterodine = 4-DAMP = oxybutynin > propiverine = pirenzepine > methoctramine. Tolterodine (10(-9)-10(-6) M) and DD 01 (10(-9)-10(-6) M) did not inhibit the KCl-induced (80 mM) and CaCl2-induced (5 mM) contractions, while oxybutynin (10(-8)-10(-5) M) and propiverine (10(-8)-10(-5) M) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contraction of human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 10(-6) M atropine, tolterodine and DD 01 did not inhibit the residual contractions induced by electrical field stimulation at any of the frequencies, while oxybutynin (10(-5) M) and propiverine (10(-5) M) significantly inhibited the atropine-resistant part of the contractions. The results suggest that the inhibitory effects of tolterodine and DD 01 are mediated only by their antimuscarinic action, which is equal to that of oxybutynin and significantly greater than that of propiverine, and that tolterodine and DD 01 have neither Ca2+ channel antagonist action nor inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tolterodine as a therapeutic drug for overactive bladder with symptoms of frequency, urgency and urge incontinence.

Aged↗